bluuebunny/crossref_metadata_2025 huggingface dataset:
RBC and WBC fatty acid composition following consumption of an omega 3 supplement: Lessons for future clinical trials
Authors: Witte Theodore R , Salazar Alexander J , Ballester Oscar F , Hardman W Elaine
Published: March 2010

Background

Results from increasing numbers of in vitro and in vivo studies have demonstrated that omega 3 fatty acids incorporated in cell culture media or in the diet of the animals can suppress the growth of cancers. When human clinical trials are initiated to determine the ability of omega 3 fatty acids to alter growth or response to chemotherapeutic interventions of cancers, it will be essential to determine the omega 3 intake of individuals in the trial to determine compliance with consumption of the supplement and to correlate with endpoints of efficacy. We wondered if the fatty acid composition of RBCs might accurately indicate incorporation of omega 3 fatty acids in the WBCs. In this report we determine and compare the changes in fatty acid compositions of red blood cells and white blood cells in response to consumption of three doses of an omega 3 fatty acid supplement.

Results

We found that the fraction of omega 3 fatty acids in both red blood cells and white blood cells increased following consumption of the supplement. There was a linear, dose responsive increase in the fraction of omega 3 fatty acids in red blood cells but the increase in omega 3 in white blood cells was not linear. The magnitude of increase in omega 3 fatty acids was different between the two cell types.

Conclusions

Fatty acid analysis of red blood cells is a good measure of compliance with supplement consumption. However, fatty acid analysis of white blood cells is needed to correlate changes in fatty acid composition of white blood cells with other biochemical changes in the white blood cells.

Trial Registration

ClinicalTrials.gov NCT00899353.
Ultrafine particles from diesel vehicle emissions at different driving cycles induce differential vascular pro-inflammatory responses: Implication of chemical components and NF-κB signaling
Authors: Li Rongsong , Ning Zhi , Majumdar Rohit , Cui Jeffery , Takabe Wakako , Jen Nelson , Sioutas Constantinos , Hsiai Tzung
Published: March 2010

Background

Epidemiological evidence supports the association between exposure to ambient particulate matter (PM) and cardiovascular diseases. Chronic exposure to ultrafine particles (UFP; D
p <100 nm) is reported to promote atherosclerosis in ApoE knockout mice. Atherogenesis-prone factors induce endothelial dysfunction that contributes to the initiation and progression of atherosclerosis. We previously demonstrated that UFP induced oxidative stress via c-Jun N-terminal Kinases (JNK) activation in endothelial cells. In this study, we investigated pro-inflammatory responses of human aortic endothelial cells (HAEC) exposed to UFP emitted from a diesel truck under an idling mode (UFP1) and an urban dynamometer driving schedule (UFP2), respectively. We hypothesize that UFP1 and UFP2 with distinct chemical compositions induce differential pro-inflammatory responses in endothelial cells.

Results

UFP2 contained a higher level of redox active organic compounds and metals on a per PM mass basis than UFP1. While both UFP1 and UFP2 induced superoxide production and up-regulated stress response genes such as heme oxygenease-1 (HO-1), OKL38, and tissue factor (TF), only UFP2 induced the expression of pro-inflammatory genes such as IL-8 (2.8 ± 0.3-fold), MCP-1 (3.9 ± 0.4-fold), and VCAM (6.5 ± 1.1-fold) (n = 3, P < 0.05). UFP2-exposed HAEC also bound to a higher number of monocytes than UFP1-exposed HAEC (Control = 70 ± 7.5, UFP1 = 106.7 ± 12.5, UFP2 = 137.0 ± 8.0, n = 3, P < 0.05). Adenovirus NF-κB Luciferase reporter assays revealed that UFP2, but not UFP1, significantly induced NF-κB activities. NF-κB inhibitor, CAY10512, significantly abrogated UFP2-induced pro-inflammatory gene expression and monocyte binding.

Conclusion

While UFP1 induced higher level of oxidative stress and stress response gene expression, only UFP2, with higher levels of redox active organic compounds and metals, induced pro-inflammatory responses via NF-κB signaling. Thus, UFP with distinct chemical compositions caused differential response patterns in endothelial cells.
In utero exposure to a low concentration of diesel exhaust affects spontaneous locomotor activity and monoaminergic system in male mice
Authors: Suzuki Tomoharu , Oshio Shigeru , Iwata Mari , Saburi Hisayo , Odagiri Takashi , Udagawa Tadashi , Sugawara Isamu , Umezawa Masakazu , Takeda Ken
Published: March 2010

Background

Epidemiological studies have suggested that suspended particulate matter (SPM) causes detrimental health effects such as respiratory and cardiovascular diseases, and that diesel exhaust particles from automobiles is a major contributor to SPM. It has been reported that neonatal and adult exposure to diesel exhaust damages the central nervous system (CNS) and induces behavioral alteration. Recently, we have focused on the effects of prenatal exposure to diesel exhaust on the CNS. In this study, we examined the effects of prenatal exposure to low concentration of diesel exhaust on behaviour and the monoaminergic neuron system. Spontaneous locomotor activity (SLA) and monoamine levels in the CNS were assessed.

Methods

Mice were exposed prenatally to a low concentration of diesel exhaust (171 μg DEP/m3) for 8 hours/day on gestational days 2-16. SLA was assessed for 3 days in 4-week-old mice by analysis of the release of temperature-associated infrared rays. At 5 weeks of age, the mice were sacrificed and the brains were used for analysis by high-performance liquid chromatography (HPLC).

Results and Discussion

Mice exposed to a low concentration of diesel exhaust showed decreased SLA in the first 60 minutes of exposure. Over the entire test period, the mice exposed prenatally to diesel exhaust showed decreased daily SLA compared to that in control mice, and the SLA in each 3 hour period was decreased when the lights were turned on. Neurotransmitter levels, including dopamine and noradrenaline, were increased in the prefrontal cortex (PFC) in the exposure group compared to the control group. The metabolites of dopamine and noradrenaline also increased in the PFC. Neurotransmitter turnover, an index of neuronal activity, of dopamine and noradrenaline was decreased in various regions of the CNS, including the striatum, in the exposure group. The serum corticosterone level was not different between groups. The data suggest that decreased SLA in mice exposed prenatally to diesel exhaust is due to facilitated release of dopamine in the PFC.

Conclusions

These results indicate that exposure of mice in utero to a low concentration of diesel exhaust decreases SLA and alters the neurochemical monoamine metabolism of several regions of the brain.
Serotonin Receptors are Involved in the Spinal Mediation of Descending Facilitation of Surgical Incision-Induced Increase of Fos-Like Immunoreactivity in Rats
Authors: Silveira João Walter S , Dias Quintino M , Del Bel Elaine A , Prado Wiliam A
Published: March 2010

Background:

Descending pronociceptive pathways may be implicated in states of persistent pain. Paw skin incision is a well-established postoperative pain model that causes behavioral nociceptive responses and enhanced excitability of spinal dorsal horn neurons. The number of spinal c-Fos positive neurons of rats treated intrathecally with serotonin, noradrenaline or acetylcholine antagonists where evaluated to study the descending pathways activated by a surgical paw incision.

Results:

The number of c-Fos positive neurons in laminae I/II ipsilateral, lamina V bilateral to the incised paw, and in lamina X significantly increased after the incision. These changes: remained unchanged in phenoxybenzamine-treated rats; were increased in the contralateral lamina V of atropine-treated rats; were inhibited in the ipsilateral lamina I/II by 5-HT1/2B/2C(methysergide), 5-HT2A(ketanserin) or 5-HT1/2A/2C/5/6/7(methiothepin) receptors antagonists, in the ipsilateral lamina V by methysergide or methiothepin, in the contralateral lamina V by all the serotonergic antagonists and in the lamina X by LY 278,584, ketanserin or methiothepin.

Conclusions:

We conclude: (1) muscarinic cholinergic mechanisms reduce incision-induced response of spinal neurons inputs from the contralateral paw; (2) 5-HT1/2A/2C/3receptors-mediate mechanisms increase the activity of descending pathways that facilitates the response of spinal neurons to noxious inputs from the contralateral paw; (3) 5-HT1/2A/2Cand 5-HT1/2Creceptors increases the descending facilitation mechanisms induced by incision in the ipsilateral paw; (4) 5-HT2A/3receptors contribute to descending pronociceptive pathways conveyed by lamina X spinal neurons; (5) α-adrenergic receptors are unlikely to participate in the incision-induced facilitation of the spinal neurons.
Effects of antenatal dexamethasone treatment on glucocorticoid receptor and calcyon gene expression in the prefrontal cortex of neonatal and adult common marmoset monkeys
Authors: Diaz Heijtz Rochellys , Fuchs Eberhard , Feldon Joram , Pryce Christopher R , Forssberg Hans
Published: March 2010

Background

Synthetic glucocorticoids such as dexamethasone (DEX) are commonly used to promote fetal lung maturation in at-risk preterm births, but there is emerging evidence of subsequent neurobehavioral abnormalities in these children e.g. problems with inattention/hyperactivity. However, molecular pathways mediating effects of glucocorticoid overexposure on motor and cognitive development are poorly understood.

Methods

In this study with common marmoset monkeys, we investigated for neonatal and adulthood effects of antenatal DEX treatment on the expression of the corticosteroid receptors and also calcyon, a risk gene for attention-deficit/hyperactivity disorder, in the prefrontal cortex (PFC). Pregnant marmosets were exposed to DEX (5 mg/kg body weight) or vehicle during early (days 42-48) or late (days 90-96) stages of the 144-day pregnancy.

Results

In neonates, relative to controls, glucocorticoid receptor (GR) mRNA levels were significantly reduced after the late DEX treatment in the medial, orbital and dorsal PFC and after the early DEX treatment in the dorsal PFC. The early DEX exposure, specifically, resulted in significant reduction in calcyon mRNA expression in the medial, orbital, dorsal and lateral PFC relative to controls. Mineralocorticoid receptor (MR) mRNA levels were not significantly affected by DEX treatment. In adults, PFC GR, calcyon, and MR mRNA levels were not significantly affected by early or late prenatal DEX treatment.

Conclusion

These findings indicate that antenatal DEX treatment could lead to short-term alterations in PFC expression of the GR and calcyon genes, with possible neurodevelopmental functional consequences.
Genome-scale metabolic analysis of Clostridium thermocellum for bioethanol production
Authors: Roberts Seth B , Gowen Christopher M , Brooks J Paul , Fong Stephen S
Published: March 2010

Background

Microorganisms possess diverse metabolic capabilities that can potentially be leveraged for efficient production of biofuels. Clostridium thermocellum (ATCC 27405) is a thermophilic anaerobe that is both cellulolytic and ethanologenic, meaning that it can directly use the plant sugar, cellulose, and biochemically convert it to ethanol. A major challenge in using microorganisms for chemical production is the need to modify the organism to increase production efficiency. The process of properly engineering an organism is typically arduous.

Results

Here we present a genome-scale model of C. thermocellum metabolism, i SR432, for the purpose of establishing a computational tool to study the metabolic network of C. thermocellum and facilitate efforts to engineer C. thermocellum for biofuel production. The model consists of 577 reactions involving 525 intracellular metabolites, 432 genes, and a proteomic-based representation of a cellulosome. The process of constructing this metabolic model led to suggested annotation refinements for 27 genes and identification of areas of metabolism requiring further study. The accuracy of the i SR432 model was tested using experimental growth and by-product secretion data for growth on cellobiose and fructose. Analysis using this model captures the relationship between the reduction-oxidation state of the cell and ethanol secretion and allowed for prediction of gene deletions and environmental conditions that would increase ethanol production.

Conclusions

By incorporating genomic sequence data, network topology, and experimental measurements of enzyme activities and metabolite fluxes, we have generated a model that is reasonably accurate at predicting the cellular phenotype of C. thermocellum and establish a strong foundation for rational strain design. In addition, we are able to draw some important conclusions regarding the underlying metabolic mechanisms for observed behaviors of C. thermocellum and highlight remaining gaps in the existing genome annotations.
A displaced stress fracture of the femoral neck in an adolescent female distance runner with female athlete triad: A case report
Authors: Okamoto Shinichi , Arai Yuji , Hara Kunio , Tsuzihara Takashi , Kubo Toshikazu
Published: March 2010

This report presents a case of a displaced stress fracture of the femoral neck in an adolescent female distance runner with amenorrhea. Both reduction and internal fixation were performed early after the injury. At 24 months postoperatively, magnetic resonance imaging and bone scintigraphy showed no positive signs of femoral head necrosis and bone union was confirmed on plain X-ray. A medical examination for the presence of the signs of the female athlete triad by checking weight, calorie intake and menstrual cycles is most important to prevent such stress fractures. Athletes as well as their coaches or parents therefore need to understand female athlete triad.
Low-density lipoprotein particle size in hepatic steatosis and metabolic syndrome
Authors: Kim Dal-Sik , Kim Young-Kon , Kim Do-Sung , Chae Han-Jung , Park Tae-Sun , Cho Young I , Jeong Seul-Ki
Published: March 2010

Background

Hepatic steatosis (HS), the most frequent liver disorder, was reported to be an independent predictor of cardiovascular disease. HS, if combined with the metabolic syndrome (MetS), might have a synergistic effect on low-density lipoprotein (LDL) particle size.

Methods

Carotid intima-media thickness (IMT) and plaque formation, and HS were diagnosed ultrasonographically, and the MetS was diagnosed using the ATP III criteria in 274 healthy workers (mean age ± SD, 43.5 ± 7.1 yrs). LDL particle size was measured with density gradient ultracentrifugation, and subfractions were classified as large, buoyant LDL I (27.2~28.5 nm) and small, dense LDL III (24.2~25.5). All participants were grouped into three categories: control, subjects with HS alone and those with both HS and the MetS.

Results

The subjects with HS alone were 84 (30.7%), whereas those with HS and the MetS were 46 (16.8%). LDL peak particle sizes showed significant negative correlations with carotid mean IMTs. LDL peak particle size and LDL I (%) decreased significantly in the HS, showing the lowest values in the subjects with both HS and the MetS, and their association was independent, even adjusted for potential confounders. LDL III also showed independent associations across the groups.

Conclusion

HS alone was more prevalent than HS combined with the MetS in general population. For the patients with HS alone, LDL particle size and carotid atherosclerosis were found to fall in the middle of the control and those with both HS and the MetS.
Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease
Authors: Cordero Mario D , De Miguel Manuel , Moreno Fernández Ana M , Carmona López Inés M , Garrido Maraver Juan , Cotán David , Gómez Izquierdo Lourdes , Bonal Pablo , Campa Francisco , Bullon Pedro , Navas Plácido , Sánchez Alcázar José A
Published: March 2010

Introduction

Fibromyalgia is a chronic pain syndrome with unknown etiology. Recent studies have shown some evidence demonstrating that oxidative stress may have a role in the pathophysiology of fibromyalgia. However, it is still not clear whether oxidative stress is the cause or the effect of the abnormalities documented in fibromyalgia. Furthermore, the role of mitochondria in the redox imbalance reported in fibromyalgia also is controversial. We undertook this study to investigate the role of mitochondrial dysfunction, oxidative stress, and mitophagy in fibromyalgia.

Methods

We studied 20 patients (2 male, 18 female patients) from the database of the Sevillian Fibromyalgia Association and 10 healthy controls. We evaluated mitochondrial function in blood mononuclear cells from fibromyalgia patients measuring, coenzyme Q10 levels with high-performance liquid chromatography (HPLC), and mitochondrial membrane potential with flow cytometry. Oxidative stress was determined by measuring mitochondrial superoxide production with MitoSOX™ and lipid peroxidation in blood mononuclear cells and plasma from fibromyalgia patients. Autophagy activation was evaluated by quantifying the fluorescence intensity of LysoTracker™ Red staining of blood mononuclear cells. Mitophagy was confirmed by measuring citrate synthase activity and electron microscopy examination of blood mononuclear cells.

Results

We found reduced levels of coenzyme Q10, decreased mitochondrial membrane potential, increased levels of mitochondrial superoxide in blood mononuclear cells, and increased levels of lipid peroxidation in both blood mononuclear cells and plasma from fibromyalgia patients. Mitochondrial dysfunction was also associated with increased expression of autophagic genes and the elimination of dysfunctional mitochondria with mitophagy.

Conclusions

These findings may support the role of oxidative stress and mitophagy in the pathophysiology of fibromyalgia.
Near-infrared spectroscopy during stagnant ischemia estimates central venous oxygen saturation and mixed venous oxygen saturation discrepancy in patients with severe left heart failure and additional sepsis/septic shock
Authors: Možina Hugo , Podbregar Matej
Published: March 2010

Introduction

Discrepancies of 5-24% between superior vena cava oxygen saturation (ScvO2) and mixed venous oxygen saturation (SvO2) have been reported in patients with severe heart failure. Thenar muscle tissue oxygenation (StO2) measured with near-infrared spectroscopy (NIRS) during arterial occlusion testing decreases slower in sepsis/septic shock patients (lower StO2 deoxygenation rate). The StO2 deoxygenation rate is influenced by dobutamine. The aim of this study was to determine the relationship between the StO2 deoxygenation rate and the ScvO2-SvO2 discrepancy in patients with severe left heart failure and additional sepsis/septic shock treated with or without dobutamine.

Methods

Fifty-two patients with severe left heart failure due to primary heart disease with additional severe sepsis/septic shock were included. SvO2 and ScvO2 were compared to the thenar muscle StO2 before and during arterial occlusion.

Results

SvO2 correlated significantly with ScvO2 (Pearson correlation 0.659, P = 0.001), however, Bland Altman analysis showed a clinically important difference between both variables (ScvO2-SvO2 mean 72 ± 8%, ScvO2-SvO2 difference 9.4 ± 7.5%). The ScvO2-SvO2 difference correlated with plasma lactate (Pearson correlation 0.400, P = 0.003) and the StO2 deoxygenation rate (Pearson correlation 0.651, P = 0.001). In the group of patients treated with dobutamine, the ScvO2-SvO2 difference correlated with plasma lactate (Pearson correlation 0.389, P = 0.011) and the StO2 deoxygenation rate (Pearson correlation 0.777, P = 0.0001).

Conclusions

In patients with severe heart failure with additional severe sepsis/septic shock the ScvO2-SvO2 discrepancy presents a clinical problem. In these patients the skeletal muscle StO2 deoxygenation rate is inversely proportional to the difference between ScvO2 and SvO2; dobutamine does not influence this relationship. When using ScvO2 as a treatment goal, the NIRS measurement may prove to be a useful non-invasive diagnostic test to uncover patients with a normal ScvO2 but potentially an abnormally low SvO2.

Trial Registration

NCT00384644 ClinicalTrials.Gov.
Evidence-ranked motif identification
Authors: Georgiev Stoyan , Boyle Alan P , Jayasurya Karthik , Ding Xuan , Mukherjee Sayan , Ohler Uwe
Published: March 2010

cERMIT is a computationally efficient motif discovery tool based on analyzing genome-wide quantitative regulatory evidence. Instead of pre-selecting promising candidate sequences, it utilizes information across all sequence regions to search for high-scoring motifs. We apply cERMIT on a range of direct binding and overexpression datasets; it substantially outperforms state-of-the-art approaches on curated ChIP-chip datasets, and easily scales to current mammalian ChIP-seq experiments with data on thousands of non-coding regions.
Linear iterative refinement method for the rapid simulation of borehole nuclear measurements: Part 2 — High-angle and horizontal wells
Authors: Mendoza Alberto , Torres-Verdín Carlos , Preeg Bill
Published: March 2010

Based on previous research, we developed and successfully tested a new linear iterative refinement method to rapidly simulate borehole nuclear measurements acquired in vertical wells. The approximation considers 2D spatial properties of Monte Carlo-derived flux-sensitivity functions (FSFs) to simulate neutron and density measurements. Based on new research, we implemented the linear iterative refinement method with explicit 3D spatial properties of FSFs to approximate nuclear borehole measurements acquired in high-angle and horizontal (HA/HZ) wells. We used generic neutron and density tools that are close to commercial tool designs to construct 3D FSFs in the proximity of a bed boundary between layers of contrasting petrophysical properties. Likewise, to benchmark the approximation, we consider adjacent layers of 5% and 30% porosity water-saturated sandstone. For the case of neutron measurements, variations of azimuthal geometric factors are as large as 20° and 57° for the near and far detectors, respectively. Variations in the radial length of investigation (J-factors) are as large as [Formula: see text] for near and far detectors. In the case of density measurements, radial and azimuthal geometric factors are approximately invariant. Linear iterative refinement approximations yield errors in the simulated neutron porosity ranging from 1.6% to 4.3% with respect to Monte Carlo-simulated logs in wells deviating from 60° to 85° from the vertical.
The velocity of energy through a dissipative medium
Authors: Carcione José M. , Gei Davide , Treitel Sven
Published: March 2010

The velocity of seismic and electromagnetic signals depends on properties such as elastic moduli, density, porosity, viscosity, dielectric permittivity, and conductivity. Hence, the identification of the correct velocity of energy transport is essential to obtain the characteristics of the medium. The energy and group velocities, defined for a monochromatic plane wave, are compared to the centrovelocity, related to the centroid of the pulse in the time and spatial domains. The comparison is performed for a 1D medium and a band-limited pulse with a given dominant frequency and taking into account that the centroid of the spectrum decreases with increasing distance. For a lossless medium, the three velocities coincide. In absorbing media, the centrovelocity is closer to the group velocity at short travel distances, in which the wave packet retains its shape. At a given distance, the centrovelocity equals the energy velocity, and beyond that distance this velocity becomes a better approximation. This is generally the case for the propagation of acoustic and electromagnetic waves in earth materials. In other cases, such as electromagnetic propagation at the atomic scale (Lorentz model), the meaning of the energy velocity needs to be revisited, and concepts such as the signal velocity are required.
Impact of EWS-ETS Fusion Type on Disease Progression in Ewing's Sarcoma/Peripheral Primitive Neuroectodermal Tumor: Prospective Results From the Cooperative Euro-E.W.I.N.G. 99 Trial
Authors: Le Deley Marie-Cecile , Delattre Olivier , Schaefer Karl-Ludwig , Burchill Sue A. , Koehler Gabriele , Hogendoorn Pancras C.W. , Lion Thomas , Poremba Christopher , Marandet Julien , Ballet Stelly , Pierron Gaelle , Brownhill Samantha C. , Nesslböck Michaela , Ranft Andreas , Dirksen Uta , Oberlin Odile , Lewis Ian J. , Craft Alan W. , Jürgens Heribert , Kovar Heinrich
Published: March 2010

Purpose

EWS-ETS fusion genes are the driving force in Ewing's sarcoma pathogenesis. Because of the variable breakpoint locations in the involved genes, there is heterogeneity in fusion RNA and protein architecture. Since previous retrospective studies suggested prognostic differences among patients expressing different EWS-FLI1 fusion types, the impact of fusion RNA architecture on disease progression and relapse was studied prospectively within the Euro-E.W.I.N.G. 99 clinical trial.

Patients and Methods

Among 1,957 patients who registered before January 1, 2007, 703 primary tumors were accessible for the molecular biology study. Fusion type was assessed by polymerase chain reaction on frozen (n = 578) or paraffin-embedded materials (n = 125). The primary end point was the time to disease progression or relapse.

Results

After exclusion of noninformative patients, 565 patients were entered into the prognostic factor analysis comparing type 1 (n = 296), type 2 (n = 133), nontype 1/nontype 2 EWS-FLI1 (n = 91) and EWS-ERG fusions (n = 45). Median follow-up time was 4.5 years. The distribution of sex, age, tumor volume, tumor site, disease extension, or histologic response did not differ between the four fusion type groups. We did not observe any significant prognostic value of the fusion type on the risk of progression or relapse. The only slight difference was that the risk of progression or relapse associated with nontype 1/nontype 2 EWS-FLI1 fusions was 1.38 (95% CI, 0.96 to 2.0) times higher than risk associated with other fusion types, but it was not significant (P = .10).

Conclusion

In contrast to retrospective studies, the prospective evaluation did not confirm a prognostic benefit for type 1 EWS-FLI1 fusions.
Major Tumor Shrinking and Persistent Molecular Remissions After Consolidation With Bortezomib, Thalidomide, and Dexamethasone in Patients With Autografted Myeloma
Authors: Ladetto Marco , Pagliano Gloria , Ferrero Simone , Cavallo Federica , Drandi Daniela , Santo Loredana , Crippa Claudia , De Rosa Luca , Pregno Patrizia , Grasso Mariella , Liberati Anna Marina , Caravita Tommaso , Pisani Francesco , Guglielmelli Tommasina , Callea Vincenzo , Musto Pellegrino , Cangialosi Clotilde , Passera Roberto , Boccadoro Mario , Palumbo Antonio
Published: March 2010

Purpose

We investigated the effect on minimal residual disease, by qualitative and real-time quantitative polymerase chain reaction (RQ-PCR), of a consolidation regimen that included bortezomib, thalidomide, and dexamethasone (VTD) in patients with multiple myeloma (MM) responding to autologous stem-cell transplantation (auto-SCT).

Patients and Methods

Patients achieving at least very good partial response who had an available molecular marker based on the immunoglobulin heavy-chain rearrangement received four courses of treatment every month: four infusions per month of bortezomib at 1.6 mg/m2, thalidomide at 200 mg/d, and dexamethasone at 20 mg/d on days 1 to 4, 8 to 11, and 15 to 18. Patients were studied with tumor-clone–specific primers by qualitative nested PCR and RQ-PCR.

Results

Of 39 patients enrolled, 31 received the four VTD courses. Immunofixation complete responses increased from 15% after auto-SCT to 49% after VTD. Molecular remissions (MRs) were 3% after auto-SCT and 18% after VTD. Median time to maximum response was 3.5 months. So far, no patient in MR has relapsed (median follow-up, 42 months). VTD consolidation induced an additional depletion of 4.14 natural logarithms of tumor burden by RQ-PCR. Patients with a tumor load less than the median value after VTD had outcomes better than those who had tumor loads above the median value after VTD (at median follow-up: progression-free survival, 100% v 57%; P < .001).

Conclusion

To the best of our knowledge, this study is the first to document the occurrence of persistent MRs in a proportion of MM patients treated without allogeneic transplantation. Moreover, the major reduction in tumor load recorded by RQ-PCR after VTD suggests that unprecedented levels of tumor cell reduction can be achieved in MM thanks to the new nonchemotherapeutic drugs.
Capecitabine in Addition to Anthracycline- and Taxane-Based Neoadjuvant Treatment in Patients With Primary Breast Cancer: Phase III GeparQuattro Study
Authors: von Minckwitz Gunter , Rezai Mahdi , Loibl Sibylle , Fasching Peter A. , Huober Jens , Tesch Hans , Bauerfeind Ingo , Hilfrich Jörn , Eidtmann Holger , Gerber Bernd , Hanusch Claus , Kühn Thorsten , du Bois Andreas , Blohmer Jens-Uwe , Thomssen Christoph , Dan Costa Serban , Jackisch Christian , Kaufmann Manfred , Mehta Keyur , Untch Michael
Published: March 2010

Purpose

Capecitabine can be integrated either concomitantly or sequentially to anthracycline-plus-taxane–based regimens.

Patients and Methods

Patients with large operable or locally advanced tumors, with hormone receptor–negative tumors, or with receptor-positive tumors but also clinically node-positive disease were recruited to receive preoperatively four cycles of epirubicin plus cyclophosphamide (EC; epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2). Patients were then randomly assigned to four cycles of docetaxel (100 mg/m2), four cycles of docetaxel + capecitabine (TX; docetaxel 75 mg/m2 plus capecitabine 1,800 mg/m2), or four cycles of docetaxel (75 mg/m2) followed by four cycles of capecitabine (1,800 mg/m2; T-X). Patients with human epidermal growth factor receptor 2 (HER-2) –positive tumors received trastuzumab concomitantly with all cycles. Primary objectives were to assess the effect of docetaxel by comparing EC plus docetaxel versus EC plus TX and to assess the effect of duration by comparing EC plus TX versus EC plus T-X on pathologic complete response (pCR, without invasive/noninvasive breast tumor, regardless of nodal status) at surgery, irrespective of trastuzumab treatment.

Results

Of 1,509 patients starting EC, 1,421 were randomly assigned to docetaxel (n = 471), TX (n = 471), or T-X (n = 479). At surgery, pCR rates were 22.3%, 19.5%, and 22.3%, respectively; the difference for docetaxel (EC plus docetaxel v EC plus TX) was 2.8% (95% CI, −2.4% to 8.0%; P = .298).The difference for duration was −2.8% (95% CI, −8.0% to 2.4%; P = .298). Breast conservation rates were 70.1%, 68.4%, and 65.3%, respectively (P = .781 for docetaxel; P = .270 for duration). Concomitant but not sequential treatment with docetaxel was associated with more diarrhea; nail changes, and hand-foot-syndrome, but it was associated with less edema.

Conclusion

Adding capecitabine to or prolonging duration of neoadjuvant EC plus docetaxel does not result in higher efficacy at surgery.
Current Treatment Protocols Have Eliminated the Prognostic Advantage of Type 1 Fusions in Ewing Sarcoma: A Report From the Children's Oncology Group
Authors: van Doorninck John A. , Ji Lingyun , Schaub Betty , Shimada Hiroyuki , Wing Michele R. , Krailo Mark D. , Lessnick Stephen L. , Marina Neyssa , Triche Timothy J. , Sposto Richard , Womer Richard B. , Lawlor Elizabeth R.
Published: March 2010

Purpose

Ewing sarcoma family tumors (ESFTs) exhibit chromosomal translocations that lead to the creation of chimeric fusion oncogenes. Combinatorial diversity among chromosomal breakpoints produces varying fusions. The type 1 EWS-FLI1 transcript is created as a result of fusion between exons 7 of EWS and 6 of FLI1, and retrospective studies have reported that type 1 tumors are associated with an improved outcome. We have re-examined this association in a prospective cohort of patients with ESFT treated according to current Children's Oncology Group (COG) treatment protocols.

Methods

Frozen tumor tissue was prospectively obtained from patients diagnosed with ESFT, and reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine translocation status. Analysis was confined to patients with localized tumors who were diagnosed after 1994 and treated according to COG protocols. Translocation status was correlated with disease characteristics, event-free survival (EFS), and overall survival (OS).

Results

RT-PCR identified chimeric fusion oncogenes in 119 of 132 ESFTs. Eighty-nine percent of identified transcripts were EWS-FLI1, and of these, 58.8% were type 1. Five-year EFS and OS rates for patients with type 1 and non–type 1 fusions diagnosed between 2001 and 2005 were equivalent (type 1: EFS, 63% ± 7%; OS, 83% ± 6%; non–type 1: EFS, 71% ± 9%; OS, 79% ± 8%).

Conclusion

Current intensive treatment protocols for localized ESFT have erased the clinical disadvantage that was formerly observed in patients with non–type 1 EWS-FLI1 fusions.
Lymphoma Recurrence 5 Years or Later Following Diffuse Large B-Cell Lymphoma: Clinical Characteristics and Outcome
Authors: Larouche Jean-François , Berger Françoise , Chassagne-Clément Catherine , Ffrench Martine , Callet-Bauchu Evelyne , Sebban Catherine , Ghesquières Hervé , Broussais-Guillaumot Florence , Salles Gilles , Coiffier Bertrand
Published: March 2010

Purpose

Patients with diffuse large B-cell lymphoma (DLBCL) usually relapse early following diagnosis but some relapses happen at 5 years or later. Few data exist regarding clinical characteristics and outcome of these patients.

Patients and Methods

We performed a retrospective analysis of all patients from two centers in Lyon, France, between 1985 and 2003 who had a biopsy-proven relapse 5 years or later following diagnosis of DLBCL. All available biopsies were reviewed and immunohistochemistry was completed.

Results

Among 1,492 patients with DLBCL, 54 were eligible. At diagnosis, 63% of patients had stage I-II, 82% had low/low-intermediate International Prognostic Index (IPI) score, 65% had extranodal involvement, 24% had an indolent component associated with DLBCL, 57% had germinal center phenotype, and 43% had non-germinal center phenotype. Median time from diagnosis to relapse was 7.4 years (range, 5 to 20.5 years). At time of relapse, 83% had DLBCL histology, and 17% had indolent histology. Having an indolent component at diagnosis was associated with indolent histology at relapse (P = .028). Five-year event free-survival (EFS) was 17% for patients with DLBCL relapse and 61% for patients with indolent relapse (P = .027). Five-year overall survival was 27% for patients with DLBCL and 75% for patients with indolent relapse (P = .029). For DLBCL relapse, 3-year EFS was 56% versus 18% with autologous stem-cell transplantation or not, respectively (P = .0661).

Conclusion

Patients with DLBCL who had a late relapse usually had localized stage, favorable IPI score, and extranodal involvement at diagnosis. The outcome of patients with DLBCL at time of relapse remains poor, and aggressive treatment such as autologous stem-cell transplantation should be pursued whenever possible. Biopsy at relapse is essential because some patients relapse with indolent histology.
Phase II Trial of Bevacizumab, Thalidomide, Docetaxel, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer
Authors: Ning Yang-Min , Gulley James L. , Arlen Philip M. , Woo Sukyung , Steinberg Seth M. , Wright John J. , Parnes Howard L. , Trepel Jane B. , Lee Min-Jung , Kim Yeong Sang , Sun Haihao , Madan Ravi A. , Latham Lea , Jones Elizabeth , Chen Clara C. , Figg William D. , Dahut William L.
Published: March 2010

Purpose

We previously demonstrated that thalidomide appears to add to the activity of docetaxel in metastatic castration-resistant prostate cancer (CRPC). Phase II studies combining docetaxel with bevacizumab have had substantial antitumor activity. We hypothesized that the combination of docetaxel plus these antiangiogenic drugs with different targets would have substantial clinical activity. To explore safety and efficacy, this was tested in mice and in human patients.

Patients and Methods

Preclinical efficacy of the combination therapy was evaluated in PC3 xenograft mice. Sixty patients with progressive metastatic CRPC received intravenous docetaxel and bevacizumab plus oral thalidomide and prednisone. The primary end point was a prostate-specific antigen (PSA) decline of ≥ 50%. Secondary end points included time to progression, overall survival, and safety.

Results

In the mouse model, combination therapy of docetaxel, bevacizumab, and thalidomide inhibited tumor growth most effectively. In the clinical trial, 90% of patients receiving the combination therapy had PSA declines of ≥ 50%, and 88% achieved a PSA decline of ≥ 30% within the first 3 months of treatment. The median time to progression was 18.3 months, and the median overall survival was 28.2 months in this group with a Halabi-predicted survival of 14 months. While toxicities were manageable, all patients developed grade 3/4 neutropenia.

Conclusion

The addition of bevacizumab and thalidomide to docetaxel is a highly active combination with manageable toxicities. The estimated median survival is encouraging, given the generally poor prognosis of this patient population. These results suggest that definitive clinical trials combining antiangiogenic agent combinations with docetaxel are warranted to improve treatment outcomes for patients with metastatic CRPC.
Detecting Disabilities in Older Patients With Cancer: Comparison Between Comprehensive Geriatric Assessment and Vulnerable Elders Survey-13
Authors: Luciani Andrea , Ascione Gilda , Bertuzzi Cecilia , Marussi Desirè , Codecà Carla , Di Maria Giuseppe , Caldiera Sarah Elisabetta , Floriani Irene , Zonato Sabrina , Ferrari Daris , Foa Paolo
Published: March 2010

Purpose

Comprehensive geriatric assessment (CGA) is a multidimensional method used by geriatricians and oncologists to detect and evaluate multiple age-related problems and to plan and coordinate interventions. Because its main drawback is the time required, efforts have been made to evaluate screening instruments suitable for preliminarily assessing elderly patients. The main aim of this study was to establish the accuracy of the Vulnerable Elders Survey-13 (VES-13) in predicting the presence of abnormalities revealed by CGA.

Patients and Methods

Patients age ≥ 70 years with a histologically or cytologically confirmed diagnosis of a solid or hematologic tumor underwent both CGA and a VES-13 assessment, and the reliability and validity of VES-13 were analyzed.

Results

Fifty-three percent of the 419 elderly patients with cancer (mean age, 76.8 years) were vulnerable on VES-13; the rates of disabilities on CGA and activities of daily living (ADLs)/instrumental activities of daily living (IADLs) scales were 30% and 25%, respectively. The sensitivity and specificity of VES-13 were 87% and 62%, respectively, versus CGA and 90% and 70%, respectively, versus ADL/IADL scales.

Conclusions

On the basis of our data, VES-13 is highly predictive of impaired functional status and can thus be considered a useful preliminary means of assessing older patients with cancer before undertaking a full CGA.
Phase II Trial of Continuous Dose-Intense Temozolomide in Recurrent Malignant Glioma: RESCUE Study
Authors: Perry James R. , Bélanger Karl , Mason Warren P. , Fulton Dorcas , Kavan Petr , Easaw Jacob , Shields Claude , Kirby Sarah , Macdonald David R. , Eisenstat David D. , Thiessen Brian , Forsyth Peter , Pouliot Jean-François
Published: March 2010

Purpose

Concomitant temozolomide (TMZ)/radiotherapy followed by adjuvant TMZ has increased survival in patients with glioblastoma multiforme (GBM). However, few options are effective for patients who experience treatment failure. We conducted a multicenter, phase II study to assess the efficacy and safety of continuous dose-intense TMZ for recurrent GBM.

Patients and Methods

Patients with malignant glioma at progression after standard TMZ 150 to 200 mg/m2 × 5 days in a 28-day cycle for three or more cycles were stratified by tumor type (anaplastic glioma group A, GBM, group B). Ninety-one patients with GBM were prospectively divided into three groups (early [B1], extended [B2], and rechallenge [B3]) according to the timing of progression during adjuvant therapy. All patients received continuous dose-intense TMZ 50 mg/m2/d for up to 1 year or until progression occurred. Response was assessed by using RECIST (Response Evaluation Criteria in Solid Tumors).

Results

A total of 116 of 120 patients were evaluable for efficacy. For patients with GBM, 6-month progression-free survival (PFS) was 23.9% (B1, 27.3%; B2, 7.4%; B3, 35.7%). One-year survival from time of study entry was 27.3%, 14.8%, and 28.6% for the B1, B2 and B3 groups, respectively. For patients with anaplastic glioma, 6-month PFS was 35.7%; 1-year survival was 60.7%. The most common grades 3 and 4 nonhematologic toxicities were nausea/vomiting (6.7%) and fatigue (5.8%). Grades 3 and 4 hematologic toxicities were uncommon.

Conclusion

Rechallenge with continuous dose-intense TMZ 50 mg/m2/d is a valuable therapeutic option for patients with recurrent GBM. Patients who experience progression during the first six cycles of conventional adjuvant TMZ therapy or after a treatment-free interval get the most benefit from therapy.
Centers and Peripheries
Authors: Long Mark C.
Published: March 2010

“Centers and Peripheries” introduces the two goals of Pedagogy's special issue: to investigate what might be possible in the small college department as well as to suggest how these possibilities might inspire comparable intellectual work in other professional and institutional contexts. The article surveys a selection of published writing produced within the small college department and points to the practices of smaller institutions and departments in which faculty and students collaborate and envision scholarly and creative activities within the mission and values of a particular institution. It suggests that if the current traditional conception of the discipline has rendered a great deal of the work of the profession invisible, then it would make sense to talk more about what our colleagues are actually doing outside the doctorate-granting institution. The article concludes that representing more fully what we do will require us to move beyond general claims for teaching as a form of scholarship and away from decontextualized arguments about the value of teaching.
Creativity and Collaboration in the Small College Department
Authors: Moffat Wendy
Published: March 2010

This article argues small departments are ideal laboratories for innovative structures of collaboration. Beginning with the smallest nit—an individual teacher “collaborating with herself” to mine good ideas from one course to another, and graduating to larger and more ambitious structures of collaboration—team- teaching, service- learning, performance and interdisciplinary syllabi, and courses taught between campuses and across the globe—Moffat shows how deliberate collaboration can yield more from less. Using examples from colleagues' work in small departments at Dickinson College, Moffat suggests how creative collaboration can expand pedagogical methods, increase student diversity and demand for a range of courses, establish interdisciplinary communities, and widen the curriculum.
A Profession of Blended Beliefs
Authors: Davis Jeffry C.
Published: March 2010

In Scholarship Reconsidered: Priorities of the Professoriate (1990), Ernest L. Boyer challenged the prevailing belief that the most significant work of higher education involved research and publication. Calling for new categories of scholarship—including the activities of discovery, integration, application, and teaching—Boyer emphasized the need for a more complete and pluralistic understanding of the academy, one curiously consistent with the aims of a Christian liberal arts college. As one who teaches English at such a place, I possess a composite of beliefs regarding my profession and my institution—beliefs not perceived as compatible by some. This essay is an examination of these beliefs and how they, in fact, interface. In the English department at Wheaton, our primary educational aim proves to be different from that of a public university: the formation of whole and effective human beings through imitatio Christi, the pedagogic integration of Christian faith and humanistic learning. Eschewing indoctrination and superficial biblical belief, we require students to engage controversial theoretical perspectives and difficult life questions, resulting in the freedom for self-critical participation in a community, a language, and a Book. This exposition concludes with a consideration of belief versus bullshit, advocating Michael Bérubé's approach for “critical pluralism.”
Here Comes Everybody
Authors: McCormick Kathleen , Shofner Melissa
Published: March 2010

Using George Hillocks's epistemic pedagogy and Michael Smith and Jeff Wilhelm's concept of “flow” as frameworks, I create a classroom in which students teach each other to read James Joyce's Ulysses. Students can do this while reading Ulysses for the first time because of the intricate scaffolding I create that requires close interaction outside of class with me, with one or two peer mentors, and with small groups of other students in the class, and that is actively supported by the library, which creates a special “Joyce room” whenever I offer my course. This essay describes how the course is organized and what students are required to do, and it attempts to explain why, in this particular course, students develop complex reading and writing skills and engage in critical work on a difficult literary text beyond what one would think could be possible in one semester on an undergraduate level. While one could teach this course in any type of college or university setting, I suggest that that the values and community of a small liberal arts college encourage faculty to create courses requiring intense student-faculty interaction and encourage students to blur intellectual and social boundaries that enable them to grow in myriad ways.
“We All Got History”
Authors: Gannett Cinthia , Brereton John C. , Tirabassi Katherine E.
Published: March 2010

This review essay places Local Histories in the context of recent books and studies examining the wide variety of composition and rhetoric courses and pedagogical practices that existed in nineteenth-century America. The book has two general foci as represented in its split title: Local Histories, or microhistories of institutions, curricula, and figures; and Reading the Archives of Composition, an extended look at several hitherto unexamined archival sources and their associated projects. The editors identify three central purposes for their book: to challenge the “Harvard narrative,” which, they claim, places the origin of “composition” at Harvard and other elite Eastern colleges; to offer several alternative “microhistories” from various institutional sites, and to document, interpret, and interrogate specific archival holdings and the nature of archival work in composition. While the reviewers find the challenges to “the Harvard model” as history and historiography overstated, overall, they find the collection important for its studies of diverse sites and its attention to less visible figures: teachers who acted as early innovators, and students whose written compositions, informal diaries and letters offer new lenses for making history. The authors of various chapters who unveil their documentary and archival work in process, disclosing both finds and gaps and offering their developing understandings of the archive as construct, perform a valuable service to future scholars of composition studies.