bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Monocarboxylate Transporter 8 Linked to Human Psychomotor Retardation Is Highly Expressed in Thyroid Hormone-Sensitive Neuron Populations
Authors: Heuer Heike , Maier Michael K. , Iden Sandra , Mittag Jens , Friesema Edith C. H. , Visser Theo J. , Bauer Karl 
Published: January 2005

Abstract
Recent genetic analysis in several patients presenting a severe form of X-linked psychomotor retardation combined with abnormal thyroid hormone (TH) levels have revealed mutations or deletions in the gene of the monocarboxylate transporter 8 (MCT8). Because in vitro MCT8 functions as a TH transporter, the complex clinical picture of these patients indicated an important role for MCT8 in TH-dependent processes of brain development. To provide a clue to the cellular function of MCT8 in brain, we studied the expression of MCT8 mRNA in the murine central nervous system by in situ hybridization histochemistry. In addition to the choroid plexus structures, the highest transcript levels were found in neo- and allocortical regions (e.g. olfactory bulb, cerebral cortex, hippocampus, and amygdala), moderate signal intensities in striatum and cerebellum, and low levels in a few neuroendocrine nuclei. Colocalization studies revealed that MCT8 is predominantly expressed in neurons. Together with the spatiotemporal expression pattern of MCT8 during the perinatal period, these results strongly indicate that MCT8 plays an important role for proper central nervous system development by transporting TH into neurons as its main target cells.
Kainate/Estrogen Receptor Involvement in Rapid Estradiol Effects in Vitro and Intracellular Signaling Pathways
Authors: Matagne V. , Lebrethon M.-C. , Gérard A. , Bourguignon J.-P. 
Published: January 2005

Abstract
Although the interactions between sex steroids and GnRH have been extensively studied, little is known about the mechanism of estradiol (E2) effects on GnRH secretion. In the present study, we used retrochiasmatic hypothalamic explants of 50-d-old male rats, and we observed that E2 significantly increased the glutamate-evoked GnRH secretion in vitro within 15 min in a dose-dependent manner. E2 also significantly increased the l-arginine-evoked GnRH secretion. E2 effects were time dependent because the initially ineffective 10−9m concentration became effective after 5 h of incubation. The E2 effects involved the estrogen receptor (ER) α because they were similarly obtained with the specific ERα agonist 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole. The use of glutamate receptor agonists and antagonists indicated that E2 effects on GnRH secretion evoked by both glutamate and l-arginine involved the 2-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid/kainate receptors. Similar E2 effects on the kainate-evoked secretion were observed throughout development in both sexes. The observation of similar E2 effects using explants containing the median eminence alone indicated that the median eminence was a direct target for E2 rapid effects on the glutamate-evoked GnRH secretion. The signaling pathways involved in E2 effects included an increase in intracellular calcium and the activation of protein kinase A, protein kinase C, and MAPK. It is concluded that E2 can stimulate the glutamate- and nitric oxide-evoked GnRH secretion in vitro through a rapid pathway involving the ER and kainate receptor as well as through a slower mechanism responding to lower E2 concentrations.
Novel Gender-Related Regulation of CYP2C12 Gene Expression in Rats
Authors: Endo Megumi , Takahashi Yoshiki , Sasaki Yasumasa , Saito Tetsuya , Kamataki Tetsuya 
Published: January 2005

AbstractThe expression of CYP2C12 by GH occurs in female but not in male rat livers. Direct injection of the CYP2C12 promoter-luciferase gene into male rat livers showed that the CYP2C12 promoter was active in both male and female rats. Thus, to further examine one or more factors that regulate the gender-related expression of CYP2C12, male rats were treated with trichostatin A, a specific inhibitor of histone deacetylase capable of condensing the chromatin structure. Interestingly, the expression of CYP2C12 by GH was seen even in the livers of male rats, indicating that histone deacetylase contributes to the suppression of CYP2C12 expression in male rats. Deoxyribonuclease I hypersensitive assay using nuclei from the livers of male or female rats revealed that the chromatin structure of the CYP2C12 gene was gender specific: a hypersensitive site at a position −4.2 kb containing GH-responsive element that bound to signal transducer and activator of transcription 5 (STAT5), termed as HS (hypersensitive site) 1, was specific for female rat livers, whereas a hypersensitive site at a position −3 kb, designated as HSm (male-specific hypersensitive site), was characteristic of male rat livers. A −3425/−3275 region within HSm functioned as a negative regulatory region, when the region was inserted in front of simian virus 40 promoter. Gel shift assay demonstrated that both CCAAT/enhancer-binding protein α and β bound to the −3425/−3275 region. Based on these results, we conclude that the gender-related expression of the CYP2C12 gene results from the inaccessibility of to STAT5 to the GH-responsive element by chromatin condensation seen in male rat livers, and from the presence of the male-specific HSm that acts as a silencer.
Hypothalamic Growth Hormone-Releasing Hormone (GHRH) Deficiency: Targeted Ablation of GHRH Neurons in Mice Using a Viral Ion Channel Transgene
Authors: Le Tissier Paul R. , Carmignac Danielle F. , Lilley Sarah , Sesay Abdul K. , Phelps Carol J. , Houston Pamela , Mathers Kathleen , Magoulas Charalambos , Ogden David , Robinson Iain C. A. F. 
Published: January 2005

Abstract
Animal and clinical models of GHRH excess suggest that GHRH provides an important trophic drive to pituitary somatotrophs. We have adopted a novel approach to silence or ablate GHRH neurons, using a modified H37A variant of the influenza virus M2 protein (H37AM2). In mammalian cells, H37AM2 forms a high conductance monovalent cation channel that can be blocked by the antiviral drug rimantadine. Transgenic mice with H37AM2 expression targeted to GHRH neurons developed postweaning dwarfism with hypothalamic GHRH transcripts detectable by RT-PCR but not by in situ hybridization and immunocytochemistry, suggesting that expression of H37AM2 had silenced or ablated virtually all the GHRH cells. GHRH-M2 mice showed marked anterior pituitary hypoplasia with GH deficiency, although GH cells were still present. GHRH-M2 mice were also deficient in prolactin but not TSH. Acute iv injections of GHRH in GHRH-M2 mice elicited a significant GH response, whereas injections of GHRP-6 did not. Twice daily injections of GHRH (100 μg/d) for 7 d in GHRH-M2 mice doubled their pituitary GH but not PRL contents. Rimantadine treatment failed to restore growth or pituitary GH contents. Our results show the importance of GHRH neurons for GH and prolactin production and normal growth.
The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours
Authors: Gleeson H K , Shalet S M 
Published: January 2005

Survival rates are improving following cancer therapy for childhood brain tumours. There is therefore a growing cohort of survivors at risk of late effects of cancer therapy. Endocrine problems are very common in these patients. The recognition and prompt management of these are essential to prevent further morbidity and impairment of quality of life.
Cranial radiation can damage hypothalamic–pituitary function, most frequently affecting GH status; however, higher radiation doses may cause more widespread hypothalamic–pituitary damage. Early puberty secondary to cranial irradiation is now being managed with gonadotrophin-releasing hormone analogues to improve final height. Prompt diagnosis and management of GH deficiency may improve final height outcome; continued GH therapy beyond final height aids the achievement of adult body composition (lean body mass and bone mass) and GH therapy in adulthood improves quality of life. Both cranial irradiation alone and with spinal irradiation can result in radiation damage to the thyroid resulting in hypothyroidism and thyroid nodules, a high proportion of which are malignant. Gonadal damage secondary to spinal irradiation and adjuvant chemotherapy may have long-term consequences including infertility.
BRAF and endocrine tumors: mutations are frequent in papillary thyroid carcinomas, rare in endocrine tumors of the gastrointestinal tract and not detected in other endocrine tumors
Authors: Perren A , Schmid S , Locher T , Saremaslani P , Bonvin C , Heitz P U , Komminoth P 
Published: January 2005

The tumorigenesis of sporadic endocrine tumors is still not fully understood. Activating point mutations of the serine/threonine kinase gene BRAF located on 7q34 are found in a wide range of malignancies, with the highest frequency (66%) occurring in malignant melanomas. Melanomas are tumors of neural-crest-derived cells as are medullary thyroid carcinomas, pheochromocytomas and paragangliomas. BRAF has not been examined in endocrine tumors of the diffuse neuroendocrine system or of neural-crest-derived cells.
We examined 130 endocrine tumors of the pancreas, parathyroid gland, adrenal medulla, paraganglia, lung and gastrointestinal tract as well as follicular and c-cell-derived thyroid tumors. We found a high rate of V559E mutations in papillary thyroid carcinomas (47%), one V599E mutation in a well-differentiated gastric endocrine carcinoma (malignant carcinoid), but no activating BRAF mutations in all other endocrine tumors examined. These results point towards different pathways in tumorigenesis of endocrine tumors of various localizations and only rare involvement of the MAP kinase (MAPK) pathway in a subset of malignant neuroendocrine tumors.
Tamoxifen exerts agonistic effects on clusterin and complement C3 gene expression in RUCA-I primary xenografts and metastases but not normal uterus
Authors: Zierau Oliver , O’Sullivan Jacintha , Morrissey Colm , McDonald Dana , Wünsche Winfried , Schneider Martin R , Tenniswood Martin P , Vollmer Günter 
Published: January 2005

Tamoxifen is the most widely prescribed anti-neoplastic drug for the treatment of both localized and metastatic breast cancer. It is also the prototype for a class of drugs that are referred to as selective estrogen receptor modifiers (SERMs), most of which have both estrogenic and anti-estrogenic activity in estrogen target tissues including the breast and endometrium. The underlying mechanisms of action of SERMs in the breast and endometrium that lead to profound differences in the tissue-specific effects of tamoxifen have not yet been elucidated.
We have compared the effects of tamoxifen and the pure anti-estrogen ICI 182,780 (Faslodex) in the RUCA-I hormone-responsive rat endometrial cell line in vitro and in vivo. In cell culture, RUCA-I cells responded to both estrogens and anti-estrogens, and the expression of clusterin and complement C3 mRNAs required the presence of estradiol and was repressed in the absence of estradiol or in the presence of the pure anti-estrogen ICI 182,780. Tamoxifen, on the other hand, induced both complement C3 and clusterin mRNA in the absence of estradiol and failed to repress their expression in the presence of estradiol. When grown as subcutaneous xenografts in syngeneic Da/Han rats for 5 weeks, the RUCA-I cells retained their sensitivity to estradiol, as demonstrated by significantly enhanced tumor growth in intact female rats compared with the growth in ovariectomized rats. But neither ICI 182,780 nor tamoxifen had a significant impact on tumor growth in cycling or ovariectomized animals. On the other hand, tamoxifen was potently estrogenic in metastatic lymph nodes, increasing the size of the lymph node tumors almost 6-fold over that seen in the intact cycling animals. In primary tumors, the expression of complement C3 mirrored that seen in vitro, although tamoxifen showed some agonist activity in ovariectomized animals. Tamoxifen also displayed marked agonist activity with respect to clusterin expression and enhanced clusterin mRNA levels and protein in both the primary tumors and lymph metastases in intact and ovariectomized animals.
Given the recent demonstration that over-expression of clusterin increases the metastatic potential of breast cancer cells, these data may provide a mechanistic explanation for the increased incidence of endometrial cancer in postmenopausal patients treated with tamoxifen.
Progesterone receptor A and B expression and progestagen treatment in growth and spread of endometrial cancer cells in nude mice
Authors: Hanekamp Eline E , Kühne Liesbeth M , Grootegoed J Anton , Burger Curt W , Blok Leen J 
Published: January 2005

In endometrial cancer, decreased expression of progesterone receptor (PR) isotypes A and B (PRA and PRB) is a feature of poorly differentiated tumours. In distant metastases, PRB is the predominantly expressed isotype and endometrial cancer cells that express PRB have been observed to be more invasive. Furthermore, PRB-associated in vitro invasion is markedly inhibited by progestagens.
In the present study, ovariectomized mice were injected intraperitoneally with Ishikawa endometrial cancer cells that express only PRA, only PRB, both PRA and PRB, or no PR. Half of the mice were substituted with medroxyprogesterone acetate (MPA). After ten weeks, growth and spread of the cancer cells were examined macroscopically, microscopically, and by PCR detection. Without MPA substitution, cells that express only PRB were found to be the most proliferative and migrative, while cells that express only PRA, both receptor isotypes, or no PR, showed minimal growth and spread. MPA appeared to inhibit growth and spread of PR-positive cells. Surprisingly, when mice that were inoculated with PR-negative cells were substituted with MPA, this resulted in massive abdominal tumour growth.
These results provide further evidence that over-expression of PRB in endometrial cancer contributes to the development of a more aggressive phenotype. MPA inhibits tumour growth and spread of PR-positive cells, but can also have an indirectly stimulating effect on PR-negative tumour cells, probably through a host-mediated response.
The TRPS1 transcription factor: androgenic regulation in prostate cancer and high expression in breast cancer
Authors: Chang Glenn T G , Jhamai Mila , van Weerden Wytske M , Jenster Guido , Brinkmann Albert O 
Published: January 2005

TRPS1 mRNA is more highly expressed in androgen-dependent lymph node carcinoma of prostate-fast growing colony (LNCaP-FGC) compared with androgen-independent lymph node carcinoma of prostate-lymph node original (LNCaP-LNO) prostate cancer cell lines. Furthermore, TRPS1 mRNA expression is down-regulated by androgens in LNCaP-FGC cells, a process mediated by the androgen receptor (AR). Here, we present TRPS1 protein expression in human prostate cancer material derived from a panel of six androgen-dependent and eight androgen-independent human prostate cancer xenografts. TRPS1 protein is expressed in all androgen-dependent xenografts, which also express AR and prostate-specific antigen (PSA). Androgen withdrawal by castration resulted in an increase in TRPS1 protein in two androgen-dependent xenografts, indicating relieved repression by action of AR. TRPS1 protein is expressed in four androgen-independent xenografts and is low or absent in the other four androgen-independent xenografts. Androgen withdrawal by castration demonstrates that TRPS1 protein levels remain the same in 1 androgen-independent xenograft, most likely due to the lack of AR expression. These data show that TRPS1 protein expression is regulated by androgens via the AR in human prostate cancer xenografts.
Analysis of TRPS1 mRNA expression in normal and tumour tissue of the prostate and 18 other human tissues, showed that TRPS1 had the highest mRNA expression levels in normal and tumour tissues of breast. In addition, high TRPS1 mRNA and protein expression levels were observed in four out of five human breast cancer cell lines.
In conclusion, TRPS1 protein expression is down-regulated by androgens in human prostate cancer, and analysis of TRPS1 mRNA expression levels in several human tissues showed that the highest levels were observed in normal and tumour breast tissue.
Homeobox gene repertoires: implications for the evolution of diversity
Authors: Kappen Claudia 
Published: January 2005

AbstractHomeobox genes are key regulators of morphogenetic processes in developing organisms, and are involved in the formation and differentiation of multiple tissues and cell types. The strong conservation of homeobox gene sequences indicates that many species share a common repertoire of homeobox genes. Experimental evidence provides support for conserved as well as divergent functions, raising the question how homeobox genes evolved in distinct species and in which way they contributed to the evolution of different morphologies. This article examines the composition of homeobox gene repertoires in diverse animals at the whole‐genome level, with the aim to understand the underlying mechanisms of evolution in this multigene family.
HumanXchromosome inactivation
Authors: Chang Samuel C. , Brown Carolyn J. 
Published: January 2005

AbstractEarly in a mammalian female's development, one of her two X chromosomes is silenced, thereby achieving dosage equivalence with the single X chromosome found in males. The process of inactivation is initiated by the untranslated XIST RNA that is expressed solely from the inactive X. Subsequent silencing involves the acquisition of many features of heterochromatin, including late DNA replication, DNA hypermethylation, and specific histone modifications. How the XIST RNA associates in cis with the chromosome from which it is expressed and mediates silencing of one X chromosome remains a focus for ongoing research. The inactive X is not completely refractive to transcription, as approximately 15% of human genes escape the silencing and continue to be expressed from both the active and inactive X chromosomes. The hemizygosity of the X chromosome in males means that X‐linked diseases are distinctively more common in males, and dosage imbalance of other genes may yield additional differences between the sexes.
Approach to common chronic disorders of adulthood
Authors: Scheuner Maren T. 
Published: January 2005

AbstractCommon chronic diseases such as coronary heart disease, stroke, diabetes, and cancer are due to the interaction of genetic and nongenetic risk factors. Recognizing genetic factors that contribute to common chronic diseases can help identify individuals with increased risk, especially at early ages of onset. Understanding genetic susceptibilities for common chronic diseases can also help determine which diseases might develop in an individual, given a particular exposure or behavior. Family history collection and interpretation is the most practical population‐based strategy for identifying individuals with a genetic susceptibility to many common chronic diseases. It represents complex interactions of genetic, environmental, cultural, and behavioral factors shared by family members. Family history characteristics that increase disease risk include early age at diagnosis, two or more close relatives affected with a disease or a related condition, a single family member with two or more related diagnoses, multifocal or bilateral disease, and occurrence of disease in the less‐often affected sex. By recognizing the magnitude of risk associated with these familial characteristics, stratification into different familial risk groups (e.g., low, medium, and high) is possible, which can guide risk‐specific recommendations for disease management and prevention. Clinical genetic evaluation should be considered for individuals with a high familial risk for common chronic diseases or when a Mendelian disorder is suspected. The process includes (1) genetic counseling and education, (2) risk assessment and diagnosis using personal and family medical history, physical examination, and genetic testing, and (3) risk‐appropriate recommendations for management and prevention.
Current approaches to molecular diagnosis
Authors: Mueller O. Thomas 
Published: January 2005

AbstractInherited human disorders are caused by different types of mutations, including large genomic rearrangements such as chromosomal translocations or duplications and deletions of genome regions that are visible, using standard or high‐resolution karyotyping procedures. Other rearrangements are smaller, but still encompass relatively large genome areas, such as the microdeletions that are readily detected using FISH technology. However, most disorders are caused by much smaller deletions, substitutions, or rearrangements of DNA that are identified by molecular genetic approaches. This review will summarize the current approaches to diagnostic techniques in a molecular genetic laboratory. A tabular listing of selected inherited syndromes identifies the genes and proteins associated with many syndromes, the types of mutations and common mutations, if any, detection methods, and their inheritance pattern. Special attention is given to disorders of complex etiology, such as those with a trinucleotide repeat expansion, which feature unusual inheritance patterns such as premutation alleles and genetic anticipation, and Prader–Willi and Angelman syndromes, which invoke genetic imprinting mechanisms.
Cardiovascular gene therapy
Authors: Bhardwaj Shalini , Roy Himadri , Ylä‐Herttuala Seppo 
Published: January 2005

Abstract
A variety of treatment modalities are presently available for the treatment of cardiovascular diseases either in the form of drug therapy or surgical intervention. A relatively new field of gene therapy for cardiovascular diseases is fast evolving. The diseases in focus are atherosclerosis, coronary and peripheral arterial diseases, coronary restenosis, and vein graft diseases. Promising results have been obtained in animal models of restenosis and vein graft thickening with transfer of genes encoding VEGF, nitric oxide synthatase, thymidine kinase, tissue inhibitors of metalloproteinases, and antisense oligonucleotides against transcription factors or cell cycle regulatory proteins. VEGF and FGF gene transfer have been successfully used in improving blood flow and development of collateral arteries in peripheral vascular disease and myocardial ischemic conditions. Here, we present a synopsis of the potential treatment genes, their therapeutic targets, mode of delivery, human clinical trials, and limitations encountered in the field of cardiovascular gene therapy.
Control of transgene expression in mammalian cells
Authors: Kramer Beat P. , Fussenegger Martin 
Published: January 2005

Abstract
Spacio‐temporal adjustment of therapeutic transgene expression represents a fundamental technology for modern gene therapy since it enables precise in vivo dosing of protein therapeutics to manage an optimal therapeutic range, adaptation to specific disease dynamics, or resetting of molecular interventions as appropriate. Heterologous transcription control systems capitalizing on (1) prokaryotic antibiotic response regulons evolved to manage bacterial adaptation to macrolide, streptogramin, and tetracycline antibiotics, (2) (modified) hormone receptors specific for estradiol, progesterone, or ecdysone derivatives, or (3) chemically induced dimerization of protein domains prevailed in animal studies, and are currently considered for clinical trials. Since sustained administration of clinically licensed, small‐molecule drugs for transgene expression fine‐tuning may result in side effects, systems responsive to nucleic acids or physical parameters including light, temperature, and electromagnetic fields are in preclinical development.