bluuebunny/crossref_metadata_2025 huggingface dataset:
Deletion of Murid Herpesvirus 4 ORF63 Affects the Trafficking of Incoming Capsids toward the Nucleus
Authors: Latif Muhammad Bilal , Machiels Bénédicte , Xiao Xue , Mast Jan , Vanderplasschen Alain , Gillet Laurent
Published: December 2015

Gammaherpesviruses are important human and animal pathogens. Despite the fact that they display the classical architecture of herpesviruses, the function of most of their structural proteins is still poorly defined. This is especially true for tegument proteins. Interestingly, a potential role in immune evasion has recently been proposed for the tegument protein encoded by Kaposi's sarcoma-associated herpesvirus open reading frame 63 (ORF63). To gain insight about the roles of ORF63 in the life cycle of a gammaherpesvirus, we generated null mutations in the ORF63 gene of murid herpesvirus 4 (MuHV-4). We showed that disruption of ORF63 was associated with a severe MuHV-4 growth deficit both
in vitro
and
in vivo
. The latter deficit was mainly associated with a defect of replication in the lung but did not affect the establishment of latency in the spleen. From a functional point of view, inhibition of caspase-1 or the inflammasome did not restore the growth of the ORF63-deficient mutant, suggesting that the observed deficit was not associated with the immune evasion mechanism identified previously. Moreover, this growth deficit was also not associated with a defect in virion egress from the infected cells. In contrast, it appeared that MuHV-4 ORF63-deficient mutants failed to address most of their capsids to the nucleus during entry into the host cell, suggesting that ORF63 plays a role in capsid movement. In the future, ORF63 could therefore be considered a target to block gammaherpesvirus infection at a very early stage of the infection.

IMPORTANCE
The important diseases caused by gammaherpesviruses in human and animal populations justify a better understanding of their life cycle. In particular, the role of most of their tegument proteins is still largely unknown. In this study, we used murid herpesvirus 4, a gammaherpesvirus infecting mice, to decipher the role of the protein encoded by the viral ORF63 gene. We showed that the absence of this protein is associated with a severe growth deficit both
in vitro
and
in vivo
that was mainly due to impaired migration of viral capsids toward the nucleus during entry. Together, our results provide new insights about the life cycle of gammaherpesviruses and could allow the development of new antiviral strategies aimed at blocking gammaherpesvirus infection at the very early stages.
Identifying research priorities in anaesthesia and perioperative care: final report of the joint National Institute of Academic Anaesthesia/James Lind Alliance Research Priority Setting Partnership
Authors: Boney Oliver , Bell Madeline , Bell Natalie , Conquest Ann , Cumbers Marion , Drake Sharon , Galsworthy Mike , Gath Jacqui , Grocott Michael P W , Harris Emma , Howell Simon , Ingold Anthony , Nathanson Michael H , Pinkney Thomas , Metcalf Leanne
Published: December 2015

Objective

To identify research priorities for Anaesthesia and Perioperative Medicine.

Design

Prospective surveys and consensus meetings guided by an independent adviser.

Setting

UK.

Participants

45 stakeholder organisations (25 professional, 20 patient/carer) affiliated as James Lind Alliance partners.

Outcomes

First ‘ideas-gathering’ survey:Free text research ideas and suggestions.Second ‘prioritisation’ survey:Shortlist of ‘summary’ research questions (derived from the first survey) ranked by respondents in order of priority.Final ‘top ten’:Agreed by consensus at a final prioritisation workshop.

Results

First survey:1420 suggestions received from 623 respondents (49% patients/public) were refined into a shortlist of 92 ‘summary’ questions.Second survey:1718 respondents each nominated up to 10 questions as research priorities.Top ten:The 25 highest-ranked questions advanced to the final workshop, where 23 stakeholders (13 professional, 10 patient/carer) agreed the 10 most important questions:

▸ What can we do to stop patients developing chronic pain after surgery?

▸ How can patient care around the time of emergency surgery be improved?

▸ What long-term harm may result from anaesthesia, particularly following repeated anaesthetics?

▸ What outcomes should we use to measure the ‘success’ of anaesthesia and perioperative care?

▸ How can we improve recovery from surgery for elderly patients?

▸ For which patients does regional anaesthesia give better outcomes than general anaesthesia?

▸ What are the effects of anaesthesia on the developing brain?

▸ Do enhanced recovery programmes improve short and long-term outcomes?

▸ How can preoperative exercise or fitness training, including physiotherapy, improve outcomes after surgery?

▸ How can we improve communication between the teams looking after patients throughout their surgical journey?

Conclusions

Almost 2000 stakeholders contributed their views regarding anaesthetic and perioperative research priorities. This is the largest example of patient and public involvement in shaping anaesthetic and perioperative research to date.
The molecular targets of approved treatments for pulmonary arterial hypertension
Authors: Humbert Marc , Ghofrani Hossein-Ardeschir
Published: December 2015

Until recently, three classes of medical therapy were available for the treatment of pulmonary arterial hypertension (PAH)—prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors. With the approval of the soluble guanylate cyclase stimulator riociguat, an additional drug class has become available targeting a distinct molecular target in the same pathway as PDE5 inhibitors. Treatment recommendations currently include the use of all four drug classes to treat PAH, but there is a lack of comparative data for these therapies. Therefore, an understanding of the mechanistic differences between these agents is critical when making treatment decisions. Combination therapy is often used to treat PAH and it is therefore important that physicians understand how the modes of action of these drugs may interact to work as complementary partners, or potentially with unwanted consequences. Furthermore, different patient phenotypes mean that patients respond differently to treatment; while a certain monotherapy may be adequate for some patients, for others it will be important to consider alternating or combining compounds with different molecular targets. This review describes how the four currently approved drug classes target the complex pathobiology of PAH and will consider the distinct target molecules of each drug class, their modes of action, and review the pivotal clinical trial data supporting their use. It will also discuss the rationale for combining drugs (or not) from the different classes, and review the clinical data from studies on combination therapy.
Interobserver agreement for the ATS/ERS/JRS/ALAT criteria for a UIP pattern on CT
Authors: Walsh Simon L F , Calandriello Lucio , Sverzellati Nicola , Wells Athol U , Hansell David M
Published: December 2015

Objectives

To establish the level of observer variation for the current ATS/ERS/JRS/ALAT criteria for a diagnosis of usual interstitial pneumonia (UIP) on CT among a large group of thoracic radiologists of varying levels of experience.

Materials and methods

112 observers (96 of whom were thoracic radiologists) categorised CTs of 150 consecutive patients with fibrotic lung disease using the ATS/ERS/JRS/ALAT CT criteria for a UIP pattern (3 categories—UIP, possibly UIP and inconsistent with UIP). The presence of honeycombing, traction bronchiectasis and emphysema was also scored using a 3-point scale (definitely present, possibly present, absent). Observer agreement for the UIP categorisation and for the 3 CT patterns in the entire observer group and in subgroups stratified by observer experience, were evaluated.

Results

Interobserver agreement across the diagnosis category scores among the 112 observers was moderate, ranging from 0.48 (IQR 0.18) for general radiologists to 0.52 (IQR 0.20) for thoracic radiologists of 10–20 years’ experience. A binary score for UIP versus possible or inconsistent with UIP was examined. Observer agreement for this binary score was only moderate. No significant differences in agreement levels were identified when the CTs were stratified according to multidisciplinary team (MDT) diagnosis or patient age or when observers were categorised according to experience. Observer agreement for each of honeycombing, traction bronchiectasis and emphysema were 0.59±0.12, 0.42±0.15 and 0.43±0.18, respectively.

Conclusions

Interobserver agreement for the current ATS/ERS/JRS/ALAT CT criteria for UIP is only moderate among thoracic radiologists, irrespective of their experience, and did not vary with patient age or the MDT diagnosis.
Three‐dimensional anatomy
Authors: Simons Vicky
Published: December 2015

After her final year studying veterinary medicine at the Royal Veterinary College (RVC) and before starting an internship, Vicky Simons took on the job of creating a life‐size equine anatomical model ‘anatohorse’ (also known as Geoff)
Input–output mapping reconstruction of spike trains at dorsal horn evoked by manual acupuncture
Authors: Wei Xile , Shi Dingtian , Yu Haitao , Deng Bin , Lu Meili , Han Chunxiao , Wang Jiang
Published: December 2015

In this study, a generalized linear model (GLM) is used to reconstruct mapping from acupuncture stimulation to spike trains driven by action potential data. The electrical signals are recorded in spinal dorsal horn after manual acupuncture (MA) manipulations with different frequencies being taken at the “Zusanli” point of experiment rats. Maximum-likelihood method is adopted to estimate the parameters of GLM and the quantified value of assumed model input. Through validating the accuracy of firings generated from the established GLM, it is found that the input–output mapping of spike trains evoked by acupuncture can be successfully reconstructed for different frequencies. Furthermore, via comparing the performance of several GLMs based on distinct inputs, it suggests that input with the form of half-sine with noise can well describe the generator potential induced by acupuncture mechanical action. Particularly, the comparison of reproducing the experiment spikes for five selected inputs is in accordance with the phenomenon found in Hudgkin–Huxley (H–H) model simulation, which indicates the mapping from half-sine with noise input to experiment spikes meets the real encoding scheme to some extent. These studies provide us a new insight into coding processes and information transfer of acupuncture.
All-loop order critical exponents for massless scalar field theory with Lorentz violation in the BPHZ method
Authors: Carvalho Paulo R. S.
Published: December 2015

We compute analytically the all-loop level critical exponents for a massless thermal Lorentz-violating (LV) O(N) self-interacting [Formula: see text] scalar field theory. For that, we evaluate, firstly explicitly up to next-to-leading loop order and later in a proof by induction up to any loop level, the respective [Formula: see text]-function and anomalous dimensions in a theory renormalized in the massless BPHZ method, where a reduced set of Feynman diagrams to be calculated is needed. We investigate the effect of the Lorentz violation in the outcome for the critical exponents and present the corresponding mathematical explanation and physical interpretation.
A BBN-Based Framework for Design Space Pruning of Application Specific Instruction Processors
Authors: Srinivasan V. Prasanna , Shanthi A. P.
Published: December 2015

During the synthesis phase of the embedded system design process, the designer has to take early decisions for selecting the optimal system components such as processors, memories, communication interfaces, etc. from the available huge design alternatives. In order to obtain the optimal design configurations from the available huge design alternatives, an efficient design space pruning technique that will ease the design space exploration (DSE) process is required. The knowledge about the target architectural parameters affecting the overall objectives of the system should be considered during the design, so that the search process for finding the optimal system configurations will be rapid and more efficient. The Bayesian belief network (BBN)-based modeling framework for design space pruning proposed in this paper attempts to resolve the existing limitation in imparting domain knowledge and provides a pioneering effort to support the designer during the process of application specific system design. The Xtensa customizable processor architecture from Tensilica and a very long instruction word (VLIW) processor architecture are considered as example target platforms to impart the domain knowledge for the proposed model. Case studies in support of the proposed model are presented in order to understand how BBN can be used for design space pruning by propagating the evidence and arriving at probabilistic inferences to ease the decision-making process. The results show that the design space reduces drastically from a few million design options available to just less than one hundred for Xtensa architecture and from a few billions of design options available to just few thousands for VLIW architecture. The work also validates the pruned design points for their optimality.
Hypoxemia, oxygen content, and the regulation of cerebral blood flow
Authors: Hoiland Ryan L. , Bain Anthony R. , Rieger Mathew G. , Bailey Damian M , Ainslie Philip N.
Published: December 2015

This review highlights the influence of oxygen (O2) availability on cerebral blood flow (CBF). Evidence for reductions in O2content (CaO2) rather than arterial O2tension (PaO2) as the chief regulator of cerebral vasodilation, with deoxyhemoglobin as the primary O2sensor and upstream response effector, is discussed. We review in vitro and in vivo data to summarize the molecular mechanisms underpinning CBF responses during changes in CaO2. We surmise that 1) during hypoxemic hypoxia in healthy humans (e.g., conditions of acute and chronic exposure to normobaric and hypobaric hypoxia), elevations in CBF compensate for reductions in CaO2and thus maintain cerebral O2delivery; 2) evidence from studies implementing iso- and hypervolumic hemodilution, anemia, and polycythemia indicate that CaO2has an independent influence on CBF; however, the increase in CBF does not fully compensate for the lower CaO2during hemodilution, and delivery is reduced; and 3) the mechanisms underpinning CBF regulation during changes in O2content are multifactorial, involving deoxyhemoglobin-mediated release of nitric oxide metabolites and ATP, deoxyhemoglobin nitrite reductase activity, and the downstream interplay of several vasoactive factors including adenosine and epoxyeicosatrienoic acids. The emerging picture supports the role of deoxyhemoglobin (associated with changes in CaO2) as the primary biological regulator of CBF. The mechanisms for vasodilation therefore appear more robust during hypoxemic hypoxia than during changes in CaO2via hemodilution. Clinical implications (e.g., disorders associated with anemia and polycythemia) and future study directions are considered.
A Method of UAVs Route Optimization Based on the Structure of the Highway Network
Authors: Niu Shuyun , Zhang Jisheng , Zhang Fan , Li Honghai
Published: December 2015

It is essential for transportation management centers to establish a network of fixed and mobile sensors to collect traffic information of highway network, especially for very important links with frequent traffic events. Emerging Unmanned Aerial Vehicles (UAVs), it is introduced as a mobile sensor to collect road traffic information and its cruise route planning problem is researched based on the highway network physical structure. First, according to existing traffic data, a method used to calculate the link importance degree index is proposed, and the index is used to evaluate the link's information. Second, a multiobjective optimization model is proposed, its aim is to minimize the total cruise time under detecting as many important links as possible and minimize the information value undetected by UAVs, and the fuzzy operator is introduced to the constraint conditions. Finally, a case study is used to demonstrate the feasibility and effectiveness of proposed model about UAVs’ route planning.
Stroke as an Unusual First Presentation of Lyme Disease
Authors: Almoussa Mohamad , Goertzen Angelika , Fauser Barbara , Zimmermann Christoph W.
Published: December 2015

Introduction. Lyme neuroborreliosis is a nervous system infection caused by spirocheteBorrelia burgdorferiwith diverse neurological complications. Stroke due to cerebral vasculitis is a rare consequence of neuroborreliosis and has been described in just a few case reports.Case Presentation. Here, we report the case of a 43-year-old patient who presented with discrete left-sided hemiparesis and amnestic cognitive impairment. Brain magnetic resonance imaging showed a thalamic infarct, and serological and cerebrospinal fluid (CSF) tests confirmed the diagnosis of active neuroborreliosis. The antibiotic treatment with intravenous ceftriaxone for three weeks led to an improvement of the symptoms and remarkable regression of radiological findings, but not to full recovery of the amnestic cognitive disorder.Conclusion. Lyme neuroborreliosis should be suspected in patients with cerebrovascular events without obvious risk factors, especially those living in endemic areas such as northern Europe or those who have been exposed to ticks and those with clinical or radiological findings suggesting Lyme neuroborreliosis, in order to establish the diagnosis and start a proper antibiotic therapy.
Activated Integrin-Linked Kinase Negatively Regulates Muscle Cell Enhancement Factor 2C in C2C12 Cells
Authors: Dong Zhenguo , Pan Wei , Wu Haiqing , Liu Dongjun , Cang Ming
Published: December 2015

Our previous study reported that muscle cell enhancement factor 2C (MEF2C) was fully activated after inhibition of the phosphorylation activity of integrin-linked kinase (ILK) in the skeletal muscle cells of goats. It enhanced the binding of promoter or enhancer of transcription factor related to proliferation of muscle cells and then regulated the expression of these genes. In the present investigation, we explored whether ILK activation depended on PI3K to regulate the phosphorylation and transcriptional activity of MEF2C during C2C12 cell proliferation. We inhibited PI3K activity in C2C12 with LY294002 and then found that ILK phosphorylation levels and MEF2C phosphorylation were decreased and that MCK mRNA expression was suppressed significantly. After inhibiting ILK phosphorylation activity with Cpd22 and ILK-shRNA, we found MEF2C phosphorylation activity and MCK mRNA expression were increased extremely significantly. In the presence of Cpd22, PI3K activity inhibition increased MEF2C phosphorylation and MCK mRNA expression indistinctively. We conclude that ILK negatively and independently of PI3K regulated MEF2C phosphorylation activity and MCK mRNA expression in C2C12 cells. The results provide new ideas for the study of classical signaling pathway of PI3K-ILK-related proteins and transcription factors.
Hairy Cell Leukemia Presenting with Isolated Skeletal Involvement Successfully Treated by Radiation Therapy and Cladribine: A Case Report and Review of the Literature
Authors: Yonal-Hindilerden Ipek , Hindilerden Fehmi , Bulut-Dereli Sanem , Yıldız Eren , Dogan Ibrahim Oner , Nalcaci Meliha
Published: December 2015

We describe an unusual case of hairy cell leukemia (HCL) in a 55-year-old male presenting with isolated skeletal disease as the initial manifestation without abnormal peripheral blood counts, bone marrow involvement, or splenomegaly. To the best of our knowledge, there have been only two previous reports of a similar case. The patient presented with pain in the right femur. Anteroposterior radiographs of both femurs revealed mixed lytic-sclerotic lesions. PET scan showed multiple metastatic lesions on axial skeleton, pelvis, and both femurs. Histopathological examination of the bone biopsy revealed an infiltrate of HCL. Localized radiation therapy to both proximal femurs and subsequently 4 weeks later, a 7-day course of 0.1 mg/kg/day cladribine provided complete remission with relief of symptoms and resolution of bone lesions. We addressed the manifestations and management of HCL patients with skeletal involvement.
Event-Driven Molecular Dynamics Simulation of Hard-Sphere Gas Flows in Microchannels
Authors: Akkaya Volkan Ramazan , Kandemir Ilyas
Published: December 2015

Classical solution of Navier-Stokes equations with nonslip boundary condition leads to inaccurate predictions of flow characteristics of rarefied gases confined in micro/nanochannels. Therefore, molecular interaction based simulations are often used to properly express velocity and temperature slips at high Knudsen numbers (Kn) seen at dilute gases or narrow channels. In this study, an event-driven molecular dynamics (EDMD) simulation is proposed to estimate properties of hard-sphere gas flows. Considering molecules as hard-spheres, trajectories of the molecules, collision partners, corresponding interaction times, and postcollision velocities are computed deterministically using discrete interaction potentials. On the other hand, boundary interactions are handled stochastically. Added to that, in order to create a pressure gradient along the channel, an implicit treatment for flow boundaries is adapted for EDMD simulations. Shear-Driven (Couette) and Pressure-Driven flows for various channel configurations are simulated to demonstrate the validity of suggested treatment. Results agree well with DSMC method and solution of linearized Boltzmann equation. At low Kn, EDMD produces similar velocity profiles with Navier-Stokes (N-S) equations and slip boundary conditions, but as Kn increases, N-S slip models overestimate slip velocities.
Wild Raspberry Subjected to Simulated Gastrointestinal Digestion Improves the Protective Capacity against Ethyl Carbamate‐Induced Oxidative Damage in Caco‐2 Cells
Authors: Chen Wei , Xu Yang , Zhang Lingxia , Li Ya , Zheng Xiaodong
Published: December 2015

Ethyl carbamate (EC), a probable human carcinogen, occurs widely in many fermented foods. Previous studies indicated that EC‐induced cytotoxicity was associated with oxidative stress. Wild raspberries are rich in polyphenolic compounds, which possess potent antioxidant activity. This study was conducted to investigate the protective effect of wild raspberry extracts produced before (RE) and after in vitro simulated gastrointestinal digestion (RD) on EC‐induced oxidative damage in Caco‐2 cells. Our primary data showed that ethyl carbamate could result in cytotoxicity and genotoxicity in Caco‐2 cells and raspberry extract after digestion (RD) may be more effective than that before digestion (RE) in attenuating toxicity caused by ethyl carbamate. Further investigation by fluorescence microscope revealed that RD may significantly ameliorate EC‐induced oxidative damage by scavenging the overproduction of intracellular reactive oxygen species (ROS), maintaining mitochondrial function and preventing glutathione (GSH) depletion. In addition, HPLC‐ESI‐MS results showed that the contents of identified polyphenolic compounds (esculin, kaempferol O‐hexoside, and pelargonidin O‐hexoside) were remarkably increased after digestion, which might be related to the better protective effect of RD. Overall, our results demonstrated that raspberry extract undergoing simulated gastrointestinal digestion may improve the protective effect against EC‐induced oxidative damage in Caco‐2 cells.
Cardioprotective Effects of Astragalin against Myocardial Ischemia/Reperfusion Injury in Isolated Rat Heart
Authors: Qu Daoxu , Han Jichun , Ren Huanhuan , Yang Wenxiao , Zhang Xinjie , Zheng Qiusheng , Wang Dong
Published: December 2015

This study aims to evaluate the cardioprotective effects of astragalin against myocardial ischemia/reperfusion (I/R) injury in isolated rat heart. The cardioprotective effects of astragalin on myocardial I/R injury were investigated on Langendorff apparatus. Adult male Sprague‐Dawley rats were randomly divided into five groups. The results showed that astragalin pretreatment improved myocardial function. Compared with I/R group, lactate dehydrogenase (LDH) and creatine kinase (CK) activities in coronary flow decreased in astragalin pretreatment groups, whereas superoxide dismutase (SOD) activity and glutathione/glutathione disulfide (GSH/GSSG) ratio significantly increased. The levels of malondialdehyde (MDA), intracellular reactive oxygen species (ROS), tumor necrosis factor‐α (TNF‐α), and interleukin‐6 (IL‐6) decreased in astragalin‐treated groups. The infarct size (IS) and apoptosis rate in hearts from astragalin‐treated groups were lower than those in hearts from the I/R group. Western blot analysis also revealed that astragalin preconditioning significantly reduced Bax level, whereas Bcl‐2 was increased in the myocardium. Therefore, astragalin exhibited cardioprotective effects via its antioxidative, antiapoptotic, and anti‐inflammatory activities.
A Comparative Field Monitoring of Column Shortenings in Tall Buildings Using Wireless and Wired Sensor Network Systems
Authors: Lee Sungho , Kim Sangdae , Ha Taehun
Published: December 2015

A comparative field measurement for column shortening of tall buildings is presented in this study, with a focus on the reliability and stability of a wireless sensor network. A wireless sensor network was used for monitoring the column shortenings of a 58-story building under construction. The wireless sensor network, which was composed of sensor and master nodes, employed the ultra-high-frequency band and CDMA communication methods. To evaluate the reliability and stability of the wireless sensor network system, the column shortenings were also measured using a conventional wired monitoring system. Two vibration wire gauges were installed in each of the selected 7 columns and 3 walls. Measurements for selected columns and walls were collected for 270 days after casting of the concrete. The results measured by the wireless sensor network were compared with the results of the conventional method. The strains and column shortenings measured using both methods showed good agreement for all members. It was verified that the column shortenings of tall buildings could be monitored using the wireless sensor network system with its reliability and stability.
HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy
Authors: Liu Tongzheng , Fang Yuan , Zhang Haoxing , Deng Min , Gao Bowen , Niu Nifang , Yu Jia , Lee SeungBaek , Kim JungJin , Qin Bo , Xie Fang , Evans Debra , Wang Liewei , Lou Wenhui , Lou Zhenkun
Published: December 2015

Elucidating mechanisms of chemoresistance is critical to improve cancer therapy, especially for the treatment of pancreatic ductal adenocarcinoma (PDAC). Genome-wide association studies have suggested the less studied gene HEAT repeat-containing protein 1 (HEATR1) as a possible determinant of cellular sensitivity to different chemotherapeutic drugs. In this study, we assessed this hypothesized link in PDAC, where HEATR1 expression is downregulated significantly. HEATR1 silencing in PDAC cells increased resistance to gemcitabine and other chemotherapeutics, where this effect was associated with increased AKT kinase phosphorylation at the Thr308 regulatory site. Mechanistically, HEATR1 enhanced cell responsiveness to gemcitabine by acting as a scaffold to facilitate interactions between AKT and the protein phosphatase PP2A, thereby promoting Thr308 dephosphorylation. Consistent with these findings, treatment with the AKT inhibitor triciribine sensitized HEATR1-depleted PDAC cells to gemcitabine, suggesting that this therapeutic combination may overcome gemcitabine resistance in patients with low HEATR1 expression. Clinically, we found that HEATR1 downregulation in PDAC patients was associated with increased AKT phosphorylation, poor response to tumor resection plus gemcitabine standard-of-care treatment, and shorter overall survival. Collectively, our findings establish HEATR1 as a novel regulator of AKT and a candidate predictive and prognostic indicator of drug responsiveness and outcome in PDAC patients. Cancer Res; 76(3); 572–81. ©2015 AACR.
Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population
Authors: Bhola Neil E. , Jansen Valerie M. , Koch James P. , Li Hua , Formisano Luigi , Williams Janice A. , Grandis Jennifer R. , Arteaga Carlos L.
Published: December 2015

Approximately 30% of triple-negative breast cancers (TNBC) harbor molecular alterations in PI3K/mTOR signaling, but therapeutic inhibition of this pathway has not been effective. We hypothesized that intrinsic resistance to TORC1/2 inhibition is driven by cancer stem cell (CSC)-like populations that could be targeted to enhance the antitumor action of these drugs. Therefore, we investigated the molecular mechanisms by which PI3K/mTOR inhibitors affect the stem-like properties of TNBC cells. Treatment of established TNBC cell lines with a PI3K/mTOR inhibitor or a TORC1/2 inhibitor increased the expression of CSC markers and mammosphere formation. A CSC-specific PCR array revealed that inhibition of TORC1/2 increased FGF1 and Notch1 expression. Notch1 activity was also induced in TNBC cells treated with TORC1/2 inhibitors and associated with increased mitochondrial metabolism and FGFR1 signaling. Notably, genetic and pharmacologic blockade of Notch1 abrogated the increase in CSC markers, mammosphere formation, and in vivo tumor-initiating capacity induced by TORC1/2 inhibition. These results suggest that targeting the FGFR–mitochondrial metabolism–Notch1 axis prevents resistance to TORC1/2 inhibitors by eradicating drug-resistant CSCs in TNBC, and may thus represent an attractive therapeutic strategy to improve drug responsiveness and efficacy. Cancer Res; 76(2); 440–52. ©2015 AACR.
Exploring the Feasibility of a Broad-Reach Physical Activity Behavior Change Intervention for Women Receiving Chemotherapy for Breast Cancer: A Randomized Trial
Authors: Vallance Jeff K. , Friedenreich Christine M. , Lavallee Celeste M. , Culos-Reed Nicole , Mackey John R. , Walley Barbara , Courneya Kerry S.
Published: December 2015

Background: Facilitating healthy levels of physical activity (PA) during chemotherapy is important for the psychosocial and physical health of breast cancer survivors. The primary objective of this feasibility study was to examine the effects of a broad-reach PA behavior change intervention among women with breast cancer receiving adjuvant chemotherapy.

Methods: Breast cancer patients receiving adjuvant chemotherapy (N = 95) were randomly assigned to receive a PA resource kit consisting of tailored print materials and a step pedometer (intervention) or a standard public health PA recommendation (standard recommendation). The primary outcome was daily pedometer steps. Secondary outcomes were self-reported light, moderate, and vigorous intensity PA, total moderate-to-vigorous PA, and sedentary time. Assessments were conducted before and after adjuvant chemotherapy.

Results: Attrition was 19% (17 of 95). Intervention patients wore their step pedometer for 85 days (range, 35–144 days; SD = 26.4) for a 95% adherence rate. Analyses of covariance suggested that the intervention was not statistically superior to standard recommendation for daily average pedometer steps (−771; 95% CI = −2024 to 482; P = 0.22), total MVPA minutes (−4; 95% CI = −62 to 570; P = 0.90), or sedentary time (+160; 95% CI = −186 to 506; P = 0.42).

Conclusion: This broach-reach and low intensive intervention was not more effective for promoting PA in breast cancer patients receiving chemotherapy than providing the standard public health guidelines for PA.

Impact: Achieving physical activity behavior change during adjuvant breast cancer chemotherapy may require some level of supervised physical activity or more intensive (e.g., face-to-face, supervised) interventions. Cancer Epidemiol Biomarkers Prev; 25(2); 391–8. ©2015 AACR.
Breast Cancer Risk Prediction Using Clinical Models and 77 Independent Risk-Associated SNPs for Women Aged Under 50 Years: Australian Breast Cancer Family Registry
Authors: Dite Gillian S. , MacInnis Robert J. , Bickerstaffe Adrian , Dowty James G. , Allman Richard , Apicella Carmel , Milne Roger L. , Tsimiklis Helen , Phillips Kelly-Anne , Giles Graham G. , Terry Mary Beth , Southey Melissa C. , Hopper John L.
Published: December 2015

Background: The extent to which clinical breast cancer risk prediction models can be improved by including information on known susceptibility SNPs is not known.

Methods: Using 750 cases and 405 controls from the population-based Australian Breast Cancer Family Registry who were younger than 50 years at diagnosis and recruitment, respectively, Caucasian and not BRCA1 or BRCA2 mutation carriers, we derived absolute 5-year risks of breast cancer using the BOADICEA, BRCAPRO, BCRAT, and IBIS risk prediction models and combined these with a risk score based on 77 independent risk-associated SNPs. We used logistic regression to estimate the OR per adjusted SD for log-transformed age-adjusted 5-year risks. Discrimination was assessed by the area under the receiver operating characteristic curve (AUC). Calibration was assessed using the Hosmer–Lemeshow goodness-of-fit test. We also constructed reclassification tables and calculated the net reclassification improvement.

Results: The ORs for BOADICEA, BRCAPRO, BCRAT, and IBIS were 1.80, 1.75, 1.67, and 1.30, respectively. When combined with the SNP-based score, the corresponding ORs were 1.96, 1.89, 1.80, and 1.52. The corresponding AUCs were 0.66, 0.65, 0.64, and 0.57 for the risk prediction models, and 0.70, 0.69, 0.66, and 0.63 when combined with the SNP-based score.

Conclusions: By combining a 77 SNP-based score with clinical models, the AUC for predicting breast cancer before age 50 years improved by >20%.

Impact: Our estimates of the increased performance of clinical risk prediction models from including genetic information could be used to inform targeted screening and prevention. Cancer Epidemiol Biomarkers Prev; 25(2); 359–65. ©2015 AACR.
QT Adaptation and Intrinsic QT Variability in Congenital Long QT Syndrome
Authors: Seethala Srikanth , Singh Prabhpreet , Shusterman Vladimir , Ribe Margareth , Haugaa Kristina H. , Němec Jan
Published: December 2015

Background

Increased variability of
QT
interval (
QTV
) has been linked to arrhythmias in animal experiments and multiple clinical situations. Congenital long
QT
syndrome (
LQTS
), a pure repolarization disease, may provide important information on the relationship between delayed repolarization and
QTV
.

Methods and Results

Twenty‐four‐hour Holter monitor tracings from 78 genotyped congenital
LQTS
patients (52 females; 51
LQT
1, 23
LQT
2, 2
LQT
5, 2
JLN
, 27 symptomatic; age, 35.2±12.3 years) were evaluated with computer‐assisted annotation of
RR
and
QT
intervals. Several models of
RR
‐
QT
relationship were tested in all patients. A model assuming exponential decrease of past
RR
interval contributions to
QT
duration with 60‐second time constant provided the best data fit. This model was used to calculate
QT
c and residual “intrinsic”
QTV
, which cannot be explained by heart rate change. The intrinsic
QTV
was higher in patients with long
QT
c (
r
=0.68;
P
<10
−4
), and in
LQT
2 than in
LQT
1/5 patients (5.65±1.28 vs 4.46±0.82;
P
<0.0002). Both
QT
c and intrinsic
QTV
were similar in symptomatic and asymptomatic patients (467±52 vs 459±53 ms and 5.10±1.19 vs 4.74±1.09, respectively).

Conclusions

In
LQTS
patients,
QT
interval adaptation to heart rate changes occurs with time constant ≈60 seconds, similar to results reported in control subjects. Intrinsic
QTV
correlates with the degree of repolarization delay and might reflect action potential instability observed in animal models of
LQTS
.
Left Atrial Inexcitability in Children With Congenital Lupus‐Induced Complete Atrioventricular Block
Authors: Abadir Sylvia , Fournier Anne , Vobecky Suzanne J. , Rohlicek Charles V. , Romeo Philippe , Khairy Paul
Published: December 2015

Background

Congenital atrioventricular block is a well‐established immunologic complication of maternal systemic lupus erythematosus. We sought to further characterize the electrophysiological manifestations of maternal systemic lupus erythematosus on neonatal atria.

Methods and Results

Cases of isolated congenital atrioventricular block treated at our center over the past 41 years were identified. Data were extracted from clinical charts, pacemaker interrogations, ECGs, echocardiograms, and histopathological reports, when available. Of 31 patients with isolated congenital atrioventricular block, 18 were negative for maternal antibodies and had normal epicardial atrial sensing and pacing thresholds. In contrast, 12 of 13 patients with positive maternal antibodies had epicardial pacemakers, 5 (42%) of whom had left atrial (
LA
) inexcitability and/or atrial conduction delay. In 3 patients, the
LA
could not be captured despite high‐output pacing. The fourth patient had acutely successful
LA
appendage and left ventricular lead placement. At early follow‐up, an increased delay between the surface P‐wave and intracardiac atrial depolarization was observed, indicative of atrial conduction delay. The fifth patient exhibited
LA
lead dysfunction, with atrial under‐sensing and an increased capture threshold, 2 weeks after implantation. Biopsies of
LA
appendages performed in 2 patients showed no evidence of atrial fibrosis or loss of atrial myocytes.

Conclusions

Herein, we report previously undescribed yet prevalent electrophysiological ramifications of maternal systemic lupus erythematosus, which extend beyond congenital atrioventricular block to encompass alterations in
LA
conduction, including
LA
inexcitability. These manifestations can complicate epicardial pacemaker implantation in newborns. In the absence of histological evidence of extensive atrial fibrosis, immune‐mediated functional impairment of electrical activity is suspected.
Semantics of the Visual Environment Encoded in Parahippocampal Cortex
Authors: Bonner Michael F. , Price Amy Rose , Peelle Jonathan E. , Grossman Murray
Published: December 2015

Semantic representations capture the statistics of experience and store this information in memory. A fundamental component of this memory system is knowledge of the visual environment, including knowledge of objects and their associations. Visual semantic information underlies a range of behaviors, from perceptual categorization to cognitive processes such as language and reasoning. Here we examine the neuroanatomic system that encodes visual semantics. Across three experiments, we found converging evidence indicating that knowledge of verbally mediated visual concepts relies on information encoded in a region of the ventral-medial temporal lobe centered on parahippocampal cortex. In an fMRI study, this region was strongly engaged by the processing of concepts relying on visual knowledge but not by concepts relying on other sensory modalities. In a study of patients with the semantic variant of primary progressive aphasia (semantic dementia), atrophy that encompassed this region was associated with a specific impairment in verbally mediated visual semantic knowledge. Finally, in a structural study of healthy adults from the fMRI experiment, gray matter density in this region related to individual variability in the processing of visual concepts. The anatomic location of these findings aligns with recent work linking the ventral-medial temporal lobe with high-level visual representation, contextual associations, and reasoning through imagination. Together, this work suggests a critical role for parahippocampal cortex in linking the visual environment with knowledge systems in the human brain.
Supply of Medicinal Raw Materials
Authors: Dejouhanet Lucie
Published: December 2015

The growth of the manufacturing sector in Ayurveda seems to be slowing down in the Indian state of Kerala as the prices of raw materials have increased inordinately, challenging the sustainability of ayurvedic drug production. Several reasons are responsible; in particular, the dwindling availability of plants, the excessive complexity of supply chains, the growing distances between plant sources and manufacturing units, and the control over the medicinal plant market by powerful middlemen. Substitution, adulteration, and quality control have become sensitive issues and may eventually damage the reputation of the ayurvedic drug sector in a context of high competition between manufacturers. Cultivating medicinal plants is considered to be the main solution for solving the supply crisis, but manufacturers’ demands are often too constraining for cultivators and this may not be such a viable alternative in a context of continuous modernisation efforts for production efficiency.
Sense and Evidence
Authors: Ganguly Ritika
Published: December 2015

This paper takes an ethnographic look at laboratory discourses and procedures in the scientific construction of contemporary ayurvedic research in India. It opens up for analysis an experiment in a ‘transdisciplinary’ research laboratory that seeks to understand the methodological and epistemic logic of ayurvedic pharmacology with the help of research methodologies specific to modern Science. In doing so, this paper unravels the various meanings that Science has for its different stakeholders. I examine—as participant, observer, and trainee—a ‘Sensory Analysis’ experiment conducted by scientists at a pharmacology and pharmacognosy laboratory for ayurvedic medicine in Bangalore. Postcolonial science studies have analysed the ways in which discourses of science lead to new knowledges and technologies as well as new ways of organising traditional medical knowledge. Yet the processes that reconcile traditional and modern methodologies of pharmacological and pharmacognostic research have received less attention. The experiment that I am discussing here revisits the ayurvedic doctrine of savours and qualities to standardise not only the parameters indicating the nature of a drug, but also standardise the human body itself as a tool to develop a specific ayurvedic methodology. I argue that in its association with the laboratory and the experimental method, the pursuit of ‘open-minded’dravyaguṇaresearch conceptualises new research in Ayurveda in terms of the right tools, simplifies complex knowledge, and reorganises the relationship of modern ayurvedic research with classical scientific thought.
A new species of Barringtonia (Lecythidaceae) from Thailand and taxonomic notes on B. schmidtii
Authors: Thammarong Woranart , Chantaranothai Pranom , Pornpongrungrueng Pimwadee
Published: December 2015

A new species of Barringtonia (Lecythidaceae), B. thailandica, is described from eastern Thailand. This species resembles B. acutangula in habit, leaf and flower characters, but differs mainly by its ellipsoid-shaped fruit with eight ribs. Additionally, B. schmidtii is reinstated as an independent species and it can be distinguished from its closely related taxa B. acutangula by its swollen leaf base, tomentose rachis, hypanthium and sepals, yellow filaments as well as obovoid-shaped, 4-angled and puberulent fruit. B. bicolor and B. badia are conspecific with B. schmidtii.
Sanghuangporus pilatii, a new combination, revealed as European relative of Asian medicinal fungi
Authors: Tomsovsky Michal
Published: December 2015

Phellinus pilatii Černý (1968: 2) was first described from the southern part of Czechoslovakia (now southeastern Czech Republic in the South Moravia region). The species grows on both the living trees and dead wood of Populus alba and P. × canescens, and is characterized by an imperfect stage that produces chlamydospores on scars left by fallen branches on living trees. Basidiomes later develop in the same place as (or on top of) the asexual structures, in tree cavities and on fallen dead trees. The species is distributed throughout south and southeast Europe and warmer parts of Central Europe. The species has been recorded in southeastern Czech Republic, southern Slovakia, Hungary, Italy, Bulgaria, Italy, Romania, countries of the former Yugoslavia and the European part of Turkey (Bernicchia 1995, Denchev and Assyov 2010, Černý 1968, Doğan et al. 2005, Ryvarden and Gilbertson 1994).
Two new species of Choerophryne (Anura, Microhylidae) from the northern versant of Papua New Guinea’s central cordillera
Authors: IANNELLA AMY , OLIVER PAUL , RICHARDS STEPHEN
Published: December 2015

We describe two new species of small microhylid frogs in the genus Choerophryne from the northern slopes of Papua New Guinea’s central cordillera. Choerophryne epirrhina sp. nov. can be distinguished from congeners by the combination of moderately small size (SUL 14.9–15.0 mm), distinctly elongated snout (OHG/SUL 0.09–0.10), first finger without expanded disk, and advertisement call consisting of 3–4 distinctly pulsed notes repeated in long sequences. Choerophryne grylloides sp. nov. can be distinguished from congeners by the combination of very small size (SUL 12.5 mm), moderately long snout (OHG/SUL 0.08), long legs (TL/SUL 0.42), first finger without expanded disk and advertisement call consisting of 4–5 distinctly pulsed notes, the last of which has many more pulses than preceding notes (9–10 vs. 3–4).
A new species of Pontonema (Oncholaimidae, Nematoda) and a redescription of Pontonema incisum Wieser, 1953 from Santa Cruz and Chubut Provinces, Argentina
Authors: Villares Gabriela , Russo Virginia Lo , Pastor Catalina
Published: December 2015

Pontonema golfonuevensis sp. nov. from Chubut Province, Argentina is described and a description of the male of Pontonema incisum Wieser, 1953 from Chubut and Santa Cruz Provinces is provided. Pontonema golfonuevensis sp. nov. is characterized by having the slender sub-ventral teeth 25 µm long located at 24 % of stoma length, a short, broad dorsal tooth at 60 % of stoma length, excretory pore opening at level of base of the buccal cavity, and by having a ventral precloacal sensory field with four papillae and a glandular sub-ventral area with seven papilliform sensillae. The male of P. incisum has long slender sub-ventral teeth at 36 % of stoma length, a short broad dorsal tooth at 72 % of stoma length, excretory pore about two buccal cavity lengths from the anterior end, and a ventral precloacal sensory field without papillae and a glandular sub-ventral area with twelve to fourteen papilliform sensillae. A key for identification of males of Pontonema is presented.