bluuebunny/crossref_metadata_2025 huggingface dataset:
A weighty problem
Authors: Stanley Sarah A.
Published: January 2017

Altered dopamine signaling in obesity might decrease physical activity without contributing to weight gain.
Making Home Sweet and Sturdy:Toxoplasma gondiippGalNAc-Ts Glycosylate in Hierarchical Order and Confer Cyst Wall Rigidity
Authors: Tomita Tadakimi , Sugi Tatsuki , Yakubu Rama , Tu Vincent , Ma Yanfen , Weiss Louis M.
Published: January 2017

The protozoan intracellular parasiteToxoplasma gondiiforms latent cysts in the central nervous system (CNS) and persists for the lifetime of the host. This cyst is cloaked with a glycosylated structure called the cyst wall. Previously, we demonstrated that a mucin-like glycoprotein, CST1, localizes to the cyst wall and confers structural rigidity on brain cysts in a mucin-like domain-dependent manner. The mucin-like domain of CST1 is composed of 20 units of threonine-rich tandem repeats that areO-GalNAc glycosylated. A family of enzymes termed polypeptideN-acetylgalactosaminyltransferases (ppGalNAc-Ts) initiatesO-GalNAc glycosylation. To identify which isoforms of ppGalNAc-Ts are responsible for the glycosylation of the CST1 mucin-like domain and to evaluate the function of each ppGalNAc-T in the overall glycosylation of the cyst wall, all five ppGalNAc-T isoforms were deleted individually from theT. gondiigenome. The ppGalNAc-T2 and -T3 deletion mutants produced various glycosylation defects on the cyst wall, implying that many cyst wall glycoproteins are glycosylated by T2 and T3. Both T2 and T3 glycosylate the CST1 mucin-like domain, and this glycosylation is necessary for CST1 to confer structural rigidity on the cyst wall. We established that T2 is required for the initial glycosylation of the mucin-like domain and that T3 is responsible for the sequential glycosylation on neighboring acceptor sites, demonstrating hierarchical glycosylation by two distinct initiating and filling-in ppGalNAc-Ts in an intact organism.

IMPORTANCEToxoplasma gondiiis an obligate intracellular parasite that infects a third of the world’s population. It can cause severe congenital disease and devastating encephalitis in immunocompromised individuals. We identified two glycosyltransferases, ppGalNAc-T2 and -T3, which are responsible for glycosylating cyst wall proteins in a hierarchical fashion. This glycosylation confers structural rigidity on the brain cyst. Our studies provide new insights into the mechanisms ofO-GalNAc glycosylation inT. gondii.
Primary sarcomatoid carcinoma of the small intestine: very rare and aggressive tumour
Authors: Andrawes Peter Abotaga , Shariff Masood , Chang Qing , Grinberg Roman
Published: January 2017

Sarcomatoid carcinoma of the small intestine is a very rare and aggressive variant of small intestinal cancers with poor prognosis. The tumour primarily affects middle-aged and older patients with a mean age of 57 years at the time of presentation. We report a woman aged 58 years without any relevant medical history who presented with small intestinal obstruction. She underwent radiologic and endoscopy investigation with persistent features of small bowel obstruction. The patient was found to have a small bowel tumour causing the obstruction and underwent surgical excision of the tumour. Pathology revealed malignant neoplasm with sarcomatoid and epithelioid features involving the terminal ileum. The use of immunohistochemical markers helps in wide range of differential diagnoses. Surgical resection is still considered the best and first-line therapy with poor response to chemotherapy and radiotherapy.
Republished: Intercostal artery pseudoaneurysm with spontaneous resolution in the setting of an artery of Adamkiewicz
Authors: Agarwal Aanchal , Weerakkody Yuranga , Marshall Martin , Singh Tejinder
Published: January 2017

We report an extremely unique and previously unreported case of a pseudoaneurysm arising from an intercostal artery that also gave origin to the artery of Adamkiewicz. Due to the potential risk of losing the artery of Adamkiewicz, a conservative approach was indicated. On short interval follow-up imaging, the pseudoaneurysm and associated hematoma spontaneously resolved with preservation of the intercostal artery. We performed a literature review of the natural course of pseudoaneurysm as well as their occurrence in the intercostal arteries.
Delayed enhancing lesions after coil embolization of aneurysms: clinical experience and benchtop analyses
Authors: Oh Se Won , Shin Na Young , Lee Ho-Joon , Kim Byung Moon , Kim Dong Joon
Published: January 2017

Background

Foreign body emboli during endovascular treatment (EVT) may cause delayed enhancing lesions (DELs).

Objective

To report our experiences of this complication in patients treated for cerebral aneurysms and to investigate the cause of the lesions by benchtop analyses.

Methods

Three patients with DELs on MRI after EVT were retrospectively investigated. Unusual friction had occurred in the midst of coil delivery in two patients. The imaging findings, cause of the lesions due to the devices used for the procedure, treatment, and follow-up results were assessed. Two benchtop analyses were performed. First, a microcatheter that showed similar unusual friction during coiling was retrieved and dissected at the point of friction. Second, the EVT procedure was simulated with multiple coil advancement and withdrawal maneuvers within an acutely angulated microcatheter to identify downstream foreign body material emboli.

Results

The DELs were identified 27–37 days (mean 32.7) after the procedure. The patients presented with left arm weakness, headache, and no other symptoms. The lesions were located in the hemisphere corresponding to the treatment. The symptoms subsided after conservative therapy. The dissected microcatheter showed whitish semitransparent material adherent to the inner lumen. Similar material was sieved after multiple coil advancement and withdrawal maneuvers.

Conclusions

DELs may be caused by fragmentation and emboli of the inner coating wall of the microcatheter. Development of unusual friction during coil delivery may be a sign of damage of the microcatheter inner wall and the device should be discarded.
Does capture method or the presence of aquatic protected areas influence the selective harvest of behavioural types in largemouth bass?
Authors: Cooke Emma L.L. , Wilson Alexander D.M. , Elvidge Chris K. , Cooke Steven J.
Published: January 2017

Selectively removing fish based on particular traits, such as body size, may shift trait abundance in the remaining population, resulting in a phenomenon called fisheries-induced evolution. Recently, there is growing interest in evaluating the effects of fisheries-induced evolution on fish behaviour. Aquatic protected areas (APAs) have been designated in some habitats in efforts to prohibit harvesting and maintain natural ranges of phenotypic variation for impacted species. Here, we attempted to test whether APAs that prohibit all forms of fishing have an evolutionary influence on adult largemouth bass (Micropterus salmoides) behaviour by investigating the relationship between capture method and behavioural type. Fish, caught via active (angling) and passive (hoop net) capture techniques in both protected (70+ year old APAs in eastern Ontario) and adjacent nonprotected areas, were subjected to standard tests of boldness (refuge emergence, general activity, and flight-initiation-distance). A behavioural syndrome characterized by consistent within-individual variation and correlation of boldness behaviours (activity and refuge emergence) was present. Our results provide evidence that APAs may promote behavioural diversification and protect traits selectively targeted by recreational angling.
Ecological factors influencing lifetime productivity of pink salmon (Oncorhynchus gorbuscha) in an Alaskan stream
Authors: Manhard Christopher V. , Joyce John E. , Smoker William W. , Gharrett Anthony J.
Published: January 2017

Ecological factors underlying freshwater productivity and marine survival of pink salmon (Oncorhynchus gorbuscha) were evaluated by analyzing a 30 year time series of local environmental data and censuses of migrating adult and juvenile fish collected at Auke Creek, Alaska. Freshwater productivity was influenced primarily by spawning habitat limitation and less so by stream temperature and flow. Furthermore, a trend of declining freshwater productivity was detected over the time series, which may be related to observed declines in spawning substrate quality and in the duration of the adult migration. Marine survival was highly variable among brood years and was influenced by physical conditions in the nearshore marine environment; warm sea-surface temperatures during nearshore residency were associated with higher marine survival rates, whereas high stream flows late in the fry emigration period were associated with reduced marine survival. Simulations of adult recruitment, based on ecological factors in the freshwater and marine environments, indicated that the productivity of pink salmon in this stream is determined primarily by early marine survival.
Aptamers as Therapeutics
Authors: Nimjee Shahid M. , White Rebekah R. , Becker Richard C. , Sullenger Bruce A.
Published: January 2017

Aptamers are single-stranded nucleic acid molecules that bind to and inhibit proteins and are commonly produced by systematic evolution of ligands by exponential enrichment (SELEX). Aptamers undergo extensive pharmacological revision, which alters affinity, specificity, and therapeutic half-life, tailoring each drug for a specific clinical need. The first therapeutic aptamer was described 25 years ago. Thus far, one aptamer has been approved for clinical use, and numerous others are in preclinical or clinical development. This review presents a short history of aptamers and SELEX, describes their pharmacological development and optimization, and reviews potential treatment of diseases including visual disorders, thrombosis, and cancer.
New Targets for Drug Treatment of Obesity
Authors: Valsamakis Georgios , Konstantakou Panagiota , Mastorakos George
Published: January 2017

Antiobesity medical management has shown unsatisfactory results to date in terms of efficacy, safety, and long-term maintenance of weight loss. This poor performance could be attributed to the complexity of appetite regulation mechanisms; the serious drug side effects; and, crucially, the lack of profile-matching treatment strategies and individualized, multidisciplinary follow-up. Nevertheless, antiobesity pharmacotherapy remains a challenging, exciting field of intensive scientific interest. According to the latest studies, the future of bariatric medicine lies in developing drugs acting at multiple levels of the brain-gut axis. Currently, research is focused on the generation of combination treatments based on gut hormones in a way that mimics changes underlying surgically induced weight loss, in addition to centrally acting agents; these aim to restore energy balance disruptions and enhance energy expenditure. Collectively, the pharmacological resolution of obesity could potentially be achieved with combination regimens targeting different molecules and levels of the energy homeostasis system, in parallel with matching patients' needs, resulting in a favorable metabolic profile.
Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics
Authors: Dawson Ted M. , Dawson Valina L.
Published: January 2017

Mitochondria lie at the crossroads of neuronal survival and cell death. They play important roles in cellular bioenergetics, control intracellular Ca2+ homeostasis, and participate in key metabolic pathways. Mutations in genes involved in mitochondrial quality control cause a myriad of neurodegenerative diseases. Mitochondria have evolved strategies to kill cells when they are not able to continue their vital functions. This review provides an overview of the role of mitochondria in neurologic disease and the cell death pathways that are mediated through mitochondria, including their role in accidental cell death, the regulated cell death pathways of apoptosis and parthanatos, and programmed cell death. It details the current state of parthanatic cell death and discusses potential therapeutic strategies targeting initiators and effectors of mitochondrial-mediated cell death in neurologic disorders.
A Modified Nonlinear Conjugate Gradient Method for Engineering Computation
Authors: Zhu Tiefeng , Yan Zaizai , Peng Xiuyun
Published: January 2017

A general criterion for the global convergence of the nonlinear conjugate gradient method is established, based on which the global convergence of a new modified three‐parameter nonlinear conjugate gradient method is proved under some mild conditions. A large amount of numerical experiments is executed and reported, which show that the proposed method is competitive and alternative. Finally, one engineering example has been analyzed for illustrative purposes.
Cloud Service Scheduling Algorithm Research and Optimization
Authors: Cui Hongyan , Liu Xiaofei , Yu Tao , Zhang Honggang , Fang Yajun , Xia Zongguo
Published: January 2017

We propose a cloud service scheduling model that is referred to as the Task Scheduling System (TSS). In the user module, the process time of each task is in accordance with a general distribution. In the task scheduling module, we take a weighted sum of makespan and flowtime as the objective function and use an Ant Colony Optimization (ACO) and a Genetic Algorithm (GA) to solve the problem of cloud task scheduling. Simulation results show that the convergence speed and output performance of our Genetic Algorithm-Chaos Ant Colony Optimization (GA-CACO) are optimal.
Comparison ofT-Square, Point Centered Quarter, andN-Tree Sampling Methods inPittosporum undulatumInvaded Woodlands
Authors: Silva Lurdes Borges , Alves Mário , Elias Rui Bento , Silva Luís
Published: January 2017

Tree density is an important parameter affecting ecosystems functions and management decisions, while tree distribution patterns affect sampling design.Pittosporum undulatumstands in the Azores are being targeted with a biomass valorization program, for which efficient tree density estimators are required. We comparedT-Square sampling, Point Centered Quarter Method (PCQM), andN-tree sampling with benchmark quadrat (QD) sampling in six 900 m2plots established atP. undulatumstands in São Miguel Island. A total of 15 estimators were tested using a data resampling approach. The estimated density range (344–5056 trees/ha) was found to agree with previous studies using PCQM only. Although with a tendency to underestimate tree density (in comparison with QD), overall,T-Square sampling appeared to be the most accurate and precise method, followed by PCQM. Tree distribution pattern was found to be slightly aggregated in 4 of the 6 stands. Considering (1) the low level of bias and high precision, (2) the consistency among three estimators, (3) the possibility of use with aggregated patterns, and (4) the possibility of obtaining a larger number of independent tree parameter estimates, we recommend the use ofT-Square sampling inP. undulatumstands within the framework of a biomass valorization program.
Self-Reported Childhood Maltreatment and Traumatic Events among Israeli Patients Suffering from Fibromyalgia and Rheumatoid Arthritis
Authors: Hellou Raneen , Häuser Winfried , Brenner Inbal , Buskila Dan , Jacob Giris , Elkayam Ori , Aloush Valerie , Ablin Jacob N.
Published: January 2017

Objective. The association between Fibromyalgia Syndrome (FMS) and childhood maltreatment and adversity has frequently been proposed but limited data exists regarding the transcultural nature of this association. Methods. 75 Israeli FMS patients and 23 Rheumatoid Arthritis (RA) patients were compared. Childhood maltreatment was assessed by the Childhood Trauma Questionnaire (CTQ) and potential depressive and anxiety disorders were assessed by the Patient Health Questionnaire-4. FMS severity was assessed by the Widespread Pain Index (WPI), the Symptom Severity Score (SSS), and the FIQ. PTSD was diagnosed according to the DSM IV. RA severity was assessed by the RA Disease Activity Index. Health status was assessed by the SF-36. Results. Similar to reports in other countries, high levels of self-reported childhood adversity were reported by Israeli FMS patients. PTSD was significantly more common among FMS patients compared with RA patients, as well as childhood emotional abuse and physical and emotional neglect. Levels of depression and anxiety were significantly higher among FMS patients. Conclusion. The study demonstrated the cross cultural association between FMS and childhood maltreatment, including neglect, emotional abuse, and PTSD. Significant differences were demonstrated between FMS patients and patients suffering from RA, a model of an inflammatory chronic rheumatic disease.
Enhanced Efficiency of PTB7 : PC61BM Organic Solar Cells by Adding a Low Efficient Polymer Donor
Authors: Farinhas Joana , Oliveira Ricardo , Ferreira Quirina , Morgado Jorge , Charas Ana
Published: January 2017

Ternary blend polymer solar cells combining two electron-donor polymers, poly[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b′]dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl] (PTB7) and poly[2,5-bis(3-dodecylthiophen-2-yl)thieno[3,2-b]thiophene] (pBTTT) and [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM), as electron-acceptor, were fabricated. The power conversion efficiency of the ternary cells was enhanced by 18%, with respect to the reference binary cells, for a blend composition with 25% (wt%) of pBTTT in the polymers content. The optimized device performance was related to the blend morphology, nonrevealing pBTTT aggregates, and improved charge extraction within the device.
Coinfection withSchistosoma haematobiumandPlasmodium falciparumand Anaemia Severity among Pregnant Women in Munyenge, Mount Cameroon Area: A Cross-Sectional Study
Authors: Anchang-Kimbi Judith K. , Elad Dillys Mansoh , Sotoing Gemain Taiwe , Achidi Eric Akum
Published: January 2017

Background. Malaria and urogenital schistosomiasis are coendemic in Mount Cameroon Area. This study investigated the prevalence ofS. haematobium,P. falciparum,and coinfections and their effect on anaemia in pregnancy.Methods. Pregnant women reporting for antenatal care (ANC) clinic visit in Munyenge were enrolled.S. haematobiumandP. falciparuminfections were determined by urine filtration and microscopy, respectively. Haemoglobin (Hb) levels were measured using haemoglobinometer. Of 250 women, 46.8%, 39.2%, and 15.2% hadS. haematobium,P. falciparum,and coinfections, respectively. Schistosomes infection was higher in younger women (≤25 years) and those who bathe in and had domestic contact with stream compared with older age (>25 years) women and those who had only domestic contact with stream. Lower infection rate was associated with less water contact (≤2 times/day) compared with more water contact (>2 times/day). Compared with no sulphadoxine-pyrimethamine (SP) usage, malaria parasitaemia was less among women who used SP. Stream usage increased risk of coinfection while less water contact and SP usage decreased its risk. All coinfected cases were anaemic and coinfection accounted for 93.8% of severe anaemia.Conclusion. Coinfection contributes to anaemia severity. Less water contact and SP usage will reduce coinfection in pregnancy in Munyenge.
Unusual Presentation of Hydatid Cyst in Breast with Magnetic Resonance Imaging Findings
Authors: Koc Ali , Sarici Inanc Samil , Vurdem Umit Erkan , Karabiyik Ozgur , Gumus Ummugulsum Ozgul
Published: January 2017

We report a case of 59-year-old woman with a painful left breast mass, compatible with types II-III hydatid cyst. Lesion was evaluated with mammography, ultrasound, computed tomography, and magnetic resonance imaging modalities. Magnetic resonance imaging had important diagnostic role with demonstrating characteristic features of the lesion and had capability of showing complications. Surgery also confirmed the diagnosis of a hydatid cyst.
Quick Performance Assessment of Improved Nyquist Pulses
Authors: Alexandru Nicolae Dumitru , Diaconu Felix
Published: January 2017

An explanation is proposed for the improved behavior of the improved Nyquist pulses with an asymptotic decay rate of t-2 when sampled with a timing offset. Three figures of merit that indicate the energy distribution into the sidelobes of the time response and allow a quick assessment of their performance in terms of error probability when the impulse response is sampled with a timing error have been proposed and verified on several improved Nyquist pulses reported in the literature. In order to check the validity of the proposed figures of merit a novel family of Nyquist pulses denoted as power sine was introduced. Using the proposed approach the design process was expedited as the volume of necessary calculations was significantly decreased. To explain the difference in close pulse performance a figure of merit based on limited ISI distortion was introduced.
ELECTRE I Based Relevance Decision-Makers Feedback to the Location Selection of Distribution Centers
Authors: Agrebi Maroi , Abed Mourad , Omri Mohamed Nazih
Published: January 2017

The location selection of distribution centers is one of the important strategies to optimize the logistics system. To solve this problem, under certain environment, this paper presents a new multicriteria decision-making method based on ELECTRE I. The proposed method helps decision-makers to select the best location from a given set of locations for implementing. After having identified decision-makers, the criteria, and the set of locations, the factors influencing the selection are analyzed in order to identify the best location. A sensitivity analysis is then performed to determine the influence of criteria weights on the selection decision. The strength of the proposed method is to incorporate decision-makers’ preferences into the decision-making process. In addition, the proposed method considers both quantitative and qualitative criteria. Finally, the selected solution is validated by both tests of concordance and discordance simultaneously. A case study is provided to illustrate the proposed method.
Safety and Efficacy of Small Bowel Examination by Capsule Endoscopy for Patients before Liver Transplantation
Authors: Seiji Kawano , Akinobu Takaki , Masaya Iwamuro , Tetsuya Yasunaka , Yoshiyasu Kono , Kou Miura , Toshihiro Inokuchi , Yoshiro Kawahara , Yuzo Umeda , Takahito Yagi , Hiroyuki Okada
Published: January 2017

Background and Aims. Gastrointestinal surveillance is a requirement prior to liver transplantation (LT), but small intestine examination is not generally undertaken. The aim of the present study was to evaluate the safety and efficacy of capsule endoscopy (CE) for patients with end-stage liver disease.Methods. 31 patients who needed LT were enrolled, and 139 patients who underwent CE over the same period of time acted as controls.Results. Frequency of successful achievement of evaluation of the full length of the small bowel, the mean gastric transit time, and the mean small bowel transit time were not significantly different between the two groups. Abnormalities in the small bowel were found in 26 patients. Comparative analysis revealed that history of EV rupture, history of EV treatment, red color sign of EV, and presence of PHG or HCC were significantly associated with patients with >2 two such findings (high score group).Conclusions. Small bowel examination by CE in patients before liver transplantation could be performed safely and is justified by the high rate of abnormal lesions detected particularly in patients with history of EV therapy or bleeding, red color sign, and presence of PHG or HCC. This study was registered in the UMIN Clinical Trial Registry (UMIN000008672).
Mixed-Integer Linear Programming Models for Teaching Assistant Assignment and Extensions
Authors: Qu Xiaobo , Yi Wen , Wang Tingsong , Wang Shuaian , Xiao Lin , Liu Zhiyuan
Published: January 2017

In this paper, we develop mixed-integer linear programming models for assigning the most appropriate teaching assistants to the tutorials in a department. The objective is to maximize the number of tutorials that are taught by the most suitable teaching assistants, accounting for the fact that different teaching assistants have different capabilities and each teaching assistant’s teaching load cannot exceed a maximum value. Moreover, with optimization models, the teaching load allocation, a time-consuming process, does not need to be carried out in a manual manner. We have further presented a number of extensions that capture more practical considerations. Extensive numerical experiments show that the optimization models can be solved by an off-the-shelf solver and used by departments in universities.
Facial Expression Recognition Using Stationary Wavelet Transform Features
Authors: Qayyum Huma , Majid Muhammad , Anwar Syed Muhammad , Khan Bilal
Published: January 2017

Humans use facial expressions to convey personal feelings. Facial expressions need to be automatically recognized to design control and interactive applications. Feature extraction in an accurate manner is one of the key steps in automatic facial expression recognition system. Current frequency domain facial expression recognition systems have not fully utilized the facial elements and muscle movements for recognition. In this paper, stationary wavelet transform is used to extract features for facial expression recognition due to its good localization characteristics, in both spectral and spatial domains. More specifically a combination of horizontal and vertical subbands of stationary wavelet transform is used as these subbands contain muscle movement information for majority of the facial expressions. Feature dimensionality is further reduced by applying discrete cosine transform on these subbands. The selected features are then passed into feed forward neural network that is trained through back propagation algorithm. An average recognition rate of 98.83% and 96.61% is achieved for JAFFE and CK+ dataset, respectively. An accuracy of 94.28% is achieved for MS‐Kinect dataset that is locally recorded. It has been observed that the proposed technique is very promising for facial expression recognition when compared to other state‐of‐the‐art techniques.
Perineural Invasion and Risk of Lethal Prostate Cancer
Authors: Zareba Piotr , Flavin Richard , Isikbay Masis , Rider Jennifer R. , Gerke Travis A. , Finn Stephen , Pettersson Andreas , Giunchi Francesca , Unger Robert H. , Tinianow Alex M. , Andersson Swen-Olof , Andrén Ove , Fall Katja , Fiorentino Michelangelo , Mucci Lorelei A.
Published: January 2017

Background: Prostate cancer has a propensity to invade and grow along nerves, a phenomenon called perineural invasion (PNI). Recent studies suggest that the presence of PNI in prostate cancer has been associated with cancer aggressiveness.

Methods: We investigated the association between PNI and lethal prostate cancer in untreated and treated prostate cancer cohorts: the Swedish Watchful Waiting Cohort of 615 men who underwent watchful waiting, and the U.S. Health Professionals Follow-Up Study of 849 men treated with radical prostatectomy. One pathologist performed a standardized histopathologic review assessing PNI and Gleason grade. Patients were followed from diagnosis until metastasis or death.

Results: The prevalence of PNI was 7% and 44% in the untreated and treated cohorts, respectively. PNI was more common in high Gleason grade tumors in both cohorts. PNI was associated with enhanced tumor angiogenesis, but not tumor proliferation or apoptosis. In the Swedish study, PNI was associated with lethal prostate cancer [OR 7.4; 95% confidence interval (CI), 3.6–16.6; P < 0.001]. A positive, although not statistically significant, association persisted after adjustment for age, Gleason grade, and tumor volume (OR 1.9; 95% CI, 0.8–5.1; P = 0.17). In the U.S. study, PNI predicted lethal prostate cancer independent of clinical factors (HR 1.8; 95% CI, 1.0, 3.3; P =0.04).

Conclusions: These data support the hypothesis that perineural invasion creates a microenvironment that promotes cancer aggressiveness.

Impact: Our findings suggest that PNI should be a standardized component of histopathologic review, and highlights a mechanism underlying prostate cancer metastasis. Cancer Epidemiol Biomarkers Prev; 26(5); 719–26. ©2017 AACR.
FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma
Authors: Beaver Julia A. , Theoret Marc R. , Mushti Sirisha , He Kun , Libeg Meredith , Goldberg Kirsten , Sridhara Rajeshwari , McKee Amy E. , Keegan Patricia , Pazdur Richard
Published: January 2017

On November 23, 2015, the FDA approved nivolumab (OPDIVO; Bristol-Myers Squibb) as a single agent for the first-line treatment of patients with BRAFV600 wild-type, unresectable or metastatic melanoma. An international, double-blind, randomized (1:1) trial conducted outside of the United States allocated 418 patients to receive nivolumab 3 mg/kg intravenously every 2 weeks (n = 210) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 208). Patients with disease progression who met protocol-specified criteria (∼25% of each trial arm) were permitted to continue with the assigned treatment in a blinded fashion until further disease progression is documented. Overall survival was statistically significantly improved in the nivolumab arm compared with the dacarbazine arm [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.30–0.60; P < 0.0001]. Progression-free survival was also statistically significantly improved in the nivolumab arm (HR, 0.43; 95% CI, 0.34–0.56; P < 0.0001). The most common adverse reactions (≥20%) of nivolumab were fatigue, diarrhea, constipation, nausea, musculoskeletal pain, rash, and pruritus. Nivolumab demonstrated a favorable benefit–risk profile compared with dacarbazine, supporting regular approval; however, it remains unclear whether treatment beyond disease progression contributes to the overall clinical benefit of nivolumab. Clin Cancer Res; 23(14); 3479–83. ©2017 AACR.
Extended Treatment with Single-Agent Ibrutinib at the 420 mg Dose Leads to Durable Responses in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Authors: Coutré Steven E. , Furman Richard R. , Flinn Ian W. , Burger Jan A. , Blum Kristie , Sharman Jeff , Jones Jeffrey , Wierda William , Zhao Weiqiang , Heerema Nyla A. , Johnson Amy J. , Tran Anh , Zhou Cathy , Bilotti Elizabeth , James Danelle F. , Byrd John C. , O'Brien Susan
Published: January 2017

Purpose: Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naïve (TN) or had relapsed/refractory (R/R) CLL after ≥1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL.

Experimental Design: We report data with 44 months of follow-up on 94 patients with TN and R/R CLL/SLL receiving ibrutinib 420 mg once-daily in PCYC-1102 and the long-term extension study PCYC-1103.

Results: Ninety-four CLL/SLL patients (27 TN, 67 R/R) were treated with ibrutinib (420 mg/day). Patients with R/R disease had received a median of four prior therapies (range, 1–12). Responses were rapid and durable and median duration of response was not reached. Best overall response was 91% [85% TN (complete response, CR 26%) and 94% R/R (9% CR)]. Median progression-free survival (PFS) was not reached in either group. The 30-month PFS rate was 96% and 76% for TN and R/R patients, respectively. Ibrutinib was well tolerated with extended follow-up; rates of grade ≥3 cytopenias and fatigue, as well as discontinuations due to toxicities decreased over time.

Conclusions: Single-agent ibrutinib at 420 mg once-daily resulted in durable responses and was well tolerated with up to 44 months follow-up in patients with TN and R/R CLL/SLL. Currently, 66% of patients continue on ibrutinib. Clin Cancer Res; 23(5); 1149–55. ©2017 AACR.
Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens
Authors: Andersen Courtney L. , Sikora Matthew J. , Boisen Michelle M. , Ma Tianzhou , Christie Alec , Tseng George , Park Yongseok , Luthra Soumya , Chandran Uma , Haluska Paul , Mantia-Smaldone Gina M. , Odunsi Kunle , McLean Karen , Lee Adrian V. , Elishaev Esther , Edwards Robert P. , Oesterreich Steffi
Published: January 2017

Purpose: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha (ERα) in approximately 80% of HGSOC and some small but promising clinical trials of endocrine therapy, ERα has been understudied as a target in this disease. We sought to identify hormone-responsive, ERα-dependent HGSOC.

Experimental Design: We characterized endocrine response in HGSOC cells across culture conditions [ two-dimensional (2D), three-dimensional (3D), forced suspension] and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression. Estrogen-regulated transcriptome data were overlapped with public datasets to develop a comprehensive panel of ERα target genes. Expression of this panel and ERα H-score were assessed in HGSOC samples from patients who received endocrine therapy. Time on endocrine therapy was used as a surrogate for clinical response.

Results: Proliferation is ERα-regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ERα targets. The selective ERα downregulator (SERD) fulvestrant is more effective than tamoxifen in blocking ERα action. ERα H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3.

Conclusions: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ERα and endocrine responsiveness. Assessing ERα function (e.g., IGFBP3 expression) in conjunction with H-score may help select patients who would benefit from endocrine therapy. Preclinical data suggest that SERDs might be more effective than tamoxifen. Clin Cancer Res; 23(14); 3802–12. ©2017 AACR.
Long-term Survival and Clinical Benefit from Adoptive T-cell Transfer in Stage IV Melanoma Patients Is Determined by a Four-Parameter Tumor Immune Signature
Authors: Melief Sara M. , Visconti Valeria V. , Visser Marten , van Diepen Merel , Kapiteijn Ellen H.W. , van den Berg Joost H. , Haanen John B.A.G. , Smit Vincent T.H.B.M. , Oosting Jan , van der Burg Sjoerd H. , Verdegaal Els M.E.
Published: January 2017

The presence of tumor-infiltrating immune cells is associated with longer survival and a better response to immunotherapy in early-stage melanoma, but a comprehensive study of the in situ immune microenvironment in stage IV melanoma has not been performed. We investigated the combined influence of a series of immune factors on survival and response to adoptive cell transfer (ACT) in stage IV melanoma patients. Metastases of 73 stage IV melanoma patients, 17 of which were treated with ACT, were studied with respect to the number and functional phenotype of lymphocytes and myeloid cells as well as for expression of galectins-1, -3, and -9. Single factors associated with better survival were identified using Kaplan–Meier curves and multivariate Cox regression analyses, and those factors were used for interaction analyses. The results were validated using The Cancer Genome Atlas database. We identified four parameters that were associated with a better survival: CD8+ T cells, galectin-9+ dendritic cells (DC)/DC-like macrophages, a high M1/M2 macrophage ratio, and the expression of galectin-3 by tumor cells. The presence of at least three of these parameters formed an independent positive prognostic factor for long-term survival. Patients displaying this four-parameter signature were found exclusively among patients responding to ACT and were the ones with sustained clinical benefit. Cancer Immunol Res; 5(2); 170–9. ©2017 AACR.
Computational Prediction of the Global Functional Genomic Landscape: Applications, Methods, and Challenges
Authors: Zhou Weiqiang , Sherwood Ben , Ji Hongkai
Published: January 2017

Technological advances have led to an explosive growth of high-throughput functional genomic data. Exploiting the correlation among different data types, it is possible to predict one functional genomic data type from other data types. Prediction tools are valuable in understanding the relationship among different functional genomic signals. They also provide a cost-efficient solution to inferring the unknown functional genomic profiles when experimental data are unavailable due to resource or technological constraints. The predicted data may be used for generating hypotheses, prioritizing targets, interpreting disease variants, facilitating data integration, quality control, and many other purposes. This article reviews various applications of prediction methods in functional genomics, discusses analytical challenges, and highlights some common and effective strategies used to develop prediction methods for functional genomic data.
Potential Applications of Smart Multifunctional Wearable Materials to Gerontology
Authors: Armstrong David G. , Najafi Bijan , Shahinpoor Mohsen
Published: January 2017

Smart multifunctional materials can play a constructive role in addressing some very important aging-related issues. Aging affects the ability of older adults to continue to live safely and economically in their own residences for as long as possible. Thus, there will be a greater need for preventive, acute, rehabilitative, and long-term health care services for older adults as well as a need for tools to enable them to function independently during daily activities. The objective of this paper is, thus, to present a comprehensive review of some potential smart materials and their areas of applications to gerontology. Thus, brief descriptions of various currently available multifunctional smart materials and their possible applications to aging-related problems are presented. It is concluded that some of the most important applications to geriatrics may be in various sensing scenarios to collect health-related feedback or information and provide personalized care. Further described are the applications of wearable technologies to aging-related needs, including devices for home rehabilitation, remote monitoring, social well-being, frailty monitoring, monitoring of diabetes and wound healing and fall detection or prediction. It is also concluded that wearable technologies, when combined with an appropriate application and with appropriate feedback, may help improve activities and functions of older patients with chronic diseases. Finally, it is noted that methods developed to measure what one collectively manages in this population may provide a foundation to establish new definitions of quality of life.
Intracardiac Pressures Measured Using an Implantable Hemodynamic Monitor
Authors: Zile Michael R. , Bennett Tom D. , El Hajj Stephanie , Kueffer Fred J. , Baicu Catalin F. , Abraham William T. , Bourge Robert C. , Warner Stevenson Lynne
Published: January 2017

Background—

The purpose of this analysis was to examine whether implantable hemodynamic monitor–derived baseline estimated pulmonary artery diastolic pressure (ePAD) and change from baseline ePAD were independent predictors of all-cause mortality in patients with chronic heart failure.

Methods and Results—

Retrospective analysis used data from 3 studies (n=790 patients; 216 deaths). Baseline ePAD was related to mortality using a multivariable model including baseline and demographic data. Changes in ePAD defined as change from baseline to 6 months and from baseline to 14 days before death or exit from study were related to subsequent mortality, and analysis was adjusted for baseline ePAD. Area under the pressure versus time curve during 180 days before death or exit from study was related to mortality. Baseline ePAD, independent of other covariates, was a significant predictor of mortality (hazard ratio=1.07; 95% confidence interval=1.05–1.09;
P
<0.0001). Change in ePAD was an independent predictor of mortality (hazard ratio=1.07; 95% confidence interval=1.05–1.100;
P
=0.0008). Increased ePAD of 3, 4, or 5 mm Hg from baseline to 6 months was associated with increased mortality risk of 23.8%, 32.9%, or 42.8%. Change in ePAD from baseline to 14 days before death or exit from study was higher in patients who died (3.0±8 versus 1.7±10 mm Hg;
P
=0.003). Area under the pressure versus time curve in the final 180 days before death or exit from study was higher in patients who died versus those alive at end of study (185±668 versus 17±482 mm Hg.days;
P
=0.006).

Conclusions—

Implantable hemodynamic monitor–derived baseline ePAD and change from baseline ePAD were independent predictors of mortality in chronic heart failure patients.
Heat Maps of Hypertension, Diabetes Mellitus, and Smoking in the Continental United States
Authors: Loop Matthew Shane , Howard George , de los Campos Gustavo , Al-Hamdan Mohammad Z. , Safford Monika M. , Levitan Emily B. , McClure Leslie A.
Published: January 2017

Background—

Geographic variations in cardiovascular mortality are substantial, but descriptions of geographic variations in major cardiovascular risk factors have relied on data aggregated to counties. Herein, we provide the first description of geographic variation in the prevalence of hypertension, diabetes mellitus, and smoking within and across US counties.

Methods and Results—

We conducted a cross-sectional analysis of baseline risk factor measurements and latitude/longitude of participant residence collected from 2003 to 2007 in the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Of the 30 239 participants, all risk factor measurements and location data were available for 28 887 (96%). The mean (±SD) age of these participants was 64.8(±9.4) years; 41% were black; 55% were female; 59% were hypertensive; 22% were diabetic; and 15% were current smokers. In logistic regression models stratified by race, the median(range) predicted prevalence of the risk factors were as follows: for hypertension, 49% (45%–58%) among whites and 72% (68%–78%) among blacks; for diabetes mellitus, 14% (10%–20%) among whites and 31% (28%–41%) among blacks; and for current smoking, 12% (7%–16%) among whites and 18% (11%–22%) among blacks. Hypertension was most prevalent in the central Southeast among whites, but in the west Southeast among blacks. Diabetes mellitus was most prevalent in the west and central Southeast among whites but in south Florida among blacks. Current smoking was most prevalent in the west Southeast and Midwest among whites and in the north among blacks.

Conclusions—

Geographic disparities in prevalent hypertension, diabetes mellitus, and smoking exist within states and within counties in the continental United States, and the patterns differ by race.
Impact of Beta‐Blocker Initiation Timing on Mortality Risk in Patients With Diabetes Mellitus Undergoing Noncardiac Surgery: A Nationwide Population‐Based Cohort Study
Authors: Chen Ray‐Jade , Chu Hsi , Tsai Lung‐Wen
Published: January 2017

Background

Relevant clinical studies have been small and have not convincingly demonstrated whether the perioperative initiation of beta‐blockers should be considered in patients with diabetes mellitus undergoing noncardiac surgery.

Methods and Results

In this nationwide propensity score–matched study, we included patients with diabetes mellitus undergoing noncardiac surgery between 2000 and 2011 from Taiwan's National Health Insurance Research Database. Patients were classified as beta‐blocker and non–beta‐blocker cohorts. We further stratified beta‐blocker users into cardioprotective beta‐blocker (atenolol, bisoprolol, metoprolol, or carvedilol) and other beta‐blocker users. To investigate time of initiation of beta‐blocker use, initiation time was stratified into 2 periods (>30 and ≤30 days preoperatively). The outcomes of interest were in‐hospital and 30‐day mortality. After propensity score matching, we identified 50 952 beta‐blocker users and 50 952 matched controls. Compared with non–beta‐blocker users, cardioprotective beta‐blocker users were associated with lower risks of in‐hospital (odds ratio 0.75, 95% CI 0.68–0.82) and 30‐day (odds ratio 0.75, 95% CI 0.70–0.81) mortality. Among initiation times, only the use of cardioprotective beta‐blockers for >30 days was associated with decreased risk of in‐hospital (odds ratio 0.72, 95% CI 0.65–0.78) and 30‐day (odds ratio 0.72, 95% CI 0.66–0.78) mortality. Of note, use of other beta‐blockers for ≤30 days before surgery was associated with increased risk of both in‐hospital and 30‐day mortality.

Conclusions

The use of cardioprotective beta‐blockers for >30 days before surgery was associated with reduced mortality risk, whereas short‐term use of beta‐blockers was not associated with differences in mortality in patients with diabetes mellitus.
Mean Dietary Salt Intake in Urban and Rural Areas in India: A Population Survey of 1395 Persons
Authors: Johnson Claire , Mohan Sailesh , Rogers Kris , Shivashankar Roopa , Thout Sudhir Raj , Gupta Priti , He Feng J. , MacGregor Graham A. , Webster Jacqui , Krishnan Anand , Maulik Pallab K. , Reddy K. Srinath , Prabhakaran Dorairaj , Neal Bruce
Published: January 2017

Background

The scientific evidence base in support of population‐wide salt reduction is strong, but current high‐quality data about salt intake levels in India are mostly absent. This project sought to estimate daily salt consumption levels in selected communities of Delhi and Haryana in north India and Andhra Pradesh in south India.

Methods and Results

In this study, 24‐hour urine samples were collected using an age‐ and sex‐stratified sampling strategy in rural, urban, and slum areas. Salt intake estimates were made for the overall population of each region and for major subgroups by weighting the survey data for the populations of Delhi and Haryana, and Andhra Pradesh. Complete 24‐hour urine samples were available for 637 participants from Delhi and Haryana and 758 from Andhra Pradesh (65% and 68% response rates, respectively). Weighted mean population 24‐hour urine excretion of salt was 8.59 g/day (95%
CI
7.68–9.51) in Delhi and Haryana and 9.46 g/day (95%
CI
9.06–9.85) in Andhra Pradesh (
P
=0.097). Estimates inflated to account for the minimum likely nonurinary losses of sodium provided corresponding estimates of daily salt intake of 9.45 g/day (95%
CI
8.45–10.46) and 10.41 g/day (95%
CI
9.97–10.84), respectively.

Conclusions

Salt consumption in India is high, with mean population intake well above the World Health Organization recommended maximum of 5 g/day. A national salt reduction program would likely avert much premature death and disability.