bluuebunny/crossref_metadata_2025 huggingface dataset:
The Androgen and Progesterone Receptors Regulate Distinct Gene Networks and Cellular Functions in Decidualizing Endometrium
Authors: Cloke Brianna , Huhtinen Kaisa , Fusi Luca , Kajihara Takeshi , Yliheikkilä Maria , Ho Ka-Kei , Teklenburg Gijs , Lavery Stuart , Jones Marius C. , Trew Geoffrey , Kim J. Julie , Lam Eric W.-F. , Cartwright Judith E. , Poutanen Matti , Brosens Jan J.
Published: May 2008

Progesterone is indispensable for differentiation of human endometrial stromal cells (HESCs) into decidual cells, a process that critically controls embryo implantation. We now show an important role for androgen receptor (AR) signaling in this differentiation process. Decreased posttranslational modification of the AR by small ubiquitin-like modifier (SUMO)-1 in decidualizing cells accounted for increased responsiveness to androgen. By combining small interfering RNA technology with genome-wide expression profiling, we found that AR and progesterone receptor (PR) regulate the expression of distinct decidual gene networks. Ingenuity pathway analysis implicated a preponderance of AR-induced genes in cytoskeletal organization and cell motility, whereas analysis of AR-repressed genes suggested involvement in cell cycle regulation. Functionally, AR depletion prevented differentiation-dependent stress fiber formation and promoted motility and proliferation of decidualizing cells. In comparison, PR depletion perturbed the expression of many more genes, underscoring the importance of this nuclear receptor in diverse cellular functions. However, several PR-dependent genes encode for signaling intermediates, and knockdown of PR, but not AR, compromised activation of WNT/β-catenin, TGFβ/SMAD, and signal transducer and activator of transcription (STAT) pathways in decidualizing cells. Thus, the nonredundant function of the AR in decidualizing HESCs, centered on cytoskeletal organization and cell cycle regulation, implies an important role for androgens in modulating fetal-maternal interactions. Moreover, we show that PR regulates HESC differentiation, at least in part, by reprogramming growth factor and cytokine signal transduction.
Evaluation of thyroid-mediated otolith growth of larval and juvenile tilapia
Authors: Shiao Jen-Chieh , Wu Su-Mei , Hwang Yi-Ping , Wu Done-Ping , Hwang Pung-Pung
Published: May 2008

Thyroid-mediated otolith growth in tilapia was evaluated by the ontogenic triiodothyronine (T3) profile revealed by radioimmunoassay during the first month after hatching. Thyroid hormone receptor genes(TRα and TRβ) were cloned and only the expression of TRα mRNA, quantified by real-time PCR, was similar to the T3 profile. Variations in otolith growth showed median correlation with the T3 profile and TRα mRNA expression pattern. Hypothyroidism and hyperthyroidism were induced in tilapia juveniles and larvae by administration of different concentrations of thiourea (TU) and T3, respectively, for 13 days. T3 and TU had little effect on otolith growth during the larval stage. However, T3increased otolith growth and TU retarded, or stopped, otolith growth during the juvenile stage. Furthermore, TU treatment caused permanent changes in otolith shape in the ventral area. Otolith growth recovered slowly from hypothyroidism, requiring 2 days to form an increment during the first week. These results suggest that otolith growth, at least during the juvenile stage,is regulated by the thyroid hormones and the process may be mediated by TRα.
Two-voice complexity from a single side of the syrinx in northern mockingbirdMimus polyglottosvocalizations
Authors: Zollinger Sue Anne , Riede Tobias , Suthers Roderick A.
Published: May 2008

The diverse vocal signals of songbirds are produced by highly coordinated motor patterns of syringeal and respiratory muscles. These muscles control separate sound generators on the right and left side of the duplex vocal organ, the syrinx. Whereas most song is under active neural control, there has been a growing interest in a different class of nonlinear vocalizations consisting of frequency jumps, subharmonics, biphonation and deterministic chaos that are also present in the vocal repertoires of many vertebrates,including many birds. These nonlinear phenomena may not require active neural control, depending instead on the intrinsic nonlinear dynamics of the oscillators housed within each side of the syrinx. This study investigates the occurrence of these phenomena in the vocalizations of intact northern mockingbirds Mimus polyglottos. By monitoring respiratory pressure and airflow on each side of the syrinx, we provide the first analysis of the contribution made by each side of the syrinx to the production of nonlinear phenomena and are able to reliably discriminate two-voice vocalizations from potentially similar appearing, unilaterally produced, nonlinear events. We present the first evidence of syringeal lateralization of nonlinear dynamics during bilaterally produced chaotic calls. The occurrence of unilateral nonlinear events was not consistently correlated with fluctuations in air sac pressure or the rate of syringeal airflow. Our data support previous hypotheses for mechanical and acoustic coupling between the two sides of the syrinx. These results help lay a foundation upon which to understand the communicative functions of nonlinear phenomena.
The effects of fasting and cold exposure on metabolic rate and mitochondrial proton leak in liver and skeletal muscle of an amphibian, the cane toad Bufo marinus
Authors: Trzcionka M. , Withers K. W. , Klingenspor M. , Jastroch M.
Published: May 2008

Futile cycling of protons across the mitochondrial inner membrane contributes significantly to standard metabolic rate in a variety of ectothermic and endothermic animals, but adaptations of the mitochondrial bioenergetics to different environmental conditions have rarely been studied in ectotherms. Changes in ambient temperature and nutritional status have a great effect on the physiological demands of ectothermic amphibians and may require the adjustment of mitochondrial efficiency. In order to investigate the effect of temperature and nutritional status on the mitochondrial level,we exposed male cane toads to either 10°C or 30°C and fasted half of the animals in each group. Cold exposure resulted in a fourfold reduction of the resting metabolic rate whereas nutritional status had only minor effects. The mitochondrial adjustments to each condition were observed by comparing the proton leak kinetics of isolated liver and skeletal muscle mitochondria at 25°C. In response to cold exposure, liver mitochondria showed a decrease in proton conductance while skeletal muscle mitochondria were unchanged. Additional food deprivation had minor effects in skeletal muscle, but in liver we uncovered surprising differences in energy saving mechanisms between the acclimation temperatures: in warm-acclimated toads, fasting resulted in a decrease of the proton conductance whereas in cold-acclimated toads, the activity of the respiratory chain was reduced. To investigate the molecular mechanism underlying mitochondrial proton leakage, we determined the adenine-nucleotide transporter (ANT) content, which explained tissue-specific differences in the basal proton leak, but neither the ANT nor uncoupling protein (UCP) gene expression correlated with alterations of the proton leak in response to physiological stimuli.
Population origin, development and temperature of development affect the amounts of HSP70, HSP90 and the putative hypoxia-inducible factor in the tadpoles of the common frogRana temporaria
Authors: Nikinmaa Mikko , Leveelahti Lotta , Dahl Emma , Rissanen Eeva , Rytkönen Kalle T. , Laurila Anssi
Published: May 2008

We raised Rana temporaria tadpoles from three different populations from southern, mid and northern Sweden (the total north-to-south distance between populations is approximately 1500 km) at two temperatures,and measured the differences in HSP70, HSP90 and putative HIF-1α levels(Rana temporaria HIF-1α was sequenced in the present study)with immunoblotting. The levels of the studied proteins increased with developmental stage. Also, the levels increased with latitude at the lower but not at the higher developmental temperature. This shows that there is a clear difference between the populations at the molecular level but that this difference can be modified by the environmental conditions experienced during development. The proteins analyzed may be involved in the regulation of developmental processes. If this is the case, the tadpoles from the northernmost population have the most advanced complement of regulatory proteins at developmental stages approaching metamorphosis.
Female choice by electric pulse duration: attractiveness of the males'communication signal assessed by female bulldog fish,Marcusenius pongolensis(Mormyridae, Teleostei)
Authors: Machnik Peter , Kramer Bernd
Published: May 2008

In adult males of the South African weakly electric bulldog fish, Marcusenius pongolensis, the duration of the electric organ discharge(EOD) increases with body size over lifetime. Although there is experimental support for intrasexual selection (male–male competition) having shaped the males' EOD pulse duration in evolution, nothing is known about intersexual selection, such as female choice. Playback of 25 natural male EODs of pulse duration varying from 320 μs (close to the average female value) to 716μs, to eight female experimental subjects elicited approach, head butts and circling behaviour. The rate of head butts on the dipole electrode model increased significantly with stimulus pulse duration in seven out of eight experimental subjects. In ten experimental female subjects we contrasted the shortest playback pulse with simultaneous playback of one of four longer ones(424, 524, 628 and 716 μs). Pooled responses for all experimental subjects were stronger for the dipole playing back the longer pulse in a pulse pair. The difference in the number of head butts (Δhead butts) that were dealt the two dipoles per 60 s test session increased significantly with the difference in pulse duration (Δpulse duration). The increase followed a significant linear trend (P<0.0001). Similar results were obtained for Δassociation time, Δcircles with head butts, andΔcircles without head butts. These results suggest that a male's reproductive success is enhanced by longer, i.e. more attractive EODs, and that both intra- and intersexual selection must have played a significant role in shaping the EOD of male M. pongolensis.
Slow desiccation improves dehydration tolerance and accumulation of compatible osmolytes in earthworm cocoons (Dendrobaena octaedraSavigny)
Authors: Petersen Christina R. , Holmstrup Martin , Malmendal Anders , Bayley Mark , Overgaard Johannes
Published: May 2008

The earthworm, Dendrobaena octaedra, is a common species in temperate and subarctic regions of the northern hemisphere. The egg capsules(`cocoons') of D. octaedra are deposited in the upper soil layers where they may be exposed to desiccation. Many previous studies on desiccation tolerance in soil invertebrates have examined acute exposure to harsh desiccating conditions, however, these animals are often more likely to be exposed to a gradually increasing drought stress. In the present study we slowly desiccated D. octaedra cocoons to simulate ecologically realistic drought conditions and the results clearly demonstrate that gradually dehydrated cocoons show an increased tolerance of extreme drought compared with acutely dehydrated cocoons. NMR spectroscopic analysis of compatible osmolytes revealed the presence of sorbitol, glucose, betaine,alanine and mannitol in dehydrated embryos. The superior drought survival of gradually desiccated embryos could partly be attributed to a higher accumulation of osmolytes (especially sorbitol). Thus, gradually and acutely desiccated embryos accumulated ∼2 mol l–1 and 1 mol l–1 total osmolytes, respectively. However, in addition to osmolyte accumulation, the gradually desiccated cocoons also tolerated a higher degree of water loss, demonstrating that gradually dehydrated D. octaedra cocoons are able to survive loss of ∼95% of the original water content. Although D. octaedra embryos can probably not be categorized as a truly anhydrobiotic organism we propose that they belong in a transition zone between the desiccation sensitive and the truly anhydrobiotic organisms. Clearly, these earthworm embryos share many physiological traits with anhydrobiotic organisms.
Redundancy of olfactory sensory pathways for odor-aversion memory in the terrestrial slug Limax valentianus
Authors: Yamagishi Miki , Ito Etsuro , Matsuo Ryota
Published: May 2008

Terrestrial slugs have the ability to learn and remember a food odor paired with an aversive stimulus. Olfaction in slugs involves the tips of two pairs of tentacles, the superior and the inferior tentacles. Sensory nerves in both pairs of the tentacles transmit olfactory information to the structure in the CNS, the procerebrum where learning and memory formation occur. We investigated the role of each pair of tentacles in odor-aversion learning, and examined the ability of slugs to recall memory after selective surgical amputation. Our results show that memory formation was not altered by the amputation of either one of the pairs before or after odor-aversion learning,while the odor sensibility of the slugs was maintained. These data suggest that either pair of tentacles is sufficient for the acquisition and retrieval of aversive olfactory memory.
Media influence on Herceptin subsidization in Australia: application of the rule of rescue?
Authors: MacKenzie Ross , Chapman Simon , Salkeld Glenn , Holding Simon
Published: May 2008

Summary

Background

In August 2006, the Australian government announced that Herceptin (Trastuzumab) would be added to the national Pharmaceutical Benefits Scheme (PBS) of government-subsidized drugs, for treatment with adjuvant chemotherapy of HER2 breast cancer. Following initial reticence, the health minister responded to a campaign by patients and patient advocacy groups by announcing PBS subsidization which lowered the cost of a weekly dose from A$1000 to A$30. The cost to the government would be A$470 million over three years for treatment of an estimated 2100 women annually.

Design

We analysed the news frames used in all direct and attributed statements ( n=239) in television news coverage of the discourse preceding the Herceptin decision by the Australian government.

Setting

Five Sydney free-to-air channels between October 2005 and August 2006.

Main outcome measures

News frames or themes.

Results

Of five news frames identified, one (‘desperate, sick women in double jeopardy because of callous government/incompetent bureaucracy’) accounted for 54% of all reported statements. Government financial parsimony was framed as responsible for the women's plight, with drug industry pricing never mentioned. Claimed benefits of Herceptin often conflated cancer non-recurrence and survival and favoured quantification rhetoric which emphasized percentage increases in improvement rather than the more modest increases in absolute survival.

Conclusions

News frames invoking key tenets of the ‘rule of rescue’ dominated television discourse on Herceptin. Clinicians, patients, their families and patient advocacy groups invoking the rule of rescue can increase the likelihood of achieving their objective of gaining access to expensive healthcare such as pharmaceuticals. Rational, criteria-based public health policy will find it hard to resist the rule of rescue imperative.
Setting up non-commercial clinical trials takes too long in the UK: findings from a prospective study
Authors: Hackshaw Allan , Farrant Hannah , Bulley Sue , Seckl Michael J , Ledermann Jonathan A
Published: May 2008

Summary

Objective

To evaluate the specific components of setting up a simple multicentre clinical study four years after the new UK law on clinical trials was implemented in 2004.

Design

Timelines associated with activating a randomized multicentre trial in lung cancer patients using an investigational medicinal product (statins) were prospectively recorded.

Setting

84 trial centres in the UK.

Main outcome measures

The time taken to go through the three stages necessary to activate a trial at a centre was examined: that is, the time from when Site Specific Information was electronically transferred to a participating centre until local research ethics committee (LREC) or research and development (R&D) approvals were obtained, and a signed Clinical Trials Site Agreement (CTSA) was received.

Results

It took at least six months to obtain LREC approval in 21% of centres and R&D approval in 52% of centres. Twelve centres (14%) took at least 12 months to obtain R&D approval. 31% of centres took at least three months to return a signed CTSA. Although 52% of centres took at least six months to be activated, 13% were able to complete all three stages in two months or less.

Conclusions

While some centres can activate trials relatively quickly, there is considerable variation the time taken to set up a trial, much of which is due to the delay in obtaining R&D approval. This is having a major adverse effect on UK health research. There is a national need to streamline the process for considering multi-centre non-commercial clinical trials, in particular, having fixed timelines for R&D assessment. Without this, the costs of trials will increase because of extended duration, and the time to answer a research question and alter clinical practice will be significantly prolonged.
Pharmacotherapy for obesity in menopausal women
Authors: Samat Ashish , Rahim Asad , Barnett Anthony
Published: May 2008

Weight gain, during and after the menopause is common. Contributing factors include ethnicity, reduced physical activity reduced lean mass, reduced resting metabolic rate and treatment with certain drugs, e.g. steroids, insulin, glitazones. Excess body weight increases the risk of medical conditions including type 2 diabetes, hypertension, osteoarthritis, certain cancers and is associated with increased mortality. This review examines pharmacological approaches to promote weight loss. Pharmacological therapy should be considered as an adjunct to diet and lifestyle changes. The licensed drugs orlistat, sibutramine and rimonabant are discussed. Obesity increases the risk of type 2 diabetes. Thus, the effects of metformin and exenatide are examined.
Use of unopposed systemic estrogen therapy in non-hysterectomized women: A population-based study in the UK
Authors: Rees Margaret , Hope Sally
Published: May 2008

A population study of 28 general practices in Oxfordshire, UK found that 0.028% of 17,712 non-hysterecto-mized women aged 45-60 years were using systemic unopposed estrogen. This is significantly lower than that reported in the Million Women Study.
Non-estrogen-based treatments for menopausal symptoms
Authors: Pitkin Joan , Rees Margaret C P , Gray Sarah , Lumsden Mary Ann , Marsden Jo , Stevenson John C , Williamson Jennifer
Published: May 2008

The British Menopause Society Council is committed to provide up-to-date authoritative reviews to aid health professionals to inform and advise women about key issues in postreproductive health. This guidance refers to non-estrogen-based treatments for menopausal symptoms, such as hot flushes, symptoms of urogenital atrophy and lack of sexual desire. Treatment of choice should be based on up to-date information and targeted to individual women's needs. Non-hormonal strategies may be useful for women with estrogen-dependent disease such as breast cancer.
Ciceronian and Hermogenean Influences on George of Trebizond's Rhetoricorum Libri V
Authors: Montefusco Lucia Calboli
Published: May 2008

Giorgio Trebisonda era un emigrante Greco che già nel suo paese aveva imparato molto bene la grammatica e la retorica. Arrivò a Venezia molto giovane per lavorare nella biblioteca di Francesco Barbaro e passò gran parte della sua vita in Italia insegnando. Nell'ultimo libro del suo manuale, Rhetoricorum Libri V, egli, dedicando un'attenzione particolare all'elocutio, elabora un insieme molto interessante di precetti, intrecciando la teoria degli stili con la dottrina ermogenea delle ιδεαι fino ad allora sconosciuta agli autori di manuali latini. Giorgio Trebisonda aveva già trattato brevemente questa questione, una prima volta, in una lettera indirizzata al suo maestro Vittorino da Feltre e concernente esplicitamente i genera dicendi, una seconda volta, in una lunga lettera mandata a Girolamo Bragadin per dargli consigli su come ottenere la suavitas dicendi. Lamentando di non potere fare riferimento a fonti latine e di conseguenza di trovarsi nella duplice difficoltà di dovere tradurre in latino la terminologia specifica della dottrina Ermogenea e di dovere trovare esempi latini per illustrarla, Giorgio Trebisonda cerca di superare questa difficoltà sostituendo a Demostene, l'autore paradigmatico in Ermogene, Cicerone, dalle cui opere attinge la maggior parte del materiale che inserisce nella dottrina Ermogenea con un risultato veramente eccezionale.
Subclinical thyroid dysfunction and mortality: an estimate of relative and absolute excess all-cause mortality based on time-to-event data from cohort studies
Authors: Haentjens Patrick , Van Meerhaeghe Alain , Poppe Kris , Velkeniers Brigitte
Published: May 2008

Objectives

To what extent persons with subclinical hyper- or hypothyroidism are more (or less) likely to die than euthyroid control subjects remains a matter of controversy.

Methods

We searched electronic reference databases up to July 31, 2007. Three reviewers independently assessed eligibility. Cohort studies published in full that reported data on the hazard ratio (HR) for mortality from all causes in persons with subclinical thyroid dysfunction versus euthyroid controls were included.

Results

Based on seven cohorts including 290 participants with subclinical hyperthyroidism, random-effects models estimated that the pooled HR for all-cause mortality was 1.41 (95% confidence interval (CI), 1.12–1.79; P=0.004). Using the pooled HR and standard life-table methods applied to a US reference population, we estimated that a white US woman, when diagnosed with subclinical hyperthyroidism at age of 70, has an excess mortality of 1.5, 4.0, and 8.7% at 2, 5, and 10 years respectively after diagnosis. Likewise, a white US man has an excess mortality of 2.3, 5.7, and 10.7%. For the nine cohorts including 1580 participants with subclinical hypothyroidism, observed heterogeneity (Q test P=0.006; I2=63%) disappeared after pooling cohorts in predefined subgroups according to the presence or absence of a comorbid condition. In doing so, the pooled HR for all-cause mortality was 1.03 (95% CI, 0.78–1.35; P=0.83) in cohorts from the community and 1.76 (95% CI, 1.36–2.30; P<0.001) in cohorts of participants with comorbidities (P=0.014 for heterogeneity among study groups).

Conclusions

Individuals with subclinical hyperthyroidism demonstrate a 41% increase in relative mortality from all causes versus euthyroid control subjects. Mathematical modeling suggests that absolute excess mortality after diagnosis might depend on age, with an increase beyond the age of 60, especially in aging men. For patients with subclinical hypothyroidism, the relative risk of all-cause mortality is increased only in patients with comorbid conditions.
Exploring the use of recombinant human TSH in the diagnosis of central hypothyroidism
Authors: Filipsson Helena , Nyström Ernst , Johannsson Gudmundur
Published: May 2008

Context

The diagnosis of central hypothyroidism (CH) is often difficult to establish as serum TSH levels may be low, normal, or slightly increased.

Objective

To explore the use of recombinant human TSH (rhTSH) in the diagnosis of CH.

Design

Randomized single-blind clinical trial.

Setting

Outpatient clinic of a tertiary care referral center.

Intervention

A single intramuscular injection of 0.1 and 0.9 mg rhTSH in random order with 1-week interval.

Participants

Eighteen adult patients with pituitary insufficiency and six healthy age-, sex-, and body mass index-matched controls. Six patients had untreated CH (newCH), six had treated CH (CH), and six patients were TSH sufficient (nonCH). Five weeks before TSH stimulation, levothyroxine was replaced with tri-iodothyronine (T3) for 4 weeks. One week before stimulation, treatment was withdrawn.

Main outcome measures

Thyroid hormones and thyroglobulin (Tg) before and 2, 3½, 7, 24, 48, and 72 h after each injection.

Results

In the newCH group, basal free thyroxine (FT4) levels were lower than in controls (P<0.05). After 0.9 mg rhTSH, the increases in FT4 and reverse T3 (rT3) were less marked in the newCH group than in controls (FT4±s.e.m. 9.2±0.5 to 19.7±1.2 vs 11.3±0.5 to 27.8.2±2.4 pmol/l, P<0.05). The CH group exhibited reduced basal and stimulated FT4 compared with the TSH-sufficient groups. Tg increased similarly among all study groups after rhTSH injection.

Conclusion

In this pilot study, patients with untreated CH had lower response to 0.9 mg rhTSH in FT4 and rT3 than controls. An rhTSH test may be useful in the diagnosis of CH, but further studies are required.
Pharmacology Review
Authors: Ramanathan Rangasamy
Published: May 2008

Bronchopulmonary dysplasia (BPD) continues to be a major morbidity in preterm infants, especially among the most immature neonates. Although BPD is a multifactorial disease, persistent inflammation is believed to be the final common pathway in its evolution. BPD initially presents with an exudative phase primarily in the immature preterm neonate still receiving respiratory support around 7 to 10 days of age. During this phase, pulmonary edema develops due to proinflammatory cytokine-induced increased alveolar-capillary membrane permeability. Persistence of a patent ductus arteriosus (PDA) with left-to-right shunting or administration of excessive intravenous fluids during this period also promotes pulmonary overcirculation, thus contributing to the pulmonary edema. The associated increased lung water content results in decreased lung compliance both in evolving and established BPD. Diuretics are administered to prevent or treat the pulmonary edema and control total body sodium content. The most commonly used diuretics are furosemide (a loop diuretic), chlorothiazide, and spironolactone. Loop diuretics primarily exert their effects by inhibiting the 2Cl−,Na+-K+ cotransporter in the kidney and the lungs, resulting in diuresis and decreased pulmonary edema formation, respectively. Treatment with diuretics is associated with decreased pulmonary edema and airway resistance as well as improvements in lung compliance. However, diuretics have potentially significant adverse effects, including fluid and electrolyte imbalance, osteopenia, nephrocalcinosis, hearing impairment, and growth failure. There is no evidence that the use of diuretics has an effect on the long-term pulmonary or nonpulmonary outcomes in infants who have BPD.
Possible Anaphylactic Reaction Due to Pulmonary Hydatid Cyst Rupture Following Blunt Chest Trauma: A Case Report and Review of the Literature
Authors: Topuzlar Mehmet , Eken Cenker , Ozkurt Birsen , Khan Feras
Published: May 2008

A hydatid cyst is a parasitic disease caused by the tapeworm Echinococcus granulosus. It is endemic in many areas, including New Zealand, Australia, and the Mediterranean region. Pulmonary hydatid disease can be diagnosed incidentally in asymptomatic patients or may cause symptoms such as cough, chest pain, dyspnea, fever, and hemoptysis both in patients with ruptured and nonruptured cysts. Anaphylactic reaction is a rare presentation of pulmonary hydatid cyst disease. In this case report, we report an unusual anaphylactic reaction following pulmonary hydatid cyst rupture secondary to blunt chest trauma.
Hypoxia Causes Downregulation of Mismatch Repair System and Genomic Instability in Stem Cells
Authors: Rodríguez-Jiménez Francisco Javier , Moreno-Manzano Victoria , Lucas-Dominguez Rut , Sánchez-Puelles José-María
Published: May 2008

The DNA mismatch repair (MMR) system maintains genomic integrity by correcting replication errors: its malfunction causes genomic instability in several tumor types. Hypoxia-inducible factor-1α (HIF1α), the major regulator of the processes that occur in hypoxia and certain epigenetic events downregulate the expression of MMR genes in cancer cells. However, there is a lack of information regarding MMR regulation and the genetic stability of stem cells under hypoxic conditions. The expression of the MMR system is downregulated in murine and human stem cells cultured in hypoxia, which correlates with lower DNA repair activity in neural stem cells. We observed, through the use of short hairpin loop RNAi expression constructs, that HIF1α positively regulated MLH1 and MSH6 when the C17.2 neural stem cells were exposed to short-term hypoxia. However, in prolonged exposure to oxygen depletion, the reduced transcriptional activation of MMR genes was directed by specific epigenetic events. Chromatin immunoprecipitation experiments showed a hypoacetylated/hypermethylated histone H3 and lower SP1 binding within MLH1 and MSH6 adjacent promoter regions. Treatment with the histone deacetylase inhibitor trichostatin A increased histone H3 acetylation and SP1 occupancy and enhanced MMR expression. Sequencing of microsatellite markers revealed genomic instability in the murine and human stem cells grown under hypoxia. Thus, the present article reports, for the first time in the stem cell field, experimental data that indicate that hypoxic niches are an environment in which stem cells might undergo genomic instability, which could lie at the origin of subpopulations with cancer stem cell properties.

Disclosure of potential conflicts of interest is found at the end of this article.
Diverse Adult Stem Cells Share Specific Higher-Order Patterns of Gene Expression
Authors: Doherty Jason M. , Geske Michael J. , Stappenbeck Thaddeus S. , Mills Jason C.
Published: May 2008

Adult tissue stem cells (SCs) share functional properties regardless of their tissue of residence. It had been thought that SCs might also share expression of certain “stemness” genes, although early investigations for such genes were unsuccessful. Here, we show that SCs from diverse tissues do preferentially express certain types of genes and that SCs resemble other SCs in terms of global gene expression more than they resemble the differentiated cells (DCs) of the tissues that they supply. Genes associated with nuclear function and RNA binding were over-represented in SCs. In contrast, DCs from diverse tissues shared enrichment in genes associated with extracellular space, signal transduction, and the plasma membrane. Further analysis showed that transit-amplifying cells could be distinguished from both SCs and DCs by heightened expression of cell division and DNA repair genes and decreased expression of apoptosis-related genes. This transit-amplifying cell-specific signature was confirmed by de novo generation of a global expression profile of a cell population highly enriched for transit-amplifying cells: colonic crypt-base columnar cells responding to mucosal injury. Thus, progenitor cells preferentially express intracellular or biosynthetic genes, and differentiation correlates with increased expression of genes for interacting with other cells or the microenvironment. The higher-order, Gene Ontology term-based analysis we use to distinguish SC- and DC-associated gene expression patterns can also be used to identify intermediate differentiation states (e.g., that of transit-amplifying cells) and, potentially, any biological state that is reflected in changes in global gene expression patterns.

Disclosure of potential conflicts of interest is found at the end of this article.
Clinical Efficacy of Taxane–Trastuzumab Combination Regimens for HER-2–Positive Metastatic Breast Cancer
Authors: Bullock Karen , Blackwell Kimberly
Published: May 2008

Learning Objectives

After completing this course, the reader will be able to: Evaluate the results of trials assessing the efficacy of monotherapy and doublet therapy of the taxanes, paclitaxel and docetaxel, plus trastuzumab in HER-2–positive MBC patients.Administer the optimal dosing schedule of taxanes in HER-2–positive MBC patients.Explain the possible benefits and toxicity of using anthracycline-sparing platinum chemotherapy in combination with taxane–trastuzumab therapy for HER-2–positive MBC.

CME This article is available for continuing medical education credit at CME.TheOncologist.com

The taxanes docetaxel (Taxotere®; Sanofi-Aventis U.S. LLC, Bridgewater, NJ) and paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ) are highly active agents in metastatic breast cancer and may represent a safer alternative to anthracycline-based regimens when combined with the human epidermal growth factor receptor (HER)-2–targeted agent trastuzumab (Herceptin®; Genentech Inc., South San Francisco, CA). A number of preclinical and early clinical studies have evaluated the feasibility, duration, and appropriate dosing schedule(s) for taxane–trastuzumab combinations in HER-2–positive metastatic breast cancer. Preclinical studies of the taxanes in combination with trastuzumab demonstrate synergistic interactions of trastuzumab with docetaxel and additive interactions with paclitaxel. Even though not supported by head-to-head studies, clinical trial results indicate the response rates with docetaxel–trastuzumab combinations may be higher than those with paclitaxel–trastuzumab, although there is a lack of clear crosstrial differences in other clinical benefits. Weekly taxane–trastuzumab regimens have been shown to offer superior disease control. Results from two large, phase III trials that examined the addition of carboplatin to a taxane–trastuzumab doublet did not demonstrate a difference in survival with carboplatin. In one study, the addition of carboplatin to paclitaxel–trastuzumab therapy resulted in a higher response rate and longer progression-free survival time; in the second study, the docetaxel–trastuzumab and docetaxel–trastuzumab–carboplatin combinations were equally effective. Ongoing correlative studies of taxanes, as well as newer formulations such as nanoparticle albumin-bound paclitaxel, in combination with trastuzumab will inform clinical practice regarding the optimal agent, schedule, and use of these highly effective regimens.
Molecular Markers and the Pathogenesis of Adrenocortical Cancer
Authors: Soon Patsy S. H. , McDonald Kerrie L. , Robinson Bruce G. , Sidhu Stan B.
Published: May 2008

Adrenal tumors are common, with an estimated incidence of 7.3% in autopsy cases, while adrenocortical carcinomas (ACCs) are rare, with an estimated prevalence of 4–12 per million population. Because the prognoses for adrenocortical adenomas (ACAs) and ACCs are vastly different, it is important to be able to accurately differentiate the two tumor types. Advancement in the understanding of the pathophysiology of ACCs is essential for the development of more sensitive means of diagnosis and treatment, resulting in better clinical outcome. Adrenocortical tumors (ACTs) occur as a component of several hereditary tumor syndromes, which include the Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia 1, Carney complex, and congenital adrenal hyperplasia. The genes involved in these syndromes have also been shown to play a role in the pathogenesis of sporadic ACTs. The adrenocorticotropic hormone–cAMP–protein kinase A and Wnt pathways are also implicated in adrenocortical tumorigenesis. The aim of this review is to summarize the current knowledge on the molecular mechanisms involved in adrenocortical tumorigenesis, including results of comparative genomic hybridization, loss of heterozygosity, and microarray gene-expression profiling studies.
Commercialized Multigene Predictors of Clinical Outcome for Breast Cancer
Authors: Ross Jeffrey S. , Hatzis Christos , Symmans W. Fraser , Pusztai Lajos , Hortobágyi Gabriel N.
Published: May 2008

Learning Objectives

After completing this course, the reader will be able to: Assess the strengths and weaknesses of the four main techniques used to measure multiple gene expression using clinical breast cancer specimens.Compare the advantages and disadvantages of the oncotype DX™ and MammaPrint® multigene assays and compare the TAILORx and MINDACT clinical trials for the prediction of clinical outcome in breast cancer.Evaluate the costs versus benefits associated with the use of expensive multigene breast cancer predictors in the management of breast cancer.

CME This article is available for continuing medical education credit at CME.TheOncologist.com

In the past 5 years, a number of commercialized multigene prognostic and predictive tests have entered the complex and expanding landscape of breast cancer companion diagnostics. These tests have used a variety of formats ranging from the familiar slide-based assays of immunohistochemistry and fluorescence in situ hybridization to the nonmorphology-driven molecular platforms of quantitative multiplex real-time polymerase chain reaction and genomic microarray profiling. In this review, 14 multigene assays are evaluated as to their scientific validation, current clinical utility, regulatory approval status, and estimated cost–benefit ratio. Emphasis is placed on two tests: oncotype DX™ and MammaPrint®. Current evidence indicates that the oncotype DX™ test has the advantages of earlier commercial launch, wide acceptance for payment by third-party payors in the U.S., ease of use of formalin-fixed paraffin-embedded tissues, recent listing by the American Society of Clinical Oncology Breast Cancer Tumor Markers Update Committee as recommended for use, continuous scoring system algorithm, ability to serve as both a prognostic test and predictive test for certain hormonal and chemotherapeutic agents, demonstrated cost-effectiveness in one published study, and a high accrual rate for the prospective validation clinical trial (Trial Assigning Individualized Options for Treatment). The MammaPrint® assay has the advantages of a 510(k) clearance by the U.S. Food and Drug Administration, a larger gene number, which may enhance further utility, and a potentially wider patient eligibility, including lymph node–positive, estrogen receptor (ER)-negative, and younger patients being accrued into the prospective trial (Microarray in Node-Negative Disease May Avoid Chemotherapy). A number of other assays have specific predictive goals that are most often focused on the efficacy of tamoxifen in ER-positive patients, such as the two-gene ratio test and the cytochrome P450 CYP2D6 genotyping assay.
Dewatering of oily slurry using drying bed with geotextile filter
Authors: Mendonça M. B. , Ehrlich M. , Cammarota M. C. , Freire D. D. C.
Published: May 2008

A new proposal for treatment of oily slurry is presented in this paper. The proposed technique consists of using drying beds with geotextile filters for water content and volume reduction of the slurry. Owing to the high concentration of contaminants, the disposal of this slurry may potentially be an environmentally hazardous practice. Hence techniques for dewatering pretreatment were developed, aiming at reducing the quantity of waste before disposal in landfills, land farms or incineration. Dewatering of the slurry may lead to reduced environmental impact and reduced cost for transport and disposal. Laboratory tests were performed for technical evaluation of the efficiency of the proposed procedure. Column tests were carried out using four types of filter: two nonwoven geotextiles and one woven geotextile, and a sand filter for performance comparison. Prototype tests were also performed, and results are included in this paper. No matter which filter type was used, the test results show good retention filter capacity and satisfactory drainage capacity. The process of dewatering the slurry brought considerable reduction in its water content and volume, minimising the volume of the final waste to be discharged. After dehydration, the treated slurry shows a tenfold concentration increase in oil and grease content, which contributes to its high calorific value. Hence the dehydrated slurry may be used as an alternative source of energy.
Numerical evaluation of prefabricated vertical drain enhanced soil vapour extraction system
Authors: Abuel-Naga H. , Bouazza A. , Bowders J. , Collazos O.
Published: May 2008

The aim of this study is to investigate numerically the performance of a prefabricated vertical drain (PVD) as a soil vapour extraction well, and the pattern of the induced air flow. A validated numerical model for a single PVD extraction well is developed based on the result of a well-designed laboratory air-pumping test. The results of the validated numerical model are used to evaluate the flow efficiency of a PVD extraction well. The validity of the simple analytical approach to determine air permeability based on the results of air-pumping tests is also discussed. The output of this study highlights the influence of PVD well resistance on the overall performance of soil vapour extraction systems, and the effect of the PVD's oblong cross-section on the air flow characteristics.
Relation Between the Level of American Indian and Alaska Native Diabetes Education Program Services and Quality-of-Care Indicators
Authors: Roubideaux Yvette , Noonan Carolyn , Goldberg Jack H. , Valdez S. Lorraine , Brown Tammy L. , Manson Spero M. , Acton Kelly
Published: May 2008

Objectives. We examined the relation between the level of diabetes education program services in the Indian Health Service (IHS) and indicators of the quality of diabetes care to determine if more-comprehensive diabetes services were associated with better quality of diabetes care.

Methods. In this cross-sectional study, we used the IHS Integrated Diabetes Education Recognition Program to rank program services into 1 of 3 levels of comprehensiveness, ranging from lowest (developmental) to highest (integrated). We compared quality-of-care indicators among programs of differing levels with the 2001 IHS Diabetes Care and Outcomes Audit. Quality indicators included patients having recommended yearly examinations, education, and laboratory tests and achieving recommended levels of intermediate outcomes of care.

Results. Most of the 86 participating programs were classified at or below the developmental level; only 9 programs (11%) were ranked at higher levels. After adjusting for patient characteristics, program factors, and correlation of patients within programs, we associated programs that were more comprehensive with higher completion rates of yearly lipid and hemoglobin A1C tests (P < .05).

Conclusions. System-wide improvements in diabetes education are associated with better diabetes care. The results can help inform the development of diabetes education programs.
Perceived Discrimination and Mortality in a Population-Based Study of Older Adults
Authors: Barnes Lisa L. , de Leon Carlos F. Mendes , Lewis Tené T. , Bienias Julia L. , Wilson Robert S. , Evans Denis A.
Published: May 2008

Objectives. We examined the relation of individual-level perceived discrimination to mortality in a biracial, population-based sample.

Methods. Participants were 4154 older adults from the Chicago Health and Aging Project who underwent up to 2 interviews over 4.5 years. Perceived discrimination was measured at baseline, and vital status was obtained at each follow-up and verified through the National Death Index.

Results. During follow-up, 1166 deaths occurred. Participants reporting more perceived discrimination had a higher relative risk of death (hazard ratio [HR]= 1.05; 95% confidence interval [CI]=1.01, 1.09). This association was independent of differences in negative affect or chronic illness and appeared to be stronger among Whites than among Blacks (Whites: HR=1.12; 95% CI=1.04, 1.20; Blacks: HR=1.03; 95% CI=0.99, 1.07). Secondary analyses revealed that the relation to mortality was related to discriminatory experiences of a more demeaning nature and that racial differences were no longer significant when the sample was restricted to respondents interviewed by someone of the same race.

Conclusions. Perceived discrimination was associated with increased mortality risk in a general population of older adults. The results suggest that subjective experience of interpersonal mistreatment is toxic in old age. This study adds to a growing literature documenting discrimination as an important social determinant of health.
Gender and Race/Ethnicity Differences in Lead Dose Biomarkers
Authors: Theppeang Keson , Glass Thomas A. , Bandeen-Roche Karen , Todd Andrew C. , Rohde Charles A. , Schwartz Brian S.
Published: May 2008

Objectives. We sought to identify predictors of lead concentrations in the blood, tibias, and patellae of older adults and to describe differences by gender, race/ethnicity, and other factors that can influence lead toxicokinetics and, thus modify health effects.

Methods. Participants aged 50 to 70 years (N=1140) were randomly identified from selected neighborhoods in Baltimore, Maryland. We measured lead concentrations by anodic stripping voltammetry (in blood) and 109Cd-induced K-shell x-ray fluorescence (in bone). We used multiple linear regression to identify predictors of lead concentrations.

Results. Mean (SD) lead concentrations in blood, tibias, and patellae were 3.5 (2.4) μg/dL, 18.9 (12.5) μg/g, and 6.8 (18.1) μg/g, respectively. Tibia concentrations were 29% higher in African Americans than in Whites (P < .01). We observed effect modification by race/ethnicity on the association of gender and physical activity to blood lead concentrations and by gender on the association of age to tibia lead concentrations. Patella lead concentrations differed by gender; apolipoprotein E genotype modified this relation.

Conclusions. African Americans evidenced a prominent disparity in lifetime lead dose. Women may be at higher risk of release of lead from bone and consequent health effects because of increased bone demineralization with aging.
Detection of Very Early Oral Cancers in Puerto Rico
Authors: Morse Douglas E. , Psoter Walter J. , De La Torre Feliciano Taína , Cruz Gustavo , Figueroa Nayda
Published: May 2008

We evaluated a possible disparity in the detection of very early oral cancers in Puerto Rico relative to the United States. The percentage of in situ (noninvasive) cases among all oral cancer cases was calculated separately for Puerto Rico and the United States using population-based cancer registry data (1992–2001). In situ cancers constituted 1.2% of oral cancer cases in Puerto Rico and 3.4% in the United States (P<.001). These findings suggest a disparity in very early oral cancer detection in Puerto Rico compared with the United States.