bluuebunny/crossref_metadata_2025 huggingface dataset:
Phragmites karkaas a Biosorbent for the Removal of Mercury Metal Ions from Aqueous Solution: Effect of Modification
Authors: Raza Muhammad Hamid , Sadiq Aqsa , Farooq Umar , Athar Makshoof , Hussain Tajamal , Mujahid Adnan , Salman Muhammad
Published: February 2015

Batch scale studies for the adsorption potential of novel biosorbentPhragmites karka(Trin), in its natural and treated forms, were performed for removal of mercury ions from aqueous solution. The study was carried out at different parameters to obtain optimum conditions of pH, biosorbent dose, agitation speed, time of contact, temperature, and initial metal ion concentration. To analyze the suitability of the process and maximum amount of metal uptake, Dubinin-Radushkevich (D-R) model, Freundlich isotherm, and Langmuir isotherm were applied. The values ofqmaxfor natural and treated biosorbents were found at 1.79 and 2.27 mg/g, respectively. The optimum values of contact time and agitation speed were found at 50 min and 150 rpm for natural biosorbent whereas 40 min and 100 rpm for treated biosorbent, respectively. The optimum biosorption capacities were observed at pH 4 and temperature 313 K for both naturalP. karkaand treatedP. karka.RLvalues indicate that comparatively treatedP. karkawas more feasible for mercury adsorption compared to naturalP. karka. Both pseudo-first-order and pseudo-second-order kinetic models were applied and it was found that data fit best to the pseudo-second-order kinetic model. Thermodynamic studies indicate that adsorption process was spontaneous, feasible, and endothermic.
Therapeutic Effects of TianDiJingWan on the Aβ25–35-Induced Alzheimer’s Disease Model Rats
Authors: Li Zhijie , Tong Qing , Xu Huifang , Hu Li , Zhao Rong , Zhou Fang , Pan Wei , Zhou Li
Published: February 2015

The main purpose of this study was to demonstrate the therapeutic effects and mechanism of TDJW, a modern Chinese medicine prescription developed based on the basic traditional Chinese medicine theory of “tonifying the kidney essence,” on the Aβ25–35-induced AD rats. The AD model was established by the intracerebroventricular administrations of Aβ25–35into the hippocampus CA1 tissue of SD male rats. 72 rats were randomly divided into six groups: sham operation, AD model, donepezil, high TDJW group, medium TDJW group, and low TDJW group. After oral administration of TDJW, the results of Morris water maze and step-down test showed that the learning and memory abilities of AD rats were significantly improved. And biochemical measurement demonstrated that Ach and Glu in hippocampus tissues of AD rats were increased as well. Moreover, the Aβdeposits and p-Tau aggregations in hippocampus CA1 tissues of AD rats were attenuated as observed in the micrographs of immunohistochemistry study, and the results of ELISA indicated that the expressions of TNF-α, IL-1β, and IL-6 in hippocampus tissues were significantly decreased. In conclusion, the present study demonstrated that TDJW could be used as a promising therapeutic agent for the clinical applications of AD treatment in patients.
Community-Based Decision Making and Priority Setting Using the R Software: The Community Priority Index
Authors: Salihu Hamisu M. , Salinas-Miranda Abraham A. , Paothong Arnut , Wang Wei , King Lindsey M.
Published: February 2015

This paper outlines how to compute community priority indices in the context of multicriteria decision making in community settings. A simple R function was developed and validated with community needs assessment data. Particularly, the first part of this paper briefly overviews the existing methods for priority setting and reviews the utility of a multicriteria decision-making approach for community-based prioritization. The second part illustrates how community priority indices can be calculated using the freely available R program to handle community data by showing the computational and mathematical steps of CPI (Community Priority Index) with bootstrapped 95% confidence intervals.
Introduction to Neutrosophic BCI/BCK-Algebras
Authors: Agboola A. A. A. , Davvaz B.
Published: March 2015

We introduce the concept of neutrosophic BCI/BCK-algebras. Elementary properties of neutrosophic BCI/BCK algebras are presented.
Inflammasome in Platelets: Allying Coagulation and Inflammation in Infectious and Sterile Diseases?
Authors: Hottz Eugenio D. , Monteiro Ana Paula T. , Bozza Fernando A. , Bozza Patrícia T.
Published: February 2015

Platelets are crucial effector cells in hemostasis. In addition, platelets are increasingly recognized as major inflammatory cells with key roles in innate and adaptive immune responses. Activated platelets have key thromboinflammatory activities linking coagulation to inflammatory response in a variety of coagulation disorders and vasculopathies. Recently identified inflammatory activities of platelets include the synthesis of IL‐1β from spliced pre‐RNA, as well as the presence and assembly of inflammasome which intermediate IL‐1β secretion. Here we review the mechanisms by which platelets activate translation machinery and inflammasome assembly to synthesize and release IL‐1β. The contributions of these processes to protective and pathogenic responses during infectious and inflammatory diseases are discussed.
Hepatocellular Carcinoma with Both Fibrolamellar and Classical Components: An Unusual Morphological Pattern
Authors: Castro-Villabón Diana , Barrera-Herrera Luis E. , Rodríguez-Urrego Paula A. , Hudacko Rachel , Vera Alonso , Álvarez Johanna , Andrade Rafael , López Rocío
Published: February 2015

Fibrolamellar carcinoma (FLC) is an uncommon form of primary liver malignancy with unique clinical, histological, and biological characteristics. It is usually seen in young adults without underlying liver disease. Histologically, it shows large cells with abundant eosinophilic cytoplasm, large vesicular nuclei, prominent nucleoli, and lamellar type fibrosis. In contrast, classical hepatocellular carcinoma (HCC) is typically present in elderly male patients with cirrhosis. It is the most common histological subtype, and it is characterized by its resemblance to the normal liver, both in its growth pattern and its cytology. The unusual case of a liver carcinoma that presented with histological features of both FLC and classical HCC is herein reported. This was the case of a 37-year-old female complaining of diffuse abdominal discomfort and epigastric pain for two months. She was referred to us for further management after she was diagnosed with HCC in a noncirrhotic liver. She underwent a left-sided hepatectomy. A yellow nodular mass with well-defined borders and a necrotic center was present in the resection specimen. The morphological features and immunohistochemical studies were consistent with a diagnosis of FLC mixed with classical HCC. The patient was followed up for five months, and no signs of recurrence were evident.
The Spiral Coaxial Cable
Authors: Fabbri I. M.
Published: February 2015

A new concept of metal spiral coaxial cable is introduced. The solution to
Maxwell’s equations for the fundamental propagating TEM eigenmode, using a
generalization of the Schwarz-Christoffel conformal mapping of the spiral transverse
section, is provided together with the analysis of the impedances and the
Poynting vector of the line. The new cable may find application as a medium for
telecommunication and networking or in the sector of the Microwave Photonics.
A spiral plasmonic coaxial cable could be used to propagate subwavelength surface
plasmon polaritons at optical frequencies. Furthermore, according to the present model, the myelinated nerves can be considered natural examples of spiral coaxial cables. This study suggests that a malformation of the Peters angle, which determines the power of the neural signal in the TEM mode, causes higher/lower power to be transmitted in the neural networks
with respect to the natural level. The formulas of the myelin sheaths thickness, the
diameter of the axon, and the spiral g factor of the lipid bilayers, which are mathematically
related to the impedances of the spiral coaxial line, can make it easier to analyze the neural line impedance mismatches and the signal disconnections typical of the neurodegenerative diseases.
Comparisons of Mouse Mesenchymal Stem Cells in Primary Adherent Culture of Compact Bone Fragments and Whole Bone Marrow
Authors: Cai Yiting , Liu Tianshu , Fang Fang , Xiong Chengliang , Shen Shiliang
Published: March 2015

The purification of mouse bone marrow mesenchymal stem cells (BMSCs) by using the standard method of whole bone marrow adherence to plastic still remains ineffective. An increasing number of studies have indicated compact bone as an alternative source of BMSCs. We isolated BMSCs from cultured compact bone fragments and investigated the proliferative capacity, surface immunophenotypes, and osteogenic and adipogenic differentiations of the cells after the first trypsinization. The fragment culture was based on the fact that BMSCs were assembled in compact bones. Thus, the procedure included flushing bone marrow out of bone cavity and culturing the fragments without any collagenase digestion. The cell yield from cultured fragments was slightly less than that from cultured bone marrow using the same bone quantity. However, the trypsinized cells from cultured fragments exhibited significantly higher proliferation and were accompanied with more CD90 and CD44 expressions and less CD45 expression. The osteogenic and adipogenic differentiation capacity of cells from cultured fragments were better than those of cells from bone marrow. The directly adherent culture of compact bone is suitable for mouse BMSC isolation, and more BMSCs with potentially improved proliferation capacity can be obtained in the primary culture.
Relationships between Plant Biodiversity and Soil Fertility in a Mature Tropical Forest, Costa Rica
Authors: Nadeau Martin B. , Sullivan Thomas P.
Published: February 2015

We aimed to study relationships between plant biodiversity and soil chemical fertility in a mature tropical forest of Costa Rica. Soil samples were collected in nine sampling plots (5 m by 25 m) in order to identify P, K, Ca, Mg, Fe, Zn, Mn, Cu, and Al and total N contents, soil fertility index, CEC, pH, and C/N ratio. Furthermore, species richness, Shannon-Wiener and Simpson’s species diversities, structural richness, and structural diversity were calculated for each plot. Simple linear regression analyses were conducted. Tree species richness was inversely related to concentration levels of K, Ca, and P, CEC, and soil fertility index. Therefore, higher tree species richness tended to be found on sites with lower soil fertility, which is the complete opposite of temperate forests. As a result, tropical and temperate forest ecology should be considered separately. Shannon-Wiener tree species diversity was positively correlated to C/N ratio. Herb structural richness was positively correlated with soil fertility index and P concentration. Therefore, herb structural richness may be a good indicator of soil fertility. This study gives important insights on ecological relationships between plant biodiversity and soil chemical fertility in a primary tropical forest.
Preparation and Characterization of Biocompatible Polymer Particles as Potential Nanocarriers for Inhalation Therapy
Authors: Jabłczyńska Katarzyna , Janczewska Magdalena , Kulikowska Aleksandra , Sosnowski Tomasz R.
Published: February 2015

Aim.Investigation of the possibility of manufacturing biocompatible polymer particles which have the required properties for pulmonary delivery via inhalation and simultaneously act as vehicles of nanotherapeutics.Methods.Nanostructures were obtained from biocompatible polysaccharides by successive oxidation and reactive coiling in the aqueous phase. The resultant nanosuspensions of PAD (polyaldehyde dextran) and DACMC (dialdehyde carbomethylcellulose) were used as precursors in spray drying production of powders at variable process conditions. The resultant dry microparticles were characterized by SEM observations, and their properties related to delivery by inhalation were determined by laser diffraction spectrometry following the dispersion in the commercial inhaler. Finally, the possibility of the reconstitution of nanosuspensions by powders rehydration was evaluated.Results.Synthesized nanoparticles had size of 120–170 nm. Microparticles after drying had size of 0.5–5 µm and different surface morphology. Aerosolized particles obtained from powder dispersion in the inhaler had the volumetric median diameter of ~2 and ~1 µm for PAD and DACMC, respectively. Hydration of powders led to restoring the nanosuspensions with the average particle size similar to the precursor.Conclusions.PAD and DACMC can be used to obtain nanostructures which, after processing, take a form suitable for effective delivery to the lungs via inhalation.
Ischemic Cardiomyopathy and Cerebral Infarction in a Young Patient Associated with Khat Chewing
Authors: Meulman T. J. , Bakker J. , van den Bos E. J.
Published: February 2015

Khat is a stimulating agent used by many people in the Horn of Africa and the Arabian peninsula. Khat chewing is a known cardiovascular risk factor and is thought to cause vasoconstriction, systemic hypertension, and thrombogenicity. A 33-year-old Somalian man initially presented with loss of neurological function of the left arm, hazy vision, and headache. He smokes tobacco and chews two bundles of khat a week for more than 10 years. His ECG on admission showed a Q wave in V1 and V2 and 2 mm ST-elevations in V1, V2, and V3 and a terminal negative T wave in I, aVL, V2, V3, and V4, consistent with a recent, evolving anterior infarction. A noncontrast enhanced CT of the brain showed ischemia in the right middle cerebral artery vascular territory. An MRI showed recent ischemia in the vascular territory of the posterior division of the right middle cerebral artery. Coronary angiography showed a 70% stenosis with haziness of the proximal left anterior descending artery. Diagnostic tests and imaging are consistent with recent myocardial infarction in the LAD vascular territory because of coronary spasm and cerebral infarction in the middle cerebral artery vascular territory probably related to khat chewing.
Diabetes and Alzheimer Disease, Two Overlapping Pathologies with the Same Background: Oxidative Stress
Authors: Rosales-Corral Sergio , Tan Dun-Xian , Manchester Lucien , Reiter Russel J.
Published: February 2015

There are several oxidative stress-related pathways interconnecting Alzheimer’s disease and type II diabetes, two public health problems worldwide. Coincidences are so compelling that it is attractive to speculate they are the same disorder. However, some pathological mechanisms as observed in diabetes are not necessarily the same mechanisms related to Alzheimer’s or the only ones related to Alzheimer’s pathology. Oxidative stress is inherent to Alzheimer’s and feeds a vicious cycle with other key pathological features, such as inflammation and Ca2+dysregulation. Alzheimer’s pathology by itself may lead to insulin resistance in brain, insulin resistance being an intervening variable in the neurodegenerative disorder. Hyperglycemia and insulin resistance from diabetes, overlapping with the Alzheimer’s pathology, aggravate the progression of the neurodegenerative processes, indeed. But the same pathophysiological background is behind the consequences, oxidative stress. We emphasize oxidative stress and its detrimental role in some key regulatory enzymes.
Assessments ofk-kLTurbulence Model Based on Menter’s Modification to Rotta’s Two-Equation Model
Authors: Abdol-Hamid Khaled S.
Published: February 2015

The main objective of this paper is to construct a turbulence model with a more reliable second equation simulating length scale. In the present paper, we assess the length scale equation based on Menter’s modification to Rotta’s two-equation model. Rotta shows that a reliable second equation can be formed in an exact transport equation from the turbulent length scale and kinetic energy. Rotta’s equation is well suited for a term-by-term modeling and shows some interesting features compared to other approaches. The most important difference is that the formulation leads to a natural inclusion of higher order velocity derivatives into the source terms of the scale equation, which has the potential to enhance the capability of Reynolds-averaged Navier-Stokes to simulate unsteady flows. The model is implemented in the CFD solver with complete formulation, usage methodology, and validation examples to demonstrate its capabilities. The detailed studies include grid convergence. Near-wall and shear flows cases are documented and compared with experimental and large eddy simulation data. The results from this formulation are as good or better than the well-known shear stress turbulence model and much better thank-εresults. Overall, the study provides useful insights into the model capability in predicting attached and separated flows.
Promjene u okolišu i ljudske migracije
Authors:   Filozofski fakultet Sveučilišta u Zagrebu, Zagreb, Hrvatska, Mesić Milan , Župarić-Iljić Drago ,   Institut za migracije i narodnosti, Zagreb, Hrvatska
Published: March 2015

Tridesetu obljetnicu časopisa Migracijske i etničke teme (MET) autori su shvatili kao prigodu da najave novu ključnu problematiku suvremenoga svijeta i njegove budućnosti, koja po njihovu sudu postaje upravo i središnja tema multidisciplinarnog i interdisciplinarnog područja migracijskih studija. Riječ je o raseljavanju ljudi u lokalnim i državnim okvirima te migracijama preko državnih granica, na regionalnoj i globalnoj razini, izazvanima, neposredno ili posredno, promjenama okoliša. Recentna genetska istraživanja nastanka i razvoja ljudske vrste dodatno potvrđuju da su ljudske ekološke migracije prvi i najstariji tip migracija uopće. K tome, kako sugeriraju arheološki i drugi nalazi, upravo su one ponekad igrale i ključnu ulogu u nastanku, propadanju i mijenjanju starih civilizacija. Čini se da su rani istraživači migracijskih studija imali dosta toga u vidu kad su promjene prirodnoga okoliša smatrali važnom odrednicom ljudskoga kretanja u prostoru. Taj je interes u društvenim znanostima zamro sve do druge polovine osamdesetih godina 20. stoljeća, kada se ponovno javlja. Autori prihvaćaju podjelu na uzročne kategorije »okolišnih migracija«: a) »prirodne« katastrofe; b) »urbanoindustrijske« katastrofe i c) iskorištavanje i degradacija resursa. Zatim se bave određenjem osnovnih pojmova, ponajprije prijeporom u vezi s određenjem »okolišnih izbjeglica« naspram »okolišnih migranata«. Naposljetku sistematiziraju dva glavna suprotstavljena pristupa migracijama i migrantima uvjetovanim promjenama okoliša. Prvi predstavljaju »alarmatičari«, a drugi »skeptici«. Skeptici, srećom, mogu (za sada) dokazivati da se zastrašujući crni scenariji o sve snažnijim i nezaustavljivim valovima okolišnih migranata (izbjeglica) ipak nisu ostvarili te da okolišni pokretači ljudskih migracija ne djeluju izolirano, nego u složenim sklopovima ekonomskoga, socijalnog i političkoga (ne)razvoja pojedinih političkih zajednica i cijelih regija. Ipak, oni, kao ni bilo tko drugi, ne mogu, nažalost, uvjerljivo osporiti da samo jedna kataklizmička prirodna katastrofa (kao što je udar meteora u Zemlju) može izazvati uništenje (dijela) čovječanstva i pretvaranje velikih dijelova našeg planeta u beživotna područja. Ako je ova naša (protuprirodna) civilizacija osuđena na propast, okolišni čimbenici, po svemu sudeći, bit će među njezinim grobarima.
Migracijske i etničke teme – bibliometrijska analiza časopisa za razdoblje od 1985. do 2013.
Authors:   Tekstilno-tehnološki fakultet, Sveučilište u Zagrebu, Zagreb, Hrvatska, Jokić Davor , Bartulović-Barnjak Delfa ,   Zagreb
Published: March 2015

This paper analyzes the journal Migration and Ethnic Themes during the last three decades of its publishing. The research sample consists of all the published issues of the journal from 1985 to 2013, which gives a total number of 497 papers which were subjected to bibliometric analysis. The analyzed papers were divided into the following categories: original scientific paper, preliminary report, scientific review paper, and conference paper and professional paper. The bibliographic description components that were considered relevant for the bibliometric analysis were the type of the paper, year of publication, volume/number, author, number of authors, institutions, number of pages and language of paper. Special attention was given to the analysis of the references cited in the papers. This citation analysis provided the information on the type of cited publications, the amount of cited publications, authors, year of publication of the cited publication, the name of the journal and whether it was a domestic or foreign publication. The analysis was performed on samples from three types of cited publications: books, collection of papers and journals. In order to gain insight into the reception of the research results published in Migration and Ethnic Themes, a citation analysis through the journals indexed in Web of Science and Scopus citation databases was provided. The results of this study could serve as guidelines for the future development of the journal.
FOXP3–miR-146–NF-κB Axis and Therapy for Precancerous Lesions in Prostate
Authors: Liu Runhua , Yi Bin , Wei Shi , Yang Wei-Hsiung , Hart Karen M. , Chauhan Priyanka , Zhang Wei , Mao Xicheng , Liu Xiuping , Liu Chang-Gong , Wang Lizhong
Published: February 2015

The tumor-suppressive activity of FOXP3 has been observed in tumor initiation, but the underlying mechanism still remains largely unknown. Here, we identified a FOXP3–microRNA-146 (miR-146)–NF-κB axis in vitro and in vivo in prostate cancer cells. We observed that FOXP3 dramatically induced the expression of miR-146a/b, which contributed to transcriptional inhibition of IRAK1 and TRAF6, in prostate cancer cell lines. Tissue-specific deletion of Foxp3 in mouse prostate caused a significant reduction of miR-146a and upregulation of NF-κB activation. In addition, prostatic intraepithelial neoplasia lesions were observed in miR-146a–mutant mice as well as in Foxp3-mutant mice. Notably, the NF-κB inhibitor bortezomib inhibited cell proliferation and induced apoptosis in prostate epithelial cells, attenuating prostatic intraepithelial neoplasia formation in Foxp3-mutant mice. Our data suggest that the FOXP3–miR-146–NF-κB axis has a functional role during tumor initiation in prostate cancer. Targeting the miR-146–NF-κB axis may provide a new therapeutic approach for prostate cancers with FOXP3 defects. Cancer Res; 75(8); 1714–24. ©2015 AACR.
TWIST1-Induced miR-424 Reversibly Drives Mesenchymal Programming while Inhibiting Tumor Initiation
Authors: Drasin David J. , Guarnieri Anna L. , Neelakantan Deepika , Kim Jihye , Cabrera Joshua H. , Wang Chu-An , Zaberezhnyy Vadym , Gasparini Pierluigi , Cascione Luciano , Huebner Kay , Tan Aik-Choon , Ford Heide L.
Published: February 2015

Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity. Recently, the process of an oncogenic EMT, followed by a reverse mesenchymal-to-epithelial transition (MET), has been implicated as critical in the metastatic colonization of carcinomas. Unlike governance of epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here, we describe and characterize the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that miR-424 is upregulated early during a TWIST1 or SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Furthermore, miR-424 increases motility, decreases adhesion, and induces a growth arrest, changes associated with a complete EMT that can be reversed when miR-424 expression is lowered, concomitant with an MET-like process. Breast cancer patient miR-424 levels positively associate with TWIST1/2 and EMT-like gene signatures, and miR-424 is increased in primary tumors versus matched normal breast. However, miR-424 is downregulated in patient metastases versus matched primary tumors. Correspondingly, miR-424 decreases tumor initiation and is posttranscriptionally downregulated in macrometastases in mice, suggesting the need for biphasic expression of miR-424 to transit the EMT–MET axis. Next-generation RNA sequencing revealed miR-424 regulates numerous EMT and cancer stemness-associated genes, including TGFBR3, whose downregulation promotes mesenchymal phenotypes, but not tumor-initiating phenotypes. Instead, we demonstrate that increased MAPK–ERK signaling is critical for miR-424–mediated decreases in tumor-initiating phenotypes. These findings suggest miR-424 plays distinct roles in tumor progression, potentially facilitating earlier, but repressing later, stages of metastasis by regulating an EMT–MET axis. Cancer Res; 75(9); 1908–21. ©2015 AACR.
Development and Validation of a Melanoma Risk Score Based on Pooled Data from 16 Case–Control Studies
Authors: Davies John R. , Chang Yu-mei , Bishop D. Timothy , Armstrong Bruce K. , Bataille Veronique , Bergman Wilma , Berwick Marianne , Bracci Paige M. , Elwood J. Mark , Ernstoff Marc S. , Green Adele , Gruis Nelleke A. , Holly Elizabeth A. , Ingvar Christian , Kanetsky Peter A. , Karagas Margaret R. , Lee Tim K. , Le Marchand Loïc , Mackie Rona M. , Olsson Håkan , Østerlind Anne , Rebbeck Timothy R. , Reich Kristian , Sasieni Peter , Siskind Victor , Swerdlow Anthony J. , Titus Linda , Zens Michael S. , Ziegler Andreas , Gallagher Richard P. , Barrett Jennifer H. , Newton-Bishop Julia
Published: February 2015

Background: We report the development of a cutaneous melanoma risk algorithm based upon seven factors; hair color, skin type, family history, freckling, nevus count, number of large nevi, and history of sunburn, intended to form the basis of a self-assessment Web tool for the general public.

Methods: Predicted odds of melanoma were estimated by analyzing a pooled dataset from 16 case–control studies using logistic random coefficients models. Risk categories were defined based on the distribution of the predicted odds in the controls from these studies. Imputation was used to estimate missing data in the pooled datasets. The 30th, 60th, and 90th centiles were used to distribute individuals into four risk groups for their age, sex, and geographic location. Cross-validation was used to test the robustness of the thresholds for each group by leaving out each study one by one. Performance of the model was assessed in an independent UK case–control study dataset.

Results: Cross-validation confirmed the robustness of the threshold estimates. Cases and controls were well discriminated in the independent dataset [area under the curve, 0.75; 95% confidence interval (CI), 0.73–0.78]. Twenty-nine percent of cases were in the highest risk group compared with 7% of controls, and 43% of controls were in the lowest risk group compared with 13% of cases.

Conclusion: We have identified a composite score representing an estimate of relative risk and successfully validated this score in an independent dataset.

Impact: This score may be a useful tool to inform members of the public about their melanoma risk. Cancer Epidemiol Biomarkers Prev; 24(5); 817–24. ©2015 AACR.
Dense and Nondense Mammographic Area and Risk of Breast Cancer by Age and Tumor Characteristics
Authors: Bertrand Kimberly A. , Scott Christopher G. , Tamimi Rulla M. , Jensen Matthew R. , Pankratz V. Shane , Norman Aaron D. , Visscher Daniel W. , Couch Fergus J. , Shepherd John , Chen Yunn-Yi , Fan Bo , Wu Fang-Fang , Ma Lin , Beck Andrew H. , Cummings Steven R. , Kerlikowske Karla , Vachon Celine M.
Published: February 2015

Background: Mammographic density (MD) is a strong breast cancer risk factor. We previously reported associations of percent mammographic density (PMD) with larger and node-positive tumors across all ages, and estrogen receptor (ER)–negative status among women ages <55 years. To provide insight into these associations, we examined the components of PMD [dense area (DA) and nondense area (NDA)] with breast cancer subtypes.

Methods: Data were pooled from six studies including 4,095 breast cancers and 8,558 controls. DA and NDA were assessed from digitized film-screen mammograms and standardized across studies. Breast cancer odds by density phenotypes and age according to histopathologic characteristics and receptor status were calculated using polytomous logistic regression.

Results: DA was associated with increased breast cancer risk [OR for quartiles: 0.65, 1.00 (Ref), 1.22, 1.55; Ptrend <0.001] and NDA was associated with decreased risk [ORs for quartiles: 1.39, 1.00 (Ref), 0.88, 0.72; Ptrend <0.001] across all ages and invasive tumor characteristics. There were significant trends in the magnitude of associations of both DA and NDA with breast cancer by increasing tumor size (Ptrend < 0.001) but no differences by nodal status. Among women <55 years, DA was more strongly associated with increased risk of ER+ versus ER− tumors (Phet = 0.02), while NDA was more strongly associated with decreased risk of ER− versus ER+ tumors (Phet = 0.03).

Conclusions: DA and NDA have differential associations with ER+ versus ER− tumors that vary by age.

Impact: DA and NDA are important to consider when developing age- and subtype-specific risk models. Cancer Epidemiol Biomarkers Prev; 24(5); 798–809. ©2015 AACR.
Association between Regular Aspirin Use and Circulating Markers of Inflammation: A Study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Lang Kuhs Krystle A. , Hildesheim Allan , Trabert Britton , Kemp Troy J. , Purdue Mark P. , Wentzensen Nicolas , Katki Hormuzd A. , Pinto Ligia A. , Loftfield Erikka , Safaeian Mahboobeh , Chaturvedi Anil K. , Shiels Meredith S.
Published: February 2015

Background: Regular aspirin use may decrease cancer risk by reducing chronic inflammation. However, associations between aspirin use and circulating markers of inflammation have not been well studied.

Methods: Serum levels of 78 inflammatory markers were measured in 1,819 55- to 74-year-old men and women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Data were combined from three completed case–control studies and reweighted to the PLCO screening arm. Self-reported aspirin and ibuprofen use (number of tablets taken per day/week/month) over the previous 12 months was collected at baseline. Associations between (i) nonregular (<4 tablets/month), (ii) low (1–4 tablets/week), (iii) moderate (1 tablet/day), or (iv) high (2+ tablets/day) regular aspirin or ibuprofen use and marker levels were assessed with weighted logistic regression.

Results: Aspirin use was nominally associated with (Ptrend across categories ≤ 0.05) decreased levels of chemokine C-C motif ligand 15 [CCL15; OR, 0.5; 95% confidence intervals (CI), 0.3–0.8; moderate versus nonregular use]; soluble vascular endothelial growth factor receptor 2 (sVEGFR2; OR, 0.7; 95% CI, 0.4–1.0); soluble tumor necrosis factor receptor 1 (sTNFR1; OR, 0.6; 95% CI, 0.4–0.9) and increased levels of CCL13 (OR, 1.3; 95% CI, 0.8–2.1); CCL17 (OR, 1.1; 95% CI, 0.7–1.9) and interleukin 4 (IL4; OR, 1.6; 95% CI, 0.9–2.8). Trends were not statistically significant following correction for multiple comparisons. Likewise, no statistically significant associations were observed between ibuprofen use and marker levels.

Conclusions: No significant associations were observed between regular aspirin use and the inflammatory markers assessed.

Impact: Additional studies are needed to better understand the relationship between aspirin use, chronic inflammation, and cancer risk. Cancer Epidemiol Biomarkers Prev; 24(5); 825–32. ©2015 AACR.
Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer
Authors: Azad Arun A. , Volik Stanislav V. , Wyatt Alexander W. , Haegert Anne , Le Bihan Stephane , Bell Robert H. , Anderson Shawn A. , McConeghy Brian , Shukin Robert , Bazov Jenny , Youngren Jack , Paris Pamela , Thomas George , Small Eric J. , Wang Yuzhuo , Gleave Martin E. , Collins Colin C. , Chi Kim N.
Published: February 2015

Purpose: Although novel agents targeting the androgen–androgen receptor (AR) axis have altered the treatment paradigm of metastatic castration-resistant prostate cancer (mCRPC), development of therapeutic resistance is inevitable. In this study, we examined whether AR gene aberrations detectable in circulating cell-free DNA (cfDNA) are associated with resistance to abiraterone acetate and enzalutamide in mCRPC patients.

Experimental Design: Plasma was collected from 62 mCRPC patients ceasing abiraterone acetate (n = 29), enzalutamide (n = 19), or other agents (n = 14) due to disease progression. DNA was extracted and subjected to array comparative genomic hybridization (aCGH) for chromosome copy number analysis, and Roche 454 targeted next-generation sequencing of exon 8 in the AR.

Results: On aCGH, AR amplification was significantly more common in patients progressing on enzalutamide than on abiraterone or other agents (53% vs. 17% vs. 21%, P = 0.02, χ2). Missense AR exon 8 mutations were detected in 11 of 62 patients (18%), including the first reported case of an F876L mutation in an enzalutamide-resistant patient and H874Y and T877A mutations in 7 abiraterone-resistant patients. In patients switched onto enzalutamide after cfDNA collection (n = 39), an AR gene aberration (copy number increase and/or an exon 8 mutation) in pretreatment cfDNA was associated with adverse outcomes, including lower rates of PSA decline ≥ 30% (P = 0.013, χ2) and shorter time to radiographic/clinical progression (P = 0.010, Cox proportional hazards regression).

Conclusions: AR gene aberrations in cfDNA are associated with resistance to enzalutamide and abiraterone in mCRPC. Our data illustrate that genomic analysis of cfDNA is a minimally invasive method for interrogating mechanisms of therapeutic resistance in mCRPC. Clin Cancer Res; 21(10); 2315–24. ©2015 AACR.
Nrf2-Dependent Suppression of Azoxymethane/Dextran Sulfate Sodium–Induced Colon Carcinogenesis by the Cinnamon-Derived Dietary Factor Cinnamaldehyde
Authors: Long Min , Tao Shasha , Rojo de la Vega Montserrat , Jiang Tao , Wen Qing , Park Sophia L. , Zhang Donna D. , Wondrak Georg T.
Published: February 2015

The progressive nature of colorectal cancer and poor prognosis associated with the metastatic phase of the disease create an urgent need for the development of more efficacious strategies targeting colorectal carcinogenesis. Cumulative evidence suggests that the redox-sensitive transcription factor Nrf2 (nuclear factor-E2–related factor 2), a master regulator of the cellular antioxidant defence, represents a promising molecular target for colorectal cancer chemoprevention. Recently, we have identified cinnamon, the ground bark of Cinnamomum aromaticum (cassia cinnamon) and Cinnamomum verum (Ceylon cinnamon), as a rich dietary source of the Nrf2 inducer cinnamaldehyde (CA) eliciting the Nrf2-regulated antioxidant response in human epithelial colon cells, conferring cytoprotection against electrophilic and genotoxic insult. Here, we have explored the molecular mechanism underlying CA-induced Nrf2 activation in colorectal epithelial cells and have examined the chemopreventive potential of CA in a murine colorectal cancer model comparing Nrf2+/+ with Nrf2−/− mice. In HCT116 cells, CA caused a Keap1-C151–dependent increase in Nrf2 protein half-life via blockage of ubiquitination with upregulation of cytoprotective Nrf2 target genes and elevation of cellular glutathione. After optimizing colorectal Nrf2 activation and target gene expression by dietary CA-supplementation regimens, we demonstrated that CA suppresses AOM/DSS-induced inflammatory colon carcinogenesis with modulation of molecular markers of colorectal carcinogenesis. Dietary suppression of colorectal cancer using CA supplementation was achieved in Nrf2+/+ but not in Nrf2−/− mice confirming the Nrf2 dependence of CA-induced chemopreventive effects. Taken together, our data suggest feasibility of colorectal cancer suppression by dietary CA, an FDA-approved food additive derived from the third most consumed spice in the world. Cancer Prev Res; 8(5); 444–54. ©2015 AACR.
CXCR4 Is a Novel Target of Cancer Chemopreventative Isothiocyanates in Prostate Cancer Cells
Authors: Sakao Kozue , Vyas Avani R. , Chinni Sreenivasa R. , Amjad Ali I. , Parikh Rahul , Singh Shivendra V.
Published: February 2015

Isothiocyanates (ITCs) derived from cruciferous vegetables, including phenethyl isothiocyanate (PEITC) and sulforaphane (SFN), exhibit in vivo activity against prostate cancer in a xenograft and transgenic mouse model, and thus are appealing for chemoprevention of this disease. Watercress constituent PEITC and SFN-rich broccoli sprout extract are under clinical investigations but the molecular mechanisms underlying their cancer chemopreventive effects are not fully understood. The present study demonstrates that chemokine receptor CXCR4 is a novel target of ITCs in prostate cancer cells. Exposure of prostate cancer cells (LNCaP, 22Rv1, C4-2, and PC-3) to pharmacologically applicable concentrations of PEITC, benzyl isothiocyanate (BITC), and SFN (2.5 and 5 μmol/L) resulted in downregulation of CXCR4 expression. None of the ITCs affected secretion of CXCR4 ligand (stromal-derived factor-1). In vivo inhibition of PC-3 xenograft growth upon PEITC treatment was associated with a significant decrease in CXCR4 protein level. A similar trend was discernible in the tumors from SFN-treated TRAMP mice compared with those of control mice, but the difference was not significant. Stable overexpression of CXCR4 in PC-3 cells conferred significant protection against wound healing, cell migration, and cell viability inhibition by ITCs. Inhibition of cell migration resulting from PEITC and BITC exposure was significantly augmented by RNAi of CXCR4. This study demonstrates, for the first time, that cancer chemopreventive ITCs suppress CXCR4 expression in prostate cancer cells in vitro as well as in vivo. These results suggest that CXCR4 downregulation may be an important pharmacodynamic biomarker of cancer chemopreventative ITCs in prostate adenocarcinoma. Cancer Prev Res; 8(5); 365–74. ©2015 AACR.
Fenretinide Perturbs Focal Adhesion Kinase in Premalignant and Malignant Human Oral Keratinocytes. Fenretinide's Chemopreventive Mechanisms Include ECM Interactions
Authors: Han Byungdo B. , Li Suyang , Tong Meng , Holpuch Andrew S. , Spinney Richard , Wang Daren , Border Michael B. , Liu Zhongfa , Sarode Sachin , Pei Ping , Schwendeman Steven P. , Mallery Susan R.
Published: February 2015

The membrane-associated protein, focal adhesion kinase (FAK), modulates cell–extracellular matrix interactions and also conveys prosurvival and proliferative signals. Notably, increased intraepithelial FAK levels accompany transformation of premalignant oral intraepithelial neoplasia (OIN) to oral squamous cell carcinoma (OSCC). OIN chemoprevention is a patient-centric, optimal strategy to prevent OSCC's comorbidities and mortality. The cancer chemopreventive and synthetic vitamin A derivative, fenretinide, has demonstrated protein-binding capacities, for example, mTOR- and retinol-binding protein interactions. These studies used a continuum of human oral keratinocytes (normal-HPV E6/E7-transduced-OSCC) to assess potential fenretinide–FAK drug protein interactions and functional consequences on cellular growth regulation and motility. Molecular modeling studies demonstrated that fenretinide has approximately 200-fold greater binding affinity relative to the natural ligand (ATP) at FAK's kinase domain. Fenretinide also shows intermediate binding at FAK's FERM domain and interacts at the ATP-binding site of the closest FAK analogue, PYK2. Fenretinide significantly suppressed proliferation via induction of apoptosis and G2–M cell-cycle blockade. Fenretinide-treated cells also demonstrated F-actin disruption, significant inhibition of both directed migration and invasion of a synthetic basement membrane, and decreased phosphorylation of growth-promoting kinases. A commercially available FAK inhibitor did not suppress cell invasion. Notably, although FAK's FERM domain directs cell invasion, FAK inhibitors target the kinase domain. In addition, FAK-specific siRNA–treated cells showed an intermediate cell migration capacity; data which suggest cocontribution of the established migrating-enhancing PYK2. Our data imply that fenretinide is uniquely capable of disrupting FAK's and PYK2′s prosurvival and mobility-enhancing effects and further extend fenretinide's chemopreventive contributions beyond induction of apoptosis and differentiation. Cancer Prev Res; 8(5); 419–30. ©2015 AACR.
A Randomised Phase II Trial Comparing Docetaxel Plus Prednisone with Docetaxel Plus Prednisone Plus Low-Dose Cyclophosphamide in Castration-Resistant Prostate Cancer
Authors: Porsch Markus , Ulrich Matthias , Wendler Johann Jakob , Liehr Uwe-Bernd , Reiher Frank , Janitzky Andreas , Baumunk Daniel , Schindele Daniel , Seseke Florian , Lux Anke , Schostak Martin
Published: February 2015

Background: Docetaxel plus prednisone is a standard treatment for castration-resistant prostate cancer. Cyclophosphamide may be an effective combination partner. Methods: This randomised, multicentre, phase II trial compared the combination therapy of docetaxel plus prednisone plus cyclophosphamide with the standard therapy of docetaxel plus prednisone. Results: Thirty-three patients received six 3-week treatment cycles (in total 171 cycles). During treatment, an adequate decline in prostate-specific antigen was seen in both groups (p = 0.068) without between-group differences (p = 0.683). No relevant differences between within-group changes were observed for blood pressure, weight, pain score, laboratory variables or quality of life. There were no serious side effects apart from leucopenia requiring treatment (docetaxel + prednisone + cyclophosphamide arm) and no drug-related withdrawals; all three fatalities were considered to be cancer related. Conclusions: The oncological effectiveness and tolerability of docetaxel plus prednisone were supported; an additional effect of cyclophosphamide was not detected. However, the small number of patients and short observation period restrict the generalisability of the results.
Suppressive Effect of Matrine on Tumor Invasion in N-Butyl-N-(4-Hydroxybutyl)Nitrosamine-Induced Urinary Bladder Carcinogenesis
Authors: Gao Hua , Guo Yafang , Deng Ning , Fei Pingxia , Qiu Xiaofeng , Zheng Ping , Feng Jun , Dai Guidong
Published: February 2015

Aims: This study was designed to investigate the mechanisms and suppressive effects of matrine on the development of urinary bladder cancers induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in rats. Methods: Male Sprague-Dawley rats were given BBN (200 mg/rat) twice a week for a period of 8 weeks. Oral administration of matrine (50 and 100 mg/kg) was started 1 week before BBN exposure for 35 weeks. Half of each bladder was histopathologically analyzed and the remainder was extracted for protein analysis by Western blot. Results: The bladders of BBN-treated rats demonstrated progression from epithelial hyperplasia to papillary urothelial neoplasia and even poorly differentiated invasive cancer. Matrine (50 and 100 mg/kg) treatment decreased the formation of large bladder tumors by 31.6 and 21.1%, respectively. An incidence of cancer cells was detected in rats given BBN [70% (14/20)] and matrine [50 mg/kg: 68.4% (13/19) and 100 mg/kg: 57.9% (11/19), respectively]. The frequency of invasive tumors in the matrine treatment groups [50 mg/kg: 15.4% (2/13), 100 mg/kg: 9.1% (1/11)] was significantly lower than in the BBN-alone group [57% (8/14)]. Furthermore, oral administration of matrine (50 and 100 mg/kg) markedly attenuated the BBN-induced upregulation of bladder cyclooxygenase-2 (COX-2) expression and the elevation of bladder cytosolic phospholipase A2 (cPLA2) levels. Although the contents of 15-prostaglandin dehydrogenase (PGDH), which degrades PGE2, were dramatically reduced by BBN, matrine exerted no effects on reduced PGDH contents. Conclusion: Our results suggest that matrine suppressed bladder tumor invasion in a rat model, and this might be primarily mediated through regulation of the protein contents, COX-2 and cPLA2 in the bladder.
Vitamin K Antagonists Predispose to Calciphylaxis in Patients with End-Stage Renal Disease
Authors: Galloway Peter A.G. , El-Damanawi Ragada , Bardsley Victoria , Pritchard Nicholas R. , Fry Andrew C. , Ojha Sanjay K. , Hiemstra Thomas F.
Published: February 2015

Background/Aims: Calciphylaxis is associated with a poor prognosis in dialysis patients, and its pathogenesis remains incompletely understood. Although the use of vitamin K antagonists (VKA) has been implicated, previous reports are conflicting. We aimed to determine if vitamin K antagonists conferred an increased risk of calciphylaxis in patients on dialysis. Methods: We performed a single-centre, retrospective cohort study of 2,234 patients receiving dialysis, and compared the characteristics of those with and without calciphylaxis. Results: We identified 5 cases of calciphylaxis (all female) between January 2009 and December 2013. Overall, 142 patients (6.4%) were treated with VKA during the study period. Calciphylaxis was more common in the VKA group (4 of 142 patients, OR = 61, 95% CI 6.7-546, p = 0.0001). VKA was withdrawn in all cases and treatment instituted with sodium thiosulphate, cinacalcet and supportive measures. All patients recovered, although there was one sudden cerebrovascular death during follow-up. Conclusion: Treatment with VKA predisposes to the development of calciphylaxis.
Phase Changing Material: An Alternative Method for Cooling Babies with Hypoxic Ischaemic Encephalopathy
Authors: Thomas Niranjan , Chakrapani Yogeshwar , Rebekah Grace , Kareti Kalyani , Devasahayam Suresh
Published: February 2015

Background: Therapeutic hypothermia for hypoxic ischaemic encephalopathy (HIE) has been proved effective. Standard equipment is expensive, while ice packs used in low resource settings are labour intensive and associated with wider temperature fluctuations. Objectives: To assess the feasibility of using phase changing material (PCM) as an alternative method for providing therapeutic hypothermia. Methods: We retrospectively analysed 41 babies with HIE who had been cooled with PCM (OM 32™ or HS 29™) to a target rectal temperature of 33-34°C. Rectal temperature was continuously monitored and recorded every hour. If the rectal temperature was >33.8°C, cool gel packs were applied, and if the temperature was <33.2°C, the baby was covered with sheets and the warmer output turned on till the temperature stabilized at 33.5°C. The unit's standard protocol for cooling was followed for monitoring and treatment. The outcome measures were stability and fluctuation of the rectal temperature and the need for interventions to maintain the target temperature. Results: The mean (±SD) temperature during the cooling phase was 33.45 ± 0.26°C. Throughout the cooling phase, the target temperature range was maintained in 96.2% of the time. There was no temperature reading <32°C. With HS 29, ice packs were not used in any baby, and the warmer was used for a median of 7 h (interquartile range 1.5-14). Conclusions: PCM provides a low cost and effective method to maintain therapeutic hypothermia. However, careful monitoring is required during induction and the rewarming phase to avoid hypothermia outside the therapeutic range.