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The mTOR pathway is pivotal not only in tumorigenesis but also in chemotherapy and hormonal drug sensitivity. It is clear
that improvements in using new targeted therapies are required to improve breast cancer (BC) outcome. Nevertheless, to achieve
this, new molecular biomarkers are required to define the potential sensitivity or resistance of cancer cells. By targeting
the mTOR pathway, several critical central transduction pathways that sustain BC are abrogated (HER-2/Neu and the estrogen
receptor pathway). Thus, the compounds that inhibit mTOR have a double mechanism of toxicity on BC cells when used in combination
with a currently used drug: (1) overcoming primary drug resistance and (2) restoring sensitivity when resistance arises after
long-term exposure. This review covers the utility of inhibitors of the mTOR pathway in BC and emphasizes the new paradigm
of close symbiosis between oncology and molecular biology to better profiling and treating BC with a targeted approach. In
particular, we focused on the new drug RAD001 (Everolimus) due to the great results from preclinical and clinical trials make
it the most hopeful compound among mTOR inhibitors for the treatment of BC. 相似文献
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Cavazzoni A Bonelli MA Fumarola C La Monica S Airoud K Bertoni R Alfieri RR Galetti M Tramonti S Galvani E Harris AL Martin LA Andreis D Bottini A Generali D Petronini PG 《Cancer letters》2012,323(1):77-87
Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ERα plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling. 相似文献
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Mara A. Bonelli Claudia Fumarola Roberta R. Alfieri Silvia La Monica Andrea Cavazzoni Maricla Galetti Rita Gatti Silvana Belletti Adrian L. Harris Stephen B. Fox Dean B. Evans Mitch Dowsett Lesley-Ann Martin Alberto Bottini Daniele Generali Pier Giorgio Petronini 《Breast cancer research and treatment》2010,124(1):79-88
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Everolimus Plus Exemestane in Advanced Breast Cancer: Safety Results of the BALLET Study on Patients Previously Treated Without and with Chemotherapy in the Metastatic Setting
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Daniele Generali Filippo Montemurro Roberto Bordonaro Antonino Mafodda Sante Romito Andrea Michelotti Pierluigi Piovano Maria Teresa Ionta Claudia Bighin Donata Sartori Antonio Frassoldati Marina Elena Cazzaniga Ferdinando Riccardi Franco Testore Patrizia Vici Carlo Antonio Barone Alessio Schirone Federico Piacentini Franco Nolè Annamaria Molino Luciano Latini Edda Lucia Simoncini Fausto Roila Francesco Cognetti Francesco Nuzzo Jennifer Foglietta Alessandro Marco Minisini Francesca Goffredo Giuseppe Portera Gilda Ascione Gabriella Mariani 《The oncologist》2017,22(6):648-654
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Chiara Foroni Manuela Milan Carla Strina Mariarosa Cappelletti Claudia Fumarola Mara Bonelli Ramona Bertoni Giuseppina Ferrero Mara Maldotti Elena Takano Daniele Andreis Sergio Venturini Giulia Brugnoli Pier Giorgio Petronini Vanessa Zanoni Laura Pritzker Kenneth Pritzker Amadeo Parissenti Daniele Santini Stephen B. Fox Alberto Bottini Daniele Generali 《Breast cancer research and treatment》2014,144(1):113-121
The study investigated the anti-tumour effect of zoledronic acid (ZA) administered alone in a biological window therapy in naïve bone-only metastatic and locally advanced breast cancer (LABC) patients. 33 patients with LABC (Group 1) and 20 patients with a first diagnosis of bone metastasis only (Group 2) received 4 mg single dose of ZA, 14 days (biological window) before starting any treatment. In Group 1, Ki67, CD34, p53/bcl-2 and caspase 3 expression along with the adenosine triphosphate (ATP) levels and RNA disruption index were evaluated as markers of tumor growth in tumour specimens obtained before and after ZA administration (basal, day 14). In Group 2, the total enumeration of circulating tumour cells (CTCs), and of M30+ve CTCs along with the soluble marker of cell death (M30/M65) were carried-out as markers of tumor dissemination at baseline, at 48 h and day 14th. In Group 1, there was a significant reduction in Ki67, CD34, bcl-2 expression after 14 days ZA based-treatment (p = 0.0032; p = 0.0001, p < 0.00001 respectively). ZA showed a significant increase of RNA disruption (p < 0.0076). In Group 2, we observed a significant reduction of CTCs number after 48 h (p = 0.0012), followed by a significant rebound at 14 days (p = 0.012). The apoptotic CTCs/M30+ve and M65 levels significantly increased under treatment (p = 0.018 and p = 0.039 respectively) after drug administration when compared to the baseline. These results are the first prospective in vivo data showing the direct pure anti-tumour effect (either on the tumour cell or on CTCs) of ZA. 相似文献
39.
Berruti A Brizzi MP Generali D Ardine M Dogliotti L Bruzzi P Bottini A 《The oncologist》2008,13(11):1137-1148
There are several advantages of administering primary systemic therapy (PST) instead of adjuvant therapy in the management of early breast cancer patients: (a) PST allows for a quantifiable evaluation of the sensitivity or resistance of any treated case and (b) the response assessment offers the opportunity to "cross over" to a different regimen for an individual patient, leading to more flexible, "tailored" therapies. Indeed, these advantages are tenable if one assumes that the primary tumor response serves as a surrogate marker of the efficacy of PST in terms of survival. Unfortunately, this has not yet been validated. The data that are actually available show that both clinical complete response (cCR) and pathological (p)CR have prognostic significance. pCR after chemotherapy has a greater prognostic impact than cCR; however, it is frequently observed in a subset of tumors-such as those that are estrogen receptor negative, are human epidermal growth factor receptor positive, and have elevated proliferative activity-but occurs rarely in their human epidermal growth factor receptor-2/neu counterparts. cCR is more sensitive than pCR, but its assessment presents many hindrances. cCR after chemotherapy can predict early on which tumors are destined to undergo pCR, suggesting a role for this endpoint guiding further treatment decisions early on. The pCR rate in small randomized PST studies comparing chemotherapy with chemotherapy plus trastuzumab was able to predict the difference in survival observed in large, randomized adjuvant trials with a similar study design. Conversely pCR cannot predict the outcome benefit of patients undergoing different hormonal therapies. In conclusion, pCR may be a reliable surrogate endpoint for PST efficacy in a subset of patients undergoing chemotherapy. 相似文献
40.
Generali D Dovio A Tampellini M Tucci M Tedoldi S Torta M Bonardi S Allevi G Aguggini S Milani M Harris AL Bottini A Dogliotti L Angeli A Berruti A 《British journal of cancer》2008,98(11):1753-1758
Persistent circadian rhythm of bone turnover in bone metastatic breast cancer suggests greater skeletal retention of bisphosphonates if administered in the night. We assessed differential effects of night vs morning administration of zoledronic acid (ZA) on bone turnover. Forty-four breast cancer patients with bone metastases were randomised to receive intravenous ZA (4 mg) at 1100 or 2300 hours every 28 days for four times. Urinary concentration N-telopeptide of type-I collagen (NTX) and deoxypyridinolines, and serum C-telopeptide of type-I collagen (CTX), bone alkaline phosphatase (ALP), osteocalcin and Parathyroid hormone (PTH) was measured in the morning at baseline and after 4, 7, 14, 28, 56 and 84 days. Urinary ZA concentration was also measured. Zoledronic acid caused significant decreases of NTX and CTX (P<0.001), without any difference in percent changes between night and morning arms. Bone ALP and osteocalcin were also significantly affected by ZA (P=0.001), without any difference between arms. Parathyroid hormone significantly increased in both the arms; PTH increase was lower in the night arm (P=0.001). From the second administration onwards, urinary ZA level was significantly higher in the night arm (P<0.01). Administration of ZA at two opposite phases of the circadian cycle causes similar changes of bone-turnover marker levels, but has differential effects on the level of serum PTH. 相似文献