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81.
Sarquis MS Weber F Shen L Broelsch CE Jhiang SM Zedenius J Frilling A Eng C 《The Journal of clinical endocrinology and metabolism》2006,91(1):262-269
CONTEXT: Many mammalian genes that are imprinted regulate cell growth, differentiation, and apoptosis. Because imprinting silences one of the two alleles, resulting in functional haploinsufficiency, we hypothesized that loss of heterozygosity (LOH) at an imprinted locus may result in the deletion of the only functional copy of an imprinted tumor suppressor gene. OBJECTIVE: The goal of this study was to specifically address this hypothesis that in thyroid neoplasias loss of imprinted loci becomes enriched during oncogenesis. DESIGN: In total, thyroid tissue was obtained from 72 patients with thyroid neoplasias comprising 34 follicular thyroid carcinomas (FTCs) and 38 follicular adenomas. We performed PCR-based LOH analysis of DNA from paired normal-tumor samples using 18 markers mapped to imprinted regions (IR) and 13 markers in nonimprinted regions (NIR). RESULTS: Overall LOH frequencies for the IR markers were 26% for the adenomas and 38% for the carcinomas. In the NIR, the overall LOH frequency was 23 and 26% for adenomas and FTCs, respectively. The difference in LOH frequencies between IR and NIR was statistically significant only for the carcinomas (P = 0.001), although there was a similar trend for the atypical adenomas (ATY, P = 0.06). CONCLUSIONS: Our observations suggest that IRs are more prone to genomic instability in FTCs. The fact that the ATY trended toward differential IR/NIR LOH, similar to FTC, may suggest that loss of IR might be instrumental in the adenoma-carcinoma sequence in thyroid carcinogenesis and that ATY could be an important intermediate in this pathway. 相似文献
82.
83.
Apostolos Zarros Charis Liapi Hussam Al-Humadi Marianna Almpani Vasileios Stolakis Nikolina Skandali Konstantinos Voumvourakis Eleni Katsouni Stylianos Tsakiris 《Metabolic brain disease》2013,28(3):387-396
Wernicke’s encephalopathy (WE) is a serious neuropsychiatric syndrome caused by chronic alcoholism and thiamine (T) deficiency. Our aim was to shed more light on the pathophysiology of WE, by introducing a modified in vivo experimental model of WE and by focusing on changes provoked in the total antioxidant status (TAS) and three crucial brain enzyme activities in adult rats. Rats were placed on ethanol (EtOH) consumption (20 %?v/v) for a total of 5 weeks. By the end of the third week, rats were fed a T-deficient diet (TDD) and were treated with pyrithiamine (PT; 0.25 mg/kg) for the remaining 2 weeks. Following the induction of WE symptomatology, rats were treated with three consecutive (every 8 h) injections of saline or T (100 mg/kg) and were sacrificed. Brain homogenates were generated and used for spectrophotometrical evaluation of TAS and enzymatic activities. Additionally, in vitro experiments were conducted on brain homogenates or pure enzymes incubated with T or neuromodulatory antioxidants. Pre-exposure to EtOH provided a successful protocol modification that did not affect the expected time of WE symptomatology onset. Administration of T ameliorated this symptomatology. WE provoked oxidative stress that was partially limited by T administration, while T itself also caused oxidative stress to a smaller extent. Brain acetylcholinesterase (AChE) was found inhibited by WE and was further inhibited by T administration. In vitro experiments demonstrated a potential neuroprotective role for L-carnitine (Carn). Brain sodium-potassium adenosine triphosphatase (Na+,K+-ATPase) activity was found increased in WE and was reduced to control levels by in vivo T administration; this increase was also evident in groups exposed to PT or to TDD, but not to EtOH. In vitro experiments demonstrated a potential neuroprotective role for this Na+,K+-ATPase stimulation through T or L-cysteine (Cys) administration. Brain magnesium adenosine triphosphatase (Mg2+-ATPase) activity was found decreased by prolonged exposure to EtOH, but was not affected by the experimental induction of WE. Our data suggest that T administration inhibits AChE, which is also found inhibited in WE. Moreover, increased brain Na+,K+-ATPase activity could be a marker of T deficiency in WE, while combined T and antioxidant co-supplementation of Cys and/or Carn could be neuroprotective in terms of restoring the examined crucial brain enzyme activities to control levels. 相似文献
84.
Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors 总被引:5,自引:0,他引:5 下载免费PDF全文
Lehtonen R Kiuru M Vanharanta S Sjöberg J Aaltonen LM Aittomäki K Arola J Butzow R Eng C Husgafvel-Pursiainen K Isola J Järvinen H Koivisto P Mecklin JP Peltomäki P Salovaara R Wasenius VM Karhu A Launonen V Nupponen NN Aaltonen LA 《The American journal of pathology》2004,164(1):17-22
Germline mutations in the fumarate hydratase (FH) gene at 1q43 predispose to dominantly inherited cutaneous and uterine leiomyomas, uterine leiomyosarcoma, and papillary renal cell cancer (HLRCC syndrome). To evaluate the role of FH inactivation in sporadic tumorigenesis, we analyzed a series of 299 malignant tumors representing 10 different malignant tumor types for FH mutations. Additionally, 153 uterine leiomyomas from 46 unselected individuals were subjected to and informative in loss of heterozygosity analysis at the FH locus, and the five (3.3%) tumors displaying loss of heterozygosity were subjected to FH mutation analysis. Although mutation search in the 299 malignant tumors was negative, somatic FH mutations were found in two nonsyndromic leiomyomas; a splice site change IVS4 + 3A>G, leading to deletion of exon four, and a missense mutation Ala196Thr. The occurrence of somatic mutations strongly suggests that FH is a true target of the 1q43 deletions. Although uterine leiomyomas are the most common tumors of women, specific inactivating somatic mutations contributing to the formation of nonsyndromic leiomyomas have not been reported previously. Taking into account the apparent risk of uterine leiomyosarcoma associated with FH germline mutations, the finding raises the possibility that also some nonsyndromic leiomyomas may have a genetic profile that is more prone to malignant degeneration. Our data also indicate that somatic FH mutations appear to be limited to tumor types observed in hereditary leiomyomatosis and renal cell cancer. 相似文献
85.
Charis Girvalaki Manolis Tzatzarakis Christina N. Kyriakos Alexander I. Vardavas Polychronis D. Stivaktakis Matthaios Kavvalakis 《Inhalation toxicology》2013,25(9-10):361-369
AbstractBackground: The aim of the present study was to identify the composition and reported chemical health hazards of the most common electronic cigarette liquids (e-liquids) in nine European Union (EU) Member States (MS) prior to adoption of the Tobacco Product Directive (TPD).Materials and methods: Within the Horizon2020, EUREST-PLUS study, 122 of the most commonly sold e-liquids in 9 EU MS were randomly selected and purchased. A quantitative and qualitative chemical analysis was performed using a previously validated based gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry method. The most commonly detected compounds were then divided according to the Danger Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and Warning GHS codes.Results: Within our qualitative analysis, 171 different compounds were detected. Discrepancies in measured versus reported nicotine concentration were identified. Forty-one (85.4%) of the most commonly detected compounds were registered with Warning GHS codes, 11 with Danger GHS codes and 9 with both codes. Of the total number of the detected compounds, 293 were attributable to fruits flavor, followed by tobacco flavor (204), nonalcoholic drinks (n?=?64), desserts–sweets (n?=?50), menthol – mint (n?=?42) and alcohol (n?=?39). Menthol which is classified as a strong irritant to skin and eye was the most frequently detected compound.Conclusion: A large plethora of compounds with varying warning codes was identified in e-cigarette samples. The systematic monitoring and chemical evaluation of e-liquids are warranted, so as to ensure consumer protection. 相似文献
86.
A 39-bp deletion polymorphism in PTEN in African American individuals: implications for molecular diagnostic testing 下载免费PDF全文
Zhou XP Hampel H Roggenbuck J Saba N Prior TW Eng C 《The Journal of molecular diagnostics : JMD》2002,4(2):114-117
Germline mutations in the PTEN/MMAC1/TEP1 tumor suppressor gene cause Cowden syndrome (CS), a hereditary hamartoma-tumor syndrome with an increased risk of breast, thyroid, and endometrial cancers, and seemingly unrelated developmental disorders, such as Bannayan-Riley-Ruvalcaba (BRR) syndrome, Proteus, and Proteus-like syndromes. Data to date suggest that irrespective of the clinical presentation, the identification of a PTEN mutation should trigger medical management which includes cancer surveillance. Clinic-based molecular diagnostic testing for germline PTEN mutations has been available for at least 2 years. This study reports on the finding of a previously unobserved heterozygous alteration (IVS7–15→53del39) found in an African American individual who had features of CS. Further investigation revealed that 12 of 42 (28.6%) African American controls, but not individuals of Caucasian or Japanese origin, also carried this heterozygous 39-bp deletion in PTEN. Due to its location immediately upstream of the splicing site of exon 8, this polymorphism could be mistaken for a deleterious mutation in the PTEN. 相似文献
87.
Rigelsky CM Jennings C Lehtonen R Minai OA Eng C Aldred MA 《American journal of medical genetics. Part A》2008,(19):2551-2556
Pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT) are distinct clinical entities caused by germline mutations in genes encoding members of the TGFbeta/BMP superfamily: BMPR2 in PAH and ACVRL1, ENG, or SMAD4 in HHT. When PAH and HHT occasionally co-exist within the same family, ACVRL1 mutations predominate. We report a 36-year-old woman initially diagnosed with PAH at age 24. At 35, following massive hemoptysis, multiple pulmonary arteriovenous malformations were discovered, prompting evaluation for HHT. She met the Cura?ao diagnostic criteria for suspected HHT based on additional findings of nasal telangiectases and epistaxis. Mutation analysis of ACVRL1, ENG, and SMAD4 was normal, but a germline nonsense mutation in BMPR2 was identified. This is the first known report of HHT features, particularly pulmonary AVMs, associated with a BMPR2 mutation. It adds further weight to a common molecular pathogenesis in PAH and HHT, and highlights that BMPR2 gene analysis is indicated in patients affected with both HHT and PAH. 相似文献
88.
Pasini B McWhinney SR Bei T Matyakhina L Stergiopoulos S Muchow M Boikos SA Ferrando B Pacak K Assie G Baudin E Chompret A Ellison JW Briere JJ Rustin P Gimenez-Roqueplo AP Eng C Carney JA Stratakis CA 《European journal of human genetics : EJHG》2008,16(1):79-88
Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs. 相似文献
89.
Purified IgG from Patients with Obstetric but not IgG from Non‐obstetric Antiphospholipid Syndrome Inhibit Trophoblast Invasion 下载免费PDF全文
90.
Joanne Kotsopoulos Jacek Gronwald Henry T. Lynch Andrea Eisen Susan L. Neuhausen Nadine Tung Peter Ainsworth Jeffrey N. Weitzel Tuya Pal William D. Foulkes Charis Eng Christian F. Singer Leigha Senter Ping Sun Jan Lubinski Steven A. Narod the Hereditary Breast Cancer Clinical Study Group 《Breast cancer research and treatment》2018,168(2):421-431