bluuebunny/crossref_metadata_2025 huggingface dataset:
Review: Targeted therapy in renal cancer
Authors: Dorff Tanya B. , Goldkorn Amir , Quinn David I.
Published: November 2009

Renal cell cancer (RCC) has an increasing incidence internationally and is a disease for which there have been limited therapeutic options until recently. The last decade has seen a vastly improved understanding of the biological and clinical factors that predict the outcome of this disease. We now understand some of the different molecular underpinnings of renal clear cell carcinoma by mutation or silencing of the von Hippel Lindau (VHL) gene and subsequent deregulated proliferation and angiogenesis. Survival in advanced disease is predicted by factors (performance status, anemia, hypercalcemia, and serum lactate dehydrogenase, time from diagnosis to recurrence) incorporated into the Memorial Sloan Kettering Cancer Center (MSKCC) criteria (also referred to as ‘Motzer’ criteria). These criteria allow classification of patients with RCC into good, intermediate and poor risk categories with median overall survivals of 22 months, 12 months and 5.4 months, respectively. Predicated upon these advances, six new targeted drugs (sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab and pazopanib) have been tested in well-designed phase III trials, selected or stratified for MSKCC risk criteria, with positive results. All of these new drugs act at least in part through vascular endothelial growth factor (VEGF) mediated pathways with other potential therapeutic impact on platelet-derived growth factor (PDGF), raf kinase and mammalian target of rapamycin (mTOR) pathways. Importantly, data from each of these trials show a consistent doubling of progression-free survival (PFS) over prior standard of care treatments. In addition, sorafenib, sunitinib and temsirolimus, have demonstrated significant overall survival (OS) benefits as well; further follow-up is required to determine whether the disease control exhibited by everolimus and pazopanib will translate into a survival advantage. These drugs are generally well tolerated, as demonstrated by quality-of-life improvement in clinical trials, and result in clinical benefit for in excess of 70% of patients treated. They have challenged the traditional outcomes of clinical trial design by achieving their benefits with relatively few radiographic responses, but high rates of disease stability. The unique side-effect profile coupled with the chronicity of therapy requires increased vigilance to maximize exposure to the drugs while maintaining quality of life and minimizing toxicity. This review focuses on the background, clinical development and practical use of these new drugs in RCC.
Naming Differences in Divided Germany
Authors: Huschka Denis , Gerhards Jürgen , Wagner Gert G.
Published: November 2009

AbstractThis article analyzes differences in naming between East and West Germany. After World War II, Germany was split by the allied forces. Two Germanies emerged: the Federal Republic of Germany (FRG) and the German Democratic Republic (GDR). The country's division lasted about forty years (1949–1989), a time span in which vastly different geo-political frameworks — Eastern bloc versus Western bloc — shaped people's lives and eventually their name choices as well. The results of this complex relationship are addressed here with the following questions: to what extent can different naming patterns and name preferences be observed in the two parts of divided Germany, regardless of their common language and cultural heritage? Can differences in taste be identified, and how did these differences develop over time? These questions are answered here using the German Socio-Economic Panel Study (SOEP). The SOEP offers the rare opportunity of examining patterns of occurrence of first names among a representative sample of 56,000 individuals born since 1900. Moreover, this study includes a wide range of variables revealing the social and economic backgrounds of the “name givers”: the parents.
“Onomastic Emphasis” in Julia Álvarez's Saving the World
Authors: Marshall April D
Published: November 2009

AbstractIn her 2007 novel, Saving the World, Julia Álvarez uses alternating chapters to narrate both a modern tale and a corresponding historical saga. She employs nomenclature emphatically on multiple levels in the work in order to make the theme of identity central to the narrative. This study will examine the connection between name and character in Álavarez's novel. At the same time, it will also analyze the link between that connection and the various onomastic elements that serve to unite and even blend the two parallel stories.
Force-induced cleavage of single VWFA1A2A3 tridomains by ADAMTS-13
Authors: Wu Tao , Lin Jiangguo , Cruz Miguel A. , Dong Jing-fei , Zhu Cheng
Published: November 2009

A disintegrin and metalloprotease with a thrombospondin type 1 motifs 13 (ADAMTS-13) regulates hemostasis by cleaving the folded A2 domain of von Willebrand factor (VWF). The cleavage is regulated by forces as it occurs in flowing blood. We tested the hypothesis that force-induced A2 domain unfolding facilitates cleavage using atomic force microscopy to pull single VWF A1A2A3 tridomain polypeptides by platelet glycoprotein Ibα or antibodies to measure time, distance, and force. Structural destabilization of A1A2A3 was induced by 5- to 80-pN forces, manifesting as an abrupt molecular length increase distributed around 20 and 50 nm, probably because of uncoupling A1A2A3 (or partially unfolding A2) and fully unfolding A2, respectively. Time required to destabilize A1A2A3 first increased (catch), reaching a maximum of 0.2 seconds at 20pN, then decreased (slip) with increasing force, independent of ADAMTS-13. The time required to rupture A1A2A3 exhibited a similar catch-slip behavior when pulled by glycoprotein Ibα but only slip behavior when pulled by antibody, which was progressively shortened by increasing concentration of ADAMTS-13 after (but not before) structural destabilization, indicating that cleavage of A2 requires the force-induced A2 unfolding. Analysis with a model for single-substrate trimolecular enzymatic kinetics estimated a cleavage rate kcat of 2.9 (± 59) seconds and a Kd of 5.6 (± 3.4) nM for ADAMTS-13/A1A2A3 binding. These findings quantify the mechanical regulation of VWF cleavage by ADAMTS-13 at the level of single A1A2A3 tridomain.
The AC133+CD38−, but not the rhodamine-low, phenotype tracks LTC-IC and SRC function in human cord blood ex vivo expansion cultures
Authors: Ito Caryn Y. , Kirouac Daniel C. , Madlambayan Gerard J. , Yu Mei , Rogers Ian , Zandstra Peter W.
Published: November 2009

Phenotypic markers associated with human hematopoietic stem cells (HSCs) were developed and validated using uncultured cells. Because phenotype and function can be dissociated during culture, better markers to prospectively track and isolate HSCs in ex vivo cultures could be instrumental in advancing HSC-based therapies. Using an expansion system previously shown to increase hematopoietic progenitors and SCID-repopulating cells (SRCs), we demonstrated that the rhodamine-low phenotype was lost, whereas AC133 expression was retained throughout culture. Furthermore, the AC133+CD38− subpopulation was significantly enriched in long-term culture-initiating cells (LTC-IC) and SRCs after culture. Preculture and postculture analysis of total nucleated cell and LTC-IC number, and limiting dilution analysis in NOD/SCID mice, showed a 43-fold expansion of the AC133+CD38− subpopulation that corresponded to a 7.3-fold and 4.4-fold expansion of LTC-ICs and SRCs in this subpopulation, respectively. Thus, AC133+CD38− is an improved marker that tracks and enriches for LTC-IC and SRC in ex vivo cultures.
Asymmetric introgression between sympatric molestus and pipiens forms of Culex pipiens (Diptera: Culicidae) in the Comporta region, Portugal
Authors: Gomes Bruno , Sousa Carla A , Novo Maria T , Freitas Ferdinando B , Alves Ricardo , Côrte-Real Ana R , Salgueiro Patrícia , Donnelly Martin J , Almeida António PG , Pinto João
Published: November 2009

Background

Culex pipiensL. is the most widespread mosquito vector in temperate regions. This species consists of two forms, denoted molestus and pipiens, that exhibit important behavioural and physiological differences. The evolutionary relationships and taxonomic status of these forms remain unclear. In northern European latitudes molestus and pipiens populations occupy different habitats (undergroundvs. aboveground), a separation that most likely promotes genetic isolation between forms. However, the same does not hold in southern Europe where both forms occur aboveground in sympatry. In these southern habitats, the extent of hybridisation and its impact on the extent of genetic divergence between forms under sympatric conditions has not been clarified. For this purpose, we have used phenotypic and genetic data to characteriseCx. pipienscollected aboveground in Portugal. Our aims were to determine levels of genetic differentiation and the degree of hybridisation between forms occurring in sympatry, and to relate these with both evolutionary and epidemiological tenets of this biological group.

Results

Autogeny and stenogamy was evaluated in the F1 progeny of 145 individualCx. pipiensfemales. Bayesian clustering analysis based on the genotypes of 13 microsatellites revealed two distinct genetic clusters that were highly correlated with the alternative traits that define pipiens and molestus. Admixture analysis yielded hybrid rate estimates of 8-10%. Higher proportions of admixture were observed in pipiens individuals suggesting that more molestus genes are being introgressed into the pipiens form than the opposite.

Conclusion

Both physiological/behavioural and genetic data provide evidence for the sympatric occurrence of molestus and pipiens forms ofCx. pipiensin the study area. In spite of the significant genetic differentiation between forms, hybridisation occurs at considerable levels. The observed pattern of asymmetric introgression probably relates to the different mating strategies adopted by each form. Furthermore, the differential introgression of molestus genes into the pipiens form may induce a more opportunistic biting behaviour in the latter thus potentiating its capacity to act as a bridge-vector for the transmission of arboviral infections.
Evolution of genomic sequence inhomogeneity at mid-range scales
Authors: Prakash Ashwin , Shepard Samuel S , He Jie , Hart Benjamin , Chen Miao , Amarachintha Surya P , Mileyeva-Biebesheimer Olga , Bechtel Jason , Fedorov Alexei
Published: November 2009

Background

Mid-range inhomogeneity or MRI is the significant enrichment of particular nucleotides in genomic sequences extending from 30 up to several thousands of nucleotides. The best-known manifestation of MRI is CpG islands representing CG-rich regions. Recently it was demonstrated that MRI could be observed not only for G+C content but also for all other nucleotide pairings (e.g. A+G and G+T) as well as for individual bases. Various types of MRI regions are 4-20 times enriched in mammalian genomes compared to their occurrences in random models.

Results

This paper explores how different types of mutations change MRI regions. Human, chimpanzee and Macaca mulatta genomes were aligned to study the projected effects of substitutions and indels on human sequence evolution within both MRI regions and control regions of average nucleotide composition. Over 18.8 million fixed point substitutions, 3.9 million SNPs, and indels spanning 6.9 Mb were procured and evaluated in human. They include 1.8 Mb substitutions and 1.9 Mb indels within MRI regions. Ancestral and mutant (derived) alleles for substitutions have been determined. Substitutions were grouped according to their fixation within human populations: fixed substitutions (from the human-chimp-macaca alignment), major SNPs (> 80% mutant allele frequency within humans), medium SNPs (20% - 80% mutant allele frequency), minor SNPs (3% - 20%), and rare SNPs (<3%). Data on short (< 3 bp) and medium-length (3 - 50 bp) insertions and deletions within MRI regions and appropriate control regions were analyzed for the effect of indels on the expansion or diminution of such regions as well as on changing nucleotide composition.

Conclusion

MRI regions have comparable levels of de novo mutations to the control genomic sequences with average base composition. De novo substitutions rapidly erode MRI regions, bringing their nucleotide composition toward genome-average levels. However, those substitutions that favor the maintenance of MRI properties have a higher chance to spread through the entire population. Indels have a clear tendency to maintain MRI features yet they have a smaller impact than substitutions. All in all, the observed fixation bias for mutations helps to preserve MRI regions during evolution.
Plasmodium falciparum exposure in utero, maternal age and parity influence the innate activation of foetal antigen presenting cells
Authors: Fievet Nadine , Varani Stefania , Ibitokou Samad , Briand Valérie , Louis Stéphanie , Perrin René Xavier , Massougbogji Achille , Hosmalin Anne , Troye-Blomberg Marita , Deloron Philippe
Published: November 2009

Background

Malaria in pregnancy is associated with immunological abnormalities in the newborns, such as hampered T-helper 1 responses and increased T-regulatory responses, while the effect of maternal Plasmodium falciparum infection on foetal innate immunity is still controversial.

Materials and methods

The immunophenotype and cytokine release by dendritic cells (DC) and monocytes were evaluated in cord blood from 59 Beninese women with or without malaria infection by using flow cytometry.

Results

Accumulation of malaria pigment in placenta was associated with a partial maturation of cord blood myeloid and plasmacytoid DC, as reflected by an up-regulated expression of the major histocompatibility complex class II molecules, but not CD86 molecules. Cells of newborns of mothers with malaria pigment in their placenta also exhibited significantly increased cytokine responses upon TLR9 stimulation. In addition, maternal age and parity influenced the absolute numbers and activation status of cord blood antigen-presenting cells. Lastly, maternal age, but not parity, influenced TLR3, 4 and 9 responses in cord blood cells.

Discussion

Our findings support the view that placental parasitization, as indicated by the presence of malaria pigment in placental leukocytes, is significantly associated with partial maturation of different DC subsets and also to slightly increased responses to TLR9 ligand in cord blood. Additionally, other factors, such as maternal age and parity should be taken into consideration when analysing foetal/neonatal innate immune responses.

Conclusion

These data advocate a possible mechanism by which PAM may modulate foetal/neonatal innate immunity.
Aurora-A down-regulates IkappaBα via Akt activation and interacts with insulin-like growth factor-1 induced phosphatidylinositol 3-kinase pathway for cancer cell survival
Authors: Yao Jin-e , Yan Min , Guan Zhong , Pan Chao-bin , Xia Liang-ping , Li Chuan-xing , Wang Li-hui , Long Zi-jie , Zhao Yan , Li Ming-wei , Zheng Fei-meng , Xu Jie , Lin Dong-jun , Liu Quentin
Published: November 2009

Background

The mitotic Aurora-A kinase exerts crucial functions in maintaining mitotic fidelity. As a bona fide oncoprotein, Aurora-A aberrant overexpression leads to oncogenic transformation. Yet, the mechanisms by which Aurora-A enhances cancer cell survival remain to be elucidated.

Results

Here, we found that Aurora-A overexpression was closely correlated with clinic stage and lymph node metastasis in tongue carcinoma. Aurora-A inhibitory VX-680 suppressed proliferation, induced apoptosis and markedly reduced migration in cancer cells. We further showed that insulin-like growth factor-1, a PI3K physiological activator, reversed VX-680-decreased cell survival and motility. Conversely, wortmannin, a PI3K inhibitor, combined with VX-680 showed a synergistic effect on inducing apoptosis and suppressing migration. In addition, Aurora-A inhibition suppressed Akt activation, and VX-680-induced apoptosis was attenuated by Myr-Akt overexpression, revealing a cross-talk between Aurora-A and PI3K pathway interacting at Akt activation. Significantly, we showed that suppression of Aurora-A decreased phosphorylated Akt and was associated with increased IkappaBα expression. By contrast, Aurora-A overexpression upregulated Akt activity and downregulated IkappaBα, these changes were accompanied by nuclear translocation of nuclear factor-κB and increased expression of its target gene Bcl-xL. Lastly, Aurora-A overexpression induced IkappaBα reduction was abrogated by suppression of Akt either chemically or genetically.

Conclusion

Taken together, our data established that Aurora-A, via activating Akt, stimulated nuclear factor-κB signaling pathway to promote cancer cell survival, and promised a novel combined chemotherapy targeting both Aurora-A and PI3K in cancer treatment.
STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect
Authors: Pitroda Sean P , Wakim Bassam T , Sood Ravi F , Beveridge Mara G , Beckett Michael A , MacDermed Dhara M , Weichselbaum Ralph R , Khodarev Nikolai N
Published: November 2009

Background

The Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumour suppressor. Recent data have identified new functions of STAT1 associated with tumourigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumourigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis and found that STAT1 is associated with regulation of energy metabolism with potential implication in the Warburg effect.

Methods

We generated a stable knockdown of STAT1 in the SCC61 human squamous cell carcinoma cell line, established tumour xenografts in athymic mice, and compared transcriptomic and proteomic profiles of STAT1 wild-type (WT) and knockdown (KD) untreated or irradiated (IR) tumours. Transcriptional profiling was based on Affymetrix Human GeneChip® Gene 1.0 ST microarrays. Proteomes were determined from the tandem mass spectrometry (MS/MS) data by searching against the human subset of the UniProt database. Data were analysed using Significance Analysis of Microarrays for ribonucleic acid and Visualize software for proteins. Functional analysis was performed with Ingenuity Pathway Analysis with statistical significance measured by Fisher's exact test.

Results

Knockdown of STAT1 led to significant growth suppression in untreated tumours and radio sensitization of irradiated tumours. These changes were accompanied by alterations in the expression of genes and proteins of glycolysis/gluconeogenesis (GG), the citrate cycle (CC) and oxidative phosphorylation (OP). Of these pathways, GG had the most concordant changes in gene and protein expression and demonstrated a STAT1-dependent expression of genes and proteins consistent with tumour-specific glycolysis. In addition, IR drastically suppressed the GG pathway in STAT1 KD tumours without significant change in STAT1 WT tumours.

Conclusion

Our results identify a previously uncharacterized function of STAT1 in tumours: expressional regulation of genes encoding proteins involved in glycolysis, the citrate cycle and mitochondrial oxidative phosphorylation, with predominant regulation of glycolytic genes. STAT1-dependent expressional regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect.
Phylogenetic analysis of Newcastle disease viruses isolated from waterfowl in the Upper Midwest Region of the United States
Authors: Jindal Naresh , Chander Yogesh , Chockalingam Ashok K , de Abin Martha , Redig Patrick T , Goyal Sagar M
Published: November 2009

Background

This study was conducted to characterize Newcastle disease virus (NDV) isolates obtained from waterfowl from the Upper Midwest region of the United States. A total of 43 NDVs were isolated by inoculation of cloacal samples in embryonated chicken eggs. These isolates were obtained from 24 mallards, seven American green-winged teals, six northern pintails, four blue-winged teals, and two wood ducks. Partial sequences of fusion gene were analyzed to determine the pathotypes and genotypes involved.

Results

Deduced amino acid sequence of the cleavage site of fusion (F) protein revealed that all isolates had avirulent motifs. Of the 43 isolates, 23 exhibited sequence motif of 111GGKQGRL117 at the cleavage site, 19 exhibited 111GEKQGRL117 while one isolate showed 111GERQGRL117. Phylogenetic analysis based on comparison with different classes of NDVs revealed that all 43 isolates clustered with class II NDVs and none with class I NDVs. Within class II, five isolates were phylogenetically close to genotype I NDVs while the remaining 38 were close to genotype II.

Conclusion

We conclude that more than one genotype of NDV circulates in waterfowl in the Upper Midwest region of the US. Continuous surveillance may help better understand the epidemiology of NDVs maintained in wild bird populations and their relationship to NDVs in domestic poultry, if any.
Hes-6, an inhibitor of Hes-1, is regulated by 17β-estradiol and promotes breast cancer cell proliferation
Authors: Hartman Johan , Lam Eric W-F , Gustafsson Jan-Åke , Ström Anders
Published: November 2009

Introduction

Hes-6 is a member of the basic helix-loop-helix (bHLH) family of transcription factors, and its overexpression has been reported in metastatic cancers of different origins. Hes-6 has been described as an inhibitor of Hes-1 during neuronal development, although its function in cancer is not known. In this study, we investigated the function of Hes-6 in breast cancer and tested the hypothesis that Hes-6 enhances breast cancer cell proliferation and is regulated by estrogen.

Methods

To investigate the function of Hes-6, T47D cells stably expressing Hes-6 were generated by lentiviral transduction, and conversely, siRNA also was used to knock down Hes-6 expression in breast cancer cells. The Hes-6-expressing T47D cells were transplanted into immunodeficient mice to study effects on tumor growth.

Results

We found that Hes-6 expression was significantly higher in the high-grade, estrogen receptor (ER)α-negative SKBR3 and MDA-MB-231 cells compared with the ERα-positive, non-metastasizing T47D and MCF-7 breast carcinoma cells. Moreover, the level of Hes-6 mRNA was 28 times higher in breast cancer samples compared with normal breast samples. In Hes-6-expressing T47D cells, Hes-6 ectopic expression was shown to stimulate cell proliferation in vitro as well as breast tumor growth in xenografts. Moreover, expression of Hes-6 resulted in induction of E2F-1, a crucial target gene for the transcriptional repressor Hes-1. Consistently, silencing of Hes-6 by siRNA resulted in downregulation of E2F-1 expression, whereas estrogen treatment caused induction of Hes-6 and downstream targets hASH-1 and E2F-1 in MCF-7 cells.

Conclusions

Together, the data suggest that Hes-6 is a potential oncogene overexpressed in breast cancer, with a tumor-promoting and proliferative function. Furthermore, Hes-6 is a novel estrogen-regulated gene in breast cancer cells. An understanding of the role and regulation of Hes-6 could provide insights into estrogen signaling and endocrine resistance in breast cancer and, hence, could be important for the development of novel anticancer drugs.
Management of severe crush injury in a front-line tent ICU after 2008 Wenchuan earthquake in China: an experience with 32 cases
Authors: Li Wenfang , Qian Jun , Liu Xuefen , Zhang Qiang , Wang Lv , Chen Dechang , Lin Zhaofen
Published: November 2009

Introduction

The experience on management of crush injury after a devastating earthquake is lacking, and there are even less reports on the front-line critical care of these patients. A front-line intensive care unit (ICU) was set up in a tent after the disastrous Wenchuan earthquake (May, 12, 2008, China), where 32 patients suffering from crush injury were treated from May 12 to May 26. This study summarized our experience on management of 32 crush injury patients in a front-line tent ICU.

Methods

We retrospectively analyzed the clinical data of 32 crush injury patients treated in our frontline tent ICU. Using limited equipment, we observed the arterial blood gas parameters, blood routine, alanine aminotransferase, lactate dehydrogenase, creatine kinase, creatinine, blood urea nitrogen, and urine protein of patients. We also closely watched for changes in crush injury symptoms, urine output, and the dangerous complications of crush injury.

Results

Eighteen of the 32 patients developed traumatic shock, 9 had acute renal failure, 6 had acute heart failure, 2 had stress ulcers and 4 had multiple organ dysfunction syndrome (MODS). The symptoms of 17 patients met the criteria of crush syndrome; hemodialysis and prompt surgical intervention were given to them when necessary. Prompt treatment in our tent ICU improved the symptoms of patients to different degrees. The limb distension and sensory dysfunction were improved and the urine output was increased or even restored to the normal level in some patients. Serological parameters were improved in most patients after admission. Five (15.63%) patients underwent amputation due to severe infection in our group. Six (18.75%) patients died, 4 due to MODS and 2 due to acute renal failure.

Conclusions

Severe crushing injuries and life-threatening complications are major causes of death after major disasters like earthquakes. Prompt treatment and close monitoring of the severe complications are of great importance in saving patients' lives. Establishment of a well-equipped front-line ICU close to the epicentre of the earthquake allows for prompt on the spot rescue of critical patients with crush injury, greatly decreasing the mortality rate and complications and avoiding amputation. There should be sufficient equipment to meet the needs of more patients.
Generalized immune activation as a direct result of activated CD4+T cell killing
Authors: Marques Rute , Williams Adam , Eksmond Urszula , Wullaert Andy , Killeen Nigel , Pasparakis Manolis , Kioussis Dimitris , Kassiotis George
Published: November 2009

Background

In addition to progressive CD4+ T cell immune deficiency, HIV infection is characterized by generalized immune activation, thought to arise from increased microbial exposure resulting from diminishing immunity.

Results

Here we report that, in a virus-free mouse model, conditional ablation of activated CD4+ T cells, the targets of immunodeficiency viruses, accelerates their turnover and produces CD4+ T cell immune deficiency. More importantly, activated CD4+ T cell killing also results in generalized immune activation, which is attributable to regulatory CD4+ T cell insufficiency and preventable by regulatory CD4+ T cell reconstitution. Immune activation in this model develops independently of microbial exposure. Furthermore, microbial translocation in mice with conditional disruption of intestinal epithelial integrity affects myeloid but not T cell homeostasis.

Conclusions

Although neither ablation of activated CD4+ T cells nor disruption of intestinal epithelial integrity in mice fully reproduces every aspect of HIV-associated immune dysfunction in humans, ablation of activated CD4+ T cells, but not disruption of intestinal epithelial integrity, approximates the two key immune alterations in HIV infection: CD4+ T cell immune deficiency and generalized immune activation. We therefore propose activated CD4+ T cell killing as a common etiology for both immune deficiency and activation in HIV infection.

See minireview http://www.jbiol.com/content/8/10/91
Activation-induced accumulation of B and T lymphocyte attenuator at the immunological synapse in CD4+ T cells
Authors: Owada Takayoshi , Watanabe Norihiko , Oki Mie , Oya Yoshihiro , Saito Yasushi , Saito Takashi , Iwamoto Itsuo , Murphy Theresa L , Murphy Kenneth M , Nakajima Hiroshi
Published: November 2009

The surface expression of BTLA and its accumulation at the immunological synapse are tightly regulated by TCR and HVEM stimulation in CD4+ T cells.

BTLA, a recently cloned coreceptor expressed on lymphocytes, negatively regulates cell activation by recruiting SHP-1/SHP-2. However, the mechanisms that regulate the intracellular localization of BTLA and its trafficking to the cell surface in T cells are still unknown. To determine the mechanisms that regulate the expression of BTLA on the surface of T cells, we examined the subcellular localization of BTLA in mouse T cells in a steady state, as well as upon activation by using a confocal laser-scanning microscopy. We found that BTLA was localized mainly in the Golgi apparatus and secretory lysosomes in resting CD4+ T cells. We also found that intracellular BTLA was translocated to the cell surface and accumulated at the immunological synapse upon TCR stimulation. Furthermore, we found that the BTLA-HVEM interaction was required for the association of BTLA with lipid rafts. These results indicate that the surface expression of BTLA and its accumulation at the immunological synapse are tightly regulated by TCR and HVEM stimulation to deliver efficient inhibitory signals in the regulation of CD4+ T cell activation.
Induction of HIF-1α and the glycolytic pathway alters apoptotic and differentiation profiles of activated human T cells
Authors: Larbi Anis , Zelba Henning , Goldeck David , Pawelec Graham
Published: November 2009

T cell differentiation and functions are altered at low oxygen, possibly via HIF-1α and glycolysis up-regulation.

The majority of in vitro studies involving lymphocytes is performed in AtmO2, and the PhysO2 that T cells encounter are variable but commonly much lower. Previous studies showed changed kinetics and delayed proliferation of human T cells at PhysO2. Here, we show that CD3/CD28-dependent T cell activation induces faster cell cycling at AtmO2 than at PhysO2 (here taken to be 2%). Concomitantly with HIF-1α expression, we observed a switch in the T cell respiratory pathway toward glycolysis at PhysO2. Thus, modulating available glucose levels showed that at PhysO2, T cells rely more on glycolysis, associated with a higher phosphorylation of Aktser473. Although no difference in spontaneous apoptosis of resting cells was detected, it was increased significantly at PhysO2 after T cell activation and was different within the different T cell subsets. This may explain at least partly the differently altered proliferation and subset distribution observed in CD4+ and CD8+ T cells as a result of differences in naïve and memory subset distribution. Together, these findings suggest that T cell activation thresholds, subsequent proliferative capacity, and susceptibility to apoptosis, hitherto studied in air and thought to be crucial for monitoring immune responsiveness, may require re-assessment.
Stress‐induced Alternative Splicing Modulations in Brain and Periphery
Authors: Shaked Iftach , Zimmerman Gabriel , Soreq Hermona
Published: November 2009

Mammalian stress responses present a case study for investigating alternative splicing reactions in general, and changes in acetylcholinesterase (AChE) gene expression in particular, under endangered homeostasis. Acetylcholine (ACh) is a major regulator of stress responses, which was recently found to function as an essential route by which neurons can “talk” to immune cells. Therefore, chemical, physical, or psychological insults to the brain might all be traced in peripheral immune cells, which serve as key determinants in the physiological reactions to stress. Stress‐induced changes in the alternative splicing patterns of AChE pre‐mRNA give this gene and its different protein products diverse stress responsive functions that are associated with both the enzymatic and noncatalytic properties of AChE variants. Transgenic manipulations of AChE gene expression uncovered previously nonperceived aspects of stress responses, including brain‐to‐blood as well as immune‐to‐neuronal communication. Herein we discuss the newly gained understanding achieved by using genomic manipulations of AChE gene expression as tools for approaching the alternative splicing features of mammalian stress responses.
Gender‐specific Regulation of the Hypothalamo‐pituitary‐adrenal axis and the Role of Vasopressin during the Neonatal Period
Authors: Makara Gábor B. , Domokos Ágnes , Mergl Zsuzsa , Csabai Katalin , Barna István , Zelena Dóra
Published: November 2009

Studies in arginine vasopressin (AVP)‐deficient Brattleboro rats suggest that AVP is the predominant secretagogue during the perinatal period. Here we tested the hypothesis that congenital lack of vasopressin differentially modifies the stress reactivity of male and female rat pups. Vasopressin‐producing (heterozygous, AVP+) and AVP‐deficient (AVP−) Brattleboro rat pups of both genders were used. In 10‐day‐old pups, 24‐h maternal separation and single, as well as repeated, ether inhalation induced remarkable adrenocorticotropin (ACTH) elevation only in AVP+ pups, supporting the role of vasopressin in hypothalamo‐pituitary‐adrenal (HPA) axis regulation. Surprisingly, the corticosterone elevations were even more pronounced in AVP− pups, suggesting the possibility of an ACTH‐independent corticosterone‐secretion regulation. In the case of maternal separation, both the plasma ACTH and corticosterone levels were higher in females than in males, while in case of ether inhalation only the ACTH levels were higher in females. Gender did not influence the stress reactivity or the effect of the genotype. We conclude that the gender of the pups did not profoundly influence HPA axis activity (the mechanism seems to be the same), but in contrast to the general view, we suggest that the females have a more active HPA axis than the males already during the neonatal period. However, the resting corticosterone elevation—well known in adult females— is missing.
Contribution of Glucocorticoids to Protective Influence of Preconditioning Mild Stress against Stress‐induced Gastric Erosions
Authors: Filaretova L. P. , Bagaeva T. R. , Amagase K. , Takeuchi K.
Published: November 2009

It is known that preconditioning stress may attenuate stress‐induced gastric injury and that this effect is mediated by prostaglandins. In the present study we investigated the contribution of glucocorticoids to the gastroprotective effect of preconditioning stress. The effects of mild stress on gastric erosion caused by severe stress were compared in rats with normal and deficient corticosterone response to preconditioning mild stress. Mild stress decreased the gastric ulceration caused by severe stress, and this effect was prevented by glucocorticoid deficiency during mild stress. The results suggest that glucocorticoids released during preconditioning mild stress contribute to the gastroprotective effect of this stress.
From Hans Selye's Discovery of Biological Stress to the Identification of Corticotropin‐ Releasing Factor Signaling Pathways
Authors: Taché Yvette , Brunnhuber Stefan
Published: November 2009

Selye pioneered the concept of biological stress in 1936, culminating in the identification of the corticotropin‐releasing factor (CRF) signaling pathways by Vale's group in the last two decades. The characterization of the 41 amino‐acid CRF and other peptide members of the mammalian CRF family, urocortin 1, urocortin 2, and urocortin 3, and the cloning of CRF1and CRF2receptors, which display distinct affinity for CRF ligands, combined with the development of selective CRF receptor antagonists enable us to unravel the importance of CRF1receptor in the stress‐related endocrine (activation of pituitary‐adrenal axis), behavioral (anxiety/depression, altered feeding), autonomic (activation of sympathetic nervous system), and immune responses. The activation of CRF1receptors is also one of the key mechanisms through which various stressors impact the gut to stimulate colonic propulsive motor function and to induce hypersensitivity to colorectal distension as shown by the efficacy of the CRF1receptor antagonists in blunting these stress‐related components. The importance of CRF1signaling pathway in the visceral response to stress in experimental animals provided new therapeutic approaches for treatment of functional bowel disorder such as irritable bowel syndrome, a multifactor functional disorder characterized by altered bowel habits and visceral pain, for which stress has been implicated in the pathophysiology and is associated with anxiety‐depression in a subset of patients.
Limbic Regulation of Hypothalamo‐Pituitary‐Adrenocortical Function during Acute and Chronic Stress
Authors: Jankord Ryan , Herman James P.
Published: November 2009

The hypothalamo‐pituitary‐adrenocortical (HPA) axis is responsible for initiation of glucocorticoid stress responses in all vertebrate animals. Activation of the axis is regulated by diverse afferent input to the hypothalamic paraventricular nucleus (PVN). This review discusses brain mechanisms subserving generation and inhibition of stress responses focusing on the contribution of the limbic system and highlighting recent conceptual advances regarding organization of stress response pathways in the brain. First, control of HPA axis responses to psychogenic stimuli is exerted by a complex neurocircuitry that involves oligosynaptic networks between limbic forebrain structures and the PVN. Second, individual stress‐modulatory structures can have a heterogeneous impact on HPA axis responses, based on anatomical micro‐organization and/or stimulus properties. Finally, HPA axis hyperactivity pursuant to chronic stress involves a substantial functional and perhaps anatomical reorganization of central stress‐integrative circuits. Overall, the data suggest that individual brain regions do not merely function as monolithic activators or inhibitors of the HPA axis and that network approaches need be taken to fully understand the nature of the neuroendocrine stress response.
Chronic Stress and Individual Vulnerability
Authors: Schmidt Mathias V. , Sterlemann Vera , Müller Marianne B.
Published: November 2009

Over the last decades the burden of disease in Western countries has shifted from comparably easily treated infectious diseases to more complex diseases, such as the metabolic syndrome, cardiovascular disease, and psychiatric disorders. A common characteristic of these illnesses is the interplay of multiple genetic and nongenetic factors, which eventually results in the manifestation of disease symptoms. Large‐scale epidemiological studies in humans have resulted in the identification of various environmental and genetic risk factors, which contribute to the onset, duration, and severity of disease. While tremendous progress has been made, it is still impossible to predict which combination of risk factors will result in the manifestation of a specific illness. This lack of knowledge is also frequently reflected in inadequate treatment strategies, which mainly focus on symptom reversal rather than targeting the cause of the diseases. One of the most prominent environmental risk factors described for numerous diseases is chronic exposure to stressful situations. In this paper we address clinical and preclinical evidence of chronic stress as a risk factor for disease and introduce a novel, high‐throughput mouse model for chronic social stress. We can show that this model has a high degree of construct, face, and predictive validity in terms of physiological, behavioral, and gene expression changes. We further illustrate how novel animal models of chronic social stress can help to unravel the complex interaction of individual genetic vulnerability and environmental risk factors.
Sex‐specific Prenatal Programming
Authors: Klingmann P. O. , Kugler I. , Steffke T. S. , Bellingrath S. , Kudielka B. M. , Hellhammer D. H.
Published: November 2009

Women are four to eight times more likely to be affected by fibromyalgia syndrome (FMS). A lack of cortisol, potentially due to an adrenocortical deficit is postulated in FMS. The cause of such adrenal insufficiency is unknown. It could be assumed that stress exposure during critical periods contributes to vulnerability for FMS. These critical periods might include prenatal periods in which adversities may lead to an impaired development of the adrenal cortex, especially in females. More than 50% of FMS patients report major life events before the onset of the disease. Possibly due to adrenal insufficiency they may not be able to dampen their stress response by secreting sufficient glucocorticoids. Thus, stress mediators, such as catecholamines and pro‐inflammatory cytokines, may be disinhibited and affect brain function. This might result in an enhanced responsiveness to external and internal pain‐ and fatigue‐eliciting stimuli. In a study with female FMS patients (N= 93) those patients with a shorter gestational length (<38 weeks) showed a lower cortisol awakening response (CAR) than FMS subjects with a gestational length >38 weeks (F(3,31)= 2.94,P= 0.038). Additionally, more than 70% reported severe psychological stress alone or in combination with other factors at disease onset.
Gene Expression of Adrenoceptors in the Hearts of Cold‐Acclimated Rats Exposed to a Novel Stressor
Authors: Tillinger Andrej , Mysliveček Jaromír , Nováková Martina , Krizanova Olga , Kvetňanský Richard
Published: November 2009

Changes in the heart rate and force of contraction are regulated by catecholamines via adrenoceptors (AR). In this work, we measured gene expression of AR in left heart atria and ventricles in rats exposed to cold stress and in cold‐acclimated rats exposed to a novel stressor (immobilization). We found a significant increase in β3‐AR in left ventricle of rats exposed to acute (1 day) and long‐term (28 days) cold, but no changes in β1‐ and β2‐AR mRNA levels. However, single immobilization significantly decreased β2‐AR mRNA levels both in left atria and ventricles compared to acute cold stress. Application of a novel stressor (immobilization) to previously cold‐acclimated animals did not show decrease of β2‐AR mRNA levels as seen in intact animals. Moreover, β1‐ and β2‐AR did not show any significant changes. Surprisingly, the most prominent changes in the heart were detected for α1B‐AR gene expression. We found decreased levels of α1B‐AR mRNA in the heart of rats exposed to cold and immobilization. We also found that exposure of cold‐acclimated rats to immobilization is responsible for additional decrease of α1B‐AR mRNA levels in heart. It seems that while β‐AR undergoes adaptation, α1B‐AR is probably prepared to modulate heart functions. Proposed mechanism of β‐AR adaptation needs to be elucidated. Thus, we have shown that gene expression of different AR subtypes in the heart is regulated differently by various stressors. A protective role of β2‐, β3‐AR, and α1B‐AR in the process of heart adaptation to chronic stress exposure is proposed.
Regulation of Adrenoceptor and Muscarinic Receptor Gene Expression after Single and Repeated Stress
Authors: Myslivecek Jaromir , Tillinger Andrej , Novakova Martina , Kvetňanský Richard
Published: November 2009

Although stress is tightly connected with elevated levels of catecholamines, stress effects on target structures of catecholamine action—adrenoceptors (ARs)—has not been deeply studied yet. Similarly, very little is known about changes of muscarinic receptors (MRs) during stress. We determined changes in these receptors in the individual parts of the heart (right atria and ventricles) of animals (rats and mice) exposed to a single and repeated immobilization stress. Changes of tissue catecholamines, β2‐AR gene expression, protein levels, and binding sites were determined in rat right ventricles, and changes in β1‐, β2‐, and β3‐AR gene expression were followed in murine right atria. Tissue catecholamines were elevated, while β2‐AR mRNA levels and β2‐AR proteins and binding were decreased, in rat right ventricles. In murine right atria, β1‐ and β2‐AR gene expression was elevated, while β3‐AR mRNA levels and M2‐MR were reduced. Taken together, our data show that interaction of AR and MR is important for the organism coping with stress and that different heart regions reveal distinct reactions to stress.
Reduced Hypothalamo‐pituitary‐adrenal Axis Stress Responses in Late Pregnancy
Authors: Russell John A. , Douglas Alison J. , Brunton Paula J.
Published: November 2009

In late pregnancy, the hypothalamo‐pituitary‐adrenal (HPA) axis is less responsive to a range of psychological and physical stressors as a result of reduced central drive to the corticotropin‐releasing hormone (CRH) neurons in the paraventricular nucleus (PVN). Most stressors activate the brain stem noradrenergic system, which innervates the majority of networks involved in regulating stress responses, including the PVN. Forced swimming, systemic interleukin‐1β (IL‐1β), and cholecystokinin (CCK) all activate brain stem noradrenergic cell groups, stimulate noradrenaline release in the PVN, and activate the HPA axis in nonpregnant rats. However, in late pregnancy we have shown that forced swimming and IL‐1β fail to evoke noradrenaline release in the PVN and hence HPA axis responses are suppressed. HPA axis responses to IL‐1β and CCK can be reinstated in pregnant rats by systemic administration of the opioid receptor antagonist naloxone, and when infused directly into the PVN, naloxone restores noradrenaline release in the PVN following IL‐1β treatment. Adrenaline release into the blood following stress is also attenuated in late pregnancy, despite increased adrenomedullary expression of tyrosine hydroxylase mRNA at this time. This review describes the mechanisms underlying attenuated HPA axis stress responses in pregnancy, focusing on the role of endogenous opioids and the central noradrenergic system.
Stress‐induced Intercellular Communication Remodeling in the Rat Adrenal Medulla
Authors: Colomer Claude , Lafont Chrystel , Guérineau Nathalie C.
Published: November 2009

To understand the mechanisms by which a prolonged exposure to stress enhances catecholamine secretion, we examined the effects of 5‐day cold exposure on cell–cell communication pathways in the rat adrenal medulla. Upon stress, the neurosecretory tissue undergoes dramatic morphofunctional changes resulting in increased chromaffin cell excitability, upregulation of both chemical transmission at the splanchnic nerve terminal–chromaffin cell synapses and spreading of gap junction–permeant Lucifer yellow between cells. All these changes converge to improve the stimulus‐secretion coupling efficiency within the adrenal medulla and subsequently to adapt catecholamine release to a sustained organism demand.
Response of the Adrenomedullary System to Early Postnatal Stress in the Brattleboro Rat
Authors: Zelena Dóra , Barna István , Csabai Katalin , Orlando Gabriella F. , Makara Gábor B. , Engelmann Mario
Published: November 2009

The sympathetic‐adrenomedullary system and the pituitary‐adrenocortical axis are linked to each other by chemical signals transferring information between both endocrine systems. Here we addressed the question of whether the neuropeptide arginine vasopressin (AVP) is involved in this type of information transfer during early postnatal development. The impact of congenital absence of AVP on the endocrine stress response was investigated using the AVP‐deficient Brattleboro rat. Under resting conditions, we failed measure a significant difference in plasma norepinephrine levels between 10‐day‐old AVP‐deficient homozygous juveniles versus heterozygous AVP‐producing littermates. Interestingly, repeated ether exposure resulted in a reduction of plasma epinephrine levels in both genotypes. In the adrenal, we detected increased levels of the epinephrine‐synthesizing enzyme phenylethanolamine‐N‐methyltransferase (PNMT) after ether inhalation in vasopressin‐deficient pups only. These data provide insight into the development of the regulation of stress‐related epinephrine secretion during ontogenesis. Furthermore, our results imply that the congenital absence of AVP affects the synthesis of PNMT in response to defined stressor exposure.