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This article is centered on those factors that are relevant forinvestors in equity Mutual Funds. More specifically it focuses on net flows that go to a fund and its relation with performance, costs and other variables. The methodology is based on Fama and MacBeth (1973), and results indicate a strong sensitivity of flows to past returns, and some evidence that investors react asymmetrically to bad or good past performance. Costs charged by the fund is a statistically significant variable and relevant for investor’s decisions. Other results indicate some evidence on the relevance of fund size, and mutual funds related to banking firms apparently have no advantage to other funds in the industry.

This article is centered on those factors that are relevant for investors in equity Mutual Funds. More specifically it focuses on net flows that go to a fund and its relation with performance, costs and other variables. The methodology is based on Fama and MacBeth (1973), and results indicate a strong sensitivity of flows to past returns, and some evidence that investors react asymmetrically to bad or good past performance. Costs charged by the fund is a statistically significant variable and relevant for investor's decisions. Other results indicate some evidence on the relevance of fund size, and mutual funds related to banking firms apparently have no advantage to other funds in the industry. [ABSTRACT FROM AUTHOR]

Cells of two closely related strains of the Ehrlich mouse ascites tumour synthesize glycogen in vitro. The glycogen is mainly deposited intranuclearly. [ABSTRACT FROM AUTHOR]

Background: Batch variability of sera used for cell culture is of considerable experimental concern. A novel fetal calf serum product, FCS Gold, was claimed to be the first defined fetal calf serum free of batch variation., Materials and Methods: The efficacy of methotrexate (MTX) and LY231514 (multitargeted antifolate, MTA) in CCRF-CEM cells and KB cells was compared using media supplemented with FCS Gold or conventional fetal bovine serum., Results: IC50 values from tests using conventional serum corresponded to published data. FCS Gold fully protected the cells from antifolate drug cytotoxicity. Dialysis of FCS Gold restored responsiveness to antifolate drugs. Elevated levels of hypoxanthine and thymidine were present in FCS Gold. They were approximately 10-fold greater than the concentrations required to overcome growth arrest mediated by 2 microM MTX., Conclusion: FCS Gold or identical products, e.g. FBS Gold, should not be used in studies on antifolate drug action.

Background: Vinorelbine has been identified as an effective cytostatic drug in head and neck squamous cell carcinoma (HNSCC). To predict the individual chemoresponse, the application of an ex vivo assay to quantify the response of HNSCC to vinorelbine is presented., Patients and Methods: Twelve biopsies from primary HNSCC sites and five biopsies from metastatic lesions were analyzed (n = 17). The specimens were investigated ex vivo for the overall, epithelial and stromal chemoresponse to vinorelbine., Results: By selective evaluation of the epithelial chemoresponse, the applied assay identified three specimens as vinorelbine-sensitive (18%), including one de novo sensitivity in a metastatic lesion of a vinorelbine-resistant hypopharyngeal carcinoma., Conclusion: Applying flavin-protecting culture methods and with careful correction for the stromal cell effect, the assay generated reliable data for the assessment of the individual chemoresponse of HNSCC specimens to vinorelbine. The assay may, therefore, facilitate the implementation of individualized chemotherapy protocols.

Previous studies focusing on response prediction to chemotherapy by chemosensitivity testing of tumor explants has focused on the response determination of single cytostatic drugs, in contrast to the common clinical application of cytostatic drug combinations. Therefore, the present study was aimed at determining the quantitative ex vivo chemoreactivity of epithelial cells from head and neck squamous cell carcinoma (HNSCC) specimens to cytostatic drug combinations. Specimens from 12 histologically-confirmed HNSCC were investigated. According to a previously established ex vivo colony formation assay, the individual cellular chemoreactivity was determined quantitatively for combinations of 4 cytostatic drugs: cis-platinum (cis-DDP), carboplatin (CBDCA), 5-Fluorouracil (5-FU) and docetaxel (DTX). The tests were performed using drug combinations according to recent clinical therapy regimens in the treatment of solid tumors: i) cis-DDP + 5FU, ii) CBDCA + 5FU, iii) cis-DDP + DTX and iv) CBDCA + DTX. The approach provides individual drug response patterns of epithelial as well as of stromal cells. Individual, selective sensitivities were found for each drug combination tested. The stromal and epithelial chemoreactivity profiles differed in most of the specimens. Moreover, stromal cell chemoresistance dominated selective epithelial chemosensitivities in the majority of cases. The determination of the epithelial ex vivo chemoreactivity identified individual chemosensitivities which were verified by the clinical history of the patient. Therefore, the described protocol to determine the ex vivo chemoresponse of HNSCC specimens to cytostatic drug combinations may help to provide clinicaly useful information concerning the individual chemoresponse of HNSCC with regard to individualization of oncological decision making.

A study was performed to improve cytotoxicity determinations by eliminating flavin-mediated photosensitization from tests with KB cells, NCI-H69 cells, P-glycoprotein expressing KBC5-8 cells, MRP1-expressing H69AR cells, and A240286S human lung adenocarcinoma cells. Growth inhibition by cis-platin, doxorubicin, etoposide, gemcitabine, taxol, vincristine, vinblastine, and vinorelbine was determined under flavin-protecting conditions using flavin-free culture media with fetal bovine serum as the only source of flavins. As compared to conventional tests, the IC50 values determined under flavin-protecting conditions reflected increased apparent drug cytotoxicities, and were flawlessly reproducible. Flavin-mediated photosensitization should, therefore, be strictly eliminated from in vitro experiments involving cytotoxic and other drugs.

Background: Glufosfamide is a novel alkylating agent in which the active metabolite of isophosphoramide mustard is glycosidically linked to beta-D-glucose. Targeting the elevated glucose uptake of tumor cells expressing the SAAT1 glucose transporter, glufosfamide represents an attractive new drug for cancer chemotherapy. The present study investigates the ex vivo responsiveness of Head and Neck Squamous Cell Carcinoma (HNSCC) specimens to glufosfamide., Patients and Methods: Twenty-one unselected HNSCC specimens were investigated using a novel ex vivo colony formation assay to determine the epithelial drug response. The individual responsiveness to glufosfamide and to cis-platinum was determined., Results: Five out of 21 evaluable HNSCC specimens were sensitive to glufosfamide. There was a tendency for glufosfamide sensitivity in platinum-resistant specimens and vice versa., Conclusion: The effectiveness of glufosfamide observed in the present ex vivo study suggests at least an equipotentiality of glufosfamide in comparison to cis-platinum. The potential clinical usefulness of glufosfamide in HNSCC warrants further evaluation.

The synthesis of a new ortho-carborane derivative, tetracarboranylketone 4, is reported here. Ketone 4 was prepared from a tetraalkynylated ketone by the addition of decaborane. The keto group was then easily modified to yield the glycosides 17alpha and 18beta, which contain glucose or galactose, respectively, and the nucleotide 13b. In addition to ketone 4, which is acyclic, cyclic ketone 8 was also synthesised. X-ray diffraction analysis of compound 4 indicated the presence of two toluene guest molecules per molecule of the host compound. Furthermore, compound 4 displays a rather low cytotoxicity. These novel products can be used as building blocks to create a new class of biomolecules containing high-density carborane clusters. Such molecules may constitute powerful tools for applications like Boron Neutron Capture Therapy or Energy-Filtering Transmission Electron Microscopy.

Background: Reliable chemosensitivity testing of head and neck squamous cell carcinoma (HNSCC) still faces methodical limitations. Since stromal cell contamination has been found to preclude reliable radiosensitivity testing of HNSCC as well as chemosensitivity testing of lung tumors, the present study investigates the impact of stromal cell contamination on chemosensitivity testing of HNSCC., Patients and Methods: Seventeen biopsies from HNSCC were analyzed. The specimens were investigated using an ex vivo colony formation assay which allows for the quantitative and separate determination of the overall, as well as the epithelial, and stromal response to carboplatin, 5-fluorouracil and docetaxel., Results: The overall chemoresponse was dominated by stromal cell multidrug resistance. However, by selective evaluation of the epithelial chemoresponse, individual chemosensitivity patterns could be identified., Conclusion: Multidrug-resistant stromal cells preclude the reliable assessment of the chemoresponse of HNSCC specimens. Carefiul correction for stromal cell effects is a prerequisite for the generation of therapeutically useful information.

Heparin has long been known to slow the growth of vascular smooth muscle cells. However, the mechanism(s) by which heparin acts has yet to be resolved. The identification of a putative heparin receptor in endothelial cells with antibodies that blocked heparin binding to the cells provided the means to further examine the possible involvement of a heparin receptor in smooth muscle cell responses to heparin. Immunoprecipitation of a smooth muscle cell protein with the anti-heparin receptor antibodies provided evidence that the protein was present in smooth muscle cells. Experiments with the anti-heparin receptor antibodies indicate that the antibodies can mimic heparin in decreasing PDGF induced thymidine and BrdU incorporation. The anti-heparin receptor antibodies were also found to decrease MAPK activity levels after activation similarly to heparin. These results support the identification of a heparin receptor and its role in heparin effects on vascular smooth muscle cell growth., (Copyright 2001 Wiley-Liss, Inc.)

Poor reproducibility of cytotoxicity tests with Vinca alkaloids has frequently been reported. A commonly presumed light sensitivity of the drugs could not be confirmed. However, we found that they are photosensitized by riboflavin (vitamin B2), an obligatory component of cell culture media. Light of wavelengths below 500 nm triggered rapid photoreactions of riboflavin with vinblastine, vincristine, and vindesine in aqueous solutions. The photoreactions altered the absorption spectra of these alkaloids and yielded degradation products that could be separated by TLC. In cell cultures, both immediate and persisting, riboflavin-mediated photoreactivity could be distinguished. They preclude reliable determinations of sensitivity and resistance to Vinca alkaloids, as exemplified on chemosensitive and multidrug-resistant mouse ascites cells. In experiments involving photosensitization, the 50% inhibitory concentration values of sensitive and resistant cells were overlapping and fluctuated in the ranges from 3 to 30 nM and 15 to 360 nM vinblastine, respectively. Corresponding values from series of experiments protected from photosensitization were 1.02 +/- 0.22 nM and 18.5 +/- 3.42 nM. Hence, riboflavin-mediated photoreactions must be fully prevented in assays of cellular drug sensitivity. Procedures for eliminating immediate as well as persisting photoreactivity were established.

Preclinical studies have established that Sch 37370 (1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta [1,2-b]pyridin-11-ylidene)piperidine) is an orally active antagonist of platelet-activating factor (PAF) and histamine H1-receptors with potential therapeutic use in the treatment of asthma. To evaluate the efficacy and duration of anti-PAF and antihistamine actions of oral Sch 37370 in humans, a single dose (5 mg/kg) of Sch 37370 was given orally to each of 10 male subjects in a placebo-controlled, double-blind crossover study. Blood samples were drawn before and at various times (2 to 48 hours) after Sch 37370 or placebo. Plasma samples were analyzed for Sch 37370 by a gas chromatographic method, for the anti-PAF activity by measuring the aggregation of platelets stimulated with PAF, and for the antihistamine activity by measuring displacement of [3H]pyrilamine from rat brain membrane binding sites. The plasma anti-PAF activity declined from high levels at 2 hours to barely detectable levels at 24 hours; however, significant activity was still present at 12 hours. The plasma levels of Sch 37370 closely paralleled the anti-PAF profile. The plasma antihistamine activity reached a maximum within 2 to 8 hours and declined thereafter. However, 48 hours after Sch 37370, the antihistamine activity was still present at a significant level in most subjects. It is concluded that, in humans, oral Sch 37370 antagonizes both PAF and histamine with plasma antihistamine activity lasting longer than plasma anti-PAF activity.

Preferential involvement of chromosome 12, the carrier of Ig heavy chain, in structural rearrangements has been documented in an in vitro derivative of Ehrlich-Lettré mouse ascites tumor. Both copies of chromosome 12 have been found to be involved in Robertsonian and tandem translocations with certain other members of the tumor complement in this near-diploid ascites tumor cell line.

Mouse ascites tumors are generally characterized by the presence of one or more marker chromosomes. Mar-A, the chromosome hallmark of Ehrlich-Lettré mouse tumors has been characterized differently by different investigators since the time of its first description by Bayreuther in the early 1950s. Our critical analysis of band profiles of mar-A showed that this marker is actually a dicentric (dic) chromosome with asynchrony in centromere separation at the time of mitotic anaphase.

We have synthesized a new photoreactive vinblastine derivative, 3-[[[2-amino(4-azido-2-nitrophenyl)ethyl]amino] carbonyl]-O4-deacetyl-3-de-(methoxycarbonyl)-vincaleukoblastine (NAPAVIN), which absorbs light at around 450 nm. We report here its effects in vitro on multidrug-resistant mouse HD33 Ehrlich-Lettré ascites cells, on Chinese hamster ovary CHRC5S3 cells, on the corresponding drug-sensitive cells, on chemosensitive rat TMA1 mammary carcinoma, and on human SW48 colon carcinoma cells. Cells were incubated with the drug prior to activation by laser light at 457 nm. In Vinca alkaloid-sensitive cells, the short-term effects (30 to 72 h after treatment) of NAPAVIN with and without irradiation on cell proliferation are comparable to those of vinblastine. In drug-resistant cells, NAPAVIN without irradiation reduces the 50% inhibitory concentration 2- to 9-fold, compared with vinblastine. Upon irradiation with an argon laser at 457 nm, the concentration causing 50% inhibition of cell proliferation is further decreased to a total of 9- to 33-fold. Long-term effects (up to 6 wk after treatment) are seen in both sensitive and resistant cells. A single dose of the photoactivated drug causes a 6- to 9-fold larger delay (5 wk) in proliferation, compared with an equal dose of vinblastine.

Mutant cells of the HD33 subline of the Ehrlich-Lettré ascites tumor synthesize and store glycogen mainly intranuclearly, when growing in vivo, and exclusively in the cytoplasm, when permanently cultivated as a suspension cell strain. To investigate whether there exist differences between glycogen of nuclear and cytoplasmic origin, the ultrastructure and the biophysical and biochemical properties of glycogen from in vivo and in vitro grown HD33 ascites cells were compared. Pronounced heterogeneity and differences in glycogen particle ultrastructure were evident in situ and after isolation of the native, high-molecular polysaccharide. Nuclear glycogen contains a fraction of heavier molecules (up to 2 X 10(9)) and larger particles (up to 340 nm) which could not be found in the cytoplasmic preparations, which contained only particles smaller than 140 nm. The subparticles of beta-type are similar in both nuclear and cytoplasmic glycogen. The absorption spectra and glucose analysis after degradation with phosphorylase and debranching enzyme indicate that nuclear glycogen has a higher degree of branching, associated with a decrease in the average chain length between the branching points, and shorter external polyglucosidic chains than cytoplasmic glycogen. This is the first report about the analysis and properties of isolated nuclear glycogen.

According to Oron et al. [FEBS Lett. (1980) 118, 255-258], nuclear glycogen synthase represents an artifact of preparation in rat liver nuclei. We investigated the nuclei isolated from in vitro growing HD33 ascites cells with exclusively cytoplasmic, and from in vivo growing HD33 Ehrlich-Lettré ascites tumor cells with mainly intranuclear, glycogen deposition. Biochemical and ultracytochemical analyses revealed the complete absence of any contamination of the isolated nuclei by cytoplasmic glycogen particles and associated glycogen synthase activity. The glycogen synthase residing in isolated nuclei of in vivo growing HD33 ascites tumor cells represents a truly nuclear enzyme activity.