bluuebunny/crossref_metadata_2025 huggingface dataset:
From human somatic stem cells to human iPS cells – State of the art and future needs
Authors: Sakurada K.
Published: October 2009

The term environmental epigenetics refers the alterations in phenotype influenced by environmental exposures with the elucidation of epigenetic mechanisms responsible for altered gene expression. Epigenome of a stem cell is sensitive to environmental exposures. This character would cause phenotypic instability during in vitro expansion of a stem cell and disease susceptibility originated from a somatic stem cell. Although a reprogramming technology is to erase these disease‐inducing epigenetic marks, recent knowledge indicate the incompleteness of the artificial reprogramming and the physiological reprogramming.
Oral cancer screening: Practices, knowledge, and opinions of dentists working in Ohio nursing homes
Authors: Mahalaha Suparna A. , Cheruvu Vinay K. , Smyth Kathleen A.
Published: October 2009

The state of oral health of nursing homes residents is less than satisfactory. The oral health care in nursing homes is also deficient, therefore it is likely that oral cancer (OC) screening of residents will be inadequate. The purpose of this cross‐sectional study was to determine OC screening practices, knowledge, and opinions of dentists working in nursing homes throughout Ohio. A 28‐item pretested questionnaire was mailed to 75 dentists who were serving 606 nursing homes.

The response rate was 49%. The main outcome measures of interest included: OC screening practices of the Ohio dentists, their knowledge of OC detection, and their opinions regarding OC screening competency. Age was found to be a significant factor, with younger dentists being more likely to have higher knowledge scores after adjusting for all other covariates.
Two Kinds of Knowledge in Scientific Discovery
Authors: Bridewell Will , Langley Pat
Published: October 2009

Research on computational models of scientific discovery investigates both the induction of descriptive laws and the construction of explanatory models. Although the work in law discovery centers on knowledge‐lean approaches to searching a problem space, research on deeper modeling tasks emphasizes the pivotal role of domain knowledge. As an example, our own research on inductive process modeling uses information about candidate processes to explain why variables change over time. However, our experience with IPM, an artificial intelligence system that implements this approach, suggests that process knowledge is insufficient to avoid consideration of implausible models. To this end, the discovery system needs additional knowledge that constrains the model structures. We report on an extended system, SC‐IPM, that uses such information to reduce its search through the space of candidates and to produce models that human scientists find more plausible. We also argue that although people carry out less extensive search than SC‐IPM, they rely on the same forms of knowledge—processes and constraints—when constructing explanatory models.
Singchia and Gunnaria, two new genera of Orchidaceae
Authors: LIU Zhong‐Jian , CHEN Li‐Jun
Published: October 2009

Abstract  Singchia Z. J. Liu & L. J. Chen, a new orchid genus, is established based on the new species S. malipoensis Z. J. Liu & L. J. Chen found in southeast Yunnan, China. The new genus is related to Pteroceras, from which it differs by having a lip with its basal margins immovably adnate to the lower part of the pendent column foot, a thin‐walled spur, and very unequally and deeply split pollinia, each with a distinct caudicle. In addition to a discussion on Ascocentrum pusillum, a species of questionable placement, another new genus, namely Gunnaria S. C. Chen ex Z. J. Liu & L. J. Chen, is set up and a new combination, namely G. pusilla (Aver.) Z. J. Liu & L. J. Chen, is made. The new genus Gunnaria differs from its ally Ascocentrum by having a cross‐shaped pollinarium, sulcate or split pollinia, each with a distinct caudicle attached to a common linear stipe much longer than either pollinia or viscidium, and strongly incurved side lobes of the lip.
The Effect of Delayed Incentives on Supply Chain Profits and Consumer Surplus
Authors: Khouja Moutaz , Zhou Jing
Published: October 2009

We examine the use of consumer cash mail‐in rebates offered by a manufacturer in a Stackelberg game where the manufacturer is the leader and the retailer is the follower. Our analysis indicates that rebates are profitable for manufacturers if consumers are inconsistent in the sense that their rebate valuation when they make purchase decisions is independent of their redemption probabilities when they make redemption decisions. If the manufacturer keeps the wholesale price unchanged, then the rebate increases the retailer's profit by a larger amount than the increase in the manufacturer's profit. If the manufacturer jointly optimizes the wholesale price and rebate, then the increase in the manufacturer's profit is twice the increase in the retailer's profit. The retailer responds to rebates by increasing the retail price, which increases the margin paid by consumers who do not redeem the rebate. On average, consumer surplus decreases when it is optimal for manufacturers to offer rebates. We suggest incentive schemes that make it worthwhile for retailers to limit the price increase. In these incentive schemes, the manufacturer imposes a negative relationship between the rebate value and the retail price. We show that such incentives increase supply chain profits.
Fabrication and Modeling of Dynamic Multipolymer Nanofibrous Scaffolds
Authors: Baker Brendon M. , Nerurkar Nandan L. , Burdick Jason A. , Elliott Dawn M. , Mauck Robert L.
Published: October 2009

Aligned nanofibrous scaffolds hold tremendous potential for the engineering of dense connective tissues. These biomimetic micropatterns direct organized cell-mediated matrix deposition and can be tuned to possess nonlinear and anisotropic mechanical properties. For these scaffolds to function in vivo, however, they must either recapitulate the full dynamic mechanical range of the native tissue upon implantation or must foster cell infiltration and matrix deposition so as to enable construct maturation to meet these criteria. In our recent studies, we noted that cell infiltration into dense aligned structures is limited but could be expedited via the inclusion of a distinct rapidly eroding sacrificial component. In the present study, we sought to further the fabrication of dynamic nanofibrous constructs by combining multiple-fiber populations, each with distinct mechanical characteristics, into a single composite nanofibrous scaffold. Toward this goal, we developed a novel method for the generation of aligned electrospun composites containing rapidly eroding (PEO), moderately degradable (PLGA and PCL/PLGA), and slowly degrading (PCL) fiber populations. We evaluated the mechanical properties of these composites upon formation and with degradation in a physiologic environment. Furthermore, we employed a hyperelastic constrained-mixture model to capture the nonlinear and time-dependent properties of these scaffolds when formed as single-fiber populations or in multipolymer composites. After validating this model, we demonstrated that by carefully selecting fiber populations with differing mechanical properties and altering the relative fraction of each, a wide range of mechanical properties (and degradation characteristics) can be achieved. This advance allows for the rational design of nanofibrous scaffolds to match native tissue properties and will significantly enhance our ability to fabricate replacements for load-bearing tissues of the musculoskeletal system.
Using a Modified Failure Modes and Effects Analysis Within the Structured Design Recovery Framework
Authors: Urbanic R. J. , ElMaraghy W. H.
Published: October 2009

Design recovery is defined as determining the relevant form and functions and their relationships for a component in order to generate a complete engineering representation. To lead to a more complete model, an integrated approach that assesses the component from different perspectives is presented here, as no one perspective or set of tools can provide a comprehensive engineering representation. There is always the potential for error; hence, the necessity to assess latent design and/or design recovery issues in rigorous manner. A modified failure modes and effects analysis (FMEA) was developed to provide a foundation for the reconstructed model’s design validation. The modified FMEA is designed to interface directly with the design recovery framework. A matrix based procedure, which considers feature functions and relationships, is developed to assist the designer to quickly assess the feature design using a consistent structured approach. The results are plotted, and subsequent testing strategies are suggested based on the characteristics of the features being assessed. Examples illustrate the proposed methodologies and highlight their merits.
Failure of Brittle and Ductile Hard Disks Due to High Shock Levels
Authors: Xu Jianfeng , Etsion Izhak , Talke Frank E.
Published: October 2009

The failure due to accidental drop of magnetic recording disks made of brittle or ductile materials is of great interest in the design of small form factor hard disk drives. In this study, fracture of glass disks (brittle material) and plastic deformation of aluminum disks (ductile material) at very high shock levels caused by accidental drop are investigated using finite element analysis. It is found that failure inception for both disk types occurs at the inside perimeter of the disk. For glass disks, cracks are found to propagate toward the outer perimeter of the disk along distinct radial lines associated with the largest bending moment of the disk. The critical shock level at which failure originates increases with an increase in the clamp diameter, a reduction in the disk diameter, and an increase in the thickness of the disk. Some experimental results are presented to validate the numerical model.
A Systematic Approach for Designing Multifunctional Thermally Conducting Polymer Structures With Embedded Actuators
Authors: Bejgerowski Wojciech , Gupta Satyandra K. , Bruck Hugh A.
Published: October 2009

Thermally conductive filled polymers enable the creation of multifunctional structures that offer both anchoring points for the embedded actuators, as well as heat-dissipation functions, in order to facilitate the miniaturization of devices. However, there are two important challenges in creating these structures: (1) sufficient thermal management to prevent failure of the actuator and (2) the ability of the actuator to survive the manufacturing process. This paper describes a systematic approach for design of multifunctional structures with embedded heat-generating components using an in-mold assembly process to address these challenges. For the first challenge, the development of appropriate thermal models is presented along with incorporation of in-mold assembly process constraints in the optimization process. For the second challenge, a simulation of the molding process is presented and demonstrated to enable the determination of processing conditions ensuring survival of the in-mold assembly process for the embedded actuator. Thus, the design methodology described in this paper was utilized to concurrently optimize the choice of material, size of the structure, and processing conditions in order to demonstrate the feasibility of creating multifunctional structures from thermally conductive polymers by embedding actuators through an in-mold assembly process.
Arvid Carlsson: An Early Pioneer in Translational Medicine
Authors: Andersen Julie K.
Published: October 2009

Translational medicine has recently experienced an upsurge in interest and funding, yet the idea is not new. More than half a century ago, the Swedish scientist Arvid Carlsson performed basic research on the neurotransmitter dopamine that was rapidly translated into the first clinical treatment for Parkinson ’s disease. For his contributions, Carlsson shared the Nobel Prize in Physiology or Medicine in the year 2000.
More Than Baby Steps: Perspectives on Pediatric Translational Research
Authors: Connor Edward , Lombardi Donald , van den Anker John
Published: October 2009

The challenges of product development and the unique issues that pertain to pediatric research represent both obstacles to and opportunities for the translation of scientific knowledge into advancements in pediatric clinical medicine.
Extreme Polymorphism in a Vaccine Antigen and Risk of Clinical Malaria: Implications for Vaccine Development
Authors: Takala Shannon L. , Coulibaly Drissa , Thera Mahamadou A. , Batchelor Adrian H. , Cummings Michael P. , Escalante Ananias A. , Ouattara Amed , Traoré Karim , Niangaly Amadou , Djimdé Abdoulaye A. , Doumbo Ogobara K. , Plowe Christopher V.
Published: October 2009

Children from Mali who are repeatedly infected with malaria are more likely to get sick if the parasite is highly variable, a possible obstacle to an effective vaccine.
New Target for Anti-Leukemia Attack
Authors: McDonald Heather B.
Published: October 2009

Complementary proteomic and genetic experiments identify a possible therapeutic strategy for acute myeloid leukemia.
Temporal Variation of Bacterial Respiration and Growth Efficiency in Tropical Coastal Waters
Authors: Lee Choon Weng , Bong Chui Wei , Hii Yii Siang
Published: October 2009

We investigated the temporal variation of bacterial production, respiration, and growth efficiency in the tropical coastal waters of Peninsular Malaysia. We selected five stations including two estuaries and three coastal water stations. The temperature was relatively stable (averaging around 29.5°C), whereas salinity was more variable in the estuaries. We also measured dissolved organic carbon and nitrogen (DOC and DON, respectively) concentrations. DOC generally ranged from 100 to 900 μM, whereas DON ranged from 0 to 32 μM. Bacterial respiration ranged from 0.5 to 3.2 μM O
2
h
−1
, whereas bacterial production ranged from 0.05 to 0.51 μM C h
−1
. Bacterial growth efficiency was calculated as bacterial production/(bacterial production + respiration), and ranged from 0.02 to 0.40. Multiple correlation analyses revealed that bacterial production was dependent upon primary production (

r
2

= 0.169, df = 31, and
P
< 0.02) whereas bacterial respiration was dependent upon both substrate quality (i.e., DOC/DON ratio) (

r
2

= 0.137, df = 32, and
P
= 0.03) and temperature (

r
2

= 0.113, df = 36, and
P
= 0.04). Substrate quality was the most important factor (

r
2

= 0.119, df = 33, and
P
= 0.04) for the regulation of bacterial growth efficiency. Using bacterial growth efficiency values, the average bacterial carbon demand calculated was from 5.30 to 11.28 μM C h
−1
. When the bacterial carbon demand was compared with primary productivity, we found that net heterotrophy was established at only two stations. The ratio of bacterial carbon demand to net primary production correlated significantly with bacterial growth efficiency (

r
2

= 0.341, df = 35, and
P
< 0.001). From nonlinear regression analysis, we found that net heterotrophy was established when bacterial growth efficiency was <0.08. Our study showed the extent of net heterotrophy in these waters and illustrated the importance of heterotrophic microbial processes in coastal aquatic food webs.
Protistan Predation Affects Trichloroethene Biodegradation in a Bedrock Aquifer
Authors: Cunningham Joseph J. , Kinner Nancy E. , Lewis Maureen
Published: October 2009

Despite extensive research on the bottom-up force of resource availability (e.g., electron donors and acceptors), slow biodegradation rates and stalling at
cis
-dichloroethene (cDCE) and vinyl chloride continue to be observed in aquifers contaminated with trichloroethene (TCE). The objective of this research was to gauge the impact of the top-down force of protistan predation on TCE biodegradation in laboratory microcosms. When indigenous bacteria from an electron donor-limited TCE-contaminated bedrock aquifer were present, the indigenous protists inhibited reductive dechlorination altogether. The presence of protists during organic carbon-amended conditions caused the bacteria to elongate (length:width, ≥10:1), but reductive dechlorination was still inhibited. When a commercially available dechlorinating bacterial culture and an organic carbon amendment were added in he presence of protists, the elongated bacteria predominated and reductive dechlorination stalled at cDCE. When protists were removed under organic carbon-amended conditions, reductive dechlorination stalled at cDCE, whereas in the presence organic carbon and bacterial amendments, the total chlorinated ethene concentration decreased, indicating TCE was converted to ethene and/or CO
2
. The data suggested that indigenous protists grazed dechlorinators to extremely low levels, inhibiting dechlorination altogether. Hence, in situ bioremediation/bioaugmentation may not be successful in mineralizing TCE unless the top-down force of protistan predation is inhibited.
Occupational determinants of serum cholinesterase inhibition among organophosphate-exposed agricultural pesticide handlers in Washington State
Authors: Hofmann Jonathan N , Keifer Matthew C , De Roos Anneclaire J , Fenske Richard A , Furlong Clement E , van Belle Gerald , Checkoway Harvey
Published: October 2009

Objective

To identify potential risk factors for serum cholinesterase (BuChE) inhibition among agricultural pesticide handlers exposed to organophosphate (OP) and N-methyl-carbamate (CB) insecticides.

Methods

We conducted a longitudinal study among 154 agricultural pesticide handlers who participated in the Washington State cholinesterase monitoring program in 2006 and 2007. BuChE inhibition was analysed in relation to reported exposures before and after adjustment for potential confounders using linear regression. ORs estimating the risk of BuChE depression (>20% from baseline) were also calculated for selected exposures based on unconditional logistic regression analyses.

Results

An overall decrease in mean BuChE activity was observed among study participants at the time of follow-up testing during the OP/CB spray season relative to pre-season baseline levels (mean decrease of 5.6%, p<0.001). Score for estimated cumulative exposure to OP/CB insecticides in the past 30 days was a significant predictor of BuChE inhibition (β=−1.74, p<0.001). Several specific work practices and workplace conditions were associated with greater BuChE inhibition, including mixing/loading pesticides and cleaning spray equipment. Factors that were protective against BuChE inhibition included full-face respirator use, wearing chemical-resistant boots and storing personal protective equipment in a locker at work.

Conclusions

Despite existing regulations, agricultural pesticide handlers continue to be exposed to OP/CB insecticides at levels resulting in BuChE inhibition. These findings suggest that modifying certain work practices could potentially reduce BuChE inhibition. Replication from other studies will be valuable.
THE DIMENSION OF A VARIETY AND THE KERNEL OF A HYPERSUBSTITUTION
Authors: DENECKE K. , WISMATH S. L.
Published: October 2009

The dimension of a variety V of algebras of a given type was introduced by E. Graczyńska and D. Schweigert in [7] as the cardinality of the set of all derived varieties of V which are properly contained in V. In this paper, we characterize all solid varieties of dimensions 0, 1, and 2; prove that the dimension of a variety of finite type is at most ℵ0; give an example of a variety which has infinite dimension; and show that for every n ∈ ℕ there is a variety with dimension n. Finally, we show that the dimension of a variety is related to the concept of the semantical kernel of a hypersubstitution and apply this connection to calculate the dimension of the class of all algebras of type τ = (n).
WHAT'S SMALL SIZE GOT TO DO WITH IT? PROTECTION OF INTELLECTUAL ASSETS IN SMEs
Authors: OLANDER HEIDI , HURMELINNA-LAUKKANEN PIA , MÄHÖNEN JUKKA
Published: October 2009

The knowledge protection/sharing dilemma related to innovation activities is becoming known to all firms, even though it is generally more notable for SMEs: the small size of the firms inherently creates a need for inter-organizational collaboration, but it also makes dealing with the related contradictories more challenging. One factor behind this is that the needed tools — such as the protection mechanisms of intellectual assets — may be more limited. In line with this notion, we examine the protection available for and used by small firms in their innovation activities. We approach the issue by conducting a review on the relevant literature, and use a qualitative multiple case study conducted in eight small companies to empirically study the issue. Departing from prior research, we consider protection of innovations by distinguishing between the intangibles needed in innovation activities and the actual innovation outputs, and combine these considerations to the knowledge protection/sharing dilemma.
THE EFFECTS OF TEACHER FIRMS' CHARACTERISTICS AND STUDENT FIRMS' ABSORPTIVE CAPACITY ON FIRM PERFORMANCE IN TECHNOLOGY ALLIANCES
Authors: PARK GUNNO , KANG JINA
Published: October 2009

With the dramatically changing technology and market environments, the importance of technology alliance to develop new products and technologies by utilizing firms' external knowledge has increased. In order to provide insight on the relationship between teacher characteristics and technology alliance performances, this study conceptualized an alliance structure according to Lane and Lubatkin's 'dyadic construct,' consisting of student firms which absorb knowledge and teacher firms that transfer knowledge. Then we analyzed the relationship between teacher firms' relative characteristics and student firms' performance of the technology alliance, using the empirical data of the Korean IT firms that are listed on Korean stock market during 1999–2005. From this analysis, we find that teacher characteristics, such as technology capability, technology similarity, and capability for knowledge transfer, influence the performance of technology alliance.
The detachment era (1977–1982) and its role in revolutionizing continental tectonics
Authors: Wernicke B.
Published: October 2009

After the discovery of thrust-and-nappe structure near the turn of the twentieth century, mountain belts were viewed as a direct expression of horizontal shortening of the continental crust, and continental rifting was viewed as a phenomenon distinct from it. By mid-century, broad consensus had emerged, mainly on the basis of physical reasoning, that thrust-and-nappe structure instead reflected gravity sliding secondary to vertical motions of the crust, as embodied in the influential
stockwerk
folding hypothesis. In a noteworthy period from 1977 to 1982, informally referred to here as the ‘detachment era’, not only did the last vestiges of support for the
stockwerk
hypothesis evaporate, but large-magnitude extension was discovered throughout the Cordillera, manifest primarily by extensional detachments and metamorphic core complexes. Soon afterward extensional detachments were recognized as a global phenomenon, forcing first-order reinterpretation of field relations in most orogens. Although plate tectonics is indisputably the most profound discovery in Earth sciences in the twentieth century, the detachment era arguably had commensurate impact on field-based interpretations of continental tectonics. Three decades later, controversy persists over the origin of metamorphic tectonites in core complexes, and over the existence and mechanics of slip on shallowly dipping extensional detachments.
Sensory Recalibration of Hand Position Following Visuomotor Adaptation
Authors: Cressman Erin K. , Henriques Denise Y. P.
Published: October 2009

Goal-directed reaches are rapidly adapted following exposure to misaligned visual feedback of the hand. It has been suggested that these changes in reaches result in sensory recalibration (i.e., realigning proprioceptive estimates of hand position to match the visual estimates). In the current study we tested whether visuomotor adaptation results in recalibration of hand proprioception by comparing subjects' estimates of the position at which they felt their hand was aligned with a reference marker (visual or proprioceptive) before and after aiming with a misaligned cursor. The misaligned cursor was either translated or rotated to the right of the actual hand location. On the estimation trials, we did not allow subjects to freely move their hands into position. Instead, a robot manipulandum either passively positioned the hand ( experiments 1 and 2) or subjects moved their hand along a robot-generated constrained pathway ( experiments 3 and 4). We found that regardless of experimental manipulation, subjects' proprioceptive estimates of hand position were more biased to the left after visuomotor adaptation. The leftward shift in subjects' estimates was in the same direction and one third of the magnitude of the adapted movement. This suggests that in addition to recalibrating the sensorimotor transformations underlying reaching movements, visuomotor adaptation results in partial proprioceptive recalibration.
Candidate Gene Association Study of Esophageal Squamous Cell Carcinoma in a High-Risk Region in Iran
Authors: Akbari Mohammad R. , Malekzadeh Reza , Shakeri Ramin , Nasrollahzadeh Dariush , Foumani Maryam , Sun Yulong , Pourshams Akram , Sadjadi Alireza , Jafari Elham , Sotoudeh Masoud , Kamangar Farin , Boffetta Paolo , Dawsey Sanford M. , Ghadirian Parviz , Narod Steven A.
Published: October 2009

There is a region with a high risk for esophageal squamous cell carcinoma (ESCC) in the northeast of Iran. Previous studies suggest that hereditary factors play a role in the high incidence of cancer in the region. We selected 22 functional variants (and 130 related tagSNPs) from 15 genes that have been associated previously with the risk of ESCC. We genotyped a primary set of samples from 451 Turkmens (197 cases and 254 controls). Seven of 152 variants were associated with ESCC at the P = 0.05 level; these single nucleotide polymorphisms were then studied in a validation set of 549 cases and 1,119 controls, which included both Turkmens and non-Turkmens. The association observed for a functional variant in ADH1B was confirmed in the validation set, and that of a tagSNP in MGMT, the association was borderline significant in the validation set, after correcting for multiple testing. The other 5 variants that were associated in the primary set were not significantly associated in the validation set. The histidine allele at codon 48 of ADH1B gene was associated with a significantly decreased risk of ESCC in the joint data set (primary and validation set) under a recessive model (odds ratio, 0.41; 95% confidence interval, 0.29-0.76; P = 4 × 10−4). The A allele of the rs7087131 variant of MGMT gene was associated with a decreased risk of ESCC under a dominant model (odds ratio, 0.79; 95% confidence interval, 0.64-0.96; P = 0.02). These results support the hypothesis that genetic predisposition plays a role in the high incidence of ESSC in Iran. [Cancer Res 2009;69(20):7994–8000]
Role for Krüppel-Like Factor 4 in Determining the Outcome of p53 Response to DNA Damage
Authors: Zhou Qibing , Hong Yuan , Zhan Qimin , Shen Yan , Liu Zhihua
Published: October 2009

Cells are incessantly exposed to many sources of genotoxic stress. A critical unresolved issue is how the resulting activation of the p53 tumor suppressor can lead to either cell cycle arrest or apoptosis depending on the extent of DNA damage. The present study shows that the level of Krüppel-like factor 4 (KLF4) expression is inversely correlated with the extent of DNA damage. KLF4 is activated by p53 following cytostatic, mild DNA damage, whereas it is strongly repressed via enhanced turnover of mRNA on severe DNA damage that irreversibly drives cells to apoptosis. Blocking the repression of KLF4 on severe DNA damage suppresses p53-mediated apoptosis, whereas ablation of the KLF4 induction on mild DNA damage shifts the p53 response from cell cycle arrest to cell death. Our results suggest that coordinate regulation of KLF4 expression depending on the extent of DNA damage may be an important mechanism that dictates the life and death decisions of p53. [Cancer Res 2009;69(21):8284–92]
Inhibition of Azoxymethane-Induced Colorectal Cancer by CP-31398, a TP53 Modulator, Alone or in Combination with Low Doses of Celecoxib in Male F344 Rats
Authors: Rao Chinthalapally V. , Steele Vernon E. , Swamy Malisetty V. , Patlolla Jagan M.R. , Guruswamy Suresh , Kopelovich Levy
Published: October 2009

Tumor suppressor p53 plays a major role in colorectal cancer development. The present study explores the effects of p53-modulating agent CP-31398 alone and combined with celecoxib on azoxymethane-induced aberrant crypt foci (ACF) and colon adenocarcinomas in F344 rats. Maximum tolerated doses were 400 and 3,000 ppm for CP-31398 and celecoxib, respectively. ACF and tumor efficacy endpoints were carried out on azoxymethane-treated 7-week-old rats (48 per group) fed the control AIN-76A diet. Two weeks after carcinogen treatment, rats were fed the diets containing 0, 150, or 300 ppm CP-31398, 300 ppm celecoxib, or 150 ppm CP-31398 plus 300 ppm celecoxib. ACF and colon adenocarcinomas were determined at 8 and 48 weeks after azoxymethane treatment, respectively. Dietary CP-31398 was shown to suppress mean colonic total ACF by 43% and multicrypt ACF by 63%; dietary CP-31398 at 150 and 300 ppm suppressed adenocarcinoma incidence by 30.4% (P < 0.02) and 44% (P < 0.005), respectively, and adenocarcinoma multiplicity by 51% (P < 0.005) and 65% (P < 0.0001), respectively. Dietary celecoxib suppressed colon adenocarcinoma incidence (60%; P < 0.0003) and multiplicity (70%; P < 0.0001). Importantly, combination of low-dose CP-31398 and celecoxib suppressed colon adenocarcinoma incidence by 78% and multiplicity by 90%. Rats that were fed the high-dose CP-31398 or a combination of low-dose CP-31398 and celecoxib showed considerable enhancement of p53 and p21WAF1/CIP expression, apoptosis, and reduced tumor cell proliferation in colonic tumors. These observations show, for the first time, that CP-31398 possesses significant dose-dependent chemopreventive activity in a well-established colon cancer model and that a combination of low-dose CP-31398 and celecoxib significantly enhanced colon cancer chemopreventive efficacy. [Cancer Res 2009;69(20):8175–82]
Inhibition of the Androgen Receptor as a Novel Mechanism of Taxol Chemotherapy in Prostate Cancer
Authors: Gan Lu , Chen Shuai , Wang Yuwei , Watahiki Akira , Bohrer Laura , Sun Zhen , Wang Yuzhuo , Huang Haojie
Published: October 2009

Taxol chemotherapy is one of the few therapeutic options for men with castration-resistant prostate cancer (CRPC). However, the working mechanisms for Taxol are not fully understood. Here, we showed that treatment of 22Rv1, a PTEN-positive CRPC cell line, with paclitaxel and its semisynthetic analogue docetaxel decreases expression of the androgen receptor (AR)–activated genes prostate-specific antigen (PSA) and Nkx3.1 but increases expression of the AR repression gene maspin, suggesting that Taxol treatment inhibits AR activity. This was further supported by the observation that the activity of AR luciferase reporter genes was inhibited by paclitaxel. In contrast, paclitaxel treatment failed to inhibit AR activity in the PTEN-null CRPC cell line C4-2. However, pretreatment of C4-2 cells with the phosphoinositide 3-kinase inhibitor LY294002 restored paclitaxel inhibition of the AR. Treatment of 22Rv1 xenografts in mice with docetaxel induced mitotic arrest and a decrease in PSA expression in tumor cells adjacent to vascular vessels. We further showed that paclitaxel induces nuclear accumulation of FOXO1, a known AR suppressive nuclear factor, and increases the association of FOXO1 with AR proteins in the nucleus. FOXO1 knockdown with small interfering RNA attenuated the inhibitory effect of paclitaxel on AR transcriptional activity, expression of PSA and Nkx3.1, and cell survival. These data reveal a previously uncharacterized, FOXO1-mediated, AR-inhibitory effect of Taxol in CRPC cells that may play an important role in Taxol-mediated inhibition of CRPC growth. [Cancer Res 2009;69(21):8386–94]
Widespread Estrogen-Dependent Repression of microRNAs Involved in Breast Tumor Cell Growth
Authors: Maillot Gérard , Lacroix-Triki Magali , Pierredon Sandra , Gratadou Lise , Schmidt Sabine , Bénès Vladimir , Roché Henri , Dalenc Florence , Auboeuf Didier , Millevoi Stefania , Vagner Stéphan
Published: October 2009

Altered expression of microRNAs (miRNA), an abundant class of small nonprotein-coding RNAs that mostly function as negative regulators of protein-coding gene expression, is common in cancer. Here, we analyze the regulation of miRNA expression in response to estrogen, a steroid hormone that is involved in the development and progression of breast carcinomas and that is acting via the estrogen receptors (ER) transcription factors. We set out to thoroughly describe miRNA expression, by using miRNA microarrays and real-time reverse transcription-PCR (RT-PCR) experiments, in various breast tumor cell lines in which estrogen signaling has been induced by 17β-estradiol (E2). We show that the expression of a broad set of miRNAs decreases following E2 treatment in an ER-dependent manner. We further show that enforced expression of several of the repressed miRNAs reduces E2-dependent cell growth, thus linking expression of specific miRNAs with estrogen-dependent cellular response. In addition, a transcriptome analysis revealed that the E2-repressed miR-26a and miR-181a regulate many genes associated with cell growth and proliferation, including the progesterone receptor gene, a key actor in estrogen signaling. Strikingly, miRNA expression is also regulated in breast cancers of women who had received antiestrogen neoadjuvant therapy. Overall, our data indicate that the extensive alterations in miRNA regulation upon estrogen signaling pathway play a key role in estrogen-dependent functions and highlight the utility of considering miRNA expression in the understanding of antiestrogen resistance of breast cancer. [Cancer Res 2009;69(21):8332–40]
Cross-Talk between Estrogen Receptor and Epidermal Growth Factor Receptor in Head and Neck Squamous Cell Carcinoma
Authors: Egloff Ann Marie , Rothstein Mary E. , Seethala Raja , Siegfried Jill M. , Grandis Jennifer Rubin , Stabile Laura P.
Published: October 2009

Purpose: This study aimed to characterize estrogen receptor expression and signaling in head and neck squamous cell carcinoma (HNSCC) cell lines and patient tissues, and to evaluate estrogen receptor and epidermal growth factor (EGF) receptor (EGFR) cross-activation in HNSCC.

Experimental Design: Estrogen receptor expression and signaling in HNSCC cell lines were assessed by immunoblotting. In vitro proliferation and invasion were evaluated in HNSCC cell lines in response to estrogen receptor and EGFR ligands or inhibitors. Estrogen receptor and EGFR protein expression in patient tissues was assessed by immunohistochemical staining.

Results: Phospho–mitogen-activated protein kinase (P-MAPK) levels were significantly increased following combined estrogen and EGF treatment. Treatment of HNSCC cells with estrogen and EGF significantly increased cell invasion compared with either treatment alone, whereas inhibiting these two pathways resulted in reduced invasion compared with inhibiting either pathway alone. EGFR (P = 0.008) and nuclear estrogen receptor α (ERαnuc; P < 0.001) levels were significantly increased in HNSCC tumors (n = 56) compared with adjacent mucosa (n = 30), whereas nuclear estrogen receptor β (ERβnuc) levels did not differ (P = 0.67). Patients with high ERαnuc and EGFR tumor levels had significantly reduced progression-free survival compared with patients with low tumor ERαnuc and EGFR levels (hazards ratio, 4.09; P = 0.01; Cox proportional hazards). In contrast, high ERβnuc tumor levels were not associated with reduced progression-free survival alone or when combined with EGFR.

Conclusions: ERα and ERβ were expressed in HNSCC, and stimulation with estrogen receptor ligands resulted in both cytoplasmic signal transduction and transcriptional activation. Estrogen receptor and EGFR cross-talk was observed. Collectively, these studies indicate that estrogen receptor and EGFR together may contribute to HNSCC development and disease progression. (Clin Cancer Res 2009;15(21):6529–40)
Trastuzumab: A Picky Partner?
Authors: McArthur Heather L. , Hudis Clifford A.
Published: October 2009

Preclinical and clinical models of HER2-positive breast cancer show that human epidermal growth factor receptor 2 (HER2)-targeted therapy with trastuzumab adds significant benefits and modest risks to conventional cytotoxic therapies. Building on this advance will likely depend on elucidation of relevant signaling pathways and mechanisms of action for effective HER2-targeted therapies. (Clin Cancer Res 2009;15(20):6311–3)
Estrogen Receptor–Negative Breast Cancer: New Insights into Subclassification and Targeting
Authors: Zhao Jean J. , Silver Daniel P.
Published: October 2009

Classification schemes for disease states can help identify distinctions with useful implications for therapy and prognosis. Speers and colleagues provide a new subclassification scheme for estrogen receptor-negative breast cancer based upon kinome-wide gene expression profiling with interesting findings that are potentially relevant for both treatment and clinical outcome. (Clin Cancer Res 2009;15(20):6309–10)
PU.1 Activation Relieves GATA-1–Mediated Repression of Cebpa and Cbfb during Leukemia Differentiation
Authors: Burda Pavel , Curik Nikola , Kokavec Juraj , Basova Petra , Mikulenkova Dana , Skoultchi Arthur I. , Zavadil Jiri , Stopka Tomas
Published: October 2009

Hematopoietic transcription factors GATA-1 and PU.1 bind each other on DNA to block transcriptional programs of undesired lineage during hematopoietic commitment. Murine erythroleukemia (MEL) cells that coexpress GATA-1 and PU.1 are blocked at the blast stage but respond to molecular removal (downregulation) of PU.1 or addition (upregulation) of GATA-1 by inducing terminal erythroid differentiation. To test whether GATA-1 blocks PU.1 in MEL cells, we have conditionally activated a transgenic PU.1 protein fused with the estrogen receptor ligand-binding domain (PUER), resulting in activation of a myeloid transcriptional program. Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein α (Cebpa) and core-binding factor, β subunit (Cbfb), which encode two key hematopoietic transcription factors. Inhibition of GATA-1 by small interfering RNA resulted in derepression of PU.1 target genes. Chromatin immunoprecipitation and reporter assays identified PU.1 motif sequences near Cebpa and Cbfb that are co-occupied by PU.1 and GATA-1 in the leukemic blasts. Significant derepression of Cebpa and Cbfb is achieved in MEL cells by either activation of PU.1 or knockdown of GATA-1. Furthermore, transcriptional regulation of these loci by manipulating the levels of PU.1 and GATA-1 involves quantitative increases in a transcriptionally active chromatin mark: acetylation of histone H3K9. Collectively, we show that either activation of PU.1 or inhibition of GATA-1 efficiently reverses the transcriptional block imposed by GATA-1 and leads to the activation of a myeloid transcriptional program directed by PU.1. (Mol Cancer Res 2009;7(10):1693–703)
H3 Histamine Receptor–Mediated Activation of Protein Kinase Cα Inhibits the Growth of CholangiocarcinomaIn vitroandIn vivo
Authors: Francis Heather , Onori Paolo , Gaudio Eugenio , Franchitto Antonio , DeMorrow Sharon , Venter Julie , Kopriva Shelley , Carpino Guido , Mancinelli Romina , White Mellanie , Meng Fanyin , Vetuschi Antonella , Sferra Roberta , Alpini Gianfranco
Published: October 2009

Histamine regulates functions via four receptors (HRH1, HRH2, HRH3, and HRH4). The d-myo-inositol 1,4,5-trisphosphate (IP3)/Ca2+/protein kinase C (PKC)/mitogen-activated protein kinase pathway regulates cholangiocarcinoma growth. We evaluated the role of HRH3 in the regulation of cholangiocarcinoma growth. Expression of HRH3 in intrahepatic and extrahepatic cell lines, normal cholangiocytes, and human tissue arrays was measured. In Mz-ChA-1 cells stimulated with (R)-(α)-(−)-methylhistamine dihydrobromide (RAMH), we measured (a) cell growth, (b) IP3 and cyclic AMP levels, and (c) phosphorylation of PKC and mitogen-activated protein kinase isoforms. Localization of PKCα was visualized by immunofluorescence in cell smears and immunoblotting for PKCα in cytosol and membrane fractions. Following knockdown of PKCα, Mz-ChA-1 cells were stimulated with RAMH before evaluating cell growth and extracellular signal–regulated kinase (ERK)-1/2 phosphorylation. In vivo experiments were done in BALB/c nude mice. Mice were treated with saline or RAMH for 44 days and tumor volume was measured. Tumors were excised and evaluated for proliferation, apoptosis, and expression of PKCα, vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF receptor 2, and VEGF receptor 3. HRH3 expression was found in all cells. RAMH inhibited the growth of cholangiocarcinoma cells. RAMH increased IP3 levels and PKCα phosphorylation and decreased ERK1/2 phosphorylation. RAMH induced a shift in the localization of PKCα expression from the cytosolic domain into the membrane region of Mz-ChA-1 cells. Silencing of PKCα prevented RAMH inhibition of Mz-ChA-1 cell growth and ablated RAMH effects on ERK1/2 phosphorylation. In vivo, RAMH decreased tumor growth and expression of VEGF and its receptors; PKCα expression was increased. RAMH inhibits cholangiocarcinoma growth by PKCα-dependent ERK1/2 dephosphorylation. Modulation of PKCα by histamine receptors may be important in regulating cholangiocarcinoma growth. (Mol Cancer Res 2009;7(10):1704–13)
Hepatitis B-Associated Acute Liver Failure: Immediate Treatment with Entecavir Inhibits Hepatitis B Virus Replication and Potentially Its Sequelae
Authors: Jochum Christoph , Gieseler Robert K. , Gawlista Isabella , Fiedler A. , Manka Paul , Saner Fuat H. , Roggendorf Michael , Gerken Guido , Canbay Ali
Published: October 2009

Background: Acute hepatitis B virus (HBV) infection is followed by high viral replication rates leading to hepatocyte death and ultimately, in some cases, to acute liver failure (ALF) necessitating liver transplantation. Thus, the objective of treating HBV-induced ALF is to eliminate or significantly suppress HBV replication. Methods/Results: This prospective study (02/2008–02/2009) included 6 patients (1 female and 5 males, median age 35.5 years). HBV DNA and hepatitis B surface antigen (HBsAg) levels were detected, and hepatocyte death was quantified in patients’ sera by (a) M65 ELISA and (b) M30 ELISA. All patients received entecavir treatment at 1 mg daily within 1–18 days after admission. Upon treatment, pathologic parameters rapidly decreased and returned to normal values or trace amounts (HBV DNA) within 3 months in all of the cases. A seroconversion to anti-HBsAg was achieved in 5 out of 6 patients; one patient with late onset of treatment did not seroconvert. M65 and the difference of M65-M30 as a marker for cell necrosis dropped significantly within 1 week of treatment. Conclusion: This preliminary series of 6 patients reveals that immediate treatment of HBV-induced ALF with entecavir is well tolerated and beneficially affects the course of the disease.
Human Factors in Surgery: From Three Mile Island to the Operating Room
Authors: D’Addessi Alessandro , Bongiovanni Luca , Volpe Andrea , Pinto Francesco , Bassi PierFrancesco
Published: October 2009

Human factors is a definition that includes the science of understanding the properties of human capability, the application of this understanding to the design and development of systems and services, the art of ensuring their successful applications to a program. The field of human factors traces its origins to the Second World War, but Three Mile Island has been the best example of how groups of people react and make decisions under stress: this nuclear accident was exacerbated by wrong decisions made because the operators were overwhelmed with irrelevant, misleading or incorrect information. Errors and their nature are the same in all human activities. The predisposition for error is so intrinsic to human nature that scientifically it is best considered as inherently biologic. The causes of error in medical care may not be easily generalized. Surgery differs in important ways: most errors occur in the operating room and are technical in nature. Commonly, surgical error has been thought of as the consequence of lack of skill or ability, and is the result of thoughtless actions. Moreover the ‘operating theatre’ has a unique set of team dynamics: professionals from multipledisciplines are required to work in a closely coordinated fashion. This complex environment provides multiple opportunities for unclear communication, clashing motivations, errors arising not from technical incompetence but from poor interpersonal skills. Surgeons have to work closely with human factors specialists in future studies. By improving processes already in place in many operating rooms, safety will be enhanced and quality increased.
Methodology of Superficial Bladder Cancer Trials: Objective Evaluation of Treatment – The Need for Standardization
Authors: Bassi P.F. , Volpe A. , Racioppi M. , D’Agostino D. , Gardi M. , Totaro A. , Pinto F. , Sacco E. , Bongiovanni L.
Published: October 2009

The formulation of proper evaluation criteria after superficial bladder cancer therapy poses several methodological problems that are often peculiar to the disease. The Achilles’ heel of many trials is possibly found in the criteria used in the evaluation of the trial’s outcome. As a consequence, total agreement regarding the criteria for response and the evaluation of response is needed. The adoption of standard response criteria should be given high priority. Uniform criteria of response should be chosen because they meet standards of reliability and statistical validity. Thus, the criteria must be reproducible and correlate with some measures of patient benefit such as quantity and quality of survival. A proposal for standardization in superficial bladder cancer clinical trials is presented based upon the current knowledge of methodology used for conducting clinical trials and upon the experience coming from clinical research groups.
Pressure-Flow Relationship in Swine Ureter: Effect of Nitric Oxide Synthase Inhibition by L-NAME
Authors: Rubini Alessandro , Redaelli Marco , Bondì Michela
Published: October 2009

Introduction: The purpose of this report is to elucidate the possible role of nitric oxide (NO) in modulating smooth muscle tone of swine ureteral wall and its hydraulic resistance to urinary flow. Materials and Methods: We performed direct monitoring of perfusion pressure for different flows in isolated fresh swine ureter. Fluid used for perfusions was saline or L-NAME 200 μmol saline added, and relative pressure-flow relationships were obtained. Results: The general shape of pressure-flow relationships indicates a decrease of ureteral hydraulic resistance with increasing flow. NO synthase inhibition by L-NAME caused a statistically significant increase of perfusion pressures for every tested flow, hence of ureteral hydraulic resistance. Conclusions: Our data show an effective role of NO in modulating ureteral flow resistance, and suggest possible pharmacological implications. A simple mathematical approach to define hydraulic ureteral flow resistance for low and high urinary flows is also suggested.