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https://www.readbyqxmd.com/read/29215700/novel-smoothened-antagonists-as-anti-neoplastic-agents-for-the-treatment-of-osteosarcoma
#1
Giulia Bernardini, Michela Geminiani, Silvia Gambassi, Maurizio Orlandini, Elena Petricci, Barbara Marzocchi, Marcella Laschi, Maurizio Taddei, Fabrizio Manetti, Annalisa Santucci
Osteosarcoma (OS) is an ultra-rare highly malignant tumor of the skeletal system affecting mainly children and young adults and it is characterized by an extremely aggressive clinical course. OS patients are currently treated with chemotherapy and complete surgical resection of cancer tissue. However, resistance to chemotherapy and the recurrence of disease, as pulmonary metastasis, remain the two greatest challenges in the management and treatment of this tumour. For these reasons, it is of primary interest to find alternative therapeutic strategies for OS...
December 7, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29211017/sliding-mode-observer-based-current-sensor-fault-reconstruction-and-unknown-load-disturbance-estimation-for-pmsm-driven-system
#2
Kaihui Zhao, Peng Li, Changfan Zhang, Xiangfei Li, Jing He, Yuliang Lin
This paper proposes a new scheme of reconstructing current sensor faults and estimating unknown load disturbance for a permanent magnet synchronous motor (PMSM)-driven system. First, the original PMSM system is transformed into two subsystems; the first subsystem has unknown system load disturbances, which are unrelated to sensor faults, and the second subsystem has sensor faults, but is free from unknown load disturbances. Introducing a new state variable, the augmented subsystem that has sensor faults can be transformed into having actuator faults...
December 6, 2017: Sensors
https://www.readbyqxmd.com/read/29208776/losers-of-primary-cilia-gain-the-benefit-of-survival
#3
Gladiola Goranci-Buzhala, Elke Gabriel, Aruljothi Mariappan, Jay Gopalakrishnan
In this issue, Zhao and colleagues demonstrate that loss of primary cilia in medulloblastoma cells confers resistance to the Smoothened (SMO) inhibitor sonidegib. When treated with sonidegib, medulloblastoma cells lost their cilia and gained resistance. Surprisingly, loss of cilia is associated with recurrent mutations in ciliogenesis genes that are eventually able to drive drug resistance. These findings uncover a previously unknown mechanism of cancer cells in gaining a "persister-like" state against anticancer agents at the expense of losing primary cilia...
December 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29208033/evaluating-the-oxysterol-combination-of-22-s-hydroxycholesterol-and-20-s-hydroxycholesterol-in-periodontal-regeneration-using-periodontal-ligament-stem-cells-and-alveolar-bone-healing-models
#4
Jin-Sun Lee, EunJi Kim, Seonggu Han, Kyung Lhi Kang, Jung Sun Heo
BACKGROUND: Oxysterols, oxygenated by-products of cholesterol biosynthesis, play roles in various physiological and pathological systems. However, the effects of oxysterols on periodontal regeneration are unknown. This study investigated the effects of the specific oxysterol combination of 22(S)-hydroxycholesterol and 20(S)-hydroxycholesterol (SS) on the regeneration of periodontal tissues using in-vitro periodontal ligament stem cells (PDLSCs) and in-vivo models of alveolar bone defect...
December 6, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29206716/primary-epithelioid-angiosarcoma-of-finger-masquerading-as-epithelioid-hemangioma-report-of-a-case-and-analysis-of-mutational-pattern-in-epithelioid-hemangiomas-and-angiosarcomas-by-next-generation-sequencing
#5
Manish M Subramaniam, Nur L Salleh, Bingcheng Wu, Michelle A Rozario, HueyJin Lim, Mark E Puhaindran, Richie Soong, Victor K Lee
AIMS: We report an unusual case of epithelioid angiosarcoma (AS) mimicking an epithelioid hemangioma (EH) and analyze mutational patterns in EHs and ASs. METHODS AND RESULTS: A 58-year-old woman presented with a finger lump and metastatic lung nodules. Initial needle biopsies showed an EH, with only focal atypical histologic features. The patient underwent finger amputation and resection of lung nodules. The amputation specimen and lung nodules revealed features of AS...
January 2018: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/29200875/rkip-reduction-enhances-radioresistance-by-activating-the-shh-signaling-pathway-in-non-small-cell-lung-cancer
#6
Shi-Yang Xie, Guang Li, Chong Han, Yang-Yang Yu, Nan Li
Non-small-cell lung cancer (NSCLC) is exceptionally deadly because the tumors lack sensitive early-stage diagnostic biomarkers and are resistant to radiation and chemotherapy. Here, we investigated the role and mechanism of Raf kinase inhibitory protein (RKIP) in NSCLC radioresistance. The clinical data showed that the RKIP expression level was generally lower in radioresistant NSCLC tissues than in radiosensitive tissues. Reduced RKIP expression was related to NSCLC radioresistance and poor prognosis. In vitro experiments showed that RKIP knockdown increased radioresistance and metastatic ability in NSCLC cell lines...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29178885/severe-maternal-outcomes-and-quality-of-care-at-district-hospitals-in-rwanda-a-multicentre-prospective-case-control-study
#7
Felix Sayinzoga, Leon Bijlmakers, Koos van der Velden, Jeroen van Dillen
BACKGROUND: Despite a significant decrease in maternal mortality in the last decade, Rwanda needs further progress in order to achieve Sustainable Development Goals (SDG)3 which addresses among others maternal mortality. Analysis of severe maternal outcomes (SMO) was performed to identify their characteristics, causes and contributory factors, using standard indicators for quality of care. METHODS: A prospective case-control study was conducted for which data were collected between November 2015 and April 2016 in four rural district hospitals...
November 25, 2017: BMC Pregnancy and Childbirth
https://www.readbyqxmd.com/read/29175550/molecular-modeling-study-on-resistance-of-wt-d473h-smo-to-antagonists-lde-225-and-leq-506
#8
Jing Tu, Jiao Jiao Li, Li Ting Song, Hong Lin Zhai, Juan Wang, Xiao Yun Zhang
The smoothened (SMO) receptor, an essential signal transducer in the Hedgehog pathway, was targeted with antagonists to suppress the tumor. It is interesting that SMO D473H mutation confers resistance on inhibitor LDE-225 rather than LEQ-506. In this paper, the binding modes of them against the wild type and mutant SMO receptors were identified to gain insights into the resistant and non-resistant factors, based on a comprehensive protocol involving molecular docking, molecular dynamic simulations, free energy calculation and decomposition...
November 21, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29167177/smoothened-signaling-in-the-mouse-osteoblastoid-lineage-is-required-for-efficient-b-lymphopoiesis
#9
Wenyan Lu, Dominic Dordai, David Huso, Stephen Desiderio
The stromal signals that promote B lymphopoiesis remain poorly understood. Hedgehog (Hh) signaling promotes B lymphopoiesis in a non-cell autonomous fashion in vitro and depletion of the Hh effector smoothened (Smo) from stromal cells is associated with the loss of osteoblastoid markers. These observations suggested that Hh signaling in the osteoblastoid lineage promotes B lymphopoiesis in vivo. To test this we developed a mouse model for conditional ablation of Smo in the osteoblastoid lineage. Depletion of Smo from osteoblastoid cells is associated with profound and selective reductions in the number and proportion of bone marrow B lymphoid progenitors...
November 22, 2017: Blood
https://www.readbyqxmd.com/read/29165358/understanding-the-molecular-genetics-of-basal-cell-carcinoma
#10
REVIEW
Cristina Pellegrini, Maria Giovanna Maturo, Lucia Di Nardo, Valeria Ciciarelli, Carlota Gutiérrez García-Rodrigo, Maria Concetta Fargnoli
Basal cell carcinoma (BCC) is the most common human cancer and represents a growing public health care problem. Several tumor suppressor genes and proto-oncogenes have been implicated in BCC pathogenesis, including the key components of the Hedgehog pathway, PTCH1 and SMO, the TP53 tumor suppressor, and members of the RAS proto-oncogene family. Aberrant activation of the Hedgehog pathway represents the molecular driver in basal cell carcinoma pathogenesis, with the majority of BCCs carrying somatic point mutations, mainly ultraviolet (UV)-induced, and/or copy-loss of heterozygosis in the PTCH1 gene...
November 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29164817/regulation-of-hedgehog-signaling-in-cancer-by-natural-and-dietary-compounds
#11
REVIEW
Cheng Bao, Pavel Kramata, Hong Jin Lee, Nanjoo Suh
The aberrant Hedgehog (Hh) signaling induced by mutations or overexpression of the signaling mediators has been implicated in cancer, associated with processes including inflammation, tumor cell growth, invasion and metastasis, as well as cancer stemness. Small molecules targeting the regulatory components of the Hh signaling pathway, especially Smoothened (Smo), have been developed for the treatment of cancer. However, acquired resistance to a Smo inhibitor vismodegib observed in clinical trials suggests that other Hh signaling components need to be explored as potential anticancer targets...
November 21, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/29142103/an-intracellular-activation-of-smoothened-independent-of-hedgehog-stimulation-in-drosophila
#12
Kai Jiang, Yajuan Liu, Jie Zhang, Jianhang Jia
Smoothened (Smo), a GPCR family protein, plays a critical role in the reception and transduction of Hedgehog (Hh) signal. Smo is phosphorylated and activated on the cell surface, however, it is unknown whether Smo can be intracellularly activated. Here, we demonstrate that inactivation of the ESCRT-III causes dramatic accumulation of Smo, and subsequent activation of Hh signaling. In contrast, inactivation of ESCRTs 0-II induces mild Smo accumulation. We provide evidence that Kurtz (Krz), the Drosophila β-arrestin2, acts in parallel with the ESCRTs 0-II pathway to sort Smo to the multivesicular bodies and lysosome-mediated degradation...
November 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29133390/recovery-of-taste-organs-and-sensory-function-after-severe-loss-from-hedgehog-smoothened-inhibition-with-cancer-drug-sonidegib
#13
Archana Kumari, Alexandre N Ermilov, Marina Grachtchouk, Andrzej A Dlugosz, Benjamin L Allen, Robert M Bradley, Charlotte M Mistretta
Striking taste disturbances are reported in cancer patients treated with Hedgehog (HH)-pathway inhibitor drugs, including sonidegib (LDE225), which block the HH pathway effector Smoothened (SMO). We tested the potential for molecular, cellular, and functional recovery in mice from the severe disruption of taste-organ biology and taste sensation that follows HH/SMO signaling inhibition. Sonidegib treatment led to rapid loss of taste buds (TB) in both fungiform and circumvallate papillae, including disruption of TB progenitor-cell proliferation and differentiation...
November 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29131041/skin-manifestations-of-targeted-antineoplastic-therapy
#14
Onofre Sanmartín
The management of oncology patients has changed significantly over recent years, with the development of new targeted anticancer therapies. Cutaneous adverse effects are among the most frequently observed toxicities with many targeted agents; their intensity can be dose-limiting or lead to the discontinuation of therapy. Tyrosine kinase inhibitors can cause maculopapular rash and hand-foot reaction, whereas papulopustular rash, paronychia, regulatory changes in hair, and dryness are caused by epidermal growth factor receptor inhibitors...
2018: Current Problems in Dermatology
https://www.readbyqxmd.com/read/29126187/med12-regulates-ovarian-steroidogenesis-uterine-development-and-maternal-effects-in-the-mammalian-egg
#15
Xinye Wang, Priya Mittal, Carlos A Castro, Gabriel Rajkovic, Aleksandar Rajkovic
The transcriptional factor MED12 is part of the essential mediator transcriptional complex that acts as a transcriptional coactivator in all eukaryotes. Missense gain of function mutations in human MED12 are associated with uterine leiomyomas, yet the role of MED12 deficiency in tumorigenesis and reproductive biology has not been fully explored. We generated a Med12 reproductive conditional knockout mouse model to evaluate its role in uterine mesenchyme, granulosa cells, and oocytes. Mice heterozygous for Med12 deficiency in granulosa cells and uterus (Med12fl/+ Amhr2-Cre) were subfertile, while mice homozygous for Med12 deficiency in granulosa cells and uterus (Med12fl/fl Amhr2-Cre) were infertile...
November 8, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/29115520/ccl2-ccr2-axis-induces-hepatocellular-carcinoma-invasion-and-epithelial-mesenchymal-transition-in%C3%A2-vitro-through-activation-of-the-hedgehog-pathway
#16
Huijie Zhuang, Gang Cao, Changhua Kou, Tao Liu
Chemokine (C-C motif) ligand 2 (CCL2) has been shown to play an important role in the regulation of tumor cell growth, metastasis and host immune response. CCL2 preferentially binds to the C-C chemokine receptor type 2 (CCR2), which is expressed in various tissues. However, the role of the CCL2/CCR2 axis in hepatocellular carcinoma (HCC) invasion and its molecular mechanisms remain unclear. The aim of this study was to elucidate this issue. The human HCC cell line MHCC-97H was treated with CCL2. Cyclopamine, a smoothened (SMO) antagonist, was used to inhibit SMO activity...
November 2, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29103956/mtorc1-mediated-inhibition-of-4ebp1-is-essential-for-hedgehog-signaling-driven-translation-and-medulloblastoma
#17
Chang-Chih Wu, Shirui Hou, Brent A Orr, Bryan R Kuo, Yong Ha Youn, Taren Ong, Fanny Roth, Charles G Eberhart, Giles W Robinson, David J Solecki, Makoto M Taketo, Richard J Gilbertson, Martine F Roussel, Young-Goo Han
Mechanistic target of rapamycin (MTOR) cooperates with Hedgehog (HH) signaling, but the underlying mechanisms are incompletely understood. Here we provide genetic, biochemical, and pharmacologic evidence that MTOR complex 1 (mTORC1)-dependent translation is a prerequisite for HH signaling. The genetic loss of mTORC1 function inhibited HH signaling-driven growth of the cerebellum and medulloblastoma. Inhibiting translation or mTORC1 blocked HH signaling. Depleting 4EBP1, an mTORC1 target that inhibits translation, alleviated the dependence of HH signaling on mTORC1...
October 31, 2017: Developmental Cell
https://www.readbyqxmd.com/read/29093271/combined-inhibition-of-atypical-pkc-and-histone-deacetylase-1-is-cooperative-in-basal-cell-carcinoma-treatment
#18
Amar N Mirza, Micah A Fry, Nicole M Urman, Scott X Atwood, Jon Roffey, Gregory R Ott, Bin Chen, Alex Lee, Alexander S Brown, Sumaira Z Aasi, Tyler Hollmig, Mark A Ator, Bruce D Dorsey, Bruce R Ruggeri, Craig A Zificsak, Marina Sirota, Jean Y Tang, Atul Butte, Ervin Epstein, Kavita Y Sarin, Anthony E Oro
Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29081338/effect-of-mono-2-ethyhexyl-phthalate-on-dna-methylation-in-human-prostate-cancer-lncap-cells
#19
Jian Hui Wu, Jiao Chen, Yong Wang, Bin Xia, Rong Wang, Yan Zhao, Qin Xia Wang, Qi Song, Shun Heng Yao, Yun Hui Zhang, Zu Yue Sun
OBJECTIVE: To evaluate whether mono (2-ethylhexyl) phthalate (MEHP) affects genomic DNA methylation and the methylation status of some specific genes such as patched gene (PTCH) and smoothened gene (SMO) in LNCaP cells. METHODS: LNCaP cells were treated with MEHP (0, 1, 5, 10, and 25 μmol/L) for 3 days. An ELISA assay was preformed to detect genomic methylation, including 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) content. A pyrosequencing assay was applied to assess DNA methylation in PTCH and SMO gene promoters...
September 2017: Biomedical and Environmental Sciences: BES
https://www.readbyqxmd.com/read/29080157/development-of-amine-oxidase-based-biosensors-for-spermine-and-spermidine-analysis
#20
Cristina Tortolini, Gabriele Favero, Franco Mazzei
In this work a detailed description of the development of amine oxidase-based electrochemical biosensors for the selective determination of the biogenic amines is presented. The enzymes required for this operation are Polyamine Oxidase (PAO) and Spermine Oxidase (SMO) which are physically entrapped in poly(vinyl alcohol) bearing styrylpyridinium groups (PVA-SbQ), a photo-cross-linkable gel, onto screen printed electrode (SPE) surface. The developed biosensors are deeply characterized in the analysis of biogenic amines by using flow injection amperometric (FIA) technique...
2018: Methods in Molecular Biology
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