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1.
Phys Rev Lett ; 125(7): 076803, 2020 Aug 14.
Article in English | MEDLINE | ID: mdl-32857578

ABSTRACT

Employing femtosecond laser pulses in front and back side pumping of Au/Fe/MgO(001) combined with detection in two-photon photoelectron emission spectroscopy, we analyze local relaxation dynamics of excited electrons in buried Fe, injection into Au across the Fe-Au interface, and electron transport across the Au layer at 0.6 to 2.0 eV above the Fermi energy. By analysis as a function of Au film thickness we obtain the electron lifetimes of bulk Au and Fe and distinguish the relaxation in the heterostructure's constituents. We also show that the excited electrons propagate through Au in a superdiffusive regime and conclude further that electron injection across the epitaxial interface proceeds ballistically by electron wave packet propagation.

2.
J Phys Condens Matter ; 31(12): 124002, 2019 Mar 27.
Article in English | MEDLINE | ID: mdl-30625433

ABSTRACT

We demonstrate a novel method for the excitation of sizable magneto-optical effects in Au by means of the laser-induced injection of hot spin-polarized electrons in Au/Fe/MgO(0 0 1) heterostructures. It is based on the energy- and spin-dependent electron transmittance of Fe/Au interface which acts as a spin filter for non-thermalized electrons optically excited in Fe. We show that after crossing the interface, majority electrons propagate through the Au layer with the velocity on the order of 1 nm fs-1 (close to the Fermi velocity) and the decay length on the order of 100 nm. Featuring ultrafast functionality and requiring no strong external magnetic fields, spin injection results in a distinct magneto-optical response of Au. We develop a formalism based on the phase of the transient complex MOKE response and demonstrate its robustness in a plethora of experimental and theoretical MOKE studies on Au, including our ab initio calculations. Our work introduces a flexible tool to manipulate magneto-optical properties of metals on the femtosecond timescale that holds high potential for active magneto-photonics, plasmonics, and spintronics.

3.
Eur J Neurol ; 25(1): 111-119, 2018 01.
Article in English | MEDLINE | ID: mdl-28940973

ABSTRACT

BACKGROUND AND PURPOSE: There are numerous grading scales to describe the severity of aneurysmal subarachnoid hemorrhage (aSAH) and to predict outcome. Historically, outcome measures are heterogeneous and the comparability of grading scales is therefore limited. We designed this study to compare radiographic, clinical and combined grading systems in aSAH. METHODS: Data from 423 consecutive patients with aSAH were analyzed. Modified Fisher (mFish), Barrow Neurological Institute (BNI), Hunt and Hess (HH), World Federation of Neurosurgical Societies (WFNS), VASOGRADE (VG) and HAIR scores were calculated from clinical and radiographic data or the combination of both. Outcome measures included the development of new cerebral infarction (CI) and functional patient outcome assessed by the modified Rankin scale. RESULTS: Cerebral infarction and unfavorable outcome were predicted by radiographic, clinical and combined measures (each with P ≤ 0.001). Clinical (HH, WFNS) and combined (VG, HAIR) scores had superior predictive power for CI compared with mFish grading but not BNI [area under the curve (AUC)mFish 0.612, AUCBNI 0.616, AUCWFNS 0.672, AUCHH 0.673, AUCVG 0.674, AUCHAIR 0.638]. Predictive performances of clinical gradings (HH, WFNS) for patient outcome were superior to radiographic measures and of similar quality or better than combined systems (AUCBNI 0.628, AUCmFish 0.654, AUCWFNS 0.736, AUCHH 0.749, AUCVG 0.711, AUCHAIR 0.739). CONCLUSIONS: Knowledge of the merits and limitations of clinical, radiographic and combined scores is necessary in routine clinical practice. The new combined grading systems (HAIR, VG) showed no superiority compared with the established clinical measures (WFNS, HH) in predicting CI and unfavorable patient outcome.


Subject(s)
Cerebral Infarction/diagnostic imaging , Subarachnoid Hemorrhage/diagnostic imaging , Subarachnoid Hemorrhage/surgery , Adult , Aged , Area Under Curve , Cerebral Infarction/etiology , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Subarachnoid Hemorrhage/complications , Tomography, X-Ray Computed , Treatment Outcome
4.
Langmuir ; 33(41): 10807-10817, 2017 10 17.
Article in English | MEDLINE | ID: mdl-28938076

ABSTRACT

The scanning Kelvin probe (SKP) is a versatile method for the measurement of the Volta potential difference between a sample and the SKP-tip (ΔψsampleSKP-tip). Based on suitable calibration, this technique is highly suited for the application in corrosion science due to its ability to serve as a very sensitive noncontact and nondestructive method for determining the electrode potential, even at buried interfaces beneath coatings or on surfaces covered by ultrathin electrolyte layers, which are not accessible by standard reference electrodes. However, the potential of the reference (i.e., the SKP-tip) will be influenced by variations of the surrounding atmosphere, resulting in errors of the electrode potential referred to the sample. The objective of this work is to provide a stable SKP-tip which can be used in different or changing atmosphere, e.g., within a wide range of relative humidity (approximately 0-99%-rh) or varying O2 partial pressure, without showing a change of its potential (note that the work functions measured in non-UHV atmospheres are electrochemical in nature [Hausbrand et al. J. Electrochem. Soc. 2008, 155 (7), C369-C379], and hence in the following we will refer to the potential of the SKP-tip instead of its work function). In that regard, the SKP-tip is in a first approach modified with self-assembled monolayers (SAMs) in order to create a hydrophobic barrier between the metallic surface and the surrounding atmosphere. The changes in potential upon varying relative humidity (ΔErh) of different bare metallic substrates are quantified, and it is shown that these potential differences cannot be minimized by SAMs. On the contrary, the ΔErh increases for every examined material system modified with SAMs. The major explanation for this observation is the dipole layer at the interface metal|SAM, causing an interfacial adsorption of water molecules even in a preferred orientation of their dipole moments, which leads to a changed work function and consequently to the correlated electrode potential. However, thin paraffin coatings were found to lead to a strongly reduced ΔErh, finally validated with novel robust Ag/Ag+ reference electrodes. It is also shown that nickel as SKP-tip material is seemingly more stable in varying atmospheric conditions compared to widely used Ni/Cr, stainless steel, or gold as SKP-tip material.

5.
J Phys Condens Matter ; 29(17): 174002, 2017 May 04.
Article in English | MEDLINE | ID: mdl-28349899

ABSTRACT

We discuss fundamental aspects of laser-induced ultrafast demagnetization probed by the time-resolved magneto-optical Kerr effect (MOKE). Studying thin Fe films on MgO substrate in the absence of electronic transport, we demonstrate how to disentangle pump-induced variations of magnetization and magneto-optical coefficients. We provide a mathematical formalism for retrieving genuine laser-induced magnetization dynamics and discuss its applicability in real experimental situations. We further stress the importance of temporal resolution achieved in the experiments and argue that measurements of both time-resolved MOKE rotation and ellipticity are needed for the correct assessment of magnetization dynamics on sub-picosecond timescales. The framework developed here sheds light onto the details of the time-resolved MOKE technique and contributes to the understanding of the interplay between ultrafast laser-induced optical and magnetic effects.

6.
Orthopade ; 44(2): 146-53, 2015 Feb.
Article in German | MEDLINE | ID: mdl-25600107

ABSTRACT

BACKGROUND: The rationale for the increasing use of bone graft replacement lies in the need for increased graft volume, the avoidance of typical autograft donor site morbidity, and the potential improvement of fusion rates in revision and complex reconstructive surgery. OBJECTIVES: The purpose of this work is to offer the spinal surgeon an evidence-based guide for choosing the appropriate grafting material and for using it effectively. MATERIAL AND METHODS: Evidence-based overview of physical and biological properties, clinical indications and results of osteoconductive and osteoinductive bone replacement materials. RESULTS: The ideal bone replacement material should be osteoinductive and conductive, non-pathogenic, minimally antigenic, and (if required) mechanically stable. Compared to autograft, vascularization and remodeling of the fusion mass are delayed using allograft. Allogenous bone and demineralized bone matrix (DBM) possess limited osteoinductive properties and carry the risk of potential infectious disease transmission. Plasma-rich plasma (PRP) and bone marrow aspirate are commonly used in conjunction with an osteoconductive carrier materials. On-label use of bone morphogenetic proteins (BMPs) is currently restricted to mono- and bisegmental anterior lumbar fusion. The fusion rates obtained with BMPs match those of autologous bone graft. Potential risks of rhBMP in clinical use include soft tissue reactions, radiculitis and potentially increased risk of cancer. Osteoconductive ceramics (HA, CC, CS, ß-TCP) are useful graft extenders and carriers for bone growth enhancers and antibiotics. CONCLUSIONS: Osteoconductive bioceramics with different mechanical and biological properties are available for use as graft extenders. In a defined group of anterior interbody fusion procedures (ACDF, ALIF), satisfactory fusion rates (> 90%) may be obtained with exclusive use of graft extenders, whereas their solitary use in posterolateral fusions is not advisable. Genuine bone replacement is currently feasible with BMPs. Their use should be restricted to specific indications such as complex revision surgery and pseudarthrosis.


Subject(s)
Bone Substitutes/therapeutic use , Bone Transplantation/instrumentation , Bone Transplantation/methods , Spinal Fusion/instrumentation , Spinal Fusion/methods , Combined Modality Therapy/methods , Humans
7.
ACS Appl Mater Interfaces ; 5(23): 12375-9, 2013 Dec 11.
Article in English | MEDLINE | ID: mdl-24256205

ABSTRACT

We report on the effect of temperature on the electric current induced in the mesoporous Pt/TiO2 structure by the room temperature surface chemical reaction of hydrogen and oxygen,13,14 which helps to unveil the physical origin of this current and the related electromotive force (chemi-EMF). We found that the temperature dependence of this reaction current has a clear multipeak structure, suggesting that at least two distinct processes contribute to the current generation. We suggest that the output current represents the interplay of both chemical and electrical processes, evidenced by the metastability of the room temperature reaction and by matching one of the current peaks with a water desorption peak for TiO2.

8.
Ultramicroscopy ; 112(1): 22-31, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22088505

ABSTRACT

The combination of high-brilliance synchrotron radiation with scanning tunneling microscopy opens the path to high-resolution imaging with chemical, electronic, and magnetic contrast. Here, the design and experimental results of an in-situ synchrotron enhanced x-ray scanning tunneling microscope (SXSTM) system are presented. The system is designed to allow monochromatic synchrotron radiation to enter the chamber, illuminating the sample with x-ray radiation, while an insulator-coated tip (metallic tip apex open for tunneling, electron collection) is scanned over the surface. A unique feature of the SXSTM is the STM mount assembly, designed with a two free-flex pivot, providing an angular degree of freedom for the alignment of the tip and sample with respect to the incoming x-ray beam. The system designed successfully demonstrates the ability to resolve atomic-scale corrugations. In addition, experiments with synchrotron x-ray radiation validate the SXSTM system as an accurate analysis technique for the study of local magnetic and chemical properties on sample surfaces. The SXSTM system's capabilities have the potential to broaden and deepen the general understanding of surface phenomena by adding elemental contrast to the high-resolution of STM.

9.
J Steroid Biochem Mol Biol ; 103(3-5): 326-9, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17287116

ABSTRACT

1,25-Dihydroxyvitamin D(3) (calcitriol) is the most active natural metabolite of Vitamin D(3). It has strong antiproliferative and differentiating effects on various cell types including breast cancer cells. 25-Hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase, CYP27B1) is one of the key enzymes in the formation of calcitriol. It has been found in breast cancer cells suggesting an autocrine regulation of formation of calcitriol in these cells. Alternative splicing of the encoding genes for this enzyme can possibly play a role in regulating the enzyme level and can explain tissue specific variations of 1alpha-hydroxylase activity. Splice variants containing intron 1 may encode for truncated proteins with deletion of protein domains which are essential for its enzymatic activity. In order to obtain more information on the abundance of 1alpha-hydroxylase splice variants, we performed a highly specific nested touchdown PCR in MCF-7 cells. The full-length sequence of 1alpha-hydroxylase and two different splice variants of this enzyme containing intron 1 were isolated. By Western blot technique we then confirmed the protein products of the full-length enzyme and its splice variants. We hypothesize that that the expression of splice variants can lead to a quantitatively lower expression of the mRNA of the full-length enzyme. The abundance of less active 1alpha-hydroxylase protein variants can alter the local synthesis of calcitriol in the cells and may explain variations of enzymatic activity in different cells and tissues.


Subject(s)
25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism , Alternative Splicing/genetics , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Gene Expression Regulation, Enzymologic , Genetic Variation/genetics , Cell Line, Tumor , Cloning, Molecular , Humans
10.
Anticancer Res ; 26(4A): 2749-53, 2006.
Article in English | MEDLINE | ID: mdl-16886687

ABSTRACT

1alpha-25-Dihydroxyvitamin D3 (calcitriol), the biologically active metabolite of vitamin D, is known to regulate calcium and phosphate levels in bone metabolism. It is also known to influence proliferation and differentiation in carcinoma cells mediated by the vitamin D receptor (VDR). The antiproliferative effects of calcitriol are believed to be mediated by the nuclear pathway via binding the activated receptor to vitamin D-responsive elements. This induces the vitamin D-responsive genes. Another possible pathway might be the MAPK-cascade or rapid response pathway. The interaction of calcitriol and the MAP-kinase-cascade was evaluated on VDR-positive MCF-7 cells and VDR-negative MDA-MB-231 breast cancer cells. The cells were incubated with calcitriol solution at 10(-7) M and 10(-9) M, or ethanol as controls, for up to 48 h. The effects of calcitriol were measured by semi-quantitative Western blotting. Calcitriol stimulated the MAP-kinases ERK1 and ERK2. A biphasic activation was found for calcitriol in VDR-positive cells after incubation for 5 to 20 min and from 2 to 24 h. However, early activation of ERK1 and ERK2 was also demonstrated in VDR-negative cells. In the controls, ethanol also induced the MAPK-cascade at 5 to 10 min. Calcitriol induction was demonstrated after incubation from 2 to 24 h. In conclusion, it seems that the early induction of the MAPK-cascade was independent of the VDR. A calcitriol-induced MAPK activation was shown after 4 h, which may have been caused by activation of the nuclear receptor pathway.


Subject(s)
Breast Neoplasms/enzymology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Receptors, Calcitriol/biosynthesis , Breast Neoplasms/metabolism , Calcitriol/pharmacology , Cell Line, Tumor , Humans , MAP Kinase Signaling System , Phosphorylation
11.
Anticancer Res ; 26(1B): 655-61, 2006.
Article in English | MEDLINE | ID: mdl-16739335

ABSTRACT

BACKGROUND: Endometrial stromal sarcoma (ESS) is a malignant tumour with its origin in the endometrial stroma. Little is known about the pathogenesis, risk factors, optimal therapy or outcome of this disease. PATIENTS AND METHODS: Eleven patients with ESS, treated between 1972 and 1996, are reported on. The hospital records of all the patients, including pathology and operative reports, were reviewed and information on treatment, recurrence and survival was obtained. RESULTS: The mean age of our patients was 56.6 years. The main symptom was abnormal vaginal bleeding. Most patients were diagnosed at FIGO stage I. Treatment modalities were surgery, radiation and, in one patient, chemotherapy. The median follow-up time was 42.1 months; 27.3% of the patients had local recurrence. The 1-year, 2-year and 5-year survival rates were 36.3%, 18.1% and 9.1%, respectively. CONCLUSION: ESS is a uterine sarcoma with a difficult differential diagnosis. Patients are frequently diagnosed in an early tumour stage but still experience local or distant recurrence. The prognosis is poor, with early recurrence and low long-time survival rates. The treatment includes surgery and adjuvant radiation, with endocrine therapy being a promising new approach. In order to obtain more information about the pathogenesis of the tumour and to find the optimal therapy, it is necessary that studies, even with small numbers of patients, are undertaken.


Subject(s)
Endometrial Neoplasms/pathology , Endometrial Neoplasms/therapy , Sarcoma, Endometrial Stromal/pathology , Sarcoma, Endometrial Stromal/therapy , Adult , Aged , Combined Modality Therapy , Endometrial Neoplasms/diagnosis , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Recurrence, Local , Neoplasm Staging , Parity , Pregnancy , Retrospective Studies , Sarcoma, Endometrial Stromal/diagnosis
12.
Anticancer Res ; 26(6C): 4817-23, 2006.
Article in English | MEDLINE | ID: mdl-17214346

ABSTRACT

BACKGROUND: Carcinosarcomas (CS) are mixed epithelial and stromal tumours with both components being malignant. Twenty-one patients with carcinosarcomas who were treated at the University of Saarland, Germany, are presented. PATIENTS AND METHODS: The hospital records of all patients were reviewed. RESULTS: The mean age range for homologue CS (homCS) was 60.7 years and for heterologue CS (hetCS) 68.4 years. Post-menopausal bleeding and abdominal pain were the main symptoms. Treatment modalities included surgery, adjuvant radiation therapy and various chemotherapy regimens. The median follow-up time was 17.6 months (homCS) and 31.1 months (hetCS). The 1-year survival rate was 55.6% (hetCS 58.3%) and the 5-year survival rate was 11.1% (hetCS 8.3%). CONCLUSION: Carcinosarcoma is a uterine sarcoma with a poor prognosis. Treatment includes surgery and adjuvant chemotherapy, whereas radiotherapy does not necessarily lead to a benefit. Treatment with trastuzumab might be a new approach in the therapy of HER-2/neu-positive CS.


Subject(s)
Carcinosarcoma/diagnosis , Carcinosarcoma/therapy , Uterine Neoplasms/diagnosis , Uterine Neoplasms/therapy , Aged , Aged, 80 and over , Carcinosarcoma/pathology , Female , Humans , Middle Aged , Retrospective Studies , Uterine Neoplasms/pathology
13.
Zentralbl Gynakol ; 127(4): 222-7, 2005 Aug.
Article in German | MEDLINE | ID: mdl-16037903

ABSTRACT

Usually, the therapy of metastatic breast cancer consists of chemotherapy or endocrine therapy, because even in the case of isolated metastases in one organ, diffuse tumor cell dissemination exists, so that local surgical treatment does not seem sensible. Particurlarly in patients with hepatic or pulmonary metastases the indication for hepatic or pulmonary metastasectomy should be individualized, as hepatic or pulmonary metastases usually develop during a phase of disease, when extrahepatic or -pulmonary metastases also can be detected. Only in patients with long disease-free interval, with isolated hepatic or pulmonary metastases, and the possibility of R0-resection is hepatic or pulmonary metastasectomy a therapeutic option in selected cases.


Subject(s)
Breast Neoplasms/pathology , Neoplasm Metastasis , Breast Neoplasms/surgery , Female , Humans , Prognosis
14.
Zentralbl Gynakol ; 127(2): 71-5, 2005 Apr.
Article in German | MEDLINE | ID: mdl-15800837

ABSTRACT

Treatment of patients with brain metastases is based on an interdisciplinary approach. It is essential to perform a differenciated indication for procedures with consideration of all therapeutical options like modalities of radiotherapy, surgery and oncology. In the case of multiple brain metastases the whole brain radiotherapy is the standard of treatment, while in case of a single or solitary brain metastasis surgical procedures followed by radiotherapy should be preferred.


Subject(s)
Brain Neoplasms/secondary , Breast Neoplasms/pathology , Brain Neoplasms/radiotherapy , Brain Neoplasms/surgery , Female , Humans
15.
Phys Rev Lett ; 93(13): 137601, 2004 Sep 24.
Article in English | MEDLINE | ID: mdl-15524760

ABSTRACT

The kinetic excitation of electrons upon bombardment of a solid surface with energetic ions is investigated. Using a metal-insulator-metal junction, hot electrons produced by the projectile impact are detected with excitation energies well below the vacuum level. The results provide information that cannot be accessed by electron emission experiments. The observed tunneling current depends on the projectile energy and the bias voltage across the junction, opening the possibility of internal excitation spectroscopy.

16.
Eur J Gynaecol Oncol ; 25(5): 555-8, 2004.
Article in English | MEDLINE | ID: mdl-15493164

ABSTRACT

The resection of liver metastases in breast cancer patients is a controversial therapeutical approach. No data of prospective randomized trials are available, thus evidence for the potential role of hepatic metastasectomy rests on retrospective studies with a small number of patients. Techniqual advances however have rendered hepatic metastasectomy safe and the long-term results of some studies possibly support the role of a surgical approach in selected patients.


Subject(s)
Breast Neoplasms/pathology , Liver Neoplasms/surgery , Female , Humans , Liver Neoplasms/pathology , Neoplasm Metastasis , Retrospective Studies
17.
Eur J Gynaecol Oncol ; 25(1): 66-70, 2004.
Article in English | MEDLINE | ID: mdl-15053065

ABSTRACT

Taxanes belong to the most effective agents in the treatment of advanced and non-hormone responsive breast cancer. Several recently published phase III studies have examined the role of taxane-anthracycline combinations in the first line treatment of metastatic breast cancer. Especially, patients with symptomatic visceral spread seem to benefit from taxanes containing polychemotherapy that is adequately dosed. Polychemotherapy with taxanes appears to be more effective than monotherapy. But at present, there are no adequate data concerning the comparison of taxane-monotherapy and anthracycline-containing polychemotherapy. New hopeful results with respect to efficacy and toxicity are reported from the docetaxel-capecitabine polychemotherapy. Thus, the combination of anthracyclines (adriamycin, doxorubicin) and taxanes (docetaxel, paclitaxel) is a promising tool in the treatment of metastatic breast cancer. New interesting combinations are under investigation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Taxoids/administration & dosage , Anthracyclines/administration & dosage , Breast Neoplasms/pathology , Clinical Trials, Phase III as Topic , Female , Humans , Neoplasm Metastasis
18.
Horm Res ; 60(2): 73-8, 2003.
Article in English | MEDLINE | ID: mdl-12876417

ABSTRACT

BACKGROUND: We investigated the effects of androgens, estradiol (E2) and insulin-like growth factor (IGF)-I on IGF-II, insulin-like growth factor binding protein (IGFBP)-2, -3 and -5 and mRNA in genital fibroblasts (GF) from patients with complete androgen insensitivity (CAIS) and normally virilized males (C). METHODS: Proteins were measured by specific RIA and Western ligand blot, and specific mRNA levels by RT-PCR normalized by GAPDH levels. RESULTS: Secretion of IGF-II was lowered in CAIS (p<0.001) GF and by testosterone + IGF-I in C GF. Secretion of IGFBP-2 was higher (p<0.001) in CAIS GF and IGFBP-2 mRNA levels were increased by E2 in C GF (p<0.05). E2 stimulated IGFBP-2, -3 and -5 expression in CAIS GF. CAIS GF also secreted more IGFBP-3 (p<0.001) and accumulated 3-5 times more IGFBP-5 mRNA than C GF (p<0.001). CONCLUSION: In contrast to C GF, the availability of IGF-II in CAIS GF is apparently decreased by two facts: by the decreased expression and by increased expression of IGFBP-2, -3 and -5. Furthermore, E2 and IGF-I modulate the expression of IGF-II and IGFBP in GF. This may play a role in the failure to develop male external genitals in CAIS patients.


Subject(s)
Androgen-Insensitivity Syndrome/genetics , Fibroblasts/metabolism , Genitalia, Male , Insulin-Like Growth Factor Binding Proteins/metabolism , Skin/metabolism , Blotting, Western , Humans , Insulin-Like Growth Factor Binding Protein 2/metabolism , Insulin-Like Growth Factor Binding Protein 3/metabolism , Insulin-Like Growth Factor Binding Protein 5/metabolism , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor II/metabolism , Male , RNA, Messenger/metabolism , Radioimmunoassay , Receptors, Androgen/metabolism , Reverse Transcriptase Polymerase Chain Reaction
19.
J Steroid Biochem Mol Biol ; 84(2-3): 255-7, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12711011

ABSTRACT

Endocrine therapy is widely accepted for the treatment of hormone receptor-positive breast cancer. However, in many cases eventually resistance will develop and tumor regrows. Combination therapy may be one way to resolve this problem. In the present study we investigated the effect of a combination of the widely used antiestrogen tamoxifen with the endogenous estradiol metabolite 2-methoxyestradiol (2-ME) on the proliferation of human estrogen receptor-positive and receptor-negative breast cancer cells. The receptor-positive cell line MCF-7 and the receptor-negative cell line BM were treated with 4-hydroxytamoxifen (4-OHTam) and 2-methoxyestradiol in the concentration range of 0.8-25 microM alone and equimolar combinations for 4 days. The proliferation of the cells was determined using the ATP-chemosensitivity test.4-Hydroxytamoxifen inhibited proliferation of MCF-7 and BM cells with IC(50) values of 31 and 10 microM, the corresponding figures for 2-methoxyestradiol were 52 and 8 microM. The combination showed IC(50) values of 6 microM and 4 microM. These results indicate that a combination of tamoxifen with 2-methoxyestradiol showed an additive inhibitory effect concerning the proliferation of estrogen receptor-positive and receptor-negative breast cancer cell lines. Thus a combination of these substances may allow ameliorating of adverse events of tamoxifen by reducing its concentrations and probably also drug resistance and should be tested in clinical trials.


Subject(s)
Breast Neoplasms/drug therapy , Estradiol/pharmacology , Tamoxifen/pharmacology , 2-Methoxyestradiol , Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Combined Chemotherapy Protocols , Cell Division , Dose-Response Relationship, Drug , Estradiol/analogs & derivatives , Humans , Inhibitory Concentration 50 , Receptors, Estrogen/metabolism , Tumor Cells, Cultured
20.
J Clin Endocrinol Metab ; 86(10): 4741-6, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11600534

ABSTRACT

The action of androgen by way of the AR is required for the development of male gonads and external genitalia. The interplay between androgens and the somatotropic axis, in particular the IGFs in sexual development, is currently under thorough investigation. The IGF system is thought to mediate the androgen action in androgen-responsive cells. To investigate the interaction of androgens with the IGF system, we compared the expression of IGFs and IGF-binding proteins in cultured genital skin fibroblasts from nine patients with the syndrome of complete androgen insensitivity with that in genital skin fibroblasts from 10 normally virilized males. Mutations in the AR gene and/or abnormalities of the AR protein in the immunoblot were detected in all complete androgen insensitivity genital skin fibroblast strains. They caused a complete failure of DHT binding. RIA and RT-PCR demonstrated that the genital skin fibroblast strains expressed IGF-II, IGF-binding protein-2, and IGF-binding protein-3, but no IGF-I. Most strikingly, complete androgen insensitivity genital skin fibroblast strains produced significantly lower IGF-II (P < 0.001; 42.2 +/- 9.7 vs. 106.9 +/- 11.8 ng/mg protein) and IGF-II mRNA (P < 0.01, by RT-PCR) than control genital skin fibroblast strains. The production of IGF-binding protein-2 was also decreased (P < 0.03) in complete androgen insensitivity genital skin fibroblasts, whereas that of IGF-binding protein-3 did not differ. Furthermore, high levels of IGF-binding protein-5 mRNA were detected in all genital skin fibroblast strains, whereby the 28-kDa band in the ligand blot, probably representing IGF-binding protein-5, was more abundant in complete androgen insensitivity genital skin fibroblasts. Exposure of the genital skin fibroblasts to T (5 x 10(-8) M) had only weak effects on the expression of IGFs and IGF-binding proteins. In conclusion, although the mechanism underlying these differences requires further study, it is conceivable that in addition to the endocrine actions of IGF-I, IGF-II and IGF-binding protein-2, as local growth factors, are involved in the mediation of androgen action and growth of genital tissues.


Subject(s)
Androgen-Insensitivity Syndrome/metabolism , Genitalia, Male/metabolism , Insulin-Like Growth Factor Binding Protein 2/biosynthesis , Insulin-Like Growth Factor II/biosynthesis , Cells, Cultured , Fibroblasts/metabolism , Humans , Insulin-Like Growth Factor Binding Protein 2/genetics , Insulin-Like Growth Factor II/genetics , Male , RNA, Messenger/analysis , Receptors, Androgen/chemistry
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