bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment and characterization of the total geometric uncertainty in Gamma Knife radiosurgery using polymer gels
Authors: Moutsatsos A. , Karaiskos P. , Petrokokkinos L. , Sakelliou L. , Pantelis E. , Georgiou E. , Torrens M. , Seimenis I.
Published: February 2013

Purpose:

This work proposes and implements an experimental methodology, based on polymer gels, for assessing the total geometric uncertainty and characterizing its contributors in Gamma Knife (GK) radiosurgery.

Methods:

A treatment plan consisting of 26, 4‐mm GK single shot dose distributions, covering an extended region of the Leksell stereotactic space, was prepared and delivered to a polymer gel filled polymethyl methacrylate (PMMA) head phantom (16 cm diameter) used to accurately reproduce every link in the GK treatment chain. The center of each shot served as a “control point” in the assessment of the GK total geometric uncertainty, which depends on (a) the spatial dose delivery uncertainty of the PERFEXION GK unit used in this work, (b) the spatial distortions inherent in MR images commonly used for target delineation, and (c) the geometric uncertainty contributor associated with the image registration procedure performed by the Leksell GammaPlan (LGP) treatment planning system (TPS), in the case that registration is directly based on the apparent fiducial locations depicted in each MR image by the N‐shaped rods on the Leksell localization box. The irradiated phantom was MR imaged at 1.5 T employing a T2‐weighted pulse sequence. Four image series were acquired by alternating the frequency encoding axis and reversing the read gradient polarity, thus allowing the characterization of the MR‐related spatial distortions.

Results:

MR spatial distortions stemming from main field (B0) inhomogeneity as well as from susceptibility and chemical shift phenomena (also known as sequence dependent distortions) were found to be of the order of 0.5 mm, while those owing to gradient nonlinearities (also known as sequence independent distortions) were found to increase with distance from the MR scanner isocenter extending up to 0.47 mm at an Euclidean distance of 69.6 mm. Regarding the LGP image registration procedure, the corresponding average contribution to the total geometric uncertainty ranged from 0.34 to 0.80 mm. The average total geometric uncertainty, which also includes the GK spatial dose delivery uncertainty, was found equal to (0.88 ± 0.16), (0.88 ± 0.26), (1.02 ± 0.09), and (1.15 ± 0.24) mm for the MR image series acquired with the read gradient polarity (direction) set toward right, left, posterior, and anterior, respectively.

Conclusions:

The implemented methodology seems capable of assessing the total geometric uncertainty, as well as of characterizing its contributors, ascribed to the entire GK treatment delivery (i.e., from MR imaging to GK dose delivery) for an extended region of the Leksell stereotactic space. Results obtained indicate that the selection of both the frequency encoding axis and the read gradient polarity during MRI acquisition may affect the magnitude as well as the spatial components of the total geometric uncertainty.
Moments of Inertia of Disks and Spheres Without Integration
Authors: Hong Seok-Cheol , Hong Seok-In
Published: February 2013

Calculation of moments of inertia is often challenging for introductory-level physics students due to the use of integration, especially in non-Cartesian coordinates. Methods that do not employ calculus have been described for finding the rotational inertia of thin rods and other simple bodies.1–3 In this paper we use the parallel axis theorem and the perpendicular axis theorem (both of which may be proved without calculus4), along with rotational symmetry, to determine, without using integration, the moments of inertia of uniform disks and spheres.
Adding Albedo and Atmospheres
Authors: LoPresto Michael C.
Published: February 2013

In a previous article in this journal,1 we reported on a laboratory activity in which students used a derivation from the Stefan-Boltzmann law to calculate planetary temperatures and compare them to measured values from various (mostly online) sources. The calculated temperatures matched observed values very well with the exceptions of Venus and the dwarf planet Pluto.
Beautiful Science: Worth a Visit
Authors: Bingham Frederick M.
Published: February 2013

For those in the profession of teaching physics who reside in or plan to visit the Los Angeles area, I would highly recommend a trip to the Huntington Library in San Marino, specifically to a permanent exhibit entitled “Beautiful Science: Ideas that Changed the World” in the Dibner Hall of the History of Science. The exhibit contains original books and manuscripts from the library's own collections. The sheer magnitude of human achievement represented here and the amount of effort and money that must have been required to amass these books boggles the mind.
Hands-On Nuclear Physics
Authors: Whittaker Jeff
Published: February 2013

Nuclear science is an important topic in terms of its application to power generation, medical diagnostics and treatment, and national defense. Unfortunately, the subatomic domain is far removed from daily experience, and few learning aids are available to teachers. What follows describes a low-tech, hands-on method to teach important concepts in nuclear physics, including the quark model, anti-matter, nuclear binding energy, stability, the nuclear shell model, and the importance of symmetry, by making use of neodymium disc magnets.
Yo-yo Pull Demonstration
Authors: Layton William
Published: February 2013

A popular demonstration involves placing a yo-yo on a level table and gently pulling the string horizontally when it is wrapped to come out below the center of the yo-yo's axis. Students are then asked to predict which way the yo-yo will move.1 A similar demonstration is performed with a tricycle by pulling forward on a pedal with the pedal down in its lowest position.2,3 As well as pulling the yo-yo horizontally, often the string is lifted until the angle it makes with the table causes no motion. This occurs when the line extended from the string intersects the point of contact of the yo-yo with the table.4 This paper describes an apparatus that extends these demonstrations to the situation where the force pulling the yo-yo is still horizontal yet is below the level of the table.
The Genetic Basis for Bacterial Mercury Methylation
Authors: Parks Jerry M. , Johs Alexander , Podar Mircea , Bridou Romain , Hurt Richard A. , Smith Steven D. , Tomanicek Stephen J. , Qian Yun , Brown Steven D. , Brandt Craig C. , Palumbo Anthony V. , Smith Jeremy C. , Wall Judy D. , Elias Dwayne A. , Liang Liyuan
Published: February 2013

Mercury Methylating Microbes

Mercury (Hg) most commonly becomes bioavailable and enters the food web as the organic form methylmercury, where it induces acute toxicity effects that can be magnified up the food chain. But most natural and anthropogenic Hg exists as inorganic Hg
2+
and is only transformed into methylmercury by anaerobic microorganisms—typically sulfur-reducing bacteria. Using comparative genomics,

Parks
et al.

(p.
1332
, published online 7 February; see the Perspective by

Poulain and Barkay

) identified two genes that encode a corrinoid and iron-sulfur proteins in six known Hg-methylating bacteria but were absent in nonmethylating bacteria. In two distantly related model Hg-methylating bacteria, deletion of either gene—or both genes simultaneously—reduced the ability for the bacteria to produce methylmercury but did not impair cellular growth. The presence of this two-gene cluster in several other bacterial and lineages for which genome sequences are available suggests the ability to produce methylmercury may be more broadly distributed in the microbial world than previously recognized.
(
R
)-2-Hydroxyglutarate Is Sufficient to Promote Leukemogenesis and Its Effects Are Reversible
Authors: Losman Julie-Aurore , Looper Ryan E. , Koivunen Peppi , Lee Sungwoo , Schneider Rebekka K. , McMahon Christine , Cowley Glenn S. , Root David E. , Ebert Benjamin L. , Kaelin William G.
Published: February 2013

Focusing on the Right Metabolite

A variety of human cancers, including acute leukemias and brain tumors, have mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1, IDH2), which cause overproduction of a metabolite called 2-hydroxyglutarate (2HG).

Losman
et al.

(p.
1621
, published online 7 February) show that the
R
- but not the
S
-enantiomer of 2HG can transform cells and that
R
-2HG mediates transformation at least in part through effects on protein modifying EglN prolyl hydroxylases. Importantly, the transforming activity of
R
-2HG was reversible, suggesting that therapeutic strategies focusing on inhibition of
R
-2HG production or inhibition of EglN prolyl hydroxylases merit further investigation.
Complete Genome Sequences of Edwardsiella tarda-Lytic Bacteriophages KF-1 and IW-1
Authors: Yasuike Motoshige , Sugaya Emi , Nakamura Yoji , Shigenobu Yuya , Kawato Yasuhiko , Kai Wataru , Fujiwara Atushi , Sano Motohiko , Kobayashi Takanori , Nakai Toshihiro
Published: February 2013

We report the complete genome sequences of two
Edwardsiella tarda
-lytic bacteriophages isolated from flounder kidney (KF-1) and seawater (IW-1). These newly sequenced phage genomes provide a novel resource for future studies on phage-host interaction mechanisms and various applications of the phages for control of edwardsiellosis in aquaculture.
Complete Genome Sequence of a Novel Recombinant Human Norovirus Genogroup II Genotype 4 Strain Associated with an Epidemic during Summer of 2012 in Hong Kong
Authors: Chan Martin C. W. , Chan Paul K. S.
Published: February 2013

Beginning in July 2012, a community-wide increase in the number of norovirus-associated acute gastroenteritis cases was observed during the summer months in Hong Kong. Here, we report the complete genome sequence of a novel recombinant norovirus genogroup II genotype 4 (GII.4) strain, named “2012v,” which is associated with this “early” epidemic outside the usual winter season.
Complete Genome Sequence of the Novel Duck Circovirus Strain GH01 from Southwestern China
Authors: Zhang Zhilong , Jia Renyong , Wang Mingshu , Lu Yanyan , Zhu Dekang , Chen Shun , Yin Zhongqiong , Wang Yin , Chen Xiaoyue , Cheng Anchun
Published: February 2013

A novel duck circovirus (DuCV) strain, designated GH01, was isolated from ducklings in southwestern China. We report the genome sequence of GH01 and the genomic organization and genetic relationship to other DuCVs. The availability of the genome sequence will be helpful to investigations of epidemiology and the evolutionary biology of this organism and the development of preventive vaccines.
Injury patterns and severity among motorcyclists treated in US emergency departments, 2001–2008: a comparison of younger and older riders
Authors: Jackson Tracy L , Mello Michael J
Published: February 2013

Objective

To examine differences across age groups in patterns of injuries sustained from motorcycle crashes.

Methods

Cross-sectional data from the National Electronic Injury Surveillance System-All Injury Program were used to assess emergency department-treated injuries resulting from motorcycle crashes in the USA from 2001 to 2008. Trends in injury frequency, the types of injuries and severity of injuries sustained among those aged 20–39 years, 40–59 years, and 60 years and older were compared.

Results

An estimated 65 660 patients 60 years and older, 466 125 patients aged 40–59 years and 921 229 patients aged 20–39 years were treated in US emergency rooms for injuries sustained in motorcycle crashes from 2001 to 2008. The number of injuries increased in all groups from 2001 to 2008, with the greatest rate of increase occurring in the oldest age group. Older adults had the greatest odds of hospitalisation with a threefold increased rate of hospitalisation (OR=3.05; 95% CI 2.58 to 3.59) compared with younger adults. Middle age adults had a nearly twofold increased odds of hospitalisation (OR=1.89; 95% CI 1.70 to 2.11; p<0.0001) compared with younger adults. Analysis of injury severity showed a similar pattern with both older adults (OR=2.46; 95% CI 2.02 to 3.01) and middle age adults (OR=1.66, 95% CI 1.52 to 1.82) having significantly increased odds of severe injury compared with young adults.

Conclusions

Older adults involved in motorcycle crashes are prone to more severe injuries than younger adults. The increased number of older adults riding motorcycles should put further focus on risk of injury to this population.
Composite intestinal adenoma-microcarcinoid clues to diagnosing an under-recognised mimic of invasive adenocarcinoma
Authors: Salaria Safia N , Abu Alfa Amer K , Alsaigh Nada Y , Montgomery Elizabeth , Arnold Christina A
Published: February 2013

Aims

Microcarcinoids refer to microscopic nests of monotonous cells with endocrine and squamoid features. Their peculiar morphology can appear infiltrative with a desmoplastic-like background, raising concerns for an infiltrating adenocarcinoma. To further characterise microcarcinoids, we undertook a prospective clinicopathological study.

Methods

11 specimens originating from five men and six women (average age=58.9 years) were prospectively collected from December 2004 to December 2011.

Results

Microcarcinoids were most commonly identified in high-risk adenomas (size ≥10 mm (n=10), villous components (n=8) and/or high-grade dysplasia (n=4)). All polyps had mucosal prolapse and four displayed background fibrosis reminiscent of desmoplasia. The microcarcinoid component was most often multifocal (n=7) within the individual polyp and extended over an average length of 3.9 mm. The individual microcarcinoid cells were cuboidal with abundant eosinophilic cytoplasm. All cases had monotonous nuclei which lacked pleomorphism, hyperchromasia and mitotic activity. All available microcarcinoids were β-catenin and synaptophysin reactive and non-reactive for chromogranin and p53 with a negligible Ki-67 proliferation index (<2%). In addition, the microcarcinoids were variably reactive for p63 and/or CK 5/6, thereby demonstrating focal squamoid features. Two of the study cases were submitted with a concern for invasive carcinoma. Clinical information was available in 10 patients with up to 24 months of follow-up: all patients are alive and well and no subsequent malignancy has been reported.

Conclusions

Awareness of this unique morphology is important to avoid overdiagnosing microcarcinoids as invasive adenocarcinoma. Moreover, this immunohistochemical panel can be helpful in discriminating microcarcinoids from its malignant mimic in challenging cases.
Protective effect of dietary tender cluster beans (Cyamopsis tetragonoloba) in the gastrointestinal tract of experimental rats
Authors: Pande Shubhra , Srinivasan Krishnapura
Published: February 2013

In this study, the gastrointestinal protective effect of soluble, dietary fiber-rich tender cluster beans, with respect to the activities of antioxidant enzymes and the concentration of antioxidant molecules, was examined in Wistar rats. Dietary intervention with tender cluster beans (15% freeze-dried powder in the diet for 8 weeks) significantly enhanced the activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione reductase, glutathione-S-transferase, and GPX) and the concentrations of antioxidant molecules in both gastric and intestinal mucosa. Further, in combination with capsaicin (0.01%), the beneficial effect was even higher. There is a strong indication that tender cluster beans offer a significant gastroprotective effect, and a much greater effect when combined with capsaicin in terms of increased antioxidant status. In a separate study, these dietary components were found to alleviate the diminished activities of antioxidant enzymes and antioxidant molecules in gastric and intestinal mucosa under conditions of ethanol-induced oxidative stress. The gastroprotective effect of the cluster bean was also reflected in its positive effect on gastric mucosal glycoproteins, resulting in a lowering of mucosal injury. Incidentally, the serum and liver also showed an elevated antioxidant status, thus suggesting desirable lowered oxidative stress results when tender cluster beans are consumed.
Studies of target-evaporated particle production in forward and backward hemispheres in 16O-emulsion interactions at 60A and 200A GeV
Authors: Abdelsalam A. , Kamel S. , Rashed N. , Fayed M.
Published: February 2013

The multiplicity distribution of the target-evaporated black particles emitted in the interactions of 16O beams with emulsion nuclei at 60A and 200A GeV in both the forward and backward hemispheres are examined. The asymmetry parameters, the forward–backward ratios as well as multiplicity distribution moments are evaluated. The investigated scaled variances and the second Mueller moments are observed to indicate the strongly correlated emission of target-evaporated black particles in the forward direction. The ratio of entropy to average multiplicity of target fragments is evaluated, and is found to be energy-independent in both the forward and backward hemispheres.
EXAMINING THE RISK OF BRAIN DRAIN AND LOWER REMITTANCES
Authors: MENDOZA RONALD U.
Published: February 2013

Developing countries could be facing two linked trends that are potentially detrimental to their development prospects: outmigration of high-skilled professionals and the potential decline in remittances as migrants with higher skills may be less likely to remit or may remit less if they do. This paper examines this policy issue by empirically analyzing a cross-national dataset spanning 70 countries during the period 1985–2000, as well as a country-specific dataset for the Philippines. It finds little evidence that high-skilled migration is linked to lower remittances at the aggregate level. This finding coheres with more recent studies leveraging microlevel data.
EFFECT OF RELAXATION TIME ON MHD PULSATILE FLOW OF BLOOD THROUGH POROUS MEDIUM IN AN ARTERY UNDER THE EFFECT OF PERIODIC BODY ACCELERATION
Authors: ELDESOKY ISLAM M.
Published: February 2013

In this investigation, the influence of relaxation time on magnetohydrodynamic (MHD) pulsatile flow of blood through porous medium in an artery under the effect of periodic body acceleration is investigated. The applied magnetic field is assumed to be constant and perpendicular to the blood flow in the artery, and blood is considered as an incompressible electrically conducting fluid. An analytical solution of the equation of motion is obtained by applying the Laplace Transform. With a view of illustrating the applicability of the mathematical model developed here, the analytic explicit expressions of axial velocity and wall shear stress are given. The results show that the values of the axial velocity and shear stress are affected by the relaxation time. Numerical results are reported for different values of the physical parameters of interest.
PROTEIN SUPERFAMILY CLASSIFICATION USING ADAPTIVE EVOLUTIONARY RADIAL BASIS FUNCTION NETWORK
Authors: VIPSITA SWATI , RATH SANTANU KU.
Published: February 2013

In this paper, the concept of adaptive multiobjective genetic algorithm (AMOGA) is applied for the structure optimization of radial basis function network (RBFN). The problem of finding the number of hidden centers remains a critical issue in the design of RBFN. The number of basis function controls the complexity and generalization ability of the network. The most parsimonious network obtained from the pareto front is applied in one of the challenging research area of proteomics and computational biology: Protein superfamily classification. The problem deals with predicting the family membership of a newly discovered amino acid sequence. The modification to the earlier approach of multiobjective genetic algorithm (MOGA) is done based on the two key controlling parameters such as probability of crossover and probability of mutation. These values are adaptively varied based on the performance of the algorithm i.e., based on the percentage of total population present in the best nondomination level. Principal component analysis (PCA) is used for dimension reduction and significant features are extracted from long feature vector of amino acid sequences. Numerical simulation results illustrates the efficiency of our approach in terms of faster convergence, optimal architecture and high level of classification accuracy.
SURFACE PROPERTIES OF INDIUM-TIN-OXIDE MODIFIED BY OXYGEN PLASMA IMMERSION ION IMPLANTATION
Authors: HE LONG , WU ZHONGHANG , HE KONGDUO , FAN XIAOXUAN , LI ZEBIN , CHENG WEIHAI , JU JIAQI , OU QIONGRONG , LIANG RONGQING
Published: February 2013

Indium tin oxide (ITO) was modified by oxygen inductive coupled plasma (O-ICP) and oxygen plasma immersion ion implantation (O-PIII) respectively to compare the effects of both techniques on the surface properties. X-ray photoelectron spectroscopy (XPS) was applied to characterize the electronic state of ITO surface. The oxygen content enhancement and band bending at the surface of ITO were found after treatment by both O-ICP and O-PIII. The surface work function of ITO thin film depends on the oxygen composition at the surface. A surface work function increment of 0.8 eV by O-PIII was estimated from the shift of O1s core levels to low binding energy, which was the double of that by O-ICP. The conductivity increment of ITO films was less than 1% after O-ICP and O-PIII treatment. The transparency of ITO films increased by about 1% resulted from surface texture by O-PIII sputtering.
Classic “broken cell” techniques and newer live cell methods for cell cycle assessment
Authors: Henderson Lindsay , Bortone Dante S. , Lim Curtis , Zambon Alexander C.
Published: February 2013

Many common, important diseases are either caused or exacerbated by hyperactivation (e.g., cancer) or inactivation (e.g., heart failure) of the cell division cycle. A better understanding of the cell cycle is critical for interpreting numerous types of physiological changes in cells. Moreover, new insights into how to control it will facilitate new therapeutics for a variety of diseases and new avenues in regenerative medicine. The progression of cells through the four main phases of their division cycle [G0/G1, S (DNA synthesis), G2, and M (mitosis)] is a highly conserved process orchestrated by several pathways (e.g., transcription, phosphorylation, nuclear import/export, and protein ubiquitination) that coordinate a core cell cycle pathway. This core pathway can also receive inputs that are cell type and cell niche dependent. “Broken cell” methods (e.g., use of labeled nucleotide analogs) to assess for cell cycle activity have revealed important insights regarding the cell cycle but lack the ability to assess living cells in real time (longitudinal studies) and with single-cell resolution. Moreover, such methods often require cell synchronization, which can perturb the pathway under study. Live cell cycle sensors can be used at single-cell resolution in living cells, intact tissue, and whole animals. Use of these more recently available sensors has the potential to reveal physiologically relevant insights regarding the normal and perturbed cell division cycle.
Elevated SOCS3 and altered IL-6 signaling is associated with age-related human muscle stem cell dysfunction
Authors: McKay Bryon R. , Ogborn Daniel I. , Baker Jeff M. , Toth Kyle G. , Tarnopolsky Mark A. , Parise Gianni
Published: February 2013

Aging is associated with increased circulating interleukin-6 (IL-6) and a reduced myogenic capacity, marked by reduced muscle stem cell [satellite cell (SC)] activity. Although IL-6 is important for normal SC function, it is unclear whether elevated IL-6 associated with aging alters SC function. We hypothesized that mild chronically elevated IL-6 would be associated with a blunted SC response through altered IL-6 signaling and elevated suppressor of cytokine signaling-3 (SOCS3) in the elderly. Nine healthy older adult men (OA; 69.6 ± 3.9 yr) and 9 young male controls (YC; 21. 3 ± 3.1 yr) completed 4 sets of 10 repetitions of unilateral leg press and knee extension (75% of 1-RM). Muscle biopsies and blood were obtained before and 3, 24, and 48 h after exercise. Basal SC number was 33% lower in OA vs. YC, and the response was blunted in OA. IL-6+/Pax7+ cells demonstrated a divergent response in OA, with YC increasing to 69% at 3 h and peaking at 24 h (72%), while IL-6+/Pax7+ cells were not increased until 48 h in OA (61%). Type II fiber-associated phosphorylated signal transducer and activator of transcription (pSTAT3)+/Pax7+ cells demonstrated a similar delay in OA, not increasing until 48 h (vs. 3 h in YC). SOCS3 protein was 86% higher in OA. These data demonstrate an age-related impairment in normal SC function that appears to be influenced by SOCS3 protein and delayed induction of IL-6 and pSTAT3 in the SCs of OA. Collectively, these data suggest dysregulated IL-6 signaling as a consequence of aging contributes to the blunted muscle stem cell response.
H. pyloriacutely inhibits gastric secretion by activating CGRP sensory neurons coupled to stimulation of somatostatin and inhibition of histamine secretion
Authors: Zaki Muhammad , Coudron Philip E. , McCuen Robert W. , Harrington Leslie , Chu Shijian , Schubert Mitchell L.
Published: February 2013

Acute Helicobacter pylori infection produces hypochlorhydria. The decrease in acid facilitates survival of the bacterium and its colonization of the stomach. The present study was designed to identify the pathways in oxyntic mucosa by which acute H. pylori infection inhibits acid secretion. In rat fundic sheets in an Ussing chamber, perfusion of the luminal surface with H. pylori in spent broth (103–108cfu/ml) or spent broth alone (1:105to 1:100final dilution) caused a concentration-dependent increase in somatostatin (SST; maximal: 200 ± 20 and 194 ± 9% above basal; P < 0.001) and decrease in histamine secretion (maximal: 45 ± 5 and 48 ± 2% below basal; P < 0.001); the latter was abolished by SST antibody, implying that changes in histamine secretion reflected changes in SST secretion. Both responses were abolished by the axonal blocker tetrodotoxin (TTX), the sensory neurotoxin capsaicin, or the CGRP antagonist CGRP8-37, implying that the reciprocal changes in SST and histamine secretion were due to release of CGRP from sensory neurons. In isolated rabbit oxyntic glands, H. pylori inhibited basal and histamine-stimulated acid secretion in a concentration-dependent manner; the responses were not affected by TTX or SST antibody, implying that H. pylori can directly inhibit parietal cell function. In conclusion, acute administration of H. pylori is capable of inhibiting acid secretion directly as well as indirectly by activating intramural CGRP sensory neurons coupled to stimulation of SST and inhibition of histamine secretion. Activation of neural pathways provides one explanation as to how initial patchy colonization of the superficial gastric mucosa by H. pylori can acutely inhibit acid secretion.
Sex differences in brain response to anticipated and experienced visceral pain in healthy subjects
Authors: Kano Michiko , Farmer Adam D. , Aziz Qasim , Giampietro Vincent P. , Brammer Michael J. , Williams Steven C. R. , Fukudo Shin , Coen Steven J.
Published: February 2013

Women demonstrate higher pain sensitivity and prevalence of chronic visceral pain conditions such as functional gastrointestinal disorders than men. The role of sex differences in the brain processing of visceral pain is still unclear. In 16 male and 16 female healthy subjects we compared personality, anxiety levels, skin conductance response (SCR), and brain processing using functional MRI during anticipation and pain induced by esophageal distension at pain toleration level. There was no significant difference in personality scores, anxiety levels, SCR, and subjective ratings of pain between sexes. In group analysis, both men and women demonstrated a similar pattern of brain activation and deactivation during anticipation and pain consistent with previous reports. However, during anticipation women showed significantly greater activation in the cuneus, precuneus, and supplementary motor area (SMA) and stronger deactivation in the right amygdala and left parahippocampal gyrus, whereas men demonstrated greater activation in the cerebellum. During pain, women demonstrated greater activation in the midcingulate cortex, anterior insula, premotor cortex, and cerebellum and stronger deactivation in the caudate, whereas men showed increased activity in the SMA. The pattern of brain activity suggests that, during anticipation, women may demonstrate stronger limbic inhibition, which is considered to be a cognitive modulation strategy for impending painful stimulation. During pain, women significantly activate brain areas associated with the affective and motivation components of pain. These responses may underlie the sex differences that exist in pain conditions, whereby women may attribute more emotional importance to painful stimuli compared with men.
Amplification of FRS2 and Activation of FGFR/FRS2 Signaling Pathway in High-Grade Liposarcoma
Authors: Zhang Keqiang , Chu Kevin , Wu Xiwei , Gao Hanlin , Wang Jinhui , Yuan Yate-Ching , Loera Sofia , Ho Kimberley , Wang Yafan , Chow Warren , Un Frank , Chu Peiguo , Yen Yun
Published: February 2013

Fibroblast growth factor (FGF) receptor (FGFR) substrate 2 (FRS2) is an adaptor protein that plays a critical role in FGFR signaling. FRS2 is located on chromosome 12q13-15 that is frequently amplified in liposarcomas. The significance of FRS2 and FGFR signaling in high-grade liposarcomas is unknown. Herein, we first comparatively examined the amplification and expression of FRS2 with CDK4 and MDM2 in dedifferentiated liposarcoma (DDLS) and undifferentiated high-grade pleomorphic sarcoma (UHGPS). Amplification and expression of the three genes were identified in 90% to 100% (9–11 of 11) of DDLS, whereas that of FRS2, CDK4, and MDM2 were observed in 55% (41 of 75), 48% (36 of 75), and 44% (33/75) of clinically diagnosed UHGPS, suggesting that these “UHGPS” may represent DDLS despite lacking histologic evidence of lipoblasts. Immunohistochemical analysis of phosphorylated FRS2 protein indicated that the FGFR/FRS2 signaling axis was generally activated in about 75% of FRS2-positive high-grade liposarcomas. Moreover, we found that FRS2 and FGFRs proteins are highly expressed and functional in three high-grade liposarcoma cell lines: FU-DDLS-1, LiSa-2, and SW872. Importantly, the FGFR selective inhibitor NVP-BGJ-398 significantly inhibited the growth of FU-DDLS-1 and LiSa-2 cells with a concomitant suppression of FGFR signal transduction. Attenuation of FRS2 protein in FU-DDLS-1 and LiSa-2 cell lines decreased the phosphorylated extracellular signal–regulated kinase 1/2 and AKT and repressed cell proliferation. These findings indicate that analysis of FRS2 in combination with CDK4 and MDM2 will more accurately characterize pathologic features of high-grade liposarcomas. Activated FGFR/FRS2 signaling may play a functional role in the development of high-grade liposarcomas, therefore, serve as a potential therapeutic target. Cancer Res; 73(4); 1298–307. ©2012 AACR.
Regulation of the Na+/H+ Exchanger (NHE1) in Breast Cancer Metastasis
Authors: Amith Schammim R. , Fliegel Larry
Published: February 2013

The pH gradient in normal cells is tightly controlled by the activity of various pH-regulatory membrane proteins including the isoform protein of the Na+/H+ exchanger (NHE1). NHE1 is constitutively active in a neoplastic microenvironment, dysregulating pH homeostasis and altering the survival, differentiation, and proliferation of cancer cells, thereby causing them to become tumorigenic. Cytoplasmic alkalinization in breast cancer cells occurs as a result of increased NHE1 activity and, while much is known about the pathophysiologic role of NHE1 in tumor progression with regard to ion flux, the regulation of its activity on a molecular level is only recently becoming evident. The membrane domain of NHE1 is sufficient for ion exchange. However, its activity is regulated through the phosphorylation of key amino acids in the cytosolic domain as well as by its interaction with other intracellular proteins and lipids. Here, we review the importance of these regulatory sites and what role they may play in the disrupted functionality of NHE1 in breast cancer metastasis. Cancer Res; 73(4); 1259–64. ©2013 AACR.
Impaired Long-Term Expansion and Self-Renewal Potential of Pediatric Acute Myeloid Leukemia–Initiating Cells By PTK787/ZK 222584
Authors: Weidenaar Alida C. , ter Elst Arja , Kampen Kim R. , Meeuwsen-de Boer Tiny , Kamps Willem A. , Schuringa Jan Jacob , de Bont Eveline S.J.M.
Published: February 2013

Although most children with acute myeloid leukemia (AML) achieve complete remission, the relapse rate is 30% to 40%. Because it is thought that leukemia-initiating cells (LIC) are responsible for AML relapses, targeting these cells might improve outcome. Treatment of pediatric AML blasts with the receptor tyrosine kinase (RTK) inhibitor PTK787/ZK 222584 (PTK/ZK) induces cell death in vitro. However, the role of PTK/ZK inhibition on outgrowth of (pediatric) LICs is unknown. In this study, we cultured CD34+ cells from pediatric patients with AML on MS5 stromal cells in long-term cocultures. In analogy to adult AML, long-term expansion of leukemic cells up to 10 weeks could be generated in 9 of 13 pediatric AMLs. Addition of PTK/ZK to long-term cocultures significantly inhibited leukemic expansion in all samples, ranging from 4% to 80% growth inhibition at week 5 compared with untreated samples. In 75% of the samples, the inhibitory effect was more pronounced at week 10. Proteome profiler array analysis of downstream kinases revealed that PTK/ZK reduced activation of PI3K/Akt kinase signaling. Although main targets of PTK/ZK are VEGF receptors (VEGFR), no effect was seen on outgrowth of LICs when cultured with bevacizumab (monoclonal VEGFA-antibody), specific antibodies against VEGFR2 or VEGFR3, or exposed to stroma-derived VEGFA. These data suggest that the effect of PTK/ZK on LICs is not only dependent on inhibition of VEGFA/VEGFR signaling. Taken together, our data elucidated antileukemic properties of PTK/ZK in long-term expansion cultures, and suggest that targeting multiple RTKs by PTK/ZK might be a potential effective approach in eradicating (pediatric) LICs. Mol Cancer Res; 11(4); 339–48. ©2013 AACR.
Effects on Cervical Cytology Screening Productivity Associated with Implementation of the BD FocalPoint™ Guided Screener Imaging System
Authors: Sweeney Brenda J. , Wilbur David C.
Published: February 2013

Objectives: Automated screening will become important due to an aging workforce, declining numbers of new cytotechnologists, and the need for increased screening sensitivity in the vaccine era, where high-grade abnormalities will decline. This study documents workload in gynecologic cytology throughput before and after the implementation of the BD FocalPoint™ Guided Screener (GS) System. Study Design: We collected daily screening data from 3 time periods: the 12 months prior to GS implementation, the 6 months immediately after implementation, and the ensuing 7–18 months after implementation. Data was tabulated at the individual and total laboratory levels. Results: In the 6-month period immediately following implementation, productivity increased in 3 of 5 cytotechnologists, as compared to the figures 12 months before implementation. The laboratory increased productivity slightly (+2.4%), with individual changes ranging from –6.9 to +14.7%. In the 7- to 18-month ‘mature’ period after implementation, productivity increased in all 5 cytotechnologists with an average of +15.4%. Individual increases ranged from +6.1 to +26.9%. Conclusions: Overall productivity increased in the period beyond 6 months, and this increase was eventually noted in all personnel. Increased productivity was associated with a short period of learning in which the magnitude of the effect was less than in the mature period.
Xanthogranuloma of Bone: A Challenging Imitator of Malignancy
Authors: Holmes Brittany J. , Castelino-Prabhu Shobha , Rosenthal Dorothy L. , Ali Syed Z.
Published: February 2013

Xanthogranulomatous disease of bone is exceptionally uncommon. Clinically, radiologically and pathologically, it is a great imitator of malignancy. While there are few reports on the surgical pathology of this rare entity, there is no published report on its cytopathologic characteristics. We report herein the case of a 44-year-old male who was evaluated at The Johns Hopkins Hospital for a 2.3-cm painful soft tissue mass present within the medullary canal of the distal tibia with destruction of the overlying cortex. A computed tomography-guided fine needle aspiration biopsy revealed abundant histiocytes and occasional giant cells in an inflammatory background. This was interpreted as a ‘histiocyte-rich lesion,’ and an excisional biopsy was recommended. Subsequent curettage was performed, and the histological material was diagnosed as ‘xanthogranuloma of bone.’ The rarity of xanthogranuloma of bone and its resemblance to the more common reactive and malignant bone neoplasms may present diagnostic challenges.
Acral Myxoinflammatory Fibroblastic Sarcoma: Cytopathologic Findings on Fine-Needle Aspiration
Authors: Toll Adam D. , Wakely Jr. Paul E. , Ali Syed Z.
Published: February 2013

Background: Acral myxoinflammatory fibroblastic sarcoma (AMFS) is a rare low-grade sarcoma with somewhat unique morphologic characteristics. While recurrences are relatively common, distant metastases are infrequent. Cytopathologic descriptions of AMFS are limited, prompting the current study. Methods: A retrospective review was performed at two tertiary-care hospitals, and 3 patients with this diagnosis were identified. The cytopathologic and clinical features were reviewed. The following clinical data was collected for each case: age, gender, site of lesion, treatment, and follow-up information. Results: Pertinent cytologic features included large atypical epithelioid cells with occasional macronucleoli and lipoblast-like features in a background of bland spindle cells, myxoid stroma, and inflammation. All patients presented with acral mass lesions. Metastatic disease to an inguinal lymph node was found in 1 patient. Conclusions: AMFS is a low-grade sarcoma which shows some characteristic cytologic features. However, due to the presence of occasional bizarre and pleomorphic giant cells, there can be overlap with higher-grade sarcomas, and correlation with histology, immunohistochemistry, and imaging are required to make this diagnosis.
Cytologic Features of Low-Grade Cribriform Cystadenocarcinoma of the Submandibular Gland: A Case Report
Authors: Obokata Akane , Sakurai Shinji , Hirato Junko , Sakamoto Kazuha , Takekoshi Tetsuo , Aoki Jun
Published: February 2013

Background: Low-grade cribriform cystadenocarcinomas (LGCCC) are rare salivary gland tumors, classified into a variant of cystadenocarcinoma by the 2005 WHO classification. All previously reported cases arose from parotid glands, except for a case from a minor salivary gland. We report here for the first time a case of LGCCC arising from the submandibular gland. Case: A 65-year-old man presented with a 4-cm multicystic mass in the left submandibular gland. Smears from fine-needle aspiration cytology showed tumor cells, appearing solitarily or partly in clusters, with thick cytoplasm and central nuclei. Some clustering tumor cells showed large cytoplasmic vacuoles and peripherally dislocated nuclei. Although these findings indicated a possible mucoepidermoid carcinoma in the submandibular gland, the final diagnosis of the resected specimen was LGCCC. Conclusion: LGCCC can arise not only from the parotid glands, but also in the submandibular glands. LGCCC is thought to be of low-grade malignancy; no reported cases have shown tumor metastasis and there are no patients who are known to have died of this disease. Thus, differential diagnosis of this tumor from other malignant salivary gland tumors is quite important; however, this might be difficult when based solely on cytological findings.
Considering the Embryopathogenesis of VACTERL Association
Authors: Stevenson R.E. , Hunter A.G.W.
Published: February 2013

The nonrandom co-occurrence of vertebral, anorectal, cardiac, tracheoesophageal, genitourinary, and limb malformations, recognized as the VACTERL association, has not been satisfactorily explained from either a causation or embryopathogenesis standpoint. Few familial cases have been identified and maternal diabetes is the only environmental influence implicated to date. Mutations in single genes have been found in a number of syndromes with one or more of the VACTERL malformations, but these syndromes usually have other features which distinguish them from the VACTERL association. Animal models have provided clues to molecular pathways that may be involved in the embryogenesis of the VACTERL structures. What is lacking is the systematic study of individual genes and pathways in well-composed cohorts of patients, which is now possible with high throughput molecular technologies.
The Differential Diagnosis of Squamous Cells in Pancreatic Aspirates: From Contamination to Adenosquamous Carcinoma
Authors: Olson Matthew T. , Siddiqui Momin T. , Ali Syed Z.
Published: February 2013

Background: This study was conducted to describe the frequency and significance of squamous cells in fine needle aspiration (FNA) specimens of the pancreas in benign and malignant processes. Methods: A retrospective review was performed of 102 patients with squamous cells in their pancreatic FNA specimens from 1986 to 2012. The malignant cases were classified as adenosquamous carcinoma (ASqC) or metastatic squamous cell carcinoma, and a double institutional review of the ASqC cases was undertaken to characterize the clinical and pathological features and survival statistics of patients who present with unresectable or metastatic ASqC and have no follow-up surgery. Survival analyses were performed. Results: Of the 4,094 pancreas FNA procedures performed in the study, squamous features were found in 102 (2.5%) of all cases, and 48% of these cases represented ASqC. The other cases were contamination (52%) or atypical (<1%). ASqC constituted 4.5% (46/1,025) of all primary pancreatic exocrine malignancies. When compared with conventional adenocarcinoma, ASqC demonstrated a significantly poorer overall median survival (11.0 vs. 6.51 months; p = 0.023), and this difference was also seen in patients presenting with metastatic disease (median survival of 9.1 vs. 4.2 months; p = 0.025). Conclusions: Squamous cells in FNA specimens from the pancreas have a broad differential diagnosis that ranges from contamination to ASqC.
Ectopic Thymoma Can Mimic Benign and Malignant Thyroid Lesions on Fine Needle Aspiration Cytology: A Case Report and Literature Review
Authors: Taweevisit Mana , Sampatanukul Pichet , Thorner Paul Scott
Published: February 2013

Background: Ectopic cervical thymomas are rare and there are few descriptions of the cytologic findings based on fine needle aspiration. Their appearances can be misinterpreted as either benign or malignant lesions of the thyroid. The authors report such a case occurring in a patient with Sotos syndrome, a genetic disorder characterized by somatic overgrowth and cognitive impairment. Case Report: The patient developed a neck mass that was examined first by fine needle aspiration and then by pathologic examination of the resected specimen. On fine needle aspiration, a diagnosis of papillary carcinoma of the thyroid was favoured, based on the presence of large cohesive sheets of anastomosing papillary tissue fragments with fibrovascular cores. Pathologic examination of the resection specimen showed a thymoma, subtype B3. The cytologic findings correlated with the presence of nuclear palisading of tumour cells around perivascular spaces. Conclusion: To the best of our knowledge, this histologic subtype of thymoma has never been reported in ectopic cervical thymic tissue, nor these particular cytologic findings that can lead to an erroneous diagnosis of thyroid carcinoma. Moreover, this is the first description of thymoma in association with Sotos syndrome.
Role of Cytology in the Diagnosis and Management of HPV-Associated Head and Neck Carcinoma
Authors: Krane Jeffrey F.
Published: February 2013

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) accounts for up to 25% of all HNSCCs. These tumors largely arise from the oropharynx, particularly the tonsil and base of tongue. The first manifestation of HPV-associated HNSCC is frequently as metastasis to cervical lymph nodes that can be documented by fine-needle aspiration. These metastases are often cystic with a predominantly non-keratinizing, basaloid morphology. Knowledge of the HPV status of metastatic HNSCC has significant treatment and prognostic implications as HPV-associated tumors have a more favorable prognosis than conventional HNSCC. Accordingly, HPV testing should be performed on any squamous cell carcinoma of unknown primary identified in neck lymph nodes. HPV detection may be performed using a variety of methods including p16 as a surrogate immunohistochemical marker, in situ hybridization and/or polymerase chain reaction detection of viral DNA or RNA. Further investigation is needed to determine the optimal method for HPV detection in fine-needle aspiration specimens. Cytology screening for HPV-associated HNSCC does not appear to be effective. Greater understanding of the natural history of oral HPV infections is needed before knowing if oral HPV testing may be useful as a screening test.
Peroxisome Proliferator-Activated Receptor-γ Mutations Responsible for Lipodystrophy With Severe Hypertension Activate the Cellular Renin–Angiotensin System
Authors: Auclair Martine , Vigouroux Corinne , Boccara Franck , Capel Emilie , Vigeral Catherine , Guerci Bruno , Lascols Olivier , Capeau Jacqueline , Caron-Debarle Martine
Published: February 2013

Objective—

Inactivating peroxisome proliferator-activated receptor-γ (PPARγ) mutations lead to a syndrome of familial partial lipodystrophy (FPLD3) associated with early-onset severe hypertension. PPARγ can repress the vascular renin–angiotensin system (RAS) and angiotensin II receptor 1 expression. We evaluated the relationships between PPARγ inactivation and cellular RAS using FPLD3 patients’ cells and human vascular smooth muscle cells expressing mutant or wild-type PPARγ.

Approach and Results—

We identified 2 novel
PPAR
G mutations, R165T and L339X, located in the DNA and ligand-binding domains of PPARγ, respectively in 4 patients from 2 FPLD3 families. In cultured skin fibroblasts and peripheral blood mononuclear cells from the 4 patients and healthy controls, we compared markers of RAS activation, oxidative stress, and inflammation, and tested the effect of modulators of PPARγ and angiotensin II receptor 1. We studied the impact of the 2 mutations on the transcriptional activity of PPARγ and on the vascular RAS in transfected human vascular smooth muscle cells. Systemic RAS was not altered in patients. However, RAS markers were overexpressed in patients’ fibroblasts and peripheral blood mononuclear cells, as in vascular cells expressing mutant PPARγ. Angiotensin II–mediated mitogen-activated protein kinase activity increased in patients’ fibroblasts, consistent with RAS constitutive activation. Patients’ cells also displayed oxidative stress and inflammation. PPARγ activation and angiotensin II receptor 1 mRNA silencing reversed RAS overactivation, oxidative stress, and inflammation, arguing for a role of angiotensin II receptor 1 in these processes.

Conclusions—

Two novel FPLD3-linked
PPAR
G mutations are associated with a defective transrepression of cellular RAS leading to cellular dysfunction, which might contribute to the specific FPLD3-linked severe hypertension.