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https://www.readbyqxmd.com/read/28330163/probing-an-optimal-class-distribution-for-enhancing-prediction-and-feature-characterization-of-plant-virus-encoded-rna-silencing-suppressors
#1
Abhigyan Nath, Karthikeyan Subbiah
To counter the host RNA silencing defense mechanism, many plant viruses encode RNA silencing suppressor proteins. These groups of proteins share very low sequence and structural similarities among them, which consequently hamper their annotation using sequence similarity-based search methods. Alternatively the machine learning-based methods can become a suitable choice, but the optimal performance through machine learning-based methods is being affected by various factors such as class imbalance, incomplete learning, selection of inappropriate features, etc...
June 2016: 3 Biotech
https://www.readbyqxmd.com/read/28318003/small-molecule-hedgehog-pathway-antagonists
#2
Trieu N Trinh, Eileen A McLaughlin, Christopher P Gordon, Ilana R Bernstein, Victoria J Pye, Kate A Redgrove, Adam McCluskey
Leveraging our quinolone-1-(2H)-one based Hedgehog signalling pathway (HSP) inhibitors we have developed two new classes of HSP inhibitors based on: l-tryptophan and benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amine. Synthesis of focused compound libraries identified six l-tryptophan based inhibitors, and two stimulators, of Gli at 10 μM compound concentration. 2,4-Dichloro-13 and indole 16 suppressed mRNA expression of Ptch1 in Shh LIGHT2 cells, with 13 suppressing and 16 stimulating Gli2 mRNA expression...
March 20, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28317088/phase-i-trial-of-the-oral-smoothened-inhibitor-sonidegib-in-combination-with-paclitaxel-in-patients-with-advanced-solid-tumors
#3
A Stathis, D Hess, R von Moos, K Homicsko, G Griguolo, M Joerger, M Mark, C J Ackermann, S Allegrini, C V Catapano, A Xyrafas, M Enoiu, S Berardi, P Gargiulo, C Sessa
Purpose To establish a recommended phase II dose (RP2D) for the oral smoothened inhibitor sonidegib in combination with paclitaxel; secondary objectives include evaluation of safety, tolerability, markers of Hedgehog (Hh) signaling and preliminary antitumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating sonidegib dose levels (400mg, 600mg and 800mg orally, once daily on days 1-28) in combination with paclitaxel 80 mg/m(2) on days 1, 8 and 15 in 4-weekly cycles. Dose-limiting toxicities (DLTs) were assessed using CTCAE v4...
March 20, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28302010/discovery-of-hedgehog-antagonists-for-cancer-therapy
#4
Harleen Khatra, Chandra Bose, Surajit Sinha
BACKGROUND: The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeutic avenue for the treatment of Hedgehog-dependent cancers. This review covers the mechanism of hedgehog signaling in vertebrate cells, provides an overview of reported small molecule Hh pathway inhibitors, with the synthetic routes and SAR studies of some of them discussed briefly...
March 16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28294058/recognizing-and-predicting-thioether-bridges-formed-by-lanthionine-and-%C3%AE-methyllanthionine-in-lantibiotics-using-a-random-forest-approach-with-feature-selection
#5
ShaoPeng Wang, Yu-Hang Zhang, Ning Zhang, Lei Chen, Tao Huang, Yu-Dong Cai
Lantibiotics, which are usually produced from Gram-positive bacteria, are regarded as one type of special bacteriocins. Lantibiotics have unsaturated amino acid residues formed by lanthionine (Lan) and β-methyllanthionine (MeLan) residues as a ring structure in the peptide. They are derived from the serine and threonine residues and are essential to preventing the growth of other similar strains. In this pioneering work, we firstly proposed a machine learning method to recognize and predict the Lan and MeLan residues in the protein sequences of lantibiotics...
March 10, 2017: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/28276480/selective-targeting-of-hdac1-2-elicits-anticancer-effects-through-gli1-acetylation-in-preclinical-models-of-shh-medulloblastoma
#6
Sonia Coni, Anna Barbara Mancuso, Laura Di Magno, Giulia Sdruscia, Simona Manni, Silvia Maria Serrao, Dante Rotili, Eleonora Spiombi, Francesca Bufalieri, Marialaura Petroni, Monika Kusio-Kobialka, Enrico De Smaele, Elisabetta Ferretti, Carlo Capalbo, Antonello Mai, Pawel Niewiadomski, Isabella Screpanti, Lucia Di Marcotullio, Gianluca Canettieri
SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28275010/epithelial-and-non-epithelial-patched-1-ptch1-play-opposing-roles-to-regulate-proliferation-and-morphogenesis-of-the-mouse-mammary-gland
#7
Teresa Monkkonen, John D Landua, Adriana P Visbal, Michael T Lewis
Patched-1 (Ptch1) has epithelial, stromal, and systemic roles in murine mammary gland organogenesis, yet specific functions remain undefined. Cre-recombinase-mediated Ptch1 ablation in mammary epithelium increased proliferation and branching, but did not phenocopy transgenic expression of activated Smoothened (SmoM2). Epithelium showed no evidence of canonical hedgehog signaling, and hyperproliferation was not blocked by SMO inhibition, suggesting a non-canonical function of PTCH1. Consistent with this possibility, nuclear localization of Cyclin B1 was increased...
March 8, 2017: Development
https://www.readbyqxmd.com/read/28261216/smoothened-regulates-migration-of-fibroblast-like-synoviocytes-in-rheumatoid-arthritis-via-activation-of-rho-gtpase-signaling
#8
Wei-Xiang Peng, Shang-Ling Zhu, Bai-Yu Zhang, Yi-Ming Shi, Xiao-Xue Feng, Fang Liu, Jian-Lin Huang, Song Guo Zheng
Fibroblast-like synoviocytes (FLSs) acquire aggressive phenotypes characterized with enhanced migration abilities and inherent invasive qualities in rheumatoid arthritis (RA). Smoothened (Smo) is a key component of sonic hedgehog (Shh) signaling and contributes to tumor cell invasion and metastasis. The objective of this study is to investigate the role of Smo in the modulation of cell migration and explore the underlying molecular mechanism(s). FLSs were isolated from RA synovium. Shh levels were regulated by a Smo agonist (purmorphamine), Smo antagonist (KAAD-cyclopamine), or small interfering RNA targeting the Smo gene (Smo-siRNA) in RA-FLSs...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28260041/metformin-suppresses-the-expression-of-sonic-hedgehog-in-gastric-cancer-cells
#9
Zhou Song, Bo Wei, Canrong Lu, Xiaohui Huang, Peiyu Li, Lin Chen
The traditional anti-diabetic drug, metformin, has been found to have anticancer effects. The Sonic hedgehog (Shh) signaling pathway is involved in the on cogenesis of gastric cancer. The aim of the present study was to investigate whether metformin has an effect on the Shh signaling pathway in gastric cancer cells. HGC‑27 and MKN‑45 human gastric cancer cells were treated with metformin at different concentrations and for different durations. Subsequently the mRNA and protein levels of Shh, Smoothened (SMO), and Glioma‑associated oncogene (Gli)‑1, Gli‑2 and Gli‑3 were examined using western blot and reverse transcription‑quantitative polymerase chain reaction analyses...
February 15, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28245563/nanog-expression-as-a-responsive-biomarker-during-treatment-with-hedgehog-signal-inhibitor-in-acute-myeloid-leukemia
#10
Seiji Kakiuchi, Yosuke Minami, Yoshiharu Miyata, Yu Mizutani, Hideaki Goto, Shinichiro Kawamoto, Kimikazu Yakushijin, Keiji Kurata, Hiroshi Matsuoka, Hironobu Minami
Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in the maintenance of leukemic stem cell (LSCs) populations. PF-0444913 (PF-913) is a novel inhibitor that selectively targets Smoothened (SMO), which regulates the Hh pathway. Treatment with PF-913 has shown promising results in an early phase study of acute myeloid leukemia (AML). However, a detailed mode of action for PF-913 and relevant biomarkers remain to be elucidated. In this study, we examined bone marrow samples derived from AML patients under PF-913 monotherapy...
February 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28219952/enthesis-regeneration-a-role-for-gli1-progenitor-cells
#11
Andrea G Schwartz, Leesa M Galatz, Stavros Thomopoulos
The tendon enthesis originates from a specific pool of hedgehog-active Gli1+ progenitor cells that differentiate and produce mineralized fibrocartilage. The current study investigated the regenerative capacity of this cell population by comparing the responses of early postnatal and mature entheses to injury. Lineage tracing studies demonstrated that the original Gli1+ cell population had the capacity to heal immature entheses after injury but this capacity was lost after the cells differentiated into mature fibrochondrocytes...
February 20, 2017: Development
https://www.readbyqxmd.com/read/28207233/nanoscale-pdo-catalyst-functionalized-co3o4-hollow-nanocages-using-mof-templates-for-selective-detection-of-acetone-molecules-in-exhaled-breath
#12
Won-Tae Koo, Sunmoon Yu, Seon-Jin Choi, Ji-Soo Jang, Jun Young Cheong, Il-Doo Kim
The increase of surface area and the functionalization of catalyst are crucial to development of high-performance semiconductor metal oxide (SMO) based chemiresistive gas sensors. Herein, nanoscale catalyst loaded Co3O4 hollow nanocages (HNCs) by using metal-organic framework (MOF) templates have been developed as a new sensing platform. Nanoscale Pd nanoparticles (NPs) were easily loaded on the cavity of Co based zeolite imidazole framework (ZIF-67). The porous structure of ZIF-67 can restrict the size of Pd NPs (2-3 nm) and separate Pd NPs from each other...
February 22, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28206942/mixed-hepatocellular-carcinoma-neuroendocrine-carcinoma-of-the-liver
#13
REVIEW
Erin Baker, Carl Jacobs, John Martinie, David A Iannitti, Dionisios Vrochides, Ryan Z Swan
We present the case of a 76-year-old male found to have a large tumor involving the left lateral lobe of the liver, presumed to be hepatocellular carcinoma (HCC). After resection, pathologic features demonstrated both high-grade HCC and high-grade neuroendocrine carcinoma (NEC). Areas of NEC stained strongly for synaptophysin, which was not present in HCC component. The HCC component stained strongly for Hep-Par 1, which was not present in the NEC component. The patient underwent genetic analysis for biomarkers common to both tumor cell types...
November 1, 2016: American Surgeon
https://www.readbyqxmd.com/read/28195188/sumo-regulates-the-activity-of-smoothened-and-costal-2-in-drosophila-hedgehog-signaling
#14
Jie Zhang, Yajuan Liu, Kai Jiang, Jianhang Jia
In Hedgehog (Hh) signaling, the GPCR-family protein Smoothened (Smo) acts as a signal transducer that is regulated by phosphorylation and ubiquitination, which ultimately change the cell surface accumulation of Smo. However, it is not clear whether Smo is regulated by other post-translational modifications, such as sumoylation. Here, we demonstrate that knockdown of the small ubiquitin-related modifier (SUMO) pathway components Ubc9 (a SUMO-conjugating enzyme E2), PIAS (a SUMO-protein ligase E3), and Smt3 (the SUMO isoform in Drosophila) by RNAi prevents Smo accumulation and alters Smo activity in the wing...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28195165/smoothened-is-a-poor-prognosis-factor-and-a-potential-therapeutic-target-in-glioma
#15
Yiming Tu, Mingshan Niu, Peng Xie, Chenglong Yue, Ning Liu, Zhenglei Qi, Shangfeng Gao, Hongmei Liu, Qiong Shi, Rutong Yu, Xuejiao Liu
Malignant gliomas are associated with a high mortality rate. Thus, there is an urgent need for the development of novel targeted therapeutics. Aberrant Hedgehog signaling has been directly linked to glioma. GDC-0449 is a novel small molecule inhibitor of Hedgehog signaling that blocks the activity of smoothened (Smo). In this study, we evaluated the in vitro and in vivo effects of the smoothened inhibitor GDC-0449 on cell proliferation in human gliomas. We found that high expression of smoothened in glioma is a predictor of short overall survival and poor patient outcome...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28187190/widespread-gli-expression-but-limited-canonical-hedgehog-signaling-restricted-to-the-ductular-reaction-in-human-chronic-liver-disease
#16
Candice Alexandra Grzelak, Nicholas David Sigglekow, Janina Elke Eleonore Tirnitz-Parker, Elizabeth Jane Hamson, Alessandra Warren, Bharvi Maneck, Jinbiao Chen, Bramilla Patkunanathan, Jade Boland, Robert Cheng, Nicholas Adam Shackel, Devanshi Seth, David Geoffrey Bowen, Luciano Gastón Martelotto, D Neil Watkins, Geoffrey William McCaughan
Canonical Hedgehog (Hh) signaling in vertebrate cells occurs following Smoothened activation/translocation into the primary cilia (Pc), followed by a GLI transcriptional response. Nonetheless, GLI activation can occur independently of the canonical Hh pathway. Using a murine model of liver injury, we previously identified the importance of canonical Hh signaling within the Pc+ liver progenitor cell (LPC) population and noted that SMO-independent, GLI-mediated signals were important in multiple Pc-ve GLI2+ intrahepatic populations...
2017: PloS One
https://www.readbyqxmd.com/read/28178321/ampa-glua1-flip-targeted-oligonucleotide-therapy-reduces-neonatal-seizures-and-hyperexcitability
#17
Nicole M Lykens, David J Coughlin, Jyoti M Reddi, Gordon J Lutz, Melanie K Tallent
Glutamate-activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) mediate the majority of excitatory neurotransmission in brain and thus are major drug targets for diseases associated with hyperexcitability or neurotoxicity. Due to the critical nature of AMPA-Rs in normal brain function, typical AMPA-R antagonists have deleterious effects on cognition and motor function, highlighting the need for more precise modulators. A dramatic increase in the flip isoform of alternatively spliced AMPA-R GluA1 subunits occurs post-seizure in humans and animal models...
2017: PloS One
https://www.readbyqxmd.com/read/28152829/prevalence-and-predictors-of-second-opinions-from-medical-oncologists-for-early-stage-breast-cancer-results-from-the-icancare-study
#18
Christopher Ryan Friese, Irina Bondarenko, Reshma Jagsi, Steven J Katz
185 Background: A second medical oncology opinion (SMO) may facilitate chemotherapy decision-making. However, little is known about the interplay between SMOs, treatment decision-making and chemotherapy use. METHODS: We surveyed women newly diagnosed with early-stage invasive breast cancer and treated in 2013-2014 (response rate 70%), accrued approximately 3 months after surgery through 2 population-based SEER registries (Georgia and Los Angeles), about their experiences with medical oncologists, decision-making, and chemotherapy use...
March 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28149415/upper-respiratory-tract-diseases-in-athletes-in-different-sports-disciplines
#19
Anna Gałązka-Franta, Edyta Jura-Szołtys, Wojciech Smółka, Radosław Gawlik
Upper respiratory tract diseases in athletes are a very common medical problem. Training conditions in different sports disciplines increase the risk of upper respiratory disease. Epidemiological evidence suggests that heavy acute or chronic exercise is related to an increased incidence of upper respiratory tract infections in athletes. Regular physical exercise at high intensity may lead to transient immunosuppression due to high prevalence of allergic diseases in athletes. Regardless of the cause they can exclude athletes from the training program and significantly impair their performance...
December 1, 2016: Journal of Human Kinetics
https://www.readbyqxmd.com/read/28149414/neuroendocrine-responses-and-body-composition-changes-following-resistance-training-under-normobaric-hypoxia
#20
Jakub Chycki, Miłośz Czuba, Artur Gołaś, Adam Zając, Olga Fidos-Czuba, Adrian Młynarz, Wojciech Smółka
The aim of the present study was to evaluate the effects of a 6 week resistance training protocol under hypoxic conditions (FiO2 = 12.9%, 4000 m) on muscle hypertrophy. The project included 12 resistance trained male subjects, randomly divided into two experimental groups. Group 1 (n = 6; age 21 ± 2.4 years; body height [BH] 178.8 ± 7.3 cm; body mass [BM] 80.6 ± 12.3 kg) and group 2 (n = 6; age 22 ± 1.5 years; BH 177.8 ± 3.7cm; BM 81.1 ± 7.5 kg). Each group performed resistance exercises alternately under normoxic and hypoxic conditions (4000 m) for 6 weeks...
December 1, 2016: Journal of Human Kinetics
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