bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
An Accelerating Iterative Learning Control Based on an Adjustable Learning Interval
Authors: Ma Dongqi , Lin Hui
Published: March 2017

An iterative learning control algorithm with an adjustable interval is proposed for nonlinear systems to accelerate the convergence rate of iterative learning control. Forλ-norm, the monotonic convergence of ILC was analyzed, and the corresponding convergence conditions were obtained. The results showed that the convergence rate was mainly determined by the controlled object, the control law gain, the correction factor, and the iteration interval size and that the control law gain was corrected in real time in the modified interval and the modified interval shortened as the number of iterations increased, further accelerating the convergence. The numerical simulation shows the effectiveness of the proposed method.
Antiurolithiasis Activity of Bioactivity Guided Fraction ofBergenia ligulataagainst Ethylene Glycol Induced Renal Calculi in Rat
Authors: Sharma Ikshit , Khan Washim , Parveen Rabea , Alam Md. Javed , Ahmad Iftekhar , Ansari Mohd Hafizur Rehman , Ahmad Sayeed
Published: March 2017

Dried rhizome ofBergenia ligulata(pashanbhed) is commonly used as a traditional herbal medicine with a wide range of therapeutic applications including urolithiasis. Aqueous extract ofB. ligulatawas prepared through maceration followed by decoction (mother extract, 35.9% w/w). Further, polarity based fractions were prepared successively from mother extract which yielded 3.4, 2.9, 5.4, 7.5, and 11.3% w/w of hexane, toluene, dichloromethane (DCM),n-butanol, and water fractions, respectively. The in vitro, ex vivo, and real-time antiurolithiasis activity of mother extract and fractions were carried out using aggregation assay in synthetic urine and in rat plasma. The study revealed that DCM fraction has significantly (p<0.05) greater inhibitory potential than other fractions. Ethylene glycol in drinking water (0.75%, v/v) for 28 days was used for induction of urolithiasis and the curative effects of mother extract and DCM fraction were checked for the level of oxalate, calcium, creatinine, uric acid, and urea of both urine and serum. Treatment with mother extract and DCM fraction at a dose of 185 mg/kg and 7 mg/kg, respectively, in ethylene glycol induced rats resulted in a significant (p<0.05) decrease in serum and urine markers. Histological study revealed lower number of calcium oxalate deposits with minimum damage in the kidneys of mother extract and DCM fraction treated rats. This result provides a scientific basis for its traditional claims.
Ethnic Differences in Risk Factors for Obesity among Adults in California, the United States
Authors: Wang Liang , Southerland Jodi , Wang Kesheng , Bailey Beth A. , Alamian Arsham , Stevens Marc A. , Wang Youfa
Published: March 2017

Little attention has been given to differences in obesity risk factors by racial/ethnic groups. Using data from the 2011-2012 California Health Interview Survey, we examined differences in risk factors for obesity among Whites, Latinos, Asians, and African Americans among 42,935 adults (24.8% obese). Estimates were weighted to ensure an unbiased representation of the Californian population. Multiple logistic and linear regression analyses were used to examine the differences in risk factors for obesity. Large ethnic disparities were found in obesity prevalence: Whites (22.0%), Latinos (33.6%), African Americans (36.1%), and Asians (9.8%). Differences in risk factors for obesity were also observed: Whites (gender, age, physical activity, smoking, arthritis, and diabetes medicine intake), Latinos (age, arthritis, and diabetes medicine intake), Asians (age, binge drinking, arthritis, and diabetes medicine intake), and African Americans (gender, physical activity, smoking, binge drinking, and diabetes medicine intake). Females were more likely to be obese among African Americans (odds ratio (OR) = 1.43, 95% confidence interval (CI) = 1.05–1.94), but less likely among Whites (OR = 0.80, 95% CI = 0.74–0.87). Race/ethnicity should be considered in developing obesity prevention strategies.
Characteristics and Etiologies of Chronic Scrotal Pain: A Common but Poorly Understood Condition
Authors: Aljumaily Aosama , Al-Khazraji Hind , Gordon Allan , Lau Susan , Jarvi Keith A.
Published: March 2017

Chronic scrotal pain (CSP) is a common and debilitating condition, but the underlying characteristics and etiology of CSP are poorly understood. The objective of this study is to identify the characteristic and etiologies of CSP. Men presenting for management of CSP completed a standardized questionnaire and underwent a complete physical examination. From Feb 2014 to Sep 2015, a total of 131 men (mean age 43) with CSP were studied. The CSP was of long duration (mean of4.7±5.95years) and dramatically affected men’s lives, with adverse effects on normal activities (71.%), ability to work (51.90%), and sexual functioning (61.8%). 50.4% felt depressed on most days, and 67.17% felt either unhappy or terrible with their present condition. Physical examination revealed that the epididymis was the most common tender area found in 70/131 men (53.43%), though a musculoskeletal source for the pain was found in 9.9%. Neuropathic changes were found in 30%. For close to half of the men (43.5%) we were unable to identify any potential cause for the CSP. This study characterizes the dramatic impact that CSP has on the lives of men, while providing an understanding of the common etiologies.
Physicochemical and Biological Characterization of the Proposed Biosimilar Tocilizumab
Authors: Miao Shiwei , Fan Li , Zhao Liang , Ding Ding , Liu Xiaohui , Wang Haibin , Tan Wen-Song
Published: March 2017

HS628 has been developed as a proposed biosimilar product of originator tocilizumab (Actemra®). An extensive physicochemical and biological characterization was conducted to assess similarity between HS628 and originator tocilizumab. The amino acid sequence was shown to be identical between HS628 and originator tocilizumab. The higher order structure was found to be indistinguishable from originator tocilizumab. Concerning purity and heterogeneity, HS628 was demonstrated to have similar posttranslational modifications, charge heterogeneity, size heterogeneity, and glycosylation to originator tocilizumab. Moreover, HS628 exhibited highly similar binding affinity and antiproliferative activity as well as capability of inhibiting STAT3 phosphorylation compared to originator tocilizumab. Taken together, HS628 can be considered as a highly similar molecule to originator tocilizumab in terms of physicochemical and biological properties.
Topological Measurements of DWI Tractography for Alzheimer’s Disease Detection
Authors: Amoroso Nicola , Monaco Alfonso , Tangaro Sabina , Neuroimaging Initiative Alzheimer’s Disease
Published: March 2017

Neurodegenerative diseases affect brain morphology and connectivity, making complex networks a suitable tool to investigate and model their effects. Because of its stereotyped pattern Alzheimer’s disease (AD) is a natural benchmark for the study of novel methodologies. Several studies have investigated the network centrality and segregation changes induced by AD, especially with a single subject approach. In this work, a holistic perspective based on the application of multiplex network concepts is introduced. We define and assess a diagnostic score to characterize the brain topology and measure the disease effects on a mixed cohort of 52 normal controls (NC) and 47 AD patients, from Alzheimer’s Disease Neuroimaging Initiative (ADNI). The proposed topological score allows an accurate NC-AD classification: the average area under the curve (AUC) is 95% and the 95% confidence interval is 92%–99%. Besides, the combination of topological information and structural measures, such as the hippocampal volumes, was also investigated. Topology is able to capture the disease signature of AD and, as the methodology is general, it can find interesting applications to enhance our insight into disease with more heterogeneous patterns.
Imaging of Myocardial Fibrosis in Patients with End-Stage Renal Disease: Current Limitations and Future Possibilities
Authors: Graham-Brown M. P. M. , Patel A. S. , Stensel D. J. , March D. S. , Marsh A.-M. , McAdam J. , McCann G. P. , Burton J. O.
Published: March 2017

Cardiovascular disease in patients with end-stage renal disease (ESRD) is driven by a different set of processes than in the general population. These processes lead to pathological changes in cardiac structure and function that include the development of left ventricular hypertrophy and left ventricular dilatation and the development of myocardial fibrosis. Reduction in left ventricular hypertrophy has been the established goal of many interventional trials in patients with chronic kidney disease, but a recent systematic review has questioned whether reduction of left ventricular hypertrophy improves cardiovascular mortality as previously thought. The development of novel imaging biomarkers that link to cardiovascular outcomes and that are specific to the disease processes in ESRD is therefore required. Postmortem studies of patients with ESRD on hemodialysis have shown that the extent of myocardial fibrosis is strongly linked to cardiovascular death and accurate imaging of myocardial fibrosis would be an attractive target as an imaging biomarker. In this article we will discuss the current imaging methods available to measure myocardial fibrosis in patients with ESRD, the reliability of the techniques, specific challenges and important limitations in patients with ESRD, and how to further develop the techniques we have so they are sufficiently robust for use in future clinical trials.
Cost of Living with Parkinson’s Disease over 12 Months in Australia: A Prospective Cohort Study
Authors: Bohingamu Mudiyanselage Shalika , Watts Jennifer J. , Abimanyi-Ochom Julie , Lane Lisa , Murphy Anna T. , Morris Meg E. , Iansek Robert
Published: March 2017

Background. Parkinson disease (PD) is a costly chronic condition in terms of managing both motor and nonmotor symptoms. The burden of disease is high for individuals, caregivers, and the health system. The aim of this study is to estimate the annual cost of PD from the household, health system, and societal perspectives. Methods. A prospective cohort study of newly referred people with PD to a specialist PD clinic in Melbourne, Australia. Participants completed baseline and monthly health resource use questionnaires and Medicare data were collected over 12 months. Results. 87 patients completed the 12-month follow-up assessments. The mean annual cost per person to the health care system was $32,556 AUD. The burden to society was an additional $45,000 per annum per person with PD. The largest component of health system costs were for hospitalisation (69% of total costs). The costs for people with moderate to severe disease were almost 4 times those with mild PD ($63,569 versus $17,537 p<0.001). Conclusion. PD is associated with significant costs to individuals and to society. Costs escalated with disease severity suggesting that the burden to society is likely to grow with the increasing disease prevalence that is associated with population ageing.
Variability in Diagnosing Brain Death at an Academic Medical Center
Authors: Pandey Ashutosh , Sahota Pradeep , Nattanmai Premkumar , Newey Christopher R.
Published: March 2017

Objective. Research continues to highlight variability in hospital policy and documentation of brain death. The aim of our study was to characterize how strictly new guidelines of American Academy of Neurology (AAN) for death by neurological criteria were practiced in our hospital prior to appointment of neurointensivists. Method. This is a retrospective study of adults diagnosed as brain dead from 2011 to 2015. Descriptive statistics compared five categories: preclinical testing, neurological examination, apnea tests, ancillary test, and documentation of time of death. Strict adherence to AAN guidelines for brain death determination was determined. Result. 76 patients were included in this study. Preclinical prerequisites were fulfilled in 53.9% and complete neurological examinations were documented in 76.3%. Apnea test was completed in 39.5%. Ancillary test was completed in 29.8%. Accurate documentation of time of death occurred in 59.2%. Overall, strict adherence to current AAN guidelines for death by neurological criteria was correctly documented in 38.2%. Conclusion. Our study shows wide variability in diagnosing brain death. These findings led us to update our death by neurological criteria policy and increase awareness of brain death determination with the goal of improving our documentation following current AAN guidelines.
Outcome and Genetic Factors in IgG4-Associated Autoimmune Pancreatitis and Cholangitis: A Single Center Experience
Authors: Buechter Matthias , Manka Paul , Heinemann Falko Markus , Lindemann Monika , Juntermanns Benjamin , Canbay Ali , Gerken Guido , Kahraman Alisan
Published: March 2017

Introduction. Most investigations on autoimmune pancreatitis (AIP) were published on Asian cohorts while those on Caucasians are limited. However, there might be differences related to the origin.Patients and Methods. We analyzed 36 patients and compared type 1 (AIP1) with type 2 (AIP2).Results. The majority of patients suffered from AIP1 (55.6%). AIP1 patients were significantly older than AIP2 patients (54.4 versus 40.8 years). Moreover, 85.0% of AIP1 patients had concurrent autoimmune cholangitis (AIC) while 18.8% of AIP2 patients suffered from overlap to ulcerative colitis (UC). However, AIP1 patients revealed a cholestatic course and had significantly higher immunoglobulin G4 levels (IgG4). When compared to allele frequencies in healthy controls, in patients with AIP1 HLA-B8 reached statistical significance. Response to steroids was excellent in both groups, but we noticed high rates of relapse especially in AIP1 patients. Finally, 3 patients with AIP1 were diagnosed with cholangiocellular carcinoma (CCC).Conclusion. In contrast to Asian studies, we found an almost equal distribution of AIP1 and AIP2 patients in our German cohort. AIP2 patients were younger and mostly of female gender whereas AIP1 patients revealed higher IgG4 levels and involvement of the biliary tract in sense of IgG4-associated cholangitis.
Factors Associated with Mortality among Patients on TB Treatment in the Southern Region of Zimbabwe, 2013
Authors: Takarinda Kudakwashe C. , Sandy Charles , Masuka Nyasha , Hazangwe Patrick , Choto Regis C. , Mutasa-Apollo Tsitsi , Nkomo Brilliant , Sibanda Edwin , Mugurungi Owen , Harries Anthony D. , Siziba Nicholas
Published: March 2017

Background. In 2013, the tuberculosis (TB) mortality rate was highest in southern Zimbabwe at 16%. We therefore sought to determine factors associated with mortality among registered TB patients in this region.Methodology. This was a retrospective record review of registered patients receiving anti-TB treatment in 2013.Results. Of 1,971 registered TB patients, 1,653 (84%) were new cases compared with 314 (16%) retreatment cases. There were 1,538 (78%) TB/human immunodeficiency virus (HIV) coinfected patients, of whom 1,399 (91%) were on antiretroviral therapy (ART) with median pre-ART CD4 count of 133 cells/uL (IQR, 46–282). Overall, 428 (22%) TB patients died. Factors associated with increased mortality included being ≥65 years old [adjusted relative risk (ARR) = 2.48 (95% CI 1.35–4.55)], a retreatment TB case [ARR = 1.34 (95% CI, 1.10–1.63)], and being HIV-positive [ARR = 1.87 (95% CI, 1.44–2.42)] whilst ART initiation was protective [ARR = 0.25 (95% CI, 0.22–0.29)]. Cumulative mortality rates were 10%, 14%, and 21% at one, two, and six months, respectively, after starting TB treatment.Conclusion. There was high mortality especially in the first two months of anti-TB treatment, with risk factors being recurrent TB and being HIV-infected, despite a high uptake of ART.
Low Cost Skin Segmentation Scheme in Videos Using Two Alternative Methods for Dynamic Hand Gesture Detection Method
Authors: Thabet Eman , Khalid Fatimah , Suhaiza Sulaiman Puteri , Yaakob Razali
Published: March 2017

Recent years have witnessed renewed interest in developing skin segmentation approaches. Skin feature segmentation has been widely employed in different aspects of computer vision applications including face detection and hand gestures recognition systems. This is mostly due to the attractive characteristics of skin colour and its effectiveness to object segmentation. On the contrary, there are certain challenges in using human skin colour as a feature to segment dynamic hand gesture, due to various illumination conditions, complicated environment, and computation time or real-time method. These challenges have led to the insufficiency of many of the skin color segmentation approaches. Therefore, to produce simple, effective, and cost efficient skin segmentation, this paper has proposed a skin segmentation scheme. This scheme includes two procedures for calculating generic threshold ranges in Cb-Cr colour space. The first procedure uses threshold values trained online from nose pixels of the face region. Meanwhile, the second procedure known as the offline training procedure uses thresholds trained out of skin samples and weighted equation. The experimental results showed that the proposed scheme achieved good performance in terms of efficiency and computation time.
Interspecies In Vitro Evaluation of Stereoselective Protein Binding for 3,4-Methylenedioxymethamphetamine
Authors: Wan Aasim Wan Raihana , Tan Soo Choon , Gan Siew Hua
Published: March 2017

Abuse of 3,4-methylenedioxymethamphetamine (MDMA) is becoming more common worldwide. To date, there is no information available on stereoselectivity of MDMA protein binding in humans, rats, and mice. Since stereoselectivity plays an important role in MDMA’s pharmacokinetics and pharmacodynamics, in this study we investigated its stereoselectivity in protein binding. The stereoselective protein binding ofrac-MDMA was investigated using two different concentrations (20 and 200 ng/mL) in human plasma and mouse and rat sera using an ultrafiltration technique. No significant stereoselectivity in protein binding was observed in both human plasma and rat serum; however, a significant stereoselective binding (p<0.05) was observed in mouse serum. Since the protein binding of MDMA in mouse serum is considerably lower than in humans and rats, caution should be exercised when using mice for in vitro studies involving MDMA.
Research on Simulink/Fluent Collaborative Simulation Zooming of Marine Gas Turbine
Authors: Wang Zhi-tao , Li Jian , Li Tie-lei , Li Shu-ying
Published: March 2017

Based on the detailed analysis of collaborative running interface of Simulink/Fluent, a system simulation for the rated working condition as well as variable working condition of marine gas turbine has been achieved, which can improve the simulation efficiency of marine gas turbine by developing simulation model of combustor with Fluent and simulation models of other components with Simulink. The result shows that the Simulink/Fluent collaborative simulation zooming can make the inner working conditions of combustor be observed specifically, based on the overall performance matching analysis; thus an effective technical means for the structural optimization design of combustor has been provided.
Dynamic Optimization Design of Cranes Based on Human–Crane–Rail System Dynamics and Annoyance Rate
Authors: Xin Yunsheng , Xu Gening , Su Nina
Published: March 2017

The operators of overhead traveling cranes experience discomfort as a result of the vibrations of crane structures. These vibrations are produced by defects in the rails on which the cranes move. To improve the comfort of operators, a nine-degree-of-freedom (nine-DOF) mathematical model of a “human–crane–rail” system was constructed. Based on the theoretical guidance provided in ISO 2631-1, an annoyance rate model was established, and quantization results were determined. A dynamic optimization design method for overhead traveling cranes is proposed. A particle swarm optimization (PSO) algorithm was used to optimize the crane structural design, with the structure parameters as the basic variables, the annoyance rate model as the objective function, and the acceleration amplitude and displacement amplitude of the crane as the constraint conditions. The proposed model and method were used to optimize the design of a double-girder 100 t–28.5 m casting crane, and the optimal parameters are obtained. The results show that optimization decreases the human annoyance rate from 28.3% to 9.8% and the root mean square of the weighted acceleration of human vibration from 0.59 m/s2to 0.38 m/s2. These results demonstrate the effectiveness and practical applicability of the models and method proposed in this paper.
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

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

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

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

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

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.
Birth Rates after Adolescent and Young Adult Cancer in North Carolina, 2000–2014
Authors: Nichols HB , Anderson C , Black KZ , Engel S , Mersereau J
Published: March 2017

Each year, >45,000 U.S. women are diagnosed with cancer during adolescence and young adulthood (AYA), defined by the National Cancer Institute as ages 15–39 years. ASCO first published guidelines on fertility counseling and preservation for cancer patients in 2006. Few studies have assessed birth rates after cancer among AYAs. We identified women with an incident cancer diagnosis at ages 15–39 during 2000–2013 in the North Carolina Cancer Registry. Cancer records were linked with statewide birth certificates through 2014 using a probabilistic algorithm. Hazard ratios (HR) and 95% confidence intervals (CI) for childbirth were calculated using Cox proportional hazards regression, with person-time accrued from cancer diagnosis until death, 46th birthday or December 31, 2014 and adjusted for age at diagnosis. Among 19,507 AYA cancer survivors, 2,343 had ≥1 post-diagnosis birth during 110,216 person-years. The 5- and 10-year cumulative incidence of post-diagnosis birth was 12% and 18%, respectively. The most common cancers were breast (25%), thyroid (14%), gynecologic (10%), melanoma (10%), and lymphoma (7%). The percent with a birth after diagnosis was lowest for breast and gynecologic cancer (6% for both) and highest for Hodgkin lymphoma (23%) and melanoma (24%). Survivors with a birth after diagnosis were more often younger, had not received radiation or chemotherapy, and had lower stage disease. African American women were less likely to have a post-diagnosis birth than white women overall (HR = 0.82; 0.73, 0.92), due in part to a higher proportion of breast cancers (35% vs. 23%). About 30% of births were <2 years from cancer diagnosis and 20% were >5 years after (mean = 3.5 years). Half (48%) were to women who were nulliparous at diagnosis. The 5-year cumulative incidence of post-diagnosis birth was 11.7% for women diagnosed during 2007–2012 (after ASCO's 2006 guidelines), compared to 11.6% during 2000–2005 (HR = 0.98; 0.89, 1.08) and varied little by cancer type. Despite advances in fertility preservation options and recognition of fertility counseling as a part of high quality cancer care, birth rates have remained stable over the last 15 years. Low implementation of fertility counseling and limited access to fertility preservation may be contributing factors.
Explaining Disparities in Ovarian Cancer Incidence Rates between Women of African and European Ancestry: The Role of Genetic Factors
Authors: Mullins M , Mukherjee B , Wu AH , Pike M , Pharoah PDP , Berchuck A , Pearce CL
Published: March 2017

Non-Hispanic White (NHW) women are at higher risk of ovarian cancer than African-American (AA) women. Approximately 30% of the difference in age-adjusted invasive epithelial ovarian cancer incidence rates (AAIR) between the two groups can be explained by differing oophorectomy rates and the prevalence of non-genetic risk and protective factors. Our purpose was to determine how much of the remaining difference in AAIRs could be explained by varying allele frequencies between NHWs and AAs for 18 genome-wide significant common susceptibility variants for ovarian cancer. Using data on 13,385 cases and 24,875 controls from the Ovarian Cancer Association Consortium, a genetic risk score (GRS) was created from 18 single nucleotide polymorphisms (SNPs) associated with ovarian cancer risk following the Collaborative Oncological Gene-environment Study (COGS) effort. Relative risks for each GRS quintile were estimated using conditional logistic regression, adjusting for genetic ancestry and conditioning on study site, age, and race. The population attributable risk percent (PAR) for GRS above the lowest quintile was calculated using the Bruzzi method. Previously reported oophorectomy and non-genetic risk factor (talc, oral contraceptive use, family history of ovarian cancer, endometriosis, parity and tubal ligation) adjusted incidence rates for ovarian cancer in NHWs and AA's were 7.2 and 5.8 per 100,000 respectively. These incidence rates were further adjusted for the contribution of the GRS from this analysis. The subsequent genetic PAR adjusted rate was 5.1 per 100,000 for the European ancestry group and 4.9 for the African ancestry group, after taking into account the different oophorectomy rates and prevalence of non-genetic risk factors. These incidence rates show the unexplained difference in incidence rates between NHWs and AAs is only 3.9%. Future efforts should focus on incorporating novel non-genetic and genetic factors into this analysis to determine whether essentially all of the difference in incidence between these groups can be explained.
Patterns of Multivitamin Use after Colorectal Cancer Diagnosis in Association with Long-term Survival
Authors: Kocarnik JM , Hua X , Lindor N , Gallinger S , Casey G , Jenkins M , Hardikar S , Robinson J , Newcomb PA
Published: March 2017

Multivitamin use has been related to a modest reduced risk of colorectal cancer (CRC), but evidence on its use after diagnosis in relation to survival has been limited. Incident, invasive CRC cases were identified through cancer registries from 1997–2008 and enrolled in four population-based sites of the Colon Cancer Family Registry (Fred Hutchinson Cancer Research Center, Cancer Care Ontario, Mayo Clinic, and the Universities of Queensland and Melbourne). At enrollment, a standardized interview ascertained multivitamin use in the year prior to diagnosis. A follow-up questionnaire was administered approximately 5 years after baseline, with 2,586 participants providing information on their multivitamin use at both time points. Survival outcomes were identified through linkage to national death registries. Delayed-entry Cox regression was used to estimate the association between patterns of multivitamin use and overall or CRC-specific survival (Hazard Ratio (HR) and 95% Confidence Interval (CI)), with survival time beginning at the 5-year follow-up survey. Models were adjusted for age at diagnosis, sex, body mass index, smoking history, stage, study center, and number of days from diagnosis to baseline survey. Over a median 4.8 years after the follow-up survey, 397 participants died (103 from CRC). Multivitamin use was common: at the 5-year follow-up, 37% reported continued use since before diagnosis, 12% had initiated use, 17% had discontinued use, and only 34% participants reported never using multivitamins. Compared to never use of multivitamins, continued use was significantly associated with increased subsequent overall survival (HR = 0.71, 95% CI: 0.55–0.91). However, this association did not reach statistical significance for CRC-specific survival (HR = 0.76, 95% CI: 0.47–1.24). No significant association was observed for discontinuing (HR = 0.92, 95% CI: 0.68–1.25) or initiating (HR = 0.80, 95% CI: 0.55–1.13) multivitamin use from baseline to follow-up, compared to never users, though initiating use trended towards increased survival. These findings suggest that continuing multivitamin use after a CRC diagnosis may increase survival; replication and details on the specific micronutrients included are needed.
Pilot-Testing a Survivorship Needs Assessment Planning Tool for Head and Neck Cancer Survivors and Caregivers
Authors: Sterba KR , Zapka J , Armeson K , Garris TK , Scallion M , Day TD
Published: March 2017

The purpose of this study was to develop and pilot-test a tablet-based survivorship needs assessment planning (SNAP) tool to assess head and neck cancer (HNC) survivor and caregiver needs after treatment and generate tailored care plans. We recruited survivors completing treatment <24 months ago, and their caregivers. Participants completed baseline surveys, a clinic session with SNAP assessments (symptoms, unmet needs, behaviors) and care plan delivery, and 6-week follow-up surveys. We tracked intervention delivery/acceptability and used paired t-tests to explore changes in psychosocial factors over time. We enrolled 25 survivors (65% male, mean age = 63, 65% stage IVA) and their caregivers (73% female, mean age = 56, 77% partners). The average time to complete SNAP assessments was 11 and 6 minutes for survivors and caregivers, respectively. Algorithm-driven care plans included messages (mean = 19), educational materials (mean = 13) and referrals (mean = 4.5). Top referrals included Behavioral Medicine, Nutrition and Physical Therapy (84, 77 and 65% flagged, respectively). In those declining referrals, main reasons included being overwhelmed, seeing local provider or lacking interest. Participants rated SNAP favorably with >80% reporting high comfort using tablets and navigating questions. Dyads strongly agreed that care plans were helpful emotionally (>75%) and provided practical information (>73%). After the session, both survivors and caregivers reported significantly fewer unmet needs (7.7 versus 2.9, P = 0.001 survivors; 7.0 versus 4.1, P = 0.02, caregivers) and higher survivorship preparedness (4.9 versus 5.2 in both, P = 0.02 and P = 0.03). While depression, symptom distress and symptom management abilities were stable in survivors, caregivers had significantly lower depression (P = 0.01) and symptom distress (P = 0.03), and higher ratings of perceived patient symptom management abilities (P = 0.004) at follow-up. Open-ended responses highlighted that SNAP visits helped pull together complex medical information and made families feel supported. Participants desired more information about cancer stage and caregivers preferred earlier intervention. Results support the feasibility of implementing SNAP in the HNC clinic and highlighted needed modifications for system improvement.
Using Global Metabolomics to Identify Novel Biomarkers of Treatment-Associated Cognitive Impairment in Pediatric Acute Lymphoblastic Leukemia
Authors: Brown AL , Rodgers CC , Taylor OA , Moore IM , Hooke MC , Pan W , Hockenberry MJ , Scheurer ME , Lupo PJ
Published: March 2017

Central nervous system-directed chemotherapy is a critical component of pediatric acute lymphoblastic leukemia (ALL) treatment, but is associated with long-term cognitive impairment. Because few strategies exist to identify children who are at risk for this adverse outcome, we employed global metabolomics to identify biomarkers of cognitive impairment using routinely collected, biologically relevant cerebrospinal fluid (CSF) samples from patients undergoing ALL chemotherapy. Methods: CSF samples were collected at 4 months post-induction on pediatric ALL patients enrolled in a multicenter prospective study of symptom toxicity. Metabolomics of CSF detected 314 metabolites by gas chromatography-mass spectrometry (MS) and liquid chromatography-MS/MS. Cognitive performance at 12 months post-induction was assessed with the validated Parent-Perceived Child Cognitive Function scale and categorized using published cut-points: mild (≥50), moderate (41–49), and severe (≤40). Ordinal logistic regression evaluated associations between normalized median-scaled metabolite values and cognitive function, adjusting for patient and treatment factors. A false discovery rate-corrected p-value (q) was calculated to account for multiple comparisons. Results: Among the 96 patients (diagnosed 2012–14), 43% exhibited moderate (n = 25) or severe (n = 16) cognitive impairment. Significant alterations were observed in several biomarkers, including methionine sulfoxide (Log2 Fold Change [FC] = 0.83, P = 5.2e−7, q = 0.001) and citramalate (FC = −0.29, P = 4.6e−5, q = 0.008). A pathway analysis of the top biomarkers (q < 0.3) revealed an enrichment of metabolites involved in methionine (P = 0.0015) and carnitine (P = 0.0052) metabolism. Finally, compared to clinical factors alone, CSF biomarkers significantly improved the ability to predict cognitively impaired patients (area under curve [AUC] = 0.68 vs. AUC = 0.91, P < 0.001). Conclusion: We identified several novel CSF biomarkers of treatment-related cognitive impairment among pediatric ALL patients. These findings may translate to clinical improvements in the management of cognitive outcomes by introducing the opportunity to deliver targeted interventions to high-risk patients prior to detectable or irreversible cognitive impairment.