bluuebunny/crossref_metadata_2025 huggingface dataset:
Fenretinide (4-HPR): A Preventive Chance for Women at Genetic and Familial Risk?
Authors: Cazzaniga Massimiliano , Varricchio Clara , Montefrancesco Chiara , Feroce Irene , Guerrieri-Gonzaga Aliana
Published: March 2012

The incidence and mortality of breast cancer have been recently influenced by several new therapeutic strategies. In particular our knowledge on cancer precursors, risk biomarkers, and genetics has considerably increased, and prevention strategies are being successfully explored. Since their discovery, retinoids, the natural and synthetic derivatives of vitamin A, have been known to play a crucial role in cell and tissue differentiation and their ability to inhibit carcinogenesis has made them the ideal chemopreventive agents studied in several preclinical and clinical trials. Fenretinide (4-HPR) is the most studied retinoid in breast cancer chemoprevention clinical trials due to its selective accumulation in breast tissue and its favorable toxicological profile. This agent showed a significative reduction of the incidence of second breast tumors in premenopausal women confirmed after 15-year followups. Considering Fenretinide protective action, a similar trend on ovarian cancer, this drug warrants reevaluations as a preventive agent for high-risk young women, such as BRCA-1 and 2 mutation carriers or with a high familial risk. This favorable effect therefore provides a strong rationale for a primary prevention trial in these unaffected cohort of women.
Analysis of Insulin in Human Breast Milk in Mothers with Type 1 and Type 2 Diabetes Mellitus
Authors: Whitmore T. J. , Trengove N. J. , Graham D. F. , Hartmann P. E.
Published: March 2012

Despite the important role that insulin plays in the human body, very little is known about its presence in human milk. Levels rapidly decrease during the first few days of lactation and then, unlike other serum proteins of similar size, achieve comparable levels to those in serum. Despite this, current guides for medical treatment suggest that insulin does not pass into milk, raising the question of where the insulin in milk originates. Five mothers without diabetes, 4 mothers with type 1, and 5 mothers with type 2 diabetes collected milk samples over a 24-hour period. Samples were analysed for total and endogenous insulin content and for c-peptide content. All of the insulin present in the milk of type 1 mothers was artificial, and c-peptide levels were 100x lower than in serum. This demonstrates that insulin is transported into human milk at comparable concentration to serum, suggesting an active transport mechanism. The role of insulin in milk is yet to be determined; however, there are a number of potential implications for the infant of the presence of artificial insulins in milk.
Laminoplasty Techniques for the Treatment of Multilevel Cervical Stenosis
Authors: Mitsunaga Lance K. , Klineberg Eric O. , Gupta Munish C.
Published: March 2012

Laminoplasty is one surgical option for cervical spondylotic myelopathy. It was developed to avoid the significant risk of complications associated with alternative surgical options such as anterior decompression and fusion and laminectomy with or without posterior fusion. Various laminoplasty techniques have been described. All of these variations are designed to reposition the laminae and expand the spinal canal while retaining the dorsal elements to protect the dura from scar formation and to preserve postoperative cervical stability and alignment. With the right surgical indications, reliable results can be expected with laminoplasty in treating patients with multilevel cervical myelopathy.
Major Achievements and Prospect of the ATLAS Integral Effect Tests
Authors: Choi Ki-Yong , Kim Yeon-Sik , Song Chul-Hwa , Baek Won-Pil
Published: March 2012

A large-scale thermal-hydraulic integral effect test facility, ATLAS (Advanced Thermal-hydraulic Test Loop for Accident Simulation), has been operated by KAERI. The reference plant of ATLAS is the APR1400 (Advanced Power Reactor, 1400 MWe). Since 2007, an extensive series of experimental works were successfully carried out, including large break loss of coolant accident tests, small break loss of coolant accident tests at various break locations, steam generator tube rupture tests, feed line break tests, and steam line break tests. These tests contributed toward an understanding of the unique thermal-hydraulic behavior, resolving the safety-related concerns and providing validation data for evaluation of the safety analysis codes and methodology for the advanced pressurized water reactor, APR1400. Major discoveries and lessons found in the past integral effect tests are summarized in this paper. As the demand for integral effect tests is on the rise due to the active national nuclear R&D program in Korea, the future prospects of the application of the ATLAS facility are also discussed.
Laser Process for Selective Emitter Silicon Solar Cells
Authors: Poulain G. , Blanc D. , Focsa A. , Bazer-Bachi B. , Gauthier M. , Semmache B. , Pellegrin Y. , Le Quang N. , Lemiti M.
Published: March 2012

Selective emitter solar cells can provide a significant increase in conversion efficiency. However current approaches need many technological steps and alignment procedures. This paper reports on a preliminary attempt to reduce the number of processing steps and therefore the cost of selective emitter cells. In the developed procedure, a phosphorous glass covered with silicon nitride acts as the doping source. A laser is used to open locally the antireflection coating and at the same time achieve local phosphorus diffusion. In this process the standard chemical etching of the phosphorous glass is avoided. Sheet resistance variation from 100 Ω/sq to 40 Ω/sq is demonstrated with a nanosecond UV laser. Numerical simulation of the laser-matter interaction is discussed to understand the dopant diffusion efficiency. Preliminary solar cells results show a 0.5% improvement compared with a homogeneous emitter structure.
The Effects of Motion on Distributed Detection in Mobile Ad Hoc Sensor Networks
Authors: Sun Xusheng , Coyle Edward J.
Published: March 2012

We consider a set of mobile wireless sensors that collect observations about a brief, localized event. As they continue to move about, one of them processes its observations, decides that an event of interest occurred, and wants to determine if other sensors confirm its results. This sensor assumes the role of a Cluster Head (CH) and requests that all other sensors that collected observations at that time/location reply to it with their decisions. The motion of the sensors since the observation time determines how many wireless hops their decision must cross to reach the CH. We analyze the effect of this motion in the 1D case by modeling each sensor's motion as a Correlated Random Walk (CRW). We also account for measurement errors and communication or processing errors in each wireless hop. Quantities, such as the error probability of the final decision at the CH and the minimum energy required to collect the local decisions from all relevant sensors, can then be directly calculated as functions of time and the parameters of the CRW, the measurement noise and the channel noise. These results allow rapid characterization of the time-dependence of distributed detection algorithms that are executed in mobile sensor networks.
From Murine to Human Nude/SCID: The Thymus, T-Cell Development and the Missing Link
Authors: Romano Rosa , Palamaro Loredana , Fusco Anna , Iannace Leucio , Maio Stefano , Vigliano Ilaria , Giardino Giuliana , Pignata Claudio
Published: March 2012

Primary immunodeficiencies (PIDs) are disorders of the immune system, which lead to increased susceptibility to infections. T-cell defects, which may affect T-cell development/function, are approximately 11% of reported PIDs. The pathogenic mechanisms are related to molecular alterations not only of genes selectively expressed in hematopoietic cells but also of the stromal component of the thymus that represents the primary lymphoid organ for T-cell differentiation. With this regard, the prototype of athymic disorders due to abnormal stroma is the Nude/SCID syndrome, first described in mice in 1966. In man, the DiGeorge Syndrome (DGS) has long been considered the human prototype of a severe T-cell differentiation defect. More recently, the human equivalent of the murine Nude/SCID has been described, contributing to unravel important issues of the T-cell ontogeny in humans. Both mice and human diseases are due to alterations of the FOXN1, a developmentally regulated transcription factor selectively expressed in skin and thymic epithelia.
Magnetic and Electric Properties of Amorphous Co40Fe40B20 Thin Films
Authors: Chen Yuan-Tsung , Xie S. M.
Published: March 2012

C40Fe40B20 was deposited on a glass substrate to a thickness (tf) of between 100 Å and 500 Å. X‐ray diffraction patterns (XRD) indicate that C40Fe40B20 films are in an amorphous state. The plane‐view microstructures and grain size distributions of CoFeB thin films are observed under a high‐resolution transmission electron microscope (HRTEM). The thicker CoFeB films have larger grain size distribution than thinner CoFeB films. The saturation magnetization (Ms) exhibits a size effect, meaning that Ms increases as tf increases. The magnetic remanence magnetization (Mr) of CoFeB thin films are sensitive to thinner CoFeB films, and the refined grain size of thinner CoFeB films can induce ferromagnetic stronger spin exchange‐coupling behavior than thicker CoFeB films, resulting in higher remanence. The highest magnetic squareness ratio (Mr/Ms) of the CoFeB films occurs at thickness of 100 Å, suggesting the 100 Å of the as‐deposited CoFeB film is suitable for magnetic memory application. These results also demonstrate that coercivity (Hc) is increased by an increase in the width of the distribution of grain sizes. The electrical resistivity (ρ) of such a film is typically higher than normally exceeding 100 μΩ cm, revealing that the amorphous phase dominates. These results are consistent with the XRD results.
Validation Study of Kim's Sham Needle by Measuring Facial Temperature: An N-of-1 Randomized Double-Blind Placebo-Controlled Clinical Trial
Authors: Lee Sanghun , Lim Nara , Choi Sun Mi , Kim Sungchul
Published: March 2012

Introduction. In 2008, Kim's sham needle was developed to improve the quality of double-blinded studies. The aim of this study is to validate Kim's sham needle by measuring facial temperature.Methods. We designed “N-of-1” trials involving 7 smokers. One session was composed of 2 stimulations separated by a 2 h washout period. Six sessions were applied daily for all subjects. Infrared thermal imaging was used to examine the effects of acupuncture (HT8, KI2) on facial temperature following smoking-induced decrease.Results. All subjects demonstrated decreased temperatures after sham needle treatment, but 5 of the 7 subjects showed increased temperatures after real needle treatment. 6 of the 7 subjects showed a significant difference(P<0.05)between treatments with real and sham needles. Thus, the physiological stimulation of Kim's sham needle is different from that of a real needle, suggesting that Kim's sham needle is a potential inactive control intervention.
Endoplasmic Reticulum Stress and Insulin Biosynthesis: A Review
Authors: Kim Mi-Kyung , Kim Hye-Soon , Lee In-Kyu , Park Keun-Gyu
Published: March 2012

Insulin resistance and pancreatic beta cell dysfunction are major contributors to the pathogenesis of diabetes. Various conditions play a role in the pathogenesis of pancreatic beta cell dysfunction and are correlated with endoplasmic reticulum (ER) stress. Pancreatic beta cells are susceptible to ER stress. Many studies have shown that increased ER stress induces pancreatic beta cell dysfunction and diabetes mellitus using genetic models of ER stress and by various stimuli. There are many reports indicating that ER stress plays an important role in the impairment of insulin biosynthesis, suggesting that reduction of ER stress could be a therapeutic target for diabetes. In this paper, we reviewed the relationship between ER stress and diabetes and how ER stress controls insulin biosynthesis.
Trends in Snag Populations in Drought-Stressed Mixed-Conifer and Ponderosa Pine Forests (1997–2007)
Authors: Ganey Joseph L. , Vojta Scott C.
Published: March 2012

Snags provide important biological legacies, resources for numerous species of native wildlife, and contribute to decay dynamics and ecological processes in forested ecosystems. We monitored trends in snag populations from 1997 to 2007 in drought-stressed mixed-conifer and ponderosa pine (Pinus ponderosaDougl.exLaws) forests, northern Arizona. Median snag density increased by 75 and 90% in mixed-conifer and ponderosa pine forests, respectively, over this time period. Increased snag density was driven primarily by a large pulse in drought-mediated tree mortality from 2002 to 2007, following a smaller pulse from 1997 to 2002. Decay-class composition and size-class composition of snag populations changed in both forest types, and species composition changed in mixed-conifer forest. Increases in snag abundance may benefit some species of native wildlife in the short-term by providing increased foraging and nesting resources, but these increases may be unsustainable in the long term. Observed changes in snag recruitment and fall rates during the study illustrate the difficulty involved in modeling dynamics of those populations in an era of climate change and changing land management practices.
Sequence Analysis of Inducible Prophage phIS3501 Integrated into the Haemolysin II Gene of Bacillus thuringiensis var israelensis ATCC35646
Authors: Moumen Bouziane , Nguen-The Christophe , Sorokin Alexei
Published: March 2012

Diarrheic food poisoning by bacteria of the Bacillus cereus group is mostly due to several toxins encoded in the genomes. One of them, cytotoxin K, was recently identified as responsible for severe necrotic syndromes. Cytotoxin K is similar to a class of proteins encoded by genes usually annotated as haemolysin II (hlyII) in the majority of genomes of the B. cereus group. The partially sequenced genome of Bacillus thuringiensis var israelensis ATCC35646 contains several potentially induced prophages, one of them integrated into the hlyII gene. We determined the complete sequence and established the genomic organization of this prophage-designated phIS3501. During induction of excision of this prophage with mitomycin C, intact hlyII gene is formed, thus providing to cells a genetic ability to synthesize the active toxin. Therefore, this prophage, upon its excision, can be implicated in the regulation of synthesis of the active toxin and thus in the virulence of bacterial host. A generality of selection for such systems in bacterial pathogens is indicated by the similarity of this genetic arrangement to that of Staphylococcus aureus  β-haemolysin.
Thin Films with Low Zn Content Prepared by Chemical Bath Deposition
Authors: Tian Caijuan , Gao Jingjing , Li Wei , Feng Lianghuan , Zhang Jingquan , Wu Lili
Published: March 2012

Chemical bath deposition (CBD) was used for the growth of thin films with low Zn content. The influence of preparation conditions, such as pH, temperature, and concentration, on film properties was investigated. The chemical growth mechanism of thin films was analyzed, and optimized growth conditions for the thin films were established. The fill factor and short-circuit current were improved while was used to replace CdS as the window layer in CdTe solar cells.
Least‐Mean‐Square Receding Horizon Estimation
Authors: Kwon Bokyu , Han Soohee
Published: March 2012

We propose a least‐mean‐square (LMS) receding horizon (RH) estimator for state estimation. The proposed LMS RH estimator is obtained from the
conditional expectation of the estimated state given a finite number of inputs and outputs over the recent finite horizon. Any a priori state information is not required,
and existing artificial constraints for easy derivation are not imposed. For a general
stochastic discrete‐time state space model with both system and measurement noise,
the LMS RH estimator is explicitly represented in a closed form. For numerical reliability, the iterative form is presented with forward and backward computations. It is shown through a numerical example that the proposed LMS RH estimator has better
robust performance than conventional Kalman estimators when uncertainties exist.
An Improved AAM Method for Extracting Human Facial Features
Authors: Zhou Tao , Wu Xiao-Jun , Wu Tao , Feng Zhen-Hua
Published: March 2012

Active appearance model is a statistically parametrical model, which is widely used to extract human facial features and recognition. However, intensity values used in original AAM cannot provide enough information for image texture, which will lead to a larger error or a failure fitting of AAM. In order to overcome these defects and improve the fitting performance of AAM model, an improved texture representation is proposed in this paper. Firstly, translation invariant wavelet transform is performed on face images and then image structure is represented using the measure which is obtained by fusing the low‐frequency coefficients with edge intensity. Experimental results show that the improved algorithm can increase the accuracy of the AAM fitting and express more information for structures of edge and texture.
Development of Tyrosine-Based RadiotracerTc99m-N4-Tyrosine for Breast Cancer Imaging
Authors: Kong Fan-Lin , Ali Mohammad S. , Rollo Alex , Smith Daniel L. , Zhang Yinhan , Yu Dong-Fang , Yang David J.
Published: March 2012

The purpose of this study was to develop an efficient way to synthesizeTc99m-O-[3-(1,4,8,11-tetraazabicyclohexadecane)-propyl]-tyrosine (Tc99m-N4-Tyrosine), a novel amino acid-based radiotracer, and evaluate its potential in breast cancer gamma imaging. Precursor N4-Tyrosine was synthesized using a 5-step procedure, and its total synthesis yield was 38%. It was successfully labeled withTc99mwith high radiochemical purity (>95%). Cellular uptake ofTc99m-N4-Tyrosine was much higher than that ofTc99m-N4 and the clinical gold standard18F-2-deoxy-2-fluoro-glucose (18F-FDG) in rat breast tumor cellsin vitro. Tissue uptake and dosimetry estimation in normal rats revealed thatTc99m-N4-Tyrosine could be safely administered to humans. Evaluation in breast tumor-bearing rats showed that althoughTc99m-N4-Tyrosine appeared to be inferior to18F-FDG in distinguishing breast tumor tissue from chemical-induced inflammatory tissue, it had high tumor-to-muscle uptake ratios and could detect breast tumors clearly by planar scintigraphic imaging.Tc99m-N4-Tyrosine could thus be a useful radiotracer for use in breast tumor diagnostic imaging.
Noninvasive Approach to Focal Cortical Dysplasias: Clinical, EEG, and Neuroimaging Features
Authors: Seifer Gustavo , Blenkmann Alejandro , Princich Juan Pablo , Consalvo Damián , Papayannis Cristina , Muravchik Carlos , Kochen Silvia
Published: March 2012

Purpose. The main purpose is to define more accurately the epileptogenic zone (EZ) with noninvasive methods in those patients with MRI diagnosis of focal cortical dysplasia (FCD) and epilepsy who are candidates of epilepsy surgery.Methods. Twenty patients were evaluated prospectively between 2007 and 2010 with comprehensive clinical evaluation, video-electroencephalography, diffusion tensor imaging (DTI), and high-resolution EEG to localize the equivalent current dipole (ECD).Key Findings. In 11 cases with white matter asymmetries in DTI the ECDs were located next to lesion on MRI with mean distance of 14.63 millimeters with topographical correlation with the EZ.Significance. We could establish a hypothesis of EZ based on Video-EEG, high-resolution EEG, ECD method, MRI, and DTI. These results are consistent with the hypothesis that the EZ in the FCD is complex and is often larger than visible lesion in MRI.
The Autoimmune Tautology: An In Silico Approach
Authors: Cifuentes Ricardo A. , Restrepo-Montoya Daniel , Anaya Juan-Manuel
Published: March 2012

There is genetic evidence of similarities and differences among autoimmune diseases (AIDs) that warrants looking at a general panorama of what has been published. Thus, our aim was to determine the main shared genes and to what extent they contribute to building clusters of AIDs. We combined a text-mining approach to build clusters of genetic concept profiles (GCPs) from the literature in MedLine with knowledge of protein-protein interactions to confirm if genes in GCP encode proteins that truly interact. We found three clusters in which the genes with the highest contribution encoded proteins that showed strong and specific interactions. After projecting the AIDs on a plane, two clusters could be discerned: Sjögren’s syndrome—systemic lupus erythematosus, and autoimmune thyroid disease—type1 diabetes—rheumatoid arthritis. Our results support the common origin of AIDs and the role of genes involved in apoptosis such asCTLA4,FASLG,andIL10.
Osteogenesis Imperfecta with Celiac Disease and Type II Diabetes Mellitus Associated: Improvement with a Gluten-Free Diet
Authors: Rodrigo Luis , Pérez-Martinez Isabel
Published: March 2012

Osteogenesis imperfecta (OI) is a genetic disease, with a connective tissue alteration, consisting in the presence of multiple spontaneous fractures or after minimal traumatism. Its association with other metabolic processes is rarely described. We present the clinical case of a female adult patient of 43 years. From her infancy, she has had multiple fractures, needing several surgical interventions, and she was diagnosed of OI type 2 at adolescence age. Due mainly to difficulties in walking remaining in wheel-chair in the last three years, she was overweight with morbid obesity (BMI=45.4) and had a type-II DM associated. She suffered from recurrent abdominal pain and chronic diarrhea and was diagnosed of celiac disease (CD) with increased intraepithelial duodenal infiltration, being classified as lymphocytic enteritis, Marsh I type. She was put on a gluten-free diet (GFD), having lost 6 kg of weight after 6 months, with a good control of DM-II and presenting a significant clinical improvement. It is rewarding to search the presence of two coincidental metabolic diseases associated to OI, specially CD, because of the dramatic clinical benefit in the general found after putting on a GFD.
A Review of Psychosocial Risk Factors for Pediatric Atopy
Authors: Duncan Christina L. , Simon Stacey L.
Published: March 2012

Pediatric atopy is increasing in prevalence and creates a significant financial and quality of life burden for children and families (e.g., frequent clinic visits, academic, and social challenges). Thus, it is important to understand modifiable risk factors related to disease onset or exacerbation in young children. The existing research base suggests that while a genetic link has been identified, specific family psychological factors (e.g., parent stress) also appear to play a significant role in the development of pediatric atopy. The function of psychological stress in the clinical expression and exacerbation of allergic diseases in young children is hypothesized to be due to neuroendocrine and immunologic systems. Specifically, stress-related activation of the sympathetic and adrenomedullary (SAM) system as well as the hypothalamic-pituitary-adrenocortical (HPA) axis from both the intrauterine environment and early childhood experiences may increase risk of childhood atopy above and beyond genetic risk. Consequently, prevention and intervention strategies aimed at reducing children’s early exposure to stress and psychological difficulties in parents may prove beneficial in preventing or reducing the likelihood that their children will develop atopy.
The Construction of Inference Engine for Meaningful Context and Prediction Based on USN Environment
Authors: Im So-Young , Oh Ryum-Duck
Published: March 2012

Currently, with gradually increasing movement to live with nature, artificial wetlands are increasing as well. All these change blows at rivers and streams thereby need for wetland management systems to increase. To measure environmental situations on the wetlands, people should go outside and check with measurement tools regularly. However, with these tools only it is difficult to know the exact situations on that wetland. Thus, we attached various sensors on the wetland and made sensor network environment. We used sensing data from sensor network to assume the situation of the wetland. This paper proposes a design for this through application of context inference of USN (Ubiquitous Sensor Network) and inference production rules for context inference engine of wetland management system by using JESS. In this study, we made rules using actual eutrophication criteria as a standard of water quality. The produced rules in this paper can decide the grade of eutrophication on wetland environment then predict the status of the wetland based on facts collected from sensor networks. Sensors sense data such as DO, BOD, SS, PH. And production rules divided the grades of each fact and then final rules can decide the eutrophication grades which mean water quality grades.
Antenatal Corticosteroids: A Risk Factor for the Development of Chronic Disease
Authors: Asztalos Elizabeth
Published: March 2012

Preterm birth remains a major health issue worldwide. Since the 1990s, women at risk for preterm birth received a single course of exogenous antenatal corticosteroids (ACSs) to facilitate fetal lung maturity. More recently, repeated or multiple courses of ACS have been supported to provide continued fetal maturity support for women with continued risk of preterm birth. However, exogenous ACS reduces birth weight which, in turn, is associated with adverse adult outcomes such as coronary heart disease, stroke, hypertension, and type 2 diabetes. The long-term effects of ACS exposure on HPA axis activity and neurological function are well documented in animal studies, and it appears that ACS, regardless of dose exposure, is capable of affecting fetal HPA axis development causing permanent changes in the HPA axis that persists through life and is manifested by chronic illness and behavioral changes. The challenge in human studies is to demonstrate whether an intervention such as ACS administration in pregnancy contributes to developmental programming and how this is manifested in later life.
Pharmacokinetics and Antitumor Efficacy of XMT-1001, a Novel, Polymeric Topoisomerase I Inhibitor, in Mice Bearing HT-29 Human Colon Carcinoma Xenografts
Authors: Walsh Mark D. , Hanna Suzan K. , Sen Jeremy , Rawal Sumit , Cabral Carolina B. , Yurkovetskiy Alex V. , Fram Robert J. , Lowinger Timothy B. , Zamboni William C.
Published: March 2012

Purpose: To evaluate the pharmacokinetics and tissue disposition of macromolecular camptothecin (CPT) drug conjugate, XMT-1001, and irinotecan (CPT-11) in mice bearing HT-29 xenograft tumors.

Experimental Design: The antitumor efficacy of XMT-1001 was evaluated in the mouse HT-29 human colon carcinoma xenograft model. XMT-1001 was administered intravenously to female athymic nude (nu/nu) mice bearing established HT-29 xenograft tumors (n = 10) at 15, 30, and 60 mg CPT equivalents/kg on weekly or biweekly schedules. The tumor growth inhibition and tumor growth delay endpoints were used for efficacy evaluation. In the pharmacokinetic study, XMT-1001 was administered intravenously at a pharmacologically relevant dose of 60 mg CPT equivalents/kg × 1 via tail vein or an equimolar dose of CPT-11 at 100 mg/kg i.p. × 1. Mice (n = 3 per time point) were euthanized from 0.083 to 336 hours after XMT-1001 administration and from 0.083 to 24 hours after CPT-11. Plasma, tumor, and tissues were collected from all animals. A liquid chromatography–tandem mass spectrometry assay was used to measure XMT-1001, conjugate release products, CPT-20-O-(N-succinimido-glycinate; CPT-SI) and CPT-20-O-(N-succinamidoyl-glycinate; CPT-SA), and CPT.

Results: After XMT-1001 administration, the majority of the plasma exposure is accounted for by conjugated CPT. XMT-1001 exhibited a prolonged exposure of conjugated drug, active conjugate primary release products, CPT-SI and CPT-SA, and active CPT, which was associated with greater antitumor response compared with CPT-11.

Conclusions: XMT-1001 provides an extended systemic and tumor exposure of conjugated drug and shows improved antitumor effect compared with CPT-11. Clin Cancer Res; 18(9); 2591–602. ©2012 AACR.
The HDAC Inhibitor LBH589 Enhances the Antimyeloma Effects of the IGF-1RTK Inhibitor Picropodophyllin
Authors: Lemaire Miguel , Fristedt Charlotte , Agarwal Prasoon , Menu Eline , Van Valckenborgh Els , De Bruyne Elke , Österborg Anders , Atadja Peter , Larsson Olle , Axelson Magnus , Van Camp Ben , Jernberg-Wiklund Helena , Vanderkerken Karin
Published: March 2012

Purpose: We have previously shown the use of the insulin-like growth factor type 1 receptor tyrosine kinase (IGF-1RTK) inhibitor picropodophyllin (PPP) as an attractive strategy to combat multiple myeloma (MM) in vitro and in vivo. After a combinatorial drug screening, the histone deacetylase inhibitor LBH589 was shown to act in synergy with PPP reducing survival of MM cells. In this study, we tried to elucidate the molecular mechanisms underlying this combinatorial effect.

Experimental Design: The in vitro anti-MM effects of PPP and LBH589 alone and in combination were evaluated by studying apoptosis, cell cycle distribution, and downstream transcriptome using both human MM cell lines and cells from the murine 5T3MM model. In vivo the effect on survival of 5T33MM-inoculated mice was evaluated.

Results: In the human MM cell line RPMI8226, treatment with PPP and LBH589 in combination resulted in a five-fold increase of apoptosis, and an additive effect on the cleavage of the active forms of caspase-8 was observed as compared with the single drug treatments. Cell cycle analysis revealed an accumulation of cells in the G2–M phase and subsequent downregulation of cell cycle regulating proteins. These data were also confirmed in the 5T33MM cells in vitro. Also, the transcriptome was analyzed by Affymetrix arrays showing gene expression alterations mainly in categories of genes regulating apoptosis and cell adhesion. Combined treatment in vivo resulted in a significantly prolonged survival of 5T33MM-inoculated mice.

Conclusions: The results indicate an improved MM treatment opportunity in using a combination of PPP and LBH589. Clin Cancer Res; 18(8); 2230–9. ©2012 AACR.
Inhibition of MEK and PI3K/mTOR Suppresses Tumor Growth but Does Not Cause Tumor Regression in Patient-Derived Xenografts of RAS-Mutant Colorectal Carcinomas
Authors: Migliardi Giorgia , Sassi Francesco , Torti Davide , Galimi Francesco , Zanella Eugenia R. , Buscarino Michela , Ribero Dario , Muratore Andrea , Massucco Paolo , Pisacane Alberto , Risio Mauro , Capussotti Lorenzo , Marsoni Silvia , Di Nicolantonio Federica , Bardelli Alberto , Comoglio Paolo M. , Trusolino Livio , Bertotti Andrea
Published: March 2012

Purpose: Gene mutations along the Ras pathway (KRAS, NRAS, BRAF, PIK3CA) occur in approximately 50% of colorectal cancers (CRC) and correlate with poor response to anti–EGF receptor (EGFR) therapies. We assessed the effects of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphoinositide 3-kinase (PI3K)/mTOR inhibitors, which neutralize the major Ras effectors, in patient-derived xenografts from RAS/RAF/PIK3CA-mutant metastatic CRCs (mCRC).

Experimental Design: Forty mCRC specimens harboring KRAS, NRAS, BRAF, and/or PIK3CA mutations were implanted in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Each xenograft was expanded into four treatment arms: placebo, the MEK inhibitor AZD6244, the PI3K/mTOR inhibitor, BEZ235, or AZD6244 + BEZ235. Cases initially treated with placebo crossed over to AZD6244, BEZ235, and the anti-EGFR monoclonal antibody cetuximab.

Results: At the 3-week evaluation time point, cotreatment of established tumors with AZD6244 + BEZ235 induced disease stabilization in the majority of cases (70%) but did not lead to overt tumor regression. Monotherapy was less effective, with BEZ235 displaying higher activity than AZD6244 (disease control rates, DCRs: AZD6244, 27.5%; BEZ235, 42.5%). Triple therapy with cetuximab provided further advantage (DCR, 88%). The extent of disease control declined at the 6-week evaluation time point (DCRs: AZD6244, 13.9%; BEZ235, 16.2%; AZD6244 + BEZ235, 34%). Cross-analysis of mice harboring xenografts from the same original tumor and treated with each of the different modalities revealed subgroups with preferential sensitivity to AZD6244 (12.5%), BEZ235 (35%), or AZD6244 + BEZ235 (42.5%); another subgroup (10%) showed equivalent response to any treatment.

Conclusions: The prevalent growth-suppressive effects produced by MEK and PI3K/mTOR inhibition suggest that this strategy may retard disease progression in patients. However, data offer cautionary evidence against the occurrence of durable responses. Clin Cancer Res; 18(9); 2515–25. ©2012 AACR.
Whole Blood Stem Cell Reinfusion and Escalated Dose Melphalan in Castration-Resistant Prostate Cancer: A Phase 1 Study
Authors: Shamash Jonathan , Jacob Jimmy , Agrawal Samir , Powles Thomas , Mutsvangwa Katherine , Wilson Peter , Stebbing Justin
Published: March 2012

Purpose: Nontaxane-based chemotherapeutic options in castrate-resistant prostate cancer (CRPC) are limited despite the long natural history of the disease. We carried out a phase 1 dose-escalation study of the alkylating agent melphalan with autologous stem cell transplantation, comparing rapid changes in circulating tumor cells (CTC) and prostate-specific antigen (PSA) as a measure of response.

Experimental Design: Cohorts of individuals with advanced CRPC received high-dose intravenous melphalan, and autologous blood was returned to patients during treatment. The efficacy endpoints were the PSA reduction rate, CTC response, survival parameters, toxicity and whether reinduction of endocrine sensitivity occurred.

Results: Twenty-four patients were recruited. Dose escalation was feasible with the highest dose cohort being reached. Of 23 individuals evaluable for response, 16 had a PSA response of more than 30%; of 11 patients with soft tissue disease, 4 achieved a partial response and 7 had stable disease. Patients with CTC counts that decreased to less than 5 within 2 weeks from the start of therapy had a longer overall survival (30.6 months vs. 15.3 months, P = 0.03) Treatment was associated with myelosuppression and frequent hospitalizations. In 20 patients after the study, hormone therapy was reintroduced when PSA increased again; response rates were high.

Conclusions: Autologous transplantation following high-dose alkylating agent chemotherapy induces responses but proved toxic, although dose escalation proved possible. The possibility of using CTCs to identify responders at two weeks may be used to justify such an intensive approach. Many individuals went on to further respond to both docetaxel and hormonal therapy. Clin Cancer Res; 18(8); 2352–9. ©2012 AACR.
Farmer’s Lung in a Case after Bullectomy
Authors: Koschel Dirk , Holfert Jan , Rolle Axel , Holotiuk Olaf , Höffken Gert
Published: March 2012

We present a case of farmer’s lung (FL) with the primary presenting feature of a large bulla in the lung. A 70-year-old nonsmoking woman with dyspnea on exercise was referred for surgical resection of a large bulla in the lung. The postoperative evaluation of the lung tissue revealed a follicular lymphocytic alveolitis and loosely formed granulomas suspicious for hypersensitivity pneumonitis (HP). The patient had worked in farming since her youth. Dyspnea on exercise was the only symptom, but it was related to the large bulla. No other radiologic features of HP were shown in a high-resolution CT of the lung. Specific IgG antibodies against typical antigens of FL were detected, bronchoalveolar lavage demonstrated no lymphocytic alveolitis but an inhalative challenge with own hay was positive. A diagnosis of chronic FL was made. Despite lung emphysema being a possible reaction in FL, giant bullae as primary and single manifestation of this disease have not been reported before.
How Important Is the Context of an Adolescent’s First Alcoholic Drink? Evidence that Parental Provision May Reduce Later Heavy Episodic Drinking
Authors: Kelly Adrian , Chan Gary C.K. , O’Flaherty Martin
Published: March 2012

Objective: This study examined the extent to which a retrospective measure of parental provision of the first alcoholic beverage was related to current heavy episodic drinking and current responsible drinking practices. Sample: 608 14- to 17-year-olds from the 2007 Australian National Drug Strategy Household Survey. Measures: Source of first alcoholic beverage (friends/parents/others), source of current alcohol, age of onset of alcohol use, current responsible drinking practices, and proportion of current friends who drink. Results: Binary logistic and multiple regression procedures revealed that parental provision of an adolescent’s first alcoholic beverage predicted lower current heavy episodic drinking, and responsible drinking mediated this association. Discussion: The results suggested that for adolescents who become alcohol users, parental provision of the first drink may reduce subsequent alcohol-related risks compared to introduction to alcohol by friends and other sources. Alcohol-related risks remain significant for adolescents who consume alcohol, independent of who is the provider.
Prolonged Viral RNA Detection in the Central Nervous System of One-Week-Old Swiss Albino Mice following Coxsackievirus B4 and Echovirus 9 Infection
Authors: El Hiar Raida , Hober Didier , Jaidane Hela , Sané Famara , M’hadheb-Gharbi Manel Ben , Caloone Delphine , Gharbi Jawhar , Aouni Mahjoub
Published: March 2012

Objectives: Type B coxsackieviruses (CV-B), together with echoviruses (E), are among the most common pathogens encountered in aseptic meningitis and meningoencephalitis. They frequently infect the central nervous system (CNS). The mechanisms of virus spreading in the CNS are poorly understood. In the present study, we investigated CV-B4 and E-9 spreading and neurotropism within intraperitoneally inoculated one-week-old Swiss albino mice. Methods: Seminested RT-PCR and virus isolation were used to assay viral distribution. Results: Viral RNA was present in various organs: brain, spinal cord, spleen and heart at various times post-infection (p.i.); ranging from 1 day p.i. up to 30, 60 and 90 days p.i, respectively, for CV-B4-JVB-, E-9 Barty- and CV-B4-E2-infected mice. Organs became negative for virus isolation after 5 days p.i., except for brain and heart from CV-B4 E2-infected mice, which remained positive for up to 10 and 15 days p.i., respectively. Negative viral RNA strand was detected mainly in brain and spinal cord of infected mice until 30 and 60 days p.i. Conclusion: This is the first report on the persistence of CV-B4 and E-9 in the CNS of intraperitoneally inoculated mice.
Intrauterine Upper Extremity Thrombosis Successfully Treated with Recombinant Tissue Plasminogen Activator, Enoxaparin and Collagenase
Authors: Yurttutan Sadık , Ozdemir Ramazan , Erdeve Omer , Calisici Erhan , Oncel Mehmet Yekta , Oguz Serife Suna , Dilmen Ugur
Published: March 2012

Intrauterine ischemia of the limbs is a rare condition involving thrombosis and ischemia of the extremities before birth. The clinical presentation depends on the extremity affected as well as the timing of thrombosis. Very few cases with extremity hypoperfusion and gangrene due to intrauterine thrombosis have been reported in the literature, and therefore there is no consensus on the optimal therapeutic strategy for such cases. Presented here is a case of a newborn with intrauterine brachial arterial thrombosis of the right upper extremity who was successfully treated by a combination of recombinant tissue plasminogen activator, enoxaparin and collagenase application followed by surgery.
Road to Fulfilment: Taming the Immune Response to Restore Vision
Authors: Dick Andrew D.
Published: March 2012

While traditionally considered to be an immune privileged site, the eye, and in particular the retina, is nonetheless endowed with immune-competent cells capable of engaging powerful immune regulatory networks. By understanding the mechanisms that promote immune well-being in the eye, we are able to generate therapies which combat undue immune-mediated damage not only by revealing mechanisms that promote tissue damage, but also by an ability to restore tissue immune homeostasis by harnessing intrinsic immune-regulatory mechanisms. The result is to maintain or restore immune health as well as combat tissue damage evoked during, for example, intra-ocular inflammatory disease (uveitis), angiogenesis (age-related macular degeneration) and retinal degenerative disorders. Immune activation and regulation is a balance that is dictated by cognate and soluble factors at both a tissue and cellular level. These continuously respond to and eradicate danger and pathogenic signals whilst maintaining tissue function by controlling, and not exclusively, vascular barriers, complement activation, macrophage activation and keeping in check local T cell proliferation. Loss of the balance between activation and inhibitory signals leads to uncontrolled tissue damage. Understanding the mechanisms has gained potential therapeutic opportunities not only to suppress on-going inflammation, but also to restore homeostasis and prevent recrudescence.
Illicit Drug Use in the Flemish Nightlife Scene between 2003 and 2009
Authors: Van Havere Tina , Lammertyn Jan , Vanderplasschen Wouter , Bellis Mark , Rosiers Johan , Broekaert Eric
Published: March 2012

Aims: Given the importance of party people as innovators and early adaptors in the diffusion of substance use, and given the lack of longitudinal scope in studies of the nightlife scene, we explored changes in illicit drug use among young people participating in the nightlife scene in Flanders. Methods: A survey among party people selected at dance events, rock festivals and clubs was held in the summer of 2003 and repeated in 2005, 2007 and 2009. In total, 2,812 respondents filled in a questionnaire on the use of cannabis, ecstasy, cocaine, amphetamines, GHB and ketamine. Results: The results of the multiple logistic regression analyses show that in the group of frequent pub visitors, the predicting probability of cannabis use increased over time, while the gap in drug use between dance music lovers and non-lovers of dance music narrowed. For cocaine use during the last year, an increase was found related to the housing situation (alone or with parents) of respondents. While the odds of using ecstasy decreased over the years, the odds of using GHB increased. Conclusion: We can conclude that monitoring emerging trends, which can be quickly observed in the nightlife scene, provides meaningful information for anticipating possible trends.
Electrolyte-Free Water Clearance versus Modified Electrolyte-Free Water Clearance: Do the Results Justify the Effort
Authors: Lindner Gregor , Schwarz Christoph
Published: March 2012

Background: Calculation of electrolyte-free water clearance (EFWC) allows for quantification of renal losses of free water and was shown to be helpful in the differential diagnosis of dysnatremias and might help in the correction of the electrolyte disorders. A modified EFWC formula (MEFWC) was described to be more accurate than the conventional one; however, it has never been evaluated clinically. Methods: In order to evaluate the performance of MEFWC compared to EFWC under clinical circumstances, we gathered data from a total of 912 patient days of 138 critically ill patients. EFWC and MEFWC were calculated on the basis of these data. Additionally, from data of critically ill patients, we calculated a prediction of serum sodium based on the Edelman equation using either EFWC or MEFWC and compared results. Results: Altogether, 343 normonatremic, 124 hyponatremic and 445 hypernatremic days were analyzed. Results for EFWC and MEFWC correlated significantly (R = 0.98). In patients with hyponatremia, the absolute difference between EFWC and MEFWC was significantly larger than in patients with normonatremia (437 vs. 256 ml, p < 0.01). The absolute difference between EFWC and MEFWC correlated significantly with the level of serum sodium (R = –0.41). The mean difference in the prediction of serum sodium change as calculated based on the Edelman equation between the formula using EFWC and the formula using MEFWC was 0.7 mmol/l (SD 0.68) and was highest in hyponatremia and lowest in hypernatremia. Conclusion: Results of EFWC and MEFWC were comparable in critically ill patients. Under normal circumstances, the use of the more complicated MEFWC is not justified. In hyponatremia, the difference between EFWC and MEFWC is larger and thus might justify the use of the more complicated formula.
Rapid High Resolution Electroanatomical Mapping
Authors: Nakagawa Hiroshi , Ikeda Atsushi , Sharma Tushar , Lazzara Ralph , Jackman Warren M.
Published: March 2012

Background—

A canine right atrial (RA) linear lesion model was used to produce a complex pattern of RA activation to evaluate a novel mapping system for rapid, high resolution (HR) electroanatomical mapping.

Methods and Results—

The mapping system (Rhythmia Medical, Incorporated) uses an 8F deflectable catheter with a minibasket (1.8 cm diameter), containing 8 splines of 8 electrodes (total 64 electrodes, 2.5 mm spacing). The system automatically acquires electrograms and location information based on electrogram stability and respiration phase. In 10 anesthetized dogs, HR-RA map was obtained by maneuvering the minibasket catheter during sinus rhythm and coronary sinus pacing. A right thoracotomy was performed, and either 1 or 2 (to create a gap) epicardial linear lesions were created on the RA free wall (surgical incision or epicardial radiofrequency lesions). RA maps during RA pacing close to the linear lesions were obtained. A total of 73 maps were created, with 44 to 729 (median 237) beats and 833 to 12 412 (median 3589) electrograms (≤2 to ≤5 mm from surface geometry), resolution 1.8 to 5.3 (median 2.7) mm, and 2.6 to 26.3 (median 7.3) minutes mapping time. Without manual annotation, the system accurately created RA geometry and demonstrated RA activation, identifying the location of lines of block and presence or absence of a gap in all 10 dogs. Endocardial radiofrequency catheter ablation of a gap (guided by activation map) produced complete block across the gap in all 3 dogs tested.

Conclusions—

The new HR mapping system accurately and quickly identifies geometry and complex patterns of activation in the canine RA, with little or no manual annotation of activation time.
Exercise Physiology and Rehabilitation in
Circulation
and the
Circulation
Subspecialty Journals
Authors:   The Editors
Published: March 2012

The following articles are being highlighted as part of
Circulation's
Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in
Circulation
and the
Circulation
subspecialty journals. The studies included in this article represent the articles related to exercise physiology and rehabilitation that were published in
Circulation
and its subspecialty journals in 2010 and 2011.