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81.
Liu Y Luscombe NM Alexandrov V Bertone P Harrison P Zhang Z Gerstein M 《Genome biology》2002,3(2):reports4004.1-reports40043
A report on the 15th Annual Center for Advanced Biotechnology and Medicine Symposium on structural genomics in pharmaceutical design, Princeton, USA, 24-25 October 2001. 相似文献
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Taryn D. Treger Tasnim Chagtai Robert Butcher George D. Cresswell Reem Al-Saadi Jesper Brok Richard D. Williams Chrissy Roberts Nicholas M. Luscombe Kathy Pritchard Jones William Mifsud 《Translational oncology》2018,11(6):1301-1306
BACKGROUND: Diffuse anaplastic Wilms tumor (DAWT) is a rare, high-risk subtype that is often missed on diagnostic needle biopsy. Somatic mutations in TP53 are associated with the development of anaplasia and with poorer survival, particularly in advanced-stage disease. Early identification of DAWT harboring TP53 abnormalities could improve risk stratification of initial therapy and monitoring for recurrence. METHODS: Droplet digital polymerase chain reaction (ddPCR) was used to evaluate 21 samples from 4 patients with DAWT. For each patient, we assessed TP53 status in frozen tumor, matched germline DNA, and circulating tumor DNA (ctDNA) from plasma, serum, and urine collected throughout treatment. RESULTS: Mutant TP53 was detectable in ctDNA from plasma and serum in all patients. We did not detect variant TP53 in the same volume (200 μl) of urine. One patient displayed heterogeneity of TP53 in the tumor despite both histological sections displaying anaplasia. Concentration of ctDNA from plasma/serum taken prenephrectomy varied significantly between patients, ranging from 0.44 (0.05-0.90) to 125.25 (109.75-140.25) copies/μl. We observed variation in ctDNA throughout treatment, and in all but one patient, ctDNA levels fell significantly following nephrectomy. CONCLUSION: We demonstrate for the first time that ddPCR is an effective method for detection of mutant TP53 in ctDNA from children with DAWT even when there is intratumoral somatic heterogeneity. This should be further explored in a larger cohort of patients, as early detection of circulating variant TP53 may have significant clinical impact on future risk stratification and surveillance. 相似文献
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Hashem?A?Shihab Julian?Gough Matthew?Mort David?N?Cooper Ian?NM?Day Tom?R?GauntEmail author 《Human genomics》2014,8(1):11
As the number of non-synonymous single nucleotide polymorphisms (nsSNPs) identified through whole-exome/whole-genome sequencing programs increases, researchers and clinicians are becoming increasingly reliant upon computational prediction algorithms designed to prioritize potential functional variants for further study. A large proportion of existing prediction algorithms are ‘disease agnostic’ but are nevertheless quite capable of predicting when a mutation is likely to be deleterious. However, most clinical and research applications of these algorithms relate to specific diseases and would therefore benefit from an approach that discriminates between functional variants specifically related to that disease from those which are not. In a whole-exome/whole-genome sequencing context, such an approach could substantially reduce the number of false positive candidate mutations. Here, we test this postulate by incorporating a disease-specific weighting scheme into the Functional Analysis through Hidden Markov Models (FATHMM) algorithm. When compared to traditional prediction algorithms, we observed an overall reduction in the number of false positives identified using a disease-specific approach to functional prediction across 17 distinct disease concepts/categories. Our results illustrate the potential benefits of making disease-specific predictions when prioritizing candidate variants in relation to specific diseases. A web-based implementation of our algorithm is available at http://fathmm.biocompute.org.uk. 相似文献
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Michael R. Wood Meredith J. Noetzel Michael S. Poslusney Bruce J. Melancon James C. Tarr Atin Lamsal Sichen Chang Vincent B. Luscombe Rebecca L. Weiner Hyekyung P. Cho Michael Bubser Carrie K. Jones Colleen M. Niswender Michael W. Wood Darren W. Engers Nicholas J. Brandon Mark E. Duggan P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(2):171-175
This letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration). 相似文献
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James C. Tarr Michael R. Wood Meredith J. Noetzel Bruce J. Melancon Atin Lamsal Vincent B. Luscombe Alice L. Rodriguez Frank W. Byers Sichen Chang Hyekyung P. Cho Darren W. Engers Carrie K. Jones Colleen M. Niswender Michael W. Wood Nicholas J. Brandon Mark E. Duggan P. Jeffrey Conn Thomas M. Bridges Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(23):5179-5184
Herein we describe the continued optimization of M4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology. 相似文献