bluuebunny/crossref_metadata_2025 huggingface dataset:
Shrinking and showing functions
Authors: Claessen Koen
Published: January 2013

Although quantification over functions in QuickCheck properties has been supported from the beginning, displaying and shrinking them as counter examples has not. The reason is that in general, functions are infinite objects, which means that there is no sensible show function for them, and shrinking an infinite object within a finite number of steps seems impossible. This paper presents a general technique with which functions as counter examples can be shrunk to finite objects, which can then be displayed to the user. The approach turns out to be practically usable, which is shown by a number of examples. The two main limitations are that higher-order functions cannot be dealt with, and it is hard to deal with terms that contain functions as subterms.
Surveyor
Authors: Allen Wyatt , Erwig Martin
Published: January 2013

Polls and surveys are increasingly employed to gather information about attitudes and experiences of all kinds of populations and user groups. The ultimate purpose of a survey is to identify trends and relationships that can inform decision makers. To this end, the data gathered by a survey must be appropriately analyzed.

Most of the currently existing tools focus on the user interface aspect of the data collection task, but pay little attention to the structure and type of the collected data, which are usually represented as potentially tag-annotated, but otherwise unstructured, plain text. This makes the task of writing data analysis programs often difficult and error-prone, whereas a typed data representation could support the writing of type-directed data analysis tools that would enjoy the many benefits of static typing.

In this paper we present Surveyor, a DSEL that allows the compositional construction of typed surveys, where the types describe the structure of the data to be collected. A survey can be run to gather typed data, which can then be subjected to analysis tools that are built using Surveyor's typed combinators. Altogether the Surveyor DSEL realizes a strongly typed and type-directed approach to data gathering and analysis.

The implementation of our DSEL is based on GADTs to allow a flexible, yet strongly typed representation of surveys. Moreover, the implementation employs the Scrap-Your-Boilerplate library to facilitate the type-dependent traversal, extraction, and combination of data gathered from surveys.
Wormholes
Authors: Winograd-Cort Daniel , Hudak Paul
Published: January 2013

Functional reactive programming (FRP) is a useful model for programming real-time and reactive systems in which one defines a
signal function
to process a stream of input values into a stream of output values. However, performing side effects (e.g. memory mutation or input/output) in this model is tricky and typically unsafe. In previous work, Winograd-Cort et al. [2012] introduced
resource types
and
wormholes
to address this problem.

This paper better motivates, expands upon, and formalizes the notion of a wormhole to fully unlock its potential. We show, for example, that wormholes can be used to define the concept of causality. This in turn allows us to provide behaviors such as looping, a core component of most languages, without building it directly into the language. We also improve upon our previous design by making wormholes less verbose and easier to use.

To formalize the notion of a wormhole, we define an extension to the simply typed lambda calculus, complete with typing rules and operational semantics. In addition, we present a new form of semantic transition that we call a
temporal
transition to specify how an FRP program behaves over time and to allow us to better reason about causality. As our model is designed for a Haskell implementation, the semantics are lazy. Finally, with the language defined, we prove that our wormholes indeed allow side effects to be performed safely in an FRP framework.
Safe haskell
Authors: Terei David , Marlow Simon , Peyton Jones Simon , Mazières David
Published: January 2013

Though Haskell is predominantly type-safe, implementations contain a few loopholes through which code can bypass typing and module encapsulation. This paper presents
Safe Haskell
, a language extension that closes these loopholes. Safe Haskell makes it possible to confine and safely execute untrusted, possibly malicious code. By strictly enforcing types, Safe Haskell allows a variety of different policies from API sandboxing to information-flow control to be implemented easily as monads. Safe Haskell is aimed to be as unobtrusive as possible. It enforces properties that programmers tend to meet already by convention. We describe the design of Safe Haskell and an implementation (currently shipping with GHC) that infers safety for code that lies in a safe subset of the language. We use Safe Haskell to implement an online Haskell interpreter that can securely execute arbitrary untrusted code with no overhead. The use of Safe Haskell greatly simplifies this task and allows the use of a large body of existing code and tools.
Endoscopic Revision (StomaphyX) versus Formal Surgical Revision (Gastric Bypass) for Failed Vertical Band Gastroplasty
Authors: Bolton Johan , Gill Richdeep S. , Al-Jahdali Akram , Byrns Simon , Shi Xinzhe , Birch Daniel W. , Karmali Shahzeer
Published: January 2013

Background. Weight regain secondary to VBG pouch dilation is a typical referral for Bariatric surgeons. In this study we compare an endoluminal pouch reduction (Stomaphyx) to RYGB for revision.Methods. A retrospective review was completed for patients with a previous VBG presenting with weight regain between 2003–2010.Results. Thirty patients were identified for study 23 RYGB, 14 StomaphyX. Significant post procedure BMI loss was seen in each cohort (RYGB,47.7 ± 7 kg/m2to35 ± 7 kg/m2; StomaphyX43 ± 10 kg/m2to40 ± 9 kg/m2,P=0.0007). Whereas nausea and headache were the only complications observed in StomaphyX patients, the RYGB group had a 43.5% complication rate and 1 mortality. Complications following RYGB include: incisional hernia (13%), anastomotic leak (8.7%), respiratory failure (8.7%), fistula (8.7%), and perforation (4.35%). The median length of stay following RYGB was 6 days compared to1.5 ± 0.5days following StomaphyX.Conclusion. This study suggests that while RYGB revision may achieve greater weight loss, the complication rates and severity is discouraging. StomaphyX may be a safe alternative. Further technical modifications of the device and longer follow-up may clarify the role of this approach.
Gab Docking Proteins in Cardiovascular Disease, Cancer, and Inflammation
Authors: Nakaoka Yoshikazu , Komuro Issei
Published: January 2013

The docking proteins of the Grb2-associated binder (Gab) family have emerged as crucial signaling compartments in metazoans. In mammals, the Gab proteins, consisting of Gab1, Gab2, and Gab3, are involved in the amplification and integration of signal transduction evoked by a variety of extracellular stimuli, including growth factors, cytokines, antigens, and other molecules. Gab proteins lack the enzymatic activity themselves; however, when phosphorylated on tyrosine residues, they provide binding sites for multiple Src homology-2 (SH2) domain-containing proteins, such as SH2-containing protein tyrosine phosphatase 2 (SHP2), phosphatidylinositol 3-kinase regulatory subunit p85, phospholipase Cγ, Crk, and GC-GAP. Through these interactions, the Gab proteins transduce signals from activated receptors into pathways with distinct biological functions, thereby contributing to signal diversification. They are known to play crucial roles in numerous physiological processes through their associations with SHP2 and p85. In addition, abnormal Gab protein signaling has been linked to human diseases including cancer, cardiovascular disease, and inflammatory disorders. In this paper, we provide an overview of the structure, effector functions, and regulation of the Gab docking proteins, with a special focus on their associations with cardiovascular disease, cancer, and inflammation.
Cranial Nerve Palsies: Sarcoidosis to Systemic Lupus Erythematosus
Authors: Aslam Fawad , Bannout Firas , Russell Elizabeth B.
Published: January 2013

Cranial palsies are a very rare feature of SLE. Similarly, peripheral sensory-motor axonal neuropathy is very uncommon in SLE. The combination of the two as the presenting symptoms of SLE is a diagnostic challenge particularly in an elderly male patient with a known diagnosis of sarcoidosis. This case serves to highlight the diagnostic considerations in such a patient. The lack of response to standard therapy and the presence of subtle clues like anemia, proteinuria, and mild serositis should prompt the physician to look for alternate diagnoses. The potential association of SLE and sarcoidosis is also discussed. SLE can be present in elderly male patients with cranial and peripheral neuropathy.
Time Course of Muscle Damage and Inflammatory Responses to Resistance Training with Eccentric Overload in Trained Individuals
Authors: Neme Ide Bernardo , Alessandro Soares Nunes Lázaro , Brenzikofer René , Macedo Denise Vaz
Published: January 2013

The purpose of this study was to observe the time course of muscle damage and inflammatory responses following an eccentric overload resistance-training (EO) program. 3 females (23.8 ± 2.6 years; 70.9 ± 12.7 kg; 1.6 ± 0.08 m) and 5 males (23.8 ± 2.6 years; 75.1 ± 11.2 kg; 1.8 ± 0.1 m) underwent thirteen training sessions (4 × 8–10 eccentric-only repetitions—80% of eccentric 1RM, one-minute rest, 2x week−1, during 7 weeks, for three exercises). Blood samples were collected prior to (Pre) and after two (P2), seven (P7), nine (P9), eleven (P11), and thirteen (P13) sessions, always 96 hours after last session. The reference change values (RCV) analysis was employed for comparing the responses, and the percentual differences between the serial results were calculated for each subject and compared with RCV95%. Four subjects presented significant changes for creatine kinase at P2, and another two at P13; six for C-reactive protein at P2, and three at P11; two for neutrophils at P2, P4, and P13, respectively; and only one for white blood cells at P2, P4, P7, and P9, for lymphocyte at P7, P9, and P13, and for platelet at P4. We conclude that EO induced high magnitude of muscle damage and inflammatory responses in the initial phase of the program with subsequent attenuation.
Rapid Nongenomic Action of Aldosterone on Protein Expressions of Hsp90(αandβ) and pc-Src in Rat Kidney
Authors: Eiam-Ong Somchit , Sinphitukkul Kittisak , Manotham Krissanapong , Eiam-Ong Somchai
Published: January 2013

Previousin vitrostudies indicated that aldosterone nongenomically phosphorylates epidermal growth factor receptor (EGFR) through activation of upstream signals, heat shock protein 90β(Hsp90β), and cytosolic (c)-Src kinase. We demonstrated that aldosterone rapidly elevates EGFR phosphorylation in rat kidney. There are noin vivodata regarding renal Hsp90(αandβ) and phosphorylated (p)c-Src protein expressions. The present study further investigates the expressions of these proteins. Male Wistar rats were intraperitoneally injected with normal saline solution or aldosterone (Aldo: 150 μg/kg BW). After 30 minutes, abundances and localizations of these proteins were determined. Aldosterone enhanced renal Hsp90βprotein abundance (P<0.001), but Hsp90αand pc-Src protein levels remained unaltered. Expression of Hsp90(αandβ) was induced prominently in the proximal convoluted tubules (PCTs). Activation of Hsp90αwas observed in vascular and outer medulla regions, whereas Hsp90βwas induced in the cortex. Immunoreactivity of pc-Src was elevated in PCT with obvious staining at the luminal membrane. Thisin vivostudy is the first to demonstrate that aldosterone nongenomically elevates Hsp90(αandβ) protein expressions in rat kidney. Aldosterone had no effect on pc-Src protein levels but modulated localization. These results indicate that aldosterone regulates upstream mediators of EGFR transactivationin vivo.
Reactive Oxygen Species in Vascular Formation and Development
Authors: Zhou Yijiang , Yan Hui , Guo Meiqun , Zhu Jianhua , Xiao Qingzhong , Zhang Li
Published: January 2013

Reactive oxygen species (ROS) are derived from the metabolism of oxygen and are traditionally viewed as toxic byproducts that cause damage to biomolecules. It is now becoming widely acknowledged that ROS are key modulators in a variety of biological processes and pathological states. ROS mediate key signaling transduction pathways by reversible oxidation of certain signaling components and are involved in the signaling of growth factors, G-protein-coupled receptors, Notch, and Wnt and its downstream cascades including MAPK, JAK-STAT, NF-κB, and PI3K/AKT. Vascular formation and development is one of the most important events during embryogenesis and is vital for postnasal tissue repair. In this paper, we will discuss how ROS regulate different steps in vascular development, including smooth muscle cell differentiation, angiogenesis, endothelial progenitor cells recruitment, and vascular cell migration.
Computational Nanochemistry Study of the Molecular Structure and Properties of Chlorophyll a
Authors: Alvarado-González Mónica , Flores-Holguín Norma , Glossman-Mitnik Daniel
Published: January 2013

The M06 family of density functionals has been assessed for the calculation of the molecular structure and properties of the chlorophyll a molecule. Besides the determination of the molecular structures, the UV-Vis spectra have been computed using TD-DFT in the presence of a solvent, and the results were compared with the experimental data available. The chemical reactivity descriptors have been calculated through conceptual DFT. The active sites for nucleophilic and electrophilic attacks have been chosen by relating them to the Fukui function indices. A comparison between the descriptors calculated through vertical energy values and those arising from the Koopmans' theorem approximation have been performed in order to check for the validity of the last procedure.
Enhanced Production of Acarbose and Concurrently Reduced Formation of Impurity C by Addition of Validamine in Fermentation ofActinoplanes utahensisZJB-08196
Authors: Xue Ya-Ping , Qin Jun-Wei , Wang Ya-Jun , Wang Yuan-Shan , Zheng Yu-Guo
Published: January 2013

Commercial production of acarbose is exclusively via done microbial fermentation with strains from the genera ofActinoplanes. The addition of C7N-aminocyclitols for enhanced production of acarbose and concurrently reduced formation of impurity C by cultivation ofA. utahensisZJB-08196 in 500-mL shake flasks was investigated, and validamine was found to be the most effective strategy. Under the optimal conditions of validamine addition, acarbose titer was increased from3560±128 mg/L to4950±156 mg/L, and impurity C concentration was concurrently decreased from289±24 mg/L to107±29 mg/L in batch fermentation after 168 h of cultivation. A further fed-batch experiment coupled with the addition of validamine (20 mg/L) in the fermentation medium prior to inoculation was designed to enhance the production of acarbose. When twice feedings of a mixture of 6 g/L glucose, 14 g/L maltose, and 9 g/L soybean flour were performed at 72 h and 96 h, acarbose titer reached6606±103 mg/L and impurity C concentration was only212±12 mg/L at 168 h of cultivation. Acarbose titer and proportion of acarbose/impurity C increased by 85.6% and 152.9% when compared with control experiments. This work demonstrates for the first time that validamine addition is a simple and effective strategy for increasing acarbose production and reducing impurity C formation.
The Impact of Ethnicity on Objectively Measured Physical Activity in Children
Authors: Eyre Emma Lisa Jane , Duncan Michael J.
Published: January 2013

Obesity and obesity-related diseases (cardiovascular disease/metabolic risk factors) are experienced differently in individuals from different ethnic backgrounds, which originate in childhood. Physical activity is a modifiable risk factor for obesity and related diseases. Both physical activity and metabolic risk factors track to adulthood, and thus understanding the physical activity patterns in children from different ethnic backgrounds is important. Given the limitations of self-report measures in children, this study provides a review of studies which have objectively measured physical activity patterns in children from different ethnic backgrounds. From a total of 16 studies, it can be concluded that physical activity does seem to vary amongst the ethnic groups especially South Asian and Black compared to White EU (European Union). The findings are less consistent for Hispanic/Mexican American children. However, there are several methodological limitations which need to be considered in future studies. Firstly, there is a need for consistency in the measurement of physical activity. Secondly, there are a range of complex factors such as socioeconomic status and body composition which affect both physical activity and ethnicity. Studies have failed to account for these differences limiting the ability to generalise that ethnicity is an independent risk factor for physical activity.
Silencing ofEntamoeba histolyticaGlucosamine 6-Phosphate Isomerase by RNA Interference Inhibits the Formation of Cyst-Like Structures
Authors: Aguilar-Díaz Hugo , Laclette Juan Pedro , Carrero Julio César
Published: January 2013

Encystment is an essential process in the biological cycle of the human parasiteEntamoeba histolytica. In the present study, we evaluated the participation ofE. histolyticaGln6Pi in the formation of amoeba cyst-like structures by RNA interference assay. Amoeba trophozoites transfected with two Gln6Pi siRNAs reduced the expression of the enzyme in 85%, which was confirmed by western blot using an anti-Gln6Pi antibody. TheE. histolyticaGln6Pi knockdown with the mix of both siRNAs resulted in the loss of its capacity to form cyst-like structures (CLSs) and develop a chitin wall under hydrogen peroxide treatment, as evidenced by absence of both resistance to detergent treatment and calcofluor staining. Thus, only 5% of treated trophozoites were converted to CLS, from which only 15% were calcofluor stained. These results represent an advance in the understanding of chitin biosynthesis inE. histolyticaand provide insight into the encystment process in this parasite, which could allow for the developing of new control strategies for this parasite.
Improved Reconstruction Quality of Bioluminescent Images by Combining SP3Equations and Bregman Iteration Method
Authors: Wu Qiang , Feng Jinchao , Jia Kebin , Wang Xiangyu
Published: January 2013

Bioluminescence tomography (BLT) has a great potential to provide a powerful tool for tumor detection, monitoring tumor therapy progress, and drug development; developing new reconstruction algorithms will advance the technique to practical applications. In the paper, we propose a BLT reconstruction algorithm by combining SP3equations and Bregman iteration method to improve the quality of reconstructed sources. The numerical results for homogeneous and heterogeneous phantoms are very encouraging and give significant improvement over the algorithms without the use of SP3equations and Bregman iteration method.
Distinct Effects of Ligand-Induced PDGFRα and PDGFRβ Signaling in the Human Rhabdomyosarcoma Tumor Cell and Stroma Cell Compartments
Authors: Ehnman Monika , Missiaglia Edoardo , Folestad Erika , Selfe Joanna , Strell Carina , Thway Khin , Brodin Bertha , Pietras Kristian , Shipley Janet , Östman Arne , Eriksson Ulf
Published: January 2013

Platelet-derived growth factor receptors (PDGFR) α and β have been suggested as potential targets for treatment of rhabdomyosarcoma, the most common soft tissue sarcoma in children. This study identifies biologic activities linked to PDGF signaling in rhabdomyosarcoma models and human sample collections. Analysis of gene expression profiles of 101 primary human rhabdomyosarcomas revealed elevated PDGF-C and -D expression in all subtypes, with PDGF-D as the solely overexpressed PDGFRβ ligand. By immunohistochemistry, PDGF-CC, PDGF-DD, and PDGFRα were found in tumor cells, whereas PDGFRβ was primarily detected in vascular stroma. These results are concordant with the biologic processes and pathways identified by data mining. While PDGF-CC/PDGFRα signaling associated with genes involved in the reactivation of developmental programs, PDGF-DD/PDGFRβ signaling related to wound healing and leukocyte differentiation. Clinicopathologic correlations further identified associations between PDGFRβ in vascular stroma and the alveolar subtype and with presence of metastases. Functional validation of our findings was carried out in molecularly distinct model systems, where therapeutic targeting reduced tumor burden in a PDGFR-dependent manner with effects on cell proliferation, vessel density, and macrophage infiltration. The PDGFR-selective inhibitor CP-673,451 regulated cell proliferation through mechanisms involving reduced phosphorylation of GSK-3α and GSK-3β. Additional tissue culture studies showed a PDGFR-dependent regulation of rhabdosphere formation/cancer cell stemness, differentiation, senescence, and apoptosis. In summary, the study shows a clinically relevant distinction in PDGF signaling in human rhabdomyosarcoma and also suggests continued exploration of the influence of stromal PDGFRs on sarcoma progression. Cancer Res; 73(7); 2139–49. ©2013 AACR.
G-protein Inactivator RGS6 Mediates Myocardial Cell Apoptosis and Cardiomyopathy Caused By Doxorubicin
Authors: Yang Jianqi , Maity Biswanath , Huang Jie , Gao Zhan , Stewart Adele , Weiss Robert M. , Anderson Mark E. , Fisher Rory A.
Published: January 2013

Clinical use of the widely used chemotherapeutic agent doxorubicin is limited by life-threatening cardiotoxicity. The mechanisms underlying doxorubicin-induced cardiomyopathy and heart failure remain unclear but are thought to involve p53-mediated myocardial cell apoptosis. The tripartite G-protein inactivating protein RGS6 has been implicated in reactive oxygen species (ROS) generation, ATM/p53 activation, and apoptosis in doxorubicin-treated cells. Thus, we hypothesized that RGS6, the expression of which is enriched in cardiac tissue, might also be responsible for the pathologic effects of doxorubicin treatment in heart. In this study, we show that RGS6 expression is induced strongly by doxorubicin in the ventricles of mice and isolated ventricular myocytes via a posttranscriptional mechanism. While doxorubicin-treated wild-type (WT) mice manifested severe left ventricular dysfunction, loss of heart and body mass, along with decreased survival 5 days after doxorubicin administration, mice lacking RGS6 were completely protected against these pathogenic responses. Activation of ATM/p53 apoptosis signaling by doxorubicin in ventricles of WT mice was also absent in their RGS6−/− counterparts. Doxorubicin-induced ROS generation was dramatically impaired in both the ventricles and ventricular myocytes isolated from RGS6−/− mice, and the apoptotic response to doxorubicin in ventricular myocytes required RGS6-dependent ROS production. These results identify RGS6 as an essential mediator of the pathogenic responses to doxorubicin in heart, and they argue that RGS6 inhibition offers a rational means to circumvent doxorubicin cardiotoxicity in human patients with cancer. Cancer Res; 73(6); 1662–7. ©2012 AACR.
Murine Microenvironment Metaprofiles Associate with Human Cancer Etiology and Intrinsic Subtypes
Authors: Nguyen David H. , Fredlund Erik , Zhao Wei , Perou Charles M. , Balmain Allan , Mao Jian-Hua , Barcellos-Hoff Mary Helen
Published: January 2013

Purpose: Ionizing radiation is a well-established carcinogen in rodent models and a risk factor associated with human cancer. We developed a mouse model that captures radiation effects on host biology by transplanting unirradiated Trp53-null mammary tissue to sham or irradiated hosts. Gene expression profiles of tumors that arose in irradiated mice are distinct from those that arose in naïve hosts. We asked whether expression metaprofiles could discern radiation-preceded human cancer or be informative in sporadic breast cancers.

Experimental Design: Affymetrix microarray gene expression data from 56 Trp53-null mammary tumors were used to define gene profiles and a centroid that discriminates tumors arising in irradiated hosts. These were applied to publicly available human cancer datasets.

Results: Host irradiation induces a metaprofile consisting of gene modules representing stem cells, cell motility, macrophages, and autophagy. Human orthologs of the host irradiation metaprofile discriminated between radiation-preceded and sporadic human thyroid cancers. An irradiated host centroid was strongly associated with estrogen receptor–negative breast cancer. When applied to sporadic human breast cancers, the irradiated host metaprofile strongly associated with basal-like and claudin-low breast cancer intrinsic subtypes. Comparing host irradiation in the context of TGF-β levels showed that inflammation was robustly associated with claudin-low tumors.

Conclusions: Detection of radiation-preceded human cancer by the irradiated host metaprofile raises possibilities of assessing human cancer etiology. Moreover, the association of the irradiated host metaprofiles with estrogen receptor–negative status and claudin-low subtype suggests that host processes similar to those induced by radiation underlie sporadic cancers. Clin Cancer Res; 19(6); 1353–62. ©2013 AACR.
Microenvironmental Regulation of BRCA1 Gene Expression by c-Jun and Fra2 in Premalignant Human Ovarian Surface Epithelial Cells
Authors: Zhou Lixin , Graves Marcia , MacDonald Gwen , Cipollone Jane , Mueller Christopher R. , Roskelley Calvin D.
Published: January 2013

Reduced BRCA1 gene expression is common in the sporadic form of ovarian carcinoma. The spread of this highly lethal cancer often begins when tumor cell clusters are shed into the fluid of the abdominopelvic cavity such that they can float freely before seeding distant sites on the peritoneal walls and organs. Thus, the microenvironment that tumor cells find themselves in changes dramatically during these early shedding and floating stages of transperitoneal metastasis. To mimic this microenvironmental change in vitro, we released premalignant human ovarian surface epithelial cells from the substratum and forced them to cluster in suspension. Under these conditions, steady state levels of BRCA1 mRNA and protein fell significantly and the transcriptional activation state of the BRCA1 promoter was suppressed. Analysis of the promoter indicated that the previously identified “CRE” element located within the “positive regulatory region” (PRR) contributed to this suppression. More specifically, we show that the suppression was mediated, at least in part, by a suspension culture–driven decrease in the levels of two members of the AP1 transcription factor complex, c-Jun and Fra2, that bind to the CRE element. Therefore, a microenvironmental change that is manifested during the initial stages of ovarian carcinoma dissemination may, potentially, help suppress BRCA1 expression in sporadic tumors and thus promote their progression. Mol Cancer Res; 11(3); 272–81. ©2013 AACR.
The Heterochronic microRNA let-7 Inhibits Cell Motility by Regulating the Genes in the Actin Cytoskeleton Pathway in Breast Cancer
Authors: Hu Xiaowen , Guo Jinyi , Zheng Lan , Li Chunsheng , Zheng Tim M. , Tanyi Janos L. , Liang Shun , Benedetto Chiara , Mitidieri Marco , Katsaros Dionyssios , Zhao Xia , Zhang Youcheng , Huang Qihong , Zhang Lin
Published: January 2013

The heterochronic gene let-7 serves as a tumor suppressor microRNA by targeting various oncogenic pathways in cancer cells. Considerable evidence indicates that reduced expression of let-7 might be associated with poor clinical outcome in patients with cancer. Here, we report that the expression levels of three let-7 family members, let-7a, let-7b, and let-7g, were significantly decreased in the patients with breast cancer with lymph node metastasis compared with those without lymph node metastasis. Enforced expression of let-7b significantly inhibits breast cancer cell motility and affects actin dynamics. Using bioinformatic and experimental approaches, four genes in the actin cytoskeleton pathway, including PAK1, DIAPH2, RDX, and ITGB8, were identified as let-7 direct targets. Blocking the expression of PAK1, DIAPH2, and RDX significantly inhibits breast cancer cell migration induced by let-7b repression. Our results indicate that reconstitution of let-7 expression in tumor cells could provide a novel therapeutic strategy for the treatment of metastatic disease. Mol Cancer Res; 11(3); 240–50. ©2013 AACR.
Targeting Constitutively Activated β1 Integrins Inhibits Prostate Cancer Metastasis
Authors: Lee Yu-Chen , Jin Jung-Kang , Cheng Chien-Jui , Huang Chih-Fen , Song Jian H. , Huang Miao , Brown Wells S. , Zhang Sui , Yu-Lee Li-Yuan , Yeh Edward T. , McIntyre Bradley W. , Logothetis Christopher J. , Gallick Gary E. , Lin Sue-Hwa
Published: January 2013

Disseminated prostate cancer cells must survive in circulation for metastasis to occur. Mechanisms by which these cells survive are not well understood. By immunohistochemistry of human tissues, we found that levels of β1 integrins and integrin-induced autophosphorylation of FAK (pFAK-Y397) are increased in prostate cancer cells in primary prostate cancer and lymph node metastases, suggesting that β1 integrin activation occurs in metastatic progression of prostate cancer. A conformation-sensitive antibody, 9EG7, was used to examine β1 integrin activation. We found that β1 integrins are constitutively activated in highly metastatic PC3 and PC3-mm2 cells, with less activation in low metastatic LNCaP and C4-2B4 cells. Increased β1 integrin activation as well as the anoikis resistance in prostate cancer cells correlated with metastatic potential in vivo. Knockdown of β1 integrin abrogated anoikis resistance in PC3-mm2 cells. In agreement with β1 integrin activation, PC3-mm2 cells strongly adhered to type I collagen and fibronectin, a process inhibited by the β1 integrin-neutralizing antibody mAb 33B6. mAb 33B6 also inhibited the phosphorylation of β1 integrin downstream effectors, focal adhesion kinase (FAK) and AKT, leading to a 3-fold increase in PC3-mm2 apoptosis. Systemic delivery of mAb 33B6 suppressed spontaneous metastasis of PC3-mm2 from the prostate to distant lymph nodes following intraprostatic injection and suppressed metastasis of PC3-mm2 to multiple organs following intracardiac injection. Thus, constitutively activated β1 integrins play a role in survival of PC3-mm2 cells in circulation and represent a potential target for metastasis prevention.

Visual Overview: http://mcr.aacrjournals.org/content/11/4/405/F1.large.jpg.

Mol Cancer Res; 11(4); 405–17. ©2013 AACR.
Dietary Protein Restriction and Preservation of Kidney Function in Chronic Kidney Disease
Authors: Kaysen George A. , Odabaei Golaun
Published: January 2013

Dietary protein augmentation elicits an increase in single nephron glomerular filtration rate (GFR) and increased transglomerular pressure. This is similar to the hemodynamic response to reduction in renal mass. Among patients and experimental animals with proteinuric renal disease, these changes also cause an increase in glomerular permselectivity, which in experimental animals accelerates loss of renal function. A meta-analysis of a group of prospective randomized trials including over 2,000 patients found a significant effect on reducing dietary protein decreasing the risk of end-stage renal disease or death (defined as renal death). This differs somewhat in the outcomes of clinical trials using intermediate outcomes, such as the Modification of Diet in Renal Disease study that used change in GFR in part because of the initial hemodynamic effect of reduction in GFR mediated by dietary protein restriction.
Peritoneal Dialysis in the Pediatric Intensive Care Unit Setting: Techniques, Quantitations and Outcomes
Authors: Bonilla-Félix Melvin
Published: January 2013

Acute kidney injury (AKI) is a common complication in pediatric and neonatal intensive care units (ICU). Renal replacement therapy (RRT) is frequently needed in children in whom supportive therapy is not enough to satisfy their metabolic demands or to be able to provide adequate nutrition. The decision to begin dialysis should not be delayed since experience in infants shows that the shorter the time from the insult to the beginning of dialysis, the higher the survival rate. As the use of continuous RRT in pediatric patients in the ICU has almost tripled, the use of peritoneal dialysis (PD) and intermittent hemodialysis has markedly decreased. The patient’s age seems to be the most important factor influencing the decision on the choice of dialysis modality. PD is still the most common modality used in patients younger than 6 years of age. The relatively low cost, technical simplicity, no need for anticoagulation or placement of central venous catheters, and excellent tolerance in hemodynamically unstable patients are among the most significant advantages of PD. Much controversy exists regarding the adequacy of PD in hypercatabolic patients in the ICU. Nonetheless, when Kt/V has been applied to acutely ill children, it has been shown that PD can provide adequate clearances for most infants. The outcomes of critically ill patients with AKI treated with PD are comparable to other dialysis modalities. Therefore, the decision about dialysis modality should be based on local expertise, resources available, and patient’s clinical status.
Nasal High-Mobility Group Box-1 Protein in Children with Allergic Rhinitis
Authors: Salpietro C. , Cuppari C. , Grasso L. , Tosca M.A. , Miraglia Del Giudice M. , La Rosa M. , Marseglia G.L. , Salpietro A. , Ciprandi G.
Published: January 2013

Background: Allergic rhinitis (AR) is characterized by an inflammatory reaction. High-mobility group box-1 protein (HMGB1) has many characteristics similar to classic proinflammatory cytokines. No study has yet investigated its role in AR. The aim of this study was to measure HMGB1 levels in the fluid recovered from nasal lavage in children with untreated AR and in control subjects. Materials: The study was conducted on 104 AR subjects (48 males and 56 females, median age 10.3 ± 3.4 years) and 97 healthy children (42 males and 55 females) who were age-matched (median age 9.8 ± 4.1 years). Total serum immunoglobulin E, peripheral eosinophils and nasal symptoms assessed by visual analog scale (VAS) were considered. HMGB1 was measured using an ELISA assay. Results: HMGB1 levels in nasal lavage fluid were higher in AR children than in the control group (96.9 ± 19.3 vs. 9.27 ± 4.01 ng/ml; p < 0.001). There was a very strong relationship between HMGB1 levels and VAS values in AR children (r = 0.919). Considering the symptom severity assessed by VAS, there was a relationship between HMGB1 and VAS in all AR subgroups: more evident in the severe subgroup (r = 0.727). Conclusions: Nasal HMGB1 has significantly increased in children with AR and is significantly related to symptom severity.
Clear Cell Sarcoma of the Neck Which Metastasized to the Mammary Gland
Authors: Fukada Ippei , Nishimura Seiichiro , Tanabe Masahiko , Morizono Hidetomo , Makita Masujiro , Gomi Naoya , Horii Rie , Akiyama Futoshi , Iwase Takuji
Published: January 2013

Malignant neoplasms very rarely metastasize to the mammary gland, the incidence of which is reported as 0.5–2%. Clear cell sarcoma is a rare neoplasm, accounting for approximately 1% of all soft tissue tumors, which commonly occurs in the distal extremities of young adults aged approximately 20 to 40 years. So it is also called malignant melanoma of soft parts because it frequently produces melanin. We report a case of a 26-year-old woman who presented with a neck mass. The mass was surgically removed, and pathological diagnosis was clear cell sarcoma of the neck, harboring the EWS-ATF1 chimeric gene. Computed tomography detected a right breast mass 11 months after operation. She was referred to our department, and the right breast tumor was resected. Histopathological examination revealed a 2.5-cm, well-defined mass composed of nests of small, spindle-shaped tumor cells with abundant, clear cytoplasm containing round nuclei and prominent nucleoli. The tumor cells were immunohistochemically positive for HMB45, S-100, and Melan-A. These findings led to a diagnosis of metastasis of clear cell sarcoma to the mammary gland. This is the first report of clear cell sarcoma of the neck which metastasized to the mammary gland.
Is Lipid Management Effective for All Stages of CKD
Authors: Ku Elaine , Campese Vito
Published: January 2013

Patients with chronic kidney disease (CKD) suffer from high rates of cardiovascular morbidity and mortality. The general approach to traditional cardiovascular risk factor modification via dyslipidemia control has not been thoroughly tested in patients with all stages of CKD. In this article, we review the evidence for statin therapy in patients at various stages of CKD, including patients with CKD on dialysis and patients with kidney transplants.
Non-Pro-Vitamin A and Pro-Vitamin A Carotenoids in Atopy Development
Authors: Rühl R.
Published: January 2013

Carotenoids are important derivatives of the human diet and occur in high concentrations in the human organism. Various carotenoids are also present in human breast milk and are transferred to breast-fed children. The alternative to breastfeeding is supplementation with an infant milk formula, but these formulas contain only a limited variety of carotenoids. Our question is: ‘What is the function of various carotenoids in human nutrition with a special emphasis on child development and the development of atopy?’ In this review, the mechanisms of action of the most important non-pro-vitamin A and pro-vitamin A carotenoids: α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, lycopene and retinoids are discussed. In summary, the combination of carotenoids, especially lycopene, seems to be of great importance, and exclusive usage of β-carotene in infant formula may yield in an increased atopy prevalence mediated in various target organs like the skin, lungs and immune competent cells. We conclude that the determination of novel bioactive metabolites of various carotenoids, at various stages in different organs during atopy development, might be the key to understanding the potential importance of carotenoids on atopy development.
Hydrodynamic Analysis of the Miniaturized Hemofilter for a Wearable Ultrafiltration Device
Authors: Ronco Claudio , Kim Jeong Chul , Garzotto Francesco , Galavotti Daniele , Bellini Corrado , Brolgli Matteo , Nalesso Federico
Published: January 2013

Background/Aims: Using a small wearable hemofiltration device, heart failure (HF) patients may have the possibility of eliminating acute hemodynamic changes and the freedom from spending many hours attached to a large stationary treatment system. Methods: We developed a miniaturized hemofilter for a vest-type wearable ultrafiltration device for the treatment of overhydration and congestive HF. In this study, we investigated the feasibility of the newly developed hemofilter based on dynamic CT imaging and in vitro evaluation of hydrodynamic properties. Results: The dynamic CT imaging technique showed development of uniform flow distribution and effective bubble removal in the hemofilter. Hydrodynamic performance of the hemofilter was also acceptable with a stable pressure drop in the blood compartment and ultrafiltration profiles in the intended operating ranges for the treatment of congestive HF patients. Conclusions: The newly developed miniaturized hemofilter for a wearable ultrafiltration device meets the technical requirements of wearable medical devices and its structural design enables uniform blood flow distribution and stable hydrodynamics during operation.
Genomics and Biological Activity of Neutrophil Gelatinase-Associated Lipocalin in Several Clinical Settings
Authors: Virzì Grazia Maria , Clementi Anna , de Cal Massimo , Cruz Dinna N. , Ronco Claudio
Published: January 2013

Recent literature has shown that neutrophil gelatinase-associated lipocalin (NGAL) is one of the most interesting and promising biomarkers in case of acute kidney injury. However, several studies indicated that this protein may be applied beyond the boundaries of renal pathophysiology and may be used in other pathophysiological settings since it is also expressed in neutrophils, and respiratory, bowel and prostate epithelia. In this review, we report NGAL genomics and biology and its possible use in several clinical settings. In particular, we review the genomic organization of the NGAL gene, the lipocalin family structure, the interaction between NGAL and ligands, and the induction and expression of NGAL in different conditions.
Tacrolimus versus Cyclophosphamide in Steroid-Dependent or Steroid-Resistant Focal Segmental Glomerulosclerosis: A Randomized Controlled Trial
Authors: Ren Hong , Shen Pingyan , Li Xiao , Pan Xiaoxia , Zhang Wen , Chen Nan
Published: January 2013

Background: The efficacy and safety of tacrolimus (TAC) and cyclophosphamide (CTX) were prospectively examined in steroid-dependent or steroid-resistant primary focal segmental glomerulosclerosis (FSGS). Methods: Patients with biopsy-proven FSGS were enrolled and randomly divided into two groups: CTX and TAC. Patients treated with CTX (0.5–0.75 g/m2·month, i.v.) received prednisone at 0.8 mg/kg·day, while patients treated with TAC (0.1 mg/kg·day) received prednisone at 0.5 mg/kg·day. The plasma concentration of TAC was monitored and maintained at 5–10 ng/ml. After a 6-month treatment the patients were evaluated. Patients with complete remission (CR) and partial remission (PR) continued the treatment for 12 months with the dose tapered, whereas the patients with no response were excluded from the study and underwent an alternative treatment. Results: A total of 33 patients were recruited and 27 completed the 12-month follow-up. The TAC-treated patients (n = 15) showed a quick remission. The initial remission time averaged 1.23 ± 0.21 versus 2.21 ± 0.77 months in the CTX group (n = 18), but no significant difference was achieved (p > 0.05). At 6 months, the two groups showed a similar outcome. Ten patients from each group showed remission (7 CR and 3 PR). At 12 months, the CTX group had 9 CR and 3 PR while the TAC group had 6 CR and 5 PR. Remission rates in TAC tended to be higher than that in CTX, but there was no difference. CTX patients had a high prevalence of infections (50.0 vs. 13.3% in TAC, p < 0.05). In contrast, TAC-treated patients showed a high incidence of hyperglycemia (26.7 vs. 0.0% in CTX, p < 0.05). Conclusion: These results suggest that CTX and TAC had a similar efficacy in steroid-dependent and steroid-resistant FSGS as manifested by reduced proteinuria, improved serum albumin level and renal function.
How Can We Improve the Solute and Fluid Transport Prescriptions in Hemodialysis to Improve Patient Outcomes?
Authors: Gotch Frank , Kotanko Peter , Levin Nathan
Published: January 2013

Improvements in the dialysis prescription can only be achieved by changes in solute and water transport which provide better control of the metabolic uremic abnormalities that are amenable to dialysis. The key abnormalities identified here are protein catabolites, fluid and electrolyte balance, calcium and phosphorus balance and bone metabolism and acid-base balance. The history of the dialysis prescription is reviewed and changes which might improve the control of these metabolic systems are described. This review concludes there is no support for the recommendation of the routine application of long treatment time and routine use of hemodiafiltration.
Implementation of a Liquid Chromatography Tandem Mass Spectrometry Assay for Eight Adrenal C-21 Steroids and Pediatric Reference Data
Authors: Kulle Alexandra E. , Welzel Maik , Holterhus Paul-Martin , Riepe Felix G.
Published: January 2013

Background: Sensitive and accurate determination of steroids is essential for diagnosing congenital and acquired adrenal diseases. Since plasma concentrations change during childhood, age-specific reference ranges are the prerequisite for clinical interpretation. The objectives of this study were to develop a sensitive and reliable method for simultaneous detection and quantification of progesterone, 17-hydroxyprogesterone, deoxycorticosterone (DOC), 11-deoxycortisol, 21-deoxycortisol, corticosterone, cortisol (F) and cortisone (E) by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and to establish age- and sex-specific reference ranges from birth to adulthood. Methods: All eight steroids were measured simultaneously in 0.1 ml plasma by UPLC-MS/MS. Samples of 905 children were measured and grouped in five age groups. Results: The assay was linear up to 70 ng/ml (700 ng/ml for F; r2 > 0.992). The limit of detection ranged between 0.01 ng/ml for DOC and 0.07 ng/ml for E. Correlations with radioimmunoassays yielded a coefficient of determination between 0.82 and 0.99. Reference data are reported as a function of age and sex. Conclusions: The UPLC-MS/MS method presented here for the simultaneous detection of eight C-21 adrenal hormones together with the detailed reference ranges for children provides a valuable methodology for assessing adrenal steroids in clinical routine and research.
Proton Beam Therapy and Continuous Intra-Arterial Chemotherapy for Polymorphous Low-Grade Adenocarcinoma in the Hard Palate
Authors: Makita Chiyoko , Nakamura Tatsuya , Takayama Kanako , Takada Akinori , Fuwa Nobukazu , Sakuma Hideo
Published: January 2013

Polymorphous low-grade adenocarcinoma is a rare malignant tumor that mainly occurs in salivary glands, particularly in the hard palate. To date, surgery has been the most commonly used treatment method with the aim of achieving negative margins of resection. Here, we report a case of a 51-year-old woman who presented with a painless growing mass in her oral cavity with Rouviere’s lymph node metastasis. Laboratory data showed severe anemia because of bleeding from the tumor. We inserted two catheters into the bilateral external carotid arteries via the superficial temporal arteries, and began continuous intra-arterial infusion with cisplatin and a cisplatin-neutralizing agent. The bleeding stopped after the first infusion, and we continued with weekly arterial cisplatin infusion and proton beam therapy (70.4 GyE in 32 fractions). A decrease in tumor volume has been maintained for 2 years, with no evidence of new metastasis.