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  • 1
    Publication Date: 2018-09-05
    Description: One of the most clinically relevant molecular aberrations in breast cancer is overexpression of human epidermal growth factor receptor type 2 (HER2). We aimed to develop a radiolabeled tyrosine kinase inhibitor for HER2-targeted breast cancer imaging. In this study, a radioiodinated analog ( 125/131 I-IBA-CP) of the HER2-selective inhibitor CP724,714 was prepared and evaluated in HER2-positive or -negative subcutaneous human breast cancer xenografts. Methods: The CP724,714 analog IBA-CP was synthesized and assayed for its inhibitory activities against HER2 and 6 other tyrosine kinases. 125/131 I-IBA-CP was prepared using a copper-mediated radioiodination method with enhanced labeling yield and molar activity. In vitro biologic activity, including specific and nonspecific binding of 131 I-IBA-CP to its HER2 kinase target, was assessed in different cell lines. In vivo small-animal 125 I-IBA-CP SPECT imaging and biodistribution studies were conducted on mice bearing HER2-positive, HER2-negative, or epidermal growth factor receptor (EGFR)-positive tumors. Nonradioactive IBA-CP and the EGFR inhibitor erlotinib were used as blocking agents to investigate the binding specificity and selectivity of 125/131 I-IBA-CP toward HER2 in vitro and in vivo. Additionally, 125/131 I-ICP was prepared by direct radioiodination of CP724,714 for comparison with 125/131 I-IBA-CP. Results: IBA-CP displayed superior in vitro inhibitory activity (half-maximal inhibitory concentration, 16 nM) and selectivity for HER2 over 6 other cancer-related tyrosine kinases. 125/131 I-IBA-CP was prepared in a typical radiochemical yield of about 65% (decay-corrected), radiochemical purity of more than 98%, and molar activity of 42 GBq/μmol at the end of synthesis. SPECT imaging revealed significantly higher uptake of 125 I-IBA-CP than of 125 I-ICP in the HER2-positive MDA-MB-453 tumors. Uptake in the HER2-negative MCF-7 tumors was much lower. Binding of 125 I-IBA-CP in the MDA-MB-453 tumors was blocked by coinjection with an excess amount of IBA-CP, but not by erlotinib. Conclusion: The radiolabeled HER2-selective inhibitor 125/131 I-IBA-CP is a promising probe for in vivo detection of HER2-positive tumors.
    Print ISSN: 0022-3123
    Topics: Medicine
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  • 2
    Publication Date: 2018-06-19
    Description: Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron-specific HuR-deficient mice were much weaker than littermate control mice. Immunostaining of the brain and cervical spinal cord showed that HuR-deficient neurons had increased levels of cleaved caspase-3, a hallmark of cell apoptosis. Caspase-3 cleavage was especially strong in pyramidal neurons and α motor neurons of HuR-deficient mice. Genome-wide microarray and real-time PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth, including trichoplein keratin filament–binding protein, Cdkn2c, G-protein signaling modulator 2, immediate early response 2, superoxide dismutase 1, and Bcl2. The additional enriched Gene Ontology terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including IFN-induced genes and complement components. Importantly, some of these HuR-regulated genes were also significantly altered in the brain and spinal cord of patients with amyotrophic lateral sclerosis. Additionally, neuronal HuR deficiency resulted in the redistribution of TDP43 to cytosolic granules, which has been linked to motor neuron disease. Taken together, we propose that this neuron-specific HuR-deficient mouse strain can potentially be used as a motor neuron disease model.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 3
    Publication Date: 2018-03-06
    Description: Dysmenorrhea is highly prevalent and is the leading cause of absence from school and work among women of reproductive age. Evidence suggests that dysmenorrhea may also be a risk factor for other chronic pain c...
    Electronic ISSN: 1472-6874
    Topics: Medicine
    Published by BioMed Central
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  • 4
    Publication Date: 2018-04-12
    Description: Objectives To evaluate the relationship between pupillary response to light, myopia and disk halo size. Design Cross-sectional study. Setting Single refractive surgery centre. Participants In this study, 197 right eyes of 197 patients between 20 and 35 years of age were evaluated for disk halo size and pupillary response to light with a vision monitor. Primary and secondary outcome measures Halo radius, age, spherical equivalent (SE), axial length (AL), initial diameter, amplitude of contraction, latency of contraction, duration of contraction, velocity of contraction, latency of dilation, duration of dilation, velocity of dilation, maximum pupil, minimum pupil, average pupil and dark pupil. Results Significant associations were found between disk halo size and SE (r=–0.219, P=0.002), AL (r=0.152, P=0.033) and minimum pupil (r=0.149, P=0.037). There were no associations between disk halo size and initial diameter, amplitude of contraction, latency of contraction, duration of contraction, velocity of contraction, latency of dilation, duration of dilation, velocity of dilation, maximum pupil, average pupil, dark pupil and age (P〉0.05). A significant difference in disk halo size was detected between the low-moderate and high myopia (SE〈 –6 D) groups (P=0.002) and between the small and large (minimum pupil≥4 mm) minimum pupil size groups (P=0.014). Conclusions Patients with a high SE and large minimum pupil size (minimum pupil ≥4 mm) suffered more disability glare than those with a low SE and small minimum pupil size.
    Keywords: Open access
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 5
    Publication Date: 2018-04-14
    Description: Purpose: Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases, including cancers. However, the overall biological roles and clinical significance of most lncRNAs in gastric carcinogenesis are not fully understood. We investigated the clinical significance, biological function, and mechanism of LINC01234 in gastric cancer. Experimental Design: First, we analyzed LINC01234 alterations in gastric cancerous and noncancerous tissues through an analysis of sequencing data obtained from The Cancer Genome Atlas. Next, we evaluated the effect of LINC01234 on the gastric cancer cell proliferation and apoptosis, and its regulation of miR-204-5p by acting as a competing endogenous RNA (ceRNA). The animal model was used to support the in vitro experimental findings. Results: We found that LINC01234 expression was significantly upregulated in gastric cancer tissues and was associated with larger tumor size, advanced TNM stage, lymph node metastasis, and shorter survival time. Furthermore, knockdown of LINC01234-induced apoptosis and growth arrest in vitro and inhibited tumorigenesis in mouse xenografts. Mechanistic investigations indicated that LINC01234 functioned as a ceRNA for miR-204-5p, thereby leading to the derepression of its endogenous target core-binding factor β (CBFB). Conclusions: LINC01234 is significantly overexpressed in gastric cancer, and LINC01234–miR-204-5p–CBFB axis plays a critical role in gastric cancer tumorigenesis. Our findings may provide a potential new target for gastric cancer diagnosis and therapy. Clin Cancer Res; 24(8); 2002–14. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 6
    Publication Date: 2018-12-15
    Description: Purpose: Circular RNAs (circRNAs), a novel class of noncoding RNAs, have recently drawn lots of attention in the pathogenesis of human cancers. However, the role of circRNAs in cancer cells epithelial–mesenchymal transition (EMT) remains unclear. In this study, we aimed to identify novel circRNAs that regulate urothelial carcinoma of the bladder (UCB) cells’ EMT and explored their regulatory mechanisms and clinical significance in UCBs. Experimental Design: We first screened circRNA expression profiles using a circRNA microarray in paired UCB and normal tissues, and then studied the clinical significance of an upregulated circRNA, circPRMT5, in a large cohort of patients with UCB. We further investigated the functions and underlying mechanisms of circPRMT5 in UCB cells’ EMT. Moreover, we evaluated the regulation effect of circPRMT5 on miR-30c, and its target genes, SNAIL1 and E-cadherin , in two independent cohorts from our institute and The Cancer Genome Atlas (TCGA). Results: We demonstrated that upregulated expression of circPRMT5 was positively associated with advanced clinical stage and worse survival in patients with UCB. We further revealed that circPRMT5 promoted UCB cell's EMT via sponging miR-30c. Clinical analysis from two independent UCB cohorts showed that the circPRMT5/miR-30c/SNAIL1/E-cadherin pathway was essential in supporting UCB progression. Importantly, we identified that circPRMT5 was upregulated in serum and urine exosomes from patients with UCB, and significantly correlated with tumor metastasis. Conclusions: CircPRMT5 exerts critical roles in promoting UCB cells’ EMT and/or aggressiveness and is a prognostic biomarker of the disease, suggesting that circPRMT5 may serve as an exploitable therapeutic target for patients with UCB.
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 7
    Publication Date: 2018-08-21
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 8
    Publication Date: 2018-12-06
    Description: The Indian government has set an ambitious target for future renewable power generation, including 60 GW of cumulative wind power capacity by 2022. However, the benefits of these substantial investments are vulnerable to the changing climate. On the basis of hourly wind data from an assimilated meteorology reanalysis dataset covering the 1980–2016 period, we show that wind power potential may have declined secularly over this interval, particularly in western India. Surface temperature data confirm that significant warming occurred in the Indian Ocean over the study period, leading to modulation of high pressure over the ocean. A multivariable linear regression model incorporating the pressure gradient between the Indian Ocean and the Indian subcontinent can account for the interannual variability of wind power. A series of numerical sensitivity experiments confirm that warming in the Indian Ocean contributes to subsidence and dampening of upward motion over the Indian continent, resulting potentially in weakening of the monsoonal circulation and wind speeds over India.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 9
    Publication Date: 2018-10-26
    Description: Clinical observations indicate that the paramedian region of the thalamus is a critical node for controlling wakefulness. However, the specific nucleus and neural circuitry for this function remain unknown. Using in vivo fiber photometry or multichannel electrophysiological recordings in mice, we found that glutamatergic neurons of the paraventricular thalamus (PVT) exhibited high activities during wakefulness. Suppression of PVT neuronal activity caused a reduction in wakefulness, whereas activation of PVT neurons induced a transition from sleep to wakefulness and an acceleration of emergence from general anesthesia. Moreover, our findings indicate that the PVT–nucleus accumbens projections and hypocretin neurons in the lateral hypothalamus to PVT glutamatergic neurons’ projections are the effector pathways for wakefulness control. These results demonstrate that the PVT is a key wakefulness-controlling nucleus in the thalamus.
    Keywords: Neuroscience
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2018-11-09
    Description: The maintenance of autoreactive B cells in a quiescent state is crucial for preventing autoimmunity. Here we identify a variant of human immunoglobulin G1 (IgG1) with a Gly 396 -〉Arg substitution (hIgG1-G396R), which positively correlates with systemic lupus erythematosus. In induced lupus models, murine homolog Gly 390 -〉Arg (G390R) knockin mice generate excessive numbers of plasma cells, leading to a burst of broad-spectrum autoantibodies. This enhanced production of antibodies is also observed in hapten-immunized G390R mice, as well as in influenza-vaccinated human G396R homozygous carriers. This variant potentiates the phosphorylation of the IgG1 immunoglobulin tail tyrosine (ITT) motif. This, in turn, alters the availability of phospho-ITT to trigger longer adaptor protein Grb2 dwell times in immunological synapses, leading to hyper–Grb2–Bruton’s tyrosine kinase (Btk) signaling upon antigen binding. Thus, the hIgG1-G396R variant is important for both lupus pathogenesis and antibody responses after vaccination.
    Keywords: Immunology, Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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