bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain Stem Glioma: Two Case Studies
Authors: Rosenblum Ruth K.
Published: February 2005

The paths taken by each family in coming to terms with the dismal prognosis associated with brain stem glioma can be quite different. The case studies of 2 school-age girls diagnosed with a brain stem glioma within weeks of each other are presented. The multi-disciplinary team response to each family was individualized at each stage of diagnosis, treatment, and end-of-life care, as expected. The ultimate chronologic union of these 2 families as each child neared death was somewhat uncanny. The experience of each family, and their relationship with the team through this process, was an intense challenge and learning experience.
The Effects of Camp on Health-Related Quality of Life in Children With Chronic Illnesses: A Review of the Literature
Authors: Epstein Iris , Stinson Jennifer , Stevens Bonnie
Published: February 2005

Chronic illness in children may negatively affect aspects of health-related quality of life (HRQL). Over many years, camps have been organized to address the physical and psychosocial needs of children with various chronic illnesses, while providing a “normal” as possible camp experience. The aim of this study was to critically review all research examining the effect of camps on HRQL in children with chronic illnesses. The literature review yielded no randomized, controlled clinical trials; 8 pretest-posttest study designs with repeated measures; 9 pre-post studies; and 1 survey design. A total of 1270 children, ranging in age from 6 to 25 years, participated in the studies.
Long-term Breast Cancer Survivors’ Use of Complementary Therapies: Perceived Impact on Recovery and Prevention of Recurrence
Authors: Hann Danette , Baker Frank , Denniston Maxine , Entrekin Nina
Published: February 2005

Objective:Many cancer survivors use some form of complementary therapy (CT); this is particularly true for women with breast cancer. The majority of reports on CT use in women with breast cancer have focused on CT use during cancer treatment or within a year or two of treatment completion. The purpose of this study was to evaluate longertermbreast cancer survivors’ (average, 8.7 years) frequency of CT use and their beliefs about the role of CT in cancer recovery and the prevention of cancer recurrence, as well as the relationship of CT use with current life satisfaction. Methods: A mail survey was completed by 608 breast cancer survivors a minimum of 2 years after their most recent cancer diagnosis. Participants were contacted through the American Cancer Society Reach to Recovery program in Florida. The self-report questionnaire inquired about the use of various CTs, beliefs about CT, current life satisfaction, demographic characteristics, and cancer treatment history. Results: Most of the respondents were older than 50, were Caucasian, were married, had attended or completed college, and were at least 5 years after breast cancer treatment. The most commonly used CTs included exercise, vitamins, prayer/spiritual practice, support groups, humor, self-help books, and relaxation. These survivors used CT therapies because they wanted to play a more active role in their cancer recovery, to manage stress, and to maintain hope. A majority of them reported that they used CT to reduce the risk of cancer recurrence. Use of CT was not correlated with life satisfaction. Conclusions: Most of the breast cancer survivors in this study had used some form of CT since the time of their most recent cancer diagnosis and believed that such therapies could be of significant benefit, despite a lack of correlation between CT use and current life satisfaction. Many believed that use of CT may prevent cancer recurrence. It is important, therefore, to investigate the efficacy of variousCTs among longer-termcancer survivors, especially with regard to their potential in preventing cancer recurrence.
Patient Perspectives
Authors: Shannahoff-Khalsa David S.
Published: February 2005

The ancient system of Kundalini Yoga (KY) includes a vast array of meditation techniques. Some were discovered to be specific for treating psychiatric disorders and others are supposedly beneficial for treating cancers. To date, 2 clinical trials have been conducted for treating obsessive-compulsive disorder (OCD). The first was an open uncontrolled trial and the second a single-blinded randomized controlled trial (RCT) comparing a KY protocol against the Relaxation Response and Mindfulness Meditation (RRMM) techniques combined. Both trials showed efficacy on all psychological scales using the KY protocol; however, the RCT showed no efficacy on any scale with the RRMM control group. The KY protocol employed an OCD-specific meditation technique combined with other techniques that are individually specific for anxiety, low energy, fear, anger, meeting mental challenges, and turning negative thoughts into positive thoughts. In addition to OCD symptoms, other symptoms, including anxiety and depression, were also significantly reduced. Elements of the KY protocol other than the OCD-specific technique also may have applications for psycho-oncology patients and are described here. Two depression-specific KY techniques are described that also help combat mental fatigue and low energy. A 7-part protocol is described that would be used in KY practice to affect the full spectrum of emotions and distress that complicate a cancer diagnosis. In addition, there are KY techniques that practitioners have used in treating cancer. These techniques have not yet been subjected to formal clinical trials but are described here as potential adjunctive therapies. A case history demonstrating rapid onset of acute relief of intense fear in a terminal breast cancer patient using a KY technique specific for fear is presented. Asecond case history is reported for a surviving male diagnosed in 1988 with terminal prostate cancer who has used KYtherapy long termas part of a self-directed integrative care approach.
Orthomolecular Oncology Review: Ascorbic Acid and Cancer 25 Years Later
Authors: González Michael J. , Miranda-Massari Jorge R. , Mora Edna M. , Guzmán Angelik , Riordan Neil H. , Riordan Hugh D. , Casciari Joseph J. , Jackson James A. , Román-Franco Angel
Published: February 2005

The effect of ascorbic acid on cancer has been a subject of great controversy. This is a follow-up review of the 1979 article by Cameron, Pauling, and Leibovitz published in Cancer Research. In this updated version, the authors address general aspects of ascorbic acid and cancer that have been presented before, while reviewing, analyzing, and updating new existing literature on the subject. In addition, they present and discuss their own mechanistic hypothesis on the effect of ascorbic acid on the cancer cell. The objective of this review is to provide an updated scientific basis for the use of ascorbic acid, especially intravenously as adjuvant treatment in pharmacological nutritional oncology.
Patient Perspectives
Authors: Moss Ralph W.
Published: February 2005

This article contains observations and historical considerations on cancer and complementary and alternative medicine (CAM) in the Tijuana, Mexico, area. There are approximately 2 dozen such clinics in Tijuana, some of which have been treating international cancer patients since 1963. Among the first clinics to be established were the Bio-Medical Center (Hoxsey therapy), Oasis of Hope (a Laetrile-oriented clinic), and a series of clinics affiliated with the Gerson diet therapy. These original clinics were established mainly by American citizens in response to increased regulation of nonstandard therapies in the United States, particularly after passage of the Kefauver-Harris Amendments to the Food, Drug and Cosmetics Act in 1962. In the 1970s, the Tijuana clinics proliferated with the upsurge of interest in Laetrile (amygdalin). By 1978, 70,000 US cancer patients had taken Laetrile for cancer treatment, and many of those had gone to Tijuana to receive it. The popularity of the Tijuana clinics peaked in the mid-1980s. Although many new clinics opened after then, a dozen have folded in the past 10 years alone. The turning point for the clinics came with passage of the North American Free Trade Agreement (NAFTA), which facilitated greater cooperation among the antifraud authorities of Canada, the United States, and Mexico. In 1994, the tripartite members of NAFTA formed the Mexico-United States-Canada Health Fraud Work Group, or MUCH, whose brief is to strengthen the 3 countries’ ability to prevent cross-border health fraud. Under the auspices of MUCH and its members, regulatory crackdowns began in earnest early in 2001. The clinics were also badly affected by the general downturn in travel after 9/11. If these trends continue, many Tijuana clinics are unlikely to survive. Some suggestions are made for how the Tijuana clinics could be reorganized and reformed to minimize the likelihood of governmental actions and to maximize public support. Such reforms center on 5 main areas: (1) research, (2) physical plant, (3) finances, (4) ethics, and (5) education.
Controlling Hyperglycemia as an Adjunct to Cancer Therapy
Authors: Krone Cheryl A. , Ely John T. A.
Published: February 2005

Hyperglycemia is commonly manifested in cancer patients. Although high intakes of sugar and refined carbohydrates and elevated blood glucose are strongly associated with the risk of cancer, much less is known about their effects on survival after cancer diagnosis. There is evidence that high carbohydrate intake is associated with poorer survival after diagnosis for early breast cancer. We measured glycated hemoglobin in a group of cancer patients (some with active disease and some in remission) and found a statistically significant lower average blood glucose in those in remission. Glycated hemoglobin provides an indication of average blood glucose over 2 to 3 months. The authors discuss lifestyle changes including diet and physical activity that can reduce average blood glucose. Ascorbic acid (AA) supplementation as an adjunct to cancer therapy is also considered. Furthermore, they present a biologically plausible explanation for how hyperglycemia can impair the actions of AA and damage immune effectiveness and hinder cancer survival. One mechanism is likely a reduction in intracellular AA; high intracellular levels of AA are necessary for optimal activity of the hexose monophosphate shunt. This metabolic pathway is important for maintaining proper cellular antioxidant status in immune cells including lymphocytes involved in cell-mediated immunity.
Dysregulation of Na+/K+ ATPase by amyloid in APP+PS1 transgenic mice
Authors: Dickey Chad A , Gordon Marcia N , Wilcock Donna M , Herber Donna L , Freeman Melissa J , Morgan Dave
Published: February 2005

Background

The pathology of Alzheimer's disease (AD) is comprised of extracellular amyloid plaques, intracellular tau tangles, dystrophic neurites and neurodegeneration. The mechanisms by which these various pathological features arise are under intense investigation. Here, expanding upon pilot gene expression studies, we have further analyzed the relationship between Na+/K+ ATPase and amyloid using APP+PS1 transgenic mice, a model that develops amyloid plaques and memory deficits in the absence of tangle formation and neuronal or synaptic loss.

Results

We report that in addition to decreased mRNA expression, there was decreased overall Na+/K+ ATPase enzyme activity in the amyloid-containing hippocampi of the APP+PS1 mice (although not in the amyloid-free cerebellum). In addition, dual immunolabeling revealed an absence of Na+/K+ ATPase staining in a zone surrounding congophilic plaques that was occupied by dystrophic neurites. We also demonstrate that cerebral Na+/K+ ATPase activity can be directly inhibited by high concentrations of soluble Aβ.

Conclusions

The data suggest that the reductions in Na+/K+ ATPase activity in Alzheimer tissue may not be purely secondary to neuronal loss, but may results from direct effects of amyloid on this enzyme. This disruption of ion homeostasis and osmotic balance may interfere with normal electrotonic properties of dendrites, blocking intraneuronal signal processing, and contribute to neuritic dystrophia. These results suggest that therapies aimed at enhancing Na+/K+ ATPase activity in AD may improve symptoms and/or delay disease progression.
Signalling crosstalk in FGF2-mediated protection of endothelial cells from HIV-gp120
Authors: Langford Dianne , Hurford Rosemary , Hashimoto Makoto , Digicaylioglu Murat , Masliah Eliezer
Published: February 2005

Background

The blood brain barrier (BBB) is the first line of defence of the central nervous system (CNS) against circulating pathogens, such as HIV. The cytotoxic HIV protein, gp120, damages endothelial cells of the BBB, thereby compromising its integrity, which may lead to migration of HIV-infected cells into the brain. Fibroblast growth factor 2 (FGF2), produced primarily by astrocytes, promotes endothelial cell fitness and angiogenesis. We hypothesized that treatment of human umbilical vein endothelial cells (HUVEC) with FGF2 would protect the cells from gp120-mediated toxicity via endothelial cell survival signalling.

Results

Exposure of HUVEC to gp120 resulted in dose- and time-dependent cell death; whereas, pre-treatment of endothelial cells with FGF2 protected cells from gp120 angiotoxicity. Treatment of HUVEC with FGF2 resulted in dose- and time-dependent activation of the extracellular regulated kinase (ERK), with moderate effects on phosphoinositol 3 kinase (PI3K) and protein kinase B (PKB), also known as AKT, but no effects on glycogen synthase kinase 3 (GSK3β) activity. Using pharmacological approaches, gene transfer and kinase activity assays, we show that FGF2-mediated angioprotection against gp120 toxicity is regulated by crosstalk among the ERK, PI3K-AKT and PKC signalling pathways.

Conclusions

Taken together, these results suggest that FGF2 may play a significant role in maintaining the integrity of the BBB during the progress of HIV associated cerebral endothelial cell damage.
Inactive enzymatic mutant proteins (phosphoglycerate mutase and enolase) as sugar binders for ribulose-1,5-bisphosphate regeneration reactors
Authors: De Debojyoti , Dutta Debajyoti , Kundu Moloy , Mahato Sourav , Schiavone Marc T , Chaudhuri Surabhi , Giri Ashok , Gupta Vidya , Bhattacharya Sanjoy K
Published: February 2005

Background

Carbon dioxide fixation bioprocess in reactors necessitates recycling of D-ribulose1,5-bisphosphate (RuBP) for continuous operation. A radically new close loop of RuBP regenerating reactor design has been proposed that will harbor enzyme-complexes instead of purified enzymes. These reactors will need binders enabling selective capture and release of sugar and intermediate metabolites enabling specific conversions during regeneration. In the current manuscript we describe properties of proteins that will act as potential binders in RuBP regeneration reactors.

Results

We demonstrate specific binding of 3-phosphoglycerate (3PGA) and 3-phosphoglyceraldehyde (3PGAL) from sugar mixtures by inactive mutant of yeast enzymes phosphoglycerate mutase and enolase. The reversibility in binding with respect to pH and EDTA has also been shown. No chemical conversion of incubated sugars or sugar intermediate metabolites were found by the inactive enzymatic proteins. The dissociation constants for sugar metabolites are in the micromolar range, both proteins showed lower dissociation constant (Kd) for 3-phosphoglycerate (655–796 μM) compared to 3-phosphoglyceraldehyde (822–966 μM) indicating higher affinity for 3PGA. The proteins did not show binding to glucose, sucrose or fructose within the sensitivity limits of detection. Phosphoglycerate mutase showed slightly lower stability on repeated use than enolase mutants.

Conclusions

The sugar and their intermediate metabolite binders may have a useful role in RuBP regeneration reactors. The reversibility of binding with respect to changes in physicochemical factors and stability when subjected to repeated changes in these conditions are expected to make the mutant proteins candidates for in-situ removal of sugar intermediate metabolites for forward driving of specific reactions in enzyme-complex reactors.
The role of glucocorticoid action in the pathophysiology of the Metabolic Syndrome
Authors: Wang Minghan
Published: February 2005

Glucocorticoids are stress hormones that modulate a large number of physiological actions involved in metabolic, inflammatory, cardiovascular and behavioral processes. The molecular mechanisms and the physiological effects of glucocorticoids have been extensively studied. However, the involvement of glucocorticoid action in the etiology of the Metabolic Syndrome has not been well appreciated. Recently, accumulating clinical evidence and animal genetics studies have attracted growing interest in the role of glucocorticoid action in obesity and insulin resistance. This review will discuss the metabolic effects in the context of glucocorticoid metabolism and establish the association of glucocorticoid action with the features of the Metabolic Syndrome, especially obesity and insulin resistance. Special discussions will be focused on corticosteroid-binding globulin and 11β-hydroxysteroid dehydrogenase type 1, two proteins that mediate glucocorticoid action and have been implicated in the Metabolic Syndrome. Due to the complexities of the glucocorticoid biology and the Metabolic Syndrome and limited space, this review is only intended to provide a general link between the two areas with broad rather than in-depth discussions of clinical, pharmacological and genetic findings.
Myeloperoxidase: friend and foe
Authors: Klebanoff Seymour J
Published: February 2005

Neutrophilic polymorphonuclear leukocytes (neutrophils) are highly specialized for their primary function, the phagocytosis and destruction of microorganisms. When coated with opsonins (generally complement and/or antibody), microorganisms bind to specific receptors on the surface of the phagocyte and invagination of the cell membrane occurs with the incorporation of the microorganism into an intracellular phagosome. There follows a burst of oxygen consumption, and much, if not all, of the extra oxygen consumed is converted to highly reactive oxygen species. In addition, the cytoplasmic granules discharge their contents into the phagosome, and death of the ingested microorganism soon follows. Among the antimicrobial systems formed in the phagosome is one consisting of myeloperoxidase (MPO), released into the phagosome during the degranulation process, hydrogen peroxide (H2O2), formed by the respiratory burst and a halide, particularly chloride. The initial product of the MPO-H2O2-chloride system is hypochlorous acid, and subsequent formation of chlorine, chloramines, hydroxyl radicals, singlet oxygen, and ozone has been proposed. These same toxic agents can be released to the outside of the cell, where they may attack normal tissue and thus contribute to the pathogenesis of disease. This review will consier the potential sources of H2O2 for the MPO-H2O2-halide system; the toxic products of the MPO system; the evidence for MPO involvement in the microbicidal activity of neutrophils; the involvement of MPO-independent antimicrobial systems; and the role of the MPO system in tissue injury. It is concluded that the MPO system plays an important role in the microbicidal activity of phagocytes.
Vascular function and sphingosine-1-phosphate regulate development of the dorsal pancreatic mesenchyme
Authors: Edsbagge Josefina , Johansson Jenny K. , Esni Farzad , Luo Yang , Radice Glenn L. , Semb Henrik
Published: February 2005

Early growth and differentiation of the pancreatic endoderm is regulated by soluble factors from the pancreatic mesenchyme. Previously, we demonstrated that N-cadherin-deficient mice lack a dorsal pancreas, due to a critical role of N-cadherin in dorsal pancreatic mesenchymal cell survival. Here, we show that restoring cardiac and circulatory function in N-cadherin null mice by cardiac-specific expression of N-cadherin, rescues formation of the dorsal pancreas, indicating that the phenotype is secondary to defects related to cardiac/vascular function. Based on this observation, we demonstrate that soluble factors present in plasma, such as sphingosine-1-phosphate, rescue formation of the dorsal pancreas in N-cadherin-deficient mice. We also show that sphingosine-1-phosphate indirectly promotes budding of the pancreatic endoderm by stimulating pancreatic mesenchymal cell proliferation. Finally, we identify sphingosine-1-phosphate receptors within the mesenchyme and show that pertussis toxin blocks the sphingosine-1-phosphate-induced actions, suggesting the involvement of G-protein-coupled sphingosine-1-phosphate receptors. Thus,we propose a new model where blood vessel-derived sphingosine-1-phosphate stimulates growth and budding of the dorsal pancreatic endoderm by induction of mesenchymal cell proliferation.
Indian hedgehog synchronizes skeletal angiogenesis and perichondrial maturation with cartilage development
Authors: Colnot Céline , de la Fuente Luis , Huang Steve , Hu Diane , Lu Chuanyong , St-Jacques Benoit , Helms Jill A.
Published: February 2005

A null mutation in the morphogen Indian hedgehog (IHH) results in an embryonic lethal phenotype characterized by the conspicuous absence of bony tissue in the extremities. We show that this ossification defect is not attributable to a permanent arrest in cartilage differentiation, since Ihh-/- chondrocytes undergo hypertrophy and terminal differentiation, express angiogenic markers such as Vegf, and are invaded, albeit aberrantly, by blood vessels. Subsequent steps, including vessel expansion and persistence, are impaired, and the net result is degraded cartilage matrix that is devoid of blood vessels. The absence of blood vessels is not because the Ihh-/- skeleton is anti-angiogenic; in fact, in an ex vivo environment, both wild-type and Ihh mutant vessels invade the Ihh-/- cartilage, though only wild-type vessels expand to create the marrow cavity. In the ex vivo setting, Ihh-/- cells differentiate into osteoblasts and deposit a bony matrix, without benefit of exogenous hedgehog in the new environment. Even more surprising is our finding that the earliest IHH-dependent skeletal defect is obvious by the time the limb mesenchyme segregates into chondrogenic and perichondrogenic condensations. Although Ihh-/- cells organize into chondrogenic condensations similar in size and shape to wild-type condensations, perichondrial cells surrounding the mutant condensations are clearly faulty. They fail to aggregate, elongate and flatten into a definitive, endothelial cell-rich perichondrium like their wild-type counterparts. Normally, these cells surrounding the chondrogenic condensation are exposed to IHH, as evidenced by their expression of the hedgehog target genes, patched (Ptch) and Gli1. In the mutant environment,the milieu surrounding the cartilage - comprising osteoblast precursors and endothelial cells - as well as the cartilage itself, develop in the absence of this important morphogen. In conclusion, the skeletal phenotype of Ihh-/- embryos represents the sum of disturbances in three separate cell populations, the chondrocytes, the osteoblasts and the vasculature, each of which is a direct target of hedgehog signaling.
Developmental stage determines the effects of MYC in the mammary epithelium
Authors: Blakely Collin M. , Sintasath Louis , D'Cruz Celina M. , Hahn Kristina T. , Dugan Katherine D. , Belka George K. , Chodosh Lewis A.
Published: February 2005

Epidemiological findings suggest that the consequences of a given oncogenic stimulus vary depending upon the developmental state of the target tissue at the time of exposure. This is particularly evident in the mammary gland, where both age at exposure to a carcinogenic stimulus and the timing of a first full-term pregnancy can markedly alter the risk of developing breast cancer. Analogous to this, the biological consequences of activating oncogenes, such as MYC, can be influenced by cellular context both in terms of cell lineage and cellular environment. In light of this, we hypothesized that the consequences of aberrant MYC activation in the mammary gland might be determined by the developmental state of the gland at the time of MYC exposure. To test this hypothesis directly, we have used a doxycycline-inducible transgenic mouse model to overexpress MYC during different stages of mammary gland development. Using this model, we find that the ability of MYC to inhibit postpartum lactation is due entirely to its activation within a specific 72-hour window during mid-pregnancy; by contrast,MYC activation either prior to or following this 72-hour window has little or no effect on postpartum lactation. Surprisingly, we find that MYC does not block postpartum lactation by inhibiting mammary epithelial differentiation,but rather by promoting differentiation and precocious lactation during pregnancy, which in turn leads to premature involution of the gland. We further show that this developmental stage-specific ability of MYC to promote mammary epithelial differentiation is tightly linked to its ability to downregulate caveolin 1 and activate Stat5 in a developmental stage-specific manner. Our findings provide unique in vivo molecular evidence for developmental stage-specific effects of oncogene activation, as well as the first evidence linking MYC with activation of the Jak2-Stat5 signaling pathway.
RBPjκ-dependent Notch function regulatesGata2and is essential for the formation of intra-embryonic hematopoietic cells
Authors: Robert-Moreno Àlex , Espinosa Lluís , de la Pompa José Luis , Bigas Anna
Published: February 2005

Definitive hematopoiesis in the mouse embryo originates from the aortic floor in the P-Sp/AGM region in close association with endothelial cells. An important role for Notch1 in the control of hematopoietic ontogeny has been recently established, although its mechanism of action is poorly understood. Here, we show detailed analysis of Notch family gene expression in the aorta endothelium between embryonic day (E) 9.5 and E10.5. Since Notch requires binding to RBPjκ transcription factor to activate transcription, we analyzed the aorta of the para-aortic splanchnopleura/AGM in RBPjκ mutant embryos. We found specific patterns of expression of Notch receptors, ligands and Hes genes that were lost in RBPjκ mutants. Analysis of these mutants revealed the absence of hematopoietic progenitors, accompanied by the lack of expression of the hematopoietic transcription factors Aml1/Runx1, Gata2 and Scl/Tal1. We show that in wild-type embryos, a few cells lining the aorta endothelium at E9.5 simultaneously expressed Notch1 and Gata2, and demonstrate by chromatin immunoprecipitation that Notch1 specifically associated with the Gata2 promoter in E9.5 wild-type embryos and 32D myeloid cells, an interaction lost in RBPjκmutants. Consistent with a role for Notch1 in regulating Gata2, we observe increased expression of this gene in 32D cells expressing activated Notch1. Taken together, these data strongly suggest that activation of Gata2 expression by Notch1/RBPjκ is a crucial event for the onset of definitive hematopoiesis in the embryo.
Sumoylation of LIN-1 promotes transcriptional repression and inhibition of vulval cell fates
Authors: Leight Elizabeth R. , Glossip Danielle , Kornfeld Kerry
Published: February 2005

The LIN-1 ETS transcription factor inhibits vulval cell fates during Caenorhabditis elegans development. We demonstrate that LIN-1 interacts with UBC-9, a small ubiquitin-related modifier (SUMO) conjugating enzyme. This interaction is mediated by two consensus sumoylation motifs in LIN-1. Biochemical studies showed that LIN-1 is covalently modified by SUMO-1. ubc-9 and smo-1, the gene encoding SUMO-1, inhibit vulval cell fates and function at the level of lin-1, indicating that sumoylation promotes LIN-1 inhibition of vulval cell fates. Sumoylation of LIN-1 promoted transcriptional repression and mediated an interaction with MEP-1, a protein previously shown to associate with the nucleosome remodeling and histone deacetylation (NuRD) transcriptional repression complex. Genetic studies showed that mep-1 inhibits vulval cell fates and functions at the level of lin-1. We propose that sumoylation of LIN-1 mediates an interaction with MEP-1 that contributes to transcriptional repression of genes that promote vulval cell fates. These studies identify a molecular mechanism for SUMO-mediated transcriptional repression.
A pair of Sox: distinct and overlapping functions of zebrafish sox9 co-orthologs in craniofacial and pectoral fin development
Authors: Yan Yi-Lin , Willoughby John , Liu Dong , Crump Justin Gage , Wilson Catherine , Miller Craig T. , Singer Amy , Kimmel Charles , Westerfield Monte , Postlethwait John H.
Published: February 2005

Understanding how developmental systems evolve after genome amplification is important for discerning the origins of vertebrate novelties, including neural crest, placodes, cartilage and bone. Sox9 is important for the development of these features, and zebrafish has two co-orthologs of tetrapod SOX9 stemming from an ancient genome duplication event in the lineage of ray-fin fish. We have used a genotype-driven screen to isolate a mutation deleting sox9b function, and investigated its phenotype and genetic interactions with a sox9a null mutation. Analysis of mutant phenotypes strongly supports the interpretation that ancestral gene functions partitioned spatially and temporally between Sox9 co-orthologs. Distinct subsets of the craniofacial skeleton, otic placode and pectoral appendage express each gene, and are defective in each single mutant. The double mutant phenotype is additive or synergistic. Ears are somewhat reduced in each single mutant but are mostly absent in the double mutant. Loss-of-function animals from mutations and morpholino injections, and gain-of-function animals injected with sox9a and sox9b mRNAs showed that sox9 helps regulate other early crest genes, including foxd3, sox10, snai1b and crestin, as well as the cartilage gene col2a1 and the bone gene runx2a;however, tfap2a was nearly unchanged in mutants. Chondrocytes failed to stack in sox9a mutants, failed to attain proper numbers in sox9b mutants and failed in both morphogenetic processes in double mutants. Pleiotropy can cause mutations in single copy tetrapod genes, such as Sox9, to block development early and obscure later gene functions. By contrast, subfunction partitioning between zebrafish co-orthologs of tetrapod genes, such as sox9a and sox9b, can relax pleiotropy and reveal both early and late developmental gene functions.
Review of The New Financial Order by Shiller
Authors: Ross Stephen A
Published: February 2005

This is a review article of The New Financial Order: Risk in the Twenty-First Century (Princeton University Press 2003) by Robert J. Shiller.
Field Experiments
Authors: Harrison Glenn W , List John A
Published: February 2005

Experimental economists are leaving the reservation. They are recruiting subjects in the field rather than in the classroom, using field goods rather than induced valuations, and using field context rather than abstract terminology in instructions. We argue that there is something methodologically fundamental behind this trend. Field experiments differ from laboratory experiments in many ways. Although it is tempting to view field experiments as simply less controlled variants of laboratory experiments, we argue that to do so would be to seriously mischaracterize them. What passes for “control” in laboratory experiments might in fact be precisely the opposite if it is artificial to the subject or context of the task. We propose six factors that can be used to determine the field context of an experiment: the nature of the subject pool, the nature of the information that the subjects bring to the task, the nature of the commodity, the nature of the task or trading rules applied, the nature of the stakes, and the environment that subjects operate in.
The Unity of Auction Theory: Milgrom's Masterclass
Authors: Maskin Eric
Published: February 2005

This is a review article of Putting Auction Theory to Work (Cambridge University Press 2004) by Paul Milgrom.
Financial Crises: Review of Eichengreen and Tirole
Authors: Fischer Stanley
Published: February 2005

This is a review article of two books: Financial Crises and What to Do about Them by Barry Eichengreen (Oxford University Press 2002) and Financial Crises, Liquidity, and the International Monetary System by Jean Tirole (Princeton University Press 2002).
Executive Insights: Market Orientation of Mexican Companies
Authors: Felix Reto , Hinck Wolfgang
Published: February 2005

This study suggests that companies from a sample in an industrialized region in northern Mexico are confident about their level of overall market orientation but that differences in their customer and competitor orientation exist. The authors test market orientation for its relationship to several other variables, such as company size, type of product, and use of a marketing plan, and they discuss the implications for marketing theory and practice.
Market Orientation and Management Practices in Ghanaian Firms: Revisiting the Jaworski and Kohli Framework
Authors: Kuada John , Buatsi Seth N.
Published: February 2005

The work of Jaworski and Kohli (1993) has inspired a substantial body of literature on market orientation, but most replications of their original framework have been in developed countries. This article reports the results of a Ghanaian study that revisits Jaworski and Kohli's framework, and the authors compare the findings with a similar study that was conducted in the Ivory Coast. The authors provide evidence in support of the robustness of the framework and draw attention to the possible variations in the interpretation of the constituent constructs in the original framework. The variations are attributable to cultural differences that affect management practices in different societies.
Stakeholder Orientation and Business Performance: The Case of Service Companies in China
Authors: Luk Chung-Leung , Yau Oliver H.M. , Tse Alan C.B. , Sin Leo Y.M. , Chow Raymond P.M.
Published: February 2005

Previous research on stakeholder orientation has examined only the main effects of its components on business performance. However, the interaction effects that result from different combinations of the components of stakeholder orientation have been overlooked. This article proposes and tests two types of interaction effects, synergy and hindering effects, using a sample of 193 service companies in China.
Regulation of gene expression in endothelial cells: the role of human follicular fluid
Authors: Gruemmer R , Klein-Hitpaß L , Neulen J
Published: February 2005

A precise regulation of angiogenesis is a prerequisite for an adequate maturation of ovarian follicles. Despite the production of vascular endothelial growth factor (VEGF) by granulosa cells in antral follicles, angiogenesis is restricted to the theca cell layer. The maturing follicle remains avascular before ovulation, implying regulatory mechanisms which prevent premature follicular vascularization. In order to investigate the role of follicular fluid and of granulosa cells in the regulation of endothelial gene expression, human umbilical vein endothelial cells (HUVECs) were incubated in vitro with media conditioned with human follicular fluid obtained from individual patients undergoing oocyte retrieval for in vitro fertilization procedures or with culture medium conditioned by human granulosa cells respectively. Using microarray technology, the gene expression pattern was compared between untreated monolayers of HUVECs and HUVECs treated either with follicular fluid or with granulosa cell conditioned media. We identified a total of 15 genes that were significantly up-regulated and 11 genes that were significantly down-regulated in endothelial cells treated with follicular fluid at least 2.5-fold in more than 70% of comparisons. Up-regulated genes involved in angiogenesis were the anti-angiogenic factors gro-beta (16.5-fold), angiopoietin-2 (3.9-fold), alpha-2-macroglobulin (24.3-fold) and the pro-angiogenic factors E-selectin (5.3-fold) and vascular cell adhesion molecule-1 (VCAM-1) (4.4-fold), whereas a significant down-regulation of the pro-angiogenic genes fibulin-5 (3.5-fold) and elastin (14.9-fold) could be observed. Culturing of HUVECs with conditioned medium from cultured human luteinized granulosa cells demonstrated a similar regulatory pattern of gene expression for fibulin-5, elastin, gro-beta, and E-selectin. The gene regulation in endothelial cells by follicular fluid could be confirmed by RT-PCR for gro-beta, angiopoietin-2, elastin, fibulin-5, and E-selectin. The present work reveals that compounds secreted by granulosa cells lead to the expression of anti-angiogenic factors on the transcript level in endothelial cells and thus could help to explain the temporal and spatial discrepancy between the high expression of VEGF and the restricted angiogenesis in the preovulatory follicle.
Identification of human myometrial target genes of the cAMP pathway: the role of cAMP-response element binding (CREB) and modulator (CREMα and CREMτ2α) proteins
Authors: Bailey Jarrod , Tyson-Capper (née Pollard) Alison J , Gilmore Kate , Robson Stephen C , Europe-Finner G Nicholas
Published: February 2005

cAMP-response element (CRE) binding (CREB) and modulator (CREM) proteins, activated by protein kinase A-mediated phosphorylation, bind as homo- and heterodimers to promoters containing CRE and activator protein 1 (AP-1) sites to alter target-gene expression. We have previously reported differential expression of CREB and CREM splice variants CREMα and CREMτ2α in human myometrium during pregnancy and labour. Via microarray studies with cultured myometrial cells stably transfected with CREB, CREMα and CREMτ2α cDNAs, CREB affected the expression of 958 genes; 522 being up-regulated and 436 down-regulated. CREMα altered the expression of 118 genes; 71 were increased and 47 decreased. CREMτ2α affected 220 genes; 148 were activated and 72 repressed. Notably, genes affected by CREB, CREMα and CREMτ2α belong to largely discrete groups: less than 9% were affected by more than one factor. Genes involved in regulation of cell death and apoptosis, growth and maintenance, signal transduction, physiological and developmental processes, protein kinase cascades, extracellular matrix, cytoskeleton, cell-cycle regulation, transport, and a variety of enzymes, intracellular components and nucleic acid-binding proteins have been described, many of which are involved in the modulation of myometrial activity during pregnancy and parturition.
Biological activities of recombinant equine luteinizing hormone/chorionic gonadotropin (eLH/CG) expressed in Sf9 and Mimic insect cell lines
Authors: Legardinier Sébastien , Duonor-Cérutti Martine , Devauchelle Gérard , Combarnous Yves , Cahoreau Claire
Published: February 2005

Equine luteinizing hormone (eLH) and chorionic gonadotropin (eCG) are composed of identical α and β polypeptide chains, but eCG subunits are much more heavily glycosylated and sialylated. Consequently, eCG exhibits a much longer half-life than eLH in blood. Recombinant eLH/CG, expressed in Sf9 and Mimic insect cells, were compared with one another and to the natural hormones eCG and eLH. Mimic cells are stably-transformed Sf9 cells, expressing five mammalian genes encoding glycosyltransferases involved in the synthesis of complex N-carbohydrate chains. Recombinant eLH/CG expressed in Mimic cells exhibited a higher apparent molecular weight (MW) than that expressed in Sf9 cells, suggesting that its N-glycosylation was, as expected, more complete. Nevertheless, the two recombinant eLH/CG exhibited lower MW than natural eCG from pregnant mare plasma. The two eLH/CG produced in Sf9 and Mimic cells were found to be active in in vitro LH and FSH bioassays, with potencies similar to those of eCG. By contrast, they exhibited no significant in vivo bioactivity, neither in the specific follicle-stimulating hormone (FSH) assay nor in the specific eCG assay. Although recombinant eLH/CG produced in Mimic cells bears more elaborate carbohydrate chains than recombinant eLH/CG from Sf9 cells, it exhibits no significant in vivo bioactivity, probably because of insufficient terminal sialylation of its carbohydrate chains, leading to its rapid removal from blood.
Integrative analysis of gene expression patterns predicts specific modulations of defined cell functions by estrogen and tamoxifen in MCF7 breast cancer cells
Authors: Gadal F , Starzec A , Bozic C , Pillot-Brochet C , Malinge S , Ozanne V , Vicenzi J , Buffat L , Perret G , Iris F , Crepin M
Published: February 2005

To explore the mechanisms whereby estrogen and antiestrogen (tamoxifen (TAM)) can regulate breast cancer cell growth, we investigated gene expression changes in MCF7 cells treated with 17β-estradiol (E2) and/or with 4-OH-TAM. The patterns of differential expression were determined by the ValiGen Gene IDentification (VGID) process, a subtractive hybridization approach combined with microarray validation screening. Their possible biologic consequences were evaluated by integrative data analysis. Over 1000 cDNA inserts were isolated and subsequently cloned, sequenced and analyzed against nucleotide and protein databases (NT/NR/EST) with BLAST software. We revealed that E2 induced differential expression of 279 known and 28 unknown sequences, whereas TAM affected the expression of 286 known and 14 unknown sequences. Integrative data analysis singled out a set of 32 differentially expressed genes apparently involved in broad cellular mechanisms. The presence of E2 modulated the expression patterns of 23 genes involved in anchors and junction remodeling; extracellular matrix (ECM) degradation; cell cycle progression, including G1/S check point and S-phase regulation; and synthesis of genotoxic metabolites. In tumor cells, these four mechanisms are associated with the acquisition of a motile and invasive phenotype. TAM partly reversed the E2-induced differential expression patterns and consequently restored most of the biologic functions deregulated by E2, except the mechanisms associated with cell cycle progression. Furthermore, we found that TAM affects the expression of nine additional genes associated with cytoskeletal remodeling, DNA repair, active estrogen receptor formation and growth factor synthesis, and mitogenic pathways. These modulatory effects of E2 and TAM upon the gene expression patterns identified here could explain some of the mechanisms associated with the acquisition of a more aggressive phenotype by breast cancer cells, such as E2-independent growth and TAM resistance.
Dexamethasone represses cAMP rapid upregulation of TRH gene transcription: identification of a composite glucocorticoid response element and a cAMP response element in TRH promoter
Authors: Cote-Vélez A , Pérez-Martínez L , Díaz-Gallardo M Y , Pérez-Monter C , Carreón-Rodríguez A , Charli J-L , Joseph-Bravo P
Published: February 2005

Hypothalamic proTRH mRNA levels are rapidly increased (at 1 h) in vivo by cold exposure or suckling, and in vitro by 8Br-cAMP or glucocorticoids. The aim of this work was to study whether these effects occurred at the transcriptional level. Hypothalamic cells transfected with rat TRH promoter (− 776/+85) linked to the luciferase reporter showed increased transcription by protein kinase (PK) A and PKC activators, or by dexamethasone (dex), but co-incubation with dex and 8Br-cAMP decreased their stimulatory effect (as observed for proTRH mRNA levels). These effects were also observed in NIH-3T3-transfected cells supporting a characteristic of TRH promoter and not of hypothalamic cells. Transcriptional regulation by 8Br-cAMP was mimicked by noradrenaline which increased proTRH mRNA levels, but not in the presence of dex. PKA inhibition by H89 avoided 8Br-cAMP or noradrenaline stimulation. TRH promoter sequences, cAMP response element (CRE)-like (− 101/− 94 and − 59/− 52) and glucocorticoid response element (GRE) half-site (− 210/− 205), were analyzed by electrophoretic mobility shift assays with nuclear extracts from hypothalamic or neuroblastoma cultures. PKA stimulation increased binding to CRE (− 101/− 94) but not to CRE (− 59/− 52); dex or 12-O-tetradecanoylphorbol-13-acetate (TPA) increased binding to GRE, a composite site flanked by a perfect and an imperfect activator protein (AP-1) site in the complementary strand. Interference was observed in the binding of CRE or GRE with nuclear extracts from cells co-incubated for 3 h with 8Br-cAMP and dex; from cells incubated for 1 h, only the binding to GRE showed interference. Rapid cross-talk of glucocorticoids with PKA signaling pathways regulating TRH transcription constitutes another example of neuroendocrine integration.
Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue
Authors: Serrano R , Villar M , Martínez C , Carrascosa J M , Gallardo N , Andrés A
Published: February 2005

The insulin receptor (IR) occurs as two alternatively spliced isoforms, IR-A (exon 11−) and IR-B (exon 11+), which exhibit functional differences and are expressed in a tissue-specific manner. The IR substrate (IRS) proteins 1, 2 and 3 also differ in function and tissue distribution. Here we show the differential gene expression of IRs and IRSs in several rat target tissues of insulin action. IR-B is significantly higher than IR-A in epididymal white adipose tissue and adipogenesis induces a shift in the alternatively spliced species of IR from the A to the B isoform. Moreover, since aging in the rat is associated with the development of insulin resistance we looked for alterations of expression of these proteins in adipocytes from old rats. Our results reveal that there is a specific decrease in the expression of the IR-B isoform, as well as both mRNA and protein levels of IR, IRS-1 and IRS-3 being significantly decreased, in epididymal adipose tissue from old compared with adult rats. It is concluded that the down-regulation of early components of the insulin transduction pathway in a primary insulin target tissue could be related to the insulin resistance of aging.
ACTH depletion represses vascular endothelial-cadherin transcription in mouse adrenal endothelium in vivo
Authors: Huber Philippe , Mallet Christine , Faure Elodie , Rampon Christine , Prandini Marie-Hélène , Féraud Olivier , Bouillot Stéphanie , Vilgrain Isabelle
Published: February 2005

Vascular endothelial-cadherin (VE-cadherin) is an endothelial cell-specific adhesion protein that is localised at cell–cell contacts. This molecule is an important determinant of vascular architecture and endothelial cell survival. In the adrenal cortex, steroidogenic and endothelial cells form a complex architecture. The adrenocorticotrophin hormone (ACTH) regulates gland homeostasis whose secretion is subjected to a negative feedback by adrenocorticosteroids. The aim of the present study was to determine whether VE-cadherin expression in the adrenal gland was regulated by hormonal challenge. We demonstrated that VE-cadherin protein levels were dramatically decreased (23.5 ± 3.7%) by dexamethasone injections in the mouse and were restored by ACTH within 7 days (94.9 ± 18.6%). Flow cytometry analysis of adrenal cells showed that the ratios of endothelial versus total adrenal cells were identical (35%) in dexamethasone- or ACTH-treated or untreated mice, suggesting that VE-cadherin expression could be regulated by ACTH. We demonstrate the existence of a transcriptional regulation of the VE-cadherin gene using transgenic mice carrying the chloramphenicol acetyl transferase gene under the control of the VE-cadherin promoter. Indeed, the promoter activity in the adrenals, but not in the lung or liver, was decreased in response to dexamethasone treatment (40 ± 1.3%) and was partially restored after gland regeneration by ACTH injection (82 ± 3%). In conclusion, our results show that transcription of a specific endothelial gene is controlled by the hypothalamo–pituitary axis and the data expand the knowledge regarding the role of ACTH in the regulation of the adrenal vascular network.