bluuebunny/crossref_metadata_2025 huggingface dataset:
A two-genome microarray for the rice pathogens Xanthomonas oryzae pv. oryzae and X. oryzae pv. oryzicola and its use in the discovery of a difference in their regulation of hrp genes
Authors: Seo Young-Su , Sriariyanun Malinee , Wang Li , Pfeiff Janice , Phetsom Jirapa , Lin Ye , Jung Ki-Hong , Chou Hui Hsien , Bogdanove Adam , Ronald Pamela
Published: June 2008

Background

Xanthomonas oryzae pv. oryzae (Xoo) and X. oryzae pv. oryzicola (Xoc) are bacterial pathogens of the worldwide staple and grass model, rice. Xoo and Xoc are closely related but Xoo invades rice vascular tissue to cause bacterial leaf blight, a serious disease of rice in many parts of the world, and Xoc colonizes the mesophyll parenchyma to cause bacterial leaf streak, a disease of emerging importance. Both pathogens depend on hrp genes for type III secretion to infect their host. We constructed a 50–70 mer oligonucleotide microarray based on available genome data for Xoo and Xoc and compared gene expression in Xoo strains PXO99A and Xoc strain BLS256 grown in the rich medium PSB vs. XOM2, a minimal medium previously reported to induce hrp genes in Xoo strain T7174.

Results

Three biological replicates of the microarray experiment to compare global gene expression in representative strains of Xoo and Xoc grown in PSB vs. XOM2 were carried out. The non-specific error rate and the correlation coefficients across biological replicates and among duplicate spots revealed that the microarray data were robust. 247 genes of Xoo and 39 genes of Xoc were differentially expressed in the two media with a false discovery rate of 5% and with a minimum fold-change of 1.75. Semi-quantitative-RT-PCR assays confirmed differential expression of each of 16 genes each for Xoo and Xoc selected for validation. The differentially expressed genes represent 17 functional categories.

Conclusion

We describe here the construction and validation of a two-genome microarray for the two pathovars of X. oryzae. Microarray analysis revealed that using representative strains, a greater number of Xoo genes than Xoc genes are differentially expressed in XOM2 relative to PSB, and that these include hrp genes and other genes important in interactions with rice. An exception was the rax genes, which are required for production of the host resistance elicitor AvrXa21, and which were expressed constitutively in both pathovars.
Synteny conservation between two distantly-related Rosaceae genomes: Prunus (the stone fruits) and Fragaria(the strawberry)
Authors: Vilanova Santiago , Sargent Daniel J , Arús Pere , Monfort Amparo
Published: June 2008

Background

The Rosaceae encompass a large number of economically-important diploid and polyploid fruit and ornamental species in many different genera. The basic chromosome numbers of these genera arex= 7, 8 and 9 and all have compact and relatively similar genome sizes. Comparative mapping between distantly-related genera has been performed to a limited extent in the Rosaceae including a comparison betweenMalus(subfamily Maloideae) andPrunus(subfamily Prunoideae); however no data has been published to date comparingMalusorPrunusto a member of the subfamily Rosoideae. In this paper we compare the genome ofFragaria, a member of the Rosoideae, toPrunus, a member of the Prunoideae.

Results

The diploid genomes ofPrunus(2n=2x= 16) andFragaria(2n=2x= 14) were compared through the mapping of 71 anchor markers – 40 restriction fragment length polymorphisms (RFLPs), 29 indels or single nucleotide polymorphisms (SNPs) derived from expressed sequence tags (ESTs) and two simple-sequence repeats (SSRs) – on the reference maps of both genera. These markers provided good coverage of thePrunus(78%) andFragaria(78%) genomes, with maximum gaps and average densities of 22 cM and 7.3 cM/marker inPrunusand 32 cM and 8.0 cM/marker inFragaria.

Conclusion

Our results indicate a clear pattern of synteny, with most markers of each chromosome of one of these species mapping to one or two chromosomes of the other. A large number of rearrangements (36), most of which produced by inversions (27) and the rest (9) by translocations or fission/fusion events could also be inferred. We have provided the first framework for the comparison of the position of genes or DNA sequences of these two economically valuable and yet distantly-related genera of the Rosaceae.
Factors associated with self-rated health status in university students: a cross-sectional study in three European countries
Authors: Mikolajczyk Rafael T , Brzoska Patrick , Maier Claudia , Ottova Veronika , Meier Sabine , Dudziak Urszula , Ilieva Snezhana , El Ansari Walid
Published: June 2008

Background

Self-rated health status (SRHS) is a reliable and valid measure for assessing the subjective and objective health of individuals. Previous studies have either focused predominantly on the elderly or investigated only a narrow range of factors potentially associated with SRHS. In examining student populations, these past studies were limited to single countries. The objectives of this study were to assess which candidate variables were independently associated with SRHS in university students, to compare these variables by country and by gender, and to investigate which of the variables was most important as a rating frame for SRHS.

Methods

The data is from the Cross-National Student Health Survey, conducted in 2005 in universities in Germany, Bulgaria, and Poland (n = 2103; mean age = 20.7 years). SRHS was assessed with a single question using a five-point scale ranging from "excellent" to "poor". The study also measured a wide range of variables including: physical and psychological health, studying, social contacts/social support, and socio-demographic status.

Results

Psychosomatic complaints (considered an aspect of physical health and, adjusted for psychological health) were the most important indicators in forming a rating frame for students' SRHS. There were few differences in the effects of variables associated with SRHS by gender (well-being: a measure of psychological health) and the variables associated with SRHS by country (well-being and self-efficacy). The remaining variables showed homogenous effects for both genders and for all three countries.

Conclusion

The results suggest that SRHS can be reasonably used to compare students' health across countries. SRHS is affected by different physical, psychological and psychosomatic aspects of health; however, its strongest association is with psychosomatic complaints.
Maintenance metabolism and carbon fluxes in Bacillus species
Authors: Tännler Simon , Decasper Seraina , Sauer Uwe
Published: June 2008

Background

Selection of an appropriate host organism is crucial for the economic success of biotechnological processes. A generally important selection criterion is a low maintenance energy metabolism to reduce non-productive consumption of substrate. We here investigated, whether various bacilli that are closely related to Bacillus subtilis are potential riboflavin production hosts with low maintenance metabolism.

Results

While B. subtilis exhibited indeed the highest maintenance energy coefficient, B. licheniformis and B. amyloliquefaciens exhibited only statistically insignificantly reduced maintenance metabolism. Both B. pumilus and B. subtilis (natto) exhibited irregular growth patterns under glucose limitation such that the maintenance metabolism could not be determined. The sole exception with significantly reduced maintenance energy requirements was the B. licheniformis strain T380B. The frequently used spo0A mutation significantly increased the maintenance metabolism of B. subtilis.

At the level of 13C-detected intracellular fluxes, all investigated bacilli exhibited a significant flux through the pentose phosphate pathway, a prerequisite for efficient riboflavin production. Different from all other species, B. subtilis featured high respiratory tricarboxylic acid cycle fluxes in batch and chemostat cultures. In particular under glucose-limited conditions, this led to significant excess formation of NADPH of B. subtilis, while anabolic consumption was rather balanced with catabolic NADPH formation in the other bacilli.

Conclusion

Despite its successful commercial production of riboflavin, B. subtilis does not seem to be the optimal cell factory from a bioenergetic point of view. The best choice of the investigated strains is the sporulation-deficient B. licheniformis T380B strain. Beside a low maintenance energy coefficient, this strain grows robustly under different conditions and exhibits only moderate acetate overflow, hence making it a promising production host for biochemicals and riboflavin in particular.
Antimicrobial resistance in community and nosocomial Escherichia coli urinary tract isolates, London 2005 – 2006
Authors: Bean David C , Krahe Daniel , Wareham David W
Published: June 2008

Background

Escherichia coli is the commonest cause of community and nosocomial urinary tract infection (UTI). Antibiotic treatment is usually empirical relying on susceptibility data from local surveillance studies. We therefore set out to determine levels of resistance to 8 commonly used antimicrobial agents amongst all urinary isolates obtained over a 12 month period.

Methods

Antimicrobial susceptibility to ampicillin, amoxicillin/clavulanate, cefalexin, ciprofloxacin, gentamicin, nitrofurantoin, trimethoprim and cefpodoxime was determined for 11,865 E. coli urinary isolates obtained from community and hospitalised patients in East London.

Results

Nitrofurantoin was the most active agent (94% susceptible), followed by gentamicin and cefpodoxime. High rates of resistance to ampicillin (55%) and trimethoprim (40%), often in combination were observed in both sets of isolates. Although isolates exhibiting resistance to multiple drug classes were rare, resistance to cefpodoxime, indicative of Extended spectrum β-lactamase production, was observed in 5.7% of community and 21.6% of nosocomial isolates.

Conclusion

With the exception of nitrofurantoin, resistance to agents commonly used as empirical oral treatments for UTI was extremely high. Levels of resistance to trimethoprim and ampicillin render them unsuitable for empirical use. Continued surveillance and investigation of other oral agents for treatment of UTI in the community is required.
Oxytocin-Induced Antinociception in the Spinal Cord is Mediated by a Subpopulation of Glutamatergic Neurons in Lamina I-II Which Amplify GABAergic Inhibition
Authors: Breton Jean-Didier , Veinante Pierre , Uhl-Bronner Sandra , Vergnano Angela Maria , Freund-Mercier Marie José , Schlichter Rémy , Poisbeau Pierrick
Published: June 2008

Background:

Recent evidence suggests that oxytocin (OT), secreted in the superficial spinal cord dorsal horn by descending axons of paraventricular hypothalamic nucleus (PVN) neurons, produces antinociception and analgesia. The spinal mechanism of OT is, however, still unclear and requires further investigation. We have used patch clamp recording of lamina II neurons in spinal cord slices and immunocytochemistry in order to identify PVN-activated neurons in the superficial layers of the spinal cord and attempted to determine how this neuronal population may lead to OT-mediated antinociception.

Results:

We show that OT released during PVN stimulation specifically activates a subpopulation of lamina II glutamatergic interneurons which are localized in the most superficial layers of the dorsal horn of the spinal cord (lamina I-II). This OT-specific stimulation of glutamatergic neurons allows the recruitment of all GABAergic interneurons in lamina II which produces a generalized elevation of local inhibition, a phenomenon which might explain the reduction of incoming Aδ and C primary afferent-mediated sensory messages.

Conclusion:

Our results obtained in lamina II of the spinal cord provide the first clear evidence of a specific local neuronal network that is activated by OT release to induce antinociception. This OT-specific pathway might represent a novel and interesting therapeutic target for the management of neuropathic and inflammatory pain.
Can single knockouts accurately single out gene functions?
Authors: Deutscher David , Meilijson Isaac , Schuster Stefan , Ruppin Eytan
Published: June 2008

Background

When analyzing complex biological systems, a major objective is localization of function – assessing how much each element contributes to the execution of specific tasks. To establish causal relationships, knockout and perturbation studies are commonly executed. The vast majority of studies perturb a single element at a time, yet one may hypothesize that in non-trivial biological systems single-perturbations will fail to reveal the functional organization of the system, owing to interactions and redundancies.

Results

We address this fundamental gap between theory and practice by quantifying how misleading the picture arising from classical single-perturbation analysis is, compared with the full multiple-perturbations picture. To this end we use a combination of a novel approach for quantitative, rigorous multiple-knockouts analysis based on the Shapley value from game theory, with an establishedin-silicomodel ofSaccharomyces cerevisiaemetabolism. We find that single-perturbations analysis misses at least 33% of the genes that contribute significantly to the growth potential of this organism, though the essential genes it does find are responsible for most of the growth potential. But when assigning gene contributions for individual metabolic functions, the picture arising from single-perturbations is severely lacking and a multiple-perturbations approach turns out to be essential.

Conclusion

The multiple-perturbations investigation yields a significantly richer and more biologically plausible functional annotation of the genes comprising the metabolic network of the yeast.
Time-resolved metabolomics reveals metabolic modulation in rice foliage
Authors: Sato Shigeru , Arita Masanori , Soga Tomoyoshi , Nishioka Takaaki , Tomita Masaru
Published: June 2008

Background

To elucidate the interaction of dynamics among modules that constitute biological systems, comprehensive datasets obtained from "omics" technologies have been used. In recent plant metabolomics approaches, the reconstruction of metabolic correlation networks has been attempted using statistical techniques. However, the results were unsatisfactory and effective data-mining techniques that apply appropriate comprehensive datasets are needed.

Results

Using capillary electrophoresis mass spectrometry (CE-MS) and capillary electrophoresis diode-array detection (CE-DAD), we analyzed the dynamic changes in the level of 56 basic metabolites in plant foliage (Oryza sativa L. ssp. japonica) at hourly intervals over a 24-hr period. Unsupervised clustering of comprehensive metabolic profiles using Kohonen's self-organizing map (SOM) allowed classification of the biochemical pathways activated by the light and dark cycle. The carbon and nitrogen (C/N) metabolism in both periods was also visualized as a phenotypic linkage map that connects network modules on the basis of traditional metabolic pathways rather than pairwise correlations among metabolites. The regulatory networks of C/N assimilation/dissimilation at each time point were consistent with previous works on plant metabolism. In response to environmental stress, glutathione and spermidine fluctuated synchronously with their regulatory targets. Adenine nucleosides and nicotinamide coenzymes were regulated by phosphorylation and dephosphorylation. We also demonstrated that SOM analysis was applicable to the estimation of unidentifiable metabolites in metabolome analysis. Hierarchical clustering of a correlation coefficient matrix could help identify the bottleneck enzymes that regulate metabolic networks.

Conclusion

Our results showed that our SOM analysis with appropriate metabolic time-courses effectively revealed the synchronous dynamics among metabolic modules and elucidated the underlying biochemical functions. The application of discrimination of unidentified metabolites and the identification of bottleneck enzymatic steps even to non-targeted comprehensive analysis promise to facilitate an understanding of large-scale interactions among components in biological systems.
Chromosomal assignment of canine THADA gene to CFA 10q25
Authors: Soller Jan T , Beuing Claudia , Escobar Hugo Murua , Winkler Susanne , Reimann-Berg Nicola , Drieschner Norbert , Dolf Gaudenz , Schelling Claude , Nolte Ingo , Bullerdiek Jörn
Published: June 2008

Background

Chromosomal translocations affecting the chromosome 2p21 cluster in a 450 kb breakpoint region are frequently observed in human benign thyroid adenomas.THADA(thyroid adenoma associated) was identified as the affected gene within this breakpoint region. In contrast to man tumours of the thyroid gland of dogs (Canis lupus familiaris) constitute mainly as follicular cell carcinomas, with malignant thyroid tumours being more frequent than benign thyroid adenomas. In order to elucidate if theTHADAgene is also a target of chromosomal rearrangements in thyroid adenomas of the dog we have physically mapped the canineTHADAgene to canine chromosome 10.

A PCR was established to screen a canine genome library for a BAC clone containing the gene sequence of canineTHADA. Further PCR reactions were done using the identified BAC clone as a template in order to verify the corresponding PCR product by sequencing.

Canine whole blood was incubated with colcemid in order to arrest the cultured cells in metaphases. The verified BAC DNA was digoxigenin labeled and used as a probe in fluorescencein situhybridization (FISH). Ten well spread metaphases were examined indicating a signal on canine chromosome 10 on both chromatids. A detailed fine mapping was performed indicating the canineTHADAgene locus on the q-arm of chromosome 10.

Results

The canineTHADAgene locus was mapped on chromosome 10q25. Our mapping results obtained in this study following the previously described nomenclature for the canine karyotype.

Conclusion

We analysed whether theTHADAgene locus is a hotspot of canine chromosomal rearrangements in canine neoplastic lesions of the thyroid and in addition might play a role as a candidate gene for a possible malignant transformation of canine thyroid adenomas. Although the available cytogenetic data of canine thyroid adenomas are still insufficient the chromosomal region to which the canineTHADAhas been mapped seems to be no hotspot of chromosomal aberrations seen in canine thyroid adenomas.
In vitro norepinephrine significantly activates isolated platelets from healthy volunteers and critically ill patients following severe traumatic brain injury
Authors: Tschuor Christoph , Asmis Lars M , Lenzlinger Philipp M , Tanner Martina , Härter Luc , Keel Marius , Stocker Reto , Stover John F
Published: June 2008

Introduction

Norepinephrine, regularly used to increase systemic arterial blood pressure and thus improve cerebral perfusion following severe traumatic brain injury (TBI), may activate platelets. This, in turn, could promote microthrombosis formation and induce additional brain damage.

Methods

The objective of this study was to investigate the influence of norepinephrine on platelets isolated from healthy volunteers and TBI patients during the first two post-traumatic weeks. A total of 18 female and 18 male healthy volunteers of different age groups were recruited, while 11 critically ill TBI patients admitted consecutively to our intensive care unit were studied. Arterial and jugular venous platelets were isolated from norepinephrine-receiving TBI patients; peripheral venous platelets were studied in healthy volunteers. Concentration-dependent functional alterations of isolated platelets were analyzed by flow cytometry, assessing changes in surface P-selectin expression and platelet-derived microparticles before and after in vitro stimulation with norepinephrine ranging from 10 nM to 100 μM. The thrombin receptor-activating peptide (TRAP) served as a positive control.

Results

During the first week following TBI, norepinephrine-mediated stimulation of isolated platelets was significantly reduced compared with volunteers (control). In the second week, the number of P-selectin- and microparticle-positive platelets was significantly decreased by 60% compared with the first week and compared with volunteers. This, however, was associated with a significantly increased susceptibility to norepinephrine-mediated stimulation, exceeding changes observed in volunteers and TBI patients during the first week. This pronounced norepinephrine-induced responsiveness coincided with increased arterio-jugular venous difference in platelets, reflecting intracerebral adherence and signs of cerebral deterioration reflected by elevated intracranial pressure and reduced jugular venous oxygen saturation.

Conclusion

Clinically infused norepinephrine might influence platelets, possibly promoting microthrombosis formation. In vitro stimulation revealed a concentration- and time-dependent differential level of norepinephrine-mediated platelet activation, possibly reflecting changes in receptor expression and function. Whether norepinephrine should be avoided in the second post-traumatic week and whether norepinephrine-stimulated platelets might induce additional brain damage warrant further investigations.
Identification of a new transmembrane adaptor protein that constitutively binds Grb2 in B cells
Authors: Liu Yan , Zhang Weiguo
Published: June 2008

Transmembrane adaptor proteins couple antigen receptor engagement to downstream signaling cascades in lymphocytes. One example of these proteins is the linker for activation of T cells (LAT), which plays an indispensable role in T cell activation and development. Here, we report identification of a new transmembrane adaptor molecule, namely growth factor receptor-bound protein 2 (Grb2)-binding adaptor protein, transmembrane (GAPT), which is expressed in B cells and myeloid cells. Similar to LAT, GAPT has an extracellular domain, a transmembrane domain, and a cytoplasmic tail with multiple Grb2-binding motifs. In contrast to other transmembrane adaptor proteins, GAPT is not phosphorylated upon BCR ligation but associates with Grb2 constitutively through its proline-rich region. Targeted disruption of the gapt gene in mice affects neither B cell development nor a nitrophenylacetyl-specific antibody response. However, in the absence of GAPT, B cell proliferation after BCR cross-linking is enhanced. In aged GAPT−/− mice, the number of marginal zone (MZ) B cells is increased, and other B cell subsets are normal. The serum concentrations of IgM, IgG2b, and IgG3 are also elevated in these mice. These data indicate that GAPT might play an important role in control of B cell activation and proper maintenance of MZ B cells.
The essential role of the in situ immune reaction in human colorectal cancer
Authors: Pagès Franck , Galon Jérôme , Fridman Wolf H
Published: June 2008

Colorectal cancer is the second most common cause of cancer-related death. Novel prognostic factors should be identified and validated to refine the present tumor-node-metastasis system. The presence of immune cells infiltrating colorectal cancers is a common phenomenon. However, the current belief is that clinically detectable human tumors escaping immune surveillance are no longer kept in check by the immune cells of the tumor microenvironment. Despite studies showing the influence of immune cell infiltrates on the behavior of colorectal carcinomas, this parameter is not currently recognized as a reliable prognostic factor. We showed that the nature, functional orientation, density, and location of immune cells within distinct tumor regions could provide a prognostic factor superior to and independent of criteria related to the anatomic extent of the tumor. The strength of the immune reaction identified in our studies could advance our understanding of cancer evolution and have important consequences for clinical practice.
Neuropsychological Outcome in Chemotherapy-Only–Treated Children With Acute Lymphoblastic Leukemia
Authors: Jansen Nathalie C.A.J. , Kingma Annette , Schuitema Arnout , Bouma Anke , Veerman Anjo J.P. , Kamps Willem A.
Published: June 2008

Purpose

To evaluate neuropsychological functioning over time in children treated for acute lymphoblastic leukemia (ALL) with chemotherapy only.

Patients and Methods

Forty-nine consecutive patients (median age at first assessment, 6.8 years; range, 4.0 to 11.8 years) treated with intrathecal and systemic chemotherapy were included in a nationwide, prospective-longitudinal, sibling-controlled study. Patients and siblings completed three extensive neuropsychological assessments: at diagnosis, 3 to 6 months after completion of (2-year) treatment and 4.5 years after diagnosis. Assessments included measures of learning, memory, attention, speed, executive functioning, visual-constructive functioning, and fine-motor functioning. Multilevel analyses were applied to evaluate patients' performances over time and to compare patients to 29 siblings (median age of siblings at first assessment, 8.2 years; range, 4.5 to 12.6 years) and to normative data.

Results

No major differences were found in neuropsychological performance between patients and siblings, with both groups performing mainly in the normal range. The patient group as a whole, however, scored significantly lower than the siblings on complex fine-motor functioning at the last evaluation. Large practice effects were found for both patients and siblings in four of 11 tasks. Patients who uttered physical complaints (ie, pain and/or tiredness) at the first pretreatment assessment scored significantly lower than siblings on attention and speed at the last two evaluations.

Conclusion

Despite intensive and potentially neurotoxic treatment, no evident negative, neuropsychological late effects were found 4.5 years after diagnosis, except for effects on complex fine-motor functioning. Both the large practice effects observed and the poorer performances on sustained attention for patients with physical complaints should be reckoned with in prospective, longitudinal neuropsychological research in children.
ERCC5 Is a Novel Biomarker of Ovarian Cancer Prognosis
Authors: Walsh Christine S. , Ogawa Seishi , Karahashi Hisae , Scoles Daniel R. , Pavelka James C. , Tran Hang , Miller Carl W. , Kawamata Norihiko , Ginther Charles , Dering Judy , Sanada Masashi , Nannya Yasuhito , Slamon Dennis J. , Koeffler H. Phillip , Karlan Beth Y.
Published: June 2008

Purpose

To identify a biomarker of ovarian cancer response to chemotherapy.

Patients and Methods

Study participants had epithelial ovarian cancer treated with surgery followed by platinum-based chemotherapy. DNA and RNA were isolated from frozen tumors and normal DNA was isolated from matched peripheral blood. A whole-genome loss of heterozygosity (LOH) analysis was performed using a high-density oligonucleotide array. Candidate genomic areas that predicted enhanced response to chemotherapy were identified with Cox proportional hazards methods. Gene expression analyses were performed through microarray experiments. Candidate genes were tested for independent effects on survival using Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test.

Results

Using a whole-genome approach to study the molecular determinants of ovarian cancer response to platinum-based chemotherapy, we identified LOH of a 13q region to predict prolonged progression-free survival (PFS; hazard ratio, 0.23; P = .006). ERCC5 was identified as a candidate gene in this region because of its known function in the nucleotide excision repair pathway, the unique DNA repair pathway that removes platinum-DNA adducts. We found LOH of the ERCC5 gene locus and downregulation of ERCC5 gene expression to predict prolonged PFS. Integration of genomic and gene expression data shows a correlation between 13q LOH and ERCC5 gene downregulation.

Conclusion

ERCC5 is a novel biomarker of ovarian cancer prognosis and a potential therapeutic target of ovarian cancer response to platinum chemotherapy.
Risk of Cancer byATMMissense Mutations in the General Population
Authors: Dombernowsky Sarah Louise , Weischer Maren , Allin Kristine Højgaard , Bojesen Stig Egil , Tybjjrg-Hansen Anne , Nordestgaard Børge Grønne
Published: June 2008

Purpose

Truncating and missense mutations in the ATM gene, which cause insufficient DNA damage surveillance, allow damaged cells to proceed into mitosis, which eventually results in increased cancer susceptibility. We tested the hypotheses that ATM Ser49Cys and ATM Ser707Pro heterozygosity increase the risk of cancer overall, of breast cancer, and of 26 other cancer subtypes in the general population.

Patients and Methods

We genotyped 10,324 individuals from the Danish general population who were observed prospectively for 36 years, during which 2,056 developed cancer.

Results

Multifactorially adjusted hazard ratios for ATM Ser49Cys heterozygotes versus noncarriers were 1.2 (95% CI, 0.9 to 1.5) for cancer overall, 0.8 (95% CI, 0.3 to 2.0) for breast cancer, 4.8 (95% CI, 2.2 to 11) for melanoma, 2.3 (95% CI, 1.1 to 5.0) for prostate cancer, and 3.4 (95% CI, 1.1 to 11) for cancer of the oral cavity/pharynx. Multifactorially adjusted hazard ratios for ATM Ser707Pro heterozygotes versus noncarriers were 0.8 (95% CI, 0.6 to 1.2) for cancer overall, 0.6 (95% CI, 0.2 to 1.6) for breast cancer, 10 (95% CI, 1.1 to 93) for thyroid/other endocrine tumors, and 2.7 (95% CI, 1.0 to 7.6) for cancer of corpus uteri.

Conclusion

ATM missense mutations do not increase the risk of cancer overall or of breast cancer in the general population; however, we observed in exploratory analyses that ATM missense mutations may be associated with an increased risk of other cancer subtypes. As we did multiple comparisons, some of these findings could represent chance findings rather than real phenomena.
Circulating 25-Hydroxyvitamin D Levels and Survival in Patients With Colorectal Cancer
Authors: Ng Kimmie , Meyerhardt Jeffrey A. , Wu Kana , Feskanich Diane , Hollis Bruce W. , Giovannucci Edward L. , Fuchs Charles S.
Published: June 2008

Purpose

Higher plasma 25-hydroxyvitamin D3(25(OH)D) levels are associated with a decreased incidence of colorectal cancer, but the influence of plasma 25(OH)D on the outcome of patients with established colorectal cancer is unknown.

Patients and Methods

We prospectively examined the association between prediagnosis 25(OH)D levels and mortality among 304 participants in the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) who were diagnosed with colorectal cancer from 1991 to 2002. Participants diagnosed within 2 years of blood collection were excluded. Patients were observed until death, June 2005 (NHS), or January 2005 (HPFS), whichever came first. The primary end point was overall mortality. Cox proportional hazards models were used to calculate hazard ratios (HR) adjusted for other risk factors for cancer survival.

Results

Higher plasma 25(OH)D levels were associated with a significant reduction in overall mortality (P for trend = .02). Compared with the lowest quartile, participants in the highest quartile had an adjusted HR of 0.52 (95% CI, 0.29 to 0.94) for overall mortality. A trend toward improved colorectal cancer–specific mortality was also seen (HR = 0.61; 95% CI, 0.31 to 1.19). The results remained unchanged after excluding patients diagnosed within 5 years of blood collection (P for trend = .04); the multivariate HR for overall mortality comparing extreme quartiles was 0.45 (95% CI, 0.19 to 1.09).

Conclusion

Among patients with colorectal cancer, higher prediagnosis plasma 25(OH)D levels were associated with a significant improvement in overall survival. Further study of the vitamin D pathway and its influence on colorectal carcinogenesis and cancer progression is warranted.
Phase II Trial of Docetaxel With Rapid Androgen Cycling for Progressive Noncastrate Prostate Cancer
Authors: Rathkopf Dana , Carducci Michael A. , Morris Michael J. , Slovin Susan F. , Eisenberger Mario A. , Pili Roberto , Denmeade Samuel R. , Kelsen Moshe , Curley Tracy , Halter Melinda , Collins Connie , Fleisher Martin , Heller Glenn , Baker Sharyn D. , Scher Howard I.
Published: June 2008

Purpose

We evaluated rapid androgen cycling in combination with docetaxel for men with progressive noncastrate prostate cancers.

Patients and Methods

Noncastrate patients with ≤ 6 months of hormone therapy were eligible. Cohort 1 (62 patients) received six 28-day cycles of docetaxel (75 mg/m2), leuprolide, and 7 days of topical testosterone. Cohort 2 (38 patients) received nine 21-day cycles of docetaxel (70 mg/m2), leuprolide, and 3 days of testosterone. The primary end point was the proportion of patients at 18 months who achieved noncastrate testosterone levels (> 150 ng/dL) and an undetectable prostate-specific antigen (PSA; ≤ 0.05, ≤ 0.5, or ≤ 2.0 ng/mL with prior prostatectomy, radiation therapy, or no definitive therapy, respectively). Cytochrome P450 3A4 (CYP3A4) activity and docetaxel pharmacokinetics were evaluated.

Results

A higher proportion of patients achieved the undetectable PSA outcome at 18 months in cohort 2 relative to cohort 1 (13% v 0%). The 16% incidence of febrile neutropenia was higher than that observed in patients was castration-resistant disease, which may have been related to a 50% reduction in overall docetaxel clearance in the noncastrate group. There was no alteration in CYP3A4 activity (P = .87) or docetaxel clearance (P = .88) between cycles.

Conclusion

The undetectable PSA end point allows for a rapid screening of interventions for further study. Increasing the number of docetaxel cycles after a shorter period of testosterone repletion, and a longer duration of testosterone depletion, increased the proportion of men who achieved an undetectable PSA. The higher-than-expected incidence of febrile neutropenia may have been related to the reduced overall docetaxel clearance in patients with noncastrate versus castrate testosterone levels.
One Hundred Years After “Carcinoid”: Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the United States
Authors: Yao James C. , Hassan Manal , Phan Alexandria , Dagohoy Cecile , Leary Colleen , Mares Jeannette E. , Abdalla Eddie K. , Fleming Jason B. , Vauthey Jean-Nicolas , Rashid Asif , Evans Douglas B.
Published: June 2008

Purpose

Neuroendocrine tumors (NETs) are considered rare tumors and can produce a variety of hormones. In this study, we examined the epidemiology of and prognostic factors for NETs, because a thorough examination of neither had previously been performed.

Methods

The Surveillance, Epidemiology, and End Results (SEER) Program registries were searched to identify NET cases from 1973 to 2004. Associated population data were used for incidence and prevalence analyses.

Results

We identified 35,618 patients with NETs. We observed a significant increase in the reported annual age-adjusted incidence of NETs from 1973 (1.09/100,000) to 2004 (5.25/100,000). Using the SEER 9 registry data, we estimated the 29-year limited-duration prevalence of NETs on January 1, 2004, to be 9,263. Also, the estimated 29-year limited-duration prevalence in the United States on that date was 103,312 cases (35/100,000). The most common primary tumor site varied by race, with the lung being the most common in white patients, and the rectum being the most common in Asian/Pacific Islander, American Indian/Alaskan Native, and African American patients. Additionally, survival duration varied by histologic grade. In multivariate analysis of patients with well-differentiated to moderately differentiated NETs, disease stage, primary tumor site, histologic grade, sex, race, age, and year of diagnosis were predictors of outcome (P < .001).

Conclusion

We observed increased reported incidence of NETs and increased survival durations over time, suggesting that NETs are more prevalent than previously reported. Clinicians need to be become familiar with the natural history and patterns of disease progression, which are characteristic of these tumors.
Stem Cell–Related “Self-Renewal” Signature and High Epidermal Growth Factor Receptor Expression Associated With Resistance to Concomitant Chemoradiotherapy in Glioblastoma
Authors: Murat Anastasia , Migliavacca Eugenia , Gorlia Thierry , Lambiv Wanyu L. , Shay Tal , Hamou Marie-France , de Tribolet Nicolas , Regli Luca , Wick Wolfgang , Kouwenhoven Mathilde C.M. , Hainfellner Johannes A. , Heppner Frank L. , Dietrich Pierre-Yves , Zimmer Yitzhak , Cairncross J. Gregory , Janzer Robert-Charles , Domany Eytan , Delorenzi Mauro , Stupp Roger , Hegi Monika E.
Published: June 2008

Purpose

Glioblastomas are notorious for resistance to therapy, which has been attributed to DNA-repair proficiency, a multitude of deregulated molecular pathways, and, more recently, to the particular biologic behavior of tumor stem-like cells. Here, we aimed to identify molecular profiles specific for treatment resistance to the current standard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide.

Patients and Methods

Gene expression profiles of 80 glioblastomas were interrogated for associations with resistance to therapy. Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy.

Results

An expression signature dominated by HOX genes, which comprises Prominin-1 (CD133), emerged as a predictor for poor survival in patients treated with concomitant chemoradiotherapy (n = 42; hazard ratio = 2.69; 95% CI, 1.38 to 5.26; P = .004). This association could be validated in an independent data set. Provocatively, the HOX cluster was reminiscent of a “self-renewal” signature (P = .008; Gene Set Enrichment Analysis) recently characterized in a mouse leukemia model. The HOX signature and EGFR expression were independent prognostic factors in multivariate analysis, adjusted for the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status, a known predictive factor for benefit from temozolomide, and age. Better outcome was associated with gene clusters characterizing features of tumor-host interaction including tumor vascularization and cell adhesion, and innate immune response.

Conclusion

This study provides first clinical evidence for the implication of a “glioma stem cell” or “self-renewal” phenotype in treatment resistance of glioblastoma. Biologic mechanisms identified here to be relevant for resistance will guide future targeted therapies and respective marker development for individualized treatment and patient selection.
Risk of Prostate Cancer Recurrence in Men Treated With Radiation Alone or in Conjunction With Combined or Less Than Combined Androgen Suppression Therapy
Authors: D'Amico Anthony V. , Chen Ming-Hui , Renshaw Andrew A. , Loffredo Brittany , Kantoff Philip W.
Published: June 2008

Purpose

We determined the risk of recurrence in men enrolled on a randomized trial for prostate cancer who were treated with radiation therapy (RT) alone or in conjunction with combined or less than combined androgen suppression therapy (AST).

Patients and Methods

Between 1995 and 2001, 206 men with localized but unfavorable-risk adenocarcinoma of the prostate were randomly assigned to receive RT or RT and AST, which was defined as 6 months of both a luteinizing hormone-releasing hormone agonist and an antiandrogen. A post–random assignment hypothesis that was generated by multivariable Cox regression analyses was used to evaluate whether the risk of prostate-specific antigen (PSA) recurrence was significantly associated with months of antiandrogen use; regression analysis adjusted for known prognostic factors, comorbidity score, and medications that can elevate liver function tests sufficiently to necessitate discontinuation of the antiandrogen.

Results

After a median follow-up of 8.2 years (interquartile range,7.0 to 9.5 years), 81 men sustained PSA recurrence. An increasing PSA level (P < .001); Gleason score of 8, 9, or 10 (P < .001); and clinical category T2 disease (P = .005) were significantly associated with an increased risk of recurrence. However, recurrence risk was significantly decreased (adjusted hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = .001) with each additional month of antiandrogen use after analysis was adjusted for these known prognostic factors.

Conclusion

Men with localized but unfavorable-risk prostate cancer who were treated with RT and 6 months of planned combined AST appear to have an increased risk of recurrence when treated with less than as compared with 6 months of the antiandrogen.
Minimal Residual Disease Values Discriminate Between Low and High Relapse Risk in Children With B-Cell Precursor Acute Lymphoblastic Leukemia and an Intrachromosomal Amplification of Chromosome 21: The Austrian and German Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster (ALL-BFM) Trials
Authors: Attarbaschi Andishe , Mann Georg , Panzer-Grümayer Renate , Röttgers Silja , Steiner Manuel , König Margit , Csinady Eva , Dworzak Michael N. , Seidel Markus , Janousek Dasa , Möricke Anja , Reichelt Carsten , Harbott Jochen , Schrappe Martin , Gadner Helmut , Haas Oskar A.
Published: June 2008

Purpose

We aimed to identify relapse predictors in children with a B-cell precursor acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21), a novel genetic entity associated with poor outcome.

Patients and Methods

We screened 1,625 patients who were enrolled onto the Austrian and German ALL–Berlin-Frankfurt-Münster (ALL-BFM) trials 86, 90, 95, and 2000 with ETV6/RUNX1-specific fluorescent in situ hybridization probes, and we identified 29 patient cases (2%) who had an iAMP21. Minimal residual disease (MRD) was quantified with clone-specific immunoglobulin and T-cell receptor gene rearrangements.

Results

Twenty-five patients were good responders to prednisone, and all achieved remission after induction therapy. Eleven patients experienced relapse, which included eight who experienced relapse after cessation of front-line therapy. Six-year event-free and overall survival rates were 37% ± 14% and 66% ± 11%, respectively. Results of MRD analysis were available in 24 (83%) of 29 patients: nine (37.5%) belonged to the low-risk, 14 (58.5%) to the intermediate-risk, and one (4%) to the high-risk group. MRD results were available in 8 of 11 patients who experienced a relapse. Seven occurred among the 14 intermediate-risk patients, and one occurred in the high-risk patient.

Conclusion

The overall and early relapse rates in the BFM study were lower than that in a previous United Kingdom Medical Research Council/Childhood Leukemia Working Party study (38% v 61% and 27% v 47%, respectively), which might result from more intensive induction and early reintensification therapy in the ALL-BFM protocols. MRD values were the only reliable parameter to discriminate between a low and high risk of relapse (P = .02).
Acylated Ghrelin Inhibits Spontaneous Luteinizing Hormone Pulsatility and Responsiveness to Naloxone But Not That to Gonadotropin-Releasing Hormone in Young Men: Evidence for a Central Inhibitory Action of Ghrelin on the Gonadal Axis
Authors: Lanfranco Fabio , Bonelli Lorenza , Baldi Matteo , Me Elisa , Broglio Fabio , Ghigo Ezio
Published: June 2008

Context: Recent evidence suggests that ghrelin exerts a negative modulation on the gonadal axis. Ghrelin was reported to suppress LH secretion in both animal and human models. Moreover, acylated ghrelin (AG) also decreases the LH responsiveness to GnRH in vitro.

Objective: The objective of the study was to evaluate the effects of AG infusion on spontaneous and stimulated gonadotropin secretion.

Design, Participants, and Intervention: In seven young healthy male volunteers (age mean ± sem 26.4 ± 2.6 yr), we evaluated LH and FSH levels every 15 min during: 1) iv isotonic saline infusion; 2) iv saline followed by AG; LH and FSH response to GnRH (100 μg iv as a bolus), 3) alone and 4) during AG infusion; LH and FSH response to naloxone (0.1 mg/kg iv as a slow bolus), 5) alone and 6) during AG infusion.

Results: Significant LH but not FSH pulses were recorded in all subjects under saline infusion. AG infusion inhibited LH levels [area under the curve(240–480): 415.8 ± 69.7 mIU/ml·min during AG vs. 744.6 ± 120.0 mIU/ml·min during saline, P < 0.02] and abolished LH pulsatility. No change in FSH secretion was recorded. The LH and FSH responses to GnRH during saline were not affected by AG administration. However, AG inhibited the LH response to naloxone [area under the curve (120–210): 229.9 ± 39.3 mIU/ml·min during AG vs. 401.1 ± 44.6 mIU/ml·min during saline, P < 0.01]. FSH levels were not modified by naloxone alone or in combination with AG.

Conclusions: AG inhibits both spontaneous LH pulsatility and the LH response to naloxone. Because AG does not affect the LH response to GnRH, these findings indicate that the ghrelin system mediates central inhibition of the gonadal axis.
Homozygous Mutation G539R in the Gene for P450 Oxidoreductase in a Family Previously Diagnosed as Having 17,20-Lyase Deficiency
Authors: Hershkovitz Eli , Parvari Ruthi , Wudy Stefan A. , Hartmann Michaela F. , Gomes Larissa G. , Loewental Neta , Miller Walter L.
Published: June 2008

Context: Very few patients have been described with isolated 17,20-lyase deficiency who have had their mutations in P450c17 (17α-hydroxylase/17,20-lyase) proven by DNA sequencing and in vitro characterization of the mutations. Most patients with 17,20-lyase deficiency have mutations in the domain of P450c17 that interact with the electron-donating redox partner, P450 oxidoreductase (POR).

Objective: Our objective was to clarify the genetic and functional basis of isolated 17,20-lyase deficiency in familial cases who were previously reported as having 17,20-lyase deficiency.

Patients: Four undervirilized males of an extended Bedouin family were investigated. One of these has previously been reported to carry mutations in the CYP17A1 gene encoding P450c17 causing isolated 17,20-lyase deficiency.

Methods: Serum hormones were evaluated before and after stimulation with ACTH. Urinary steroid metabolites were profiled by gas chromatography-mass spectrometry. Exons 1 and 8 of CYP17A1 previously reported to harbor mutations in one of these patients and all 15 coding exons of POR were sequenced.

Results: Gas chromatography-mass spectrometry (GC-MS) urinary steroid profiling and serum steroid measurements showed combined deficiencies of 17,20-lyase and 21-hydroxylase. Sequencing of exons 1 and 8 of CYP17A1 in two different laboratories showed no mutations. Sequencing of POR showed that all four patients were homozygous for G539R, a previously studied mutation that retains 46% of normal capacity to support the 17α-hydroxylase activity but only 8% of the 17,20-lyase activity of P450c17.

Conclusion: POR deficiency can masquerade clinically as isolated 17,20-lyase deficiency.