bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response rate of fibrosarcoma cells to cytotoxic drugs on the expression level correlates to the therapeutic response rate of fibrosarcomas and is mediated by regulation of apoptotic pathways
Authors: Lehnhardt Marcus , Klein-Hitpass Ludger , Kuhnen Cornelius , Homann Heinz Herbert , Daigeler Adrien , Steinau Hans Ulrich , Roehrs Sonja , Schnoor Laura , Steinstraesser Lars , Mueller Oliver 
Published: July 2005

Abstract
Background
Because of the high resistance rate of fibrosarcomas against cytotoxic agents clinical chemotherapy of these tumors is not established. A better understanding of the diverse modes of tumor cell death following cytotoxic therapies will provide a molecular basis for new chemotherapeutic strategies. In this study we elucidated the response of a fibrosarcoma cell line to clinically used cytostatic agents on the level of gene expression.

Methods
HT1080 fibrosarcoma cells were exposed to the chemotherapeutic agents doxorubicin, actinomycin D or vincristine. Total RNA was isolated and the gene expression patterns were analyzed by microarray analysis. Expression levels for 46 selected candidate genes were validated by quantitative real-time PCR.

Results
The analysis of the microarray data resulted in 3.309 (actinomycin D), 1.019 (doxorubicin) and 134 (vincristine) probesets that showed significant expression changes. For the RNA synthesis blocker actinomycin D, 99.4% of all differentially expressed probesets were under-represented. In comparison, probesets down-regulated by doxorubicin comprised only 37.4% of all genes effected by this agent. Closer analysis of the differentially regulated genes revealed that doxorubicin induced cell death of HT1080 fibrosarcoma cells mainly by regulating the abundance of factors mediating the mitochondrial (intrinsic) apoptosis pathway. Furthermore doxorubicin influences other pathways and crosstalk to other pathways (including to the death receptor pathway) at multiple levels. We found increased levels of cytochrome c, APAF-1 and members of the STAT-family (STAT1, STAT3), while Bcl-2 expression was decreased. Caspase-1, -3, -6, -8, and -9 were increased indicating that these proteases are key factors in the execution of doxorubicin mediated apoptosis.

Conclusion
This study demonstrates that chemotherapy regulates the expression of apoptosis-related factors in fibrosarcoma cells. The number and the specific pattern of the genes depend on the used cytotoxic drug. The response rates on the gene expression level, i.e. the number of genes regulated by the drugs actinomycin D, doxorubicin and vincristine, correlate to the clinical effectiveness of the drugs. Doxorubicin seems to exert its cytotoxic mechanism by regulating genes, which are involved in several different apoptosis regulating pathways. The exact knowledge of the genes affected by the drugs will help to understand the diverse modes of soft tissue sarcoma cell death in response to cytotoxic therapies.
Global gene expression analysis in time series following N-acetyl L-cysteine induced epithelial differentiation of human normal and cancer cells in vitro
Authors: Gustafsson Anna C , Kupershmidt Ilya , Edlundh-Rose Esther , Greco Giulia , Serafino Annalucia , Krasnowska Eva K , Lundeberg Thomas , Bracci-Laudiero Luisa , Romano Maria-Concetta , Parasassi Tiziana , Lundeberg Joakim 
Published: July 2005

Abstract
Background
Cancer prevention trials using different types of antioxidant supplements have been carried out at several occasions and one of the investigated compounds has been the antioxidant N-acetyl-L-cysteine (NAC). Studies at the cellular level have previously demonstrated that a single supplementation of NAC induces a ten-fold more rapid differentiation in normal primary human keratinocytes as well as a reversion of a colon carcinoma cell line from neoplastic proliferation to apical-basolateral differentiation [1]. The investigated cells showed an early change in the organization of the cytoskeleton, several newly established adherens junctions with E-cadherin/β-catenin complexes and increased focal adhesions, all features characterizing the differentiation process.

Methods
In order to investigate the molecular mechanisms underlying the proliferation arrest and accelerated differentiation induced by NAC treatment of NHEK and Caco-2 cells in vitro, we performed global gene expression analysis of NAC treated cells in a time series (1, 12 and 24 hours post NAC treatment) using the Affymetrix GeneChip™ Human Genome U95Av2 chip, which contains approximately 12,000 previously characterized sequences. The treated samples were compared to the corresponding untreated culture at the same time point.

Results
Microarray data analysis revealed an increasing number of differentially expressed transcripts over time upon NAC treatment. The early response (1 hour) was transient, while a constitutive trend was commonly found among genes differentially regulated at later time points (12 and 24 hours). Connections to the induction of differentiation and inhibition of growth were identified for a majority of up- and down-regulated genes. All of the observed transcriptional changes, except for seven genes, were unique to either cell line. Only one gene, ID-1, was mutually regulated at 1 hour post treatment and might represent a common mediator of early NAC action.
The detection of several genes that previously have been identified as stimulated or repressed during the differentiation of NHEK and Caco-2 provided validation of results. In addition, real-time kinetic PCR analysis of selected genes also verified the differential regulation as identified by the microarray platform.

Conclusion
NAC induces a limited and transient early response followed by a more consistent and extensively different expression at later time points in both the normal and cancer cell lines investigated. The responses are largely related to inhibition of proliferation and stimulation of differentiation in both cell types but are almost completely lineage specific. ID-1 is indicated as an early mediator of NAC action.
College campus smoking policies and programs and students' smoking behaviors
Authors: Borders Tyrone F , Xu K Tom , Bacchi Donna , Cohen Lee , SoRelle-Miner Danielle 
Published: July 2005

AbstractBackgroundAlthough tobacco use in the United States has declined over the past 20 years, cigarette use among college students remains high. Additional research is thus needed to determine how university tobacco control policies and preventive education programs affect college students' smoking behaviors.MethodsApproximately 13,000 undergraduate students at 12 universities or colleges in the state of Texas completed a web-based survey. College smoking policies were obtained from a survey of college administrators and from college websites. Logistic regression analyses were conducted to estimate the effects of individual smoking policies and programs on the odds of cigarette smoking.ResultsOf the individual programs, only having a preventive education program on campus was associated with lower odds of smoking. The existence of smoking cessation programs and designated smoking areas were associated with higher odds of smoking. Policies governing the sale and distribution of cigarettes were insignificantly associated with smoking.ConclusionRather than focusing on policies restricting cigarette sales and use, college administrators should consider implementing or expanding tobacco prevention and education programs to further reduce student smoking rates.
Changes in P-glycoprotein activity are mediated by the growth of a tumour cell line as multicellular spheroids
Authors: Valeria Ponce de León , Raúl Barrera-Rodríguez 
Published: July 2005

Abstract

Background
Expression of P-glycoprotein (P-gp), the multidrug resistance (MDR) 1 gene product, can lead to multidrug resistance in tumours. However, the physiological role of P-gp in tumours growing as multicellular spheroids is not well understood. Recent evidence suggests that P-gp activity may be modulated by cellular components such as membrane proteins, membrane-anchoring proteins or membrane-lipid composition. Since, multicellular spheroids studies have evidenced alterations in numerous cellular components, including those related to the plasma membrane function, result plausible that some of these changes might modulate P-gp function and be responsible for the acquisition of multicellular drug resistance. In the present study, we asked if a human lung cancer cell line (INER-51) grown as multicellular spheroids can modify the P-gp activity to decrease the levels of doxorubicin (DXR) retained and increase their drug resistance.

Results
Our results showed that INER-51 spheroids retain 3-folds lower doxorubicin than the same cells as monolayers however; differences in retention were not observed when the P-gp substrate Rho-123 was used. Interestingly, neither the use of the P-gp-modulating agent cyclosporin-A (Cs-A) nor a decrease in ATP-pools were able to increase DXR retention in the multicellular spheroids. Only the lack of P-gp expression throughout the pharmacological selection of a P-gp negative (P-gpneg) mutant clone (PSC-1) derived from INER-51 cells, allow increase of DXR retention in spheroids.

Conclusion
Thus, multicellular arrangement appears to alter the P-gp activity to maintain lower levels of DXR. However, the non expression of P-gp by cells forming multicellular spheroids has only a minor impact in the resistance to chemotherapeutic agents.
Se-methylselenocysteine inhibits phosphatidylinositol 3-kinase activity of mouse mammary epithelial tumor cells in vitro
Authors: Unni Emmanual , Koul Dimpy , Yung Wai-Kwan Alfred , Sinha Raghu 
Published: July 2005

Abstract
Introduction
Se-methylselenocysteine (MSC), a naturally occurring selenium compound, is a promising chemopreventive agent against in vivo and in vitro models of carcinogen-induced mouse and rat mammary tumorigenesis. We have demonstrated previously that MSC induces apoptosis after a cell growth arrest in S phase in a mouse mammary epithelial tumor cell model (TM6 cells) in vitro. The present study was designed to examine the involvement of the phosphatidylinositol 3-kinase (PI3-K) pathway in TM6 tumor model in vitro after treatment with MSC.

Methods
Synchronized TM6 cells treated with MSC and collected at different time points were examined for PI3-K activity and Akt phosphorylation along with phosphorylations of Raf, MAP kinase/ERK kinase (MEK), extracellular signal-related kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). The growth inhibition was determined with a [3H]thymidine incorporation assay. Immunoblotting and a kinase assay were used to examine the molecules of the survival pathway.

Results
PI3-K activity was inhibited by MSC followed by dephosphorylation of Akt. The phosphorylation of p38 MAPK was also downregulated after these cells were treated with MSC. In parallel experiments MSC inhibited the Raf–MEK–ERK signaling pathway.

Conclusion
These studies suggest that MSC blocks multiple signaling pathways in mouse mammary tumor cells. MSC inhibits cell growth by inhibiting the activity of PI3-K and its downstream effector molecules in mouse mammary tumor cells in vitro.
Functional interaction between mouse erbB3 and wild-type rat c-neu in transgenic mouse mammary tumor cells
Authors: Kim Aeree , Liu Bolin , Ordonez-Ercan Dalia , Alvarez Kathy M , Jones Lynn D , McKimmey Christine , Edgerton Susan M , Yang XiaoHe , Thor Ann D 
Published: July 2005

Abstract
Introduction
Co-expression of several receptor tyrosine kinases (RTKs), including erbB2 and erbB3, is frequently identified in breast cancers. A member of the RTK family, the kinase-deficient erbB3 can activate downstream signaling via heterodimer formation with erbB2. We studied the expression of RTK receptors in mammary tumors from the wild-type (wt) rat c-neu transgenic model. We hypothesized that physical and functional interactions between the wt rat neu/ErbB2 transgene and mouse ErbB3-encoded proteins could occur, activating downstream signaling and promoting mammary oncogenesis.

Methods
Immunohistochemical and Western blot analyses were performed to study the expression of rat c-neu/ErbB2 and mouse erbB3 in mammary tumors and tumor-derived cell lines from the wt rat c-neu transgenic mice. Co-immunoprecipitation methods were employed to quantitate heterodimerization between the transgene-encoded protein erbB2 and the endogenous mouse erbB3. Tumor cell growth in response to growth factors, such as Heregulin (HRG), epidermal growth factor (EGF), or insulin-like growth factor-1 (IGF-1), was also studied. Post-HRG stimulation, activation of the RTK downstream signaling was determined by Western blot analyses using antibodies against phosphorylated Akt and mitogen-activated protein kinase (MAPK), respectively. Specific inhibitors were then used with cell proliferation assays to study the phosphoinositide-3 kinase (PI-3K)/Akt and MAPK kinase (MEK)/MAPK pathways as possible mechanisms of HRG-induced tumor cell proliferation.

Results
Mammary tumors and tumor-derived cell lines frequently exhibited elevated co-expression of erbB2 and erbB3. The transgene-encoded protein erbB2 formed a stable heterodimer complex with endogenous mouse erbB3. HRG stimulation promoted physical and functional erbB2/erbB3 interactions and tumor cell growth, whereas no response to EGF or IGF-1 was observed. HRG treatment activated both the Akt and MAPK pathways in a dose- and time-dependent manner. Both the PI-3K inhibitor LY 294002 and MEK inhibitor PD 98059 significantly decreased the stimulatory effect of HRG on tumor cell proliferation.

Conclusion
The co-expression of wt rat neu/ErbB2 transgene and mouse ErbB3, with physical and functional interactions between these two species of RTK receptors, was demonstrated. These data strongly suggest a role for erbB3 in c-neu (ErbB2)-associated mammary tumorigenesis, as has been reported in human breast cancers.
Intra-abdominal hypertension in patients with severe acute pancreatitis
Authors: De Waele Jan J , Hoste Eric , Blot Stijn I , Decruyenaere Johan , Colardyn Francis 
Published: July 2005

Abstract
Introduction
Abdominal compartment syndrome has been described in patients with severe acute pancreatitis, but its clinical impact remains unclear. We therefore studied patient factors associated with the development of intra-abdominal hypertension (IAH), the incidence of organ failure associated with IAH, and the effect on outcome in patients with severe acute pancreatitis (SAP).

Methods
We studied all patients admitted to the intensive care unit (ICU) because of SAP in a 4 year period. The incidence of IAH (defined as intra-abdominal pressure ≥ 15 mmHg) was recorded. The occurrence of organ dysfunction during ICU stay was recorded, as was the length of stay in the ICU and outcome.

Results
The analysis included 44 patients, and IAP measurements were obtained from 27 patients. IAH was found in 21 patients (78%). The maximum IAP in these patients averaged 27 mmHg. APACHE II and Ranson scores on admission were higher in patients who developed IAH. The incidence of organ dysfunction was high in patients with IAH: respiratory failure 95%, cardiovascular failure 91%, and renal failure 86%. Mortality in the patients with IAH was not significantly higher compared to patients without IAH (38% versus 16%, p = 0.63), but patients with IAH stayed significantly longer in the ICU and in the hospital. Four patients underwent abdominal decompression because of abdominal compartment syndrome, three of whom died in the early postoperative course.

Conclusion
IAH is a frequent finding in patients admitted to the ICU because of SAP, and is associated with a high occurrence rate of organ dysfunction. Mortality is high in patients with IAH, and because the direct causal relationship between IAH and organ dysfunction is not proven in patients with SAP, surgical decompression should not routinely be performed.
CD8+ T cells produce IL-2, which is required for CD4+CD25+ T cell regulation of effector CD8+ T cell development for contact hypersensitivity responses
Authors: Kish Danielle D , Gorbachev Anton V , Fairchild Robert L 
Published: July 2005

AbstractInterleukin (IL)-2 functions to promote, as well as down-regulate, expansion of antigen-reactive CD4+ and CD8+ T cells, but the role of IL-2 in hapten-specific CD8+ T cell priming for contact hypersensitivity (CHS) responses remains untested. Using enzyme-linked immunospot to enumerate numbers of hapten-specific CD4+ and CD8+ T cells producing IL-2 in hapten-sensitized mice, the number of IL-2-producing CD8+ T cells was tenfold that of CD4+ T cells. Hapten-primed D4+ T cells produced low amounts of IL-2 during culture with hapten-presenting Langerhans cells, whereas production by hapten-primed CD8+ T cells was fivefold greater. CD8+ T cells did not express CD25 during hapten priming, but treatment with anti-IL-2 or anti-CD25 monoclonal antibodies during hapten sensitization increased hapten-specific effector CD8+ T cells as well as the magnitude and duration of the CHS response. These results indicate that CD8+ T cells are the primary source of IL-2 and that this IL-2 is required for the function of a population of CD4+CD25+ T cells to restrict the development of the hapten-reactive effector CD8+ T cells that mediate CHS responses.
Recombinant dimeric MHC antigens protect cardiac allografts from rejection and visualize alloreactive T cells
Authors: Fried Ari , Berg Martina , Sharma Bhavna , Bonde Sabrina , Zavazava Nicholas 
Published: July 2005

AbstractMonomeric and dimeric soluble major histocompatibility complex (MHC) molecules down-regulate activated T cells in an antigen-specific manner in vitro. This property could be exploited to modulate alloresponses in vivo but has remained difficult to demonstrate. Here, intraperitoneal infusion of a Lewis-derived rat MHC class I molecule, RT1.Al-Fc, in Dark Agouti (RT1.Aa) recipient rats prolonged cardiac graft survival, which led to permanent engraftment. This effect was mediated by T cell impairment of target cell lysis by CD8+ T cells and down-regulation of interferon-γ production by CD4+ T cells. The binding of the dimeric MHC allowed ex vivo visualization of alloreactive T cells in peripheral blood, splenocytes, and allografts, revealing low frequency of alloreactive CD8+ T cells after establishment of permanent engraftment of cardiac allografts. Thus, these data show the potential of dimeric MHC molecules to promote graft survival and allow visualization of alloreactive T cells.
Cytokine induction of interleukin-24 in human peripheral blood mononuclear cells
Authors: Poindexter Nancy J , Walch Eugene T , Chada Sunil , Grimm Elizabeth A 
Published: July 2005

AbstractInterleukin-24 (IL-24) is a recently identified member of the IL-10 family of cytokines. It was originally identified as a tumor suppressor molecule, melanoma differentiation-associated gene 7, and then renamed IL-24 and classified as a cytokine, based on its chromosomal location in the IL-10 locus, its mRNA expression in leukocytes, and its secretory sequence elements. Here, we correlate the kinetics of IL-24 mRNA and protein expression in human peripheral blood mononuclear cells (PBMC) stimulated by polyclonal activators phytohemagglutinin (PHA) and lipopolysaccharide (LPS) or by allogeneic major histocompatbility complex. PHA-stimulated PBMC express IL-24 mRNA, reaching peak levels at 8–12 h after stimulation. Protein expression, as measured by intracellular flow cytometry, followed the message, reaching maximum expression at 24 h. Subset analysis of mitogen-stimulated PBMC showed that IL-24 was expressed primarily in T cells and macrophages. Expression of IL-24 in mitogen-stimulated PBMC is the result of cytokine stimulation. Individual cytokines including IL-2, IL-7, IL-15, tumor necrosis factor α, granulocyte macrophage-colony stimulating factor, and IL-1β stimulate the expression of IL-24 mRNA and protein, whereas interferons and T helper cell type 2 cytokines fail to induce substantial IL-24. When LPS- or PHA-stimulated cells were treated with Actinomycin D, IL-24 mRNA persisted at high levels over the 4-h course of treatment. These data strongly suggest that the expression of IL-24 in human PBMC results from cytokine stimulation and is regulated at the post-transcriptional level through stabilization of IL-24 mRNA.
Morphine inhibits CD8+ T cell-mediated, noncytolytic, anti-HIV activity in latently infected immune cells
Authors: Wang Xu , Tan Ning , Douglas Steven D , Zhang Ting , Wang Yan-Jian , Ho Wen-Zhe 
Published: July 2005

AbstractOpiates have profound effects on the function of human immune cells and are a possible cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) disease. We investigated the impact of morphine on CD8+ T cell-mediated, noncytotoxic, anti-HIV activity in latently infected human immune cells. Morphine inhibited the noncytotoxic, anti-HIV activity of CD8+ T cells in HIV latently infected cells (U1 and J1.1). Naltrexone abrogated the morphine-mediated, inhibitory effect on the noncytotoxic, anti-HIV activity of CD8+ T cells. Interferon-γ (IFN-γ), a potent antiviral cytokine produced by CD8+ T cells, was partially responsible for CD8+ T cell-mediated, noncytotoxic, anti-HIV activity. The anti-HIV activity of IFN-γ was also compromised by morphine treatment. Further, morphine attenuated CD8+ T cell-mediated suppression of the HIV long-terminal repeat promoter activation. Morphine also inhibited CD8+ T cell-induced expression of the signal transducer and activator of transcription-1, an important transcriptional factor in the IFN signaling pathway. These data provide additional evidence to support the notion that opioids play a role in impairing the anti-HIV function of the immune system.
Nitric oxide production is regulated by fever-range thermal stimulation of murine macrophages
Authors: Pritchard Michele T , Li Zihai , Repasky Elizabeth A 
Published: July 2005

AbstractAs macrophages are often called to function at times of elevated ambient temperature (e.g., during local inflammation or systemic fever), it is possible that their production of critical effector molecules, such as nitric oxide (NO) or inducible NO synthase (iNOS), is sensitive to physiological changes in temperature. To test this possibility, the threshold requirements for production of NO and iNOS in murine peritoneal macrophages maintained under normothermic conditions (37°C) or following mild (fever-range) hyperthermia (39.5°C) were compared. We found that hyperthermia alone had no observable effect on basal NO production or iNOS protein or message. However, although interferon (IFN)-γ and lipopolysaccharide (LPS) were needed to induce NO at 37°C we observed that addition of only LPS was sufficient for production of NO if there were a pretreatment at 39.5°C. Further, if IFN-γ and LPS were given after thermal exposure, a substantial increase in NO and iNOS was observed over that seen using cells kept at normothermic conditions. Macrophages isolated from mice lacking heat shock factor-1 did not attenuate the ability of mild thermal stress to modulate NO production. Reverse transcriptase-polymerase chain reaction data revealed that thermal regulation of iNOS expression is not entirely at the transcriptional level, suggesting possible points of post-transcriptional thermal sensitivity. These data support the concept that altering the thermal microenvironment is an important means by which the host can manipulate macrophage responses. Increases in temperature (e.g., during fever) may function to lower the activation threshold needed for production of effector molecules in times of infection.