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https://www.readbyqxmd.com/read/29778738/risk-adapted-therapy-for-young-children-with-medulloblastoma-sjyc07-therapeutic-and-molecular-outcomes-from-a-multicentre-phase-2-trial
#1
Giles W Robinson, Vasilisa A Rudneva, Ivo Buchhalter, Catherine A Billups, Sebastian M Waszak, Kyle S Smith, Daniel C Bowers, Anne Bendel, Paul G Fisher, Sonia Partap, John R Crawford, Tim Hassall, Daniel J Indelicato, Frederick Boop, Paul Klimo, Noah D Sabin, Zoltan Patay, Thomas E Merchant, Clinton F Stewart, Brent A Orr, Jan O Korbel, David T W Jones, Tanvi Sharma, Peter Lichter, Marcel Kool, Andrey Korshunov, Stefan M Pfister, Richard J Gilbertson, Robert P Sanders, Arzu Onar-Thomas, David W Ellison, Amar Gajjar, Paul A Northcott
BACKGROUND: Young children with medulloblastoma have a poor overall survival compared with older children, due to use of radiation-sparing therapy in young children. Radiotherapy is omitted or reduced in these young patients to spare them from debilitating long-term side-effects. We aimed to estimate event-free survival and define the molecular characteristics associated with progression-free survival in young patients with medulloblastoma using a risk-stratified treatment strategy designed to defer, reduce, or delay radiation exposure...
May 16, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29777201/novel-smoothened-inhibitors-for-therapeutic-targeting-of-na%C3%A3-ve-and-drug-resistant-hedgehog-pathway-driven-cancers
#2
Qing-Rou Li, Hui Zhao, Xue-Sai Zhang, Henk Lang, Ker Yu
The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. The FDA-approved SMO inhibitors GDC-0449/Vismodegib and LDE225/Sonidegib demonstrated clinical antitumor efficacy. Nevertheless, relatively high percentage of treated patients would eventually develop acquired cross resistance to both drugs. Here, based on published structure and activity of GDC-0449 inhibitor class, we replaced its amide core with benzimidazole which retained bulk of the SMO-targeting activity as measured in our Hh/SMO/Gli1-reporter system...
May 18, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29776650/signaling-pathway-deregulation-and-molecular-alterations-across-pediatric-medulloblastomas
#3
REVIEW
B Lhermitte, A F Blandin, A Coca, E Guerin, A Durand, N Entz-Werlé
Medulloblastomas (MBs) account for 15% of brain tumors in children under the age of 15. To date, the overall 5-year survival rate for all children is only around 60%. Recent advances in cancer genomics have led to a fundamental change in medulloblastoma classification and is evolving along with the genomic discoveries, allowing to regularly reclassify this disease. The previous molecular classification defined 4 groups (WNT-activated MB, SHH-activated MB and the groups 3 and 4 characterized partially by NMYC and MYC driven MBs)...
May 15, 2018: Neuro-Chirurgie
https://www.readbyqxmd.com/read/29776351/a-computational-study-of-hedgehog-signalling-involved-in-basal-cell-carcinoma-reveals-the-potential-and-limitation-of-combination-therapy
#4
Antoine Buetti-Dinh, Rebecca Jensen, Ran Friedman
BACKGROUND: The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC). SMO inhibitors are indicated for BCC patients when surgical treatment or radiation therapy are not possible. Unfortunately, SMO inhibitors are not always well tolerated due to severe side effects, and their therapeutical success is limited by resistance mutations. METHODS: We investigated how common are resistance-causing mutations in two genomic databases which are not linked to BCC or other cancers, namely 1000 Genomes and ExAC...
May 18, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29773652/stromal-gli-signaling-regulates-the-activity-and-differentiation-of-prostate-stem-and-progenitor-cells
#5
Qianjin Li, Omar A Alsaidan, Sumit Rai, Meng Wu, Huifeng Shen, Zanna Beharry, Luciana L Almada, Martin E Fernandez-Zapico, Lianchun Wang, Houjian Cai
Interactions between cells in the stroma and epithelium facilitate prostate stem cell activity and tissue regeneration capacity. Numerous molecular signal transduction pathways, including the induction of sonic hedgehog (Shh) to activate the Gli transcription factors, are known to mediate the crosstalk of these two cellular compartments. However, the details of how these signaling pathways regulate prostate stem and progenitor cell activity remain elusive. Here we demonstrate that while cell autonomous epithelial Shh-Gli signaling is essential to determine the expression levels of basal cell markers and the renewal potential of epithelial stem and progenitor cells, stromal Gli signaling regulates prostate stem and progenitor cell activity by increasing the number and size of prostate spheroids in vitro...
May 17, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29771176/potential-use-of-cxcl12-cxcr4-and-sonic-hedgehog-pathways-as-therapeutic-targets-in-medulloblastoma
#6
Marla Karine Amarante, Glauco Akelinghton Freire Vitiello, Marcos Henrique Rosa, Igor Alves Mancilla, Maria Angelica Ehara Watanabe
Medulloblastoma (MB) is the most common malignant brain tumor occurring in children, and although high long-term survival rates have been reached with current therapeutic protocols, several neurological injuries are still observed among survivors. It has been shown that the development of MB is highly dependent on the microenvironment surrounding it and that the CXCL12 chemokine and its receptor, CXCR4 and the Sonic Hedgehog (SHH) pathway are crucial for cerebellar development, coordinating proliferation and migration of embryonic cells and malfunctions in these axes can lead to MB development...
May 17, 2018: Acta Oncologica
https://www.readbyqxmd.com/read/29768039/loss-of-sonic-hedgehog-gene-leads-to-muscle-development-disorder-and-megaesophagus-in-mice
#7
Xueting Jia, Li Min, Shengtao Zhu, Shutian Zhang, Xiaofeng Huang
Sonic hedgehog ( Shh) is crucial for organogenesis in the foregut. This study investigated the function of Shh at the late-gestational stage; during which, the esophagus continues to differentiate. We established cytokeratin 14 ( CK14)-Cre;Shhfl/fl mice in which the down-regulation of Shh in the epithelium occurred at approximately the same time as esophageal muscle conversion. Hematoxylin and eosin and immunohistochemical staining, with antibodies against keratin 14, Shh, patched 1 (Ptch1), Gli1, proliferating cell nuclear antigen (PCNA), α-smooth muscle actin (αSMA), high-molecular-weight caldesmon (hCD), myogenin, paired box 7 (Pax7), β3-tubulin, and protein gene product 9...
May 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29767687/hormone-responsive-genes-in-the-shh-and-wnt-%C3%AE-catenin-signaling-pathways-influence-urethral-closure-and-phallus-growth
#8
Yu Chen, Hongshi Yu, Andrew J Pask, Asao Fujiyama, Yutaka Suzuki, Sumio Sugano, Geoff Shaw, Marilyn B Renfree
Environmental endocrine disruptors (EEDs) that affect androgen or estrogen activity may disrupt gene regulation during normal phallus development to cause hypospadias or a masculinized clitoris. We treated developing male tammar wallabies with estrogen and females with androgen from day 20-40 postpartum (pp) during the established androgen imprinting window. Administration of estrogen to males inhibited phallus elongation but had no effect on urethral closure and did not significantly depress testicular androgen synthesis...
May 14, 2018: Biology of Reproduction
https://www.readbyqxmd.com/read/29760202/survey-of-human-chromosome-21-gene-expression-effects-on-early-development-in-danio-rerio
#9
Sarah Edie, Norann A Zaghloul, Carmen C Leitch, Donna K Klinedinst, Janette Lebron, Joey F Thole, Andrew S McCallion, Nicholas Katsanis, Roger H Reeves
Trisomy for human chromosome 21 (Hsa21) results in Down syndrome (DS), one of the most genetically complex conditions compatible with human survival. Assessment of the physiological consequences of dosage-driven overexpression of individual Hsa21 genes during early embryogenesis and the resulting contributions to DS pathology in mammals are not tractable in a systematic way. A recent study looked loss-of-function of C. elegans orthologues of Hsa21 genes and identified ten candidates with behavioral phenotypes, but the equivalent over-expression experiment has not been done...
May 14, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29754802/intracellular-calcium-mobilization-is-required-for-sonic-hedgehog-signaling
#10
Dana Klatt Shaw, Derrick Gunther, Michael J Jurynec, Alexis A Chagovetz, Erin Ritchie, David Jonah Grunwald
Graded Shh signaling across fields of precursor cells coordinates patterns of gene expression, differentiation, and morphogenetic behavior as precursors form complex structures, such as the nervous system, the limbs, and craniofacial skeleton. Here we discover that intracellular calcium mobilization, a process tightly controlled and readily modulated, regulates the level of Shh-dependent gene expression in responding cells and affects the development of all Shh-dependent cell types in the zebrafish embryo. Reduced expression or modified activity of ryanodine receptor (RyR) intracellular calcium release channels shifted the allocation of Shh-dependent cell fates in the somitic muscle and neural tube...
May 8, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29753759/multiple-dna-damage-dependent-and-dna-damage-independent-stress-responses-define-the-outcome-of-atr-chk1-targeting-in-medulloblastoma-cells
#11
Katharina Krüger, Katharina Geist, Fabian Stuhldreier, Lena Schumacher, Lena Blümel, Marc Remke, Sebastian Wesselborg, Björn Stork, Nicolaj Klöcker, Stefanie Bormann, Wynand P Roos, Sebastian Honnen, Gerhard Fritz
Targeting of oncogene-driven replicative stress as therapeutic option for high-risk medullobastoma was assessed using a panel of medulloblastoma cells differing in their c-Myc expression [i.e. group SHH (c-Myc low) vs. group 3 (c-Myc high)]. High c-Myc levels were associated with hypersensitivity to pharmacological Chk1 and ATR inhibition but not to CDK inhibition nor to conventional (genotoxic) anticancer therapeutics. The enhanced sensitivity of group 3 medulloblastoma cells to Chk1 inhibitors likely results from enhanced damage to intracellular organelles, elevated replicative stress and DNA damage and activation of apoptosis/necrosis...
May 10, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29753700/spectrum-and-prevalence-of-genetic-predisposition-in-medulloblastoma-a-retrospective-genetic-study-and-prospective-validation-in-a-clinical-trial-cohort
#12
Sebastian M Waszak, Paul A Northcott, Ivo Buchhalter, Giles W Robinson, Christian Sutter, Susanne Groebner, Kerstin B Grund, Laurence Brugières, David T W Jones, Kristian W Pajtler, A Sorana Morrissy, Marcel Kool, Dominik Sturm, Lukas Chavez, Aurelie Ernst, Sebastian Brabetz, Michael Hain, Thomas Zichner, Maia Segura-Wang, Joachim Weischenfeldt, Tobias Rausch, Balca R Mardin, Xin Zhou, Cristina Baciu, Christian Lawerenz, Jennifer A Chan, Pascale Varlet, Lea Guerrini-Rousseau, Daniel W Fults, Wiesława Grajkowska, Peter Hauser, Nada Jabado, Young-Shin Ra, Karel Zitterbart, Suyash S Shringarpure, Francisco M De La Vega, Carlos D Bustamante, Ho-Keung Ng, Arie Perry, Tobey J MacDonald, Pablo Hernáiz Driever, Anne E Bendel, Daniel C Bowers, Geoffrey McCowage, Murali M Chintagumpala, Richard Cohn, Timothy Hassall, Gudrun Fleischhack, Tone Eggen, Finn Wesenberg, Maria Feychting, Birgitta Lannering, Joachim Schüz, Christoffer Johansen, Tina V Andersen, Martin Röösli, Claudia E Kuehni, Michael Grotzer, Kristina Kjaerheim, Camelia M Monoranu, Tenley C Archer, Elizabeth Duke, Scott L Pomeroy, Redmond Shelagh, Stephan Frank, David Sumerauer, Wolfram Scheurlen, Marina V Ryzhova, Till Milde, Christian P Kratz, David Samuel, Jinghui Zhang, David A Solomon, Marco Marra, Roland Eils, Claus R Bartram, Katja von Hoff, Stefan Rutkowski, Vijay Ramaswamy, Richard J Gilbertson, Andrey Korshunov, Michael D Taylor, Peter Lichter, David Malkin, Amar Gajjar, Jan O Korbel, Stefan M Pfister
BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED)...
May 9, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29749693/modeling-the-complex-etiology-of-holoprosencephaly-in-mice
#13
Mingi Hong, Robert S Krauss
Holoprosencephaly (HPE) is a common developmental defect caused by failure to define the midline of the forebrain and/or midface. HPE is associated with heterozygous mutations in Nodal and Sonic hedgehog (SHH) pathway components, but clinical presentation is highly variable, and many mutation carriers are unaffected. It is therefore thought that such mutations interact with more common modifiers, genetic and/or environmental, to produce severe patterning defects. Modifiers are difficult to identify, as their effects are context-dependent and occur within the complex genetic and environmental landscapes that characterize human populations...
May 11, 2018: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
https://www.readbyqxmd.com/read/29749689/functions-of-tgif-homeodomain-proteins-and-their-roles-in-normal-brain-development-and-holoprosencephaly
#14
David Wotton, Kenichiro Taniguchi
Holoprosencephaly (HPE) is a frequent human forebrain developmental disorder with both genetic and environmental causes. Multiple loci have been associated with HPE in humans, and potential causative genes at 14 of these loci have been identified. Although TGIF1 (originally TGIF, for Thymine Guanine-Interacting Factor) is among the most frequently screened genes in HPE patients, an understanding of how mutations in this gene contribute to the pathogenesis of HPE has remained elusive. However, mouse models based on loss of function of Tgif1, and the related Tgif2 gene, have shed some light on how human TGIF1 variants might cause HPE...
May 11, 2018: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
https://www.readbyqxmd.com/read/29739868/the-dorsal-wave-of-neocortical-oligodendrogenesis-begins-embryonically-and-requires-multiple-sources-of-sonic-hedgehog
#15
Caitlin C Winkler, Odessa R Yabut, Santiago P Fregoso, Hector G Gomez, Brett E Dwyer, Samuel J Pleasure, Santos J Franco
Neural progenitor cells in the developing dorsal forebrain give rise to excitatory neurons, astrocytes and oligodendrocytes for the neocortex. Compared to neurons and astrocytes, less is known about the molecular mechanisms that instruct dorsal forebrain progenitors to an oligodendrocyte fate. In this study, we show that Sonic hedgehog (Shh) signaling is required in dorsal progenitors for their late embryonic transition to oligodendrogenesis. Using genetic lineage-tracing in mice of both sexes, we demonstrate that the majority of oligodendrocytes in the embryonic neocortex derive from Emx1+ dorsal forebrain progenitors...
May 8, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29739450/m1-macrophage-recruitment-correlates-with-worse-outcome-in-shh-medulloblastomas
#16
Chanhee Lee, Joongyub Lee, Seung Ah Choi, Seung-Ki Kim, Kyu-Chang Wang, Sung-Hye Park, Se Hoon Kim, Ji Yeoun Lee, Ji Hoon Phi
BACKGROUND: Recent progress in molecular analysis has advanced the understanding of medulloblastoma (MB) and is anticipated to facilitate management of the disease. MB is composed of 4 molecular subgroups: WNT, SHH, Group 3, and Group 4. Macrophages play a crucial role in the tumor microenvironment; however, the functional role of their activated phenotype (M1/M2) remains controversial. Herein, we investigate the correlation between tumor-associated macrophage (TAM) recruitment within the MB subgroups and prognosis...
May 8, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29738174/-hypospadias-induced-by-maternal-exposure-to-di-n-butyl-phthalate-and-its-mechanisms-in-male-rat-offspring
#17
En-Hui Li, Hai-Bin Wei, Bang-Gao Lhuangi, En-Hui Li, Qi Zhang, Zhi-Hui Xu, Da-Hong Zhang
Objective: To induce hypospadias in male rat offspring by maternal exposure to di-n-butyl phthalate (DBP) during late pregnancy and further investigate its mechanisms. METHODS: We randomly divided 20 pregnant rats into a DBP exposure and a control group, the former treated intragastrically with DBP while the latter with soybean oil at 750 mg per kilogram of the body weight per day from gestation days (GD) 14 to 18. On postnatal day (PND) 1, we recorded the incidence rate of hypospadias and observed the histopathological changes in the genital tubercle of the hypospadiac rats...
December 2017: Zhonghua Nan Ke Xue, National Journal of Andrology
https://www.readbyqxmd.com/read/29734730/glioma-associated-oncogene-homolog-inhibitors-have-the-potential-of-suppressing-cancer-stem-cells-of-breast-cancer
#18
Kuo-Shyang Jeng, Chi-Juei Jeng, I-Shyan Sheen, Szu-Hua Wu, Ssu-Jung Lu, Chih-Hsuan Wang, Chiung-Fang Chang
Overexpression of Sonic Hedgehog signaling (Shh) pathway molecules is associated with invasiveness and recurrence in breast carcinoma. Therefore, inhibition of the Shh pathway downstream molecule Glioma-associated Oncogene Homolog (Gli) was investigated for its ability to reduce progression and invasiveness of patient-derived breast cancer cells and cell lines. Human primary breast cancer T2 cells with high expression of Shh signaling pathway molecules were compared with breast cancer line MDA-MB-231 cells...
May 5, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29731823/-epigallocatechin-3-gallate-protects-pc12-cells-against-corticosterone-induced-neurotoxicity-via-the-hedgehog-signaling-pathway
#19
Sha Feng, Jue Liu, Biao Cheng, Aiping Deng, Hong Zhang
It has been acknowledged that environmental stress is a risk factor for developing mental disorders. Chronic stress may contribute to the hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis and a sustained rise in the levels of glucocorticoids (GCs). A high concentration of corticosterone (CORT) damages neuronal PC12 cells. It has been reported that (-)-Epigallocatechin-3-gallate (EGCG), a major component of green tea, exhibits neuroprotective activity. However, the protective effect of EGCG on neuronal cells injured by CORT remains to be elucidated...
May 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29730791/distinct-demographic-profile-and-molecular-markers-of-primary-cns-tumor-in-1873-adolescent-and-young-adult-patient-population
#20
Rohit Vadgaonkar, Sridhar Epari, Girish Chinnaswamy, Rahul Krishnatry, Raees Tonse, Tejpal Gupta, Rakesh Jalali
INTRODUCTION: We present detailed demographic profile, tumor types, and their molecular markers in adolescent and young adult (AYA) patients of age group between 15 and 39 years with primary central nervous system (PCNS) tumors, and compare with pediatric and adult patient populations. METHODOLOGY: Demographic- and disease-related information of 1873 PCNS tumor patients of age 15-39 years registered between 1 January 2011 and 31 December 2015 at our institution was analyzed with respect to their demographics and tumor subtypes...
May 5, 2018: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
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