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Takafumi Koyama Toshio Shimizu Satoru Iwasa Yutaka Fujiwara Shunsuke Kondo Shigehisa Kitano Kan Yonemori Akihiko Shimomura Sakura Iizumi Tatsuya Sasaki Junji Furuse Noboru Yamamoto 《Cancer science》2020,111(2):571-579
Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first‐in‐human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1‐3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1‐180 mg) was carried out to assess dose‐limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25‐(OH)2‐vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140‐mg dose; one patient in the 180‐mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose‐dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose‐dependent increases were observed in all pharmacodynamic markers and plateaued at 100‐140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow‐up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily. 相似文献
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Nanami Gotoh Yusuke Minato Takayuki Saitoh Noriyuki Takahashi Tetsuhiro Kasamatsu Kana Souma Tsukasa Oda Takumi Hoshino Toru Sakura Takuma Ishizaki Hiroaki Shimizu Makiko Takizawa Akihiko Yokohama Norifumi Tsukamoto Hiroshi Handa Hirokazu Murakami 《European journal of haematology》2020,104(6):526-537
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Christina Andica Koji Kamagata Taku Hatano Yuya Saito Wataru Uchida Takashi Ogawa Haruka Takeshige-Amano Akifumi Hagiwara Syo Murata Genko Oyama Yashushi Shimo Atsushi Umemura Toshiaki Akashi Akihiko Wada Kanako K. Kumamaru Masaaki Hori Nobutaka Hattori Shigeki Aoki 《Journal of neuroscience research》2020,98(5):936-949
Neurocognitive and psychiatric disorders have significant consequences for quality of life in patients with Parkinson's disease (PD). In the current study, we evaluated microstructural white matter (WM) alterations associated with neurocognitive and psychiatric disorders in PD using neurite orientation dispersion and density imaging (NODDI) and linked independent component analysis (LICA). The indices of NODDI were compared between 20 and 19 patients with PD with and without neurocognitive and psychiatric disorders, respectively, and 25 healthy controls using tract-based spatial statistics and tract-of-interest analyses. LICA was applied to model inter-subject variability across measures. A widespread reduction in axonal density (indexed by intracellular volume fraction [ICVF]) was demonstrated in PD patients with and without neurocognitive and psychiatric disorders, as compared with healthy controls. Compared with patients without neurocognitive and psychiatric disorders, patients with neurocognitive and psychiatric disorders exhibited more extensive (posterior predominant) decreases in axonal density. Using LICA, ICVF demonstrated the highest contribution (59% weight) to the main effects of diagnosis that reflected widespread decreases in axonal density. These findings suggest that axonal loss is a major factor underlying WM pathology related to neurocognitive and psychiatric disorders in PD, whereas patients with neurocognitive and psychiatric disorders had broader axonal pathology, as compared with those without. LICA suggested that the ICVF can be used as a useful biomarker of microstructural changes in the WM related to neurocognitive and psychiatric disorders in PD. 相似文献
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This study investigated an influence of granulation temperature during twin-screw granulation (TSG) on particle size distributions (PSDs). The influence of the granulation temperature on granule size distributions varied, depending on the liquid to solid (L/S) ratio, the kind of binders, the method of binder addition, and the filler material. The PSD of granules was broad and bimodal at a barrel temperature of 30?°C. Granules size distributions became narrow and second height decreased at high barrel temperature. While the L/S ratio had an effect on the sharpness of granule size distributions, this effect was minor compared to the granulation temperature. Granule size distributions were influenced by binder addition methods. When the binder was added as solution, PSD became broad. In formulations using lactose as filler, PSD became broad and bimodal at 90?°C. Much lactose was dissolved in granulation solution at high temperature, because the solubility of lactose rises significantly with the solution temperature leading to higher effective L/S ratio in the granulator. Hence, granulation was proceeded and large granules were formed. From these results, the granulation temperature is one of important parameters to obtain mono-modal PSD in TSG. 相似文献
8.
Masayoshi Tasaki Mitsuharu Ueda Yoshinobu Hoshii Mayumi Mizukami Sayaka Matsumoto Makoto Nakamura Taro Yamashita Akihiko Ueda Yohei Misumi Teruaki Masuda Yasuteru Inoue Tessei Torikai Toshiya Nomura Yukimoto Tsuda Kyosuke Kanenawa Aito Isoguchi Masamitsu Okada Hirotaka Matsui Konen Obayashi Yukio Ando 《The Journal of pathology》2019,247(4):444-455
Most intractable tissue-degenerative disorders share a common pathogenic condition, so-called proteinopathy. Amyloid-related disorders are the most common proteinopathies and are characterized by amyloid fibril deposits in the brain or other organs. Aging is generally associated with the development of these amyloid-related disorders, but we still do not fully understand how functional proteins become pathogenic amyloid deposits during the human aging process. We identified a novel amyloidogenic protein, named epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), in massive venous amyloid deposits in specimens that we obtained from an autopsied patient who died of gastrointestinal bleeding. Our postmortem analyses of additional patients indicate that EFEMP1 amyloid deposits frequently developed in systemic venous walls of elderly people. EFEMP1 was highly expressed in veins, and aging enhanced venous EFEMP1 expression. In addition, biochemical analyses indicated that these venous amyloid deposits consisted of C-terminal regions of EFEMP1. In vitro studies showed that C-terminal regions formed amyloid fibrils, which inhibited venous tube formation and cell viability. EFEMP1 thus caused a novel age-related venous amyloid-related disorder frequently found in the elderly population. Understanding EFEMP1 amyloid formation provides new insights into amyloid-related disorders occurring during the aging process. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
9.
Masaya Sekimizu Akihiko Yoshida Sachiyo Mitani Naofumi Asano Makoto Hirata Takashi Kubo Fumito Yamazaki Hiromi Sakamoto Mamoru Kato Naohiro Makise Taisuke Mori Naoya Yamazaki Shigeki Sekine Ichiro Oda Shun‐ichi Watanabe Hiroaki Hiraga Tsukasa Yonemoto Teruya Kawamoto Norifumi Naka Yuki Funauchi Yoshihiro Nishida Kanya Honoki Hirotaka Kawano Hiroyuki Tsuchiya Toshiyuki Kunisada Koichi Matsuda Katsunori Inagaki Akira Kawai Hitoshi Ichikawa 《Genes, chromosomes & cancer》2019,58(6):373-380
Granular cell tumors (GCTs) are rare mesenchymal tumors that exhibit a characteristic morphology and a finely granular cytoplasm. The genetic alterations responsible for GCT tumorigenesis had been unknown until recently, when loss‐of‐function mutations of ATP6AP1 and ATP6AP2 were described. Thus, we performed whole‐exome sequencing, RNA sequencing, and targeted sequencing of 51 GCT samples. From these genomic analyses, we identified mutations in genes encoding vacuolar H+‐ATPase (V‐ATPase) components, including ATP6AP1 and ATP6AP2, in 33 (65%) GCTs. ATP6AP1 and ATP6AP2 mutations were found in 23 (45%) and 2 (4%) samples, respectively, and all were truncating or splice site mutations. In addition, seven other genes encoding V‐ATPase components were also mutated, and three mutations in ATP6V0C occurred on the same amino acid (isoleucine 136). These V‐ATPase component gene mutations were mutually exclusive, with one exception. These results suggest that V‐ATPase function is impaired in GCTs not only by loss‐of‐function mutations of ATP6AP1 and ATP6AP2 but also through mutations of other subunits. Our findings provide additional support for the hypothesis that V‐ATPase dysfunction promotes GCT tumorigenesis. 相似文献
10.
Uchida Y Motoyoshi M Shigeeda T Shinohara A Igarashi Y Sakaguchi M Shimizu N 《European journal of orthodontics》2011,33(6):654-659
The aim of this study was to investigate the relationship between masseter muscle size and craniofacial morphology, focusing on the maxilla. Twenty-four patients (11 males and 13 females; mean age 27.6 ± 5.6 years) underwent cephalometric analyses. Ultrasonography was used to measure the cross-sectional area (CSA) of the masseter muscle and bite force was measured using pressure sensitive film. The results showed that CSA-relaxed was positively correlated with upper anterior face height (UAFH)/total anterior face height (TAFH) and negatively with lower anterior face height (LAFH)/TAFH and LAFH (P < 0.05). CSA-clenched was correlated positively with SN-palatal, FH-palatal, UAFH/TAFH, and lower posterior face height (LPFH)/total posterior face height (TPFH) and negatively with LAFH/TAFH, LAFH, upper posterior face height (UPFH)/TPFH, and UPFH (P < 0.05). Bite force was positively correlated with LPFH/TPFH and negatively with UPFH/TPFH (P < 0.05). As the masseter became larger, the anterior maxillary region tended to shift downwards relative to the cranial base, whereas the posterior region tended to shift upwards. The decrease in LAFH/TAFH and increase in LPFH/TPFH as the size of the masseter muscle increases may be influenced not only by the inclination of the mandibular plane but also by the clockwise rotation of the maxilla. 相似文献