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https://www.readbyqxmd.com/read/28650469/a-compartmentalized-phosphoinositide-signaling-axis-at-cilia-is-regulated-by-inpp5e-to-maintain-cilia-and-promote-sonic-hedgehog-medulloblastoma
#1
S E Conduit, V Ramaswamy, M Remke, D N Watkins, B J Wainwright, M D Taylor, C A Mitchell, J M Dyson
Sonic Hedgehog (SHH) signaling at primary cilia drives the proliferation and progression of a subset of medulloblastomas, the most common malignant paediatric brain tumor. Severe side effects associated with conventional treatments and resistance to targeted therapies has led to the need for new strategies. SHH signaling is dependent on primary cilia for signal transduction suggesting the potential for cilia destabilizing mechanisms as a therapeutic target. INPP5E is an inositol polyphosphate 5-phosphatase that hydrolyses PtdIns(4,5)P2 and more potently, the phosphoinositide (PI) 3-kinase product PtdIns(3,4,5)P3...
June 26, 2017: Oncogene
https://www.readbyqxmd.com/read/28650075/isl1-controls-patterning-and-mineralization-of-enamel-in-the-continuously-renewing-mouse-incisor
#2
Adrien Naveau, Bin Zhang, Bo Meng, McGarrett T Sutherland, Michaela Prochazkova, Timothy Wen, Pauline Marangoni, Kyle B Jones, Timothy C Cox, Bernhard Ganss, Andrew H Jheon, Ophir D Klein
Rodents are characterized by continuously renewing incisors whose growth is fueled by epithelial and mesenchymal stem cells housed in the proximal compartments of the tooth. The epithelial stem cells reside in structures known as the labial (toward the lip) and lingual (toward the tongue) cervical loops (laCL and liCL, respectively). An important feature of the rodent incisor is that enamel, the outer, highly mineralized layer, is asymmetrically distributed, as it is normally generated by the laCL but not the liCL...
June 26, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28647274/sonic-hedgehog-pathway-suppression-and-reactivation-accelerates-differentiation-of-rat-adipose-derived-mesenchymal-stromal-cells-toward-insulin-producing-cells
#3
Dian Dayer, Mahmoud Hashemi Tabar, Eskandar Moghimipour, Mohammad Reza Tabandeh, Ata A Ghadiri, Elham Allah Bakhshi, Mahmoud Orazizadeh, Mohammad Ali Ghafari
BACKGROUND AIMS: Sonic hedgehog (Shh) is an intercellular signaling molecule that regulates pancreas development in mammals. Manipulation of Shh signaling pathway can be used as reliable approach to improve the generation of functional insulin-producing cells (IPCs) from mesenchymal stromal cells (MSCs). METHODS: In the present study, a novel differentiation protocol was used to produce IPCs from adipose tissue-derived MSCs (ATDMSCs) based on sequential inhibition and reactivation of Shh pathway...
June 21, 2017: Cytotherapy
https://www.readbyqxmd.com/read/28646606/vismodegib-for-recurrent-locally-destructive-basal-cell-carcinoma-in-a-renal-transplant-patient
#4
P Koelblinger, R Dummer, M Laimer, S Hecht, J W Bauer, A Gaggl, A Kugler
Solid organ transplant patients are at an increased risk of developing cutaneous malignancies owing to long-lasting immunosuppression. The strongest increase in incidence (35-fold) has been reported for cutaneous squamous cell carcinoma [1]. Basal cell carcinoma (BCC) may occur even more frequently, especially during the first years after transplantation [2]. The hedgehog-inhibitor vismodegib has been safely used for the treatment of locally advanced or metastatic BCC in immunocompetent patients since 2012 [3]...
June 24, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28645738/human-germline-hedgehog-pathway-mutations-predispose-to-fatty-liver
#5
Maria J Guillen Sacoto, Ariel F Martinez, Yu Abe, Paul Kruszka, Karin Weiss, Joshua L Everson, Ramon Bataller, David E Kleiner, Jerrold M Ward, Kathleen K Sulik, Robert J Lipinski, Benjamin D Solomon, Maximilian Muenke
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations affecting this pathway. METHODS: Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD...
June 20, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28645539/gli1-labeled-adult-mesenchymal-stem-progenitor-cells-and-hedgehog-signaling-contribute-to-endochondral-heterotopic-ossification
#6
Chen Kan, Lijun Chen, Yangyang Hu, Na Ding, Yuyun Li, Tammy L McGuire, Haimei Lu, John A Kessler, Lixin Kan
Heterotopic ossification (HO), acquired or hereditary, endochondral or intramembranous, is the formation of true bone outside the normal skeleton. Since perivascular Gli1+ progenitors contribute to injury induced organ fibrosis, and CD133 is expressed by a variety of populations adult stem cells, this study utilized Cre-lox based genetic lineage tracing to test the contribution to endochondral HO of adult stem/progenitor cells that expressed either Gli1 or CD133. We found that both lineages contributed broadly to different normal tissues with distinct patterns, but that only Gli1-creERT labeled stem/progenitor cells contributed to all stages of endochondral HO in a BMP dependent, injury induced, transgenic mouse model...
June 20, 2017: Bone
https://www.readbyqxmd.com/read/28642332/morphine-worsens-the-severity-and-prevents-pancreatic-regeneration-in-mouse-models-of-acute-pancreatitis
#7
Usman Barlass, Raini Dutta, Hassam Cheema, John George, Archana Sareen, Ajay Dixit, Zuobiao Yuan, Bhuwan Giri, Jingjing Meng, Santanu Banerjee, Sulagna Banerjee, Vikas Dudeja, Rajinder K Dawra, Sabita Roy, Ashok K Saluja
BACKGROUND: Opioids such as morphine are widely used for the management of pain associated with acute pancreatitis. Interestingly, opioids are also known to affect the immune system and modulate inflammatory pathways in non-pancreatic diseases. However, the impact of morphine on the progression of acute pancreatitis has never been evaluated. In the current study, we evaluated the impact of morphine on the progression and severity of acute pancreatitis. METHODS: Effect of morphine treatment on acute pancreatitis in caerulein, L-arginine and ethanol-palmitoleic acid models was evaluated after induction of the disease...
June 22, 2017: Gut
https://www.readbyqxmd.com/read/28642101/introduction-of-fluorine-to-phenyl-group-of-4-2-pyrimidinylamino-benzamides-leading-to-a-series-of-potent-hedgehog-signaling-pathway-inhibitors
#8
Minhang Xin, Liandi Zhang, Jun Wen, Han Shen, Xinge Zhao, Qiu Jin, Feng Tang
In present study, a novel series of fluorine containing 4-(2-pyrimidinylamino)benzamide analogues were designed and synthesized. The hedgehog (Hh) signaling inhibitory activities for these compounds were evaluated by a luciferase reporter method. The preliminary SAR was discussed and many compounds showed potent Hh signaling inhibitory activities. Compound 15h displayed the most potent inhibitory activity, with an IC50 of 0.050nM. This paper finds the introduction of fluorine to the 4-(2-pyrimidinylamino)benzamide scaffold can lead to a novel series of potent Hh signaling pathway inhibitors...
June 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28640708/medulloblastoma-from-myth-to-molecular
#9
Vijay Ramaswamy, Michael D Taylor
Current therapies for medulloblastoma were introduced primarily in the 1980s and consist of predominantly cytotoxic, nontargeted approaches. Mortality from medulloblastoma remains significant. In addition, many survivors suffer from severe treatment-related effects of radiation and cytotoxic chemotherapy. Further intensification of nonspecific therapy is unlikely to offer additional benefits, because survival rates have reached a plateau. Recent publications in medulloblastoma have revolved largely around the recognition that medulloblastoma per se does not exist, but rather, that there are a group of histologically similar but clinically and molecularly distinct entities that have been grouped under that rubric...
June 22, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28640141/smoking-status-and-gene-susceptibility-play-important-roles-in-the-development-of-chronic-obstructive-pulmonary-disease-and-lung-function-decline-a-population-based-prospective-study
#10
Junling Zhao, Miao Li, Jinkun Chen, Xiaomei Wu, Qin Ning, Jianping Zhao, Yongjian Xu, Jungang Xie, Jun Yu
BACKGROUND: We conducted this study to identify the influences and synergistic effects of smoking status and polymorphisms in hedgehog interacting protein (HHIP) on chronic obstructive pulmonary disease (COPD) and lung function decline. METHODS: A cohort containing 306 COPD patients and 743 healthy subjects was recruited from 25,000 subjects. All selected subjects had chronic cough for over 2 years or a smoking history above 20 pack-years. After 8 years, all subjects were divided into 2 cohorts according to whether they had quit smoking or not...
June 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28639704/genome-wide-association-analysis-identifies-potential-regulatory-genes-for-eumelanin-pigmentation-in-chicken-plumage
#11
L Yang, X Du, S Wei, L Gu, N Li, Y Gong, S Li
Plumage color in chicken is determined by the proportion of eumelanin and pheomelanin pigmentation. As the main ingredient in plumage melanin, eumelanin plays a key role in the dark black, brown and grey coloration. However, very few studies have been performed to identify the related genes and mutations on a genome-wide scale. Herein, a resource family consisting of one backcross population and two F2 cross populations between a black roster and Yukou Brown I parent stockbreed was constructed for identification of genes related to eumelanin pigmentation...
June 22, 2017: Animal Genetics
https://www.readbyqxmd.com/read/28638111/transcriptome-analyses-of-taste-organoids-reveal-multiple-pathways-involved-in-taste-cell-generation
#12
Wenwen Ren, Eitaro Aihara, Weiwei Lei, Nishi Gheewala, Hironobu Uchiyama, Robert F Margolskee, Ken Iwatsuki, Peihua Jiang
Taste cells undergo constant turnover throughout life; however, the molecular mechanisms governing taste cell generation are not well understood. Using RNA-Seq, we systematically surveyed the transcriptome landscape of taste organoids at different stages of growth. Our data show the staged expression of a variety of genes and identify multiple signaling pathways underlying taste cell differentiation and taste stem/progenitor cell proliferation. For example, transcripts of taste receptors appear only or predominantly in late-stage organoids...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28637711/the-exon-junction-complex-and-srp54-contribute-to-drosophila-hedgehog-signaling-via-ci-rna-splicing
#13
Elisa Garcia Garcia, Jamie C Little, Daniel Kalderon
Hedgehog (Hh) regulates the Cubitus interruptus (Ci) transcription factor in Drosophila melanogaster by activating full-length Ci-155 and blocking processing to Ci-75 repressor. However, the interplay between regulation of Ci-155 levels and activity, as well as processing-independent mechanisms that affect Ci-155 levels have not been explored extensively. Here we identified Mago Nashi (Mago) and Y14 core Exon Junction Complex (EJC) proteins, as well as the Srp54 splicing factor as modifiers of Hh pathway activity under sensitized conditions...
June 21, 2017: Genetics
https://www.readbyqxmd.com/read/28637687/inhibition-of-cdk4-6-by-palbociclib-significantly-extends-survival-in-medulloblastoma-patient-derived-xenograft-mouse-models
#14
Michelle L Cook Sangar, Laura A Genovesi, Madison W Nakamoto, Melissa J Davis, Sue E Knoblaugh, Pengxiang Ji, Amanda Millar, Brandon Wainwright, James M Olson
  <p>Bioinformatics analysis followed by in vivo studies in patient-derived xenograft models were used to identify and validate CDK 4/6 inhibition as an effective therapeutic strategy for medulloblastoma, particularly Group 3 MYC-amplified tumors which have the worst clinical prognosis.</p> <br />Experimental Design: <p>A protein interaction network derived from a Sleeping Beauty mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets.  The top hit from this analysis was validated in vivo using patient-derived xenograft models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice...
June 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28635509/induced-pluripotent-stem-cell-derived-dopaminergic-neurons-from-adult-common-marmoset-fibroblasts
#15
Scott C Vermilyea, Scott Guthrie, Michael Meyer, Kim Smuga-Otto, Katarina Braun, Sara Howden, James A Thomson, Su-Chun Zhang, Marina Emborg, Dr Thaddeus G Golos
The common marmoset monkey (Callithrix jacchus; Cj) is an advantageous nonhuman primate species for modeling age-related disorders, including Parkinson's disease, due to their shorter lifespan compared to macaques. Cj-derived induced pluripotent stem cells (Cj-iPSCs) from somatic cells are needed for in vitro disease modeling and testing regenerative medicine approaches. Here we report the development of a novel Cj-iPSC line derived from adult marmoset fibroblasts. The Cj-iPSCs showed potent pluripotency properties including development of mesodermal lineages in tumors after injection to immunocompromised mice, as well as ectoderm and endoderm lineages after in vitro differentiation regimens, demonstrating differentiated derivatives of all three embryonic layers...
June 21, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28635133/critical-role-of-glioma-associated-oncogene-homolog-1-in-maintaining-invasive-and-mesenchymal-like-properties-of-melanoma-cells
#16
I Ketut Gunarta, Rong Li, Ryota Nakazato, Ryusuke Suzuki, Jambaldorj Boldbaatar, Takeshi Suzuki, Katsuji Yoshioka
Cutaneous melanoma is the most aggressive form of skin cancer. This aggressiveness appears to be due to the cancer cells' ability to reversibly switch between phenotypes with non-invasive and invasive potentials, and microphthalmia-associated transcription factor (MITF) is known to play a central role in this process. The transcription factor glioma-associated oncogene homolog 1 (GLI1) is a component of the canonical and noncanonical sonic hedgehog pathways. Although GLI1 has been suggested to be involved in melanoma progression, its precise role and the mechanism underlying invasion remain unclear...
June 21, 2017: Cancer Science
https://www.readbyqxmd.com/read/28633965/phosphoproteome-analysis-reveals-a-critical-role-for-hedgehog-signalling-in-osteoblast-morphological-transitions
#17
Ariane Marumoto, Renato Milani, Rodrigo A da Silva, Célio Junior da Costa Fernandes, José Mauro Granjeiro, Carmen V Ferreira, Maikel P Peppelenbosch, Willian F Zambuzzi
The reciprocal and adaptive interactions between cells and substrates governing morphological transitions in the osteoblast compartment remain largely obscure. Here we show that osteoblast cultured in basement membrane matrix (Matrigel™) exhibits significant morphological changes after ten days of culture, and we decided to exploit this situation to investigate the molecular mechanisms responsible for guiding osteoblast morphological transitions. As almost all aspects of cellular physiology are under control of kinases, we generated more or less comprehensive cellular kinome profiles employing PepChip peptide arrays that contain over 1000 consensus substrates of kinase peptide...
June 17, 2017: Bone
https://www.readbyqxmd.com/read/28631844/sonic-hedgehog-wnt-and-brain-derived-neurotrophic-factor-cell-signaling-pathway-crosstalk-potential-therapy-for-depression
#18
REVIEW
Mohd Tayyab, Mehdi H Shahi, Shirin Farheen, Mubeena P M Mariyath, Nabeela Khanam, Javier S Castresana, M Mobarak Hossain
There are various theories to explain the pathophysiology of depression and support its diagnosis and treatment. The roles of monoamines, brain-derived neurotrophic factor (BDNF), and Wnt signaling are well researched, but sonic hedgehog (Shh) signaling and its downstream transcription factor Gli1 are not well studied in depression. Shh signaling plays a fundamental role in embryonic development and adult hippocampal neurogenesis and also involved in the growth of cancer. In this article, we summarize the evidence for the Shh signaling pathway in depression and the potential crosstalk of Shh with Wnt and BDNF...
June 20, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28631369/inoperable-infiltrative-basal-cell-carcinoma-successfully-treated-with-vismodegib
#19
Omid Zargari, Seyyede Zeinab Azimi, Siamak Geranmayeh
Basal cell carcinoma (BCC) is the most common skin cancer but usually has a good prognosis. However, there is a subset of BCC cases with a less favorable prognosis. For patients with locally advanced, recurrent or metastatic BCCs who are not suitable for surgery or radiotherapy, small-molecule drug inhibitors of hedgehog pathway are a new therapeutic opportunity. Here, we present a case of infiltrative BCC with multiple recurrences. Wide excision with reconstructive plastic surgery was performed initially with adjuvant radiotherapy...
June 19, 2017: Dermatologic Therapy
https://www.readbyqxmd.com/read/28630423/thymosin-beta-4-regulates-activation-of-hepatic-stellate-cells-via-hedgehog-signaling
#20
Jieun Kim, Jeongeun Hyun, Sihyung Wang, Chanbin Lee, Jae-Wook Lee, Eun-Yi Moon, Heejae Cha, Anna Mae Diehl, Youngmi Jung
The molecular mechanisms of thymosin beta-4 (TB4) involved in regulating hepatic stellate cell (HSC) functions remain unclear. Therefore, we hypothesize that TB4 influences HSC activation through hedgehog (Hh) pathway. HSC functions declined in a TB4 siRNA-treated LX-2. TB4 suppression down-regulated both integrin linked kinase (ILK), an activator of smoothened, and phosphorylated glycogen synthase kinase 3 beta (pGSK-3B), an inactive form of GSK-3B degrading glioblastoma 2 (GLI2), followed by the decreased expression of both smoothened and GLI2...
June 19, 2017: Scientific Reports
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