bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving the power for detecting overlapping genes from multiple DNA microarray-derived gene lists
Authors: Deng Xutao , Xu Jun , Wang Charles
Published: May 2008

Background

In DNA microarray gene expression profiling studies, a fundamental task is to extract statistically significant genes that meet certain research hypothesis. Currently, Venn diagram is a frequently used method for identifying overlapping genes that meet the investigator's research hypotheses. However this simple operation of intersecting multiple gene lists, known as the Intersection-Union Tests (IUTs), is performed without knowing the incurred changes in Type 1 error rate and can lead to loss of discovery power.

Results

We developed an IUT adjustment procedure, called Relaxed IUT (RIUT), which is proved to be less conservative and more powerful for intersecting independent tests than the traditional Venn diagram approach. The advantage of the RIUT procedure over traditional IUT is demonstrated by empirical Monte-Carlo simulation and two real toxicogenomic gene expression case studies. Notably, the enhanced power of RIUT enables it to identify overlapping gene sets leading to identification of certain known related pathways which were not detected using the traditional IUT method.

Conclusion

We showed that traditional IUT via a Venn diagram is generally conservative, which may lead to loss discovery power in DNA microarray studies. RIUT is proved to be a more powerful alternative for performing IUTs in identifying overlapping genes from multiple gene lists derived from microarray gene expression profiling.
Comparative analyses of bidirectional promoters in vertebrates
Authors: Yang Mary Qu , Taylor James , Elnitski Laura
Published: May 2008

Background

Orthologous genes with deep phylogenetic histories are likely to retain similar regulatory features. In this report we utilize orthology assignments for pairs of genes co-regulated by bidirectional promoters to map the ancestral history of the promoter regions.

Results

Our mapping of bidirectional promoters from humans to fish shows that many such promoters emerged after the divergence of chickens and fish. Furthermore, annotations of promoters in deep phylogenies enable detection of missing data or assembly problems present in higher vertebrates. The functional importance of bidirectional promoters is indicated by selective pressure to maintain the arrangement of genes regulated by the promoter over long evolutionary time spans. Characteristics unique to bidirectional promoters are further elucidated using a technique for unsupervised classification, known as ESPERR.

Conclusion

Results of these analyses will aid in our understanding of the evolution of bidirectional promoters, including whether the regulation of two genes evolved as a consequence of their proximity or if function dictated their co-regulation.
Control over the morphology and segregation of Zebrafish germ cell granules during embryonic development
Authors: Strasser Markus J , Mackenzie Natalia C , Dumstrei Karin , Nakkrasae La-Iad , Stebler Jürg , Raz Erez
Published: May 2008

Background

Zebrafish germ cells contain granular-like structures, organized around the cell nucleus. These structures share common features with polar granules in Drosophila, germinal granules in Xenopus and chromatoid bodies in mice germ cells, such as the localization of the zebrafish Vasa, Piwi and Nanos proteins, among others. Little is known about the structure of these granules as well as their segregation in mitosis during early germ-cell development.

Results

Using transgenic fish expressing a fluorescently labeled novel component of Zebrafish germ cell granules termed Granulito, we followed the morphology and distribution of the granules. We show that whereas these granules initially exhibit a wide size variation, by the end of the first day of development they become a homogeneous population of medium size granules. We investigated this resizing event and demonstrated the role of microtubules and the minus-end microtubule dependent motor protein Dynein in the process. Last, we show that the function of the germ cell granule resident protein the Tudor domain containing protein-7 (Tdrd7) is required for determination of granule morphology and number.

Conclusion

Our results suggest that Zebrafish germ cell granules undergo a transformation process, which involves germ cell specific proteins as well as the microtubular network.
RPS4Ygene family evolution in primates
Authors: Andrés Olga , Kellermann Thomas , López-Giráldez Francesc , Rozas Julio , Domingo-Roura Xavier , Bosch Montserrat
Published: May 2008

Backgound

TheRPS4gene codifies for ribosomal protein S4, a very well-conserved protein present in all kingdoms. In primates,RPS4is codified by two functional genes located on both sex chromosomes: theRPS4XandRPS4Ygenes. In humans,RPS4Yis duplicated and the Y chromosome therefore carries a third functional paralog:RPS4Y2, which presents a testis-specific expression pattern.

Results

DNA sequence analysis of the intronic and cDNA regions ofRPS4Ygenes from species covering the entire primate phylogeny showed that the duplication event leading to the second Y-linked copy occurred after the divergence of New World monkeys, about 35 million years ago. Maximum likelihood analyses of the synonymous and non-synonymous substitutions revealed that positive selection was acting onRPS4Y2gene in the human lineage, which represents the first evidence of positive selection on a ribosomal protein gene. Putative positive amino acid replacements affected the three domains of the protein: one of these changes is located in the KOW protein domain and affects the unique invariable position of this motif, and might thus have a dramatic effect on the protein function.

Conclusion

Here, we shed new light on the evolutionary history ofRPS4Ygene family, especially on that ofRPS4Y2. The results point that theRPS4Y1gene might be maintained to compensate gene dosage between sexes, whileRPS4Y2might have acquired a new function, at least in the lineage leading to humans.
Comparative genomic analysis of the gut bacterium Bifidobacterium longum reveals loci susceptible to deletion during pure culture growth
Authors: Lee Ju-Hoon , Karamychev VN , Kozyavkin SA , Mills D , Pavlov AR , Pavlova NV , Polouchine NN , Richardson PM , Shakhova VV , Slesarev AI , Weimer B , O'Sullivan DJ
Published: May 2008

Background

Bifidobacteria are frequently proposed to be associated with good intestinal health primarily because of their overriding dominance in the feces of breast fed infants. However, clinical feeding studies with exogenous bifidobacteria show they don't remain in the intestine, suggesting they may lose competitive fitness when grown outside the gut.

Results

To further the understanding of genetic attenuation that may be occurring in bifidobacteria cultures, we obtained the complete genome sequence of an intestinal isolate,Bifidobacterium longumDJO10A that was minimally cultured in the laboratory, and compared it to that of a culture collection strain,B. longumNCC2705. This comparison revealed colinear genomes that exhibited high sequence identity, except for the presence of 17 unique DNA regions in strain DJO10A and six in strain NCC2705. While the majority of these unique regions encoded proteins of diverse function, eight from the DJO10A genome and one from NCC2705, encoded gene clusters predicted to be involved in diverse traits pertinent to the human intestinal environment, specifically oligosaccharide and polyol utilization, arsenic resistance and lantibiotic production. Seven of these unique regions were suggested by a base deviation index analysis to have been precisely deleted from strain NCC2705 and this is substantiated by a DNA remnant from within one of the regions still remaining in the genome of NCC2705 at the same locus. This targeted loss of genomic regions was experimentally validated when growth of the intestinalB. longumin the laboratory for 1,000 generations resulted in two large deletions, one in a lantibiotic encoding region, analogous to a predicted deletion event for NCC2705. A simulated fecal growth study showed a significant reduced competitive ability of this deletion strain againstClostridium difficileandE. coli. The deleted region was between two IS30elements which were experimentally demonstrated to be hyperactive within the genome. The other deleted region bordered a novel class of mobile elements, termed mobile integrase cassettes (MIC) substantiating the likely role of these elements in genome deletion events.

Conclusion

Deletion of genomic regions, often facilitated by mobile elements, allows bifidobacteria to adapt to fermentation environments in a very rapid manner (2 genome deletions per 1,000 generations) and the concomitant loss of possible competitive abilities in the gut.
Identification and characteristics of microRNAs from Bombyx mori
Authors: He Ping-an , Nie Zuoming , Chen Jianqing , Chen Jian , Lv Zhengbing , Sheng Qing , Zhou Songping , Gao Xiaolian , Kong Lingyin , Wu Xiangfu , Jin Yongfeng , Zhang Yaozhou
Published: May 2008

Background

MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression by targeting messenger RNAs (mRNAs) and causing mRNA cleavage or translation blockage. Of the 355 Arthropod miRNAs that have been identified, only 21 are B. mori miRNAs that were predicted computationally; of these, only let-7 has been confirmed by Northern blotting.

Results

Combining a computational method based on sequence homology searches with experimental identification based on microarray assays and Northern blotting, we identified 46 miRNAs, an additional 21 plausible miRNAs, and a novel small RNA in B. mori. The latter, bmo-miR-100-like, was identified using the known miRNA aga-miR-100 as a probe; bmo-miR-100-like was detected by microarray assay and Northern blotting, but its precursor sequences did not fold into a hairpin structure. Among these identified miRNAs, we found 12 pairs of miRNAs and miRNA*s. Northern blotting revealed that some B. mori miRNA genes were expressed only during specific stages, indicating that B. mori miRNA genes (e.g., bmo-miR-277) have developmentally regulated patterns of expression. We identified two miRNA gene clusters in the B. mori genome. bmo-miR-2b, which is found in the gene cluster bmo-miR-2a-1/bmo-miR-2a-1*/bmo-miR-2a-2/bmo-miR-2b/bmo-miR-13a*/bmo-miR-13b, encodes a newly identified member of the mir-2 family. Moreover, we found that methylation can increase the sensitivity of a DNA probe used to detect a miRNA by Northern blotting. Functional analysis revealed that 11 miRNAs may regulate 13 B. mori orthologs of the 25 known Drosophila miRNA-targeted genes according to the functional conservation. We predicted the binding sites on the 1671 3'UTR of B. mori genes; 547 targeted genes, including 986 target sites, were predicted. Of these target sites, 338 had perfect base pairing to the seed region of 43 miRNAs. From the predicted genes, 61 genes, each of them with multiple predicted target sites, should be considered excellent candidates for future functional studies. Biological classification of predicted miRNA targets showed that "binding", "catalytic activity" and "physiological process" were over-represented for the predicted genes.

Conclusion

Combining computational predictions with microarray assays, we identified 46 B. mori miRNAs, 13 of which were miRNA*s. We identified a novel small RNA and 21 plausible B. mori miRNAs that could not be located in the available B. mori genome, but which could be detected by microarray. Thirteen and 547 target genes were predicted according to the functional conservation and binding sites, respectively. Identification of miRNAs in B. mori, particularly those that are developmentally regulated, provides a foundation for subsequent functional studies.
Modified FOLFOX-6 chemotherapy in advanced gastric cancer: Results of phase II study and comprehensive analysis of polymorphisms as a predictive and prognostic marker
Authors: Keam Bhumsuk , Im Seock-Ah , Han Sae-Won , Ham Hye Seon , Kim Min A , Oh Do-Youn , Lee Se-Hoon , Kim Jee Hyun , Kim Dong-Wan , Kim Tae-You , Heo Dae Seog , Kim Woo Ho , Bang Yung-Jue
Published: May 2008

Background

The objective of this study was to evaluate the efficacy and toxicity of infusional 5-fluorouracil (5-FU), folinic acid and oxaliplatin (modified FOLFOX-6) in patients with advanced gastric cancer (AGC), as first-line palliative combination chemotherapy. We also analyzed the predictive or prognostic value of germline polymorphisms of candidate genes associated with 5-FU and oxaliplatin.

Methods

Seventy-three patients were administered a 2 hour infusion of oxaliplatin (100 mg/m2) and folinic acid (100 mg/m2) followed by a 46 hour continuous infusion of 5-FU (2,400 mg/m2). Genomic DNA from the patients' peripheral blood mononuclear cells was extracted. Ten polymorphisms within five genes were investigated including TS, GSTP, ERCC, XPD and XRCC.

Results

The overall response rate (RR) was 43.8%. Median time to progression (TTP) and overall survival (OS) were 6.0 months and 12.6 months, respectively. Toxicities were generally tolerable and manageable. The RR was significantly higher in patients with a 6-bp deletion homozygote (-6 bp/-6 bp) in TS-3'UTR (55.0% vs. 30.3% in +6 bp/+6 bp or +6 bp/-6 bp, p = 0.034), and C/A or A/A in XPD156 (52.0% vs. 26.1% in C/C, p = 0.038). The -6 bp/-6 bp in TS-3'UTR was significantly associated with a prolonged TTP and OS. In a multivariate analysis, the 6-bp deletion in TS-3'UTR was identified as an independent prognostic marker of TTP (hazard ratio = 0.561, p = 0.032).

Conclusion

Modified FOLFOX-6 chemotherapy appears to be active and well tolerated as first line chemotherapy in AGC patients. The 6-bp deletion in TS-3'UTR might be a candidate to select patients who are likely to benefit from 5-FU based modified FOLFOX-6 in future large scale trial.
Androgen receptor expresion in breast cancer: Relationship with clinicopathological characteristics of the tumors, prognosis, and expression of metalloproteases and their inhibitors
Authors: Gonzalez Luis O , Corte Maria D , Vazquez Julio , Junquera Sara , Sanchez Rosario , Alvarez Ana C , Rodriguez Juan C , Lamelas Maria L , Vizoso Francisco J
Published: May 2008

Background

In the present study we analyze, in patients with breast cancer, the tumor expression of androgen receptors (AR), its relationship with clinicopathological characteristics and with the expression of several matrix metalloproteases (MMPs) and their inhibitors (TIMPs), as well as with prognosis.

Methods

An immunohistochemical study was performed using tissue microarrays and specific antibodies against AR, MMPs -1, -2, -7, -9, -11, -13, -14, and TIMPs -1, -2 and -3. More than 2,800 determinations on tumor specimens from 111 patients with primary invasive ductal carcinoma of the breast (52 with axillary lymph node metastases and 59 without them) and controls were performed. Staining results were categorized using a score based on the intensity of the staining and a specific software program calculated the percentage of immunostained cells automatically.

Results

A total of 83 cases (74.8%) showed a positive immunostaining for AR, but with a wide variation in the staining score values. There were no significant associations between the total immunostaining scores for AR and any clinicopathological parameters. However, score values for MMP-1, -7 and -13, were significantly higher in AR-positive tumors than in AR-negative tumors. Likewise, when we considered the cellular type expressing each factor, we found that AR-positive tumors had a higher percentage of cases positive for MMP-1, -7, -11, and TIMP-2 in their malignant cells, as well as for MMP-1 in intratumoral fibroblasts. On the other hand, multivariate analysis demonstrated that patients with AR-positive tumors have a significant longer overall survival than those with AR-negative breast carcinomas (p= 0.03).

Conclusion

Our results confirm that AR are commonly expressed in breast cancer, and are correlated with the expression of some MMPs and TIMP-2. Although we found a specific value of AR expression to be a prognostic indicator in breast cancer, the functional role of AR in these neoplasms is still unclear and further data are needed in order to clarify their biological signification in breast cancer.
SOCS3 inhibiting migration of A549 cells correlates with PYK2 signaling in vitro
Authors: Zhang Siyang , Guo Dawei , Jiang Lili , Zhang Qingfu , Qiu Xueshan , Wang Enhua
Published: May 2008

Background

Suppressor of cytokine signaling 3 (SOCS3) is considered to inhibit cytokine responses and play a negative role in migration of various cells. Proline-rich tyrosine kinase 2 (PYK2) is a non-receptor kinase and has been found crucial to cell motility. However, little is known about whether SOCS3 could regulate PYK2 pro-migratory function in lung cancer.

Methods

The methylation status of SOCS3 was investigated in HBE and A549 cell lines by methylation-specific PCR. A549 cells were either treated with a demethylation agent 5-aza-2'-deoxycytidine or transfected with three SOCS3 mutants with various functional domains deleted. Besides, cells were pretreated with a proteasome inhibitor β-lactacystin where indicated. The effects of SOCS3 up-regulation on PYK2 expression, PYK2 and ERK1/2 phosphorylations were assessed by western blot using indicated antibodies. RT-PCR was used to estimate PYK2 mRNA levels. Transwell experiments were performed to evaluate cell migration.

Results

SOCS3 expression was found impaired in A549 cells and higher PYK2 activity was correlated with enhanced cell migration. We identified that SOCS3 was aberrantly methylated in the exon 2, and 5-aza-2'-deoxycytidine restored SOCS3 expression. Reactivation of SOCS3 attenuated PYK2 expression and phosphorylation, cell migration was inhibited as well. Transfection studies indicated that exogenous SOCS3 interacted with PYK2, and both the Src homology 2 (SH2) and the kinase inhibitory region (KIR) domains of SOCS3 contributed to PYK2 binding. Furthermore, SOCS3 was found to inhibit PYK2-associated ERK1/2 activity in A549 cells. SOCS3 possibly promoted degradation of PYK2 in a SOCS-box-dependent manner and interfered with PYK2-related signaling events, such as cell migration.

Conclusion

These data indicate that SOCS3 negatively regulates cell motility and decreased SOCS3 induced by methylation may confer a migration advantage to A549 cells. These results also suggest a negative role of SOCS3 in PYK2 signaling, and a previously unidentified regulatory mechanism for PYK2 function.
Associations between physical activity and depressive symptoms in women
Authors: Teychenne Megan , Ball Kylie , Salmon Jo
Published: May 2008

Background

The high prevalence of depression in women is an increasing public health concern. Although studies have found associations between physical activity (PA) and depression, little is known about the optimal domain, dose and social context of PA for reducing the risk of depression. This study aimed to investigate associations between specific components of PA (domain, dose and social context) and odds of depressive symptoms in women.

Methods

The sample included 1,501 women, aged 18–65. Analyses were performed using cross-sectional data collected from a mail-out survey in 2004. The survey included self-report measures of PA behaviours and depressive symptoms. Crude and adjusted (age, marital status and physical health) odds ratios (OR) and 95% confidence intervals (CI) were calculated for each component of PA and odds of depressive symptoms using logistic regression analyses.

Results

Those who reported more than 3.5 hours leisure-time PA per week had lower odds of depressive symptoms when compared to those who undertook less than this. No other domains of PA (eg. work-related, transport-related or domestic activity) were associated with odds of depressive symptoms. Odds of depressive symptoms were lower among women who reported more than 1.5 hours of moderate-intensity (OR = 0.67, CI = 0.45–0.98) or more than 1.75 hours vigorous-intensity (OR = 0.60, CI = 0.42–0.84) leisure-time PA per week. Being discouraged to be active by others was associated with higher odds of depressive symptoms (OR = 2.28, CI = 1.00–5.16), whilst being active with a family member was associated with lower odds of depressive symptoms (OR = 0.61, CI = 0.43–0.87).

Conclusion

Acknowledging the cross-sectional design, these findings suggest that the domain and social context of PA may be more important for mental health among women than simply the total dose of PA.
Interactions of biotic and abiotic environmental factors in an ectomycorrhizal symbiosis, and the potential for selection mosaics
Authors: Piculell Bridget J , Hoeksema Jason D , Thompson John N
Published: May 2008

Background

Geographic selection mosaics, in which species exert different evolutionary impacts on each other in different environments, may drive diversification in coevolving species. We studied the potential for geographic selection mosaics in plant-mycorrhizal interactions by testing whether the interaction between bishop pine (Pinus muricata D. Don) and one of its common ectomycorrhizal fungi (Rhizopogon occidentalis Zeller and Dodge) varies in outcome, when different combinations of plant and fungal genotypes are tested under a range of different abiotic and biotic conditions.

Results

We used a 2 × 2 × 2 × 2 factorial experiment to test the main and interactive effects of plant lineage (two maternal seed families), fungal lineage (two spore collections), soil type (lab mix or field soil), and non-mycorrhizal microbes (with or without) on the performance of plants and fungi. Ecological outcomes, as assessed by plant and fungal performance, varied widely across experimental environments, including interactions between plant or fungal lineages and soil environmental factors.

Conclusion

These results show the potential for selection mosaics in plant-mycorrhizal interactions, and indicate that these interactions are likely to coevolve in different ways in different environments, even when initially the genotypes of the interacting species are the same across all environments. Hence, selection mosaics may be equally as effective as genetic differences among populations in driving divergent coevolution among populations of interacting species.
DREAM is reduced in synovial fibroblasts of patients with chronic arthritic pain: is it a suitable target for peripheral pain management?
Authors: Reisch Nataša , Engler Andrea , Aeschlimann André , Simmen Beat R , Michel Beat A , Gay Renate E , Gay Steffen , Sprott Haiko
Published: May 2008

Introduction

The endogenous pain-relieving system depends in part on the regulation of nociceptive signals through binding of opioids to the corresponding opioid receptor. Interfering with the trans-repression effect of downstream regulatory element antagonist modulator (DREAM) on the transcription of the opioid dynorphin-encoding prodynorphin (pdyn) gene might enhance pain relief in the periphery.

Methods

Expression levels were measured in osteoarthritis (OA) synovial fibroblast-like cells (SFLCs) (n = 8) and in peripheral blood mononuclear cells (PBMCs) from OA patients (n = 53) and healthy controls (n = 26) by real-time polymerase chain reaction. Lysed OA SFLCs were analyzed by immunoprecipitation. Translation of DREAM mRNA was inhibited by small interfering RNAs (siRNAs). Expressions of DREAM,pdyn, andc-fosmRNAs were measured at 24, 48, and 72 hours after transfection.

Results

The expression of DREAM mRNA was shown in both healthy and OA SFLCs as well as PBMCs. Inhibiting transcription using siRNAs led to a marked reduction in DREAM expression after 24, 48, and 72 hours. However, no significant changes inc-fosandpdynexpression occurred. In addition, DREAM mRNA expression was significantly reduced in OA patients with chronic pain (pain intensity as measured by a visual analog scale scale of greater than 40), but nopdynexpression was detectable.

Conclusion

To our knowledge, this is the first report showing the expression of DREAM in SFLCs and PBMCs on the mRNA level. However, DREAM protein was not detectable. Since repression ofpdyntranscription persists after inhibiting DREAM translation, DREAM appears to play no functional role in the kappa opioid receptor system in OA SFLCs. Therefore, our data suggest that DREAM appears not to qualify as a target in peripheral pain management.
Racial Differences in Clinical Outcomes From Metastatic Breast Cancer: A Pooled Analysis of CALGB 9342 and 9840—Cancer and Leukemia Group B
Authors: Polite Blase N. , Cirrincione Constance , Fleming Gini F. , Berry Donald A. , Seidman Andrew , Muss Hyman , Norton Larry , Shapiro Charles , Bakri Kamal , Marcom Kelly , Lake Diana , Schwartz Joel H. , Hudis Clifford , Winer Eric P.
Published: May 2008

Purpose

African American women are more likely to be diagnosed with metastatic breast cancer at the time of presentation than whites, and have shorter survival once diagnosed. This study examines racial differences in clinical outcomes in the setting of two large cooperative group randomized clinical trials.

Patients and Methods

The study cohort consisted of 787 white (80%) and 195 African American (20%) patients with metastatic breast cancer enrolled in two successive Cancer and Leukemia Group B (CALGB) trials using taxanes in the metastatic setting. Differences in overall survival (OS), response incidence, and time to treatment failure (TTF) were examined by race. In addition, differences in the incidence of baseline and treatment-related toxicities were examined.

Results

With 779 deaths (166 African Americans and 613 whites), median OS was 14.3 months for African Americans and 18.75 months for whites (hazard ratio [HR] = 1.37; 95% CI, 1.15 to 1.63). When adjusted for prognostic factors, African Americans had a 24% increase in the hazard of death compared with whites (HR = 1.24; 95% CI, 1.02 to 1.51). No significant differences in TTF or overall response to therapy were seen. No clinically significant toxicity differences were seen.

Conclusion

African Americans with metastatic breast cancer have an increased hazard of death compared with whites despite the receipt of similar per-protocol treatment, but experience no differences in TTF or overall response to therapy. We hypothesize that more direct and robust measures of comorbidities, and perhaps other factors such as receipt of subsequent therapy could help further explain the observed survival difference.
Safety of Fertility Preservation by Ovarian Stimulation With Letrozole and Gonadotropins in Patients With Breast Cancer: A Prospective Controlled Study
Authors: Azim Amr A. , Costantini-Ferrando Maria , Oktay Kutluk
Published: May 2008

Purpose

Because of the accompanying increase in estrogen levels, safety of performing in vitro fertilization (IVF) in women with breast cancer is unknown. Our goal was to determine the effect of controlled ovarian stimulation (COS) using a combination of letrozole with standard fertility medications on disease-free survival in women undergoing embryo or oocyte cryopreservation before adjuvant chemotherapy.

Patients and Methods

A total of 215 women with breast cancer were prospectively evaluated for fertility preservation before adjuvant chemotherapy. Of those, 79 elected to undergo COS with letrozole and gonadotropins for embryo or oocyte cryopreservation. The remaining 136 patients underwent no fertility-preserving procedure and served as controls.

Results

Study and control groups were similar at enrollment except for a trend for higher estrogen-receptor positivity in the COS group (P = .08). Time between surgery and chemotherapy was longer for IVF patients (45.08 v 33.46 days; P < .01). Peak estradiol levels ranged from 58.4 to 1,166 pg/mL (mean, 405.94 ± 256.64 pg/mL or 1,486.76 ± 942.13 pmol/L) in COS patients. The median follow-up after chemotherapy was 23.4 months (range, 7.5 to 63.6 months) in the COS group and 33.05 months (range, 4.5 to 63.6) in the control group. The hazard ratio for recurrence after IVF was 0.56 (95% CI, 0.17 to 1.9), and the survival was not compromised compared with controls (P = .36).

Conclusion

Ovarian stimulation with gonadotropins and letrozole for the purpose of fertility preservation is unlikely to cause substantially increased recurrence risk. Further research, including longer-term follow-up is needed to confirm these findings.
Guidelines for the Management of Pediatric and Adult Tumor Lysis Syndrome: An Evidence-Based Review
Authors: Coiffier Bertrand , Altman Arnold , Pui Ching-Hon , Younes Anas , Cairo Mitchell S.
Published: May 2008

Purpose

Tumor lysis syndrome (TLS) has recently been subclassified into either laboratory TLS or clinical TLS, and a grading system has been established. Standardized guidelines, however, are needed to aid in the stratification of patients according to risk and to establish prophylaxis and treatment recommendations for patients at risk or with established TLS.

Methods

A panel of experts in pediatric and adult hematologic malignancies and TLS was assembled to develop recommendations and guidelines for TLS based on clinical evidence and standards of care. A review of relevant literature was also used.

Results

New guidelines are presented regarding the prevention and management of patients at risk of developing TLS. The best management of TLS is prevention. Prevention strategies include hydration and prophylactic rasburicase in high-risk patients, hydration plus allopurinol or rasburicase for intermediate-risk patients, and close monitoring for low-risk patients. Primary management of established TLS involves similar recommendations, with the addition of aggressive hydration and diuresis, plus allopurinol or rasburicase for hyperuricemia. Alkalinization is not recommended. Although guidelines for rasburicase use in adults are provided, this agent is currently only approved for use in pediatric patients in the United States.

Conclusion

The potential severity of complications resulting from TLS requires measures for prevention in high-risk patients and prompts treatment in the event that symptoms arise. Recognition of risk factors, monitoring of at-risk patients, and appropriate interventions are the key to preventing or managing TLS. These guidelines should assist in the prevention of TLS and improve the management of patients with established TLS.
Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non–Small-Cell Lung Cancer
Authors: Scagliotti Giorgio Vittorio , Parikh Purvish , von Pawel Joachim , Biesma Bonne , Vansteenkiste Johan , Manegold Christian , Serwatowski Piotr , Gatzemeier Ulrich , Digumarti Raghunadharao , Zukin Mauro , Lee Jin S. , Mellemgaard Anders , Park Keunchil , Patil Shehkar , Rolski Janusz , Goksel Tuncay , de Marinis Filippo , Simms Lorinda , Sugarman Katherine P. , Gandara David
Published: May 2008

Purpose

Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.

Patients and Methods

This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2on day 1 and gemcitabine 1,250 mg/m2on days 1 and 8 (n = 863) or cisplatin 75 mg/m2and pemetrexed 500 mg/m2on day 1 (n = 862) every 3 weeks for up to six cycles.

Results

Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.

Conclusion

In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.
Retrospective Analysis of Intravascular Large B-Cell Lymphoma Treated With Rituximab-Containing Chemotherapy As Reported by the IVL Study Group in Japan
Authors: Shimada Kazuyuki , Matsue Kosei , Yamamoto Kazuhito , Murase Takuhei , Ichikawa Naoaki , Okamoto Masataka , Niitsu Nozomi , Kosugi Hiroshi , Tsukamoto Norifumi , Miwa Hiroshi , Asaoku Hideki , Kikuchi Ako , Matsumoto Morio , Saburi Yoshio , Masaki Yasufumi , Yamaguchi Motoko , Nakamura Shigeo , Naoe Tomoki , Kinoshita Tomohiro
Published: May 2008

Purpose

To evaluate the safety and efficacy of rituximab-containing chemotherapies for intravascular large B-cell lymphoma (IVLBCL).

Patients and Methods

We retrospectively analyzed 106 patients (59 men, 47 women) with IVLBCL who received chemotherapy either with rituximab (R-chemotherapy, n = 49) or without rituximab (chemotherapy, n = 57) between 1994 and 2007 in Japan. The median patient age was 67 years (range, 34 to 84 years). The International Prognostic Index was high-intermediate/high in 97% of patients.

Results

The complete response rate was higher for patients in the R-chemotherapy group (82%) than for those in the chemotherapy group (51%; P = .001). The median duration of follow-up for surviving patients was 18 months (range, 1 to 95 months). Progression-free survival (PFS) and overall survival (OS) rates at 2 years after diagnosis were significantly higher for patients in the R-chemotherapy group (PFS, 56%; OS, 66%) than for patients in the chemotherapy group (PFS, 27% with P = .001; OS, 46% with P = 0.01). Multivariate analysis revealed that the use of rituximab was favorably associated with PFS (hazard ratio [HR], 0.45; 95% CI, 0.25 to 0.80; P = .006) and OS (HR, 0.42; 95% CI, 0.21 to 0.85; P = .016). Treatment-related death was observed in three patients (6%) who received R-chemotherapy and in five patients (9%) who received chemotherapy.

Conclusion

Our data suggest improved clinical outcomes for patients with IVLBCL in the rituximab era. Future prospective studies of rituximab-containing chemotherapies are warranted.
Elevated Levels of High-Molecular-Weight Adiponectin in Type 1 Diabetes
Authors: Leth Henrik , Andersen Kristian K. , Frystyk Jan , Tarnow Lise , Rossing Peter , Parving Hans-Henrik , Flyvbjerg Allan
Published: May 2008

Background: Several studies have shown that type 1 diabetic patients have elevated total levels of the adipocyte-derived adipocytokine adiponectin. However, adiponectin circulates in three different subforms, and the high-molecular-weight (HMW) subform is believed to be the primary biologically active form. The effects of the medium-molecular-weight (MMW) subform and the low-molecular-weight (LMW) subform are still unresolved.

Purpose: The objective of the study was to investigate the distribution of the three molecular subforms of adiponectin in well-characterized groups of type 1 diabetics with varying degrees of nephropathy as well as in healthy control subjects.

Study Population: Two hundred seven individuals were included: 58 type 1 diabetics with normoalbuminuria, 46 with microalbuminuria, 46 with macroalbuminuria, and 57 matched controls.

Methods: The HMW, MMW, and LMW subforms were measured using a validated in-house time-resolved immunoflourometric assay after separation by fast protein liquid chromatography.

Results: The absolute concentrations of total adiponectin and all subforms were higher in type 1 diabetic patients than healthy controls. However, the relative HMW fraction was up-regulated in type 1 diabetes (P < 0.001), whereas the MMW (P < 0.001) and LMW fractions (P < 0.05) were down-regulated, compared with controls. Accordingly, the increase in concentration of total adiponectin was primarily caused by a major increase of the HMW subform. Levels of total adiponectin and the HMW subform (absolute and relative) were generally unaffected by nephropathy status defined by urinary albumin excretion rate.

Conclusion: Type 1 diabetes per se is associated with higher adiponectin levels than healthy subjects. This increase is mainly explained by an elevation in the HMW subform. The elevation is unaffected by gender and diabetic kidney disease.
Evolutionary analysis and molecular dissection of caveola biogenesis
Authors: Kirkham Matthew , Nixon Susan J. , Howes Mark T. , Abi-Rached Laurent , Wakeham Diane E. , Hanzal-Bayer Michael , Ferguson Charles , Hill Michelle M. , Fernandez-Rojo Manuel , Brown Deborah A. , Hancock John F. , Brodsky Frances M. , Parton Robert G.
Published: May 2008

Caveolae are an abundant feature of mammalian cells. Integral membrane proteins called caveolins drive the formation of caveolae but the precise mechanisms underlying caveola formation, and the origin of caveolae and caveolins during evolution, are unknown. Systematic evolutionary analysis shows conservation of genes encoding caveolins in metazoans. We provide evidence for extensive and ancient, local and genomic gene duplication, and classify distinct caveolin gene families. Vertebrate caveolin-1 and caveolin-3 isoforms, as well as an invertebrate (Apis mellifera, honeybee) caveolin, all form morphologically identical caveolae in caveolin-1-null mouse cells, demonstrating that caveola formation is a conserved feature of evolutionarily distant caveolins. However, coexpression of flotillin-1 and flotillin-2 did not cause caveola biogenesis in this system. In contrast to the other tested caveolins, C. elegans caveolin is efficiently transported to the plasma membrane but does not generate caveolae, providing evidence of diversity of function in the caveolin gene family. Using C. elegans caveolin as a template to generate hybrid caveolin constructs we now define domains of caveolin required for caveolae biogenesis. These studies lead to a model for caveola formation and novel insights into the evolution of caveolin function.
Endogenous RhoG is dispensable for integrin-mediated cell spreading but contributes to Rac-independent migration
Authors: Meller Julia , Vidali Luis , Schwartz Martin Alexander
Published: May 2008

Rac activation by integrins is essential for cell spreading, migration, growth and survival. Based mainly on overexpression of dominant-negative mutants, RhoG has been proposed to mediate integrin-dependent Rac activation upstream of ELMO and Dock180. RhoG-knockout mice, however, display no significant developmental or functional abnormalities. To clarify the role of RhoG in integrin-mediated signaling, we developed a RhoG-specific antibody, which, together with shRNA-mediated knockdown, allowed analysis of the endogenous protein. Despite dramatic effects of dominant-negative constructs, nearly complete RhoG depletion did not substantially inhibit cell adhesion, spreading, migration or Rac activation. Additionally, RhoG was not detectably activated by adhesion to fibronectin. Using Rac1–/– cells, we found that constitutively active RhoG induced membrane ruffling via both Rac-dependent and -independent pathways. Additionally, endogenous RhoG was important for Rac-independent cell migration. However, RhoG did not significantly contribute to cell spreading even in these cells. These data therefore clarify the role of RhoG in integrin signaling and cell motility.
Characterization of a liquid bridge microdroplet dispenser for use in molecular diagnosis
Authors: Forget M , O'Donnell M , Davies M
Published: May 2008

Microfluidic solutions offer the possibility of minimizing time-to-result, reagents and labour costs of molecular diagnosis, while improving their quality and accuracy. The use of droplets as microreactors represents one of the points of focus of this research. The current paper presents a geometry, referred to as a ‘two-way liquid bridge’, for dispensing microdroplets upstream of a nucleid acid amplifier. A single continuous phase, drawn through a capillary tube, can be automatically segmented into droplets of a predetermined size, with each droplet separated from its nearest neighbour and the wetted surface by an immiscible phase. The device has many advantages over previously reported segmenters. An experimental study, conducted in an adjustable device, demonstrates the effect of geometric parameters on the volume of fluid dispensed. Based on these experimental observations, a quasi-empirical theory is proposed to predict the dispensed volume for a given range of dispensed volumes, which is then demonstrated to work as a first-order design tool.
Structural and Functional Model Systems for Analysis of the Active Center of Nitrile Hydratase
Authors: Yano Takuma , Ozawa Tomohiro , Masuda Hideki
Published: June 2008

The unique active site structure of nitrile hydratase (NHase) has a central metal ion (CoIII or FeIII) coordinated by two amide nitrogens from the peptide backbone, one cysteine sulfur and two oxidized cysteine sulfurs (Cys–SO and Cys–SO2). In this review, the biological implications of the nitrile hydration mechanism are discussed in context of model complexes prepared with the aim of understanding the unique structure of nitrile hydratase.
Synthesis, Structure, and Luminescent Property of a 3D Polymer Containing Silver Ions
Authors: Li Yajuan , Song Huihua , Wang Tao , Jia Miying
Published: June 2008

The hydrothermal reaction of Ag2SO4, pyridine-3,4-dicarboxylic acid (H2PDC), LiF, and H2O led to the formation of a novel complex, [Ag2(PDC)]n (1). X-ray crystal structural analysis indicates that 1 has a 3D coordinated framework, which contains a mono- and dinuclear mixed 1D polymeric chain. Fluorescent analyses of 1 show intense photoluminescence at 510 nm in the solid state, suggesting potential candidates for photoactive material.
Dynamic Behavior of Cyclic Hemiacetals of 2-Hydroxy-2-(2-hydroxyphenyl)-1,3-indandione Derivatives
Authors: Hashimoto Suzumi , Sakuma Natsumi , Wakabayashi Hidetsugu , Miyamae Hiroshi , Kobayashi Keiji
Published: June 2008

Dynamic interconversion between the two enantiomeric hemiacetal structures in acetonitrile was revealed from the variable-temperature 1H NMR spectra for the compounds obtained by the reaction of ninhydrin with phenol and p-nitrophenol.
Simultaneous On-chip Surface Plasmon Resonance Measurement of Disease Marker Protein and Small Metabolite Combined with Immuno- and Enzymatic Reactions
Authors: Nakamoto Kohei , Kurita Ryoji , Sekioka Naoyuki , Niwa Osamu
Published: June 2008

Disease marker protein and a correction marker were simultaneously measured with a portable surface plasmon resonance (SPR) system and PDMS microchannel. Two gold films in the microchannel were modified with antibody and redox polymer containing horseradish peroxidase (HRP). Creatininase, creatinase, and sarcosine oxidase were immobilized in the upstream. We could measure glycoprotein, transferrin (MW: 75 kDa) and creatinine (MW: 113) both by SPR angle shifts caused by immuno- and redox reactions, indicating that urinary transferrin concentration could be normalized with creatinine concentration by single injection.
A Convenient Method for the Lewis Base-catalyzed Synthesis of α,β-Unsaturated Carboxylic Esters Using Trimethylsilylketene Ethyl Trimethylsilyl Acetal and Carbonyl Compounds
Authors: Michida Makoto , Mukaiyama Teruaki
Published: June 2008

A highly useful method for the synthesis of α,β-unsaturated carboxylic esters from various carbonyl compounds that uses trimethylsilylbetene ethyl trimethylsilyl acetal in the presence of a Lewis base catalyst such as acetate salts was established. This procedure gives the corresponding esters in high yields with excellent E stereoselectivity under mild conditions.
Convenient Fabrication and Property Investigations of Uniform TiN Hollow Nanocages
Authors: Li Jing , Wang Liancheng , Ju Zhicheng , Xu Liqiang , Qian Yitai
Published: June 2008

Crystalline TiN hollow nanocages with pure cubic phase were prepared in large scale using TiO2, N2H4·2HCl, and Mg as reactants in autoclaves in 300–500 °C for 12 h. These hollow nanocages mainly have diameters of 300 to 500 nm and shell thicknesses from 20 to 35 nm. The product obtained with target temperature of 500 °C has a BET surface area of 68.13 m2/g and pore volume of 0.17 cm3/g.
Becoming a father/refusing fatherhood: an empirical bioethics approach to paternal responsibilities and rights
Authors: Ives Jonathan , Draper Heather , Pattison Helen , Williams Clare
Published: May 2008

In this paper, we present the first stage of an empirical bioethics project exploring the moral sources of paternal responsibilities and rights. In doing so, we present both (1) data on men's normative constructions of fatherhood and (2) the first of a two-stage methodological approach to empirical bioethics. Using data gathered from 12 focus groups run with UK men who have had a variety of different fathering experiences ( n = 50), we examine men's perspectives on how paternal responsibilities and rights are generated and the significance of the genetic connection within the father–child relationship.

We do not attempt to explore men's experiences of fatherhood or their fathering practices; and neither is the analysis driven from a particular sociological perspective. Rather, we explore men's normative constructions of fatherhood in order to present accessible data that might be of significance to the philosophical/moral debate on the sources of paternal rights and responsibilities.
Clinical Ethics Committees: a due process wasteland?
Authors: McLean Sheila A M
Published: May 2008

The development of clinical ethic support in the UK arguably brings with it a series of legal questions, which need to be addressed. Most particularly, these concern questions of due process and formal justice, which I argue are central to the provision of appropriate ethical advice. In this article, I will compare the UK position with the more developed system in the USA, which often provides a template for development in the UK. While it is not argued that the provision of clinical ethics support in the UK will necessarily follow the path mapped in the USA, there are lessons that can be learned from the US experience – particularly in terms of attention to process – from which UK clinical ethics support service might well benefit.