bluuebunny/crossref_metadata_2025 huggingface dataset:
Visible and Invisible Trends in Black Men's Health: Pitfalls and Promises for Addressing Racial, Ethnic, and Gender Inequities in Health
Authors: Gilbert Keon L. , Ray Rashawn , Siddiqi Arjumand , Shetty Shivan , Baker Elizabeth A. , Elder Keith , Griffith Derek M.
Published: March 2015

Over the past two decades, there has been growing interest in improving black men's health and the health disparities affecting them. Yet, the health of black men consistently ranks lowest across nearly all groups in the United States. Evidence on the health and social causes of morbidity and mortality among black men has been narrowly concentrated on public health problems (e.g., violence, prostate cancer, and HIV/AIDS) and determinants of health (e.g., education and male gender socialization). This limited focus omits age-specific leading causes of death and other social determinants of health, such as discrimination, segregation, access to health care, employment, and income. This review discusses the leading causes of death for black men and the associated risk factors, as well as identifies gaps in the literature and presents a racialized and gendered framework to guide efforts to address the persistent inequities in health affecting black men.
Improved Designs for Cluster Randomized Trials
Authors: Crespi Catherine M.
Published: March 2015

Studies in which clusters of individuals are randomized to conditions are increasingly common in public health research. However, the designs utilized for such studies are often suboptimal and inefficient. We review strategies to improve the design of cluster randomized trials. We discuss both older but effective design concepts that are underutilized, such as stratification and factorial designs, as well as emergent ideas including fractional factorial designs and cluster randomized crossover studies. We draw examples from the recent literature and provide resources for sample size and power planning. Given the inherent inefficiencies of cluster randomized trials, these design strategies merit wider consideration and can lead to studies that are more cost-effective and potentially more rigorous than traditional approaches.
Spatial Data Analysis
Authors: Banerjee Sudipto
Published: March 2015

With increasing accessibility to geographic information systems (GIS) software, statisticians and data analysts routinely encounter scientific data sets with geocoded locations. This has generated considerable interest in statistical modeling for location-referenced spatial data. In public health, spatial data routinely arise as aggregates over regions, such as counts or rates over counties, census tracts, or some other administrative delineation. Such data are often referred to as areal data. This review article provides a brief overview of statistical models that account for spatial dependence in areal data. It does so in the context of two applications: disease mapping and spatial survival analysis. Disease maps are used to highlight geographic areas with high and low prevalence, incidence, or mortality rates of a specific disease and the variability of such rates over a spatial domain. They can also be used to detect hot spots or spatial clusters that may arise owing to common environmental, demographic, or cultural effects shared by neighboring regions. Spatial survival analysis refers to the modeling and analysis for geographically referenced time-to-event data, where a subject is followed up to an event (e.g., death or onset of a disease) or is censored, whichever comes first. Spatial survival analysis is used to analyze clustered survival data when the clustering arises from geographical regions or strata. Illustrations are provided in these application domains.
Heat, Human Performance, and Occupational Health: A Key Issue for the Assessment of Global Climate Change Impacts
Authors: Kjellstrom Tord , Briggs David , Freyberg Chris , Lemke Bruno , Otto Matthias , Hyatt Olivia
Published: March 2015

Ambient heat exposure is a well-known health hazard, which reduces human performance and work capacity at heat levels already common in tropical and subtropical areas. Various health problems have been reported. Increasing heat exposure during the hottest seasons of each year is a key feature of global climate change. Heat exhaustion and reduced human performance are often overlooked in climate change health impact analysis. Later this century, many among the four billion people who live in hot areas worldwide will experience significantly reduced work capacity owing to climate change. In some areas, 30–40% of annual daylight hours will become too hot for work to be carried out. The social and economic impacts will be considerable, with global gross domestic product (GDP) losses greater than 20% by 2100. The analysis to date is piecemeal. More analysis of climate change–related occupational health impact assessments is greatly needed.
Metrics in Urban Health: Current Developments and Future Prospects
Authors: Prasad Amit , Gray Chelsea Bettina , Ross Alex , Kano Megumi
Published: March 2015

The research community has shown increasing interest in developing and using metrics to determine the relationships between urban living and health. In particular, we have seen a recent exponential increase in efforts aiming to investigate and apply metrics for urban health, especially the health impacts of the social and built environments as well as air pollution. A greater recognition of the need to investigate the impacts and trends of health inequities is also evident through more recent literature. Data availability and accuracy have improved through new affordable technologies for mapping, geographic information systems (GIS), and remote sensing. However, less research has been conducted in low- and middle-income countries where quality data are not always available, and capacity for analyzing available data may be limited. For this increased interest in research and development of metrics to be meaningful, the best available evidence must be accessible to decision makers to improve health impacts through urban policies.
Vasopressin: the missing link for preeclampsia?
Authors: Sandgren Jeremy A. , Scroggins Sabrina M. , Santillan Donna A. , Devor Eric J. , Gibson-Corley Katherine N. , Pierce Gary L. , Sigmund Curt D. , Santillan Mark K. , Grobe Justin L.
Published: March 2015

Preeclampsia is a devastating cardiovascular disorder of late pregnancy, affecting 5–7% of all pregnancies and claiming the lives of 76,000 mothers and 500,000 children each year. Various lines of evidence support a “tissue rejection” type reaction toward the placenta as the primary initiating event in the development of preeclampsia, followed by a complex interplay among immune, vascular, renal, and angiogenic mechanisms that have been implicated in the pathogenesis of preeclampsia beginning around the end of the first trimester. Critically, it remains unclear what mechanism links the initiating event and these pathogenic mechanisms. We and others have now demonstrated an early and sustained increase in maternal plasma concentrations of copeptin, a protein by-product of arginine vasopressin (AVP) synthesis and release, during preeclampsia. Furthermore, chronic infusion of AVP during pregnancy is sufficient to phenocopy essentially all maternal and fetal symptoms of preeclampsia in mice. As various groups have demonstrated interactions between AVP and immune, renal, and vascular systems in the nonpregnant state, elevations of this hormone are therefore positioned both in time (early pregnancy) and function to contribute to preeclampsia. We therefore posit that AVP represents a missing mechanistic link between initiating events and established midpregnancy dysfunctions that cause preeclampsia.
Reduced muscle lengthening during eccentric contractions as a mechanism underpinning the repeated-bout effect
Authors: Lau Wing Yin , Blazevich Anthony J. , Newton Michael J. , Wu Sam Shi Xuan , Nosaka Kazunori
Published: March 2015

This study investigated biceps brachii distal myotendinous junction (MTJ) displacement during maximal eccentric elbow flexor contractions to test the hypothesis that muscle length change would be smaller (less MTJ displacement) during the second than the first exercise bout. Ten untrained men performed two eccentric exercise bouts (ECC1 and ECC2) with the same arm consisting of 10 sets of six maximal isokinetic (60°/s) eccentric elbow flexor contractions separated by 4 wk. Biceps brachii distal MTJ displacement was assessed using B-mode ultrasonography, and changes in the displacement (muscle length change) from the start to the end of each contraction during each set and over 10 sets were compared between bouts by two-way repeated-measures ANOVA. Several indirect muscle damage markers were also measured and compared between bouts by two-way repeated-measures ANOVA. The magnitude of MTJ displacement (average of six contractions) increased from set 1 (8.2 ± 4.7 mm) to set 10 (16.4 ± 4.7 mm) during ECC1 ( P < 0.05), but no significant changes over sets were evident during ECC2 ( set 1: 8.5 ± 4.0 mm; set 10: 9.3 ± 3.1 mm). Changes in maximal voluntary isometric contraction strength, range of motion, muscle thickness, ultrasound echo intensity, serum creatine kinase activity, and muscle soreness (visual analog scale) were smaller ( P < 0.05) following ECC2 than ECC1, showing less damage in the repeated bout. These results indicate that the magnitude of muscle lengthening was less during the second than the first eccentric exercise bout, which appears to be a mechanism underpinning the repeated-bout effect.
Quercetin attenuates cyclooxygenase-2 expression in response to acute ureteral obstruction
Authors: Carlsen Inge , Frøkiær Jørgen , Nørregaard Rikke
Published: March 2015

Unilateral ureteral obstruction (UUO) is associated with increased hydrostatic pressure, inflammation, and oxidative stress in the renal parenchyma. Previous studies have demonstrated marked cyclooxygenase (COX)-2 induction in renal medullary interstitial cells (RMICs) in response to UUO. The aim of the present study was to evaluate the effect of quercetin, a naturally occurring antioxidant, on COX-2 induction in vivo and in vitro. Rats subjected to 24 h of UUO were treated intraperitoneally with quercetin (50 mg·kg−1·day−1). Quercetin partly prevented COX-2 induction in the renal inner medulla in response to UUO. Moreover, RMICs exposed to conditions associated with obstruction, inflammation (produced by IL-1β), oxidative stress (produced by H2O2), and mechanical stress (produced by stretch) showed increased COX-2 expression. Interestingly, quercetin reduced COX-2 induction in RMICs subjected to stretched. Similarly, PGE2 production was markedly increased in RMICs exposed to stretch and was reversed to control levels by quercetin treatment. Furthermore, stretch-induced phosphorylation of ERK1/2 was blocked by quercetin, and inhibition of ERK1/2 attenuated stretch-induced COX-2 induction in RMICs. These results indicate that quercetin attenuated the induction of COX-2 expression and activity in RMICs exposed to mechanical stress as a consequence of acute UUO and that the MAPK ERK1/2 pathway might be involved in this quercetin-mediated reduction in COX-2.
Translating genetic findings in hereditary nephrotic syndrome: the missing loops
Authors: Hall Gentzon , Gbadegesin Rasheed A.
Published: March 2015

Nephrotic syndrome (NS) is a clinicopathological entity characterized by proteinuria, hypoalbuminemia, peripheral edema, and hyperlipidemia. It is the most common cause of glomerular disease in children and adults. Although the molecular pathogenesis of NS is not completely understood, data from the study of familial NS suggest that it is a “podocytopathy.” Virtually all of the genes mutated in hereditary NS localize to the podocyte or its secreted products and the slit diaphragm. Since the completion of human genome sequence and the advent of next generation sequencing, at least 29 causes of single-gene NS have been identified. However, these findings have not been matched by therapeutic advances owing to suboptimal in vitro and in vivo models for the study of human glomerular disease and podocyte injury phenotypes. Multidisciplinary collaboration between clinicians, geneticists, cell biologists, and molecular physiologists has the potential to overcome this barrier and thereby speed up the translation of genetic findings into improved patient care.
Contrasting effects of strabismic amblyopia on metabolic activity in superficial and deep layers of striate cortex
Authors: Adams Daniel L. , Economides John R. , Horton Jonathan C.
Published: March 2015

To probe the mechanism of visual suppression, we have raised macaques with strabismus by disinserting the medial rectus muscle in each eye at 1 mo of age. Typically, this operation produces a comitant, alternating exotropia with normal acuity in each eye. Here we describe an unusual occurrence: the development of severe amblyopia in one eye of a monkey after induction of exotropia. Shortly after surgery, the animal demonstrated a strong fixation preference for the left eye, with apparent suppression of the right eye. Later, behavioral testing showed inability to track or to saccade to targets with the right eye. With the left eye occluded, the animal demonstrated no visually guided behavior. Optokinetic nystagmus was absent in the right eye. Metabolic activity in striate cortex was assessed by processing the tissue for cytochrome oxidase (CO). Amblyopia caused loss of CO in one eye's rows of patches, presumably those serving the blind eye. Layers 4A and 4B showed columns of reduced CO, in register with pale rows of patches in layer 2/3. Layers 4C, 5, and 6 also showed columns of CO activity, but remarkably, comparison with more superficial layers showed a reversal in contrast. In other words, pale CO staining in layers 2/3, 4A, and 4B was aligned with dark CO staining in layers 4C, 5, and 6. No experimental intervention or deprivation paradigm has been reported previously to produce opposite effects on metabolic activity in layers 2/3, 4A, and 4B vs. layers 4C, 5, and 6 within a given eye's columns.
Freshly dissociated mature hippocampal astrocytes exhibit passive membrane conductance and low membrane resistance similarly to syncytial coupled astrocytes
Authors: Du Yixing , Ma Baofeng , Kiyoshi Conrad M. , Alford Catherine C. , Wang Wei , Zhou Min
Published: March 2015

Mature astrocytes exhibit a linear current-to-voltage K+membrane conductance (passive conductance) and an extremely low membrane resistance ( Rm) in situ. The combination of these electrophysiological characteristics establishes a highly negative and stable membrane potential that is essential for basic functions, such as K+spatial buffering and neurotransmitter uptake. However, astrocytes are coupled extensively in situ. It remains to be determined whether the observed passive behavior and low Rmare attributable to the intrinsic properties of membrane ion channels or to gap junction coupling in functionally mature astrocytes. In the present study, freshly dissociated hippocampal tissues were used as a new model to examine this basic question in young adult animals. The morphologically intact single astrocytes could be reliably dissociated from animals postnatal day 21 and older. At this animal age, dissociated single astrocytes exhibit passive conductance and resting membrane potential similar to those exhibited by astrocytes in situ. To precisely measure the Rmfrom single astrocytes, dual-patch single-astrocyte recording was performed. We show that dissociated single astrocytes exhibit a low Rmsimilarly to syncytial coupled astrocytes. Functionally, the symmetric expression of high-K+conductance enabled rapid change in the intracellular K+concentrations in response to changing K+drive force. Altogether, we demonstrate that freshly dissociated tissue preparation is a highly useful model for study of the functional expression and regulation of ion channels, receptors, and transporters in astrocytes and that passive behavior and low Rmare the intrinsic properties of mature astrocytes.
Direct mapping rather than motor prediction subserves modulation of corticospinal excitability during observation of actions in real time
Authors: Gueugneau Nicolas , Mc Cabe Sofia I. , Villalta Jorge I. , Grafton Scott T. , Della-Maggiore Valeria
Published: March 2015

Motor facilitation refers to the specific increment in corticospinal excitability (CSE) elicited by the observation of actions performed by others. To date, the precise nature of the mechanism at the basis of this phenomenon is unknown. One possibility is that motor facilitation is driven by a predictive process reminiscent of the role of forward models in motor control. Alternatively, motor facilitation may result from a model-free mechanism by which the basic elements of the observed action are directly mapped onto their cortical representations. Our study was designed to discern these alternatives. To this aim, we recorded the time course of CSE for the first dorsal interosseous (FDI) and the abductor digiti minimi (ADM) during observation of three grasping actions in real time, two of which strongly diverged in kinematics from their natural (invariant) form. Although artificially slow movements used in most action observation studies might enhance the observer's discrimination performance, the use of videos in real time is crucial to maintain the time course of CSE within the physiological range of daily actions. CSE was measured at 4 time points within a 240-ms window that best captured the kinematic divergence from the invariant form. Our results show that CSE of the FDI, not the ADM, closely follows the functional role of the muscle despite the mismatch between the natural and the divergent kinematics. We propose that motor facilitation during observation of actions performed in real time reflects the model-free coding of perceived movement following a direct mapping mechanism.
Brain oscillatory signatures of motor tasks
Authors: Ramos-Murguialday Ander , Birbaumer Niels
Published: March 2015

Noninvasive brain-computer-interfaces (BCI) coupled with prosthetic devices were recently introduced in the rehabilitation of chronic stroke and other disorders of the motor system. These BCI systems and motor rehabilitation in general involve several motor tasks for training. This study investigates the neurophysiological bases of an EEG-oscillation-driven BCI combined with a neuroprosthetic device to define the specific oscillatory signature of the BCI task. Controlling movements of a hand robotic orthosis with motor imagery of the same movement generates sensorimotor rhythm oscillation changes and involves three elements of tasks also used in stroke motor rehabilitation: passive and active movement, motor imagery, and motor intention. We recorded EEG while nine healthy participants performed five different motor tasks consisting of closing and opening of the hand as follows: 1) motor imagery without any external feedback and without overt hand movement, 2) motor imagery that moves the orthosis proportional to the produced brain oscillation change with online proprioceptive and visual feedback of the hand moving through a neuroprosthetic device (BCI condition), 3) passive and 4) active movement of the hand with feedback (seeing and feeling the hand moving), and 5) rest. During the BCI condition, participants received contingent online feedback of the decrease of power of the sensorimotor rhythm, which induced orthosis movement and therefore proprioceptive and visual information from the moving hand. We analyzed brain activity during the five conditions using time-frequency domain bootstrap-based statistical comparisons and Morlet transforms. Activity during rest was used as a reference. Significant contralateral and ipsilateral event-related desynchronization of sensorimotor rhythm was present during all motor tasks, largest in contralateral-postcentral, medio-central, and ipsilateral-precentral areas identifying the ipsilateral precentral cortex as an integral part of motor regulation. Changes in task-specific frequency power compared with rest were similar between motor tasks, and only significant differences in the time course and some narrow specific frequency bands were observed between motor tasks. We identified EEG features representing active and passive proprioception (with and without muscle contraction) and active intention and passive involvement (with and without voluntary effort) differentiating brain oscillations during motor tasks that could substantially support the design of novel motor BCI-based rehabilitation therapies. The BCI task induced significantly different brain activity compared with the other motor tasks, indicating neural processes unique to the use of body actuators control in a BCI context.
Activity-dependent regulation of prestin expression in mouse outer hair cells
Authors: Song Yohan , Xia Anping , Lee Hee Yoon , Wang Rosalie , Ricci Anthony J. , Oghalai John S.
Published: March 2015

Prestin is a membrane protein necessary for outer hair cell (OHC) electromotility and normal hearing. Its regulatory mechanisms are unknown. Several mouse models of hearing loss demonstrate increased prestin, inspiring us to investigate how hearing loss might feedback onto OHCs. To test whether centrally mediated feedback regulates prestin, we developed a novel model of inner hair cell loss. Injection of diphtheria toxin (DT) into adult CBA mice produced significant loss of inner hair cells without affecting OHCs. Thus, DT-injected mice were deaf because they had no afferent auditory input despite OHCs continuing to receive normal auditory mechanical stimulation and having normal function. Patch-clamp experiments demonstrated no change in OHC prestin, indicating that loss of information transfer centrally did not alter prestin expression. To test whether local mechanical feedback regulates prestin, we used TectaC1509Gmice, where the tectorial membrane is malformed and only some OHCs are stimulated. OHCs connected to the tectorial membrane had normal prestin levels, whereas OHCs not connected to the tectorial membrane had elevated prestin levels, supporting an activity-dependent model. To test whether the endocochlear potential was necessary for prestin regulation, we studied TectaC1509Gmice at different developmental ages. OHCs not connected to the tectorial membrane had lower than normal prestin levels before the onset of the endocochlear potential and higher than normal prestin levels after the onset of the endocochlear potential. Taken together, these data indicate that OHC prestin levels are regulated through local feedback that requires mechanoelectrical transduction currents. This adaptation may serve to compensate for variations in the local mechanical environment.
Structural constraints on learning in the neural network
Authors: Martinez Clarisa A. , Wang Chunji
Published: March 2015

Recent research suggests the brain can learn almost any brain-computer interface (BCI) configuration; however, contrasting behavioral evidence from structural learning theory argues that previous experience facilitates, or impedes, future learning. A study by Sadtler and colleagues ( Nature 512: 423–426, 2014) used BCI to demonstrate that neural network structural characteristics constrain learning, a finding that might also provide insight into how the brain responds to and recovers after injury.
Oral Adverse Reactions Caused by Over-the-Counter Oral Agents
Authors: Vucicevic Boras Vanja , Brailo Vlaho , Andabak Rogulj Ana , Vidovic Juras Danica , Gabric Dragana , Vrdoljak Danko Velimir
Published: March 2015

Over-the-counter products rarely cause unwanted reactions in the oral cavity. Oral reactions to these agents are not specific and might present with various clinical oral findings. Detailed medical history is a key to the proper diagnosis of these lesions and fortunately other diagnostic procedures are rarely needed. Lesions are usually managed with elimination of the offending agent and with topical steroids. In more severe cases systemic steroids should be applied.
Identification of Mastication Organ Muscle Forces in the Biocybernetic Perspective
Authors: Kijak Edward , Margielewicz Jerzy , Gąska Damian , Lietz-Kijak Danuta , Więckiewicz Włodzimierz
Published: March 2015

Purpose of the Paper. This paper is an attempt to mathematically describe the mastication organ muscle functioning, taking into consideration the impact of the central nervous system.Material. To conduct model tests, three types of craniums were prepared: short, normal, and long. The necessary numeric data, required to prepare the final calculation models of different craniofacial types, were used to identify muscle and occlusion forces generated by muscles in the area of incisors and molars. The mandible in model tests was treated as a nondeformable stiff form.Methods. The formal basis for the formulated research problem was reached using the laws and principles of mechanics and control theory. The proposed method treats muscles as “black boxes,” whose properties automatically adapt to the nature of the occlusion load. The identified values of occlusion forces referred to measurements made in clinical conditions.Results. The conducted verification demonstrated a very good consistency of model and clinical tests’ results. The proposed method is an alternative approach to the so far applied methods of muscle force identification. Identification of muscle forces without taking into account the impact of the nervous system does not fully reflect the conditions of mastication organ muscle functioning.
Late Pneumolabyrinth May Be Induced by Old Penetrating Injury: Possibility of Undiagnosed Posttraumatic Perilymphatic Fistula
Authors: Nakashima Takahiro , Matsuda Keiji , Okuda Takumi , Tono Tetsuya , Takaki Minoru , Hayashi Tamon , Hanamure Yutaka
Published: March 2015

Traumatic pneumolabyrinth is a relatively rare entity. We report the case of a unilaterally deaf woman with pneumolabyrinth who had suffered penetrating injury 15 years ago. This past history indicated that the case was late pneumolabyrinth occurring from undiagnosed old posttraumatic perilymphatic fistula. In Japan, most cases of traumatic pneumolabyrinth are caused by penetrating injury with an ear pick. Dizziness often improves within several months. Immediate surgical intervention is recommended for hearing loss, but the hearing outcome is not satisfactory. An appropriate strategy should be selected based on the interval to surgery, bone conduction hearing level at disease onset, stapes lesions, and location of air.
The Diagnostic Value of Pressure Algometry for Temporomandibular Disorders
Authors: Więckiewicz Włodzimierz , Woźniak Krzysztof , Piątkowska Dagmara , Szyszka-Sommerfeld Liliana , Lipski Mariusz
Published: March 2015

The aim of this study is to determine the diagnostic value of pressure algometry in temporomandibular disorders. Two hundred volunteers aged 19.3 to 27.8 (mean 21.50, SD 0.97) participated in this study. An analogue pressure algometer was used for the evaluation of muscle tenderness of the following masticatory muscles: superficial and deep parts of the masseter muscle; anterior and posterior parts of the temporal muscle; and the tissues adjacent to the lateral and dorsal part of the temporomandibular joint capsule. Each patient described the algometry result for the individual components of the masticatory motor system, by selecting each time the intensity of pain on a 100 mm Visual Analogue Scale (VAS) ruler. The area under the receiver operating characteristic (ROC) curve, indicating the discriminatory efficiency for asymptomatic subjects and patients with temporomandibular dysfunction according to the dysfunction Di index, was the largest for the mean pain value (AUC = 0.8572; SEM = 0.0531). The 7.4 VAS cut-off point marked 95.3% specificity for this variable in identifying healthy subjects and 58.4% sensitivity in identifying patients with symptoms of dysfunctions (accuracy 68.1%). Assuming comparable sensitivity (74.9%) and specificity (74.2%) for a diagnostic test, there was test accuracy of 74.5% at the 4.2 VAS cut-off point.
Spectrogram Analysis of Complete Dentures with Different Thickness and Palatal Rugae Materials on Speech Production
Authors: Zaki Mahross Hamada , Baroudi Kusai
Published: March 2015

Objective. To investigate the influence of reproduction of different thickness and palatal rugae materials on complete dentures speech using Computerized Speech Lab (CSL) (spectrogram).Materials and Methods. Three completely edentulous male patients (aged 50–60 years) were selected for reading a paragraph. Twelve upper dentures were constructed, four for each patient. The patients’ speech groups were divided into five groups, Group I: patients without dentures; Group II: patients rehabilitated with conventional acrylic dentures; Group III: patients with conventional acrylic dentures with rugae reproduction; Group IV: patients with dentures with metallic framework of minimal thickness and direct ragged metallic palatal surface at rugae area; Group V: patients with dentures with palatal rugae constructed from resilient acrylic resin material with thickness less than conventional denture. Speech samples were recorded after insertion of each denture for groups using Computerized Speech Lab (CSL) (spectrogram). The sounds selected were lingopalatal /s/z/sh/t/d/ and /l/.Results. Group III produced high mean significant difference with /sh/t/ sound. For Group IV, the difference was noticed with /s/z/sh/t/ and /d/ sounds, while for Group V the difference was shown with /z/l/ sound (P<0.05).Conclusion. It is recommended to reproduce the rugae area in complete denture because the phonetic quality of complete denture with rugae is superior to the conventional denture.
In VitroAntitumor Activity of a Keggin Vanadium-Substituted Polyoxomolybdate and Its ctDNA Binding Properties
Authors: Qi Wen , Qin Ying , Qi Yanfei , Guo Li , Li Juan
Published: March 2015

A Keggin vanadium-substituted polyoxomolybdate, K5PMo10V2O40(PMo10V2), has been synthesized and it’s antitumor effect against Hela cells was investigated. The calf thymus DNA (ctDNA) binding ability of PMo10V2was also evaluated by UV-Vis absorption spectra and fluorescence spectra. The identity and high purity of PMo10V2was confirmed by elemental analysis and IR analysis. And the antitumor activity test of PMo10V2was carried out on Hela cancer cells line by MTT assay. The results of MTT assay show that PMo10V2significantly reduced the viability of Hela cells in a dose-dependent manner and exhibited stronger inhibitory activity against Hela cells at an IC50of 800 μg/mL, which is more effective than the positive control, 5-Fu(P<0.05). The results of the UV-Vis absorption spectra and fluorescence spectra indicated the groove or outside stacking binding between PMo10V2and ctDNA. These results show that the antitumor activity of PMo10V2may be caused by the interactions between DNA and PMo10V2.
Long Term Progression-Free Survival in a Patient with Locally Advanced Prostate Cancer under Low Dose Intermittent Androgen Deprivation Therapy with Bicalutamide Only
Authors: Latz Stefan , Fisang Christian , Ebert Wolfram , Orth Stefan , Engehausen Dirk G. , Müller Stefan C. , Anding Ralf
Published: March 2015

Androgen deprivation is a common treatment option in patients with locally advanced or metastatic prostate cancer. No case of long term treatment with an intermittent approach with only low dose bicalutamide (50 mg daily) has been described yet. We report a 60-year-old patient, initially presenting with a PSA elevation of 19.2 ng/mL in 1996. After diagnosis of well to moderately differentiated prostate cancer by transrectal biopsy, the patient underwent an open radical prostatectomy. Final diagnosis was adenocarcinoma of the prostate, classified as pT3a, pR1, pV0, and pL1. Adjuvant intermittent androgen deprivation therapy with flutamide 250 mg was applied, which was changed to bicalutamide 50 mg once daily when it became available in 2001. Six on-phases were performed and PSA values never exceeded 20 ng/mL. The patient did not experience any serious side effects. To date, there are no clinical or radiological signs of progression. Current PSA value is 3.5 ng/mL.
Full-Length Semaphorin-3C Is an Inhibitor of Tumor Lymphangiogenesis and Metastasis
Authors: Mumblat Yelena , Kessler Ofra , Ilan Neta , Neufeld Gera
Published: March 2015

Semaphorins play important regulatory roles in diverse processes such as axon guidance, angiogenesis, and immune responses. We find that semaphorin-3C (sema3C) induces the collapse of the cytoskeleton of lymphatic endothelial cells (LEC) in a neuropilin-2-, plexin-D1-, and plexin-A1–dependent manner, while most other semaphorins, including antiangiogenic semaphorins such as sema3A do not. Sema3C is cleaved, like other class-3 semaphorins, by furin-like pro-protein convertases (FPPC). Cleaved sema3C (p65-Sema3C) was unable to induce the collapse of the cytoskeleton of LEC. FPPC are strongly upregulated in tumor cells. In order to examine the effects of full-length sema3C on tumor progression, we therefore generated an active point mutated furin cleavage-resistant sema3C (FR-sema3C). FR-sema3C inhibited potently proliferation of LEC and to a lesser extent proliferation of human umbilical vein–derived endothelial cells. FR-sema3C also inhibited VEGF-C–induced phosphorylation of VEGFR-3, ERK1/2, and AKT. Expression of recombinant FR-sema3C in metastatic, triple-negative LM2-4 breast cancer cells did not affect their migration or proliferation in vitro. However, tumors derived from FR-sema3C–expressing LM2-4 cells implanted in mammary fat pads developed at a slower rate, contained a lower concentration of blood vessels and lymph vessels, and metastasized much less effectively to lymph nodes. Interestingly, p65-Sema3C, but not FR-sema3C, rendered A549 lung cancer cells resistant to serum deprivation, suggesting that previously reported protumorigenic activities of sema3C may be due to p65-Sema3C produced by tumor cells. Our observations suggest that FR-sema3C may be further developed into a novel antitumorigenic drug. Cancer Res; 75(11); 2177–86. ©2015 AACR.
Development of Resistance to EGFR-Targeted Therapy in Malignant Glioma Can Occur through EGFR-Dependent and -Independent Mechanisms
Authors: Klingler Stefan , Guo Baofeng , Yao Jun , Yan Haiyan , Zhang Ling , Vaseva Angelina V. , Chen Sida , Canoll Peter , Horner James W. , Wang Y. Alan , Paik Ji-Hye , Ying Haoqiang , Zheng Hongwu
Published: March 2015

Epidermal growth factor receptor (EGFR) is highly amplified, mutated, and overexpressed in human malignant gliomas. Despite its prevalence and growth-promoting functions, therapeutic strategies to inhibit EGFR kinase activity have not been translated into profound beneficial effects in glioma clinical trials. To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Using combined genetic and pharmacologic interventions, we revealed that EGFR*-driven gliomas were insensitive to EGFR tyrosine kinase inhibitors, although they could efficiently inhibit EGFR* autophosphorylation in vitro and in vivo. This is in contrast with the genetic suppression of EGFR* induction that led to significant tumor regression and prolonged animal survival. However, despite their initial response to genetic EGFR* extinction, all tumors would relapse and propagate independent of EGFR*. We further showed that EGFR*-independent tumor cells existed prior to treatment and were responsible for relapse following genetic EGFR* suppression. And, the addition of a PI3K/mTOR inhibitor could significantly delay relapse and prolong animal survival. Our findings shed mechanistic insight into EGFR drug resistance in glioma and provide a platform to test therapies targeting aberrant EGFR signaling in this setting. Cancer Res; 75(10); 2109–19. ©2015 AACR.
Identification of Rare High-Avidity, Tumor-Reactive CD8+ T Cells by Monomeric TCR–Ligand Off-Rates Measurements on Living Cells
Authors: Hebeisen Michael , Schmidt Julien , Guillaume Philippe , Baumgaertner Petra , Speiser Daniel E. , Luescher Immanuel , Rufer Nathalie
Published: March 2015

The avidity of the T-cell receptor (TCR) for antigenic peptides presented by the peptide–MHC (pMHC) on cells is a key parameter for cell-mediated immunity. Yet a fundamental feature of most tumor antigen-specific CD8+ T cells is that this avidity is low. In this study, we addressed the need to identify and select tumor-specific CD8+ T cells of highest avidity, which are of the greatest interest for adoptive cell therapy in patients with cancer. To identify these rare cells, we developed a peptide–MHC multimer technology, which uses reversible Ni2+-nitrilotriacetic acid histidine tags (NTAmers). NTAmers are highly stable but upon imidazole addition, they decay rapidly to pMHC monomers, allowing flow-cytometric–based measurements of monomeric TCR–pMHC dissociation rates of living CD8+ T cells on a wide avidity spectrum. We documented strong correlations between NTAmer kinetic results and those obtained by surface plasmon resonance. Using NTAmers that were deficient for CD8 binding to pMHC, we found that CD8 itself stabilized the TCR–pMHC complex, prolonging the dissociation half-life several fold. Notably, our NTAmer technology accurately predicted the function of large panels of tumor-specific T cells that were isolated prospectively from patients with cancer. Overall, our results demonstrated that NTAmers are effective tools to isolate rare high-avidity cytotoxic T cells from patients for use in adoptive therapies for cancer treatment. Cancer Res; 75(10); 1983–91. ©2015 AACR.
PLZF, a Tumor Suppressor Genetically Lost in Metastatic Castration-Resistant Prostate Cancer, Is a Mediator of Resistance to Androgen Deprivation Therapy
Authors: Hsieh Chen-Lin , Botta Ginevra , Gao Shuai , Li Tiantian , Van Allen Eliezer M. , Treacy Daniel J. , Cai Changmeng , He Housheng Hansen , Sweeney Christopher J. , Brown Myles , Balk Steven P. , Nelson Peter S. , Garraway Levi A. , Kantoff Philip W.
Published: March 2015

Whole-exome sequencing of metastatic castration-resistant prostate cancer (mCRPC) reveals that 5% to 7% of tumors harbor promyelocytic leukemia zinc finger (PLZF) protein homozygous deletions. PLZF is a canonical androgen-regulated putative tumor suppressor gene whose expression is inhibited by androgen deprivation therapy (ADT). Here, we demonstrate that knockdown of PLZF expression promotes a CRPC and enzalutamide-resistant phenotype in prostate cancer cells. Reintroduction of PLZF expression is sufficient to reverse androgen-independent growth mediated by PLZF depletion. PLZF loss enhances CRPC tumor growth in a xenograft model. Bioinformatic analysis of the PLZF cistrome shows that PLZF negatively regulates multiple pathways, including the MAPK pathway. Accordingly, our data support an oncogenic program activated by ADT. This acquired mechanism together with the finding of genetic loss in CRPC implicates PLZF inactivation as a mechanism promoting ADT resistance and the CRPC phenotype. Cancer Res; 75(10); 1944–8. ©2015 AACR.
Racial Variation in Breast Tumor Promoter Methylation in the Carolina Breast Cancer Study
Authors: Conway Kathleen , Edmiston Sharon N. , Tse Chiu-Kit , Bryant Christopher , Kuan Pei Fen , Hair Brionna Y. , Parrish Eloise A. , May Ryan , Swift-Scanlan Theresa
Published: March 2015

Background: African American (AA) women are diagnosed with more advanced breast cancers and have worse survival than white women, but a comprehensive understanding of the basis for this disparity remains unclear. Analysis of DNA methylation, an epigenetic mechanism that can regulate gene expression, could help to explain racial differences in breast tumor clinical biology and outcomes.

Methods: DNA methylation was evaluated at 1,287 CpGs in the promoters of cancer-related genes in 517 breast tumors of AA (n = 216) or non-AA (n = 301) cases in the Carolina Breast Cancer Study (CBCS).

Results: Multivariable linear regression analysis of all tumors, controlling for age, menopausal status, stage, intrinsic subtype, and multiple comparisons [false discovery rate (FDR)], identified seven CpG probes that showed significant (adjusted P < 0.05) differential methylation between AAs and non-AAs. Stratified analyses detected an additional four CpG probes differing by race within hormone receptor–negative (HR−) tumors. Genes differentially methylated by race included DSC2, KCNK4, GSTM1, AXL, DNAJC15, HBII-52, TUSC3, and TES; the methylation state of several of these genes may be associated with worse survival in AAs. TCGA breast tumor data confirmed the differential methylation by race and negative correlations with expression for most of these genes. Several loci also showed racial differences in methylation in peripheral blood leukocytes (PBL) from CBCS cases, indicating that these variations were not necessarily tumor-specific.

Conclusions: Racial differences in the methylation of cancer-related genes are detectable in both tumors and PBLs from breast cancer cases.

Impact: Epigenetic variation could contribute to differences in breast tumor development and outcomes between AAs and non-AAs. Cancer Epidemiol Biomarkers Prev; 24(6); 921–30. ©2015 AACR.
Folate Pathway Gene Polymorphisms and Risk of Childhood Brain Tumors: Results from an Australian Case–Control Study
Authors: Greenop Kathryn R. , Scott Rodney J. , Attia John , Bower Carol , de Klerk Nicholas H. , Norris Murray D. , Haber Michelle , Jamieson Sarra E. , van Bockxmeer Frank M. , Gottardo Nicholas G. , Ashton Lesley J. , Armstrong Bruce K. , Milne Elizabeth
Published: March 2015

Background: Recent research suggests that maternal folic acid supplementation is associated with a reduced risk of childhood brain tumors (CBT); polymorphisms in folate pathway genes could modify this association or directly influence CBT risk.

Methods: Associations between risk of CBT and folate pathway polymorphisms were investigated in a population-based case–control study in Australia (2005–2010). Cases were recruited through all Australian pediatric oncology centers and controls by national random digit dialing. Data were available from 321 cases and 552 controls. Six polymorphisms were genotyped in children and parents (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756A>G, MTR 5049C>A, and CBS 2199 T>C). Maternal folic acid use was ascertained via questionnaire. ORs were estimated using unconditional logistic regression. Case–parent trio analyses were also undertaken.

Results: There was weak evidence of a reduced risk of CBT for the MTRR 66GG genotype in the child or father: ORs 0.71 [95% confidence interval (CI), 0.48–1.07]; 0.54 (95% CI, 0.34–0.87), respectively. Maternal prepregnancy folic acid supplementation showed a stronger negative association with CBT risk where the child, mother, or father had the MTRR 66GG genotype (Pinteraction = 0.07, 0.10, and 0.18, respectively).

Conclusions: Evidence for an association between folate pathway genotypes and CBT is limited in this study. There was possible protection by the MTRR 66GG genotype, particularly when combined with maternal prepregnancy folic acid supplementation; these results are novel and require replication.

Impact: The possible interaction between folic acid supplementation and MTRR 66A>G, if confirmed, would strengthen evidence for prepregnancy folate protection against CBT. Cancer Epidemiol Biomarkers Prev; 24(6); 931–7. ©2015 AACR.
Molecular Pathways: GLI1-Induced Drug Glucuronidation in Resistant Cancer Cells
Authors: Zahreddine Hiba Ahmad , Borden Katherine L.B.
Published: March 2015

Drug resistance remains a major impediment in the development of durable cancer therapies. Studies in acute myelogenous leukemia (AML) patients revealed a new form of multidrug resistance. Here, increased glioma-associated protein GLI1 leads to elevation of the UDP-glucuronosyl transferase (UGT) enzymes. UGTs add glucuronic acid to xenobiotics and metabolites. Traditionally, the loss of these enzymes is thought to contribute to cancer as a result of impaired clearance of environmental carcinogens. However, we demonstrate that overexpression of UGTs can contribute to oncogenesis by promoting drug resistance. Indeed, UGT levels in AML patients treated with ribavirin and/or cytarabine were elevated at relapse relative to diagnosis. This was reversed by GLI1 inhibition, suggesting a clinically relevant strategy to overcome drug resistance. Further, overexpression of UGTs can also lead to drug resistance in other cancers, such as certain Hsp90 inhibitors and vorinostat in colorectal and chronic lymphoblastic leukemia, respectively. Not all drugs are targets of glucuronidation, suggesting that UGT status could be relevant to treatment choice. Here, we describe several facets of UGT biology and how these could be exploited clinically. These studies demonstrate how drugs in cancer cells can be metabolized differentially than their normal counterparts. In summary, we describe a new form of drug resistance relevant to a variety of cancer contexts. Clin Cancer Res; 21(10); 2207–10. ©2015 AACR.
The miR-30 Family Inhibits Pulmonary Vascular Hyperpermeability in the Premetastatic Phase by Direct Targeting of Skp2
Authors: Qi Feifei , He Ting , Jia Lin , Song Nan , Guo Lifang , Ma Xuhui , Wang Chunying , Xu Min , Fu Yan , Li Lin , Luo Yongzhang
Published: March 2015

Purpose: Before metastasis, primary tumor can create a premetastatic niche in distant organ to facilitate the dissemination of tumor cells. In the premetastatic phase, the permeability of pulmonary vasculatures is increased to accelerate the extravasation of circulating tumor cells. However, it is not clear whether local miRNAs contribute to the vascular hyperpermeability of the premetastatic niche.

Experimental Design: The expression of total miRNAs was determined using microarray in series of premetastatic lungs from tumor-bearing mice. Significantly differentially expressed miRNAs were identified and validated with qRT-PCR. Vascular permeability assays, vascular mimic systems, and orthotopic tumor models were used to investigate roles of selected miRNAs and target genes in premetastatic hyperpermeability.

Results: We identified a miRNA signature in premetastatic lungs. Among these miRNAs, miR-30a, b, c, d, and e were significantly attenuated. Subsequent investigations elucidated that lung fibroblast–derived miR-30s stabilized pulmonary vessels. Overexpression of miR-30s in lungs postponed metastasis and extended overall survival of B16 tumor–bearing mice. Following studies uncovered that Skp2 was directly targeted by miR-30s. Overexpression of Skp2 could disrupt pulmonary vessels, promote lung metastasis, and decrease overall survival of B16 tumor–bearing mice.

Conclusions: These findings illuminate a novel mechanism for the modulation of premetastatic niches by miR-30s, which suggest that miR-30s represent not only promising targets for antimetastasis therapy but also indicators for metastasis. Clin Cancer Res; 21(13); 3071–80. ©2015 AACR.