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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 27 March 2018, Vol.115(13), pp.3392-3397
    Description: The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location because SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened () mutations form more specifically in the hemispheres than those with Patched 1 () mutations. Using sporadic mouse models of SHH-MB with the two mutations commonly seen in adult MB, constitutive activation of () or loss-of-, we found that regardless of timing of induction or type of mutation, tumors developed primarily in the hemispheres, with -mutants indeed showing a stronger specificity. We further uncovered that GCPs in the hemispheres are more susceptible to high-level SHH signaling compared with GCPs in the medial cerebellum (vermis), as more or -mutant hemisphere cells remain undifferentiated and show increased tumorigenicity when transplanted. Finally, we identified location-specific GCP gene-expression profiles, and found that deletion of the genes most highly expressed in the hemispheres () or vermis (Engrailed1) showed opposing effects on GCP differentiation. Our studies thus provide insights into intrinsic differences within GCPs that impact on SHH-MB progression.
    Keywords: En1 ; Mri ; Nr2f2 ; Cerebellar Hemispheres ; Granule Cell Precursors ; Cerebellar Neoplasms -- Pathology ; Cerebellum -- Pathology ; Hedgehog Proteins -- Metabolism ; Medulloblastoma -- Pathology ; Patched-1 Receptor -- Metabolism ; Smoothened Receptor -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: 2014, Vol.9(1), p.e86187
    Description: Telomeric 3′ overhangs can fold into a four-stranded DNA structure termed G-quadruplex (G4), a formation which inhibits telomerase. As telomerase activation is crucial for telomere maintenance in most cancer cells, several classes of G4 ligands have been designed to directly disrupt telomeric structure. ; We exposed brain tumor cells to the G4 ligand 3,11-difluoro-6,8,13-trimethyl-8-quino[4,3,2-]acridinium methosulfate (RHPS4) and investigated proliferation, cell cycle dynamics, telomere length, telomerase activity and activated c-Myc levels. ; Although all cell lines tested were sensitive to RHPS4, PFSK-1 central nervous system primitive neuroectodermal cells, DAOY medulloblastoma cells and U87 glioblastoma cells exhibited up to 30-fold increased sensitivity compared to KNS42 glioblastoma, C6 glioma and Res196 ependymoma cells. An increased proportion of S-phase cells were observed in medulloblastoma and high grade glioma cells whilst CNS PNET cells showed an increased proportion of G1-phase cells. RHPS4-induced phenotypes were concomitant with telomerase inhibition, manifested in a telomere length-independent manner and not associated with activated c-Myc levels. However, anti-proliferative effects were also observed in normal neural/endothelial cells and . ; This study warrants validation of RHPS4 and alternative G4 ligands as potential anti-cancer agents for brain tumors but highlights the consideration of dose-limiting tissue toxicities.
    Keywords: Research Article ; Biology ; Medicine
    E-ISSN: 1932-6203
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  • 3
    In: Nature Genetics, 2014, Vol.46(6), p.588
    Description: Coordinate control of different classes of cyclins is fundamentally important for cell cycle regulation and tumor suppression, yet the underlying mechanisms are incompletely understood. Here we show that the PARK2 tumor suppressor mediates this coordination. The PARK2 E3 ubiquitin ligase coordinately controls the stability of both cyclin D and cyclin E. Analysis of approximately 5,000 tumor genomes shows that PARK2 is a very frequently deleted gene in human cancer and uncovers a striking pattern of mutual exclusivity between PARK2 deletion and amplification of CCND1, CCNE1 or CDK4--implicating these genes in a common pathway. Inactivation of PARK2 results in the accumulation of cyclin D and acceleration of cell cycle progression. Furthermore, PARK2 is a component of a new class of cullin-RING--containing ubiquitin ligases targeting both cyclin D and cyclin E for degradation. Thus, PARK2 regulates cyclin-CDK complexes, as does the CDK inhibitor p16, but acts as a master regulator of the stability of G1/S cyclins.
    Keywords: Cyclins – Genetic Aspects ; Tumor Suppressor Genes – Properties ; Genetic Regulation – Research;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 4
    Language: English
    In: Cancer research, 01 July 2012, Vol.72(13), pp.3350-9
    Description: Loss of neurofibromin 1 (NF1) leads to hyperactivation of RAS, which in turn signals through the RAF/MEK/ERK and phosphoinositide 3-kinase (PI3K)/mTOR pathways to regulate cell growth and survival. Because NF1-deficient acute myeloid leukemias are sensitive to MEK inhibitors, we investigated here whether NF1-deficient glioblastoma multiforme (GBM) would respond to MEK inhibition. In 19 GBM cell lines, we found that treatment with the clinically available MEK inhibitors PD0325901 or AZD6244 decreased levels of phospho-ERK, the downstream effector of MEK, regardless of NF1 status. However, growth inhibition occurred only in a subset of NF1-deficient cells, in association with decreased levels of cyclin D1, increased levels of p27, and G1 arrest. As a single agent, PD0325901 suppressed the growth of NF1-deficient, MEK inhibitor-sensitive cells in vivo as well. Mechanistically, NF1-deficient, MEK inhibitor-sensitive cells were dependent upon the RAF/MEK/ERK pathway for growth and did not activate the PI3K pathway as a mechanism of acquired resistance. Importantly, NF1-deficient cells intrinsically resistant to MEK inhibition were sensitized by the addition of the dual PI3K/mTOR inhibitor PI-103. Taken together, our findings indicate that a subset of NF1-deficient GBMs may respond to MEK inhibitors currently being tested in clinical trials.
    Keywords: Brain Neoplasms -- Pathology ; Glioblastoma -- Pathology ; Mitogen-Activated Protein Kinase Kinases -- Antagonists & Inhibitors ; Neurofibromin 1 -- Metabolism ; Protein Kinase Inhibitors -- Pharmacology
    ISSN: 00085472
    E-ISSN: 1538-7445
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  • 5
    In: Nature, 2003, Vol.424(6945), p.201
    Description: The direction of frequency-modulated (FM) sweeps is an important temporal cue in animal and human communication. FM direction-selective neurons are found in the primary auditory cortex (A1), but their topography and the mechanisms underlying their selectivity remain largely unknown. Here we report that in the rat A1, direction selectivity is topographically ordered in parallel with characteristic frequency (CF): low CF neurons preferred upward sweeps, whereas high CF neurons preferred downward sweeps. The asymmetry of 'inhibitory sidebands', suppressive regions flanking the tonal receptive field (TRF) of the spike response, also co-varied with CF. In vivo whole-cell recordings showed that the direction selectivity already present in the synaptic inputs was enhanced by cortical synaptic inhibition, which suppressed the synaptic excitation of the non-preferred direction more than that of the preferred. The excitatory and inhibitory synaptic TRFs had identical spectral tuning, but with inhibition delayed relative to excitation. The spectral asymmetry of the synaptic TRFs co-varied with CF, as had direction selectivity and sideband asymmetry, and thus suggested a synaptic mechanism for the shaping of FM direction selectivity and its topographic ordering.
    Keywords: Auditory Cortex -- Physiology;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 6
    Language: English
    In: Journal of Nanoparticle Research: An Interdisciplinary Forum for Nanoscale Science and Technology, March, 2012, Vol.14(3), p.1(11)
    Description: Byline: Mitali Kakran (1), Nanda Gopal Sahoo (1), I-Lin Tan (1), Lin Li (1) Keywords: Curcumin; Antisolvent precipitation with a syringe pump; Evaporative precipitation of nanosuspension; Solubility; Dissolution Abstract: The objective of this study was to enhance the solubility and dissolution rate of a poorly water-soluble antioxidant, curcumin, by fabricating its nanoparticles with two methods: antisolvent precipitation with a syringe pump (APSP) and evaporative precipitation of nanosuspension (EPN). For APSP, process parameters like flow rate, stirring speed, solvent to antisolvent (SAS) ratio, and drug concentration were investigated to obtain the smallest particle size. For EPN, factors like drug concentration and the SAS ratio were examined. The effects of these process parameters on the supersaturation, nucleation, and growth rate were studied and optimized to obtain the smallest particle size of curcumin by both the methods. The average particle size of the original drug was about 10--12 um and it was decreased to a mean diameter of 330 nm for the APSP method and to 150 nm for the EPN method. Overall, decreasing the drug concentration or increasing the flow rate, stirring rate, and antisolvent amount resulted in smaller particle sizes. Differential scanning calorimetry studies suggested lower crystallinity of curcumin particles fabricated. The solubility and dissolution rates of the prepared curcumin particles were significantly higher than those the original curcumin. The antioxidant activity, studied by the DPPH free radical-scavenging assay, was greater for the curcumin nanoparticles than the original curcumin. This study demonstrated that both the methods can successfully prepare curcumin into submicro to nanoparticles. However, drug particles prepared by EPN were smaller than those by APSP and hence, showed the slightly better solubility, dissolution rate, and antioxidant activity than the latter. Author Affiliation: (1) School of Mechanical and Aerospace Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore, 639798, Singapore Article History: Registration Date: 23/01/2012 Received Date: 08/07/2011 Accepted Date: 12/01/2012 Online Date: 10/02/2012
    Keywords: Precipitation (Meteorology) -- Analysis ; Precipitation (Meteorology) -- Methods ; Nanoparticles -- Analysis ; Nanoparticles -- Methods ; Mechanical Engineering -- Analysis ; Mechanical Engineering -- Methods ; Aerospace Engineering -- Analysis ; Aerospace Engineering -- Methods ; Antioxidants (Nutrients) -- Analysis ; Antioxidants (Nutrients) -- Methods
    ISSN: 1388-0764
    E-ISSN: 1572896X
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  • 7
    In: 黑龙江八一农垦大学学报 - Journal of Heilongjiang August First Land Reclamation University, 2015, Vol.27(04), pp.25-27
    Description: 隶属函数综合评定法通过对不同指标的量化、赋值,建立线性隶属函数,再依据最大原则进行排序,比较客观地描述了评价对象的综合表现。所得评价结果与实际表现相符,是较为适用的综合评价体系,适合在寒地浆果种质资源圃建立和品种优选中应用。但应尽可能集合多名专家意见,全面准确地设定各层次影响因素及其权重分配,建立科学合理的综合评价指标关系模型。
    Description: This fuzzy comprehensive evaluation used membership function to quantify the different index and sorts by the maximum principle. Describing comprehensive performance of evaluation object was objective. The results were conformed to the facts. It was suitable for establishing the resource nursery of cold land berry and optimal selecting of varieties .But more expert opinion should be collected to determine effect factor of different levels and weight,which would be more scientific and rational.
    Keywords: 评价体系 ; 隶属函数 ; 浆果 ; 醋栗 ; Evaluation System;Membership Function;Berry;Gooseberry
    ISSN: 1002-2090
    Source: 维普数据 (Chongqing VIP Information Co.)
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  • 8
    In: Magnetic Resonance in Medicine, January 2020, Vol.83(1), pp.214-227
    Description: PURPOSEGenetically engineered mouse models of sporadic cancers are critical for studying tumor biology and for preclinical testing of therapeutics. We present an MRI-based pipeline designed to produce high resolution, quantitative information about tumor progression and response to novel therapies in mouse models of medulloblastoma (MB). METHODSSporadic MB was modeled in mice by inducing expression of an activated form of the Smoothened gene (aSmo) in a small number of cerebellar granule cell precursors. aSmo mice were imaged and analyzed at defined time-points using a 3D manganese-enhanced MRI-based pipeline optimized for high-throughput. RESULTSA semi-automated segmentation protocol was established that estimates tumor volume in a time-frame compatible with a high-throughput pipeline. Both an empirical, volume-based classifier and a linear discriminant analysis-based classifier were tested to distinguish progressing from nonprogressing lesions at early stages of tumorigenesis. Tumor centroids measured at early stages revealed that there is a very specific location of the probable origin of the aSmo MB tumors. The efficacy of the manganese-enhanced MRI pipeline was demonstrated with a small-scale experimental drug trial designed to reduce the number of tumor associated macrophages and microglia. CONCLUSIONOur results revealed a high level of heterogeneity between tumors within and between aSmo MB models, indicating that meaningful studies of sporadic tumor progression and response to therapy could not be conducted without an imaging-based pipeline approach.
    Keywords: Linear Discriminant Analysis Lda ; Mri ; Segmentation; Sonic Hedgehog Shh ; Tumor Associated Macrophages And Microglia Tams
    ISSN: 0740-3194
    E-ISSN: 1522-2594
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  • 9
    Language: English
    In: Brawand, D., C. E. Wagner, Y. I. Li, M. Malinsky, I. Keller, S. Fan, O. Simakov, et al. 2014. “The genomic substrate for adaptive radiation in African cichlid fish.” Nature 513 (7518): 375-381. doi:10.1038/nature13726. http://dx.doi.org/10.1038/nature13726.
    Description: Cichlid fishes are famous for large, diverse and replicated adaptive radiations in the Great Lakes of East Africa. To understand the molecular mechanisms underlying cichlid phenotypic diversity, we sequenced the genomes and transcriptomes of five lineages of African cichlids: the Nile tilapia (Oreochromis niloticus), an ancestral lineage with low diversity; and four members of the East African lineage: Neolamprologus brichardi/pulcher (older radiation, Lake Tanganyika), Metriaclima zebra (recent radiation, Lake Malawi), Pundamilia nyererei (very recent radiation, Lake Victoria), and Astatotilapia burtoni (riverine species around Lake Tanganyika). We found an excess of gene duplications in the East African lineage compared to tilapia and other teleosts, an abundance of non-coding element divergence, accelerated coding sequence evolution, expression divergence associated with transposable element insertions, and regulation by novel microRNAs. In addition, we analysed sequence data from sixty individuals representing six closely related species from Lake Victoria, and show genome-wide diversifying selection on coding and regulatory variants, some of which were recruited from ancient polymorphisms. We conclude that a number of molecular mechanisms shaped East African cichlid genomes, and that amassing of standing variation during periods of relaxed purifying selection may have been important in facilitating subsequent evolutionary diversification.
    Keywords: Cichlids -- Genetic Aspects ; Genomics -- Research ; Evolutionary Adaptation -- Genetic Aspects ; Genetic Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 10
    Language: English
    In: PLoS ONE, 2009, Vol.4(12), p.e8453
    Description: The presentation of new influenza A(H1N1) is broad and evolving as it continues to affect different geographic locations and populations. To improve the accuracy of predicting influenza infection in an outpatient setting, we undertook a comparative analysis of H1N1(2009), seasonal influenza, and persons with acute respiratory illness (ARI) in an outpatient setting. ; Comparative analyses of one hundred non-matched cases each of PCR confirmed H1N1(2009), seasonal influenza, and ARI cases. Multivariate analysis was performed to look for predictors of influenza infection. Receiver operating characteristic curves were constructed for various combinations of clinical and laboratory case definitions. The initial clinical and laboratory features of H1N1(2009) and seasonal influenza were similar. Among ARI cases, fever, cough, headache, rhinorrhea, the absence of leukocytosis, and a normal chest radiograph positively predict for both PCR-confirmed H1N1-2009 and seasonal influenza infection. The sensitivity and specificity of current WHO and CDC influenza-like illness (ILI) criteria were modest in predicting influenza infection. However, the combination of WHO ILI criteria with the absence of leukocytosis greatly improved the accuracy of diagnosing H1N1(2009) and seasonal influenza (positive LR of 7.8 (95%CI 3.5–17.5) and 9.2 (95%CI 4.1–20.3) respectively). ; The clinical presentation of H1N1(2009) infection is largely indistinguishable from that of seasonal influenza. Among patients with acute respiratory illness, features such as a temperature greater than 38°C, rhinorrhea, a normal chest radiograph, and the absence of leukocytosis or significant gastrointestinal symptoms were all positively associated with H1N1(2009) and seasonal influenza infection. An enhanced ILI criteria that combines both a symptom complex with the absence of leukocytosis on testing can improve the accuracy of predicting both seasonal and H1N1-2009 influenza infection.
    Keywords: Research Article ; Virology -- Diagnosis ; Infectious Diseases -- Viral Infections ; Public Health And Epidemiology -- Infectious Diseases
    E-ISSN: 1932-6203
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