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Piotr Rozga Damian Kloska Sebastian Pawlak Malgorzata Teska-Kaminska Marlena Galazka Katarzyna Bukato Anna Pieczykolan Albert Jaworski Anna Molga-Kaczmarska Aleksandra Kopacz Bogna Badyra Neli Kachamakova-Trojanowska Olga Zolnierkiewicz Marta Targosz-Korecka Katarzyna Poleszak Michal Szymanik Bartlomiej Zerek Jerzy Pieczykolan Alicja Jozkowicz Anna Grochot-Przeczek 《International journal of cancer. Journal international du cancer》2020,147(4):1117-1130
Targeting of the TRAIL-DR4/5 pathway was proposed as a promising approach for specific induction of apoptosis in cancer cells. Clinical trials, however, showed inadequate efficiency of TRAIL as a monotherapy. It is a widely held view that the application of multifunctional molecules or combination therapy may lead to substantial improvement. Here, we demonstrate the effectiveness and safety of a novel chimeric protein, AD-O51.4, which is a TRAIL equipped with positively charged VEGFA-derived effector peptides. The study was performed in multiple cancer cell line- and patient-derived xenografts. A pharmacokinetic profile was established in monkeys. AD-O51.4 strongly inhibits tumor growth, even leading to complete long-term tumor remission. Neither mice nor monkeys treated with AD-O51.4 demonstrate symptoms of drug toxicity. AD-O51.4 exhibits a satisfactory half-life in plasma and accumulates preferentially in tumors. The cellular mechanism of AD-O51.4 activity involves both cytotoxic effects in tumor cells and antiangiogenic effects on the endothelium. The presence of DRs in cancer cells is crucial for AD-O51.4-driven apoptosis execution. The TRAIL component of the fusion molecule serves as an apoptosis inducer and a cellular anchor for the effector peptides in TRAIL-sensitive and TRAIL-resistant cancer cells, respectively. The FADD-dependent pathway, however, seems to be not indispensable in death signal transduction; thus, AD-O51.4 is capable of bypassing the refractoriness of TRAIL. AD-O51.4-driven cell death, which exceeds TRAIL activity, is achieved due to the N-terminally fused polypeptide, containing VEGFA-derived effector peptides. The high anticancer efficiency of AD-O51.4 combined with its safety has led to the entry of AD-O51.4 into toxicological studies. 相似文献
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Oliwia Anna Segiet Łukasz Mielańczyk Adam Piecuch Marek Michalski Szczepan Tyczyński Marlena Brzozowa-Zasada 《Journal of investigative surgery》2018,31(4):328-332
Primary hyperparathyroidism (PHPT) is defined by inappropriate elevation of parathormone, caused by parathyroid hyperplasia, also known as multi-gland disease (MGD), parathyroid adenoma (PA), or parathyroid carcinoma (PC). Although several studies have already been conducted, there is a lack of a definite diagnostic marker, which could unambiguously distinguish MGD from PA or PC. The accurate and prompt diagnosis has the key meaning for effective treatment and follow-up. This review paper presents the role of apoptosis in PHPT. The comparison of the expression of Fas, TRAIL, BCL-2 family members, p53 in MGD, PA, and PC, among others, was described. The expression of described factors varies among proliferative lesions of parathyroid gland; therefore, these could serve as additional markers to assist in the diagnosis. 相似文献
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Rossi GP Ragazzo F Seccia TM Maniero C Barisa M Calò LA Frigo AC Fassina A Pessina AC 《Hypertension》2012,59(2):431-436
Type 1 diabetes triggers protein kinase C (PKC)-dependent NADPH oxidase activation in the renal medullary thick ascending limb (mTAL), resulting in accelerated superoxide production. As acute exposure to superoxide stimulates NaCl transport by the mTAL, we hypothesized that diabetes increases mTAL Na(+) transport through PKC-dependent and NADPH oxidase-dependent mechanisms. An O(2)-sensitive fluoroprobe was used to measure O(2) consumption by mTALs from rats with streptozotocin-induced diabetes and sham rats. In sham mTALs, total O(2) consumption was evident as a 0.34±0.03 U change in normalized relative fluorescence (ΔNRF)/min per mg protein. Ouabain (2 mmol/L) reduced O(2) consumption by 69±4% and 500 μmol/L furosemide reduced O(2) consumption by 58±8%. Total O(2) consumption was accelerated in mTAL from diabetic rats (0.74±0.07 ΔNRF/min/mg protein; P<0.05 versus sham), reflecting increases in ouabain- and furosemide-sensitive O(2) consumption. NADPH oxidase inhibition (100 μmol/L apocynin) reduced furosemide-sensitive O(2) consumption by mTAL from diabetic rats to values not different from sham. The PKC inhibitor calphostin C (1 μmol/L) or the PKCα/β inhibitor G?6976 (1 μmol/L) decreased furosemide-sensitive O(2) consumption in both groups, achieving values that did not differ between sham and diabetic. PKCβ inhibition had no effect in either group. Similar inhibitory patterns were evident with regard to ouabain-sensitive O(2) consumption. We conclude that NADPH oxidase and PKC (primarily PKCα) contribute to an increase in O(2) consumption by the mTAL during type 1 diabetes through effects on the ouabain-sensitive Na(+)-K(+)-ATPase and furosemide-sensitive Na(+)-K(+)-2Cl(-) cotransporter that are primarily responsible for active transport Na(+) reabsorption by this nephron segment. 相似文献
15.
The superior soft tissue contrast and multiplanar capability of MR imaging has contributed to earlier diagnosis and implementation of effective treatment for a variety of arthropathies and infectious conditions of the elbow, wrist, and hand. Because of overlapping clinical signs and symptoms, MR imaging plays an important role in delineating the features and staging of each of these conditions. This article discusses the seropositive and seronegative inflammatory arthropathies, with emphasis on early detection and surveillance, as well as gout, synovial osteochondromatosis, pigmented villonodular synovitis, tenosynovitis, and de Quervain's tenosynovitis. Certain noninflammatory arthritides and infectious conditions are also reviewed. 相似文献
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Taraneh Gharib Nazem Lucky Sekhon Joseph A Lee Jessica Overbey Stephanie Pan Marlena Duke Christine Briton-Jones Michael Whitehouse Alan B Copperman Daniel E Stein 《Reproductive biomedicine online》2019,38(2):169-176
Research question
Does the composite morphology score or a particular developmental component (expansion stage, inner cell mass [ICM] or trophectoderm [TE]) of euploid blastocysts undergoing single frozen embryo transfer (FET) impact ongoing pregnancy/live birth (OP/LB) rates?Design
Retrospective cohort study including a total of 2236 embryos from 1629 patients who underwent single euploid FET between 2012 and 2017.Results
Embryos with an ICM grade of A compared with C had a higher OP/LB rate (55.6% versus 32.3%, P < 0.001). Blastocysts with a TE grade of A or B compared with C had a higher likelihood of OP/LB (A versus C: odds ratio [OR] 1.6, 99% confidence interval [CI] 1.1–2.3, B versus C: OR 1.5, 99% CI 1.1–2.1), and blastocysts with a developmental stage of 4 or 5 compared with 6 had higher odds of OP/LB (4 versus 6: OR 1.6, 99% CI 1.2–2.2, 5 versus 6: OR 1.6, 99% CI 1.2–2.3).Conclusions
Among euploid embryos, ICM morphology is the best predictor of sustained implantation; however, a composite score may provide additional guidance. While there is a known benefit in genomic screening prior to embryo selection, morphology provides individualized, prognostic information about implantation potential. 相似文献20.
Nathan Neckel Marlena Pelliccio Diane Nichols Joseph Hidler 《Journal of neuroengineering and rehabilitation》2006,3(1):17-11