bluuebunny/crossref_metadata_2025 huggingface dataset:
Husbandry risk factors associated with hock pododermatitis in UK pet rabbits (Oryctolagus cuniculus)
Authors: Mancinelli E. , Keeble E. , Richardson J. , Hedley J.
Published: February 2014

Pododermatitis, often called ‘sore hocks’, is a chronic, granulomatous, ulcerative dermatitis which most commonly affects the plantar aspect of the caudal metatarsal and tarsal areas. Pododermatitis is a common clinical finding in the pet rabbit population, but no data is available regarding the actual prevalence of this condition in the UK pet rabbit population or possible husbandry‐related factors which may predispose pet rabbits to development of this condition. It was the aim of this study to determine the prevalence of pododermatitis within a sample pet rabbit population, and study possible correlations with husbandry, sex, breed and origin of the rabbits. Findings suggested that young rabbits are at a lower risk of pododermatitis compared with older rabbits; female domestic rabbits are more predisposed to pododermatitis than males; and 100 per cent of the neutered females examined showed clinical evidence of pododermatitis. The effect that different types of bedding may have on the prevalence of pododermatitis was also investigated. This study also produced a scoring system which can be used to score clinical cases. Our study is of clinical importance because it helps to recognise many of the factors which predispose pet rabbits to pododermatitis, representing the first step towards increased awareness of this extremely common problem.
Seasonal variation in foraging behaviour of plains zebra (Equus quagga) may alter contact with the anthrax bacterium (Bacillus anthracis)
Authors: Havarua Zepee , Turner Wendy C. , Mfune John K.E.
Published: February 2014

Pathogens transmitted via the environment are often aggregated in space, and seasonal variation in wildlife foraging behaviour may alter contact rates with environmental pathogens. The soil-borne bacterium Bacillus anthracis Cohn, 1872 causes anthrax, and herbivores acquire gastrointestinal anthrax by ingesting spores. Therefore host foraging behaviour could be a fundamental component of anthrax epidemiology. This study investigated seasonal changes in bite density and diet of plains zebras (Equus quagga Boddaert, 1785) in relation to anthrax seasonality in Etosha National Park, Namibia, where most zebra anthrax cases are observed in wet seasons. The diet of zebras shifted from more short grasses during the wet season to more tall grasses in the dry season, suggesting a greater potential for soil ingestion in wet seasons. Zebras also foraged most intensively in the wet season with the number of bites/step declining through the dry season. This higher bite density in wet seasons may lead individuals to ingest greater concentrations of the pathogen if foraging in a localized infectious area. Although sex and reproductive state affected bite density, no sex difference in anthrax occurrence was observed. This study demonstrates how considering variation in host foraging behaviour may enhance our understanding of disease seasonality for pathogens with foraging-dependent transmission.
Eastern Newt (Notophthalmus viridescens) larvae alter morphological but not chemical defenses in response to predator cues
Authors: Brossman Kelly H. , Carlson Bradley E. , Stokes Amber N. , Langkilde Tracy
Published: February 2014

Prey traits are often modified in response to exposure to predators, a phenomenon known as predator-induced phenotypic plasticity. Morphological plasticity in response to predator cues is well documented in amphibians; however, predator-induced chemical defenses have received relatively little attention. The Eastern Newt (Notophthalmus viridescens (Rafinesque, 1820)), which possesses tetrodotoxin—a toxin for chemical defense, is most vulnerable to predation during its larval stage. We assessed whether exposing Eastern Newt larvae to predator scent cues (from dragonfly larvae) would elicit change in their morphological and chemical defenses. Newt larvae exposed to scent cues of predatory dragonfly larvae exhibited significantly greater tail depths, which should increase survival of attempted predation by allowing them to swim faster, but did not differ in mass, snout–vent length, or tail length. Toxin concentrations in newt larvae were not significantly affected by exposure to these predator cues. Larval toxicity may be derived maternally or environmentally and is inflexible, or induced toxicity may only be detectable later in development. Predator-induced phenotypic plasticity, especially of chemical defenses, warrants greater attention, as potentially important outcomes of species interactions remain unclear.
DETERMINISM VS. NONDETERMINISM FOR TWO-WAY AUTOMATA: Representing the Meaning of States by Logical Formulæ
Authors: HROMKOVIČ JURAJ , KRÁLOVIČ RASTISLAV , KRÁLOVIČ RICHARD , ŠTEFANEC RICHARD
Published: February 2014

The question whether nondeterminism is more powerful than determinism for two-way automata is one of the most famous old open problems on the border between formal language theory and automata theory. An exponential gap between the number of states of two-way nondeterministic finite automata (2NFA) and their deterministic counterparts (2DFA) was proved only for some restricted versions of two-way automata up to now. This problem is also related to the famous DLOG vs. NLOG problem. A superpolynomial gap between 2NFAs and 2DFAs on words of polynomial length in the parameter of a complete language of Sipser and Sakoda for the 2DFA vs. 2NFAs problem would imply that DLOG is a proper subset of NLOG.

The first goal of this paper is first to survey the attempts to solve the 2DFA vs. 2NFA problem. After that we discus why this problem is so hard in spite of the fact that one has a very clear intuition why nondeterminism has to be more powerful than determinism for this computing model. It seems that the hardness lies in the fact that, when trying to prove lower bounds on the number of states of 2DFAs, we are not able to force the states to have a clear meaning. When designing an automaton, we always assign an unambiguous interpretation to each state. In an attempt to capture the concept of meaning of states we introduce a new restriction on the two-way automata: Each state is assigned a logical formula expressing some properties of the input word, and transitions of the automaton must be designed in such a way that the assigned formula is true whenever the automaton is in the given state. In our approach we use propositional formulæ with various interpreted atoms. For two possible logics we prove an exponential gap between 2NFAs and 2DFAs. Moreover, using our concept of assigning meaning to the states of 2DFAs we show that there is no exponential gap between general 2NFAs and 2DFAs on inputs of a polynomial length of the complete language of Sakoda and Sipser.
COMPLEXITY OF ATOMS OF REGULAR LANGUAGES
Authors: BRZOZOWSKI JANUSZ , TAMM HELLIS
Published: February 2014

The quotient complexity of a regular language L, which is the same as its state complexity, is the number of left quotients of L. An atom of a non-empty regular language L with n quotients is a non-empty intersection of the n quotients, which can be uncomplemented or complemented. An NFA is atomic if the right language of every state is a union of atoms. We characterize all reduced atomic NFAs of a given language, i.e., those NFAs that have no equivalent states. We prove that, for any language L with quotient complexity n, the quotient complexity of any atom of L with r complemented quotients has an upper bound of 2n − 1 if r = 0 or r = n; for 1 ≤ r ≤ n − 1 the bound is[Formula: see text] For each n ≥ 2, we exhibit a language with 2n atoms which meet these bounds.
UNAMBIGUOUS CONSTRAINED AUTOMATA
Authors: CADILHAC MICHAËL , FINKEL ALAIN , MCKENZIE PIERRE
Published: February 2014

The class of languages captured by Constrained Automata (CA) that are unambiguous is shown to possess more closure properties than the provably weaker class captured by deterministic CA. Problems decidable for deterministic CA are nonetheless shown to remain decidable for unambiguous CA, and testing for regularity is added to this set of decidable problems. Unambiguous CA are then shown incomparable with deterministic reversal-bounded machines in terms of expressivity, and a deterministic model equivalent to unambiguous CA is identified.
FINE AND WILF'S THEOREM FOR k-ABELIAN PERIODS
Authors: KARHUMÄKI JUHANI , PUZYNINA SVETLANA , SAARELA ALEKSI
Published: February 2014

Two words u and v are k-abelian equivalent if they contain the same number of occurrences of each factor of length at most k. This leads to a hierarchy of equivalence relations on words which lie properly in between the equality and abelian equality. The goal of this paper is to analyze Fine and Wilf's periodicity theorem with respect to these equivalence relations. Fine and Wilf's theorem tells exactly how long a word with two periods p and q can be without having the greatest common divisor of p and q as a period. Recently, the same question has been studied for abelian periods. In this paper we show that for k-abelian periods the situation is similar to the abelian case: In general, there is no bound for the lengths of such words, but the values of the parameters p, q and k for which the length is bounded can be characterized. In the latter case we provide nontrivial upper and lower bounds for the maximal lengths of such words. In some cases (e.g., for k = 2) we found the maximal length precisely.
THE FINITENESS PROBLEM FOR AUTOMATON SEMIGROUPS IS UNDECIDABLE
Authors: GILLIBERT PIERRE
Published: February 2014

The finiteness problem for automaton groups and semigroups has been widely studied, several partial positive results are known. However, we prove that, in the most general case, the problem is undecidable. We study the case of automaton semigroups. Given a NW-deterministic Wang tile set, we construct a Mealy automaton, such that the plane admits a valid Wang tiling if and only if the Mealy automaton generates a infinite semigroup. The construction is similar to a construction by Kari for proving that the nilpotency problem for cellular automata is unsolvable. Moreover, Kari proves that the tiling of the plane is undecidable for NW-deterministic Wang tile set. It follows that the finiteness problem for automaton semigroups is undecidable.
Decomposition of quantum gates
Authors: Li Chi Kwong , Pelejo Diane Christine
Published: February 2014

A recurrence scheme is presented to decompose an n-qubit unitary gate to the product of no more than N(N - 1)/2 single qubit gates with small number of controls, where N = 2n. Detailed description of the recurrence steps and formulas for the number of k-controlled single qubit gates in the decomposition are given. Comparison of the result to a previous scheme is presented, and future research directions are discussed.
Long-lived entanglement with pulsed-driven initially entangled qubit pair
Authors: Metwally N. , Batarfi H. A. , Hassan S. S.
Published: February 2014

The entanglement of different classes of initially entangled qubit pair is investigated in the presence of short laser pulses of rectangular and exponential shapes with either one or both qubits are excited. For the rectangular pulse, the detuning parameter protects the entanglement from degradation and controls its upper and lower bounds. We show that the upper bounds of entanglement decrease if both particles are excited, but the lower bounds are much better if only one particle is excited. The phenomena of entanglement degradation, sudden-death and -birth are shown for small initial time. Long-lived entanglement behavior, but with a variable degree, appears in the presence of rectangular pulse. However, in the case of the exponential pulse one obtains an invariably long-lived entanglement. For the combined case (rectangular + exponential), we show that one can generate a long-lived entanglement with small variable by increasing the strength of the rectangular pulse area and decreasing the Rabi-frequency of the exponential pulse.
Intensity Frontier of Accelerators for Nuclear Physics
Authors: Imai Kenichi
Published: February 2014

High intensity accelerators for nuclear and hadronic physics are reviewed. The frontier of nuclear and hadronic physics with these accelerators is discussed with its perspectives. J-PARC is a world-leading accelerator of this kind and has just started its operation. As a good example, J-PARC and its physics program are reviewed.
Ion Injectors for High-Intensity Accelerators
Authors: Stockli Martin P. , Nakagawa Takahide
Published: February 2014

There are a growing number of applications for ion accelerators, with increasingly complex beam requirements and progressively higher beam intensities. The performance of the ion injector is critical to the success of these projects. First, there is the ion source that has to produce the desired ion species, with a large variety of desired species requiring vastly different ion sources. In addition, the ion source has to produce those ions with the desired rate and without debilitating impurities, as well as with the desired duty factor. Several examples will show that very successful ion sources can fail when the duty factor is increased because their lifetime becomes too short or their failure rate too high. Equally important is the extraction of those ions and their transport to the next stage of acceleration, because the slow ion velocities pose a serious challenge to increasing the intensity. As the beam intensity is increased, its emittance, stability and controllability become more important. This article cannot cover this subject in depth. It tries to provide a flavor of the complexities and serve as an introduction to further reading and studies.
Charge Strippers of Heavy Ions for High Intensity Accelerators
Authors: Nolen Jerry A. , Marti Felix
Published: February 2014

Charge strippers play a critical role in many high intensity heavy ion accelerators. Here we present some history of recent stripper technology development and indicate the capabilities and limitations of the various approaches. The properties of solid, gaseous, and liquid strippers are covered. In particular, the limitations of solid strippers for high intensity, high atomic number heavy ions and the unique features of helium gas and liquid lithium for high intensity applications are covered. The need for high quality simulation of stripper performance as important input for system optimization is explained and examples of the current simulation codes are given.
Regional controls on Lower Tertiary sandstone distribution in the North Sea and NE Atlantic margin basins
Authors: Mudge David C.
Published: February 2014

Widely distributed deep-water fan sandstones of early Tertiary age form the reservoir for one of the most successful and prolific plays in the North Sea and NE Atlantic margin. Stratigraphic interpretation of a large well database provides the basis for mapping sand distribution and depositional environments in these two hydrocarbon provinces. Sand thickness maps for five Paleocene–Lower Eocene plays illustrate the intimate relationship between pre-existing structural features and sand distribution and facies in the North Sea. Large-scale depositional environment mapping gives an insight into the similarities and differences between basin evolution and sand distribution in North Sea and NE Atlantic margin basins. Both provinces were affected by the same succession of pre-break-up and syn-break-up tectonic and magmatic events that led to early Eocene continental separation and the formation of the NE Atlantic. The impact of these events was muted within the North Sea, which was protected from Paleocene rifting on the NE Atlantic margin by the Scotland–Shetland hinterland and from Paleocene–early Eocene volcanism by its more distant location. However, it was the combination of tectonic and thermal uplift of this clastic source area that contributed the large volumes of sand that accumulated in both these provinces.
Angiogenic microenvironment augments impaired endothelial responses under diabetic conditions
Authors: Sheikh Abdul Q. , Kuesel Courtney , Taghian Toloo , Hurley Jennifer R. , Huang Wei , Wang Yigang , Hinton Robert B. , Narmoneva Daria A.
Published: February 2014

Diabetes-induced cardiomyopathy is characterized by cardiac remodeling, fibrosis, and endothelial dysfunction, with no treatment options currently available. Hyperglycemic memory by endothelial cells may play the key role in microvascular complications in diabetes, providing a potential target for therapeutic approaches. This study tested the hypothesis that a proangiogenic environment can augment diabetes-induced deficiencies in endothelial cell angiogenic and biomechanical responses. Endothelial responses were quantified for two models of diabetic conditions: 1) an in vitro acute and chronic hyperglycemia where normal cardiac endothelial cells were exposed to high-glucose media, and 2) an in vivo chronic diabetes model where the cells were isolated from rats with type I streptozotocin-induced diabetes. Capillary morphogenesis, VEGF and nitric oxide expression, cell morphology, orientation, proliferation, and apoptosis were determined for cells cultured on Matrigel or proangiogenic nanofiber hydrogel. The effects of biomechanical stimulation were assessed following cell exposure to uniaxial strain. The results demonstrate that diabetes alters cardiac endothelium angiogenic response, with differential effects of acute and chronic exposure to high-glucose conditions, consistent with the concept that endothelial cells may have a long-term “hyperglycemic memory” of the physiological environment in the body. Furthermore, endothelial cell exposure to strain significantly diminishes their angiogenic potential following strain application. Both diabetes and strain-associated deficiencies can be augmented in the proangiogenic nanofiber microenvironment. These findings may contribute to the development of novel approaches to reverse hyperglycemic memory of endothelium and enhance vascularization of the diabetic heart, where improved angiogenic and biomechanical responses can be the key factor to successful therapy.
Activation of the carotid chemoreflex secondary to muscle metaboreflex stimulation in men
Authors: Edgell H. , Stickland M. K.
Published: February 2014

Recent work has shown that the carotid chemoreceptor (CC) contributes to sympathetic control of cardiovascular function during exercise, despite no evidence of increased circulating CC stimuli, suggesting enhanced CC activity/sensitivity. As interactions between metaboreceptors and chemoreceptors have been previously observed, the purpose of this study was to isolate the metaboreflex while acutely stimulating or inhibiting the CC to determine whether the metaboreflex increased CC activity/sensitivity. Fourteen young healthy men (height: 177.0 ± 2.1 cm, weight: 85.8 ± 5.5 kg, age: 24.6 ± 1.1 yr) performed three trials of 40% maximal voluntary contraction handgrip for 2 min, followed by 3 min of postexercise circulatory occlusion (PECO) to stimulate the metaboreflex. In random order, subjects either breathed room air, hypoxia (target SPo2 = 85%), or hyperoxia (FiO2 = 1.0) during the PECO to modulate the chemoreflex. After these trials, a resting hypoxia trial was conducted without handgrip or PECO. Ventilation (V̇e), heart rate (HR), blood pressure, and muscle sympathetic nervous activity (MSNA) data were continuously obtained. Relative to normoxic PECO, inhibition of the CC during hyperoxic PECO resulted in lower MSNA ( P = 0.038) and HR ( P = 0.021). Relative to normoxic PECO, stimulation of the CC during hypoxic PECO resulted in higher HR ( P < 0.001) and V̇e ( P < 0.001). The ventilatory and MSNA responses to hypoxic PECO were not greater than the sum of the responses to hypoxia and PECO individually, indicating that the CC are not sensitized during metaboreflex activation. These results demonstrate that stimulation of the metaboreflex activates, but does not sensitize the CC, and help explain the enhanced CC activity with exercise.
Novel MAPK-dependent and -independent tubulogenes identified via microarray analysis of 3D-cultured Madin-Darby canine kidney cells
Authors: Chacon-Heszele Maria F. , Zuo Xiaofeng , Hellman Nathan E. , McKenna Sarah , Choi Soo Young , Huang Liwei , Tobias John W. , Park Kwon Moo , Lipschutz Joshua H.
Published: February 2014

Cystogenesis and tubulogenesis are basic building blocks for many epithelial organs, including the kidney. Most researchers have used two-dimensional (2D) cell culture to investigate signaling pathways downstream of hepatocyte growth factor (HGF). We hypothesize that three-dimensional (3D) collagen-grown Madin-Darby canine kidney (MDCK) cells, which form cysts and then tubulate in response to HGF, are a much more in vivo-like system for the identification of novel tubulogenes. With the use of a canine microarray containing over 20,000 genes, 2,417 genes were identified as potential tubulogenes that were differentially regulated, exclusively in 3D-grown MDCK cells. Among these, 840 were dependent on MAPK signaling. Importantly, this work shows that many putative tubulogenes, previously identified via microarray analysis of 2D cultures, including by us, do not change in 3D culture and vice versa. The use of a 3D-culture system allowed for the identification of novel MAPK-dependent and -independent genes that regulate early renal tubulogenesis in vitro, e.g., matrix metalloproteinase 1 (MMP1). Knockdown of MMP1 led to defects in cystogenesis and tubulogenesis in 3D-grown MDCK cells, most likely due to problems establishing normal polarity. We suggest that data obtained from 2D cultures, even those using MDCK cells treated with HGF, should not be automatically extrapolated to factors important for cystogenesis and tubulogenesis. Instead, 3D culture, which more closely replicates the biological environment and is therefore a more accurate model for identifying tubulogenes, is preferred. Results from the present analysis will be used to build a more accurate model of the signaling pathways that control cystogenesis and tubulogenesis.
Disturbances of motor unit rate modulation are prevalent in muscles of spastic-paretic stroke survivors
Authors: Mottram C. J. , Heckman C. J. , Powers R. K. , Rymer W. Z. , Suresh N. L.
Published: February 2014

Stroke survivors often exhibit abnormally low motor unit firing rates during voluntary muscle activation. Our purpose was to assess the prevalence of saturation in motor unit firing rates in the spastic-paretic biceps brachii muscle of stroke survivors. To achieve this objective, we recorded the incidence and duration of impaired lower- and higher-threshold motor unit firing rate modulation in spastic-paretic, contralateral, and healthy control muscle during increases in isometric force generated by the elbow flexor muscles. Impaired firing was considered to have occurred when firing rate became constant (i.e., saturated), despite increasing force. The duration of impaired firing rate modulation in the lower-threshold unit was longer for spastic-paretic (3.9 ± 2.2 s) than for contralateral (1.4 ± 0.9 s; P < 0.001) and control (1.1 ± 1.0 s; P = 0.005) muscles. The duration of impaired firing rate modulation in the higher-threshold unit was also longer for the spastic-paretic (1.7 ± 1.6 s) than contralateral (0.3 ± 0.3 s; P = 0.007) and control (0.1 ± 0.2 s; P = 0.009) muscles. This impaired firing rate of the lower-threshold unit arose, despite an increase in the overall descending command, as shown by the recruitment of the higher-threshold unit during the time that the lower-threshold unit was saturating, and by the continuous increase in averages of the rectified EMG of the biceps brachii muscle throughout the rising phase of the contraction. These results suggest that impairments in firing rate modulation are prevalent in motor units of spastic-paretic muscle, even when the overall descending command to the muscle is increasing.
Optical control of retrogradely infected neurons using drug-regulated “TLoop” lentiviral vectors
Authors: Cetin Ali , Callaway Edward M.
Published: February 2014

Many approaches that use viral vectors to deliver transgenes have limited transduction efficiency yet require high levels of transgene expression. In particular, infection via axon terminals is relatively inefficient but is a powerful means of achieving infection of specific neuron types. Combining this with optogenetic approaches requires high gene expression levels that are not typically achieved with nontoxic retrogradely infecting vectors. We generated rabies glycoprotein-pseudotyped lentiviral vectors that use a positive feedback loop composed of a Tet promoter driving both its own tetracycline-dependent transcription activator (tTA) (“TLoop”) and channelrhodopsin-2-YFP (ChR2YFP). We show that TLoop vectors strongly express proteins in a drug-controllable manner in neurons that project to injection sites within the mouse brain. After initial infection, the virus travels retrogradely, stably integrates into the host genome, and expresses gene products. The expression is robust and allows optogenetic studies of neurons projecting to the location of virus injection, as demonstrated by fluorescence-targeted intracellular recordings. ChR2YFP expression did not cause observable signs of toxicity and continued for up to 6 mo after infection. Expression can be reversibly blocked by administration of doxycycline, if necessary, for expression of gene products that might be more toxic. Overall, we present a system that will allow researchers to achieve high levels of gene expression even in the face of inefficient viral transduction. The particular vectors that we demonstrate may enhance efforts to gain a precise understanding of the contributions of specific types of projection neurons to brain function.
Different phase delays of peripheral input to primate motor cortex and spinal cord promote cancellation at physiological tremor frequencies
Authors: Koželj Saša , Baker Stuart N.
Published: February 2014

Neurons in the spinal cord and motor cortex (M1) are partially phase-locked to cycles of physiological tremor, but with opposite phases. Convergence of spinal and cortical activity onto motoneurons may thus produce phase cancellation and a reduction in tremor amplitude. The mechanisms underlying this phase difference are unknown. We investigated coherence between spinal and M1 activity with sensory input. In two anesthetized monkeys, we electrically stimulated the medial, ulnar, deep radial, and superficial radial nerves; stimuli were timed as independent Poisson processes (rate 10 Hz). Single units were recorded from M1 (147 cells) or cervical spinal cord (61 cells). Ninety M1 cells were antidromically identified as pyramidal tract neurons (PTNs); M1 neurons were additionally classified according to M1 subdivision (rostral/caudal, M1r/c). Spike-stimulus coherence analysis revealed significant coupling over a broad range of frequencies, with the strongest coherence at <50 Hz. Delays implied by the slope of the coherence phase-frequency relationship were greater than the response onset latency, reflecting the importance of late response components for the transmission of oscillatory inputs. The spike-stimulus coherence phase over the 6–13 Hz physiological tremor band differed significantly between M1 and spinal cells (phase differences relative to the cord of 2.72 ± 0.29 and 1.72 ± 0.37 radians for PTNs from M1c and M1r, respectively). We conclude that different phases of the response to peripheral input could partially underlie antiphase M1 and spinal cord activity during motor behavior. The coordinated action of spinal and cortical feedback will act to reduce tremulous oscillations, possibly improving the overall stability and precision of motor control.
Spontaneous Reversion of the Angiogenic Phenotype to a Nonangiogenic and Dormant State in Human Tumors
Authors: Rogers Michael S. , Novak Katherine , Zurakowski David , Cryan Lorna M. , Blois Anna , Lifshits Eugene , Bø Trond H. , Oyan Anne M. , Bender Elise R. , Lampa Michael , Kang Soo-Young , Naxerova Kamila , Kalland Karl-Henning , Straume Oddbjorn , Akslen Lars A. , Watnick Randolph S. , Folkman Judah , Naumov George N.
Published: February 2014

The angiogenic switch, a rate-limiting step in tumor progression, has already occurred by the time most human tumors are detectable. However, despite significant study of the mechanisms controlling this switch, the kinetics and reversibility of the process have not been explored. The stability of the angiogenic phenotype was examined using an established human liposarcoma xenograft model. Nonangiogenic cells inoculated into immunocompromised mice formed microscopic tumors that remained dormant for approximately 125 days (vs. <40 days for angiogenic cells) whereupon the vast majority (>95%) initiated angiogenic growth with second-order kinetics. These original, clonally derived angiogenic tumor cells were passaged through four in vivo cycles. At each cycle, a new set of single-cell clones was established from the most angiogenic clone and characterized for in vivo for tumorigenic activity. A total of 132 single-cell clones were tested in the second, third, and fourth in vivo passage. Strikingly, at each passage, a portion of the single-cell clones formed microscopic, dormant tumors. Following dormancy, like the original cell line, these revertant tumors spontaneously switched to the angiogenic phenotype. Finally, revertant clones were transcriptionally profiled and their angiogenic output determined. Collectively, these data demonstrate that the angiogenic phenotype in tumors is malleable and can spontaneously revert to the nonangiogenic phenotype in a population of human tumor cells.

Implications: Leveraging the rate of reversion to the nonangiogenic phenotype and tumor dormancy may be a novel anticancer strategy. Mol Cancer Res; 12(5); 754–64. ©2014 AACR.
Association between Five Lifestyle Habits and Cancer Risk: Results from the E3N Cohort
Authors: Dartois Laureen , Fagherazzi Guy , Boutron-Ruault Marie-Christine , Mesrine Sylvie , Clavel-Chapelon Françoise
Published: February 2014

Although some modifiable lifestyle characteristics have been associated with decreased cancer risk, little is known about their combined effect or about the proportion of cancer cases that could be prevented by improving lifestyle behaviors. We aimed to quantify the association between lifestyle habits and all-site and site-specific cancer risk in middle-aged women. The study included 64,732 women from the French E3N prospective cohort, ages 43 to 68 years at baseline. During a 15-year follow-up period, 6,938 cases of invasive cancer were diagnosed. We defined an index that aggregated five lifestyle characteristics: smoking, body mass index, alcohol consumption, fruit and vegetable consumption, and physical activity. Proportional hazard Cox regressions were performed to evaluate the association between lifestyle and cancer risk and to estimate multivariate HRs and their 95% confidence intervals (CI). In addition, population-attributable fractions were used to estimate the proportion of cancer cases that could be prevented by healthier behaviors. A significant decrease in all-site cancer risk was observed and was associated with a healthy lifestyle (HR, 0.81; 95% CI, 0.73–0.89 when comparing the highest with the lowest health index category; Ptrend across categories < 0.01). Combining all five characteristics would have prevented 6.3% (2.2%–10.3%) of any-site, 6.3% (0.5%–12.1%) of postmenopausal breast, and 47.5% (26.8%–64.1%) of lung cancers. In conclusion, compliance with only five modifiable lifestyle behaviors could prevent a significant number of cancers, notably postmenopausal breast and lung cancers. Cancer Prev Res; 7(5); 516–25. ©2014 AACR.
Combination of Alphavirus Replicon Particle–Based Vaccination with Immunomodulatory Antibodies: Therapeutic Activity in the B16 Melanoma Mouse Model and Immune Correlates
Authors: Avogadri Francesca , Zappasodi Roberta , Yang Arvin , Budhu Sadna , Malandro Nicole , Hirschhorn-Cymerman Daniel , Tiwari Shakuntala , Maughan Maureen F. , Olmsted Robert , Wolchok Jedd D. , Merghoub Taha
Published: February 2014

Induction of potent immune responses to self-antigens remains a major challenge in tumor immunology. We have shown that a vaccine based on alphavirus replicon particles (VRP) activates strong cellular and humoral immunity to tyrosinase-related protein-2 (TRP2) melanoma antigen, providing prophylactic and therapeutic effects in stringent mouse models. Here, we report that the immunogenicity and efficacy of this vaccine is increased in combination with either antagonist anti-CTL antigen-4 (CTLA-4) or agonist anti-glucocorticoid-induced TNF family–related gene (GITR) immunomodulatory monoclonal antibodies (mAb). In the challenging therapeutic setting, VRP–TRP2 plus anti-GITR or anti–CTLA-4 mAb induced complete tumor regression in 90% and 50% of mice, respectively. These mAbs had similar adjuvant effects in priming an adaptive immune response against the vaccine-encoded antigen, augmenting, respectively, approximately 4- and 2-fold the TRP2-specific CD8+ T-cell response and circulating Abs, compared with the vaccine alone. Furthermore, while both mAbs increased the frequency of tumor-infiltrating CD8+ T cells, anti–CTLA-4 mAb also increased the quantity of intratumor CD4+Foxp3− T cells expressing the negative costimulatory molecule programmed death-1 (PD-1). Concurrent GITR expression on these cells suggests that they might be controlled by anti-GITR mAbs, thus potentially explaining their differential accumulation under the two treatment conditions. These findings indicate that combining immunomodulatory mAbs with alphavirus-based anticancer vaccines can provide therapeutic antitumor immune responses in a stringent mouse model, suggesting potential utility in clinical trials. They also indicate that tumor-infiltrating CD4+Foxp3−PD-1+ T cells may affect the outcome of immunomodulatory treatments. Cancer Immunol Res; 2(5); 448–58. ©2014 AACR.
First Case of 18F-FACBC PET/CT-Guided Salvage Retroperitoneal Lymph Node Dissection for Disease Relapse after Radical Prostatectomy for Prostate Cancer and Negative 11C-Choline PET/CT: New Imaging Techniques May Expand Pioneering Approaches
Authors: Schiavina Riccardo , Concetti Sergio , Brunocilla Eugenio , Nanni Cristina , Borghesi Marco , Gentile Giorgio , Cevenini Matteo , Bianchi Lorenzo , Molinaroli Enrico , Fanti Stefano , Martorana Giuseppe
Published: February 2014

We present the first case of salvage retroperitoneal lymph node dissection based on the results of 18F-FACBC PET/CT performed for a prostate-specific antigen relapse after radical prostatectomy. The patients underwent 11C-choline PET/CT, which turned out negative, while 18F-FACBC PET/CT visualized two lymph node metastases confirmed at pathological examination. Preliminary clinical reports showed an improvement in the detection rate of 20-40% for 18F-FACBC in comparison with 11C-choline, rendering the 18F-FACBC the potential radiotracer of the future. Salvage surgery for prostate cancer is a fascinating but controversial approach. New diagnostic tools may improve its potential by increasing the assessment and the selection of the patients.
Clinically Staged cT2 Adenocarcinomas of the Gastroesophageal Junction: Accuracy of Staging and Therapeutic Consequences
Authors: Vallböhmer Daniel , Sisic Leila , Blank Susanne , Kraus Sebastian , Stoecklein Nikolas H. , Knoefel Wolfram T. , Büchler Markus W. , Ott Katja
Published: February 2014

Background: Multimodality treatment options in locally advanced adenocarcinomas of the esophagogastric junction (AEGs) have been established in the last years. However, the therapeutic approach in patients with clinically staged cT2 tumors remains controversial. The most important determinant is the accuracy of clinical staging. We aimed to evaluate the association of clinical and histopathological staging in patients with cT2 tumors in respect of possible therapeutic consequences. Patients and Methods: Between 2001 and 2011, 71 patients with AEG tumors were clinically staged as cT2 (cN0 = 48 (68%); cN+ = 23 (32%)) and underwent surgical resection. Results: A primary tumor resection was performed in 59 (83%) patients while 12 (17%) patients received neoadjuvant therapy. Primarily resected patients showed the following pT/pN categories: pT1: 13 (22%), pT2: 35 (59%), pT3: 11 (19%), pN0: 23 (39%), whereas the clinical/histopathological pN category included 55% of the patients. Neoadjuvantly treated patients showed the following pT/pN categories: ypT0: 3 (25%), ypT1: 3 (25%), ypT2: 6 (50%), ypN0: 6 (50%). The overall survival of primarily resected patients compared with patients undergoing neoadjuvant therapy was not significantly different. Conclusions: The accuracy of clinical staging in patients with cT2 tumors of the gastroesophageal junction is poor. As in primarily resected patients, over- and understaging balance each other; correct pretherapeutic staging occurs in just about 60% of the patients. Moreover, our study suggests that a radical surgical resection with adequate lymphadenectomy seems to be appropriate for cT2N0 and even in cT2N+ tumors, since down-categorizing and prognosis are not improved for neoadjuvantly treated patients. However, the data have to be interpreted with caution because of the small patient numbers.
Pretreatment Epstein-Barr Virus DNA Load and Cumulative Cisplatin Dose Intensity Affect Long-Term Outcome of Nasopharyngeal Carcinoma Treated with Concurrent Chemotherapy: Experience of an Institute in an Endemic Area
Authors: Wei Weihong , Huang Zeli , Li Shaoen , Chen Hemei , Zhang Guoyi , Li Shuxia , Hu Weihan , Xu Tao
Published: February 2014

Background: We retrospectively compared the long-term efficacy of concurrent chemoradiotherapy (CCRT) regimens (docetaxel vs. cisplatin), total dose intensity of cisplatin (> 200 vs. ≤ 200 mg/m2) and pretreatment plasma levels of Epstein-Barr virus (EBV) DNA for nasopharyngeal carcinoma (NPC), and investigated the prognostic factors. Methods: We enrolled 214 patients diagnosed with NPC and treated with CCRT. 41 patients received weekly docetaxel and 173 weekly cisplatin. 62 received cumulative cisplatin of ≤ 200 mg/m2 and 111, > 200 mg/m2. Pretreatment levels of EBV DNA were available for 155 patients. Results: Patients receiving concurrent weekly docetaxel and cisplatin had similar 5-year rates for overall survival (OS) (p = 0.306), progression-free survival (PFS) (p = 0.133), distant failure-free survival (DFS) (p = 0.110), and locoregional failure-free survival (LFS) (p = 0.452). Cumulative cisplatin of > 200 mg/m2 improved the 5-year rates of PFS (p = 0.018) and DFS (p = 0.042) significantly in comparison with cumulative cisplatin of ≤ 200 mg/m2. EBV DNA levels of ≥ 1,500 copies/ml was closely associated with poor DFS (p = 0.011), PFS (p = 0.006), and OS (p = 0.004). Conclusions: Weekly cisplatin was well tolerated in CCRT, during which cumulative cisplatin of > 200 mg/m2 improved PFS and DFS. The long-term efficacy of concurrent docetaxel was similar to that of concurrent cisplatin. The EBV DNA level was the most significant prognostic factor.
MYC and MXI1 Protein Expression: Potential Prognostic Significance in Women with Breast Cancer in China
Authors: Xu Lin-Ping , Sun Yan , Li Wei , Mai Ling , Guo Yong-Jun , Fan Qing-Xia
Published: February 2014

Objective: To investigate the expression levels and the clinical significance of MYC and MXI1 proteins in breast cancer. Methods: The expression levels of MYC and MXI1 were detected by immunohistochemical assay in 166 cases of breast cancer; the relationships among MYC, MXI1 and the clinicopathological parameters were analyzed by χ2 test. Univariate analysis and Cox's proportional hazards model were used to evaluate the prognostic significance of the 2 proteins. Results: 27.71% of the tumor specimens showed high staining intensity for MYC (high-expression group, HEG-MYC) and 22.89% showed high staining intensity for MXI1 (HEG-MXI1); the expression of 2 proteins was negatively correlated (r = -0.177 p = 0.022). The Kaplan-Meier method for survival analysis showed that patients of the MYC-HEG demonstrated a significantly worse disease-specific survival than those of the MYC-low-expression group (LEG) (χ2 = 11.102, p = 0.001). However, patients of the MXI1-HEG had a significantly better disease-specific survival than those of the MXI1-LEG (χ2 = 7.858, p = 0.005). Both univariate analysis and Cox's proportional hazards model indicated that MYC and MXI1 could be independent prognostic molecular markers. Conclusion: MYC-HEG and MXI1-LEG levels are associated with poor prognosis in patients with breast cancer, suggesting that they may be useful molecular markers in breast cancer prognosis prediction.
Smoking alters circulating plasma microvesicle pattern and microRNA signatures
Authors: Badrnya Sigrun , Assinger Alice , Baumgartner Roland
Published: February 2014

Circulating plasma microvesicles (PMVs) and their microRNA content are involved in the development of atherosclerosis and could serve as biomarkers for cardiovascular disease (CVD) progression. However, little is known on how smoking influences the levels of PMVs and microRNA signatures in vivo. Therefore, we aimed to investigate the effects of smoking on circulating PMV levels and CVD-related PMV-derived microRNAs in young, healthy smokers. Twenty young (10 female, 10 male; 25 ± 4 years) healthy smokers (16 ± 6 cigarettes per day for 8 ± 4 years) and age- and sex-matched controls were included in this study. While complete blood count revealed no differences between both groups, smoking significantly enhanced intracellular reactive oxygen species in platelets and leukocytes as well as platelet-leukocyte aggregate formation. Total circulating PMV counts were significantly reduced in smokers, which could be attributed to decreased platelet-derived PMVs. While the number of endothelial PMVs remained unaffected, smoking propagated circulating leukocyte-derived PMVs. Despite reduced total PMVs, PMV-derived microRNA-profiling of six smoker/control pairs revealed a decrease of only a single microRNA, the major platelet-derived microRNA miR-223. Conversely, miR-29b, a microRNA associated with aortic aneurysm and fibrosis, and RNU6–2, a commonly used reference-RNA, were significantly up-regulated. Smoking leads to alterations in the circulating PMV profile and changes in the PMV-derived microRNA signature already in young, healthy adults. These changes may contribute to the development of smoking-related cardiovascular pathologies. Moreover, these smoking-related changes have to be considered when microRNA or PMV profiles are used as disease-specific biomarkers.
Gaps in translation from trials to practice: Non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation
Authors: Ko Darae , Cove Christina L. , Hylek Elaine M.
Published: February 2014

Worldwide there is a tremendous need for affordable anticoagulants that do not require monitoring. The advent of the non-warfarin oral anticoagulant drugs represents a major advance for stroke prevention in atrial fibrillation (AF). The objectives of this review are to 1) identify gaps in our current knowledge regarding use of these single target anticoagulant drugs; 2) outline the potential implications of these gaps for clinical practice, and thereby, 3) highlight areas of research to further optimise their use for stroke prevention in AF.
The Global Burden of Ischemic Heart Disease in 1990 and 2010
Authors: Moran Andrew E. , Forouzanfar Mohammad H. , Roth Gregory A. , Mensah George A. , Ezzati Majid , Flaxman Abraham , Murray Christopher J.L. , Naghavi Mohsen
Published: February 2014

Background—

Ischemic heart disease (IHD) burden consists of years of life lost from IHD deaths and years of disability lived with 3 nonfatal IHD sequelae: nonfatal acute myocardial infarction, angina pectoris, and ischemic heart failure. Our aim was to estimate the global and regional burden of IHD in 1990 and 2010.

Methods and Results—

Global and regional estimates of acute myocardial infarction incidence and angina and heart failure prevalence by age, sex, and world region in 1990 and 2010 were estimated based on data from a systematic review and nonlinear mixed-effects meta-regression methods. Age-standardized acute myocardial infarction incidence and angina prevalence decreased globally between 1990 and 2010; ischemic heart failure prevalence increased slightly. The global burden of IHD increased by 29 million disability-adjusted life-years (29% increase) between 1990 and 2010. About 32.4% of the growth in global IHD disability-adjusted life-years between 1990 and 2010 was attributable to aging of the world population, 22.1% was attributable to population growth, and total disability-adjusted life-years were attenuated by a 25.3% decrease in per capita IHD burden (decreased rate). The number of people living with nonfatal IHD increased more than the number of IHD deaths since 1990, but >90% of IHD disability-adjusted life-years in 2010 were attributable to IHD deaths.

Conclusions—

Globally, age-standardized acute myocardial infarction incidence and angina prevalence have decreased, and ischemic heart failure prevalence has increased since 1990. Despite decreased age-standardized fatal and nonfatal IHD in most regions since 1990, population growth and aging led to a higher global burden of IHD in 2010.
Dysferlin Mediates the Cytoprotective Effects of TRAF2 Following Myocardial Ischemia Reperfusion Injury
Authors: Tzeng Huei‐Ping , Evans Sarah , Gao Feng , Chambers Kari , Topkara Veli K. , Sivasubramanian Natarajan , Barger Philip M. , Mann Douglas L.
Published: February 2014

Background

We have demonstrated that tumor necrosis factor (
TNF
) receptor‐associated factor 2 (
TRAF
2), a scaffolding protein common to
TNF
receptors 1 and 2, confers cytoprotection in the heart. However, the mechanisms for the cytoprotective effects of
TRAF
2 are not known.

Methods/Results

Mice with cardiac‐restricted overexpression of low levels of
TRAF
2 (
MHC
‐
TRAF
2

LC

) and a dominant negative
TRAF
2 (
MHC
‐
TRAF
2

DN

) were subjected to ischemia (30‐minute) reperfusion (60‐minute) injury (I/R), using a Langendorff apparatus.
MHC
‐
TRAF
2

LC

mice were protected against I/R injury as shown by a significant ≈27% greater left ventricular (
LV
) developed pressure after I/R, whereas mice with impaired
TRAF
2 signaling had a significantly ≈38% lower
LV
developed pressure, a ≈41% greater creatine kinase (
CK
) release, and ≈52% greater Evans blue dye uptake after I/R, compared to
LM
. Transcriptional profiling of
MHC
‐
TRAF
2

LC

and
MHC
‐
TRAF
2

DN

mice identified a calcium‐triggered exocytotic membrane repair protein, dysferlin, as a potential cytoprotective gene responsible for the cytoprotective effects of
TRAF
2. Mice lacking dysferlin had a significant ≈39% lower
LV
developed pressure, a ≈20% greater
CK
release, and ≈29% greater Evans blue dye uptake after I/R, compared to wild‐type mice, thus phenocopying the response to tissue injury in the
MHC
‐
TRAF
2

DN

mice. Moreover, breeding
MHC
‐
TRAF
2

LC

onto a dysferlin‐null background significantly attenuated the cytoprotective effects of
TRAF
2 after I/R injury.

Conclusion

The study shows that dysferlin, a calcium‐triggered exocytotic membrane repair protein, is required for the cytoprotective effects of
TRAF
2‐mediated signaling after I/R injury.