bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of repeat myeloablative chemotherapy with autologous stem-cell support in multiple myeloma
Authors: Menzel Helge , Hinmüller Katarzyna , Kolb Hans-Jochem , Schuster Tibor , Hoellein Alexander , Peschel Christian , Dechow Tobias , Keller Ulrich
Published: February 2012

Objective: Induction high-dose chemotherapy followed by myeloablative melphalan (HD-Mel) treatment and autologous hematopoietic stem-cell support (autoSCT) is a standard treatment for multiple myeloma (MM) either upfront or in relapse after conventional treatment. We performed a retrospective analysis of consecutive patients undergoing a late repeat HD-Mel/autoSCT treatment for MM.

Methods: Data from 24 consecutive patients with MM who underwent a myeloablative treatment with HD-Mel late after completion of upfront first high-dose therapy were assessed for toxicity, response, progression-free survival (PFS) and time to next treatment (TTNT). These data were correlated with the results obtained after the initial high dose therapy and autoSCT.

Results: A total of 23 patients were treated with novel drugs (lenalidomide, thalidomide, bortezomib) after relapse to initial autoSCT. The median overall survival (OS) of all patients was 90 months. 19 patients (79%) achieved a very good partial remission (VGPR) or complete remission (CR) after initial autoSCT, compared with 42% after late autoSCT. PFS and TTNT were 19 and 24 months after initial compared with 13 and 21 months after late autoSCT. Univariate analysis identified initial response duration and the achievement of a CR/VGPR after the initial transplantation to be associated with prolonged response after repeat autoSCT.

Conclusions: Our data indicate that late high-dose treatment followed by autoSCT is safe and effective after upfront intensive treatment, can bridge to allogeneic SCT, and encourage collection of an additional graft.
Current Changes in Portuguese School System
Authors: Esteves Maria Helena
Published: February 2012

About 100 teachers participated in a study and helped to understand how new reforms are faced by those who work in the field, in the particular case of the discipline of geography. The study that was done with geography teachers after 10 years of national curriculum revealed many gaps in terms of what teachers are expected to do. Only recently, some legislation has been issued to regulate the kind of training teachers do as they progress in their teaching careers. The national curriculum for basic education is a huge step in terms of being a part of the world agenda in what concerns a modern teaching and a new vision of what schools should prepare students to, but the instruments of that change (teachers) have been neglected.
Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia
Authors: Yokoyama Takashi , Toki Tsutomu , Aoki Yoshihiro , Kanezaki Rika , Park Myoung-ja , Kanno Yohei , Takahara Tomoko , Yamazaki Yukari , Ito Etsuro , Hayashi Yasuhide , Nakamura Takuro
Published: February 2012

Trib1 has been identified as a myeloid oncogene in a murine leukemia model. Here we identified a TRIB1 somatic mutation in a human case of Down syndrome–related acute megakaryocytic leukemia. The mutation was observed at well-conserved arginine 107 residue in the pseudokinase domain. This R107L mutation remained in leukocytes of the remission stage in which GATA1 mutation disappeared, suggesting the TRIB1 mutation is an earlier genetic event in leukemogenesis. The bone marrow transfer experiment showed that acute myeloid leukemia development was accelerated by transducing murine bone marrow cells with the R107L mutant in which enhancement of ERK phosphorylation and C/EBPα degradation by Trib1 expression was even greater than in those expressing wild-type. These results suggest that TRIB1 may be a novel important oncogene for Down syndrome–related acute megakaryocytic leukemia.
Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma via manipulation of tissue transglutaminase activities
Authors: Jung Hyun Joo , Chen Zheng , Wang Michael , Fayad Luis , Romaguera Jorge , Kwak Larry W. , McCarty Nami
Published: February 2012

Although bortezomib is clinically approved for the treatment of mantle cell lymphoma (MCL), only limited effects of this treatment have been demonstrated. To improve survival for bortezomib-resistant patients, it is necessary to develop new therapeutic strategies. In the present study, we used biochemical and molecular methodologies to demonstrate that tissue transglutaminase (TG) activates downstream NF-κB signaling pathways. The signaling axis from TG to NF-κB could be a new therapeutic target to overcome bortezomib resistance in MCL. TG2 is a calcium-dependent protein cross-linking enzyme reported to be overexpressed in various cancer cells. We found that MCL cells expressed elevated levels of TG2 and that the modification of TG2 activities altered NF-κB expression and downstream signaling in MCL cells. When TG2 signaling was inhibited by calcium blockers, the combination of a calcium blocker (perillyl alcohol) with bortezomib suppressed NF-κB expression and improved the cytotoxicity of bortezomib in MCL cells. Our study is the first to show the expression of TG2 and the contribution of TG2 to NF-κB signaling in MCL. TG2 inhibition may be used as an alternative target anti-MCL therapy, and calcium blockers may be combined with bortezomib to overcome the bortezomib resistance in MCL.
The phenotype of human STK4 deficiency
Authors: Abdollahpour Hengameh , Appaswamy Giridharan , Kotlarz Daniel , Diestelhorst Jana , Beier Rita , Schäffer Alejandro A. , Gertz E. Michael , Schambach Axel , Kreipe Hans H. , Pfeifer Dietmar , Engelhardt Karin R. , Rezaei Nima , Grimbacher Bodo , Lohrmann Sabine , Sherkat Roya , Klein Christoph
Published: February 2012

We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis. STK4 deficiency is a novel human primary immunodeficiency syndrome.
In vivo effects of eltrombopag on platelet function in immune thrombocytopenia: no evidence of platelet activation
Authors: Psaila Bethan , Bussel James B. , Linden Matthew D. , Babula Bracken , Li Youfu , Barnard Marc R. , Tate Chinara , Mathur Kanika , Frelinger Andrew L. , Michelson Alan D.
Published: February 2012

The effects of eltrombopag, a thrombopoietin-receptor agonist, on platelet function in immune thrombocytopenia (ITP) are not fully characterized. This study used whole blood flow cytometry to examine platelet function in 20 patients receiving eltrombopag treatment at days 0, 7, and 28. Platelet surface expression of activated GPIIb/IIIa, P-selectin, and GPIb was measured with and without low and high adenosine diphosphate (ADP) and thrombin receptor activating peptide (TRAP) concentrations. Before eltrombopag treatment with no ex vivo agonist, platelet activation was higher in ITP patients than controls. Platelet GPIb and activated GPIIb/IIIa expression without added agonist was unchanged following eltrombopag treatment, whereas a slight increase in P-selectin was observed. Expression of P-selectin and activated GPIIb/IIIa in response to high-dose ADP was lower during eltrombopag treatment than at baseline. Eltrombopag led to a slight increase in platelet reactivity to TRAP only in responders to eltrombopag but not to levels above those in controls; whole blood experiments demonstrated that this increase was probably because of higher platelet counts rather than higher platelet reactivity. In conclusion, although thrombocytopenic ITP patients have higher baseline platelet activation than controls, eltrombopag did not cause platelet activation or hyper-reactivity, irrespective of whether the platelet count increased.
Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function
Authors: White Michael J. , Schoenwaelder Simone M. , Josefsson Emma C. , Jarman Kate E. , Henley Katya J. , James Chloé , Debrincat Marlyse A. , Jackson Shaun P. , Huang David C. S. , Kile Benjamin T.
Published: February 2012

Apoptotic caspases, including caspase-9, are thought to facilitate platelet shedding by megakaryocytes. They are known to be activated during platelet apoptosis, and have also been implicated in platelet hemostatic responses. However, the precise requirement for, and the regulation of, apoptotic caspases have never been defined in either megakaryocytes or platelets. To establish the role of caspases in platelet production and function, we generated mice lacking caspase-9 in their hematopoietic system. We demonstrate that both megakaryocytes and platelets possess a functional apoptotic caspase cascade downstream of Bcl-2 family-mediated mitochondrial damage. Caspase-9 is the initiator caspase, and its loss blocks effector caspase activation. Surprisingly, steady-state thrombopoiesis is unperturbed in the absence of caspase-9, indicating that the apoptotic caspase cascade is not required for platelet production. In platelets, loss of caspase-9 confers resistance to the BH3 mimetic ABT-737, blocking phosphatidylserine (PS) exposure and delaying ABT-737–induced thrombocytopenia in vivo. Despite this, steady-state platelet lifespan is normal. Casp9−/− platelets are fully capable of physiologic hemostatic responses and functional regulation of adhesive integrins in response to agonist. These studies demonstrate that the apoptotic caspase cascade is required for the efficient death of megakaryocytes and platelets, but is dispensable for their generation and function.
Inequalities for convex and s-convex functions on Δ = [a, b] × [c, d]
Authors: Özdemir Muhamet Emin , Kavurmaci Havva , Akdemir Ahmet Ocak , Avci Merve
Published: February 2012

In this article, two new lemmas are proved and inequalities are established for co-ordinated convex functions and co-ordinateds-convex functions.

Mathematics Subject Classification (2000): 26D10; 26D15.
From red to white urine: a patient's nightmare with a rather benign outcome
Authors: Knier Benjamin , Büschges-Seraphin Beatrix , Hilgers Karl F , Amann Kerstin U , Uder Michael , Eckardt Kai-Uwe , Jacobi Johannes
Published: February 2012

Background

Chyluria is a medical condition with presence of chyle in the urine. The disease is most prevalent in endemic regions of Africa and the Indian subcontinent where it is mostly caused by parasitic infections, particularly lymphatic filariasis due to wucheria bancrofti. Non-parasitic chyluria, however, is a very rare finding.

Case Presentation

We report the case of a 48 year old woman who developed a lymphorenal fistula with chyluria following ureterrenoscopy with biopsies taken for urological work-up of persistent macrohematuria. Renal biopsy confirmed the diagnosis of benign familial hematuria due to thin basement nephropathy, a condition frequently associated with episodes of macrohematuria.

Conclusions

This case highlights a rare case of non-parasitic chyluria as a complication of urological work-up for macrohematuria of benign nature.
Brain metastases from hepatocellular carcinoma: clinical features and prognostic factors
Authors: Jiang Xiao-Bing , Ke Chao , Zhang Guan-Hua , Zhang Xiang-Heng , Sai Ke , Chen Zhong-Ping , Mou Yong-Gao
Published: February 2012

Background

Brain metastases (BM) from hepatocellular carcinoma (HCC) are extremely rare and are associated with a poor prognosis. The aim of this study was to define clinical outcome and prognostic determinants in patients with BM from HCC.

Methods

Between January 1994 and December 2009, all patients with HCC and BM treated in Sun Yat-sen University Cancer Center were retrospectively reviewed. Univariate and multivariate survival analyses were performed to identify possible prognostic factors.

Results

Forty-one patients were diagnosed with BM from HCC, an incidence of 0.47%. The median age at diagnosis of BM was 48.5 years. Thirty-three patients (80.5%) developed extracranial metastases at diagnosis of BM, and 30 patients (73.2%) had hepatitis B. Intracranial hemorrhage occurred in 19 patients (46.3%). BM were treated primarily either with whole brain radiation therapy (WBRT; 5 patients), stereotactic radiosurgery (SRS; 7 patients), or surgical resection (6 patients). The cause of death was systemic disease in 17 patients and neurological disease in 23. Patients in a high RPA (recursive partitioning analysis) class, treated with conservatively and without lung metastases, tended to die from neurological disease. Median survival after the diagnosis of BM was 3 months (95% confidence interval: 2.2-3.8 months). In multivariate analysis, the presence of extracranial metastases, a low RPA class and aggressive treatment, were positively associated with improved survival.

Conclusions

BM from HCC is rare and associated with an extremely poor prognosis. However, patients with a low RPA class may benefit from aggressive treatment. The clinical implication of extracranial metastases in HCC patients with BM needs further assessment.
Adenovirus-mediated delivery of CALR and MAGE-A3 inhibits invasion and angiogenesis of glioblastoma cell line U87
Authors: Liu Xin-Li , Zhao Dan , Sun Da-Peng , Wang Yang , Li Yan , Qiu Feng-Qi , Ma Ping
Published: February 2012

Background

The management of patients with glioblastoma multiforme is difficult. Poor results have led to a search for novel therapeutic approaches. Gene therapy that could be both anti-invasive and antiangiogenic would be ideal. In this study, we constructed the recombinant adenoviral vector Ad-CALR/MAGE-A3 and evaluated its antitumor effects on glioblastoma in vitro and in vivo.

Methods

In this study, CALR and MAGE-A3 genes were delivered to the glioblastoma cell line U87, using adenovirus (Ad-CALR/MAGE-A3). U87 glioblastoma cells were transfected with Ad-green fluorescent protein to identify the multiplicity of infection. The expressions of CALR and MAGE-A3 were detected by PCR and Western blot. Cell proliferation was measured by MTT assay. Cell apoptosis was assessed by Annexin-V FITC/PI double staining flow cytometry. The invasive potential of U87 cells was determined by Matrigel invasion assay. Tube formation assay was used to detect the effects on angiogenesis of human umbilical vein endothelial cells. Protein expressions of PI3K/AKT, Erk1/2 and MMP-2/-9 in transfected cells were detected by Western blot. In vivo, the effects of Ad-CALR/MAGE-A3 on tumor growth and angiogenesis of U87 glioblastoma xenografts in nude mice were investigated.

Results

The expressions of CALR and MAGE-A3 in U87 cells resulted in the suppression of cell proliferation and invasion properties, and induced cell apoptosis. The Erk MAPK, PI3K/AKT pathways and expressions of MMP-2/-9 were inhibited in Ad-CALR/MAGE-A3-transfected cells. Outcomes of the tube formation assay confirmed the antiangiogenic effect of CALR. Moreover, in the in vivo model of glioblastoma, intratumoral injection of Ad-CALR/MAGE-A3 suppressed tumor growth and angiogenesis.

Conclusion

Although Ad-CALR/MAGE-A3 and Ad-CALR demonstrated antiangiogenic effects on U87 cells, the repression of invasion was significant only in Ad-CALR/MAGE-A3-treated cells. To our knowledge, this is the first description of a role for combined CALR and MAGE-A3 in the anti-invasion and antiangiogenesis of U87.
Sensitivity of estimated elastic moduli to completeness of wave type, measurement type, and illumination apertures at a receiver in multicomponent VSP data
Authors: Rusmanugroho Herurisa , McMechan George A.
Published: February 2012

Inversion of phase slowness and polarization vectors measured from multicomponent vertical seismic profile data can yield estimates of all 21 density-normalized elastic moduli for anisotropic elastic media in the neighborhood of each 3C geophone. Synthetic test data are produced by direct evaluation of the Christoffel equation, and by finite-difference solution of the elastodynamic equations. Incompleteness of the data, with respect to illumination (polar and azimuth angle) apertures (qP and/or qS) wave types, wave-propagation directions, and the amount of data (e.g., with or without horizontal slowness components), produces solutions with variations in quality, as revealed by the distribution of model parameter correlations. In a good solution, with all parameters well constrained by the data, the correlation matrix is diagonally dominant. qP-only and qS-only solutions typically produce complementary distributions in their correlation matrices, as they are orthogonal in their sampling of the medium with respect to polarization. The elastic moduli become less independent as the data apertures decrease. If the other input data are relatively complete, the horizontal components of the slowness vector are not needed as the information they contain is redundant. The main consequence of omitting horizontal slowness components is slower convergence. When modest amounts of random noise are added to the slowness and polarization data, in otherwise adequately sampled apertures, the solution is still very close to the correct model, but with larger residual variance.
Crosshole traveltime tomography using particle swarm optimization: A near-surface field example
Authors: Tronicke Jens , Paasche Hendrik , Böniger Urs
Published: February 2012

Particle swarm optimization (PSO) is a relatively new global optimization approach inspired by the social behavior of bird flocking and fish schooling. Although this approach has proven to provide excellent convergence rates in different optimization problems, it has seldom been applied to inverse geophysical problems. Until today, published geophysical applications mainly focus on finding an optimum solution for simple, 1D inverse problems. We have applied PSO-based optimization strategies to reconstruct 2D P-wave velocity fields from crosshole traveltime data sets. Our inversion strategy also includes generating and analyzing a representative ensemble of acceptable models, which allows us to appraise uncertainty and nonuniqueness issues. The potential of our strategy was tested on field data collected at a well-constrained test site in Horstwalde, Germany. At this field site, the shallow subsurface mainly consists of sand- and gravel-dominated glaciofluvial sediments, which, as known from several boreholes and other geophysical experiments, exhibit some well-defined layering at the scale of our crosshole seismic data. Thus, we have implemented a flexible, layer-based model parameterization, which, compared with standard cell-based parameterizations, allows for significantly reducing the number of unknown model parameters and for efficiently implementing a priori model constraints. Comparing the 2D velocity fields resulting from our PSO strategy to independent borehole and direct-push data illustrated the benefits of choosing an efficient global optimization approach. These include a straightforward and understandable appraisal of nonuniqueness issues as well as the possibility of an improved and also more objective interpretation.
Imaging condition for nonlinear scattering-based imaging: Estimate of power loss in scattering
Authors: Fleury Clement , Vasconcelos Ivan
Published: February 2012

Imaging highly complex subsurface structures is a challenging problem because it must ultimately deal with nonlinear multiple-scattering effects (e.g., migration of multiples, wavefield extrapolation with nonlinear model interactions, amplitude-preserving migration) to overcome the limitations of linear imaging. Most of the current migration techniques rely on the linear single-scattering assumption, and therefore, fail to handle these complex scattering effects. Recently, seismic imaging has been related to scattering-based image-domain interferometry to address the fully nonlinear imaging problem. Building on this connection between imaging and interferometry, we define the seismic image as a locally scattered wavefield and introduce a new imaging condition that is suitable and practical for nonlinear imaging. A previous formulation of nonlinear scattering-based imaging requires the evaluation of volume integrals that cannot easily be incorporated in current imaging algorithms. Our method consisted of adapting the conventional crosscorrelation imaging condition to account for the interference mechanisms that ensure power conservation in the scattering of wavefields. To do so, we added the zero-lag autocorrelation of scattered wavefields to the zero-lag crosscorrelation of reference and scattered wavefields. In our development, we demonstrated that this autocorrelation of scattered fields fully replaces the volume scattering term required by the previous formulation. We also found that this replacement follows from the application of the generalized optical theorem. The resulting imaging condition accounts for nonlinear multiple-scattering effects, reduces imaging artifacts and improves amplitude preservation and illumination in the images. We addressed the principles of our nonlinear imaging condition and demonstrated its importance in ideal nonlinear imaging experiments, i.e., we presented synthetic data examples assuming ideal scattered wavefield extrapolation and studied the influence of different scattering regimes and aperture limitation.
Antibody-mediated encephalitis: a treatable cause of schizophrenia
Authors: Lennox Belinda R. , Coles Alasdair J. , Vincent Angela
Published: February 2012

Psychiatrists need to be vigilant for the newly recognised and treatable disorder of antibody-mediated encephalitis. Psychiatric symptoms are common, and individuals with the disorder often present initially to psychiatric services. We describe the clinical features of the disorder and make recommendations for further investigations.
Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses
Authors: Leucht Stefan , Hierl Sandra , Kissling Werner , Dold Markus , Davis John M.
Published: February 2012

Background

The efficacy of psychopharmacological treatments has been called into question. Psychiatrists are unfamiliar with the effectiveness of common medical drugs.

Aims

To put the efficacy of psychiatric drugs into the perspective of that of major medical drugs.

Method

We searched Medline and the Cochrane Library for systematic reviews on the efficacy of drugs compared with placebo for common medical and psychiatric disorders, and systematically presented the effect sizes for primary efficacy outcomes.

Results

We included 94 meta-analyses (48 drugs in 20 medical diseases, 16 drugs in 8 psychiatric disorders). There were some general medical drugs with clearly higher effect sizes than the psychotropic agents, but the psychiatric drugs were not generally less efficacious than other drugs.

Conclusions

Any comparison of different outcomes in different diseases can only serve the purpose of a qualitative perspective. The increment of improvement by drug over placebo must be viewed in the context of the disease's seriousness, suffering induced, natural course, duration, outcomes, adverse events and societal values.
Negative childhood experiences and mental health: theoretical, clinical and primary prevention implications
Authors: Read John , Bentall Richard P.
Published: February 2012

After decades of ignoring or minimising the prevalence and effects of negative events in childhood, researchers have recently established that a broad range of adverse childhood events are significant risk factors for most mental health problems, including psychosis. Researchers are now investigating the biological and psychological mechanisms involved. In addition to the development of a traumagenic neurodevelopmental model for psychosis, the exploration of a range of psychological processes, including attachment and dissociation, is shedding light on the specific aetiologies of discrete phenomena such as hallucinations and delusions. It is argued that the theoretical, clinical and primary prevention implications of our belated focus on childhood are profound.
Use of ECT in patients with an intellectual disability: review
Authors: Collins Jessica , Halder Neel , Chaudhry Nasim
Published: February 2012

Aims and method

The literature on the use of electroconvulsive therapy (ECT) in patients with an intellectual disability is scarce, despite a higher prevalence of psychiatric disorders than in the general adult population. We carried out a review of articles published before March 2010. All age ranges, severity of disability and diagnoses were included.

Results

We found 72 case reports, a retrospective chart review study and other reviews, but no controlled studies. Most patients (79%) showed a positive outcome following ECT. Complications were seen only in 13% and there were no reports of cognitive decline. Many patients relapsed following ECT (32%) and the majority were maintained with medication at follow-up (71%).

Clinical implications

Electroconvulsive therapy is a valuable treatment for this patient group and should be considered earlier as opposed to as a last resort. Obstacles to its use include diagnostic difficulties, ethical and legal issues, a lack of objective measurements and uncertainty about its safety in this population.
Recovery Star: validating user recovery
Authors: Dickens Geoff , Weleminsky Judy , Onifade Yetunde , Sugarman Philip
Published: February 2012

Aims and method

Mental Health Recovery Star is a multifaceted 10-item outcomes measure and key-working tool that has been widely adopted by service providers in the UK. We aimed to explore its factorial validity, internal consistency and responsiveness. Recovery Star readings were conducted twice with 203 working-age adults with moderate to severe mental health problems attending a range of mental health services, and a third time with 113 of these individuals.

Results

Mental Health Recovery Star had high internal consistency and appeared to measure an underlying recovery-oriented construct. Results supported a valid two-factor structure which explained 48% of variance in Recovery Star ratings data. Two Recovery Star items (‘relationships’ and ‘addictive behaviour’) did not load onto either factor. There was good statistically significant item responsiveness, and no obvious item redundancy. Data for a small number of variables were not normally distributed and the implications of this are discussed.

Clinical implications

Recovery Star has been received enthusiastically by both mental health service providers and service users. This study provides further evidence for its adoption in recovery-focused mental health services and indicates that items relating to addictive behaviour, responsibilities and work could be further developed in future.
Psychiatric in-patients, violence and the criminal justice system
Authors: Wilson Simon , Murray Kevin , Harris Mike , Brown Michael
Published: February 2012

There is ambivalence about prosecuting psychiatric in-patients for violent offences. This ambivalence is reflected in the Memorandum of Understanding that exists between the Crown Prosecution Service and the NHS Security Management Service. This has led to an unwelcome change in practice when the police ask for information from an individual's consultant psychiatrist, the police requesting information about the individual's cognitive abilities at the time of the alleged offence and using this to make decisions about prosecution. However, there is also guidance on this area from other sources. We describe this and make further suggestions for dealing with these requests.
Preclinical Characterization of a Novel Diphenyl Benzamide Selective ERα Agonist for Hormone Therapy in Prostate Cancer
Authors: Coss Christopher C. , Jones Amanda , Parke Deanna N. , Narayanan Ramesh , Barrett Christina M. , Kearbey Jeffrey D. , Veverka Karen A. , Miller Duane D. , Morton Ronald A. , Steiner Mitchell S. , Dalton James T.
Published: February 2012

Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass.
The Ubiquitin Ligase Siah2 Regulates PPARγ Activity in Adipocytes
Authors: Kilroy Gail , Kirk-Ballard Heather , Carter Lauren E. , Floyd Z. Elizabeth
Published: February 2012

Moderate reductions in peroxisome proliferator-activated receptor (PPAR)γ levels control insulin sensitivity as effectively as activation of PPARγ in adipocytes by the thiazolidinediones. That observation suggests that PPARγ activity can be regulated by modulating the amount of PPARγ protein in adipocytes. Activation of PPARγ in adipocytes is linked to changes in PPARγ protein levels via increased degradation of PPARγ proteins by the ubiquitin proteasome system. Identification of the ubiquitin ligase or ligases that recognize ligand bound PPARγ is an essential step in determining the physiological significance of the relationship between activation and ubiquitin-dependent degradation of PPARγ. Using an RNA interference-based screen, we identified five RING (really interesting new gene)-type ubiquitin ligases that alter PPARγ protein levels in adipocytes. Here, we demonstrate that Drosophila seven-in-absentia homolog 2 (Siah2), a mammalian homolog of Drosophila seven-in-absentia, regulates PPARγ ubiquitylation and ligand-dependent activation of PPARγ in adipocytes. We also demonstrate that Siah2 expression is up-regulated during adipogenesis and that PPARγ interacts with Siah2 during adipogenesis. In addition, Siah2 is required for adipogenesis. These data suggest that modulation of PPARγ protein levels by the ubiquitin ligase Siah2 is essential in determining the physiological effects of PPARγ activation in adipocytes.
The Impact of Social Ties on Group Interactions: Evidence from Minimal Groups and Randomly Assigned Real Groups
Authors: Goette Lorenz , Huffman David , Meier Stephan
Published: February 2012

Economists are increasingly interested in how group membership affects individual behavior. The standard method assigns individuals to “minimal” groups, i.e. arbitrary labels, in a lab. But real groups often involve social interactions leading to social ties between group members. Our experiments compare randomly assigned minimal groups to randomly assigned groups involving real social interactions. While adding social ties leads to qualitatively similar, although stronger, in-group favoritism in cooperation, altruistic norm enforcement patterns are qualitatively different between treatments. Our findings contribute to the micro-foundation of theories of group preferences, and caution against generalizations from “minimal” groups to groups with social context. (JEL C92, D64, D71, Z13)
Competitive Nonlinear Taxation and Constitutional Choice
Authors: Morelli Massimo , Yang Huanxing , Ye Lixin
Published: February 2012

In an economy where agents have different productivities and mobility, we compare a unified nonlinear optimal taxation with the equilibrium taxation that would be chosen by two competing tax authorities if the same economy were divided into two states. The overall level of progressivity and redistribution is unambiguously lower under competitive taxation; the “rich” are always in favor of competing authorities, whereas the “poor” are always in favor of unified taxation; the preferences of the middle class depend on the initial conditions in terms of the distribution of abilities, the relative power of the various classes, and mobility costs. (JEL D72, H21, H23, H24)
Matching in Networks with Bilateral Contracts
Authors: Hatfield John William , Kominers Scott Duke
Published: February 2012

We introduce a model in which firms trade goods via bilateral contracts which specify a buyer, a seller, and the terms of the exchange. This setting subsumes (many-to-many) matching with contracts, as well as supply chain matching. When firms' relationships do not exhibit a supply chain structure, stable allocations need not exist. By contrast, in the presence of supply chain structure, a natural substitutability condition characterizes the maximal domain of firm preferences for which stable allocations are guaranteed to exist. Furthermore, the classical lattice structure, rural hospitals theorem, and one-sided strategy-proofness results all generalize to this setting. (JEL C78, D85, D86, L14)
Inertia and Overwithholding: Explaining the Prevalence of Income Tax Refunds
Authors: Jones Damon
Published: February 2012

Over three-quarters of US taxpayers receive income tax refunds, which are effectively zero-interest loans to the government. Previous explanations include precautionary and/or forced savings motives. I present evidence on a third explanation: inertia. I find that following a change in tax liability, prepayments are only adjusted by 29 percent of the tax change after one year and 61 percent after three years. Adjustment increases with income and experience, and for EITC recipients, I rule out adjustment greater than 2 percent. Thus, policies affecting default-withholding rules are no longer neutral decisions, but rather, may affect consumption smoothing, particularly for low-income taxpayers. (JEL D14, H24, K34)
Preferences of group-housed female mice regarding structure of softwood bedding
Authors: Kirchner J , Hackbarth H , Stelzer H D , Tsai P-P
Published: February 2012

Bedding influences various parameters in the housing of laboratory mice, such as health, physiology and behaviour (often considered as being integral parts of welfare). Notwithstanding existent studies about bedding preferences of individually tested mice, data about group-housed mice are still lacking. The aim of this study was to find out the structure preference for softwood bedding of group-housed mice. One hundred and eight 8-week-old female mice (C57BL6/JOlaHsd and BALB/cOlaHsd) were housed in groups of three and were given one-week free access to two different bedding structures at a time. In three test combinations, softwood shaving bedding was tested versus softwood chip bedding products of three different particle sizes (fine/medium/coarse-grained). The preference test was performed in a DoubleCage system composed of two Makrolon type IIL cages, connected by a perspex tunnel. This validated system was able to detect the crossings of each individual animal with correct crossing time and direction. On the basis of these data, dwelling times on the particular bedding structures were statistically analysed as a parameter for bedding preferences. In all three test combinations, a highly significant shaving preference was detected. On average, mice spent 70% of their dwelling time on the shavings. This preference was more explicit during the light period and in C57BL/6J mice. The relative ranking of the bedding structures was: shavings≫coarse-grained chips>medium chips = fine chips. By means of these results, a shaving structure as bedding can be recommended for laboratory mice, whereas fine chip structures should be avoided.
Comprehensive evaluation of canonical versus Dicer-substrate siRNA in vitro and in vivo
Authors: Foster Donald J. , Barros Scott , Duncan Rick , Shaikh Sarfraz , Cantley William , Dell Amy , Bulgakova Elena , O'Shea Jonathan , Taneja Nate , Kuchimanchi Satya , Sherrill Christopher B. , Akinc Akin , Hinkle Gregory , Seila White Amy C. , Pang Bo , Charisse Klaus , Meyers Rachel , Manoharan Muthiah , Elbashir Sayda M.
Published: February 2012

Since the discovery of RNA interference (RNAi), researchers have identified a variety of small interfering RNA (siRNA) structures that demonstrate the ability to silence gene expression through the classical RISC-mediated mechanism. One such structure, termed “Dicer-substrate siRNA” (dsiRNA), was proposed to have enhanced potency via RISC-mediated gene silencing, although a comprehensive comparison of canonical siRNAs and dsiRNAs remains to be described. The present study evaluates the in vitro and in vivo activities of siRNAs and dsiRNAs targeting Phosphatase and Tensin Homolog (PTEN) and Factor VII (FVII). More than 250 compounds representing both siRNA and dsiRNA structures were evaluated for silencing efficacy. Lead compounds were assessed for duration of silencing and other key parameters such as cytokine induction. We identified highly active compounds from both canonical siRNAs and 25/27 dsiRNAs. Lead compounds were comparable in potency both in vitro and in vivo as well as duration of silencing in vivo. Duplexes from both structural classes tolerated 2′-OMe chemical modifications well with respect to target silencing, although some modified dsiRNAs demonstrated reduced activity. On the other hand, dsiRNAs were more immunostimulatory as compared with the shorter siRNAs, both in vitro and in vivo. Because the dsiRNA structure does not confer any appreciable benefits in vitro or in vivo while demonstrating specific liabilities, further studies are required to support their applications in RNAi therapeutics.
Butyrylcholinesterase Activity Predicts Long-Term Survival in Patients with Coronary Artery Disease
Authors: Goliasch Georg , Haschemi Arvand , Marculescu Rodrig , Endler Georg , Maurer Gerald , Wagner Oswald , Huber Kurt , Mannhalter Christine , Niessner Alexander
Published: February 2012

BACKGROUND

Low serum butyrylcholinesterase activity was associated with all-cause and cardiovascular mortality in a community-based study; however, there are no data from investigations of the long-term effects of butyrylcholinesterase on mortality in patients with diagnosed coronary artery disease (CAD). We therefore assessed the effect of butyrylcholinesterase activity on the outcomes of patients with CAD.

METHODS AND RESULTS

We prospectively included 720 patients in our study: 293 patients with stable CAD and 427 patients with acute coronary syndrome. During a median follow-up of 11.3 years corresponding to 6469 overall person-years, 278 deaths (38.6%) were recorded. We detected a significant and independent protective effect of butyrylcholinesterase on all-cause mortality [adjusted hazard ratio (HR) for a 1-SD increase, 0.62; 95% CI, 0.54–0.71; P < 0.001] and cardiovascular mortality (adjusted HR, 0.64; 95% CI, 0.54–0.76; P < 0.001) in a Cox proportional hazards regression analysis. The 10-year survival rates were 42%, 74%, and 87% in the first, second, and third tertiles of butyrylcholinesterase activity. The presentation of CAD affected the effect of butyrylcholinesterase on mortality (P for interaction = 0.012), with a stronger association found in patients with stable CAD (adjusted HR, 0.56; 95% CI, 0.45–0.70; P < 0.001).

CONCLUSIONS

Our study demonstrates a strong inverse association between butyrylcholinesterase activity and long-term outcome in patients with known CAD. Because butyrylcholinesterase added predictive information after adjustment for established cardiovascular risk factors, additional underlying pathophysiological mechanisms and the potential applicability of butyrylcholinesterase activity for secondary risk prediction needs to be addressed in future studies.
Calpains Are Downstream Effectors ofbax-Dependent Excitotoxic Apoptosis
Authors: D'Orsi Beatrice , Bonner Helena , Tuffy Liam P. , Düssmann Heiko , Woods Ina , Courtney Michael J. , Ward Manus W. , Prehn Jochen H. M.
Published: February 2012

Excitotoxicity resulting from excessive Ca2+influx through glutamate receptors contributes to neuronal injury after stroke, trauma, and seizures. Increased cytosolic Ca2+levels activate a family of calcium-dependent proteases with papain-like activity, the calpains. Here we investigated the role of calpain activation during NMDA-induced excitotoxic injury in embryonic (E16–E18) murine cortical neurons that (1) underwent excitotoxic necrosis, characterized by immediate deregulation of Ca2+homeostasis, a persistent depolarization of mitochondrial membrane potential (Δψm), and insensitivity tobax-gene deletion, (2) underwent excitotoxic apoptosis, characterized by recovery of NMDA-induced cytosolic Ca2+increases, sensitivity tobaxgene deletion, and delayed Δψmdepolarization and Ca2+deregulation, or (3) that were tolerant to excitotoxic injury. Interestingly, treatment with the calpain inhibitor calpeptin, overexpression of the endogenous calpain inhibitorcalpastatin, or gene silencing ofcalpainprotected neurons against excitotoxic apoptosis but did not influence excitotoxic necrosis. Calpeptin failed to exert a protective effect inbax-deficient neurons but protectedbid-deficient neurons similarly to wild-type cells. To identify when calpains became activated during excitotoxic apoptosis, we monitored calpain activation dynamics by time-lapse fluorescence microscopy using a calpain-sensitive Förster resonance energy transfer probe. We observed a delayed calpain activation that occurred downstream of mitochondrial engagement and directly preceded neuronal death. In contrast, we could not detect significant calpain activity during excitotoxic necrosis or in neurons that were tolerant to excitotoxic injury. Oxygen/glucose deprivation-induced injury in organotypic hippocampal slice cultures confirmed that calpains were specifically activated duringbax-dependent apoptosis and in this setting function as downstream cell-death executioners.
The Nucleosome Remodeling and Deacetylase Chromatin Remodeling (NuRD) Complex Is Required for Peripheral Nerve Myelination
Authors: Hung Holly , Kohnken Rebecca , Svaren John
Published: February 2012

Several key transcription factors and coregulators important to peripheral nerve myelination have been identified, but the contributions of specific chromatin remodeling complexes to peripheral nerve myelination have not been analyzed. Chromodomain helicase DNA-binding protein 4 (Chd4) is the core catalytic subunit of the nucleosome remodeling and deacetylase (NuRD) chromatin remodeling complex. Previous studies have shown Chd4 interacts with Nab (NGFI-A/Egr-binding) corepressors, which are required for early growth response 2 (Egr2/Krox20), to direct peripheral nerve myelination by Schwann cells. In this study, we examined the developmental importance of the NuRD complex in peripheral nerve myelination through the generation of conditional Chd4 knock-out mice in Schwann cells (Chd4loxP/loxP; P0-cre). Chd4 conditional null mice were found to have delayed myelination, radial sorting defects, hypomyelination, and the persistence of promyelinating Schwann cells. Loss of Chd4 leads to elevated expression of immature Schwann cell genes (Id2, c-Jun, and p75), and sustained expression of the promyelinating Schwann cell gene, Oct6/Scip, without affecting the levels of Egr2/Krox20. Furthermore, Schwann cell proliferation is upregulated in Chd4-null sciatic nerve.In vivochromatin immunoprecipitation studies reveal recruitment of Chd4 and another NuRD component, Mta2, to genes that are positively and negatively regulated by Egr2 during myelination. Together, these results underscore the necessity of Chd4 function to guide proper terminal differentiation of Schwann cells and implicate the NuRD chromatin remodeling complex as a requisite factor in timely and stable peripheral nerve myelination.
JNK1 Inhibits GluR1 Expression and GluR1-Mediated Calcium Influx through Phosphorylation and Stabilization of Hes-1
Authors: Lin Cheng H. , Lee Eminy H. Y.
Published: February 2012

The GluR1 subunit of the AMPA receptor plays an important role in excitatory synaptic transmission and synaptic plasticity in the brain, but the regulation mechanism for GluR1 expression is largely unknown. Hairy and enhancer of split 1 (Hes-1) is a mammalian transcription repressor that regulates neuronal differentiation and development, but the role of Hes-1 in differentiated neurons is also less known. Here, we examined the molecular mechanism in regulation of GluR1 expression in rat cultured cortical neurons. We found that Hes-1 suppressed GluR1 promoter activity and decreased GluR1 expression through direct binding to the N-box and through preventing Mash1/E47 from binding to the E-box of GluR1 promoter. We also found that Hes-1 could be regulated by c-Jun N-terminal kinase (JNK1). JNK1 directly phosphorylates Hes-1 at Ser-263. Furthermore, JNK1 phosphorylation of Hes-1 stabilized the Hes-1 protein and enhanced the suppressing effect of Hes-1 on GluR1 expression. These effects were demonstrated both in the soma and at the synapse. Moreover, this JNK1-mediated signaling pathway was found to inhibit AMPA-evoked calcium influx in cortical neurons and this regulation mechanism is Notch independent. Here, we provided the first evidence that Hes-1 plays an important role in synaptic function in differentiated neurons. We also identified a novel JNK1–Hes-1 signaling pathway that regulates GluR1 expression involved in synaptic function in rat cortical neurons.
Dynamic Correlation between Whisking and Breathing Rhythms in Mice
Authors: Cao Ying , Roy Snigdha , Sachdev Robert N. S. , Heck Detlef H.
Published: February 2012

Sniffing, a high-frequency, highly rhythmic inhalation and exhalation of air through the nose, plays an important role in rodent olfaction. Similarly, whisking, the active rhythmic movement of whiskers, plays an important role in rodent tactile sensation. Rodents whisk and sniff during exploratory behavior to sample odorants and surfaces. Whisking is thought to be coordinated with sniffing and normal respiratory behavior, but the precise temporal relationships between these movements are not known. Here, using direct measurements of whisking and respiratory movements, we examined the strength and temporal dynamics of the correlation between large-amplitude whisker movements and respiratory rhythm in mice. Whisking movements were detected using an optical sensor, and respiration was monitored with a thermistor placed close to the nostril. Our measurements revealed that breathing and whisking movements were significantly correlated only when the whisking rhythm was <5 Hz. Only a fraction (∼13%) of all large-amplitude whisker movements occurred during episodes of high-frequency (>5 Hz) respiration typically associated with sniffing. Our results show that that the rhythms of respiratory and whisking movements are correlated only during low-frequency whisking and respiration. High-frequency whisking and sniffing behaviors are not correlated. We conclude that whisking and respiratory rhythms are generated by independent pattern-generating mechanisms.