bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measles Virus Enters Breast and Colon Cancer Cell Lines through a PVRL4-Mediated Macropinocytosis Pathway
Authors: Delpeut Sebastien , Sisson Gary , Black Karen M. , Richardson Christopher D. 
Published: March 2017

ABSTRACT

Measles virus (MeV) is a member of the family
Paramixoviridae
that causes a highly contagious respiratory disease but has emerged as a promising oncolytic platform. Previous studies of MeV entry focused on the identification of cellular receptors. However, the endocytic and trafficking pathways utilized during MeV entry remain poorly described. The contribution of each endocytic pathway has been examined in cells that express the MeV receptors SLAM (signaling lymphocyte-activating molecule) and PVRL4 (poliovirus receptor-like 4) (nectin-4). Recombinant MeVs expressing either firefly luciferase or green fluorescent protein together with a variety of inhibitors were used. The results showed that MeV uptake was dynamin independent in the Vero.hPVRL4, Vero.hSLAM, and PVRL4-positive MCF7 breast cancer cell lines. However, MeV infection was blocked by 5-(
N
-ethyl-
N
-propyl)amiloride (EIPA), the hallmark inhibitor of macropinocytosis, as well as inhibitors of actin polymerization. By using phalloidin staining, MeV entry was shown to induce actin rearrangements and the formation of membrane ruffles accompanied by transient elevated fluid uptake. Small interfering RNA (siRNA) knockdown of p21-activated kinase 1 (PAK1) demonstrated that MeV enters both Vero.hPVRL4 and Vero.hSLAM cells in a PAK1-independent manner using a macropinocytosis-like pathway. In contrast, MeV entry into MCF7 human breast cancer cells relied upon Rac1 and its effector PAK1 through a PVRL4-mediated macropinocytosis pathway. MeV entry into DLD-1 colon and HTB-20 breast cancer cells also appeared to use the same pathway. Overall, these findings provide new insight into the life cycle of MeV, which could lead to therapies that block virus entry or methods that improve the uptake of MeV by cancer cells during oncolytic therapy.

IMPORTANCE
In the past decades, measles virus (MeV) has emerged as a promising oncolytic platform. Previous studies concerning MeV entry focused mainly on the identification of putative receptors for MeV. Nectin-4 (PVRL4) was recently identified as the epithelial cell receptor for MeV. However, the specific endocytic and trafficking pathways utilized during MeV infections are poorly documented. In this study, we demonstrated that MeV enters host cells via a dynamin-independent and actin-dependent endocytic pathway. Moreover, we show that MeV gains entry into MCF7, DLD-1, and HTB-20 cancer cells through a PVRL4-mediated macropinocytosis pathway and identified the typical cellular GTPase and kinase involved. Our findings provide new insight into the life cycle of MeV, which may lead to the development of therapies that block the entry of the virus into the host cell or alternatively promote the uptake of oncolytic MeV into cancer cells.
Parallel multicentre randomised trial of a clinical trial question prompt list in patients considering participation in phase 3 cancer treatment trials
Authors: Tattersall Martin H N , Jefford Michael , Martin Andrew , Olver Ian , Thompson John F , Brown Richard F , Butow Phyllis N 
Published: March 2017

ObjectiveTo evaluate the effect of a clinical trial question prompt list in patients considering enrolment in cancer treatment trials.SettingTertiary cancer referral hospitals in three state capital cities in Australia.Participants88 patients with cancer attending three cancer centres in Australia, who were considering enrolment in phase 3 treatment trials, were invited to enrol in an unblinded randomised trial of provision of a clinical trial question prompt list (QPL) before consenting to enrol in the treatment trial.InterventionsWe developed and pilot tested a targeted QPL for patients with cancer considering clinical trial participation (the clinical trial QPL). Consenting patients were randomised to receive the clinical trial QPL or not before further discussion with their oncologist and/or trial nurse about the treatment trial.Primary and secondary outcomesQuestionnaires were completed at baseline and within 3 weeks of deciding on treatment trial participation. Main outcome measure: scores on the Quality of Informed Consent questionnaire (QuIC).Results88 patients of 130 sought for the study were enrolled (43 males), and 45 received the clinical trial QPL. 49% of trials were chemotherapy interventions for patients with advanced disease, 35% and 16% were surgical adjuvant and radiation adjuvant trials respectively. 70 patients completed all relevant questionnaires. 28 of 43 patients in the control arm compared with 39 of 45 patients receiving the clinical trial QPL completed the QuIC (p=0.0124). There were no significant differences in the QuIC scores between the randomised groups (QuIC part A p=0.08 and QuIC part B p=0.92). There were no differences in patient satisfaction with decisions or in anxiety levels between the randomised groups.ConclusionsUse of a question prompt list did not significantly change the QuIC scores in this randomised trial. ANZCTR 12606000214538 prospectively registered 31/5/2006.Trial registration numberResults, ACTRN12606000214538.
Update on the effects of physical activity on insulin sensitivity in humans
Authors: Bird Stephen R , Hawley John A 
Published: March 2017

Purpose and methodsThis review presents established knowledge on the effects of physical activity (PA) on whole-body insulin sensitivity (SI) and summarises the findings of recent (2013–2016) studies.Discussion and conclusionsRecent studies provide further evidence to support the notion that regular PA reduces the risk of insulin resistance, metabolic syndrome and type 2 diabetes, and SI improves when individuals comply with exercise and/or PA guidelines. Many studies indicate a dose response, with higher energy expenditures and higher exercise intensities, including high intensity interval training (HIIT), producing greater benefits on whole-body SI, although these findings are not unanimous. Aerobic exercise interventions can improve SI without an associated increase in cardiorespiratory fitness as measured by maximal or peak oxygen consumption. Both aerobic and resistance exercise can induce improvements in glycaemic regulation, with some suggestions that exercise regimens including both may be more efficacious than either exercise mode alone. Some studies report exercise-induced benefits to SI that are independent of habitual diet and weight loss, while others indicate an association with fat reduction, hence the debate over the relative importance of PA and weight loss continues. During exercise, muscle contraction stimulated improvements in SI are associated with increases in AMPK activity, which deactivates TCB1D1, promoting GLUT4 translocation to the cell membrane and thereby increasing glucose uptake. Postexercise, increases in Akt deactivate TCB1D4 and thereby increase GLUT4 translocation to the cell membrane. The reduction in intramuscular saturated fatty acids and concomitant reductions in ceramides, but not diacylglycerols, provide a potential link between intramuscular lipid content and SI. Increased skeletal muscle capillarisation provides another independent adaptation through which SI is improved, as does enhanced β cell activity. Recent studies are combining exercise interventions with dietary and feeding manipulations to investigate the potential for augmenting the exercise-induced improvements in SI and glycaemic control.
‘Fish’, fossil and fake: medicinal unicorn horn
Authors: Duffin Christopher J. 
Published: March 2017

Abstract

Ctesias (fifth century BC) recounted contemporary Persian beliefs of white Indian animals which had a white horn, black in the centre and flaming red at the pointed tip, projecting from their forehead. Reinforced by classical and medieval writers, travellers, biblical warrant and trade in narwhal tusk, the unicorn became firmly established in European mythology. Increasing popularity as an alexipharmic, prophylactic and counter-poison through the fifteenth to seventeenth centuries led to rising demand and rapidly inflating prices. Debate raged as to which was the ‘true unicorn’ (
Unicornum Verum
), narwhal tusks or mammoth ivory (
Unicornu Fossile
); shavings and powders of both were incorporated into a bewildering array of medicinal mixtures while fraudulent alternatives flooding the markets required the employment of discriminatory tests. Further alternatives with supposedly similar properties included the (probably smectite) clays of
Terra Sigillata Strigoniensis
or
Terra Silesiaca
(
Unicornu Minerale
), and an alchemical preparation (
Unicornu Solare
). The supposed therapeutic application and wide range of delivery systems of all types of unicorn horn medicines are reviewed in detail for the first time. Particularly popular as an antidote in plague medicines, the use of alicorn (unicorn horn) simples declined to extinction with the increasingly empirical approach to pharmacy of the mid-eighteenth century.
Anthropometric prediction of skeletal muscle cross-sectional area in persons with spinal cord injury
Authors: Wade Rodney C. , Gorgey Ashraf S. 
Published: March 2017

Finding an accurate and affordable method to quantify muscle size following spinal cord injury (SCI) could provide benefits clinically and in research settings. The purpose of this study was to validate the use of anthropometric measurements vs. magnetic resonance imaging (MRI) to evaluate muscle cross-sectional area (CSA) and develop a field equation to predict muscle CSA specific to the SCI population. Twenty-two men with chronic (>1 yr) motor complete SCI participated in the current study. Anthropometric measurements, including midthigh circumference and anterior skinfold thickness (SFT), were taken on the right thigh. The anthropometric muscle cross-sectional area (muscle CSAanthro) was predicted using the following equation: muscle CSAanthro = π[ r − (SFT/2)]2, where r = thigh circumference/2π. MRI analysis yielded whole thigh CSA (thigh CSAMRI), midthigh muscle CSA (muscle CSAMRI), midthigh absolute muscle CSA after subtracting intramuscular fat and bone (muscle CSA-IMFMRI), subcutaneous adipose tissue (SATT) measured at one site as well as at four sites, and bone CSA. Anthropometric measurements were correlated to the thigh CSAMRI [ r2 = 0.90, standard error of the estimate (SEE) = 17.6 cm2, P < 0.001]. Muscle CSAanthro was correlated to muscle CSAMRI ( r2 = 0.78, SEE = 16.6 cm2, P < 0.001) and muscle CSA-IMFMRI ( r2 = 0.75, SEE = 17.6 cm2, P < 0.001). A single SFT was correlated to the polar four-site SATT ( r2 = 0.78, SEE = 0.37 cm, P < 0.001). The average femur CSA and average IMF CSA derived from MRI led to the following field equation: muscle CSApredicted = π[(Thighcircum/2π) − (SFT/2)]2 − 23.2. Anthropometric measurements of muscle CSA exhibited a good agreement with the gold standard MRI method and led to the development of a field equation for clinical use after accounting for bone and IMF. NEW & NOTEWORTHY This study used anthropometric measurements and magnetic resonance imaging (MRI) to evaluate muscle cross-sectional area (CSA) and developed a field equation to predict thigh muscle CSA specific to the spinal cord-injured (SCI) population. Anthropometric measurements were correlated to the whole thigh CSA and muscle CSA as measured by MRI. The correlations led to the development of a SCI-specific field equation that accounted for intramuscular fat and bone areas.
Delta and gamma oscillations in operculo-insular cortex underlie innocuous cold thermosensation
Authors: Fardo Francesca , Vinding Mikkel C. , Allen Micah , Jensen Troels Staehelin , Finnerup Nanna Brix 
Published: March 2017

Cold-sensitive and nociceptive neural pathways interact to shape the quality and intensity of thermal and pain perception. Yet the central processing of cold thermosensation in the human brain has not been extensively studied. Here, we used magnetoencephalography and EEG in healthy volunteers to investigate the time course (evoked fields and potentials) and oscillatory activity associated with the perception of cold temperature changes. Nonnoxious cold stimuli consisting of Δ3°C and Δ5°C decrements from an adapting temperature of 35°C were delivered on the dorsum of the left hand via a contact thermode. Cold-evoked fields peaked at around 240 and 500 ms, at peak latencies similar to the N1 and P2 cold-evoked potentials. Importantly, cold-related changes in oscillatory power indicated that innocuous thermosensation is mediated by oscillatory activity in the range of delta (1–4 Hz) and gamma (55–90 Hz) rhythms, originating in operculo-insular cortical regions. We suggest that delta rhythms coordinate functional integration between operculo-insular and frontoparietal regions, while gamma rhythms reflect local sensory processing in operculo-insular areas. NEW & NOTEWORTHY Using magnetoencephalography, we identified spatiotemporal features of central cold processing, with respect to the time course, oscillatory profile, and neural generators of cold-evoked responses in healthy human volunteers. Cold thermosensation was associated with low- and high-frequency oscillatory rhythms, both originating in operculo-insular regions. These results support further investigations of central cold processing using magnetoencephalography or EEG and the clinical utility of cold-evoked potentials for neurophysiological assessment of cold-related small-fiber function and damage.
LIGHT Elevation Enhances Immune Eradication of Colon Cancer Metastases
Authors: Qiao Guilin , Qin Jianzhong , Kunda Nicholas , Calata Jed F. , Mahmud Dolores L. , Gann Peter , Fu Yang-Xin , Rosenberg Steven A. , Prabhakar Bellur S. , Maker Ajay V. 
Published: March 2017

Abstract
The majority of patients with colon cancer will develop advanced disease, with the liver being the most common site of metastatic disease. Patients with increased numbers of tumor-infiltrating lymphocytes in primary colon tumors and liver metastases have improved outcomes. However, the molecular factors that could empower antitumor immune responses in this setting remain to be elucidated. We reported that the immunostimulatory cytokine LIGHT (TNFSF14) in the microenvironment of colon cancer metastases associates with improved patient survival, and here we demonstrate in an immunocompetent murine model that colon tumors expressing LIGHT stimulate lymphocyte proliferation and tumor cell–specific antitumor immune responses. In this model, increasing LIGHT expression in the microenvironment of either primary tumors or liver metastases triggered regression of established tumors and slowed the growth of liver metastases, driven by cytotoxic T-lymphocyte–mediated antitumor immunity. These responses corresponded with significant increases in tumor-infiltrating lymphocytes and increased expression of lymphocyte-homing signals in the metastatic tumors. Furthermore, we demonstrated evidence of durable tumor-specific antitumor immunity. In conclusion, increasing LIGHT expression increased T-cell proliferation, activation, and infiltration, resulting in enhanced tumor-specific immune-mediated tumor regressions in primary tumors and colorectal liver metastases. Mechanisms to increase LIGHT in the colon cancer microenvironment warrant further investigation and hold promise as an immunotherapeutic strategy. Cancer Res; 77(8); 1880–91. ©2017 AACR.
Noncoding Effects of Circular RNA CCDC66 Promote Colon Cancer Growth and Metastasis
Authors: Hsiao Kuei-Yang , Lin Ya-Chi , Gupta Sachin Kumar , Chang Ning , Yen Laising , Sun H. Sunny , Tsai Shaw-Jenq 
Published: March 2017

Abstract
Circular RNA (circRNA) is a class of noncoding RNA whose functions remain mostly unknown. Recent studies indicate circRNA may be involved in disease pathogenesis, but direct evidence is scarce. Here, we characterize the functional role of a novel circRNA, circCCDC66, in colorectal cancer. RNA-Seq data from matched normal and tumor colon tissue samples identified numerous circRNAs specifically elevated in cancer cells, several of which were verified by quantitative RT-PCR. CircCCDC66 expression was elevated in polyps and colon cancer and was associated with poor prognosis. Gain-of-function and loss-of-function studies in colorectal cancer cell lines demonstrated that circCCDC66 controlled multiple pathological processes, including cell proliferation, migration, invasion, and anchorage-independent growth. In-depth characterization revealed that circCCDC66 exerts its function via regulation of a subset of oncogenes, and knockdown of circCCDC66 inhibited tumor growth and cancer invasion in xenograft and orthotopic mouse models, respectively. Taken together, these findings highlight a novel oncogenic function of circRNA in cancer progression and metastasis. Cancer Res; 77(9); 2339–50. ©2017 AACR.
Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer
Authors: Jansen Valerie M. , Bhola Neil E. , Bauer Joshua A. , Formisano Luigi , Lee Kyung-Min , Hutchinson Katherine E. , Witkiewicz Agnieszka K. , Moore Preston D. , Estrada Mónica Valéria , Sánchez Violeta , Ericsson Paula G. , Sanders Melinda E. , Pohlmann Paula R. , Pishvaian Michael J. , Riddle David A. , Dugger Teresa C. , Wei Wenyi , Knudsen Erik S. , Arteaga Carlos L. 
Published: March 2017

Abstract
Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a kinome-wide siRNA screen to identify kinases that, when downregulated, yield sensitivity to the CDK4/6 inhibitor ribociclib. In this manner, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a key modifier of ribociclib sensitivity in estrogen receptor–positive MCF-7 breast cancer cells. Pharmacologic inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, another CDK4/6 inhibitor, synergistically inhibited proliferation and increased apoptosis in a panel of ER-positive breast cancer cell lines. Ribociclib-resistant breast cancer cells selected by chronic drug exposure displayed a relative increase in the levels of PDK1 and activation of the AKT pathway. Analysis of these cells revealed that CDK4/6 inhibition failed to induce cell-cycle arrest or senescence. Mechanistic investigations showed that resistant cells coordinately upregulated expression of cyclins A, E, and D1, activated phospho-CDK2, and phospho-S477/T479 AKT. Treatment with GSK2334470 or the CDK2 inhibitor dinaciclib was sufficient to reverse these events and to restore the sensitivity of ribociclib-resistant cells to CDK4/6 inhibitors. Ribociclib, in combination with GSK2334470 or the PI3Kα inhibitor alpelisib, decreased xenograft tumor growth more potently than each drug alone. Taken together, our results highlight a role for the PI3K–PDK1 signaling pathway in mediating acquired resistance to CDK4/6 inhibitors. Cancer Res; 77(9); 2488–99. ©2017 AACR.
Intrinsic Subtypes and Gene Expression Profiles in Primary and Metastatic Breast Cancer
Authors: Cejalvo Juan M. , Martínez de Dueñas Eduardo , Galván Patricia , García-Recio Susana , Burgués Gasión Octavio , Paré Laia , Antolín Silvia , Martinello Rosella , Blancas Isabel , Adamo Barbara , Guerrero-Zotano Ángel , Muñoz Montserrat , Nucíforo Paolo , Vidal María , Pérez Ramón M. , Chacón López-Muniz José I. , Caballero Rosalía , Peg Vicente , Carrasco Eva , Rojo Federico , Perou Charles M. , Cortés Javier , Adamo Vincenzo , Albanell Joan , Gomis Roger R. , Lluch Ana , Prat Aleix 
Published: March 2017

Abstract
Biological changes that occur during metastatic progression of breast cancer are still incompletely characterized. In this study, we compared intrinsic molecular subtypes and gene expression in 123 paired primary and metastatic tissues from breast cancer patients. Intrinsic subtype was identified using a PAM50 classifier and χ2 tests determined the differences in variable distribution. The rate of subtype conversion was 0% in basal-like tumors, 23.1% in HER2-enriched (HER2-E) tumors, 30.0% in luminal B tumors, and 55.3% in luminal A tumors. In 40.2% of cases, luminal A tumors converted to luminal B tumors, whereas in 14.3% of cases luminal A and B tumors converted to HER2-E tumors. We identified 47 genes that were expressed differentially in metastatic versus primary disease. Metastatic tumors were enriched for proliferation-related and migration-related genes and diminished for luminal-related genes. Expression of proliferation-related genes were better at predicting overall survival in metastatic disease (OSmet) when analyzed in metastatic tissue rather than primary tissue. In contrast, a basal-like gene expression signature was better at predicting OSmet in primary disease compared with metastatic tissue. We observed correlations between time to tumor relapse and the magnitude of changes of proliferation, luminal B, or HER2-E signatures in metastatic versus primary disease. Although the intrinsic subtype was largely maintained during metastatic progression, luminal/HER2-negative tumors acquired a luminal B or HER2-E profile during metastatic progression, likely reflecting tumor evolution or acquisition of estrogen independence. Overall, our analysis revealed the value of stratifying gene expression by both cancer subtype and tissue type, providing clinicians more refined tools to evaluate prognosis and treatment. Cancer Res; 77(9); 2213–21. ©2017 AACR.
Endothelin Promotes Colorectal Tumorigenesis by Activating YAP/TAZ
Authors: Wang Zhen , Liu Peng , Zhou Xin , Wang Tianxiang , Feng Xu , Sun Yi-Ping , Xiong Yue , Yuan Hai-Xin , Guan Kun-Liang 
Published: March 2017

Abstract
Endothelin receptor A (ETAR) promotes tumorigenesis by stimulating cell proliferation, migration, and survival. However, the mechanism of ETAR in promoting tumor growth is largely unknown. In this study, we demonstrate that ETAR stimulates colon cell proliferation, migration, and tumorigenesis through the activation of YAP/TAZ, two transcription coactivators of the Hippo tumor suppressor pathway. Endothelin-1 treatment induced YAP/TAZ dephosphorylation, nuclear accumulation, and transcriptional activation in multiple colon cancer cells. ETAR stimulation acted via downstream G-protein Gαq/11 and Rho GTPase to suppress the Hippo pathway, thus leading to YAP/TAZ activation, which was required for ETAR-induced tumorigenesis. Overall, these results indicate a critical role of the YAP/TAZ axis in ETAR signaling. Cancer Res; 77(9); 2413–23. ©2017 AACR.