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991.
Christina Backes Christian Harz Ulrike Fischer Jana Schmitt Nicole Ludwig Britt-Sabina Petersen Sabine C. Mueller Yoo-Jin Kim Nadine M. Wolf Hugo A. Katus Benjamin Meder Rhoikos Furtw?ngler Andre Franke Rainer Bohle Wolfram Henn Norbert Graf Andreas Keller Eckart Meese 《Oncotarget》2015,6(8):5918-5931
Glioblastoma multiforme (GBM) is the most aggressive and malignant subtype of human brain tumors. While a family clustering of GBM has long been acknowledged, relevant hereditary factors still remained elusive. Exome sequencing of families offers the option to discover respective genetic factors.We sequenced blood samples of one of the rare affected families: while both parents were healthy, both children were diagnosed with GBM. We report 85 homozygous non-synonymous single nucleotide variations (SNVs) in both siblings that were heterozygous in the parents. Beyond known key players for GBM such as ERBB2, PMS2, or CHI3L1, we identified over 50 genes that have not been associated to GBM so far. We also discovered three accumulative effects potentially adding to the tumorigenesis in the siblings: a clustering of multiple variants in single genes (e.g. PTPRB, CROCC), the aggregation of affected genes on specific molecular pathways (e.g. Focal adhesion or ECM receptor interaction) and genomic proximity (e.g. chr22.q12.2, chr1.p36.33). We found a striking accumulation of SNVs in specific genes for the daughter, who developed not only a GBM at the age of 12 years but was subsequently diagnosed with a pilocytic astrocytoma, a common acute lymphatic leukemia and a diffuse pontine glioma.The reported variants underline the relevance of genetic predisposition and cancer development in this family and demonstrate that GBM has a complex and heterogeneous genetic background. Sequencing of other affected families will help to further narrow down the driving genetic causes for this disease. 相似文献
992.
Sameh Mikhail Kristen Ciombor Anne Noonan Christina Wu Richard Goldberg Weiqiang Zhao Lai Wei Kristina Mathey Melissa Yereb Cynthia Timmers Tanios Bekaii-Saab 《Oncotarget》2015,6(26):22206-22213
Introduction
Targeting HER2 has improved outcomes in metastatic GE (mGE) cancer. In this study, we aim to explore the feasibility of molecular profiling in patients with refractory mGE cancer in routine clinical practice.Methods
Archival formalin-fixed, paraffin-embedded (FFPE) samples for patients with mGE were analyzed with commercially available targeted next generation sequencing (NGS) and/or FISH for MET amplification. We also reviewed the patients'' medical records for concurrent HER 2 testing.Results
Tumor samples from 99 patients with mGE cancer were analyzed as follows: NGS (N = 56), FISH for MET amplification (N = 65), IHC and/or FISH for HER2 (N = 87). Of patients who underwent NGS, 50/56 (89%) had at least one actionable molecular alteration. The most notable actionable alterations included cell cycle abnormalities (58%), HER2 amplification (30%), PI3KCA mutation (14%), MCL1 amplification (11%), PTEN loss (9%), CDH1 mutation (2%) and MET amplification (5%). Ninety-two percent (12/13) of patients with HER2 amplification by NGS were positive for HER2 by IHC and/or FISH. In contrast, only 12/18 (66%) patients positive for HER2 by IHC and/or FISH demonstrated HER2 amplification by NGS.Conclusion
Comprehensive molecular testing is feasible in clinical practice and provides a platform for screening patients for molecularly guided clinical trials and available targeted therapies. 相似文献993.
Fangfang Song Xiangchun Li Fengju Song Yanrui Zhao Haixin Li Hong Zheng Zhibo Gao Jun Wang Wei Zhang Kexin Chen 《Oncotarget》2015,6(31):31820-31829
Bilateral breast cancer (BBC) poses a major challenge for oncologists because of the cryptic relationship between the two lesions. The purpose of this study was to determine the origin of the contralateral breast cancer (either dependent or independent of the index tumor). Here, we used ultra-deep whole-exome sequencing and array comparative genomic hybridization (aCGH) to study four paired samples of BBCs with different tumor subtypes and time intervals between the developments of each tumor. We used two paired primary breast tumors and corresponding metastatic liver lesions as the control. We tested the origin independent nature of BBC in three ways: mutational concordance, mutational signature clustering, and clonality analysis using copy number profiles. We found that the paired BBC samples had near-zero concordant mutation rates, which were much lower than those of the paired primary/metastasis samples. The results of a mutational signature analysis also suggested that BBCs are independent of one another. A clonality analysis using aCGH data further revealed that paired BBC samples was clonally independent, in contrast to clonal related origin found for paired primary/metastasis samples. Our preliminary findings show that BBCs in Han Chinese women are origin independent and thus should be treated separately. 相似文献
994.
Katharina Auer Anna Bachmayr-Heyda Stefanie Aust Nyamdelger Sukhbaatar Agnes Teresa Reiner Christoph Grimm Reinhard Horvat Robert Zeillinger Dietmar Pils 《Oncotarget》2015,6(19):17261-17275
In this study we aimed to analyze the biological mechanisms underlying apparently different modes of peritoneal tumor spread in serous ovarian cancer: miliary (widespread, millet-like lesions) versus non-miliary (bigger, exophytically growing implants). Tumor tissues and ascites from 23 chemotherapy naive patients were analyzed by RNA-sequencing and flow cytometry. On the basis of differential gene expression between miliary and non-miliary, gene signatures were developed. A calculated tumor spread factor revealed a significant independent negative impact of miliary spread on overall survival (HR 3.77; CI95 1.14–12.39; p = 0.029) in an independent cohort of 165 serous ovarian cancer patients. Comparing previously published epithelial-mesenchymal transition (EMT) gene signatures, non-miliary spread correlated significantly with a reduced epithelial status. We conclude that serous ovarian cancer is a heterogeneous disease with distinct modes of peritoneal tumor spread, differing not only in clinical appearance, but also in molecular characteristics and outcome.. EMT, peritoneal inflammation status, and therapeutic options are discussed.
Significance
More than half of serous epithelial ovarian cancer patients present with a newly described type of intraperitoneal tumor spread, associated with differences in the inflammation status, activated oncogenic pathways, lack of EMT, and thus reduced overall survival. Both, the diminished immune reaction and the enhanced epithelial and malignant characteristics of the tumor cells open new avenues for therapeutic options and strategies, like Catumaxomab, already in clinical use. 相似文献995.
Jeeyun Lee Hee Cheol Kim Jung Yong Hong Kai Wang Sun Young Kim Jiryeon Jang Seung Tae Kim Joon Oh Park Ho Yeong Lim Won Ki Kang Young Suk Park Jiyun Lee Woo Yong Lee Yoon Ah Park Jung Wook Huh Seong Hyeon Yun In-Gu Do Seok Hyung Kim Sohail Balasubramanian Philip J. Stephens Jeffrey S. Ross Gang Gary Li Zachary Hornby Siraj M. Ali Vincent A. Miller Kyoung-Mee Kim Sai-Hong Ignatius Ou 《Oncotarget》2015,6(27):24320-24332
Purpose
Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies.Experimental designs
Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgical resection at Samsung Medical Center, Seoul, Korea were screened by IHC using ALK monoclonal antibody 5A4. IHC positive cases were confirmed by FISH, nCounter assays, and NGS-based comprehensive genomic profiling (CGP). ALK IHC was further applied to CRC patients enrolled in a pathway-directed therapeutic trial.Results
Four hundred thirty-two GC and 172 CRC cases were screened by IHC. No GC sample was ALK IHC positive. One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK FISH and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22–21p23) was identified by CGP. One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK (E21, A20) fusion variant by CGP. Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib.Conclusions
ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC. ALK rearrangement is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors. 相似文献996.
Shan-Shan Jiang Jian-Jun Li Yin Li Long-Jun He Qi-Jing Wang De-Sheng Weng Ke Pan Qing Liu Jing-Jing Zhao Qiu-Zhong Pan Xiao-Fei Zhang Yan Tang Chang-Long Chen Hong-Xia Zhang Guo-Liang Xu Yi-Xin Zeng Jian-Chuan Xia 《Oncotarget》2015,6(29):27267-27274
Familial adenomatous polyposis (FAP) is an autosomal dominant disease manifesting as colorectal cancer in middle-aged patients. Mutations of the adenomatous polyposis coli (APC) gene contribute to both FAP and sporadic or familial colorectal carcinogenesis. Here we describe the identification of the causative APC gene defects associated with FAP in a Chinese pedigree. All patients with FAP were diagnosed by their combination of clinical features, family history, colonoscopy, and pathology examinations. Blood samples were collected and genomic DNA was extracted. Mutation analysis of APC was conducted by targeted next-generation sequencing, long-range PCR and Sanger sequencing. A novel mutation in exon 14–15(c.1936-2148 del) and intron 14 of the APC gene was demonstrated in all FAP patients and was absent in unaffected family members. This novel deletion causing FAP in Chinese kindred expands the germline mutation spectrum of the APC gene in the Chinese population. 相似文献
997.
Sarah Munchel Yen Hoang Yue Zhao Joseph Cottrell Brandy Klotzle Andrew K. Godwin Devin Koestler Peter Beyerlein Jian-Bing Fan Marina Bibikova Jeremy Chien 《Oncotarget》2015,6(28):25943-25961
Current genomic studies are limited by the poor availability of fresh-frozen tissue samples. Although formalin-fixed diagnostic samples are in abundance, they are seldom used in current genomic studies because of the concern of formalin-fixation artifacts. Better characterization of these artifacts will allow the use of archived clinical specimens in translational and clinical research studies. To provide a systematic analysis of formalin-fixation artifacts on Illumina sequencing, we generated 26 DNA sequencing data sets from 13 pairs of matched formalin-fixed paraffin-embedded (FFPE) and fresh-frozen (FF) tissue samples. The results indicate high rate of concordant calls between matched FF/FFPE pairs at reference and variant positions in three commonly used sequencing approaches (whole genome, whole exome, and targeted exon sequencing). Global mismatch rates and C·G > T·A substitutions were comparable between matched FF/FFPE samples, and discordant rates were low (<0.26%) in all samples. Finally, low-pass whole genome sequencing produces similar pattern of copy number alterations between FF/FFPE pairs. The results from our studies suggest the potential use of diagnostic FFPE samples for cancer genomic studies to characterize and catalog variations in cancer genomes. 相似文献
998.
Emmanuelle Nicolas Sanjeevani Arora Yan Zhou Ilya G. Serebriiskii Mark D. Andrake Elizabeth D. Handorf Dale L. Bodian Joseph G. Vockley Roland L. Dunbrack Eric A. Ross Brian L. Egleston Michael J. Hall Erica A. Golemis Veda N. Giri Mary B. Daly 《Oncotarget》2015,6(37):39614-39633
Risk assessment for prostate cancer is challenging due to its genetic heterogeneity. In this study, our goal was to develop an operational framework to select and evaluate gene variants that may contribute to familial prostate cancer risk. Drawing on orthogonal sources, we developed a candidate list of genes relevant to prostate cancer, then analyzed germline exomes from 12 case-only prostate cancer patients from high-risk families to identify patterns of protein-damaging gene variants. We described an average of 5 potentially disruptive variants in each individual and annotated them in the context of public databases representing human variation. Novel damaging variants were found in several genes of relevance to prostate cancer. Almost all patients had variants associated with defects in DNA damage response. Many also had variants linked to androgen signaling. Treatment of primary T-lymphocytes from these prostate cancer patients versus controls with DNA damaging agents showed elevated levels of the DNA double strand break (DSB) marker γH2AX (p < 0.05), supporting the idea of an underlying defect in DNA repair. This work suggests the value of focusing on underlying defects in DNA damage in familial prostate cancer risk assessment and demonstrates an operational framework for exome sequencing in case-only prostate cancer genetic evaluation. 相似文献
999.
1000.
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next‐generation sequencing with a 25‐gene panel 下载免费PDF全文
Brian Allen MS Rajesh Kaldate MS Satish Bhatnagar PhD Karla Bowles PhD Kirsten Timms PhD Judy E. Garber MD Christina Herold MD Leif Ellisen MD PhD Jill Krejdovsky MS Kim DeLeonardis MS Kristin Sedgwick MS Kathleen Soltis MA Benjamin Roa PhD Richard J. Wenstrup MD Anne‐Renee Hartman MD 《Cancer》2015,121(1):25-33