bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+CD25+ Regulatory T-Cell Frequency in HER-2/neu(HER)-Positive and HER-Negative Advanced-Stage Breast Cancer Patients
Authors: Perez Sonia A. , Karamouzis Michael V. , Skarlos Dimosthenes V. , Ardavanis Alexandros , Sotiriadou Nectaria N. , Iliopoulou Eleni G. , Salagianni Maria L. , Orphanos George , Baxevanis Constantin N. , Rigatos Gerasimos , Papamichail Michael 
Published: May 2007

AbstractPurpose: CD4+CD25bright regulatory T cells (Tregs) are increased in patients with several malignancies and correlate with disease stage and prognosis. Breast cancer patients represent a heterogeneous population with unpredictable disease progression even at advanced stages. Circulating Tregs in correlation with HER-2/neu (HER) status and treatment with chemotherapy, either alone or in combination with trastuzumab therapy, were monitored in advanced-stage breast cancer patients.Experimental Design: Circulating Treg frequency and absolute counts of 46 HER+ and 28 HER−, stage III and IV, breast cancer patients before therapy and during trastuzumab therapy and/or chemotherapy have been compared with 24 healthy donors and correlated with plasma HER extracellular domain concentration and clinical outcome.Results: Treg frequency in HER+ patients was significantly increased compared with both HER− patients and healthy donors. Trastuzumab therapy, with or without combined chemotherapy, resulted in a progressive decrease of circulating Tregs. Percentage change in Tregs statistically correlated with percentage change in plasma HER extracellular domain. Furthermore, decrease in Tregs correlated with either objective clinical response or stable disease, whereas increased Treg frequency during trastuzumab therapy coincided with disease progression. No statistically significant change in Treg frequency following chemotherapy was observed in HER− patients.Conclusions: Treg cell frequency does not directly correlate with clinical stage in breast cancer, as stage III and IV HER+ and HER− patients exhibit significantly different Treg profiles. Trastuzumab therapy, either alone or combined with chemotherapy, results in decreased Treg frequency in HER+ advanced patients with an objective clinical response.
A Physiologically Based Pharmacokinetic Model of Docetaxel Disposition: from Mouse to Man
Authors: Bradshaw-Pierce Erica L. , Eckhardt S. Gail , Gustafson Daniel L. 
Published: May 2007

AbstractPurpose: Docetaxel (Taxotere), an important chemotherapeutic agent with shown activity in a broad range of cancers, is being investigated for use in combination therapies and as an antiangiogenic agent. Docetaxel exhibits a complex pharmacologic profile with high interpatient variability. Pharmacokinetic models capable of predicting exposure under various dosing regimens would aid the rational development of clinical protocols.Experimental Design: A pharmacokinetic study of docetaxel at 5 and 20 mg/kg was carried out in female BALB/c mice. Tissues were collected at various time points and analyzed by liquid chromatography-tandem mass spectrometry. Time course tissue distribution and pharmacokinetic data were used to build and validate a physiologically based pharmacokinetic (PBPK) model in mice. Specific and nonspecific tissue partitioning, metabolism, and elimination data were coupled with mouse physiologic variables to develop a PBPK model that describes docetaxel plasma and tissue pharmacokinetic. The PBPK model was then modified with human model variables to predict the plasma distribution of docetaxel.Results: Resulting simulation data were compared with actual measured data obtained from our pharmacokinetic study (mouse), or from published data (human), using pharmacokinetic variables calculated using compartmental or noncompartmental analysis to assess model predictability.Conclusions: The murine PBPK model developed can accurately predict plasma and tissue levels at the 5 and 20 mg/kg doses. The human PBPK model is capable of estimating plasma levels at 30, 36, and 100 mg/m2. This will enable us to develop and test various dosing regimens (e.g., metronomic schedules and combination therapies) to achieve specific tissue and plasma concentrations to maximize therapeutic benefit while minimizing toxicity.
Phase I and Pharmacokinetic Study of Pemetrexed with High-Dose Folic Acid Supplementation or Multivitamin Supplementation in Patients with Locally Advanced or Metastatic Cancer
Authors: Takimoto Chris H. , Hammond-Thelin Lisa A. , Latz Jane E. , Forero Leonardo , Beeram Muralidhar , Forouzesh Bahram , de Bono Johann , Tolcher Anthony W. , Patnaik Amita , Monroe Pamela , Wood Leslie , Schneck Karen B. , Clark Romnee , Rowinsky Eric K. 
Published: May 2007

AbstractPurpose: This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability.Patients and Methods: Patients received a 10-min infusion of 600 to 14,00 mg/m2 pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1.Results: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m2 were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation.Conclusions: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m2 in LPT patients and 800 mg/m2 in HPT patients, irrespective of the type of vitamin supplementation.
SOM230, A New Somatostatin Analogue, Is Highly Effective in the Therapy of Growth Hormone/Prolactin-Secreting Pituitary Adenomas
Authors: Fedele Monica , De Martino Ivana , Pivonello Rosario , Ciarmiello Andrea , Del Basso De Caro M. Laura , Visone Rosa , Palmieri Dario , Pierantoni Giovanna M. , Arra Claudio , Schmid Herbert A. , Hofland Leo , Lombardi Gaetano , Colao Annamaria , Fusco Alfredo 
Published: May 2007

Abstract
Purpose: We have previously shown that transgenic mice ubiquitously overexpressing the HMGA2 gene develop growth hormone/prolactin-secreting pituitary adenomas. This animal model has been used to evaluate the therapeutic efficacy of SOM230, a somatostatin analogue with high affinity for the somatostatin receptor subtypes 1, 2, 3, and 5, on the growth of the pituitary adenomas.
Experimental Design: Four groups of 3- and 9-month-old HMGA2 transgenic mice were treated for 3 months with a continuous s.c. injection of two different dosages of SOM230 (5 or 50 μg/kg/h), one dose of octreotide, corresponding to that used in human therapy, and a placebo, respectively. The development of the tumor before and after therapy was monitored by magnetic resonance imaging of the pituitary region and evaluation of the serum prolactin levels.
Results: The highest dose of SOM230 induced a drastic regression of the tumor, whereas octreotide was not able to induce any significant tumor regression, although tumor progression was significantly slowed down. No significant differences were observed between the animals treated with the lowest dose of SOM230 and those receiving placebo.
Conclusions: These results clearly support the efficacy of the SOM230 treatment in human pituitary adenomas secreting prolactin based on the dramatic tumor shrinkage and fall in prolactin levels. This beneficial effect could be of crucial clinical usefulness in patients bearing tumors resistant to dopaminergic drugs.
Bcl-2 and Glutathione Depletion Sensitizes B16 Melanoma to Combination Therapy and Eliminates Metastatic Disease
Authors: Mena Salvador , Benlloch María , Ortega Angel , Carretero Julian , Obrador Elena , Asensi Miguel , Petschen Ignacio , Brown Bob D. , Estrela José M. 
Published: May 2007

Abstract
Purpose: Advanced melanoma resists all current therapies, and metastases in the liver are particularly problematic. Prevalent resistance factors include elevated glutathione (GSH) and increased expression of bcl-2 in melanoma cells. GSH has pleiotropic effects promoting cell growth and broad resistance to therapy, whereas Bcl-2 inhibits the activation of apoptosis and contributes to elevation of GSH. This study determined the in vivo efficacy of combination therapies administered while GSH and Bcl-2 were individually and simultaneously decreased in metastatic melanoma lesions.
Experimental Design: Highly metastatic murine B16 melanoma (B16M-F10) cells have elevated levels of both GSH and Bcl-2. B16M-F10 cells were injected i.v. to establish metastatic lesions in vivo. GSH was decreased using an l-glutamine–enriched diet and administration of verapamil and acivicin, whereas Bcl-2 was reduced using oligodeoxynucleotide G3139. Paclitaxel, X-rays, tumor necrosis factor-α, and IFN-γ were administered as a combination therapy.
Results: Metastatic cells were isolated from liver to confirm the depletion of GSH and Bcl-2 in vivo. Reduction of Bcl-2 and GSH, combined with partial therapies, decreased the number and volume of invasive B16M-F10 foci in liver by up to 99% (P &lt; 0.01). The full combination of paclitaxel, X-rays, and cytokines eliminated B16M-F10 cells from liver and all other systemic disease, leading to long-term survival (&gt;120 days) without recurrence in 90% of mice receiving the full therapy. Toxicity was manageable; the mice recovered quickly, and hematology and clinical chemistry data were representative of accepted clinical toxicities.
Conclusions: Our results suggest a new strategy to induce regression of late-stage metastatic melanoma.
Overexpression of Human Papillomavirus Type 16 Oncoproteins Enhances Hypoxia-Inducible Factor 1α Protein Accumulation and Vascular Endothelial Growth Factor Expression in Human Cervical Carcinoma Cells
Authors: Tang Xudong , Zhang Qunzhou , Nishitani Junko , Brown Jimmy , Shi Shihong , Le Anh D. 
Published: May 2007

Abstract
Purpose: Human papillomavirus (HPV)-16 oncoproteins, E6 and E7, are associated with enhanced tumor angiogenesis in human cervical cancers. The purpose of this study was (a) to investigate whether expression of HPV-16 E6 and E7 oncoproteins induces hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor expression in cervical cancer cells; and (b) to assess the effect of resveratrol on 16 E6- and E7-induced HIF-1α and VEGF gene expression.
Experimental Design: Human cervical cancer cell lines C-33A and HeLa were transiently cotransfected with pSG5-HPV-16 E6 or 16 E7 constructs along with HIF-1α small interfering RNA (siRNA) or nonspecific siRNA. The expression of HIF-1α/VEGF was measured using real-time PCR, Western blot analysis, or ELISA. The in vitro angiogenic activity induced by 16 E6- and E7-transfected cells was examined. The effect of resveratrol on oncoprotein-induced HIF-1α/VEGF expression and in vitro angiogenesis was investigated.
Results: HPV-16 E6- and E7-transfected cervical cancer cells express increased HIF-1α protein and VEGF expression. These stimulatory effects were abrogated by cotransfection with either HIF-1α siRNA or treatment with resveratrol. Blocking extracellular signal-regulated kinase 1/2 (ERK 1/2) and phosphoinositide-3-kinase by PD98059 and LY294002, respectively, abolished 16 E6- and E7-induced HIF-1α and VEGF expression. Functionally, we showed that HPV-16 E6- and E7-transfected cervical cancer cells stimulated in vitro capillary or tubule formation, and these angiogenic effects could be abolished either by cotransfection with HIF-1α siRNA or by treatment with resveratrol.
Conclusion: HPV-16 oncoproteins contribute to enhanced angiogenesis in cervical cancer cells via HIF-1α–dependent VEGF expression. Resveratrol suppresses 16 E6- and E7-induced HIF-1α–mediated angiogenic activity and, thus, is a promising chemotherapeutic agent for human cervical cancer.
Insulin Treatment in Cancer Cachexia: Effects on Survival, Metabolism, and Physical Functioning
Authors: Lundholm Kent , Körner Ulla , Gunnebo Lena , Sixt-Ammilon Petra , Fouladiun Marita , Daneryd Peter , Bosaeus Ingvar 
Published: May 2007

AbstractPurpose: The present study was designed to evaluate whether daily insulin treatment for weight-losing cancer patients attenuates the progression of cancer cachexia and improves metabolism and physical functioning in palliative care.Experimental Design: One hundred and thirty-eight unselected patients with mainly advanced gastrointestinal malignancy were randomized to receive insulin (0.11 ± 0.05 units/kg/d) plus best available palliative support [anti-inflammatory treatment (indomethacin), prevention of anemia (recombinant erythropoietin), and specialized nutritional care (oral supplements + home parenteral nutrition)] according to individual needs. Control patients received the best available palliative support according to the same principles. Health-related quality of life, food intake, resting energy expenditure, body composition, exercise capacity, metabolic efficiency during exercise, and spontaneous daily physical activity as well as blood tests were evaluated during follow-up (30-824 days) according to intention to treat.Results: Patient characteristics at randomizations were almost identical in study and control groups. Insulin treatment for 193 ± 139 days (mean ± SD) significantly stimulated carbohydrate intake, decreased serum-free fatty acids, increased whole body fat, particularly in trunk and leg compartments, whereas fat-free lean tissue mass was unaffected. Insulin treatment improved metabolic efficiency during exercise, but did not increase maximum exercise capacity and spontaneous physical activity. Tumor markers in blood (CEA, CA-125, CA 19-9) did not indicate the stimulation of tumor growth by insulin; a conclusion also supported by improved survival of insulin-treated patients (P &lt; 0.03).Conclusion: Insulin is a significant metabolic treatment in multimodal palliation of weight-losing cancer patients.
Relationship between Survival and Edema in Malignant Gliomas: Role of Vascular Endothelial Growth Factor and Neuronal Pentraxin 2
Authors: Carlson Marc R.J. , Pope Whitney B. , Horvath Steve , Braunstein Jerome G. , Nghiemphu Phioanh , Tso Cho-Lea , Mellinghoff Ingo , Lai Albert , Liau Linda M. , Mischel Paul S. , Dong Jun , Nelson Stanley F. , Cloughesy Timothy F. 
Published: May 2007

AbstractPurpose: Vascular endothelial growth factor (VEGF) is a potent mediator of vascular permeability. VEGF inhibition reduces edema and tumor burden in some patients with malignant glioma, whereas others show no response. The role of VEGF expression in edema production and the relationship to survival is not well understood.Experimental Design: Using DNA microarray analysis, we examined VEGF and related gene expression in 71 newly diagnosed malignant gliomas and analyzed the relationship to edema and survival.Results and Conclusions: VEGF expression was predictive of survival in tumors with little or no edema [Cox proportional hazard model, 6.88; 95% confidence interval (95% CI), 2.61-18.1; P &lt; 0.0001], but not in tumors with extensive edema. The expression of several proangiogenic genes, including adrenomedullin (correlation coefficient, 0.80), hypoxia-inducible factor-1A (0.51), and angiopoietin-2 (0.44), was correlated with VEGF expression (all with P &lt; 0.0001), whereas that of several antiangiogenic genes was inversely correlated. The expression of six genes was increased greater than 3-fold in edematous versus nonedematous tumors in the absence of increased VEGF expression. The most increased, neuronal pentraxin 2 (NPTX2, 7-fold change), was predictive of survival in tumors with the highest levels of edema, in contrast to VEGF (hazard ratio, 2.73; 95% CI, 1.49-5.02; P = 0.049). NPTX2 was tightly correlated with expression of the water channel aquaporin-3 (0.74, P &lt; 0.0001). These results suggest that there are both VEGF-dependent and VEGF-independent pathways of edema production in gliomas and may explain why edema is not reduced in some patients following anti-VEGF treatment.
Rejected Sacrifice in Greek and Hebrew Religion
Authors:   Naiden
Published: April 2007

AbstractScholars of Greek religion, notably Walter Burkert and Jean-Pierre Vernant, have ignored the few but important examples of sacrifices that meet with rejection, and along with this oversight have minimalized the legal and moral aspect of sacrifice. The same error has led them to overlook the similarity between rejected sacrifice in Greek religion and rejected sacrifice in ancient Judaism, where the same infrequent but important phenomenon occurs. This paper proposes a typology for rejected sacrifice and attempts to balance similarities and differences to be found in Greek and Hebrew practice, notably with respect to sacrifices rejected as punishment for sacrilege.
The Myth of the Golden Fleece
Authors: Bremmer Jan 
Published: April 2007

AbstractThis contribution analyses the Greek myth of the Golden Fleece with special attention to its (possible) Oriental components. The first part of the myth, which is situated in Greece, contains a number of relevant motifs in this respect: the 'desperate housewife' (cf. the Joseph story in Genesis); the king's responsibility of the land (cf. the stories around David in the OT); the scapegoat motif, and the sacrifice of one's own child (cf. Abraham and Isaac). The second part of the myth, which is situated in Colchis, concentrates on the Golden Fleece proper. Recent investigations have argued its connection with the Hittite kurša, and my contribution tries to strengthen this connection. In Greek myth and ritual we can see its development into the Golden Fleece of the Argonauts but also into Athena's aegis; the early history of the Golden Fleece still connects it with Anatolia. The killing of the dragon that guarded the Golden Fleece seems inspired by the defeat of Illuyankaš. Both the kurša and the myth of Illuyankaš played an important role at the Hittite Purulli festival, which may have promoted their combination. The routes of transmission of the Oriental parts of the myth probably were Cilicia, Cyprus and the later Royal Road.
On the Role of Resonant Interactions in the Short-Term Evolution of Deep-Water Ocean Spectra
Authors: Tanaka Mitsuhiro 
Published: May 2007

Abstract
The temporal evolution of the energy spectrum of a field of random surface gravity waves in deep water is investigated by means of direct numerical simulations of the deterministic primitive equations. The detected rate of change of the spectrum is shown to be proportional to the cubic power of the energy density and to agree very well with the nonlinear energy transfer Snl as predicted by Hasselmann. Despite the fact that use of various asymptotic relations that are valid only for t → ∞ or integration with respect to time over a time scale much longer than O[period × (ak)−2] is necessary in the derivation of Hasselmann’s Snl, it is clearly demonstrated that the rate of change of the spectrum given by the numerical simulation agrees very well with Hasselmann’s Snl at every instance of ordinary time scale comparable to the period. The result implies that the four-wave resonant interactions control the evolution of the spectrum at every instant of time, whereas nonresonant interactions do not make any significant contribution even in a short-term evolution. It is also pointed out that the result may call for a reexamination of the process of derivation of the kinetic equation for the spectrum.
The Nonlinear Dynamics of Time-Dependent Subcritical Baroclinic Currents
Authors: Flierl G. R. , Pedlosky J. 
Published: May 2007

Abstract
The nonlinear dynamics of baroclinically unstable waves in a time-dependent zonal shear flow is considered in the framework of the two-layer Phillips model on the beta plane. In most cases considered in this study the amplitude of the shear is well below the critical value of the steady shear version of the model. Nevertheless, the time-dependent problem in which the shear oscillates periodically is unstable, and the unstable waves grow to substantial amplitudes, in some cases with strongly nonlinear and turbulent characteristics. For very small values of the shear amplitude in the presence of dissipation an analytical, asymptotic theory predicts a self-sustained wave whose amplitude undergoes a nonlinear oscillation whose period is amplitude dependent. There is a sensitive amplitude dependence of the wave on the frequency of the oscillating shear when the shear amplitude is small. This behavior is also found in a truncated model of the dynamics, and that model is used to examine larger shear amplitudes. When there is a mean value of the shear in addition to the oscillating component, but such that the total shear is still subcritical, the resulting nonlinear states exhibit a rectified horizontal buoyancy flux with a nonzero time average as a result of the instability of the oscillating shear. For higher, still subcritical, values of the shear, a symmetry breaking is detected in which a second cross-stream mode is generated through an instability of the unstable wave although this second mode would by itself be stable on the basic time-dependent current. For shear values that are substantially subcritical but of order of the critical shear, calculations with a full quasigeostrophic numerical model reveal a turbulent flow generated by the instability. If the beta effect is disregarded, the inviscid, linear problem is formally stable. However, calculations show that a small degree of nonlinearity is enough to destabilize the flow, leading to large amplitude vacillations and turbulence. When the most unstable wave is not the longest wave in the system, a cascade up scale to longer waves is observed. Indeed, this classically subcritical flow shows most of the qualitative character of a strongly supercritical flow. This result supports previous suggestions of the important role of background time dependence in maintaining the atmospheric and oceanic synoptic eddy field.