bluuebunny/crossref_metadata_2025 huggingface dataset:
Bortezomib Inhibits Nuclear Factor-κB–Dependent Survival and Has Potent In vivo Activity in Mesothelioma
Authors: Sartore-Bianchi Andrea , Gasparri Fabio , Galvani Arturo , Nici Linda , Darnowski James W. , Barbone Dario , Fennell Dean A. , Gaudino Giovanni , Porta Camillo , Mutti Luciano
Published: October 2007

Purpose: Purpose of this study has been the assessment of nuclear factor-κB (NF-κB) as a survival factor in human mesothelial cells (HMC), transformed HMC and malignant mesothelioma (MMe) cells. We aimed at verifying whether the proteasome inhibitor Bortezomib could abrogate NF-κB activity in MMe cells, leading to tumor cell death and may be established as a novel treatment for this aggressive neoplasm.

Experimental Design: In HMC and MMe cells, NF-κB nuclear translocation and DNA binding were studied by electrophoretic mobility shift assay, following treatment with tumor necrosis factor-α (TNF-α). The IKK inhibitor Bay11-7082 was also tested to evaluate its effects on HMC, transformed HMC, and MMe cell viability upon exposure to asbestos fibers. Following Bortezomib treatment, cytotoxicity of MMe cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, whereas apoptosis and cell-cycle blockade were investigated by high-content analysis. Bortezomib was also given to mice bearing i.p. xenografts of MMe cells, and its effects on tumor growth were evaluated.

Results: Here, we show that NF-κB activity is a constitutive survival factor in transformed HMC, MMe cells, and acts as a survival factor in HMC exposed to asbestos fibers. Bortezomib inhibits NF-κB activity in MMe cells and induces cell cycle blockade and apoptosis in vitro as well as tumor growth inhibition in vivo.

Conclusions: Inhibition of NF-κB constitutive activation in MMe cells by Bortezomib resulted in in vitro cytotoxicity along with apoptosis and in vivo tumor regression. Our results support the use of Bortezomib in the treatment of MMe and has led to a phase II clinical trial currently enrolling in Europe.
Exisulind in Combination with Celecoxib Modulates Epidermal Growth Factor Receptor, Cyclooxygenase-2, and Cyclin D1 against Prostate Carcinogenesis:In vivoEvidence
Authors: Narayanan Bhagavathi A. , Reddy Bandaru S. , Bosland Maarten C. , Nargi Dominick , Horton Lori , Randolph Carla , Narayanan Narayanan K.
Published: October 2007

Purpose: Nonsteroidal anti-inflammatory drugs mediate anticancer effects by modulating cyclooxygenase-2 (COX-2)-dependent and/or COX-2–independent mechanism(s); however, the toxicity issue is a concern with single agents at higher doses. In this study, we determined the combined effect of celecoxib, a COX-2 inhibitor, along with exisulind (sulindac sulfone/Aptosyn) at low doses in prostate cancer.

Experimental Design: We used a sequential regimen of N-methyl-N-nitrosourea + testosterone to induce prostate cancer in Wistar-Unilever rats. Following carcinogen treatment, celecoxib and exisulind individually and their combination at low doses were given in NIH-07 diet for 52 weeks. We determined the incidence of prostatic intraepithelial neoplasia, adenocarcinomas, rate of tumor cell proliferation, and apoptosis. Immunohistochemical and Western blot analysis were done to determine COX-2, epidermal growth factor receptor (EGFR), Akt, androgen receptor, and cyclin D1 expression. Serum prostaglandin E2 and tumor necrosis factor-α levels were determined using enzyme immunoassay/ELISA assays.

Results: The rats that received celecoxib in combination with exisulind at low doses showed a significant decrease in prostatic intraepithelial neoplasia and adenocarcinomas as well as an enhanced rate of apoptosis. An overall decrease in COX-2, EGFR, Akt, androgen receptor, and cyclin D1 expression was found associated with tumor growth inhibition. Reduced serum levels of COX-2 protein, prostaglandin E2, and tumor necrosis factor-α indicated anti-inflammatory effects. A strong inhibition of total and phosphorylated form of EGFR (Tyr992 and Tyr845) and Akt (Ser473) was significant in rats given with these agents in combination.

Conclusions: In this study, we show for the first time that the combination of celecoxib with exisulind at low doses could prevent prostate carcinogenesis by altering key molecular events.
A High Tumor-Associated Macrophage Content Predicts Favorable Outcome in Follicular Lymphoma Patients Treated with Rituximab and Cyclophosphamide-Doxorubicin-Vincristine-Prednisone
Authors: Taskinen Minna , Karjalainen-Lindsberg Marja-Liisa , Nyman Heidi , Eerola Leena-Maija , Leppä Sirpa
Published: October 2007

Purpose: Tumor-associated macrophage (TAM) content predicts survival in follicular lymphoma (FL) patients treated with chemotherapy. The aim of this study was to determine how combination of rituximab with chemotherapy influences TAM-associated clinical outcome.

Experimental Design: Expression of a macrophage marker, CD68, was determined immunohistochemically from FL samples of 96 patients treated with rituximab and cyclophosphamide-Adriamycin-vincristine-prednisone regimen. Of them, 71 received therapy at diagnosis and 25 at relapse. Neutrophil and CD3+ lymphocyte counts were also measured. The median follow-up time for the cohort was 54 months. Fourty-five patients previously treated with chemotherapy served as a control group.

Results: Consistent with previous studies, high TAM amount was associated with adverse outcome in chemotherapy-treated patients (P = 0.026). In contrast, after rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone regimen, high TAM content correlated with longer survival rates. According to Kaplan Meier estimates, the median progression free survival (PFS) was not reached for patients with high TAM content compared with 45 months for patients with low TAM scores (P = 0.006). A trend toward a better overall survival (OS) at 5 years was also observed for patients with high TAM content (OS, 97% versus 90%, P = 0.116). The positive prognostic value of TAMs was seen both for the patients treated at diagnosis and at relapse. In multivariate analyses, TAM content remained an independent prognostic factor for OS and PFS. Neutrophil and CD3+ lymphocyte counts did not correlate with outcome.

Conclusions: The data suggest that high TAM score is associated with a favorable prognosis in FL patients treated with immunochemotherapy.
N-Acetylcysteine Protects Melanocytes against Oxidative Stress/Damage and Delays Onset of Ultraviolet-Induced Melanoma in Mice
Authors: Cotter Murray A. , Thomas Joshua , Cassidy Pamela , Robinette Kyle , Jenkins Noah , Florell Scott R. , Leachman Sancy , Samlowski Wolfram E. , Grossman Douglas
Published: October 2007

Purpose: UV radiation is the major environmental risk factor for melanoma and a potent inducer of oxidative stress, which is implicated in the pathogenesis of several malignancies. We evaluated whether the thiol antioxidant N-acetylcysteine (NAC) could protect melanocytes from UV-induced oxidative stress/damage in vitro and from UV-induced melanoma in vivo.

Experimental Design: In vitro experiments used the mouse melanocyte line melan-a. For in vivo experiments, mice transgenic for hepatocyte growth factor and survivin, shown previously to develop melanoma following a single neonatal dose of UV irradiation, were given NAC (7 mg/mL; mother's drinking water) transplacentally and through nursing until 2 weeks after birth.

Results: NAC (1-10 mmol/L) protected melan-a cells from several UV-induced oxidative sequelae, including production of intracellular peroxide, formation of the signature oxidative DNA lesion 8-oxoguanine, and depletion of free reduced thiols (primarily glutathione). Delivery of NAC reduced thiol depletion and blocked formation of 8-oxoguanine in mouse skin following neonatal UV treatment. Mean onset of UV-induced melanocytic tumors was significantly delayed in NAC-treated compared with control mice (21 versus 14 weeks; P = 0.0003).

Conclusions: Our data highlight the potential importance of oxidative stress in the pathogenesis of melanoma and suggest that NAC may be useful as a chemopreventive agent.
In-Treatment Resolution or Absence of Electrocardiographic Left Ventricular Hypertrophy Is Associated With Decreased Incidence of New-Onset Diabetes Mellitus in Hypertensive Patients
Authors: Okin Peter M. , Devereux Richard B. , Harris Katherine E. , Jern Sverker , Kjeldsen Sverre E. , Lindholm Lars H. , Dahlöf Björn
Published: September 2007

Treatment of hypertensive patients with electrocardiographic left ventricular hypertrophy with losartan-based therapy is associated with lower incidence of diabetes mellitus and greater regression of hypertrophy than atenolol-based therapy. However, whether in-treatment resolution or continued absence of electrocardiographic hypertrophy is independently associated with decreased incidence of diabetes is unclear. Electrocardiographic hypertrophy was evaluated over time in 7998 hypertensive patients without diabetes at baseline in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study who were treated with losartan- or atenolol-based regimens and followed with serial electrocardiograms and blood pressure determinations. Electrocardiographic hypertrophy was defined using gender-adjusted Cornell voltage-duration product criteria >2440 mm·ms. During mean follow-up of 4.6±1.2 years, diabetes developed in 562 patients (7.0%). In a Cox model adjusting for treatment assignment, in-treatment resolution or continued absence of Cornell product hypertrophy was associated with a 38% lower risk of new diabetes (HR 0.62, 95% CI 0.50 to 0.78). After adjusting for the association of new diabetes with prior antihypertensive treatment, baseline glucose, and Framingham risk score, baseline and in-treatment systolic and diastolic pressure, HDL, uric acid, and body mass index, and the decreased incidence associated with losartan-based therapy, in-treatment continued absence, or resolution of Cornell product hypertrophy remained associated with a 26% lower risk of new diabetes (HR 0.74, 95% CI 0.58 to 0.93). Thus, compared with presence of hypertrophy by Cornell product criteria during antihypertensive treatment, resolution or continued absence of Cornell product hypertrophy is associated with a lower incidence of diabetes, even after adjusting for the impact of treatment with losartan and other risk factors for diabetes.
A Multi-Level Analysis of Organizational Justice Climate, Structure, and Employee Mental Health†
Authors: Spell Chester S. , Arnold Todd J.
Published: October 2007

This study uses a sample of 483 employees to investigate how fairness assessments and organizational structure relate to employee mental health. The authors explain these effects using a social contagion framework, which describes the creation of group effects that would occur in addition to individual-level influences. They found that the interactive effects of distributive and procedural justice climates significantly influence individual feelings of both anxiety and depression. This effect goes beyond the main effects of justice at the individual level.
Understanding Collaboration Outcomes From an Extended Resource-Based View Perspective: The Roles of Organizational Characteristics, Partner Attributes, and Network Structures†
Authors: Arya Bindu , Zhiang Lin
Published: October 2007

Whereas mainstream strategy research tends to focus on atomistic and profit-seeking firms, this study focuses on not-for-profit organizations that participate in a collaboration network. Specifically, the authors extend the resource-based view by investigating how not-for-profit organizations' collaboration outcomes, reflected through a joint consideration of monetary and nonmonetary dimensions, may be affected by their organizational characteristics, partner attributes, and network structures. Their analyses of collaboration data from 52 not-for-profit networked organizations demonstrate the importance of unique resources at individual, dyadic, and network levels that allow these organizations to develop capabilities and competencies.
“I've Been Through Something”
Authors: Kooken Wendy Carter , Haase Joan E. , Russell Kathleen M.
Published: September 2007

This article describes common experiences of African American women breast cancer survivors through poetic analysis. Group-as-a-whole theory and empirical and interpretive phenomenology guided analysis of transcripts from three focus groups ( n = 21) of African American breast cancer survivors. Familiarity with transcripts and themes led to awareness of poetic ways in which African American women described experiences. Black feminist literature and African American historical references contextualized survivors' experiences. Poetic interpretations of African American women's breast cancer experiences, from diagnosis to survivorship, were created from transcript dialogues. Verbatim words were used to construct the poems, as often as possible. Eleven poems describe the journey from diagnosis to survivorship as experienced by African American women. The poetry may raise levels of awareness of African American women's breast cancer survivorship experiences. Attention to subtleties that underpin culture within the context of health care environments may help health care providers to improve cultural competence.
Between remembering and forgetting: Uruguayan military discourse about human rights (1976—2004)
Authors: Achugar Mariana
Published: September 2007

This article investigates the Uruguayan military's argumentative narrative about the last dictatorship (1973—85) in order to understand how violations of human rights are explained and justified. Through a historical perspective the investigation traces the changes and permanence of certain representational and discursive practices that construct the memory of the period. The analysis shows how the military's argumentative narrative about the dictatorship is transformed in response to challenges from other social actors, in particular historical moments. This analysis demonstrates the dynamic, historical and discursive nature of collective memory. The article also highlights how the military as an institution deals with the effects of decisions and actions that challenge its presentation of self as a positive and moral institution of society.
Construction of Europeanization in the High Representative's discourse in Bosnia and Herzegovina
Authors: Majstorović Danijela
Published: September 2007

After the Bosnian war 1992—5, the Office of the High Representative (OHR) was assigned as the most powerful international body in the country regarding implementation of the Dayton Peace Agreement and the subsequent accession of Bosnia and Herzegovina into the European Union. This study focuses on the semiotic elements of discourses of Europe and Europeanization constructed by the OHR in Bosnia and Herzegovina only to reveal more problematic relations of the OHR's dominance in a sovereign country. By analyzing regularly published press releases aimed at the Bosnian public in the process of transition and Europeanization, it looks at the ways in which this organization represented, legitimized and coerced Europeanization in Bosnia and Herzegovina.
Type II Cryoglobulinemia and Brain Hemorrhage
Authors: Wei Hsi Chen  , Hung Sheng Lin  , Kao Yi-Fen
Published: September 2007

By virtue of an understanding of hemostasis and coagulopathy using modern techniques, the exact role of individual serum protein in vascular thrombosis or hemorrhage becomes more apparent. Cryoglobulin causes vasculitude and thrombosis in various vascular beds, but its role in brain hemorrhage is unknown. We encountered a cryoglobulinemic patient to have cryoglobulinemia, hypocomplementia, and cerebellar hemorrhage during a reactivation of cytomegalovirus infection. Because cryoglobulin is harmful to vessel and hemostasis, and often increases nonspecifically in response to incitement, its weight in vascular syndrome must seriously be reviewed. Coagulopathy in a reactivation of latent virus such as cytomegalovirus should be cautioned in older patients.
The Homozygous Leu Variant of the Factor XIII Val34Leu Polymorphism as a Risk Factor for the Manifestation of Thrombotic Microangiopathies
Authors: Sucker Christoph , Farokhzad Firuseh , Kurschat Christine , Grabensee Bernd , Scharf Rudiger E. , Zotz Rainer B. , Maruhn-Debowski Beate , Hetzel Gerd R.
Published: September 2007

The 34 Leu (100T) variant of the factor XIII Val34Leu (G100T-) polymorphism slows down fibrinolysis and has been proposed as a thrombotic risk factor. In this pilot study, we enrolled 40 patients (mean age ± SD = 38 ± 11 years) and 728 controls to assess the role of this genetic variant for the manifestation of thrombotic microangiopathies. From the genotype prevalences, an increased manifestation risk for carriers of the TT genotype (homozygous Leu variant) of the factor XIII Val34Leu (G100T-) polymorphism was calculated (odds ratio [OR] = 2.44; 95% confidence interval [CI] = 0.8-7.6; P = .11). This association was statistically significant for patients with thrombotic thrombocytopenic purpura—hemolytic-uremic syndrome (TTP-HUS) (OR = 6.6; 95% CI = 1.7-25.9; P = .006). Our data suggest a role of the homozygous Leu variant of the factor XIII Val34Leu polymorphism in the manifestation of thrombotic microangiopathies. Decreased fibrinolysis in the presence of this genetic variant provides a plausible explanation for this association.
Factor Structure and Validity of the Revised Conflict Tactics Scales for Spanish Women
Authors: Calvete Esther , Corral Susana , Estévez Ana
Published: September 2007

This study focused on the factor structure of the victimization form of the Revised Conflict Tactics Scales (CTS2). A sample of 1,266 women participated in the study, including a subgroup of battered women. Results of confirmatory factor analysis supported a model that integrates the five original scales with the severity of violence (minor, severe). In addition, the distinction between minor and severe forms of violence was supported by correlations between subscales. Except for minor injury, all of the scales and subscales presented good internal consistency. Comparisons between battered women and community women indicated significant differences in all scales and subscales.
Homicide Followed by Suicide
Authors: Wood Harper Dee , Voigt Lydia
Published: October 2007

Homicide followed by suicide is an extremely rare event, requiring an integrated theoretical understanding that goes beyond explaining it as either homicide or suicide. Police reports, newspaper articles, and interviews with families, friends, and neighbors connected with 42 homicide–suicide cases that occurred in greater metropolitan New Orleans between 1989 and 2001 form the empirical base of this study. A homicide followed by suicide typology predicated on thematic context, including victim–perpetrator relationship, age, sex, race, ethnicity, and occupation in addition to precipitating factors, motivation, type of fatal injury, and location of event, is discussed. An integrated theoretical model using structural conflict intensity factors; elements of the social stress–strain perspective focusing on frustration, failure and anomie; and power dominance issues is presented. Although additional research is certainly called for, these sociological autopsies raise important methodological and theoretical questions for future exploration.
Lessons Learned From Evaluating Maryland's Anti-Drunk Driving Campaign: Assessing the Evidence for Cognitive, Behavioral, and Public Health Impact
Authors: Beck Kenneth H.
Published: September 2007

The evidence concerning Maryland's anti-drunk driving program, Checkpoint Strikeforce, is reviewed. To date, there is no evidence to indicate that this campaign, which involves a number of sobriety checkpoints and media activities to promote these efforts, has had any impact on public perceptions, driver behaviors, or alcohol-related motor vehicle crashes and injuries. This conclusion is drawn after examining statistics for alcohol-related crashes, police citations for impaired driving, and public perceptions of alcohol-impaired driving risk. Comparisons are also made with other states in the mid-Atlantic region, where similar campaign activities have occurred. Reasons for this failure in Maryland include insufficient levels of enforcement (e.g., too few sobriety checkpoints and vehicle contacts occurred to raise public perceptions of risk pertaining to impaired driving) and inadequate publicity surrounding this campaign. Suggestions for overcoming these problems are offered.
Why Is the Australian Government Interested in Complementary Medicine? A Case Study of Economic Rationalism
Authors: Baer Hans A.
Published: October 2007

To address rising health costs, the Australian government has relied on several strategies: (1) covert rationing that entails limiting public health funds for particular patients or services; (2) the allocation of patients awaiting surgery to a priority level; (3) increased copayments for physician visits necessitated by practices such as physicians refusing to bulk bill; and (4) the establishment of an independent auditor for the private health insurance industry. However, the health economics literature rarely mentions that the growing support in various ways of the Australian government for complementary medicine may constitute another strategy for curtailing rising health costs. The government's main support for complementary medicine has come in the form of training programs in chiropractic, osteopathy, Chinese medicine, and naturopathy in public tertiary institutions and partnerships between private complementary colleges and public universities. Compared with biomedical education with its need for hospitals and sophisticated technology, complementary training programs are inexpensive. Furthermore, complementary services are generally not covered by Medicare but must be paid for either out of pocket or by a private health plan.
Training Family Caregivers in Hand and Foot Massage for Hospitalized Patients: Feasibility, Challenges, and Lessons Learned
Authors: Faurot Keturah R. , Gaylord Susan A. , Mann J. Douglas
Published: October 2007

Increasingly, research is demonstrating the safety, efficacy, and patient satisfaction associated with use of nonpharmacological, complementary interventions for pain management in hospital settings. One such intervention, massage, has been found to be effective for pain and anxiety reduction in limited forms, such as described here, massage is relatively easy to learn and apply. The pilot project was designed to develop and assess a clinical intervention using hand and foot massage for management of pain and anxiety in inpatients on a rehabilitation unit. Methods included formal training of staff nurses in hand and foot massage and subsequently having them teach key family caregivers of the patient how to deliver hand or foot massage in response to reports of pain and anxiety. The report describes study rationale, project development, challenges to implementation in an academic, tertiary care, inpatient rehabilitation facility, and lessons learned for future project design and implementation. The need for a community-based participatory research perspective is addressed.
FCRL1 on chronic lymphocytic leukemia, hairy cell leukemia, and B-cell non-Hodgkin lymphoma as a target of immunotoxins
Authors: Du Xing , Nagata Satoshi , Ise Tomoko , Stetler-Stevenson Maryalice , Pastan Ira
Published: September 2007

FCRL1 (Fc receptor–like 1) is a cell-surface membrane protein belonging to FCRL family and is preferentially expressed on B cells. To evaluate FcRL1 as an immunotherapy target for B-cell malignancies, we prepared anti-FCRL1 mAbs without cross-reactivity to other FCRL family proteins and analyzed FCRL1 protein expression on malignant cells from patients and on B-cell lines. Frequent FCRL1 expression was observed by flow cytometry on 12 B-cell non-Hodgkin lymphoma (B-NHL) cell lines and many patient samples: 12 of 14 chronic lymphocytic leukemia (CLL), 7 of 7 follicular lymphoma (FL), 13 of 17 hairy cell leukemia (HCL), and 2 of 3 mantle cell lymphoma (MCL). Two recombinant immunotoxins, E3(Fv)-PE38 and E9(Fv)-PE38, were constructed. Both immunotoxins bound to FCRL1-positive cells with similar affinities (3.4 and 3.2 nM) and were cytotoxic to cell lines, but E9(Fv)-PE38 was 4- to 20-fold more cytotoxic than E3(Fv)-PE38. The concentrations that inhibited response by 50% (IC50s) of E9(Fv)-PE38 on 11 different FCRL1-positive cell lines ranged from 1.0 ng/mL to 90 ng/mL and correlated with the FCRL1 expression levels. Our results suggest that anti-FCRL1 immunotoxin E9(Fv)-PE38 exhibits remarkably specific cytotoxicity and merits further evaluation for the treatment of FCRL1-positive malignancies, including CLL, HCL, FL, MCL, and other B-NHL.
Crystal structure of a blue laccase from Lentinus tigrinus: evidences for intermediates in the molecular oxygen reductive splitting by multicopper oxidases
Authors: Ferraroni Marta , Myasoedova Nina M , Schmatchenko Vadim , Leontievsky Alexey A , Golovleva Ludmila A , Scozzafava Andrea , Briganti Fabrizio
Published: September 2007

Background

Laccases belong to multicopper oxidases, a widespread class of enzymes implicated in many oxidative functions in pathogenesis, immunogenesis and morphogenesis of organisms and in the metabolic turnover of complex organic substances. They catalyze the coupling between the four one-electron oxidations of a broad range of substrates with the four-electron reduction of dioxygen to water. These catalytic processes are made possible by the contemporaneous presence of at least four copper ion sites, classified according to their spectroscopic properties: one type 1 (T1) site where the electrons from the reducing substrates are accepted, one type 2 (T2), and a coupled binuclear type 3 pair (T3) which are assembled in a T2/T3 trinuclear cluster where the electrons are transferred to perform the O2 reduction to H2O.

Results

The structure of a laccase from the white-rot fungus Lentinus (Panus) tigrinus, a glycoenzyme involved in lignin biodegradation, was solved at 1.5 Å. It reveals a asymmetric unit containing two laccase molecules (A and B). The progressive reduction of the copper ions centers obtained by the long-term exposure of the crystals to the high-intensity X-ray synchrotron beam radiation under aerobic conditions and high pH allowed us to detect two sequential intermediates in the molecular oxygen reduction pathway: the "peroxide" and the "native" intermediates, previously hypothesized through spectroscopic, kinetic and molecular mechanics studies. Specifically the electron-density maps revealed the presence of an end-on bridging, μ-η1:η1 peroxide ion between the two T3 coppers in molecule B, result of a two-electrons reduction, whereas in molecule A an oxo ion bridging the three coppers of the T2/T3 cluster (μ3-oxo bridge) together with an hydroxide ion externally bridging the two T3 copper ions, products of the four-electrons reduction of molecular oxygen, were best modelled.

Conclusion

This is the first structure of a multicopper oxidase which allowed the detection of two intermediates in the molecular oxygen reduction and splitting. The observed features allow to positively substantiate an accurate mechanism of dioxygen reduction catalyzed by multicopper oxidases providing general insights into the reductive cleavage of the O-O bonds, a leading problem in many areas of biology.
Differential effects of hypoxia on etoposide-induced apoptosis according to the cancer cell lines
Authors: Cosse Jean-Philippe , Sermeus Audrey , Vannuvel Kayleen , Ninane Noelle , Raes Martine , Michiels Carine
Published: September 2007

Background

It is more and more recognized that hypoxia plays a role in the resistance of cancer cells to chemotherapy. However, the mechanisms underlying this resistance still need deeper understanding. The aim of this study was to investigate the effect of hypoxia on this process since hypoxia is one of the hallmarks of tumor environment.

Results

The effect of hypoxia on the apoptosis induced by etoposide, one drug commonly used in chemotherapy, was investigated using three different cancer cell lines. Gene expression changes were also studied in order to delineate the mechanisms responsible for the hypoxia-induced chemoresistance. We observed that hypoxia differentially influenced etoposide-induced cell death according to the cancer cell type. While hypoxia inhibited apoptosis in hepatoma HepG2 cells, it had no influence in lung carcinoma A549 cells and further enhanced it in breast cancer MCF-7 cells. Etoposide increased p53 activity in all cell lines while hypoxia alone decreased it only in HepG2 cells. Hypoxia had no influence on the etoposide-induced p53 activity in A549, increased p53 abundance in MCF-7 cells but markedly decreased p53 activity in HepG2 cells. Using low density DNA arrays to detect the expression of genes involved in the regulation of apoptosis, etoposide and hypoxia were shown to each influence the expression of numerous genes, many of the ones influenced by etoposide being p53 target genes. Again, the influence of hypoxia on the etoposide-induced changes was different according to the cell type.

Conclusion

These results evidenced that there was a striking parallelism between the effect of hypoxia on the etoposide-induced p53 stabilization as well as p53 target gene expression and its effect on the etoposide-induced apoptosis according to the cell type. They are very interesting not only because they provide one possible mechanism for the induction of chemoresistance under hypoxic conditions in cells like HepG2 but also because they indicate that not all cell types respond the same way. This knowledge is of importance in designing adequate treatment according to the type of tumors.
Induction of cystine/glutamate transporter in bacterial lipopolysaccharide induced endotoxemia in mice
Authors: Taguchi Kumiko , Tamba Michiko , Bannai Shiro , Sato Hideyo
Published: September 2007

Background

Cystine/glutamate transporter, system xc-, contributes to the maintenance of intracellular glutathione levels and the redox balance in the extracellular space. The main component of the transporter, xCT, is known to be strongly induced by various stimuli like oxidative stress in mammalian cultured cells. We examined the expression of xCT mRNA in vivo in the experimental endotoxemia.

Methods

Northern blot analysis and in situ hybridization were used to investigate the expression of xCT mRNA in the tissues of the mice exposed to bacterial lipopolysaccharide (LPS).

Results

Northern blot analysis revealed that xCT mRNA was constitutively expressed in the brain, thymus, and spleen, and that the expression of xCT mRNA was strongly up-regulated in thymus and spleen by the administration of a sublethal dose of LPS. In addition to brain, thymus, and spleen, xCT mRNA was detected also in the bronchiolar epithelium of the lung by the administration of the lethal dose of LPS.

Conclusion

xCT is induced in some specific tissues by the administration of LPS. The results suggest that cystine/glutamate transporter plays an important role under the inflammatory conditions.
Characterization of EN-1078D, a poorly differentiated human endometrial carcinoma cell line: a novel tool to study endometrial invasion in vitro
Authors: Dery Marie-Claude , Van Themsche Celine , Provencher Diane , Mes-Masson Anne-Marie , Asselin Eric
Published: September 2007

Background

To date, tools to study metastasis in endometrial cancers are insufficiently developed. The aim of this study was to characterize the cell line EN-1078D, a new endometrial carcinoma cell line derived from a metastasis to the ovary.

Methods and Results

Cells were characterized using cytology, transmission electron microscopy, karyotyping and morphological appearance in culture. Molecular features were determined by RT-PCR, Western Blot, FISH and sequencing. MTT proliferation assays were performed to investigate the sensitivity of EN-1078D to anticancer agents such as cisplatin and doxorubicin. Also, subcutaneous and intravenous injections in nude mice were done to test the tumorigenic and metastatic properties of EN-1078D cells. Our results indicate that EN-1078D cells express both oestrogen receptors isoforms (ER alpha and ER beta) and also low levels of progesterone receptor B (PR-B). In addition, this cell line expresses high levels of MMP-2 and MMP-14 mRNA, low levels of TIMP-1 and TIMP-2 transcripts and no detectable levels of MMP-9 mRNA. Moreover, all nude mice developed tumors by subcutaneous injections and cell invasion was observed in vitro in response to TGF-beta 3. Her-2/neu was not overamplified but mutations in the C-2 domain of PTEN gene as well as codon 12 of the K-Ras gene were found. Finally, EN-1078D shows sensitivity to drugs commonly used in chemotherapy such as cisplatin and doxorubicin: IC50 of 2.8 μM of cisplatin after 72 hours of exposure and 0.54 μM of doxorubicin after 48 hours.

Conclusion

Taken together, these results suggest that EN-1078D will be an excellent tool to study the properties of metastatic endometrial cancer cells in vitro and their regulation by sex steroids.
Experimental iodine-125 seed irradiation of intracerebral brain tumors in nude mice
Authors: Verhoeff Joost JC , Stalpers Lukas JA , Coumou Annet W , Koedooder Kees , Lavini Cristina , Van Noorden Cornelis JF , Haveman Jaap , Vandertop William P , van Furth Wouter R
Published: September 2007

Background

High-dose radiotherapy is standard treatment for patients with brain cancer. However, in preclinical research external beam radiotherapy is limited to heterotopic murine models– high-dose radiotherapy to the murine head is fatal due to radiation toxicity. Therefore, we developed a stereotactic brachytherapy mouse model for high-dose focal irradiation of experimental intracerebral (orthotopic) brain tumors.

Methods

Twenty-one nude mice received a hollow guide-screw implanted in the skull. After three weeks, 5 × 105 U251-NG2 human glioblastoma cells were injected. Five days later, a 2 mCi iodine-125 brachytherapy seed was inserted through the guide-screw in 11 randomly selected mice; 10 mice received a sham seed. Mice were euthanized when severe neurological or physical symptoms occurred. The cumulative irradiation dose 5 mm below the active iodine-125 seeds was 23.0 Gy after 13 weeks (BEDtumor = 30.6 Gy).

Results

In the sham group, 9/10 animals (90%) showed signs of lethal tumor progression within 6 weeks. In the experimental group, 2/11 mice (18%) died of tumor progression within 13 weeks. Acute side effects in terms of weight loss or neurological symptoms were not observed in the irradiated animals.

Conclusion

The intracerebral implantation of an iodine-125 brachytherapy seed through a stereotactic guide-screw in the skull of mice with implanted brain tumors resulted in a significantly prolonged survival, caused by high-dose irradiation of the brain tumor that is biologically comparable to high-dose fractionated radiotherapy– without fatal irradiation toxicity. This is an excellent mouse model for testing orthotopic brain tumor therapies in combination with radiation therapy.
Distinct roles of Hoxa2 and Krox20in the development of rhythmic neural networks controlling inspiratory depth, respiratory frequency, and jaw opening
Authors: Chatonnet Fabrice , Wrobel Ludovic J , Mézières Valérie , Pasqualetti Massimo , Ducret Sébastien , Taillebourg Emmanuel , Charnay Patrick , Rijli Filippo M , Champagnat Jean
Published: September 2007

Background

Little is known about the involvement of molecular determinants of segmental patterning of rhombomeres (r) in the development of rhythmic neural networks in the mouse hindbrain. Here, we compare the phenotypes of mice carrying targeted inactivations of Hoxa2, the only Hox gene expressed up to r2, and of Krox20, expressed in r3 and r5. We investigated the impact of such mutations on the neural circuits controlling jaw opening and breathing in newborn mice, compatible with Hoxa2-dependent trigeminal defects and direct regulation of Hoxa2 by Krox20 in r3.

Results

We found that Hoxa2 mutants displayed an impaired oro-buccal reflex, similarly to Krox20 mutants. In contrast, while Krox20 is required for the development of the rhythm-promoting parafacial respiratory group (pFRG) modulating respiratory frequency, Hoxa2 inactivation did not affect neonatal breathing frequency. Instead, we found that Hoxa2-/- but not Krox20-/- mutation leads to the elimination of a transient control of the inspiratory amplitude normally occurring during the first hours following birth. Tracing of r2-specific progenies of Hoxa2 expressing cells indicated that the control of inspiratory activity resides in rostral pontine areas and required an intact r2-derived territory.

Conclusion

Thus, inspiratory shaping and respiratory frequency are under the control of distinct Hox-dependent segmental cues in the mammalian brain. Moreover, these data point to the importance of rhombomere-specific genetic control in the development of modular neural networks in the mammalian hindbrain.
A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity
Authors: Olsson Lina M , Lindqvist Anna-Karin , Källberg Henrik , Padyukov Leonid , Burkhardt Harald , Alfredsson Lars , Klareskog Lars , Holmdahl Rikard
Published: September 2007

Rheumatoid arthritis (RA) is a chronic inflammatory disease with a heritability of 60%. Genetic contributions to RA are made by multiple genes, but only a few gene associations have yet been confirmed. By studying animal models, reduced capacity of the NADPH-oxidase (NOX) complex, caused by a single nucleotide polymorphism (SNP) in one of its components (the NCF1 gene), has been found to increase severity of arthritis. To our knowledge, however, no studies investigating the potential role played by reduced reactive oxygen species production in human RA have yet been reported. In order to examine the role played by the NOX complex in RA, we investigated the association of 51 SNPs in five genes of the NOX complex (CYBB, CYBA, NCF4, NCF2, and RAC2) in a Swedish case-control cohort consisting of 1,842 RA cases and 1,038 control individuals. Several SNPs were found to be mildly associated in men in NCF4 (rs729749, P = 0.001), NCF2 (rs789181, P = 0.02) and RAC2 (rs1476002, P = 0.05). No associations were detected in CYBA or CYBB. By stratifying for autoantibody status, we identified a strong association for rs729749 (in NCF4) in autoantibody negative disease, with the strongest association detected in rheumatoid factor negative men (CT genotype versus CC genotype: odds ratio 0.34, 95% confidence interval 0.2 to 0.6; P = 0.0001). To our knowledge, this is the first genetic association identified between RA and the NOX complex, and it supports previous findings from animal models of the importance of reactive oxygen species production capacity to the development of arthritis.
Incidence and predictors of mental ill-health in adults with intellectual disabilities
Authors: Smiley Elita , Cooper Sally-Ann , Finlayson Janet , Jackson Alison , Allan Linda , Mantry Dipali , McGrother Catherine , McConnachie Alex , Morrison Jillian
Published: October 2007

Background

The point prevalence of mental ill-health among adults with intellectual disabilities is 40.9%, but its incidence is unknown.

Aims

To determine the incidence and possible predictors of mental ill-health.

Method

Prospective cohort study to measure mental ill-health in adults with mild to profound intellectual disabilities.

Results

Cohort retention was 70% (n=651). The 2-year incidence of mental ill-health was 16.3% (12.6% excluding problem behaviours, and 4.6% for problem behaviours) and the standardised incidence ratio was 1.87 (95%CI1.51 2.28). Factors related to incident mental ill-health have some similarities with those in the general population, but also important differences. Type of accommodation and support, previous mental ill-health, urinary incontinence, not having impaired mobility, more severe intellectual disabilities, adult abuse, parental divorce in childhood and preceding life events predicted incident ill-health; however, deprivation, other childhood abuse or adversity, daytime occupation, and marital and smoking status did not.

Conclusions

This is a first step towards intervention trials, and identifying sub-populations for more proactive measures. Public health strategy and policy that is appropriate for this population should be developed.
Neurokinin-1 receptor antagonists as novel antidepressants: trials and tribulations
Authors: Hafizi Sepehr , Chandra Prakash , Cowen Philip J.
Published: October 2007

Based upon animal experiments and early clinical trials, neurokinin-1 receptor antagonists showed promise as novel antidepressants. Subsequently, however, more extensive clinical trials did not reveal evidence of efficacy in depression. The development of novel antidepressants will require a better understanding of the neural basis of antidepressant action in humans.
Characterizing Emergency Department Discussions about Depression
Authors: Rhodes Karin V. , Kushner Hallie M. , Bisgaier Joanna , Prenoveau Elizabeth
Published: September 2007

Background: The reality of emergency health care in the United States today requires new approaches to mental health in the emergency department (ED). Major depression is a disabling condition that disproportionately affects women.

Objectives: To characterize ED provider–patient discussions about depression.

Methods: This was a secondary analysis of a database of audiotaped ED visits with women patients collected during a clinical trial of computer screening for domestic violence and other psychosocial risks. Nonemergent female patients, ages 18–65 years, were enrolled from two socioeconomically diverse academic EDs. All audio files with two or more relevant comments were identified as “significant depression discussions” and independently coded using a structured coding form.

Results: Of 871 audiorecorded ED visits, 70 (8%) included discussions containing any reference to depression and 20 (2%) constituted significant depression discussions. Qualitative analysis of the 20 significant discussions found that 16 (80%) required less than 90 seconds to complete. Ten included less than optimal provider communication characteristics. Despite the brevity or quality of the communication, 15 of the 20 yielded high patient satisfaction with their ED treatment.

Conclusions: ED providers rarely addressed depression. Qualitative analysis of significant patient–provider interactions regarding depression found that screening for depression in the ED can be accomplished with minimal expenditure of provider time and effort. Attention to psychosocial risk factors has the potential to improve the quality of ED care and patient satisfaction.
Testicular Adrenal Rest Tumors and Leydig and Sertoli Cell Function in Boys with Classical Congenital Adrenal Hyperplasia
Authors: Martinez-Aguayo A. , Rocha A. , Rojas N. , García C. , Parra R. , Lagos M. , Valdivia L. , Poggi H. , Cattani A.
Published: September 2007

Context: Infertility observed in adult males with congenital adrenal hyperplasia (CAH) has been associated with testicular adrenal rest tumors (TART) that may originate during childhood.

Objective: Our objective was to describe the prevalence of TART and Sertoli and Leydig cell function in a group of boys aged 2–10 yr with CAH and to compare prevalence with that of a control group.

Design: From August 2005 to January 2007, 19 patients with classical CAH (CAH group) were referred from seven endocrinology centers.

Methods: We studied 19 subjects in the CAH group and, as a control group, 13 boys from the community that did not have testicular diseases. A complete physical exam was performed. High-resolution ultrasound was used to determine TART prevalence. Inhibin B and anti-Müllerian hormone were used as Sertoli cell markers. The ratio between basal testosterone levels and testosterone levels 72 h after β-human chorionic gonadotropin (5000 U/m2) treatment [(T72− T0)/T0] was used to evaluate Leydig cell response.

Results: CAH and control groups were comparable in chronological age (5.9 vs. 5.6 yr; P = 0.67) and bone age/chronological age ratio (1.09 vs. 1.03; P = 0.09). TART prevalence was four of 19 (21%) in the CAH group. Lower values for inhibin B (49.2. vs. 65.2 pg/ml; P = 0.018), anti-Müllerian hormone (70.1 vs. 94.2 ng/ml; P = 0.002), and (T72− T0)/T0 (5.6 vs. 13.6; P < 0.01) were observed in the CAH group.

Conclusion: TART in prepubertal males with classic CAH could be found during childhood. We also report differences in markers of gonadal function in a subgroup of patients, especially in those with inadequate control.
Rho/ROCK and myosin II control the polarized distribution of endocytic clathrin structures at the uropod of moving T lymphocytes
Authors: Samaniego Rafael , Sánchez-Martín Lorena , Estecha Ana , Sánchez-Mateos Paloma
Published: September 2007

We have examined the spatio-temporal dynamics of clathrin-mediated endocytosis (CME) during T lymphocyte polarization and migration. Near the plasma membrane, we detected heterogeneous arrangements of GFP-clathrin that were clustered predominantly at the uropod; some diffraction limited spots (∼200 nm) and a major population of larger clathrin structures (CSs) (300-800 nm). Membrane CSs fully co-localized with the endocytic adaptor complex AP-2, which was also polarized towards the rear membrane. During the direct incorporation of the endocytic cargo transferrin, large and relatively stable clathrin/AP-2 structures at the uropod membrane transiently co-localized with spots of transferrin, which suggests that they are endocytic competent platforms. The highly polarized distribution of membrane CSs towards the uropod and their endocytic ability support the existence of a preferential region of endocytosis located at or near the rear pole of T lymphocytes. Inactivation of Rho by dominant negative RhoA or C3 exoenzyme, and inhibition of Rho-kinase (ROCK) with Y-27632, or myosin II with blebbistatin, all resulted in suppression of CS polarization, which indicates that the posterior distribution of CSs relies on Rho/ROCK signaling and myosin II contractility. In addition, blocking CME with dominant negative mutants or by clathrin RNA interference, results in a remarkable inhibition of both basal and CXCL12-promoted migration, which suggests that CME is required for successful T-cell migration. We hypothesize that enhanced endocytic rates at the cell rear could provide a mechanism to remove leftover surface to accommodate cell retraction, and/or to spatially resolve signaling for guided cell migration.
Liver tetraploidization is controlled by a new process of incomplete cytokinesis
Authors: Margall-Ducos Germain , Celton-Morizur Séverine , Couton Dominique , Brégerie Olivier , Desdouets Chantal
Published: September 2007

Cytokinesis is precisely controlled in both time and space to ensure equal distribution of the genetic material between daughter cells. Incomplete cytokinesis can be associated with developmental or pathological cell division programs leading to tetraploid progenies. In this study we decipher a new mechanism of incomplete cytokinesis taking place in hepatocytes during post-natal liver growth. This process is initiated in vivo after weaning and is associated with an absence of anaphase cell elongation. In this process, formation of a functional contractile actomyosin ring was never observed; indeed, actin filaments spread out along the cortex were not concentrated to the putative site of furrowing. Recruitment of myosin II to the cortex, controlled by Rho-kinase, was impaired. Astral microtubules failed to contact the equatorial cortex and to deliver their molecular signal, preventing activation of the RhoA pathway. These findings reveal a new developmental cell division program in the liver that prevents cleavage-plane specification.