bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metastasis of benign tumor cells in tuberous sclerosis complex
Authors: Henske Elizabeth Petri 
Published: October 2003

AbstractLymphangiomyomatosis (LAM) is a life‐threatening lung disease affecting almost exclusively young women. Histologically, LAM is characterized by the diffuse, bilateral proliferation of abnormal smooth muscle cells and cystic degeneration of the lung parenchyma. LAM can occur as an isolated disorder (sporadic LAM), or in women with tuberous sclerosis complex (TSC‐LAM). Patients with both sporadic LAM and TSC‐LAM often have benign renal angiomyolipomas. The smooth muscle cells within the angiomyolipomas are very similar to the smooth muscle cells in pulmonary LAM. Genetic data suggest that pulmonary LAM is the result of a highly unusual disease mechanism: the metastasis of benign cells. If LAM is the result of metastasis, it is remarkable that the metastasis occurs in women, but not in men. In this review, I discuss the genetic data supporting this metastatic model for LAM. The implications of the model for the functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, will also be considered. Hamartin and tuberin may play functional roles in the suppression of cell migration and/or metastasis, possibly through their regulation of the small GTPase Rho. © 2003 Wiley‐Liss, Inc.
Uterine leiomyoma in the Eker rat: A unique model for important diseases of women
Authors: Walker Cheryl Lyn , Hunter Deborah , Everitt Jeffery I. 
Published: October 2003

AbstractEker rats carry a defect in the Tsc‐2 tumor suppressor gene and female Eker rats develop uterine leiomyoma with a high frequency. The presentation, response to hormones and molecular alterations in these mesenchymal smooth muscle tumors, closely resembles their cognate human disease. Female rats and tumor‐derived cell lines from Eker rat leiomyomas (ELT lines) have been developed as an in vivo/in vitro model system for preclinical studies to identify novel therapeutic agents for this disease and for studying disease pathogenesis. In addition to serving as a model for uterine leiomyoma, Eker rats have proven valuable for studying lymphangioleiomyomatosis, a related proliferative smooth muscle disease of women. © 2003 Wiley‐Liss, Inc.
Long‐term synaptic depression in the adult entorhinal cortex in vivo
Authors: Bouras Raby , Chapman C. Andrew 
Published: October 2003

AbstractThe piriform cortex provides a major input to the entorhinal cortex. Mechanisms of long‐term depression (LTD) of synaptic transmission in this pathway may affect olfactory and mnemonic processing. We have investigated stimulation parameters for the induction of homosynaptic LTD and depotentiation in this pathway using evoked synaptic field potential recordings in the awake rat. In this study, 15 min of 1‐Hz stimulation induced a transient (<5 min) depression of evoked responses but did not induce LTD or depotentiation. To determine whether inhibitory and/or facilitatory mechanisms contribute to LTD induction, repetitive delivery of pairs of stimulation pulses was also assessed. Repetitive paired‐pulse stimulation with a 10‐ms interval between pulses, which activates inhibitory mechanisms during the second response, did not reliably induce LTD. However, repetitive paired‐pulse stimulation using a 30‐ms interval, which evokes marked paired‐pulse facilitation, resulted in synaptic depression that lasted ≥1 day, and which was reversible by tetanization. The selective induction of LTD by stimulation that evokes paired‐pulse facilitation suggests that strong synaptic activation is required for LTD induction. The N‐methyl‐D‐aspartate (NMDA) receptor antagonist MK‐801 (0.1 mg/kg) blocked the induction of LTD, indicating that NMDA receptor activation is required for LTD induction in this pathway. These results indicate that LTD in piriform cortex inputs to the entorhinal cortex in the awake rat is effectively induced by strong repetitive synaptic stimulation, and that this form of LTD is dependent on activation of NMDA receptors. © 2003 Wiley‐Liss, Inc.
Age‐dependent alterations of long‐term synaptic plasticity in thyroid‐deficient rats
Authors: Vara H. , Muñoz‐Cuevas J. , Colino A. 
Published: October 2003

AbstractThyroid hormone deficiency during a critical period of development profoundly affects cognitive functions such as attention, learning, and memory, but the synaptic alterations underlying these deficits remain unexplored. The present study examines the effect of congenital hypothyroidism on long‐term synaptic plasticity. This plasticity is believed to be essential for learning and memory and for activity‐dependent regulation of synapse formation in the developing brain. We found that the neonatal expression of long‐term potentiation (LTP), long‐term depression (LTD), depotentiation, and de‐depression in hippocampal slices from hypothyroid animals was similar to that of controls. To examine the postnatal development of these plasticities, we used slices from neonatal (2–3 weeks) and adult (7–8 weeks) rats. This work demonstrates that the ability to express all these forms of synaptic plasticity is reduced in an age‐dependent manner in control rats. LTP and depotentiation are also downregulated in adult hypothyroid rats, but we have found that de‐depression is not affected during maturation. In addition, these animals express LTD at ages at which controls fail to induce it. In contrast, input/output experiments have shown greater levels of basal synaptic efficacy in hypothyroid adults, and this effect is probably related to the higher probability of release observed by paired‐pulse experiments. Nevertheless, these effects appear to be unrelated to the differences observed in long‐term synaptic plasticity, as no correlation was found between basal synaptic efficacy and the degree of LTD and de‐depression. Furthermore, the NMDA‐receptor antagonist amino‐phosphonopentanoic acid (APV) completely blocked LTD, which suggests a postsynaptic locus of this alteration. Because LTD has been associated with novelty acquisition, we suggest that the greater LTD observed in adult hypothyroid rats might be related to the hyperactivity of these animals. However, other possibilities such as a retarded maturation of synaptic plasticity must be taken into account. © 2003 Wiley‐Liss, Inc.
Hippocampal spreading depression bilaterally activates the caudal trigeminal nucleus in rodents
Authors: Kunkler Phillip E. , Kraig Richard P. 
Published: October 2003

AbstractSpreading depression (SD) and migraine aura involve transiently altered (i.e., increased followed by decreased) electrophysiological activity that propagates at the distinctive rate of millimeters per minute (mm/min), leading to the suggestion that they (and perhaps pain from migraine) are causally related via changes in the same brain structure. Neocortex is considered the anatomical zone associated with migraine aura and is the sole area known to induce caudal trigeminal nucleus (TNC) activation from SD in rodents. However, classical evidence of SD in human neocortex is reported only with severe brain disease, while migraine is a common and comparatively benign disorder. Because SD occurs in human hippocampus, and memory dysfunction referable to hippocampus is seen in migraineurs, we determined whether recurrent SD confined to hippocampus in rat could induce TNC activation. Our work shows that recurrent hippocampal SD evoked a significant (P < 0.05–0.001) increase in bilateral c‐fos immunostaining within TNC superficial laminae compared with sham controls. Furthermore, hippocampal SD occurred with a correlated and transient change in spontaneous activity and blood flow in the ipsilateral neocortex without spread of SD to that area. Thus, hippocampal SD may be a previously unrecognized, potential trigger for nociceptive activation of TNC perhaps associated with migraine. © 2003 Wiley‐Liss, Inc.
Orthotopic treatment model of prostate cancer and metastasis in the immunocompetent mouse: Efficacy of flt3 ligand immunotherapy
Authors: Somers Kenneth D. , Brown Roy R. , Holterman Daniel A. , Yousefieh Nazita , Glass William F. , Wright George L. , Schellhammer Paul F. , Qian Jesse , Ciavarra Richard P. 
Published: October 2003

AbstractWe established an orthotopic treatment model of prostate cancer to generate reproducible primary and metastatic carcinoma in immunocompetent C57BL/6 mice. Using an in vivo selection scheme of intraprostatic implantation of TRAMP‐C1 cells, primary prostate tumors were cultured and recycled three times by intraprostatic injection resulting in the selection and establishment of the recycled cell line TRAMP‐C1P3. Prostate tumors were detected ∼30 days post‐implantation with periaortic lymph node metastasis in 19/20 (95%) of mice. Tissue culture amplification, DNA ploidy and PCR amplification of the SV40 transgene were used to detect metastatic TRAMP‐C1P3 in lymph node specimens. Tissue culture amplification and DNA ploidy were as sensitive as SV40 transgene amplification by PCR in detection of early metastatic disease in draining lymph nodes. To establish the use of the orthotopic model of prostate cancer for immunotherapy, mice were injected orthotopically with TRAMP‐C1P3 cells and 7 days post‐implantation treated daily for 28 days with either flt3L or carrier control. Carrier‐treated mice had clinically detectable prostate tumors, lymph node metastasis and were moribund at 29–35 days, whereas flt3L therapy markedly suppressed primary TRAMP‐C1P3 growth and lymph node metastasis, and prolonged survival. In summary, we have established a reproducible and clinically relevant orthotopic treatment model of prostate cancer in immunocompetent mice with application to a variety of therapeutic strategies. We demonstrate that flt3L treatment suppressed orthotopic prostate tumor growth and lymph node metastasis reinforcing a role for flt3L as an immunotherapeutic strategy for prostate cancer. © 2003 Wiley‐Liss, Inc.
Reporter gene assay demonstrates functional differences in estrogen receptor activity in purified breast cancer cells: A pilot study
Authors: Singh Anjana , Ali Simak , Kothari Manish S. , De Bella Manuela Tamburo , Smith Clive , Timms Emma , Slade Martin J. , Foxwell Brian M. , Coombes R. Charles 
Published: October 2003

AbstractTamoxifen has contributed to a dramatic reduction in breast cancer mortality and recent results indicate that aromatase inhibitors may further improve survival in some patients. Nevertheless, a substantial proportion of patients become resistant to treatment. To date, with the exception of estrogen receptor (ER) determination by ligand binding or immunohistochemical techniques, there has been no way of predicting which of several therapies is indicated in particular patients. We describe a novel assay using the adenoviral gene delivery system to assess ER function in breast cancer cells derived directly from patients. The purification and short‐term culture of these cells has been recently described by our laboratory. Adenovirus containing an estrogen‐regulated β‐galactosidase reporter gene (ERE‐lacZ) was constructed and used to test ER activity in breast cancer cells derived from 18 patients with primary and 16 patients with metastatic cancer, under varying treatment schedules. The adenoviral assay enabled ER activity to be readily determined in purified cells from primary breast cancers and secondary sites. Breast cancers cells could be categorized on the basis of ER activity in the absence of ligand, the presence of estrogen or anti‐estrogens. In primary breast cancers, our results correlated with ER determination by immunohistochemistry in 78% of cases. In patients who had become resistant to tamoxifen, however, we found some in whom reporter activity was stimulated by tamoxifen and others whose tumors were either still estrogen responsive or completely unresponsive, irrespective of the original ER content. Our findings indicate that this reporter assay could be useful in decisions regarding use of adjuvant endocrine therapies in breast cancer. © 2003 Wiley‐Liss, Inc.
Condom use promotes regression of human papillomavirus–associated penile lesions in male sexual partners of women with cervical intraepithelial neoplasia
Authors: Bleeker Maaike C.G. , Hogewoning Cornelis J.A. , Voorhorst Feja J. , van den Brule Adriaan J.C. , Snijders Peter J.F. , Starink Theo M. , Berkhof Johannes , Meijer Chris J.L.M. 
Published: October 2003

AbstractPenile HPV‐associated lesions are frequently seen in male sexual partners of women with CIN. The natural course and clinical significance of these lesions are unclear. Women with CIN and their male sexual partners were randomized for condom use (condom group n = 68, noncondom group n = 68). Males were screened for the presence of penile lesions, i.e., flat lesions, papular lesions and condylomata acuminata, and of HPV in their penile swabs by PCR testing. Median follow‐up time was 13.1 months (range 2.9–57.4). The outcome of our study was clinical regression of penile lesions defined as disappearance of lesions at penoscopy. Potentially prognostic factors, i.e., HPV status, lesion type and age, were studied as well. Outcomes were assessed in 57 men of the condom group and in 43 men of the noncondom group. Condom use shortened the median time to regression of flat penile lesions (7.4 months condom group vs. 13.9 months noncondom group; HR = 2.1, 95% CI 1.2–3.7). This effect was not found for papular lesions (HR = 0.5, 95% CI 0.1–2.8). HPV‐negative men showed a significantly shorter median time to regression of flat lesions (3.8 months) compared to men with either HPV‐positive status (8.5 months; HR = 0.4, 95% CI 0.2–0.9) or inconsistent HPV status (13.1 months; HR = 0.2, 95% CI 0.1–0.6). Regression of flat penile lesions is HPV‐dependent and accelerated by condom use. This effect is probably the result of blocking viral transmission between sexual partners. © 2003 Wiley‐Liss, Inc.
Hyaluronan synthase‐3 is upregulated in metastatic colon carcinoma cells and manipulation of expression alters matrix retention and cellular growth
Authors: Bullard Kelli M. , Kim Hyeong‐Rok , Wheeler Marie A. , Wilson Christopher M. , Neudauer Cheryl L. , Simpson Melanie A. , McCarthy James B. 
Published: October 2003

AbstractHA is a glycosaminoglycan that is synthesized on the inner surface of the plasma membrane and secreted into the pericellular matrix. HA and its biosynthetic enzymes (HAS1, HAS2 and HAS3) are thought to participate in tumor growth and cancer progression. In our study, colon carcinoma cells isolated from a lymph node metastasis (SW620) produced more pericellular HA and expressed higher levels of HAS3 mRNA compared to cells isolated from a primary colon carcinoma (SW480). To assess functionality, HAS3 expression in SW620 cells was inhibited by transfection with an asHAS3 construct. Decreased HA secretion and cell‐surface retention by asHAS3 transfectants were confirmed using competitive binding and particle exclusion assays. Anchorage‐independent growth, a correlate of tumor growth in vivo, was assessed by colony formation in soft agar. SW620 cells stably transfected with asHAS3 demonstrated significant growth inhibition, as evidenced by fewer colonies and smaller colony area than either SW620 cells or cells transfected with vector alone. Addition of exogenous HA restored growth in asHAS3 transfectants. Thus, we demonstrate that pericellular HA secretion and retention and HAS3 expression are increased in metastatic colon carcinoma cells relative to cells derived from a primary tumor. Inhibition of HAS3 expression in these cells decreased the pericellular HA matrix and inhibited anchorage‐independent growth. These data suggest that HA and HAS3 function in the growth and progression of colon carcinoma. © 2003 Wiley‐Liss, Inc.
Single amino acid substitutions in the transmembrane domains of breast cancer resistance protein (BCRP) alter cross resistance patterns in transfectants
Authors: Miwa Miyu , Tsukahara Satomi , Ishikawa Etsuko , Asada Sakiyo , Imai Yasuo , Sugimoto Yoshikazu 
Published: October 2003

AbstractBreast cancer resistance protein (BCRP) is a member of ATP‐binding cassette transporters that has an N‐terminal ATP binding domain and a C‐terminal transmembrane domain (TM). Expression of wild‐type BCRP confers resistance to multiple chemotherapeutic agents such as mitoxantrone, SN‐38 and topotecan, but not to doxorubicin. We made 32 BCRP mutants with an amino acid substitution in the TMs (7 E446‐mutants in TM2, 15 R482‐mutants in TM3, 4 N557‐mutants in TM5 and 6 H630‐mutants in TM6) and examined the effect of the substitutions on cellular drug resistance. PA317 cells transfected with any one of the 7 E446‐mutant BCRP cDNAs did not show drug resistance. Cells transfected with any one of the 13 R482X2‐BCRP cDNAs (X2 = N, C, M, S, T, V, A, G, E, W, D, Q and H, but not Y and K) showed higher resistance to mitoxantrone and doxorubicin than the wild‐type BCRP‐transfected cells. Cells transfected with N557D‐BCRP cDNA showed similar resistance to mitoxantrone but lower resistance to SN‐38 than the wild‐type BCRP‐transfected cells. Cells transfected with N557E‐, H630E‐ or H630L‐BCRP cDNA showed similar degrees of resistance to mitoxantrone and SN‐38. Estrone and fumitremorgin C reversed the drug resistance of cells transfected with R482‐, N557‐ or H630‐mutant BCRP cDNA. Cells transfected with R482G‐ or R482S‐BCRP cDNA showed less intracellular accumulation of [3H]mitoxantrone than the wild‐type BCRP‐transfected cells. These results suggest that E446 in TM2, R482 in TM3, N557 in TM5 and H630 in TM6 play important roles in drug recognition of BCRP. © 2003 Wiley‐Liss, Inc.
Tumor reversion: Correction of malignant behavior by microenvironmental cues
Authors: Kenny Paraic A. , Bissell Mina J. 
Published: October 2003

AbstractCancer is characterized by unrestrained proliferation and loss of organization, a process that is intimately linked to, and controlled by, reciprocal signaling between the genetically altered tumor epithelium, the stroma, the components of the basement membrane and inflammatory mediators. Much work has been done to characterize the genetics of cancer cells. In this review, we describe the experiments that have been performed, which point to the significant role of the tissue microenvironment in the developmental regulation of normal and neoplastic cells. Using a variety of model systems, the works of a number of laboratories have converged on a hypothesis where the correction of 1 or 2 signaling defects can revert tumor cells to a normal phenotype, both in vivo and in culture, even when the tumor cells possess multiple genetic and epigenetic lesions. This paradigm has been successfully used to treat acute promyelocytic leukemia, and it remains the task of biomedical researchers to identify additional targets for the reversion of other human malignancies. © 2003 Wiley‐Liss, Inc.
The effect of nitric oxide on cyclooxygenase‐2 (COX‐2) overexpression in head and neck cancer cell lines
Authors: Park Seok‐Woo , Lee Sang‐Goo , Song Sang‐Hyun , Heo Dae‐Seog , Park Bum‐Jung , Lee Dong‐Wook , Kim Kwang‐Hyun , Sung Myung‐Whun 
Published: October 2003

AbstractThe overexpression of cyclooxygenase‐2 (COX‐2) and inducible nitric oxide synthase (iNOS) has been previously reported in head and neck squamous cell carcinoma (HNSCC), as well as in many cancers. We hypothesized that endogenous nitric oxide (NO) might increase the expression of COX‐2 in cancer cells. Therefore, we investigated the cross‐talk between NO and the prostaglandin (PG) pathways in HNSCC cell lines. We found that COX‐2 and iNOS expressions were elevated simultaneously. On adding the NO donor, SNAP, the PGE2 level was increased 2–20 times due to increased COX‐2 expression. This increase of COX‐2 expression by SNAP or PMA (potent inducer of both iNOS and COX‐2) was blocked to various degrees by NO scavengers and NOS inhibitors (L‐NAME and 1400W). Also, the expression of COX‐2 in resting cells was inhibited by NOS inhibitors. Moreover, COX‐2 expression, induced by SNAP, was inhibited by ODQ, a soluble guanylate cyclase (sGC) inhibitor. The effect of dibutyryl‐cGMP on COX‐2 expression was similar to that of SNAP. These results imply that endogenous or exogenous NO activates sGC and that the resulting increase of cGMP induces a signaling that upregulates the expression of COX‐2 in HNSCC cell lines. We also observed that NO increased COX‐2 expression in different cancer cell lines, including cervic and gastric cancer cell lines. These findings further support the notion that NO can be associated with carcinogenesis through the upregulation of COX‐2, and that NOS inhibitor may be also useful for cancer prevention. © 2003 Wiley‐Liss, Inc.
Piroxicam selectively inhibits the growth of premalignant and malignant human oral cell lines by limiting their progression through the S phase and reducing the levels of cyclins and AP‐1
Authors: Ding Haiming , Han Chunhua , Gibson‐D′Ambrosio Ruth , Steele Vernon E. , D′Ambrosio Steven M. 
Published: October 2003

AbstractStudies have shown that nonsteroidal antiinflammatory drugs (NSAIDs) reduce the risk of and mortality from a variety of cancers. Although cyclooxygenase (COX)‐dependent and ‐independent pathways may be involved, the mechanisms responsible for these effects remain unknown. In our study, we found that piroxicam inhibited cell growth in premalignant and malignant, but not normal, human oral epithelial cell lines in a concentration‐ and time‐dependent manner. After 6 days of exposure, the concentration that inhibited growth by 50% was 181 and 211 μM for premalignant and malignant cells, respectively. Piroxicam did not induce apoptosis. The growth inhibitory effect was COX and PGE2 independent. Adding PGE2 or infecting cells with a COX‐1 transgene did not abrogate piroxicam‐induced growth inhibition. After treatment of the premalignant and malignant cell lines with piroxicam, cells accumulated in the S phase of the cell cycle. Upon removal of piroxicam, cells entered the G2 phase. The S phase block was accompanied by a reduction in the protein levels of cyclin A, cyclin B1, cyclin D1, cdc2, PCNA and the c‐jun AP‐1 component. Therefore, piroxicam may exert its growth inhibitory effects selectively on the premalignant and malignant human oral epithelial cells lines via signaling pathways regulating the progression of cells through the S phase of the cell cycle. © 2003 Wiley‐Liss, Inc.
Adhesive protein interactions with chitosan: Consequences for valve endothelial cell growth on tissue‐engineering materials
Authors: Cuy Janet L. , Beckstead Benjamin L. , Brown Chad D. , Hoffman Allan S. , Giachelli Cecilia M. 
Published: October 2003

AbstractStable endothelialization of a tissue‐engineered heart valve is essential for proper valve function, although adhesive characteristics of the native valve endothelial cell (VEC) have rarely been explored. This research evaluated VEC adhesive qualities and attempted to enhance VEC growth on the biopolymer chitosan, a novel tissue‐engineering scaffold material with promising biological and chemical properties. Aortic VEC cultures were isolated and found to preferentially adhere to fibronectin, collagen types IV and I over laminin and osteopontin in a dose‐dependent manner. Seeding of VEC onto comparison substrates revealed VEC growth and morphology to be preferential in the order: tissue culture polystyrene > gelatin, poly(DL‐lactide‐co‐glycolide), chitosan > poly(hydroxy alkanoate). Adhesive protein precoating of chitosan did not significantly enhance VEC growth, despite equivalent protein adsorption as to polystyrene. Initial cell adhesion to protein‐precoated chitosan, however, was higher than for polystyrene. Composite chitosan/collagen type IV films were investigated as an alternative to simple protein precoatings, and were shown to improve VEC growth and morphology over chitosan alone. These findings suggest potential manipulation of chitosan properties to improve amenability to valve tissue‐engineering applications. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 67A: 538–547, 2003