bluuebunny/crossref_metadata_2025 huggingface dataset:
A Rare Case of Renal Recovery in a Young Patient with Multiple Myeloma
Authors: Salameh Hasan J. , Ahmad Adeel , Kochar Tina
Published: March 2013

Multiple myeloma (MM) is an uncommon hematologic malignancy accounting for 1% of all malignancies. Renal involvement is a common complication of MM. Rapid intervention to reverse renal dysfunction may be critical for management, especially in patients with light chain cast nephropathy. Recovery rate ranges from 5% to 15%. We describe an atypical presentation of MM in a young patient who presented with severe renal insufficiency requiring renal replacement therapy and achieved complete renal recovery with chemotherapy.
Inclusion-Body Myositis Associated with Alzheimer’s Disease
Authors: Levacic Danijela , Peddareddygari Leema Reddy , Nochlin David , Sharer Leroy R. , Grewal Raji P.
Published: March 2013

Sporadic inclusion-body myositis (s-IBM) is a myopathy that is characterized by progressive weakness and muscle pathology demonstrating inflammation and rimmed vacuoles. In addition, similar to the pathology observed in the brains of patients with Alzheimer’s disease, the deposition of beta-amyloid and phosphorylated tau proteins in muscle fibers has been reported. These shared pathologic features have prompted hypotheses suggesting a shared etiology of these two conditions. We report a case of a 73-year-old woman initially diagnosed with s-IBM who later developed Alzheimer’s disease.
Travel-AssociatedSalmonella mbandakaSacroiliac Osteomyelitis in a Healthy Adolescent
Authors: Le Doare Kirsty , Brooker Elspeth , Ladhani Shamez
Published: March 2013

Pyogenic infections of the sacroiliac joint are rare and usually caused byStaphylococcus aureus. We describe a case of a 16 year-old gymnast who was subsequently diagnosed withSalmonella mbandakasacroiliac osteomyelitis with adjacent psoas abscess and hepatitis one week after returning from a holiday in Crete. This case highlights a rare presentation of a common travel-associated foodborne infection.
In Vitro Construction of Scaffold-Free Bilayered Tissue-Engineered Skin Containing Capillary Networks
Authors: Liu Yuan , Luo Hailang , Wang Xinwen , Takemura Akimichi , Fang Yi Ru , Jin Yan , Suwa Fumihiko
Published: March 2013

Many types of skin substitutes have been constructed using exogenous materials. Angiogenesis is an important factor for tissue-engineered skin constructs. In this study, we constructed a scaffold-free bilayered tissue-engineered skin containing a capillary network. First, we cocultured dermal fibroblasts with dermal microvascular endothelial cells at a ratio of 2 : 1. A fibrous sheet was formed by the interactions between the fibroblasts and the endothelial cells, and capillary-like structures were observed after 20 days of coculture. Epithelial cells were then seeded on the fibrous sheet to assemble the bilayered tissue. HE staining showed that tissue-engineered skin exhibited a stratified epidermis after 7 days. Immunostaining showed that the epithelium promoted the formation of capillary-like structures. Transmission electron microscopy (TEM) analysis showed that the capillary-like structures were typical microblood vessels. ELISA demonstrated that vascularization was promoted by significant upregulation of vascularization associated growth factors due to interactions among the 3 types of cells in the bilayer, as compared to cocultures of fibroblast and endothelial cells and monocultures.
Intrahost Diversity of Feline Coronavirus: A Consensus between the Circulating Virulent/Avirulent Strains and the Internal Mutation Hypotheses?
Authors: Hora Aline S. , Asano Karen M. , Guerra Juliana M. , Mesquita Ramon G. , Maiorka Paulo , Richtzenhain Leonardo J. , Brandão Paulo E.
Published: March 2013

To evaluate the most controversial issue concerning current feline coronavirus (FCoV) virology, the coexisting hypotheses of the intrahost and interhost origins of feline infectious peritonitis virus (FIPV) in regard to the pathogenesis of feline infectious peritonitis (FIP), this study aimed to assess the molecular diversity of the membrane gene FCoVs in 190 samples from 10 cats with signs of FIP and in 5 faecal samples from cats without signs of FIP. All samples from the non‐FIP cats and 25.26% of the samples from the FIP cats were positive for the FCoV membrane (M) gene. Mutations in this gene consisted of SNP changes randomly scattered among the sequences; few mutations resulted in amino acid changes. No geographic pattern was observed. Of the cats without FIP that harboured FECoV, the amino acid sequence identities for the M gene were 100% among cats (Cats 1–3) from the same cattery, and the overall sequence identity for the M gene was ≥91%. In one cat, two different lineages of FCoV, one enteric and one systemic, were found that segregated apart in the M gene tree. In conclusion, the in vivo mutation transition hypothesis and the circulating high virulent‐low virulent FCoV hypothesis have been found to be plausible according to the results obtained from sequencing the M gene.
Evidence for Bone Marrow Adult Stem Cell Plasticity: Properties, Molecular Mechanisms, Negative Aspects, and Clinical Applications of Hematopoietic and Mesenchymal Stem Cells Transdifferentiation
Authors: Catacchio Ivana , Berardi Simona , Reale Antonia , De Luisi Annunziata , Racanelli Vito , Vacca Angelo , Ria Roberto
Published: March 2013

In contrast to the pluripotentembryonic stem cells(ESCs) which are able to give rise to all cell types of the body, mammalianadult stem cells(ASCs) appeared to be more limited in their differentiation potential and to be committed to their tissue of origin. Recently, surprising new findings have contradicted central dogmas of commitment of ASCs by showing their plasticity to differentiate across tissue lineage boundaries, irrespective of classical germ layer designations. The present paper supports the plasticity of thebone marrow stem cells(BMSCs), bringing the most striking and the latest evidences of the transdifferentiation properties of thebone marrow hematopoietic and mesenchymal stem cells(BMHSCs, and BMMSCs), the two BM populations of ASCs better characterized. In addition, we report the possible mechanisms that may explain these events, outlining the clinical importance of these phenomena and the relative problems.
Study of Dielectric Relaxation Behavior of Liquid Crystal Copolyester Vectra-A by Thermally Stimulated Discharge Current Technique
Authors: Kalia Sapna , Sharma J. K. , Sharma Vandana
Published: March 2013

The dielectric relaxation behavior of thermotropic liquid crystal copolyester of 73% of p-hydroxy-benzoic acid (HBA) and 27% of 2-hydroxy-6-naphthoic acid (HNA) (Vectra-A) at poling temperature 80°C has been studied using thermally stimulated depolarization current (TSDC) technique in the temperature range from 15°C to 250°C. The TSD currents were obtained for different polarizing fields ranging from 3.8 kV/cm to 19.2 kV/cm. TSD current spectra in the temperature range from 15°C to 250°C show three current maxima around 25°C, 110°C, and 220°C. The maxima around 25°C and 110°C correspond to characteristic dipolar relaxations β and α, respectively. The peak around 220°C is due to space charge effects named as δ-relaxation. The various relaxation parameters like activation energy (U), relaxation strength , preexponential factor , the quantity of charge released (Q) and concentration of trap for β- and α-relaxations at polarizing temperature 80°C for different polarizing fields were evaluated using Bucci-Fieschi fit. The linear variation between activation energy and natural logarithm of preexponential factor indicates the presence of compensation effect for dipolar relaxations of Vectra-A under present poling conditions.
Iterative Methods for Pseudocontractive Mappings in Banach Spaces
Authors: Jung Jong Soo
Published: March 2013

LetEa reflexive Banach space having a uniformly Gâteaux differentiable norm. LetCbe a nonempty closed convex subset ofE,T:C→Ca continuous pseudocontractive mapping withF(T)≠∅, andA:C→Ca continuous bounded strongly pseudocontractive mapping with a pseudocontractive constantk∈(0,1). Let{αn}and{βn}be sequences in(0,1)satisfying suitable conditions and for arbitrary initial valuex0∈C, let the sequence{xn}be generated byxn=αnAxn+βnxn-1+(1-αn-βn)Txn,  n≥1.If either every weakly compact convex subset ofEhas the fixed point property for nonexpansive mappings orEis strictly convex, then{xn}converges strongly to a fixed point ofT, which solves a certain variational inequality related toA.
A Regularity Criterion for the Magneto-Micropolar Fluid Equations inB˙∞,∞−1
Authors: Tang Zhihao , Wang Gang , Guan Haiwa
Published: March 2013

The paper is dedicated to study of the Cauchy problem for the magneto-micropolar fluid equations in three-dimensional spaces. A new logarithmically improved regularity criterion for the magneto-micropolar fluid equations is established in terms of the pressure in the homogeneous Besov spaceB˙∞,∞−1.
Prevalence of High Blood Pressure, Heart Disease, Thalassemia, Sickle-Cell Anemia, and Iron-Deficiency Anemia among the UAE Adolescent Population
Authors: Barakat-Haddad Caroline
Published: March 2013

This study examined the prevalence of high blood pressure, heart disease, and medical diagnoses in relation to blood disorders, among 6,329 adolescent students (age 15 to 18 years) who reside in the United Arab Emirates (UAE). Findings indicated that the overall prevalence of high blood pressure and heart disease was 1.8% and 1.3%, respectively. Overall, the prevalence for thalassemia, sickle-cell anemia, and iron-deficiency anemia was 0.9%, 1.6%, and 5%, respectively. Bivariate analysis revealed statistically significant differences in the prevalence of high blood pressure among the local and expatriate adolescent population in the Emirate of Sharjah. Similarly, statistically significant differences in the prevalence of iron-deficiency anemia were observed among the local and expatriate population in Abu Dhabi city, the western region of Abu Dhabi, and Al-Ain. Multivariate analysis revealed the following significant predictors of high blood pressure: residing in proximity to industry, nonconventional substance abuse, and age when smoking or exposure to smoking began. Ethnicity was a significant predictor of heart disease, thalassemia, sickle-cell anemia, and iron-deficiency anemia. In addition, predictors of thalassemia included gender (female) and participating in physical activity. Participants diagnosed with sickle-cell anemia and iron-deficiency anemia were more likely to experience different physical activities.
The Antibacterial Effect of Ethanol Extract of Polish Propolis on Mutans Streptococci and Lactobacilli Isolated from Saliva
Authors: Dziedzic Arkadiusz , Kubina Robert , Wojtyczka Robert D. , Kabała-Dzik Agata , Tanasiewicz Marta , Morawiec Tadeusz
Published: March 2013

Dental caries occurrence is caused by the colonization of oral microorganisms and accumulation of extracellular polysaccharides synthesized byStreptococcus mutanswith the synergistic influence ofLactobacillusspp. bacteria. The aim of this study was to determineex vivothe antibacterial properties of ethanol extract of propolis (EEP), collected in Poland, against the main cariogenic bacteria: salivary mutans streptococci and lactobacilli. The isolation of mutans streptococci group bacteria (MS) andLactobacillusspp. (LB) from stimulated saliva was performed by in-office CRT bacteria dip slide test. The broth diffusion method and AlamarBlue assay were used to evaluate the antimicrobial activity of EEP, with the estimation of its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The biochemical composition of propolis components was assessed. The mean MIC and MBC values of EEP, in concentrations ranging from 25 mg/mL to 0.025 mg/mL, for the MS and LB were found to be 1.10 mg/mLversus0.7 mg/mL and 9.01 mg/mLversus5.91 mg/mL, respectively. The exposure to an extract of Polish propolis affected mutans streptococci andLactobacillusspp. viability, exhibiting an antibacterial efficacy on mutans streptococci group bacteria and lactobacilli saliva residents, while lactobacilli were more susceptible to EEP. Antibacterial measures containing propolis could be the local agents acting against cariogenic bacteria.
Transmigration of Mandibular Canines
Authors: Umashree N. , Kumar Avinash , Nagaraj Tejavathi
Published: March 2013

The purpose of this paper is to present the first case of unusual reverse oblique (110 degrees to midsagittal plane) migration of mandibular right canine crossing the jaw midline and piercing the lower border of the mandible at the level of the opposite canine and also to report two more cases of transmigrated mandibular canine and one case of transmigrating mandibular canine. Mandibular canines are “cornerstone” of dental arch; their importance is manifested by their efficiency in masticatory function, stability of dental arch, and aid in maintaining natural facial expression. Early detection of this anomaly can help preserving these canines by orthodontic intervention or by surgical transplantation. This developmental anomaly is properly diagnosed by radiographic evaluation, which is primarily based on the panoramic radiograph. In patients with overretained deciduous canines or missing permanent canines, an intraoral radiograph should be supplemented with panoramic radiograph. This paper discusses the importance of early diagnosis of canine transmigration in treatment planning and reviews the various possible treatment options.
Takotsubo Cardiomyopathy following a L2–L5 Laminectomy and Fusion In Situ with Bone Morphogenic Protein
Authors: Weaver John , Eubanks Jason
Published: March 2013

Takotsubo cardiomyopathy (TC) is a rare, transient cardiomyopathy, with symptoms mimicking myocardial infarction. It has been reported to typically occur in postmenopausal women and is often triggered by an intense physical or emotional event with stimulation of the sympathetic response; the exact etiology, however, is uncertain. Bone morphogenic protein (BMP) is widely used in spinal fusions and has been associated with numerous perioperative complications. BMP is known to stimulate sympathetic pathways. In this paper, we present the case of a patient with a 7-hour episode of TC after a spinal fusion with bone morphogenic protein. The patient's symptoms resolved and long-term followup has been uneventful. This is the first paper to describe TC in the setting of spine or other major orthopaedic surgery and it suggests another possible area for further investigation in peri-operative events potentially associated with the use of bone morphogenic protein.
A General Iterative Algorithm with Strongly Positive Operators for Strict Pseudo-Contractions
Authors: Xu Wei , Wang Yuanheng
Published: March 2013

This paper deals with a new iterative algorithm{xn}with a strongly positive operatorAfor ak-strict pseudo-contractionTand a non-self-Lipschitzian mappingSin Hilbert spaces. Under certain appropriate conditions, the sequence{xn}converges strongly to a fixed point ofT, which solves some variational inequality. The results here improve and extend some recent related results.
Bacterial Filtration Using Carbon Nanotube/Antibiotic Buckypaper Membranes
Authors: Sweetman Luke J. , Alcock Leighton J. , McArthur Jason D. , Stewart Elise M. , Triani Gerry , in het Panhuis Marc , Ralph Stephen F.
Published: March 2013

The preparation of free‐standing carbon nanotube “buckypaper” (BP) membranes consisting of either single‐walled carbon nanotubes (SWNTs) or multi‐walled carbon nanotubes (MWNTs), and the antibiotic ciprofloxacin (cipro), is reported. The electrical, mechanical and morphological properties of these membranes have been characterised and are compared to those of the corresponding buckypaper membranes containing the surfactant Triton X‐100 (Trix). Analysis of scanning electron microscopic images of the surfaces of SWNT/cipro and SWNT/Trix (Trix  =  Triton X‐100) buckypapers revealed that the diameter of their surface pores was significantly smaller than that of the corresponding materials prepared using MWNTs. Similarly, the average internal pore diameter of both SWNT buckypapers was found to be smaller than that of their MWNT counterparts, after analysis of binding isotherms derived from nitrogen adsorption/desorption measurements performed on the materials. All four buckypaper membranes examined were found to be >99% effective for removing Escherichia coli (E. coli) from aqueous suspensions. However, buckypapers containing ciprofloxacin outperformed their counterparts containing the surfactant. Both MWNT buckypapers were more effective at preventing passage of E. coli than their analogues containing SWNTs, while fluorescence microscopic examination of stained membrane surfaces demonstrated that buckypapers composed of SWNTs had greater bactericidal properties.
Online Monitoring and Analysis of Hydroabrasive Cutting by Vibration
Authors: Hloch Sergej , Ruggiero Alessandro
Published: March 2013

The paper deals with the investigation of accompanying physical process, vibration, arising from the abrasive waterjet cutting of stainless steel. Samples of the square cross-section with the use of preplanned range of technological factors were cut. During the cutting of target material AISI 309 vibration by piezoelectrical accelerometers PCB IMI 607 A11 was recorded. The accelerometers were oriented perpendicular to the direction of the cut. Scanned data were processed through a virtual instrument created in LabVIEW 6.8. Sampling frequency of the recorded signal was 30 kHz. Investigated was development of the RMS value in particular frequencies. In order to confirm hypothetical assumptions about direct relation between vibration emission and surface quality, further experiment will be done. Current results are possible used for detection of defects during hydroabrasive cutting of materials, in case of focusing tube fracture, orifice damage in the cutting head, in case of fragile material cutting by means of controlled penetration.
Existence of Solutions for Generalized Vector Quasi-Equilibrium Problems by Scalarization Method with Applications
Authors: Qu De-ning , Cheng Cao-zong
Published: March 2013

The aim of this paper is to study generalized vector quasi-equilibrium problems (GVQEPs) by scalarization method in locally convex topological vector spaces. A general nonlinear scalarization function for set-valued mappings is introduced, its main properties are established, and some results on the existence of solutions of the GVQEPs are shown by utilizing the introduced scalarization function. Finally, a vector variational inclusion problem is discussed as an application of the results of GVQEPs.
Test-Cost-Sensitive Attribute Reduction of Data with Normal Distribution Measurement Errors
Authors: Zhao Hong , Min Fan , Zhu William
Published: March 2013

The measurement error with normal distribution is universal in applications. Generally, smaller measurement error requires better instrument and higher test cost. In decision making, we will select an attribute subset with appropriate measurement error to minimize the total test cost. Recently, error-range-based covering rough set with uniform distribution error was proposed to investigate this issue. However, the measurement errors satisfy normal distribution instead of uniform distribution which is rather simple for most applications. In this paper, we introduce normal distribution measurement errors to covering-based rough set model and deal with test-cost-sensitive attribute reduction problem in this new model. The major contributions of this paper are fourfold. First, we build a new data model based on normal distribution measurement errors. Second, the covering-based rough set model with measurement errors is constructed through the “3-sigma” rule of normal distribution. With this model, coverings are constructed from data rather than assigned by users. Third, the test-cost-sensitive attribute reduction problem is redefined on this covering-based rough set. Fourth, a heuristic algorithm is proposed to deal with this problem. The experimental results show that the algorithm is more effective and efficient than the existing one. This study suggests new research trends concerning cost-sensitive learning.
Synthesis, Characterization, Mössbauer Parameters, and Antitumor Activity of Fe(III) Curcumin Complex
Authors: Khalil Mutasim Ibrahim , Al-Zahem Aisha Mohamed , Al-Qunaibit Maha Hamad
Published: March 2013

Curcumin-Fe(III) complex was prepared from Fe(NO3)3·9H2O precursor and curcumin by refluxing a slightly basic methanolic solution of their mixture with the objective of investigating its cytotoxicity. The enol form of curcumin ligand was established by FTIR, UV/Vis,1H NMR, and13C NMR spectroscopy. The as-prepared product was characterized by elemental analysis, FTIR, UV, and Mössbauer spectroscopic techniques. An octahedral high-spin Fe(III) complex was obtained,δ, 0.37 mms−1; Q.S., 0.79 mms−1; no magnetic relaxation was observed at liquid N2temperature, neither reduction of Fe(III). The tested cytotoxicity of the as-prepared complex on four cancer cell lines indicated inhibition of the curcumin activity upon complexing with iron.
Improved Survival with HPV among African Americans with Oropharyngeal Cancer
Authors: Worsham Maria J. , Stephen Josena K. , Chen Kang Mei , Mahan Meredith , Schweitzer Vanessa , Havard Shaleta , Divine George
Published: March 2013

Purpose: A major limitation of studies reporting a lower prevalence rate of human papilloma virus (HPV) in African American patients with oropharyngeal squamous cell cancer (OPSCC) than Caucasian Americans, with corresponding worse outcomes, was adequate representation of HPV-positive African American patients. This study examined survival outcomes in HPV-positive and HPV-negative African Americans with OPSCC.

Experimental Design: The study cohort of 121 patients with primary OPSCC had 42% African Americans. Variables of interest included age, race, gender, HPV status, stage, marital status, smoking, treatment, and date of diagnosis.

Results: Caucasian Americans are more likely to be HPV positive (OR = 3.28; P = 0.035), as are younger age (age < 50 OR = 7.14; P = 0.023 compared with age > 65) or being married (OR = 3.44; P = 0.016). HPV positivity and being unmarried were associated with being late stage (OR = 3.10; P = 0.047 and OR = 3.23; P = 0.038, respectively). HPV-negative patients had 2.7 times the risk of death as HPV-positive patients (P = 0.004). Overall, the HPV-race groups differed (log-rank P < 0.001), with significantly worse survival for HPV-negative African Americans versus (i) HPV-positive African Americans (HR = 3.44; P = 0.0012); (ii) HPV-positive Caucasian Americans (HR = 3.11; P = < 0.049); and (iii) HPV-negative Caucasian Americans (HR = 2.21; P = 0.049).

Conclusions: HPV has a substantial impact on overall survival in African American patients with OPSCC. Among African American patients with OPSCC, HPV-positive patients had better survival than HPV negative. HPV-negative African Americans also did worse than both HPV-positive Caucasian Americans and HPV-negative Caucasian Americans. This study adds to the mounting evidence of HPV as a racially linked sexual behavior life style risk factor impacting survival outcomes for both African American and Caucasian American patients with OPSCC. Clin Cancer Res; 19(9); 2486–92. ©2013 AACR.
Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET
Authors: Basilico Cristina , Pennacchietti Selma , Vigna Elisa , Chiriaco Cristina , Arena Sabrina , Bardelli Alberto , Valdembri Donatella , Serini Guido , Michieli Paolo
Published: March 2013

Purpose: MET, the high-affinity receptor for hepatocyte growth factor, is frequently deregulated in human cancer. Tivantinib (ARQ197; Arqule), a staurosporine derivative that binds to the dephosphorylated MET kinase in vitro, is being tested clinically as a highly selective MET inhibitor. However, the mechanism of action of tivantinib is still unclear.

Experimental Design: The activity of tivantinib was analyzed in multiple cellular models, including: cells displaying c-MET gene amplification, strictly ‘addicted’ to MET signaling; cells with normal c-MET gene copy number, not dependent on MET for growth; cells not expressing MET; somatic knockout cells in which the ATP-binding cleft of MET, where tivantinib binds, was deleted by homologous recombination; and a cell system ‘poisoned’ by MET kinase hyperactivation, where cells die unless cultured in the presence of a specific MET inhibitor.

Results: Tivantinib displayed cytotoxic activity independently of c-MET gene copy number and regardless of the presence or absence of MET. In both wild-type and isogenic knockout cells, tivantinib perturbed microtubule dynamics, induced G2/M arrest, and promoted apoptosis. Tivantinib did not rescue survival of cells ‘poisoned’ by MET kinase hyperactivation, but further incremented cell death. In all cell models analyzed, tivantinib did not inhibit HGF-dependent or -independent MET tyrosine autophosphorylation.

Conclusions: We conclude that tivantinib displays cytotoxic activity via molecular mechanisms that are independent from its ability to bind MET. This notion has a relevant impact on the interpretation of clinical results, on the design of future clinical trials, and on the selection of patients receiving tivantinib treatment. Clin Cancer Res; 19(9); 2381–92. ©2013 AACR.
Sorafenib in Combination with Oxaliplatin, Leucovorin, and Fluorouracil (Modified FOLFOX6) as First-line Treatment of Metastatic Colorectal Cancer: The RESPECT Trial
Authors: Tabernero Josep , Garcia-Carbonero Rocio , Cassidy James , Sobrero Alberto , Van Cutsem Eric , Köhne Claus-Henning , Tejpar Sabine , Gladkov Oleg , Davidenko Irina , Salazar Ramon , Vladimirova Liubov , Cheporov Sergey , Burdaeva Olga , Rivera Fernando , Samuel Leslie , Bulavina Irina , Potter Vanessa , Chang Yu-Lin , Lokker Nathalie A. , O'Dwyer Peter J.
Published: March 2013

Purpose: This randomized, double-blind, placebo-controlled, phase IIb study evaluated adding sorafenib to first-line modified FOLFOX6 (mFOLFOX6) for metastatic colorectal cancer (mCRC).

Experimental Design: Patients were randomized to sorafenib (400 mg b.i.d.) or placebo, combined with mFOLFOX6 (oxaliplatin 85 mg/m2; levo-leucovorin 200 mg/m2; fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion) every 14 days. Primary endpoint was progression-free survival (PFS). Target sample was 120 events in 180 patients for >85% power (two-sided α = 0.20) to detect an HR = 0.65.

Results: Of 198 patients randomized, median PFS for sorafenib plus mFOLFOX6 was 9.1 months versus 8.7 months for placebo plus mFOLFOX6 (HR = 0.88; 95% CI, 0.64–1.23; P = 0.46). There was no difference between treatment arms for overall survival. Subgroup analyses of PFS and overall survival showed no difference between treatment arms by KRAS or BRAF status (mutant and wild type). The most common grade 3/4 adverse events in the sorafenib and placebo arms were neutropenia (48% vs. 22%), peripheral neuropathy (16% vs. 21%), and grade 3 hand–foot skin reaction (20% vs. 0%). Treatment discontinuation because of adverse events was 9% and 6%, respectively. Generally, dose intensity (duration and cumulative doses) was lower in the sorafenib arm than in the placebo arm.

Conclusion: This study did not detect a PFS benefit with the addition of sorafenib to first-line mFOLFOX6 for mCRC. KRAS and BRAF status did not seem to impact treatment outcomes but the subgroups were small. These results do not support further development of sorafenib in combination with mFOLFOX6 in molecularly unselected patients with mCRC. Clin Cancer Res; 19(9); 2541–50. ©2013 AACR.
Classifying MMR Variants: Time for Revised Nomenclature in Lynch Syndrome
Authors: You Y. Nancy , Vilar Eduardo
Published: March 2013

Inactivating germline mutations in DNA mismatch repair (MMR) genes are diagnostic for Lynch syndrome. However, the clinical significance of missense variants is uncertain. A threshold level of compromised MLH1 expression, correlating with greater protein instability and MMR functional defect, has been identified to help classify the pathogenicity of missense variants. Clin Cancer Res; 19(9); 2280–2. ©2013 AACR.
Molecular Imaging of Cyclooxygenase-2 in Canine Transitional Cell Carcinomas In Vitro and In Vivo
Authors: Cekanova Maria , Uddin Md. Jashim , Bartges Joseph W. , Callens Amanda , Legendre Alfred M. , Rathore Kusum , Wright Laura , Carter Amanda , Marnett Lawrence J.
Published: March 2013

The enzyme COX-2 is induced at high levels in tumors but not in surrounding normal tissues, which makes it an attractive target for molecular imaging of cancer. We evaluated the ability of novel optical imaging agent, fluorocoxib A to detect urinary bladder canine transitional cell carcinomas (K9TCC). Here, we show that fluorocoxib A uptake overlapped with COX-2 expression in primary K9TCC cells in vitro. Using subcutaneously implanted primary K9TCC in athymic mice, we show specific uptake of fluorocoxib A by COX-2–expressing K9TCC xenograft tumors in vivo. Fluorocoxib A uptake by COX-2–expressing xenograft tumors was blocked by 70% (P < 0.005) when pretreated with the COX-2 selective inhibitor, celecoxib (10 mg/kg), 4 hours before intravenous administration of fluorocoxib A (1 mg/kg). Fluorocoxib A was taken up by COX-2–expressing tumors but not by COX-2–negative human UMUC-3 xenograft tumors. UMUC-3 xenograft tumors with no expression of COX-2 showed no uptake of fluorocoxib A. In addition, fluorocoxib A uptake was evaluated in five dogs diagnosed with TCC. Fluorocoxib A specifically detected COX-2–expressing K9TCC during cystoscopy in vivo but was not detected in normal urothelium. Taken together, our findings show that fluorocoxib A selectively bound to COX-2–expressing primary K9TCC cells in vitro, COX-2–expressing K9TCC xenografts tumors in nude mice, and heterogeneous canine TCC during cystoscopy in vivo. Spontaneous cancers in companion animals offer a unique translational model for evaluation of novel imaging and therapeutic agents using primary cancer cells in vitro and in heterogeneous cancers in vivo. Cancer Prev Res; 6(5); 466–76. ©2013 AACR.
Increased Levels of Urinary PGE-M, a Biomarker of Inflammation, Occur in Association with Obesity, Aging, and Lung Metastases in Patients with Breast Cancer
Authors: Morris Patrick G. , Zhou Xi Kathy , Milne Ginger L. , Goldstein Daniel , Hawks Laura C. , Dang Chau T. , Modi Shanu , Fornier Monica N. , Hudis Clifford A. , Dannenberg Andrew J.
Published: March 2013

Elevated levels of COX-derived prostaglandin E2 (PGE2) occur in inflamed tissues. To evaluate the potential links between inflammation and breast cancer, levels of urinary prostaglandin E metabolite (PGE-M), a stable end metabolite of PGE2, were quantified. We enrolled 400 patients with breast cancer: controls with early breast cancer (n = 200), lung metastases (n = 100), and metastases to other sites (n = 100). Patients completed a questionnaire, provided urine, and had measurements of height and weight. Urinary PGE-M was quantified by mass spectrometry. Ever smokers with lung metastasis who had not been exposed to nonsteroidal anti-inflammatory drugs (NSAIDs) had the highest PGE-M levels. PGE-M levels were increased in association with elevated body mass index (BMI; P < 0.001), aging (P < 0.001), pack-year smoking history (P = 0.02), lung metastases (P = 0.02), and recent cytotoxic chemotherapy (P = 0.03). Conversely, use of NSAIDs, prototypic inhibitors of COX activity, was associated with reduced PGE-M levels (P < 0.001). On the basis of the current findings, PGE-M is likely to be a useful biomarker for the selection of high-risk subgroups to determine the use of interventions that aim to reduce inflammation and possibly the development and progression of breast cancer, especially in overweight and obese women. Cancer Prev Res; 6(5); 428–36. ©2013 AACR.
MicroRNA and Cancer Chemoprevention
Authors: Yi Bin , Piazza Gary A. , Su Xiulan , Xi Yaguang
Published: March 2013

MicroRNAs (miRNA) are a group of naturally occurring, small, noncoding, and single-strand RNA molecules that regulate gene expression at the posttranscriptional and translational levels. By controlling the expression of oncogenic and tumor suppressor proteins, miRNAs are believed to play an important role in pathologic processes associated with malignant progression including tumor cell proliferation, apoptosis, differentiation, angiogenesis, invasion, and metastasis. However, relatively few studies have investigated the influence of chemopreventive agents on miRNA expression and their regulation of target genes. Given the significance of miRNAs in modulating gene expression, such research can provide insight into the pleiotropic biologic effects that chemopreventive agents often display and a deeper understanding of their mechanism of action to inhibit carcinogenesis. In addition, miRNAs can provide useful biomarkers for assessing antineoplastic activity of these agents in preclinical and clinical observations. In this review, we summarize recent publications that highlight a potentially important role of miRNAs in cancer chemoprevention research. Cancer Prev Res; 6(5); 401–9. ©2013 AACR.
Use of Pallidal Deep Brain Stimulation in Postinfarct Hemidystonia
Authors: Witt Jennifer , Starr Phillip A. , Ostrem Jill L.
Published: March 2013

Background/Aims: Reports of outcomes in treating dystonia secondary to stroke with deep brain stimulation (DBS) are limited. We report our experience with 3 patients, all with infarcts involving the striatum, who developed hemidystonia and were treated with unilateral globus pallidus interna DBS. Methods: Case series describing characteristics and outcomes based on the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores before and after DBS at 3, 6 and at least 12 months. Results: All patients reported subjective improvements after surgery. At 1 year or more after surgery, none of the 3 patients displayed a measureable improvement in the BFMDRS movement score. Conclusion: Our findings are consistent with previous reports of limited benefits from pallidal DBS in secondary dystonia. Future work should focus on predictive factors for DBS outcomes and the development of more sensitive assessment tools specifically for secondary dystonias as well as the exploration of alternative brain targets for stimulation.
Clinician-Identified Depression in Community Settings: Concordance with Structured-Interview Diagnoses
Authors: Mojtabai Ramin
Published: March 2013

Background: Relatively little is known about the prevalence and correlates of overdiagnosis of depression in community settings. This study examined the extent to which individuals with clinician-identified depression in the community meet the criteria for DSM-IV major depressive episodes (MDE) and characteristics of these individuals. Methods: In a sample of 5,639 participants with clinician-identified depression drawn from the 2009-2010 United States National Survey of Drug Use and Health, the proportion of participants who met the 12-month MDE criteria, ascertained by a structured interview, and variations in MDE diagnosis across different groups of participants were examined. Mental health profiles and service use of participants who met the MDE criteria were compared to those who did not meet these criteria. Results: Only 38.4% of participants with 12-month clinician-identified depression met the 12-month MDE criteria. Older adults were less likely than younger adults to meet the criteria - only 14.3% of those 65 years old or older met the criteria, whereas participants with more education and those with poorer overall health were more likely to meet the criteria. Participants who did not meet the 12-month MDE criteria reported less distress and impairment in role functioning and used fewer services. A majority of both groups, however, were prescribed and used psychiatric medications. Conclusions: Depression overdiagnosis and overtreatment is common in community settings in the USA. There is a need for improved targeting of diagnosis and treatments of depression and other mental disorders in these settings.
Effects of a Multidisciplinary Stress Treatment Programme on Patient Return to Work Rate and Symptom Reduction: Results from a Randomised, Wait-List Controlled Trial
Authors: Netterstrøm Bo , Friebel Lene , Ladegaard Yun
Published: March 2013

Background: To evaluate the efficacy of a multidisciplinary stress treatment programme. Methods: General practitioners referred 198 employed patients on sick leave with symptoms of persistent work-related stress. Using a waitlisted randomised controlled trial design, the participants were randomly divided into the following three groups: the intervention group (IG, 69 participants); treatment-as-usual control group (TAUCG, 71 participants), which received 12 consultations with a psychologist, and the waitlisted control group (WLCG, 58 participants). The stress treatment intervention consisted of nine 1-hour sessions conducted over 3 months. The goals of the sessions were the following: (1) identifying relevant stressors; (2) changing the participant's coping strategies; (3) adjusting the participant's workload and tasks, and (4) improving workplace dialogue. Each participant also attended a mindfulness-based stress reduction (MBSR) course for 2 h a week over 8 weeks. Results: The IG and TAUCG showed significantly greater symptom level (Symptom Check List 92) reductions compared to the WLCG. Regarding the return to work (RTW) rate, 67% of participants in the IG returned to full-time work after treatment, which was a significantly higher rate than in the TAUCG (36%) and WLCG (24%). Significantly more participants in the IG (97%) increased their working hours during treatment compared with the participants in the control groups, TAUCG (71%) and WLCG (64%). Conclusions: The stress treatment programme - a combination of work place-focused psychotherapy and MBSR - significantly reduced stress symptom levels and increased RTW rates compared with the WLCG and TAUCG.
Magnetic Resonance Imaging-Based versus Computed Tomography-Based Thrombolysis in Acute Ischemic Stroke: Comparison of Safety and Efficacy within a Cohort Study
Authors: Gerischer Lea Morrin , Fiebach Jochen B. , Scheitz Jan F. , Audebert Heinrich J. , Endres Matthias , Nolte Christian H.
Published: March 2013

Background: In acute ischemic stroke, brain imaging is mandatory in the decision whether to perform intravenous thrombolysis with recombinant tissue plasminogen activator. The most widespread used imaging modality to exclude intracranial hemorrhage is plain computed tomography (CT). However, there is an ongoing debate whether the information provided by magnetic resonance imaging (MRI) could improve the selection of patients for thrombolysis. We investigated whether the choice of imaging modality (MRI vs. CT) affects therapy safety and the patients' outcome. Methods: Analyses are based on data from a prospective, single-center observational study that included all patients with acute ischemic stroke who received intravenous thrombolysis within 4.5 h. Stroke severity was assessed by the National Institutes of Health Stroke Scale. Safety was assessed by rates of symptomatic intracranial hemorrhage (SICH), brain edema with mass effect and 7-day mortality. Outcome was assessed at 3 months as mortality and proportion of independent patients (modified Rankin Scale score between 0 and 2). Results: We analyzed 345 patients of whom 141 received multimodal MRI and 204 received plain CT prior to treatment. Groups did not differ significantly in terms of age, neurological deficit, rate of elevated glucose level or rate of very high blood pressure. However, patients with CT-based thrombolysis had significantly higher rates of cardiac comorbidities (coronary artery disease, heart failure). In the MRI group, we observed a lower rate of 7-day mortality (1 vs. 10%; p = 0.001), a lower rate of SICH (1 vs. 6%; p = 0.010) and a nonsignificantly lower rate of brain edema with mass effect (2 vs. 6%; n.s.). In multivariable analysis, 7-day mortality was independently associated with MRI-based thrombolysis, even if cardiac comorbidities were taken into account. For mortality at 3 months, there was a nonsignificant difference in favor of the MRI group (16 vs. 23%; n.s.). In multivariable analyses, mortality at 3 months was independently associated with older age, higher stroke severity, brain edema with mass effect, SICH, pneumonia and coronary artery disease. Neither mortality nor independent outcome was influenced by initial imaging modality. Conclusions: Thrombolysis based on multimodal MRI is associated with reduced rates of SICH and early death. Our results suggest that these complications affect survival principally in the acute phase after thrombolysis. However, nonneurological and especially cardiac comorbidities also influence survival after stroke and are underrepresented in stroke patients undergoing MRI. Selection bias has to be considered.
Variable Somatic TIE2 Mutations in Half of Sporadic Venous Malformations
Authors: Soblet J. , Limaye N. , Uebelhoer M. , Boon L.M. , Vikkula M.
Published: March 2013

Venous malformations (VMs) are the most frequent vascular malformations referred to specialized vascular anomaly centers. A rare (1-2%) familial form, termed cutaneomucosal venous malformation (VMCM), is caused by gain-of-function mutations in TIE2. More recently, sporadic VMs, characterized by the presence of large unifocal lesions, were shown to be caused by somatic mutations in TIE2. These include a frequent L914F change, and a series of double mutations in cis. All of which cause ligand-independent receptor hyperphosphorylation in vitro. Here, we expanded our study to assess the range of mutations that cause sporadic VM. To test for somatic changes, we screened the entire coding region of TIE2 in cDNA from resected VMs by direct sequencing. We detected TIE2 mutations in 17/30 (56.7%) of the samples. In addition to previously detected mutations, we identified 7 novel somatic intracellular TIE2 mutations in sporadic VMs, including 3 that cause premature protein truncation.
Downregulation of miR-145 Expression in Oral Squamous Cell Carcinomas and Its Clinical Significance
Authors: Gao Ling , Ren Wenhao , Chang Su‘e , Guo Bo , Huang Shuo , Li Menghe , Guo Youmin , Li Zongfang , Song Tusheng , Zhi Keqian , Huang Chen
Published: March 2013

Background: MicroRNAs have been reported to play roles as oncogenes or tumor suppressor genes in human cancers. However, the expression levels of miR-145 in oral squamous cell carcinoma (OSCC) are unclear. The purpose of this study was to investigate the status of miR-145 expression in OSCC and determine its clinical significance. Patients and Methods: We examined miR-145 levels in 62 OSCC tissue samples and cell lines by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The relationship between miR-145 expression and clinicopathologic factors of OSCC patients was analyzed. Results: The proportion of miR-145 low expression was 82.26% (51/62) among the 62 OSCC patients, and expression levels of miR-145 in OSCC tissue samples and cell lines were significantly lower than in non-tumor controls. miR-145 expression levels were not significantly associated with age (p = 0.607), sex (p = 0.213), location (p = 0.952), histology (p = 0.603), pT stage (p = 0.305), pTNM stage (p = 0.471), and lymphatic metastasis (p = 1.000). Conclusion: miR-145 may be involved in the early tumorigenesis of oral squamous cells, and might be a potential biomarker in the early diagnosis of OSCC.
Panitumumab-Induced Interstitial Lung Disease in a Case of Metastatic Colorectal Cancer
Authors: Yamada Takeshi , Moriwaki Toshikazu , Matsuda Kenji , Yamamoto Yoshiyuki , Sugaya Akinori , Akutsu Daisuke , Murashita Tetsuya , Endo Shinji , Hyodo Ichinosuke
Published: March 2013

Background: A Japanese postmarketing survey of panitumumab revealed that panitumumab-associated interstitial lung disease (ILD) occurred in approximately 1% (19/1767) of patients, causing death in 36.8% of these cases. Case Report: We report the case of a 60-year-old Japanese man who developed ILD associated with panitumumab therapy (third-line therapy) for metastatic sigmoid colon cancer involving the liver, lymph nodes, and lungs. 2 months after the initiation of panitumumab therapy, he developed a progressive nonproductive cough, dyspnea, and a fever, and was diagnosed with ILD. Intravenous pulse methylprednisolone treatment led to quick recovery. The patient had some risk factors for ILD associated with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. Conclusion: Further studies are required to elucidate the association between anti-EGFR antibodies and ILD.
Cells Co-Expressing Luteinising Hormone and Thyroid-Stimulating Hormone Are Present in the Ovine Pituitary Pars Distalis but Not the Pars Tuberalis: Implications for the Control of Endogenous Circannual Rhythms of Prolactin
Authors: Hodson David J. , Townsend Julie , Tortonese Domingo J.
Published: March 2013

Background/Aims: A mammalian circannual pacemaker responsible for regulating the seasonal pattern of prolactin has been recently described in sheep. This pacemaker resides within the pars tuberalis, an area of the pituitary gland that densely expresses melatonin receptors. However, the chemical identity of the cell type which acts as the pacemaker remains elusive. Mathematical-modelling approaches have established that this cell must be responsive to the static melatonin signal as well as prolactin negative feedback. Considering that in sheep the gonadotroph is the only cell in the pars tuberalis which expresses the prolactin receptor, and that in other photoperiodic species the thyrotroph is the only cell expressing the melatonin receptor in this tissue, a cell type which expresses both proteins would fulfil the theoretical criteria of a circannual pacemaker. Methods: Pituitary glands were obtained from female sheep under short days (breeding season) and long days (non-breeding season) and double immunofluorescent staining was conducted to determine the prevalence of bi-hormonal cells in the pars distalis and pars tuberalis using specific antibodies to luteinising hormone-β and thyroid-stimulating hormone-β. Results: The results reveal that whilst such a bihormonal cell is clearly present in the pars distalis and constitute 4% of the gonadotroph population in this region, the same cell type is completely absent from the pars tuberalis even though LH gonadotrophs are abundantly expressed. Conclusions: Based on these findings, together with existing data, we are able to propose an alternative model where the gonadotroph itself is controlled indirectly by neighbouring melatonin responsive cells, allowing it to act as a pacemaker.