bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlating gene and protein expression data using Correlated Factor Analysis
Authors: Tan Chuen Seng , Salim Agus , Ploner Alexander , Lehtiö Janne , Chia Kee Seng , Pawitan Yudi
Published: September 2009

Background

Joint analysis of transcriptomic and proteomic data taken from the same samples has the potential to elucidate complex biological mechanisms. Most current methods that integrate these datasets allow for the computation of the correlation between a gene and protein but only after a one-to-one matching of genes and proteins is done. However, genes and proteins are connected via biological pathways and their relationship is not necessarily one-to-one. In this paper, we investigate the use of Correlated Factor Analysis (CFA) for modeling the correlation of genome-scale gene and protein data. Unlike existing approaches, CFA considers all possible gene-protein pairs and utilizes all gene and protein information in its modeling framework. The Generalized Singular Value Decomposition (gSVD) is another method which takes into account all available transcriptomic and proteomic data. Comparison is made between CFA and gSVD.

Results

Our simulation study indicates that the CFA estimates can consistently capture the dominant patterns of correlation between two sets of measurements; in contrast, the gSVD estimates cannot do that. Applied to real cancer data, the list of co-regulated genes and proteins identified by CFA has biologically meaningful interpretation, where both the gene and protein expressions are pointing to the same processes. Among the GO terms for which the genes and proteins are most correlated, we observed blood vessel morphogenesis and development.

Conclusion

We demonstrate that CFA is a useful tool for gene-protein data integration and modeling, where the main question is in finding which patterns of gene expression are most correlated with protein expression.
Effects of genetic deficiency of cyclooxygenase-1 or cyclooxygenase-2 on functional and histological outcomes following traumatic brain injury in mice
Authors: Kelso Matthew L , Scheff Stephen W , Pauly James R , Loftin Charles D
Published: September 2009

Background

Neuroinflammation contributes to the pathophysiology of acute CNS injury, including traumatic brain injury (TBI). Although prostaglandin lipid mediators of inflammation contribute to a variety of inflammatory responses, their importance in neuroinflammation is not clear. There are conflicting reports as to the efficacy of inhibiting the enzymes required for prostaglandin formation, cyclooxygenase (COX) -1 and COX-2, for improving outcomes following TBI. The purpose of the current study was to determine the role of the COX isoforms in contributing to pathological processes resulting from TBI by utilizing mice deficient in COX-1 or COX-2.

Results

Following a mild controlled cortical impact injury, the amount of cortical tissue loss, the level of microglial activation, and the capacity for functional recovery was compared between COX-1-deficient mice or COX-2-deficient mice, and their matching wild-type controls. The deficiency of COX-2 resulted in a minor (6%), although statistically significant, increase in the sparing of cortical tissue following TBI. The deficiency of COX-1 resulted in no detectable effect on cortical tissue loss following TBI. As determined by 3[H]-PK11195 autoradiography, TBI produced a similar increase in microglial activation in multiple brain regions of both COX-1 wild-type and COX-1-deficient mice. In COX-2 wild-type and COX-2-deficient mice, TBI increased 3[H]-PK11195 binding in all brain regions that were analyzed. Following injury, 3[H]-PK11195 binding in the dentate gyrus and CA1 region of the hippocampus was greater in COX-2-deficient mice, as compared to COX-2 wild-type mice. Cognitive assessment was performed in the wild-type, COX-1-deficient and COX-2-deficient mice following 4 days of recovery from TBI. There was no significant cognitive effect that resulted from the deficiency of either COX-1 or COX-2, as determined by acquisition and spatial memory retention testing in a Morris water maze.

Conclusion

These findings suggest that the deficiency of neither COX-1 nor COX-2 is sufficient to alter cognitive outcomes following TBI in mice.
Neonatal enteral feeding tubes as loci for colonisation by members of the Enterobacteriaceae
Authors: Hurrell Edward , Kucerova Eva , Loughlin Michael , Caubilla-Barron Juncal , Hilton Anthony , Armstrong Richard , Smith Craig , Grant Judith , Shoo Shiu , Forsythe Stephen
Published: September 2009

Background

The objective of this study was to determine whether neonatal nasogastric enteral feeding tubes are colonised by the opportunistic pathogen Cronobacter spp. (Enterobacter sakazakii) and other Enterobacteriaceae, and whether their presence was influenced by the feeding regime.

Methods

One hundred and twenty-nine tubes were collected from two neonatal intensive care units (NICU). A questionnaire on feeding regime was completed with each sample. Enterobacteriaceae present in the tubes were identified using conventional and molecular methods, and their antibiograms determined.

Results

The neonates were fed breast milk (16%), fortified breast milk (28%), ready to feed formula (20%), reconstituted powdered infant formula (PIF, 6%), or a mixture of these (21%). Eight percent of tubes were received from neonates who were 'nil by mouth'. Organisms were isolated from 76% of enteral feeding tubes as a biofilm (up to 107 cfu/tube from neonates fed fortified breast milk and reconstituted PIF) and in the residual lumen liquid (up to 107
Enterobacteriaceae cfu/ml, average volume 250 μl). The most common isolates were Enterobacter cancerogenus (41%), Serratia marcescens (36%), E. hormaechei (33%), Escherichia coli (29%), Klebsiella pneumoniae (25%), Raoultella terrigena (10%), and S. liquefaciens (12%). Other organisms isolated included C. sakazakii (2%),Yersinia enterocolitica (1%),Citrobacter freundii (1%), E. vulneris (1%), Pseudomonas fluorescens (1%), and P. luteola (1%). The enteral feeding tubes were in place between < 6 h (22%) to > 48 h (13%). All the S. marcescens isolates from the enteral feeding tubes were resistant to amoxicillin and co-amoxiclav. Of additional importance was that a quarter of E. hormaechei isolates were resistant to the 3rd generation cephalosporins ceftazidime and cefotaxime. During the period of the study, K. pneumoniae and S. marcescens caused infections in the two NICUs.

Conclusion

This study shows that neonatal enteral feeding tubes, irrespective of feeding regime, act as loci for the bacterial attachment and multiplication of numerous opportunistic pathogens within the Enterobacteriaceae family. Subsequently, these organisms will enter the stomach as a bolus with each feed. Therefore, enteral feeding tubes are an important risk factor to consider with respect to neonatal infections.
Regulation of excitation-contraction coupling in mouse cardiac myocytes: integrative analysis with mathematical modelling
Authors: Koivumäki Jussi T , Korhonen Topi , Takalo Jouni , Weckström Matti , Tavi Pasi
Published: September 2009

Background

The cardiomyocyte is a prime example of inherently complex biological system with inter- and cross-connected feedback loops in signalling, forming the basic properties of intracellular homeostasis. Functional properties of cells and tissues have been studied e.g. with powerful tools of genetic engineering, combined with extensive experimentation. While this approach provides accurate information about the physiology at the endpoint, complementary methods, such as mathematical modelling, can provide more detailed information about the processes that have lead to the endpoint phenotype.

Results

In order to gain novel mechanistic information of the excitation-contraction coupling in normal myocytes and to analyze sophisticated genetically engineered heart models, we have built a mathematical model of a mouse ventricular myocyte. In addition to the fundamental components of membrane excitation, calcium signalling and contraction, our integrated model includes the calcium-calmodulin-dependent enzyme cascade and the regulation it imposes on the proteins involved in excitation-contraction coupling. With the model, we investigate the effects of three genetic modifications that interfere with calcium signalling: 1) ablation of phospholamban, 2) disruption of the regulation of L-type calcium channels by calcium-calmodulin-dependent kinase II (CaMK) and 3) overexpression of CaMK. We show that the key features of the experimental phenotypes involve physiological compensatory and autoregulatory mechanisms that bring the system to a state closer to the original wild-type phenotype in all transgenic models. A drastic phenotype was found when the genetic modification disrupts the regulatory signalling system itself, i.e. the CaMK overexpression model.

Conclusion

The novel features of the presented cardiomyocyte model enable accurate description of excitation-contraction coupling. The model is thus an applicable tool for further studies of both normal and defective cellular physiology. We propose that integrative modelling as in the present work is a valuable complement to experiments in understanding the causality within complex biological systems such as cardiac myocytes.
Complete PHB mobilization in Escherichia coli enhances the stress tolerance: a potential biotechnological application
Authors: Wang Qian , Yu Hongmin , Xia Yongzhen , Kang Zhen , Qi Qingsheng
Published: September 2009

Background

Poly-β-hydroxybutyrate (PHB) mobilization in bacteria has been proposed as a mechanism that can benefit their host for survival under stress conditions. Here we reported for the first time that a stress-induced system enabled E. coli, a non-PHB producer, to mobilize PHB in vivo by mimicking natural PHB accumulation bacteria.

Results

The successful expression of PHB biosynthesis and PHB depolymerase genes in E. coli was confirmed by PHB production and 3-hydroxybutyrate secretion. Starvation experiment demonstrated that the complete PHB mobilization system in E. coli served as an intracellular energy and carbon storage system, which increased the survival rate of the host when carbon resources were limited. Stress tolerance experiment indicated that E. coli strains with PHB production and mobilization system exhibited an enhanced stress resistance capability.

Conclusion

This engineered E. coli with PHB mobilization has a potential biotechnological application as immobilized cell factories for biocatalysis and biotransformation.
MicroRNA expression profiling in Imatinib-resistant Chronic Myeloid Leukemia patients without clinically significant ABL1-mutations
Authors: San José-Enériz Edurne , Román-Gómez José , Jiménez-Velasco Antonio , Garate Leire , Martin Vanesa , Cordeu Lucia , Vilas-Zornoza Amaia , Rodríguez-Otero Paula , José Calasanz María , Prósper Felipe , Agirre Xabier
Published: September 2009

The development of Imatinib Mesylate (IM), the first specific inhibitor of BCR-ABL1, has had a major impact in patients with Chronic Myeloid Leukemia (CML), establishing IM as the standard therapy for CML. Despite the clinical success obtained with the use of IM, primary resistance to IM and molecular evidence of persistent disease has been observed in 20-25% of IM treated patients. The existence of second generation TK inhibitors, which are effective in patients with IM resistance, makes identification of predictors of resistance to IM an important goal in CML. In this study, we have identified a group of 19 miRNAs that may predict clinical resistance to IM in patients with newly diagnosed CML.
Proteomic analysis of total cellular proteins of human neutrophils
Authors: Tomazella Gisele G , da Silva Idalete , Laure Helen J , Rosa José C , Chammas Roger , Wiker Harald G , de Souza Gustavo A , Greene Lewis J
Published: September 2009

Background

Neutrophils are the most abundant leukocytes in peripheral blood and represent one of the most important elements of innate immunity. Recent subcellular proteomic studies have focused on the identification of human neutrophil proteins in various subcellular membrane and granular fractions. Although there are relatively few studies dealing with the analysis of the total extract of human neutrophils, many biological problems such as the role of chemokines, adhesion molecules, and other activating inputs involved in neutrophil responses and signaling can be approached on the basis of the identification of the total cellular proteins.

Results

Using gel-LC-MS/MS, 251 total cellular proteins were identified from resting human neutrophils. This is more than ten times the number of proteins identified by an initial proteome analysis of human neutrophils and almost five times the number of proteins identified by the first 2-DE map of extracts of rat polymorphonuclear leukocytes. Most of the proteins identified in the present study are well-known, but some of them, such as neutrophil-secreted proteins and centaurin beta-1, a cytoplasmic protein involved in the regulation of NF-κB activity, are described here for the first-time.

Conclusion

The present report provides new information about the protein content of human neutrophils. Importantly, our study resulted in the discovery of a series of proteins not previously reported to be associated with human neutrophils. These data are relevant to the investigation of comparative pathological states and models for novel classes of pharmaceutical drugs that could be useful in the treatment of inflammatory disorders in which neutrophils participate.
Providing Undergraduate Science Partners for Elementary Teachers: Benefits and Challenges
Authors: Goebel Camille A. , Umoja Aminata , DeHaan Robert L.
Published: September 2009

Undergraduate college “science partners” provided content knowledge and a supportive atmosphere for K–5 teachers in a university–school professional development partnership program in science instruction. The Elementary Science Education Partners program, a Local Systemic Change initiative supported by the National Science Foundation, was composed of four major elements: 1) a cadre of mentor teachers trained to provide district-wide teacher professional development; 2) a recruitment and training effort to place college students in classrooms as science partners in semester-long partnerships with teachers; 3) a teacher empowerment effort termed “participatory reform”; and 4) an inquiry-based curriculum with a kit distribution and refurbishment center. The main goals of the program were to provide college science students with an intensive teaching experience and to enhance teachers' skills in inquiry-based science instruction. Here, we describe some of the program's successes and challenges, focusing primarily on the impact on the classroom teachers and their science partners. Qualitative analyses of data collected from participants indicate that 1) teachers expressed greater self-confidence about teaching science than before the program and they spent more class time on the subject; and 2) the college students modified deficit-model negative assumptions about the children's science learning abilities to express more mature, positive views.
Teaching Creativity and Inventive Problem Solving in Science
Authors: DeHaan Robert L.
Published: September 2009

Engaging learners in the excitement of science, helping them discover the value of evidence-based reasoning and higher-order cognitive skills, and teaching them to become creative problem solvers have long been goals of science education reformers. But the means to achieve these goals, especially methods to promote creative thinking in scientific problem solving, have not become widely known or used. In this essay, I review the evidence that creativity is not a single hard-to-measure property. The creative process can be explained by reference to increasingly well-understood cognitive skills such as cognitive flexibility and inhibitory control that are widely distributed in the population. I explore the relationship between creativity and the higher-order cognitive skills, review assessment methods, and describe several instructional strategies for enhancing creative problem solving in the college classroom. Evidence suggests that instruction to support the development of creativity requires inquiry-based teaching that includes explicit strategies to promote cognitive flexibility. Students need to be repeatedly reminded and shown how to be creative, to integrate material across subject areas, to question their own assumptions, and to imagine other viewpoints and possibilities. Further research is required to determine whether college students' learning will be enhanced by these measures.
Development, Implementation, and Assessment of a Lecture Course on Cancer for Undergraduates
Authors: Shuster Michèle , Peterson Karen
Published: September 2009

The war on cancer has been waged for nearly 40 years, yet the cancer burden remains high, especially among minority and underserved populations. One strategy to make strides in the war on cancer and its disparate impacts is to increase the diversity of the cancer research workforce. We describe an approach to recruit a diverse population of future cancer researchers from an undergraduate student population at a minority-serving land-grant institution. Specifically, we have addressed the following questions: Given the dearth of published reports of undergraduate cancer courses, is it possible for undergraduates at a land-grant institution (rather than a research or medical institution) to successfully learn cancer biology from a lecture-based course? Can we develop a template that has the potential to be used by others to develop and implement an undergraduate cancer course? Can such a course stimulate interest in careers in cancer research? Based on a learning gains analysis, students were able to learn cancer content and related skills, and based on student surveys, students' interest in cancer research was stimulated by course participation. We have identified aspects of our course development process that were critical for the successful development, implementation, and assessment of the course.
Using Affinity Chromatography to Investigate Novel Protein–Protein Interactions in an Undergraduate Cell and Molecular Biology Lab Course
Authors: Belanger Kenneth D.
Published: September 2009

Inquiry-driven lab exercises require students to think carefully about a question, carry out an investigation of that question, and critically analyze the results of their investigation. Here, we describe the implementation and assessment of an inquiry-based laboratory exercise in which students obtain and analyze novel data that contribute to our understanding of macromolecular trafficking between the nucleus and cytoplasm in eukaryotic cells. Although many of the proteins involved in nucleocytoplasmic transport are known, the physical interactions between some of these polypeptides remain uncharacterized. In this cell and molecular biology lab exercise, students investigate novel protein–protein interactions between factors involved in nuclear RNA export. Using recombinant protein expression, protein extraction, affinity chromatography, SDS-polyacrylamide gel electrophoresis, and Western blotting, undergraduates in a sophomore-level lab course identified a previously unreported association between the soluble mRNA transport factor Mex67 and the C-terminal region of the yeast nuclear pore complex protein Nup1. This exercise immersed students in the process of investigative science, from proposing and performing experiments through analyzing data and reporting outcomes. On completion of this investigative lab sequence, students reported enhanced understanding of the scientific process, increased proficiency with cellular and molecular methods and content, greater understanding of data analysis and the importance of appropriate controls, an enhanced ability to communicate science effectively, and an increased enthusiasm for scientific research and for the lab component of the course. The modular nature of this exercise and its focus on asking novel questions about protein–protein interactions make it easily transferable to undergraduate lab courses performed in a wide variety of contexts.
Analysis of Students' Aptitude to Provide Meaning to Images that Represent Cellular Components at the Molecular Level
Authors: Dahmani Hassen-Reda , Schneeberger Patricia , Kramer IJsbrand M.
Published: September 2009

The number of experimentally derived structures of cellular components is rapidly expanding, and this phenomenon is accompanied by the development of a new semiotic system for teaching. The infographic approach is shifting from a schematic toward a more realistic representation of cellular components. By realistic we mean artist-prepared or computer graphic images that closely resemble experimentally derived structures and are characterized by a low level of styling and simplification. This change brings about a new challenge for teachers: designing course instructions that allow students to interpret these images in a meaningful way. To determine how students deal with this change, we designed several image-based, in-course assessments. The images were highly relevant for the cell biology course but did not resemble any of the images in the teaching documents. We asked students to label the cellular components, describe their function, or both. What we learned from these tests is that realistic images, with a higher apparent level of complexity, do not deter students from investigating their meaning. When given a choice, the students do not necessarily choose the most simplified representation, and they were sensitive to functional indications embedded in realistic images.
Delineating hydrothermal stockwork copper deposits using controlled-source and radio-magnetotelluric methods: A case study from northeast Iran
Authors: Bastani Mehrdad , Malehmir Alireza , Ismail Nazli , Pedersen Laust B. , Hedjazi Farhang
Published: September 2009

Radio- and controlled-source-tensor magnetotelluric (RMT and CSTMT) methods are used to target hydrothermal veins of copper mineralization. The data were acquired along six east-west- and three north-south-trending profiles, covering an area of about [Formula: see text]. The tensor RMT data were collected in the [Formula: see text] frequency band. A double horizontal magnetic dipole transmitter in the [Formula: see text] frequency range allowed us to constrain the deeper parts of the resistivity models better. To obtain optimum field parameters, ground magnetic profiling was conducted prior to the RMT and CSTMT surveys. Although the study area (in Iran) is remote, a number of radio transmitters with acceptable signal-to-noise ratio were utilized. The 2D inversion of RMT data led to unstable resistivity models with large datamisfits. Thus, the RMT data were used to complement and analyze the near-surface resistivity anomalies observed in the 2D CSTMT models. Analyses of strike and dimensionality from the CSTMT data suggests that the low-resistivity structures are mainly three dimensional; therefore, 2D inversion of determinant data is chosen. Independent 2D inversion models of the determinant CSTMT data along crossing profiles are in good agreement. Known copper mineralization is imaged well in the CSTMT models. The thinning of the conductive overburden correlates very well with magnetic highs, indicating the bedrock is resistive and magnetic. In this sense, the magnetic and electromagnetic fields complement each other. Analysis of the 2D resistivity models indicates the volcanic rock deepens at the center of the study area. This zone is associated with a magnetic low and therefore is recommended for detailed exploration work.
Presence of Intratumoral Neutrophils Is an Independent Prognostic Factor in Localized Renal Cell Carcinoma
Authors: Jensen Hanne Krogh , Donskov Frede , Marcussen Niels , Nordsmark Marianne , Lundbeck Finn , von der Maase Hans
Published: September 2009

Purpose

We have previously demonstrated a significant negative impact of intratumoral neutrophils in metastatic renal cell carcinoma. This study assessed intratumoral neutrophils in localized clear cell renal cell carcinoma (RCC).

Patients and Methods

The study comprised 121 consecutive patients who had a nephrectomy for localized RCC. Biomarkers (intratumoral CD8+, CD57+ immune cells, CD66b+ neutrophils, and carbonic anhydrase IX [CA IX]) were assessed by immunohistochemistry, and the relationship with clinical and histopathologic features and patient outcome was evaluated.

Results

The intratumoral neutrophils ranged from zero to 289 cells/mm2tumor tissue. The presence of intratumoral neutrophils was statistically significantly associated with increasing tumor size, low hemoglobin, high creatinine, and CA IX ≤ 85%. In multivariate analysis, the presence of intratumoral neutrophils (hazard ratio [HR], 3.0; 95% CI, 1.7 to 5.4; P < .0001), pT stage T3b/T4 (HR, 2.1; 95% CI, 1.2 to 3.6; P = .007), and low hemoglobin (HR, 1.8; 95% CI, 1.0 to 3.1; P = .03) were independent prognostic factors significantly associated with short recurrence-free survival. The presence of intratumoral neutrophils was also an independent prognostic factor for cancer-specific survival (HR, 3.5; 95% CI, 1.9 to 6.4; P < .0001) and overall survival (HR, 3.1; 95% CI, 1.9 to 5.0; P < .0001). Applying the prognostic value of intratumoral neutrophils to the Leibovich low-/intermediate-risk group (n = 78) showed a 5-year recurrence-free survival of 53% (95% CI, 34.6% to 71.8%; presence of intratumoral neutrophils) versus 87% (95% CI, 77.8% to 96.8%; absence of intratumoral neutrophils). The estimated concordance index was 0.74 using the Leibovich risk score and 0.80 when intratumoral neutrophils were added.

Conclusion

The presence of intratumoral neutrophils is a new, strong, independent prognostic factor for short recurrence-free, cancer-specific, and overall survival in localized clear cell RCC.
Prospective Comparison of [18F]Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography in Patients With Melanoma With Palpable Lymph Node Metastases: Diagnostic Accuracy and Impact on Treatment
Authors: Bastiaannet Esther , Wobbes Theo , Hoekstra Otto S. , van der Jagt Eric J. , Brouwers Adrienne H. , Koelemij Ron , de Klerk John M.H. , Oyen Wim J.G. , Meijer Sybren , Hoekstra Harald J.
Published: September 2009

Purpose

Patients with melanoma with potentially resectable lymph node metastases require accurate staging to prevent unnecessary surgery. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is attractive for this because melanoma typically is FDG avid. The aim of this prospective multicenter study was to perform a head-to-head comparison of FDG-PET and computed tomography (CT) in staging of patients with melanoma with palpable lymph node metastases in terms of diagnostic accuracy and impact on treatment.

Patients and Methods

All consecutive patients with palpable, proven lymph node metastases of melanoma between mid 2003 and 2007 were prospectively included. The number/site of distant metastases detected with FDG-PET and CT were recorded. Histology/cytology or 6 months follow-up were the reference standard. Intended and performed treatment was recorded.

Results

Distant metastases were suspected by FDG-PET in 32% of the 251 patients and by CT in 29% (P = .26). Upstaging was correct in 27% by FDG-PET and in 24% by CT (P = .18). FDG-PET detected more metastatic sites (133 v 112, P = .03), detecting significantly more bone and subcutaneous metastases. Treatment changed in 19% of patients; in 79% as a result of both scans, in 17% exclusively by FDG-PET, and in 4% exclusively by CT. In 34 patients (14%), FDG-PET had an additional value over spiral CT, and in 23 patients (9%), CT had additional value over FDG-PET.

Conclusion

As a result of FDG-PET and CT, 27% of patients were upstaged, and treatment changed in one of five patients. FDG-PET and CT are equivalent in upstaging; however, FDG-PET detected more metastatic sites, especially bone and subcutaneous. FDG-PET and/or CT are indicated in the staging of patients with melanoma with palpable lymph node metastases.
High-Dose Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: High Rates of Rapid Cytogenetic and Molecular Responses
Authors: Cortes Jorge E. , Kantarjian Hagop M. , Goldberg Stuart L. , Powell Bayard L. , Giles Francis J. , Wetzler Meir , Akard Luke , Burke John M. , Kerr Robert , Saleh Mansoor , Salvado August , McDougall Karen , Albitar Maher , Radich Jerald
Published: September 2009

Purpose

Long-term clinical outcome data have established imatinib 400 mg/d as standard front-line treatment for newly diagnosed patients with chronic myeloid leukemia (CML).

Patients and Methods

The Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) trial is a multicenter study of imatinib 400 mg twice a day as initial therapy in 115 patients (70% Sokal low risk) with newly diagnosed CML in chronic phase who were observed for both molecular and cytogenetic responses for up to 18 months. Eighty-three patients (72%) completed the study, 10 patients (9%) discontinued the study because of adverse events, and six patients (5%) discontinued because of unsatisfactory therapeutic effect.

Results

Polymerase chain reaction analysis demonstrated rapid kinetics of major molecular response (MMR), with 48% of patients achieving MMR by 6 months, 54% by 12 months, and 63% by 18 months. Corresponding complete molecular response rates were 39%, 44%, and 55%, respectively. Median dose-intensity was 98%. Overall, 79% of patients who received at least 90% dose-intensity achieved MMR. The most frequent adverse events included myelosuppression, rash, fatigue, and musculoskeletal symptoms.

Conclusion

This study suggests that imatinib 400 mg twice a day results in more rapid reduction in tumor burden than imatinib 400 mg/d with minimal added toxicity.
Acute Myeloid Leukemia With Translocation (8;21) or Inversion (16) in Elderly Patients Treated With Conventional Chemotherapy: A Collaborative Study of the French CBF-AML Intergroup
Authors: Prébet Thomas , Boissel Nicolas , Reutenauer Sarah , Thomas Xavier , Delaunay Jacques , Cahn Jean-Yves , Pigneux Arnaud , Quesnel Bruno , Witz Francis , Thépot Sylvain , Ugo Valérie , Terre Christine , Recher Christian , Tavernier Emmanuelle , Hunault Mathilde , Esterni Benjamin , Castaigne Sylvie , Guilhot François , Dombret Hervé , Vey Norbert
Published: September 2009

Purpose

Acute myeloid leukemia (AML) with translocation (t) (8;21) or inversion (inv) (16) is associated with a favorable prognosis when treated with intensive chemotherapy. In elderly patients, these AML types are rare, and intensive treatments are much less tolerated. We conducted a retrospective study to evaluate the characteristics and outcome of AML with t(8;21) or inv(16) in the elderly.

Patients and Methods

Patients with t(8;21) or inv(16) AML who were age 60 years or older and who received at least one course of induction chemotherapy were included. Postremission therapy consisted of low-dose maintenance chemotherapy (n = 72) or intensive consolidation (n = 56).

Results

A total of 147 patients were analyzed. The median age was 67 years. Sixty patients had t(8;21), and 87 patients had inv(16). A total of 129 patients achieved complete response (CR) after one or two induction courses (ie, 88% CR rate), and 15 patients (10%) died early (ie, during the 8 weeks after induction). During a median follow-up of 48 months, the 5-year probabilities of overall survival (OS) and leukemia-free survival (LFS) were 31% and 27%, respectively. Multivariate analysis showed a negative impact of high WBC, impaired performance status, and deletion (9q) on OS and LFS. Administration of intensive consolidation was associated with better LFS only in patients with t(8;21). In addition, the need for critical care during induction independently predicted lower LFS.

Conclusion

Because of a high CR rate, induction chemotherapy should be considered systematically for elderly patients who have AML with t(8;21) or inv(16). The high risk of relapse suggests that alternative strategies of postremission therapy are warranted.
Prospective Study of Determinants and Outcomes of Deferred Treatment or Watchful Waiting Among Men With Prostate Cancer in a Nationwide Cohort
Authors: Shappley William V. , Kenfield Stacey A. , Kasperzyk Julie L. , Qiu Weiliang , Stampfer Meir J. , Sanda Martin G. , Chan June M.
Published: September 2009

Purpose

To examine consequences of deferred treatment (DT) as initial management of prostate cancer (PCa) in a contemporary, prospective cohort of American men diagnosed with PCa.

Participants and Methods

We evaluated deferred treatment for PCa in the Health Professionals Follow-up Study, a prospective study of 51,529 men. Cox proportional hazards models were used to calculate hazard ratios (HRs) for time to eventual treatment among men who deferred treatment for more than 1 year after diagnosis. HRs for time to metastasis or death as a result of PCa were compared between patients who deferred treatment and those who underwent immediate treatment within 1 year of diagnosis.

Results

From among 3,331 cohort participants diagnosed with PCa from 1986 to 2007, 342 (10.3%) initially deferred treatment. Of these, 174 (51%) remained untreated throughout follow-up (mean 7.7 years); the remainder were treated an average of 3.9 years after diagnosis. Factors associated with progression to treatment among DT patients included younger age, higher clinical stage, higher Gleason score, and higher prostate-specific antigen at diagnosis. We observed similar rates for development of metastases (n = 20 and n = 199; 7.2 v 8.1 per 1,000 person-years; P = .68) and death as a result of PCa (n = 8 and n = 80; 2.4 v 2.6 per 1,000 person-years; P = .99) for DT and immediate treatment, respectively.

Conclusion

In this nationwide cohort, more than half the men who opted for DT remained without treatment for 7.7 years after diagnosis. Older men and men with lesser cancer severity at diagnosis were more likely to remain untreated. PCa mortality did not differ between DT and active treatment patients.
Interleukin-12 Receptor β2: From Cytokine Receptor to Gatekeeper Gene in Human B-Cell Malignancies
Authors: Pistoia Vito , Cocco Claudia , Airoldi Irma
Published: September 2009

Interleukin (IL) -12 is a cytokine that has been extensively characterized for its immunoregulatory activities. IL-12 binds to a heterodimeric receptor composed of the β1 and β2 chains. In this review article, we discuss recent findings on the expression and function of IL-12 receptor (IL-12R) in malignant B cells frozen at various stages of differentiation and in their normal counterparts. These studies, together with others performed in Il12rb2 knockout mice, have established the concept that the IL-12Rβ2 gene is a gatekeeper from cancer. We will delineate three paradigms reflecting the differential expression of IL-12Rβ2 in different groups of malignant B cells and discuss the therapeutic perspectives stemming from these studies.
Early Postoperative Paclitaxel Followed by Concurrent Paclitaxel and Cisplatin With Radiation Therapy for Patients With Resected High-Risk Head and Neck Squamous Cell Carcinoma: Report of the Phase II Trial RTOG 0024
Authors: Rosenthal David I. , Harris Jonathan , Forastiere Arlene A. , Weber Randal S. , Ridge John A. , Myers Jeffrey N. , Garden Adam S. , Kuettel Michael R. , Sidhu Kulbir , Schultz Christopher J. , Trotti Andy , Ang K. Kian
Published: September 2009

Purpose

We sought to improve outcomes for patients with high-risk head and neck squamous cell cancer (HNSCC) after surgical resection by testing the feasibility and safety of early postoperative chemotherapy followed by concurrent chemoradiotherapy.

Patients and Methods

Eligible patients had resected, stages III to IV HNSCC with positive margins, extracapsular nodal extension, or multiple positive nodes. Paclitaxel (80 mg/m2) was given once weekly during postoperative weeks 2, 3, and 4 and was given before radiation therapy (RT). Paclitaxel (30 mg/m2) and cisplatin (20 mg/m2) were given once weekly during the last 3 weeks of RT (60 Gy over 6 weeks, beginning 4 to 5 weeks after surgery). The primary end points were treatment safety and tolerability compared with concurrent cisplatin (100 mg/m2every 3 weeks) and RT, as tested in Radiation Therapy Oncology Group trial RTOG 9501.

Results

The median follow-up time for the 70 patients enrolled was 3.3 years (range, 0.6 to 4.4 years) for surviving patients. Tolerability of all treatment components was comparable to that of RTOG 9501 treatment, which is the current standard of care (compliance rate, 75%; 95% CI, 63% to 85%). One patient died, and seven patients experienced grade 4 nonhematologic toxicities. Rates of locoregional control, disease-free survival, and overall survival exceeded those of RTOG 9501 after adjustment for important prognostic variables (ie, positive margins, extracapsular extension, primary site, and performance status).

Conclusion

Chemotherapy soon after surgery followed by concurrent chemoradiotherapy therapy was feasible; tolerance was in line with standard postoperative chemoradiotherapy; and this regimen led to excellent rates of locoregional control and disease-free survival.
Phase II, Randomized, Placebo-Controlled Trial of Neoadjuvant Celecoxib in Men With Clinically Localized Prostate Cancer: Evaluation of Drug-Specific Biomarkers
Authors: Antonarakis Emmanuel S. , Heath Elisabeth I. , Walczak Janet R. , Nelson William G. , Fedor Helen , De Marzo Angelo M. , Zahurak Marianna L. , Piantadosi Steven , Dannenberg Andrew J. , Gurganus Robin T. , Baker Sharyn D. , Parnes Howard L. , DeWeese Theodore L. , Partin Alan W. , Carducci Michael A.
Published: September 2009

Purpose

Cyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy.

Patients and Methods

Patients with localized prostate cancer and Gleason sum ≥ 7, prostate-specific antigen (PSA) ≥ 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance.

Results

Seventy-three patients consented, and 64 were randomly assigned and included in the intention-to-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P < .0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities.

Conclusion

Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.
Assessing Risk of Venous Thromboembolism in the Patient With Cancer
Authors: Khorana Alok A. , Connolly Gregory C.
Published: September 2009

Purpose

Patients with cancer are increasingly at risk for venous thromboembolism (VTE). Rates of VTE, however, vary markedly among patients with cancer.

Design

This review focuses on recent data derived from population-based, hospital-based, and outpatient cohort studies of patients with cancer that have identified multiple clinical risk factors as well as candidate laboratory biomarkers predictive of VTE.

Results

Clinical risk factors for cancer-associated VTE include primary tumor site, stage, initial period after diagnosis, presence and number of comorbidities, and treatment modalities including systemic chemotherapy, antiangiogenic therapy, and hospitalization. Candidate predictive biomarkers include elevated platelet or leukocyte counts, tissue factor, soluble P-selectin, and D-dimer. A recently validated risk model, incorporating some of these factors, can help differentiate patients at high or low risk for developing VTE while receiving chemotherapy.

Conclusion

Identifying patients with cancer who are most at risk for VTE is essential to better target thromboprophylaxis, with the eventual goal of reducing the burden as well as the consequences of VTE for patients with cancer.
Improving Cancer Outcomes Through International Collaboration in Academic Cancer Treatment Trials
Authors: Trimble Edward L. , Abrams Jeffrey S. , Meyer Ralph M. , Calvo Fabien , Cazap Eduardo , Deye James , Eisenhauer Elizabeth , Fitzgerald Thomas J. , Lacombe Denis , Parmar Max , Seibel Nita , Shankar Lalitha , Swart Ann Marie , Therasse Patrick , Vikram Bhadrasain , von Frenckell Remy , Friedlander Michael , Fujiwara Keiichi , Kaplan Richard S. , Meunier Francoise
Published: September 2009

Purpose

The need for international collaboration in cancer clinical trials has grown stronger as we have made progress both in cancer treatment and screening. We sought to identify those efforts already underway which facilitate such collaboration, as well as barriers to greater collaboration.

Methods

We reviewed the collective experiences of many cooperative groups, governmental organizations, nongovernmental organizations, and academic investigators in their work to build international collaboration in cancer clinical trials across multiple disease sites.

Results

More than a decade of work has led to effective global harmonization for many of the elements critical to cancer clinical trials. Many barriers remain, but effective international collaboration in academic cancer treatment trials should become the norm, rather than the exception.

Conclusion

Our ability to strengthen international collaborations will result in maximization of our resources and patients, permitting us to change practice by establishing more effective therapeutic strategies. Regulatory, logistical, and financial hurdles, however, often hamper the conduct of joint trials. We must work together as a global community to overcome these barriers so that we may continue to improve cancer treatment for patients around the world.
Short-Term Thalidomide Incorporated Into Double Autologous Stem-Cell Transplantation Improves Outcomes in Comparison With Double Autotransplantation for Multiple Myeloma
Authors: Cavo Michele , Di Raimondo Francesco , Zamagni Elena , Patriarca Francesca , Tacchetti Paola , Casulli Antonio Francesco , Volpe Silvestro , Perrone Giulia , Ledda Antonio , Ceccolini Michela , Califano Catello , Bigazzi Catia , Offidani Massimo , Stefani Piero , Ballerini Filippo , Fiacchini Mauro , de Vivo Antonio , Brioli Annamaria , Tosi Patrizia , Baccarani Michele
Published: September 2009

Purpose

To assess potential benefits with thalidomide incorporated into double autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM).

Patients and Methods

One hundred thirty-five patients who received thalidomide from induction until the second ASCT were retrospectively analyzed in comparison with an equal number of pair mates treated with double ASCT not including thalidomide.

Results

On an intention-to-treat basis, the addition of thalidomide to double ASCT effected a significant improvement in the rate (68% v 49%; P = .001) and duration (62% v 33% at 4 years; P < .001) of at least very good partial response (VGPR), time to progression (TTP; 61% v 41% at 4 years; P < .001) and progression-free survival (PFS; 51% v 31% at 4 years; P = .001). A trend was also noted for extended overall survival (OS) among thalidomide-treated patients (69% at 5 years v 53% for the control group), although the difference between the two groups was not statistically significant (P = .07). Benefits with thalidomide in increasing the rate of VGPR or better response, TTP, and PFS were confirmed in a multivariate analysis. Median OS after relapse was 24 months for patients receiving thalidomide added to double ASCT and 25 months for the control group. Overall, 17% of patients discontinued thalidomide, including 8% because of drug-related adverse events.

Conclusion

In comparison with double ASCT, the addition of first-line thalidomide to double ASCT improved clinical outcomes. Short-term thalidomide was generally well tolerated and had no adverse impact on postrelapse survival.
Ten Years After Mutation Testing for Lynch Syndrome: Cancer Incidence and Outcome in Mutation-Positive and Mutation-Negative Family Members
Authors: Järvinen Heikki J. , Renkonen-Sinisalo Laura , Aktán-Collán Katja , Peltomäki Päivi , Aaltonen Lauri A. , Mecklin Jukka-Pekka
Published: September 2009

Purpose

Colonoscopies with polypectomies and endometrial biopsies with transvaginal ultrasonography, repeated at 2- to 3-year intervals, are performed for prevention or early detection of cancer in patients with DNA mismatch repair gene mutation causing Lynch syndrome. The long-term effectiveness of surveillance was evaluated in Lynch syndrome family members tested approximately 10 years ago.

Materials and Methods

Cancer incidence and survival were determined after an 11.5-year follow-up in 242 mutation-positive and 367 mutation-negative participants. These participants in 57 Lynch syndrome families with 14 different mutations were at 50% risk. The median age was 36 years (range, 18 to 72 years) in mutation carriers and 42 years (range, 18 to 72 years) in mutation-negative participants, and none had had cancer of the Lynch syndrome type.

Results

Compliance was 95.9% for the colonic surveillance and 97.1% for the gynecologic surveillance. Colorectal cancer (CRC) occurred in 30 mutation-positive participants, and 74 participants had adenomas removed. Three patients died of CRC. Endometrial cancer (EC) occurred in 19 of 103 women at risk, and 48 women had prophylactic hysterectomy. Six of 112 women at risk had ovarian cancer. The overall cancer risk ratio (RR) in mutation carriers was 5.80 (95% CI, 3.4 to 9.5). Cancer mortality rate (RR = 2.28; 95% CI, 0.82 to 6.31) and overall death rate (RR = 1.26; 95% CI, 0.65 to 2.46) were not significantly increased.

Conclusion

Long-term compliance in surveillance for CRC and EC exceeded 95% in Lynch syndrome. All CRC deaths were not prevented as a result of noncompliance or missed lesions. Still, after 10 years of surveillance, no significant increase in mortality had occurred compared with mutation-negative relatives.
Retailing Poisoned Milk? New Evidence on Keynes and Jevons's Hostility to John Stuart Mill
Authors: White Michael V. , Inoue Takutoshi
Published: September 2009

In his 1936 memoir of W. Stanley Jevons, J. M. Keynes argued that Jevons's pronounced hostility to the dominance of J. S. Mill's political economy was due, in large part, to the imposition of Mill's work on Jevons's teaching at Owens College (subsequently the University of) Manchester. Keynes reported that a recently discovered set of student lecture notes confirmed his argument. He was subsequently accused of poor scholarship in that regard, because the contents of the one known set of student notes did not tally with his description. It is shown here, however, that Keynes was referring to a different set of notes that have only recently been located. Keynes was misled, nevertheless, in assuming that the notes he examined could establish his case. Moreover, although Jevons's statements could be confusing, the available evidence indicates that his complaints about the constraints on his teaching were principally concerned with logic and philosophy, rather than with political economy.