bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Imaging of Deoxycytidine Kinase Activity Using Deoxycytidine-Enhanced CEST MRI
Authors: Han Zheng , Li Yuguo , Zhang Jia , Liu Jing , Chen Chuheng , van Zijl Peter C. , Liu Guanshu 
Published: April 2019

Abstract

Deoxycytidine kinase (DCK) is a key enzyme for the activation of a broad spectrum of nucleoside-based chemotherapy drugs (e.g., gemcitabine); low DCK activity is one of the most important causes of cancer drug-resistance. Noninvasive imaging methods that can quantify DCK activity are invaluable for assessing tumor resistance and predicting treatment efficacy. Here we developed a “natural” MRI approach to detect DCK activity using its natural substrate deoxycytidine (dC) as the imaging probe, which can be detected directly by chemical exchange saturation transfer (CEST) MRI without any synthetic labeling. CEST MRI contrast of dC and its phosphorylated form, dCTP, successfully discriminated DCK activity in two mouse leukemia cell lines with different DCK expression. This dC-enhanced CEST MRI in xenograft leukemic cancer mouse models demonstrated that DCK(+) tumors have a distinctive dynamic CEST contrast enhancement and a significantly higher CEST contrast than DCK(−) tumors (AUC0–60 min = 0.47 ± 0.25 and 0.20 ± 0.13, respectively; P = 0.026, paired Student t test, n = 4) at 1 hour after the injection of dC. dC-enhanced CEST contrast also correlated well with tumor responses to gemcitabine treatment. This study demonstrates a novel MR molecular imaging approach for predicting cancer resistance using natural, nonradioactive, nonmetallic, and clinically available agents. This method has great potential for pursuing personalized chemotherapy by stratifying patients with different DCK activity.

Significance:
A new molecular MRI method that detects deoxycytidine kinase activity using its natural substrate deoxycytidine has great translational potential for clinical assessment of tumor resistance and prediction of treatment efficacy.
Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer
Authors: Seo Yongwoo David , Jiang Xiuyun , Sullivan Kevin M. , Jalikis Florencia G. , Smythe Kimberly S. , Abbasi Arezou , Vignali Marissa , Park James O. , Daniel Sara K. , Pollack Seth M. , Kim Teresa S. , Yeung Raymond , Crispe Ian Nicholas , Pierce Robert H. , Robins Harlan , Pillarisetty Venu G. 
Published: April 2019

AbstractPurpose:Pancreatic ductal adenocarcinoma (PDA) is rarely cured, and single-agent immune checkpoint inhibition has not demonstrated clinical benefit despite the presence of large numbers of CD8+ T cells. We hypothesized that tumor-infiltrating CD8+ T cells harbor latent antitumor activity that can be reactivated using combination immunotherapy.Experimental Design:Preserved human PDA specimens were analyzed using multiplex IHC (mIHC) and T-cell receptor (TCR) sequencing. Fresh tumor was treated in organotypic slice culture to test the effects of combination PD-1 and CXCR4 blockade. Slices were analyzed using IHC, flow cytometry, and live fluorescent microscopy to assess tumor kill, in addition to T-cell expansion and mobilization.Results:mIHC demonstrated fewer CD8+ T cells in juxtatumoral stroma containing carcinoma cells than in stroma devoid of them. Using TCR sequencing, we found clonal expansion in each tumor; high-frequency clones had multiple DNA rearrangements coding for the same amino acid binding sequence, which suggests response to common tumor antigens. Treatment of fresh human PDA slices with combination PD-1 and CXCR4 blockade led to increased tumor cell death concomitant with lymphocyte expansion. Live microscopy after combination therapy demonstrated CD8+ T-cell migration into the juxtatumoral compartment and rapid increase in tumor cell apoptosis.Conclusions:Endogenous tumor-reactive T cells are present within the human PDA tumor microenvironment and can be reactivated by combined blockade of PD-1 and CXCR4. This provides a new basis for the rational selection of combination immunotherapy for PDA.See related commentary by Medina and Miller, p. 3747
Chemoprevention of Azoxymethane-induced Colon Carcinogenesis by Delta-Tocotrienol
Authors: Husain Kazim , Zhang Anying , Shivers Steve , Davis-Yadley Ashley , Coppola Domenico , Yang Chung S. , Malafa Mokenge P. 
Published: April 2019

Abstract
This study evaluated the preclinical activity of δ-tocotrienol (DT3), a bioactive form of vitamin E, in the inhibition of colorectal cancer growth and development in vitro and in vivo. DT3 is the most bioactive isomer of vitamin E in inhibiting growth of colorectal cancer cells. However, it had little effect on the proliferation of normal colon mucosal cells NCM460. In HCT-116 and SW-620 colorectal cancer cells, DT3 (50 μmol/L) significantly inhibited malignant transformation (P &lt; 0.02, P &lt; 0.001), cell migration (P &lt; 0.02, P &lt; 0.05), and invasion (P &lt; 0.05, P &lt; 0.01) compared with vehicle. DT3 inhibited markers for epithelial (E-cadherin) to mesenchymal (vimentin) transition, metastasis (matrix metalloproteinase 9), angiogenesis VEGF, inflammation (NF-κB), and Wnt signaling (β-catenin) compared with vehicle in colorectal cancer cells. DT3 induced apoptosis selectively in colorectal cancer cells (SW-620 cells, HCT-116 cells, and HT-29) without affecting the normal colon cells. In the azoxymethane-induced colorectal carcinogenesis model in rats, DT3 (200 mg/kg orally twice a day) for 20 weeks significantly inhibited colorectal polyps by 70% and colorectal cancer by almost 99% compared with the vehicle treatment group (P &lt; 0.02, P &lt; 0.001), and the cancer inhibition effect was more potent than sulindac (50%). Taken together, these data demonstrate that DT3 is a potential chemopreventive agent in colorectal cancer, warranting further investigation into its clinical use in the prevention and treatment of colorectal cancer.
Suboptimal T-cell Therapy Drives a Tumor Cell Mutator Phenotype That Promotes Escape from First-Line Treatment
Authors: Evgin Laura , Huff Amanda L. , Kottke Timothy , Thompson Jill , Molan Amy M. , Driscoll Christopher B. , Schuelke Matthew , Shim Kevin G. , Wongthida Phonphimon , Ilett Elizabeth J. , Smith Karen Kaluza , Harris Reuben S. , Coffey Matt , Pulido Jose S. , Pandha Hardev , Selby Peter J. , Harrington Kevin J. , Melcher Alan , Vile Richard G. 
Published: April 2019

Abstract
Antitumor T-cell responses raised by first-line therapies such as chemotherapy, radiation, tumor cell vaccines, and viroimmunotherapy tend to be weak, both quantitatively (low frequency) and qualitatively (low affinity). We show here that T cells that recognize tumor-associated antigens can directly kill tumor cells if used at high effector-to-target ratios. However, when these tumor-reactive T cells were present at suboptimal ratios, direct T-cell–mediated tumor cell killing was reduced and the ability of tumor cells to evolve away from a coapplied therapy (oncolytic or suicide gene therapy) was promoted. This T-cell–mediated increase in therapeutic resistance was associated with C to T transition mutations that are characteristic of APOBEC3 cytosine deaminase activity and was induced through a TNFα and protein kinase C–dependent pathway. Short hairpin RNA inhibition of endogenous APOBEC3 reduced rates of tumor escape from oncolytic virus or suicide gene therapy to those seen in the absence of antitumor T-cell coculture. Conversely, overexpression of human APOBEC3B in tumor cells enhanced escape from suicide gene therapy and oncolytic virus therapy both in vitro and in vivo. Our data suggest that weak affinity or low frequency T-cell responses against tumor antigens may contribute to the ability of tumor cells to evolve away from first-line therapies. We conclude that immunotherapies need to be optimized as early as possible so that, if they do not kill the tumor completely, they do not promote treatment resistance.
Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway
Authors: Cristiani Costanza Maria , Turdo Alice , Ventura Valeria , Apuzzo Tiziana , Capone Mariaelena , Madonna Gabriele , Mallardo Domenico , Garofalo Cinzia , Giovannone Emilia Dora , Grimaldi Antonio M. , Tallerico Rossana , Marcenaro Emanuela , Pesce Silvia , Del Zotto Genny , Agosti Valter , Costanzo Francesco Saverio , Gulletta Elio , Rizzo Aroldo , Moretta Alessandro , Karre Klas , Ascierto Paolo A. , Todaro Matilde , Carbone Ennio 
Published: April 2019

AbstractImmune checkpoint blockade therapy has changed prognoses for many melanoma patients. However, immune responses that correlate with clinical progression of the disease are still poorly understood. To identify immune responses correlating with melanoma clinical evolution, we analyzed serum cytokines as well as circulating NK and T-cell subpopulations from melanoma patients. The patients' immune profiles suggested that melanoma progression leads to changes in peripheral blood NK and T-cell subsets. Stage IV melanoma was characterized by an increased frequency of CCR7+CD56bright NK cells as well as high serum concentrations of the CCR7 ligand CCL19. CCR7 expression and CCL19 secretion were also observed in melanoma cell lines. The CCR7+ melanoma cell subpopulation coexpressed PD-L1 and Galectin-9 and had stemness properties. Analysis of melanoma-derived cancer stem cells (CSC) showed high CCR7 expression; these CSCs were efficiently recognized and killed by NK cells. An accumulation of CCR7+, PD-L1+, and Galectin-9+ melanoma cells in melanoma metastases was demonstrated ex vivo. Altogether, our data identify biomarkers that may mark a CCR7-driven metastatic melanoma pathway.
Grammar Error Correction in Morphologically Rich Languages: The Case of Russian
Authors: Rozovskaya Alla , Roth Dan 
Published: April 2019

Abstract
Until now, most of the research in grammar error correction focused on English, and the problem has hardly been explored for other languages. We address the task of correcting writing mistakes in morphologically rich languages, with a focus on Russian. We present a corrected and error-tagged corpus of Russian learner writing and develop models that make use of existing state-of-the-art methods that have been well studied for English. Although impressive results have recently been achieved for grammar error correction of non-native English writing, these results are limited to domains where plentiful training data are available. Because annotation is extremely costly, these approaches are not suitable for the majority of domains and languages. We thus focus on methods that use “minimal supervision”; that is, those that do not rely on large amounts of annotated training data, and show how existing minimal-supervision approaches extend to a highly inflectional language such as Russian. The results demonstrate that these methods are particularly useful for correcting mistakes in grammatical phenomena that involve rich morphology.
Semantic Neural Machine Translation Using AMR
Authors: Song Linfeng , Gildea Daniel , Zhang Yue , Wang Zhiguo , Su Jinsong 
Published: April 2019

AbstractIt is intuitive that semantic representations can be useful for machine translation, mainly because they can help in enforcing meaning preservation and handling data sparsity (many sentences correspond to one meaning) of machine translation models. On the other hand, little work has been done on leveraging semantics for neural machine translation (NMT). In this work, we study the usefulness of AMR (abstract meaning representation) on NMT. Experiments on a standard English-to-German dataset show that incorporating AMR as additional knowledge can significantly improve a strong attention-based sequence-to-sequence neural translation model.
The Phenolyzer Suite: Prioritizing the Candidate Genes Involved in Microtia
Authors: Xin Huang , Changchen Wang , Lei Liu , Meirong Yang , Ye Zhang , Bo Pan 
Published: April 2019

Objective: Microtia is a congenital malformation of the external ear. Great progress about the genetic of microtia has been made in recent years. This article was to prioritize the potential candidate pathogenic genes of microtia based on existing studies and reports, with the purpose of narrowing the range of following study scientifically and quickly. Method: A computational tool called Phenolyzer (phenotype-based gene analyzer) was used to prioritize microtia genes. Microtia, as a query term, was input in the interface of Phenolyzer. After several steps, including disease match, gene query, gene score system, seed gene growth, and gene ranking, the final results about genetic information of microtia were provided. Then we tracked details of the top 10 genes ranked by Phenolyzer on the basis of previous reports. Results: We detected 10 348 genes associated with microtia or related syndromes, and 78 genes of those genes belonged to seed genes. Every gene was given a score, and the gene with higher scores was more likely influence microtia. The top 10 ranked genes included HOXA2, CHD7, CDT1, ORC1, ORC4, ORC6, CDC6, MED12, TWIST1, and GLI3. Otherwise, four gene-gene interactions were displayed. Conclusion: This article prioritized candidate genes of microtia for the first time. High-throughput methods provide tens of thousands of single-nucleotide variants, indels, and structural variants, and only a handful are relevant to microtia or associated syndromes. Combine the ranked potential pathogenic genes list from Phenolyzer with the results of samples provided by high-throughput methods, and more precise research directions are presented.
Integrated Otolaryngology-Anesthesiology Clinical Skills and Simulation Rotation: A Novel 1-Month Intern Curriculum
Authors: Kovatch Kevin J. , Harvey Rebecca S. , Schechtman Samuel A. , Healy David W. , Malloy Kelly M. , Prince Mark E. P. , Thorne Marc C. 
Published: April 2019

Objectives: Current Accreditation Council for Graduate Medical Education (ACGME) requirements allow PGY-1 otolaryngology-head and neck surgery (ORL-HNS) residents to spend 6 months on service, prompting reconsideration of educational best practices for the first-year resident experience. The aim of this study was to determine feasibility and value of a 1-month PGY-1 otolaryngology clinical skills rotation integrated with anesthesiology to complement clinical ORL-HNS rotations. Methods: Our institution developed a 1-month rotation focusing on procedural simulation and airway management as a collaborative effort between ORL-HNS and anesthesiology. Logistics of curriculum design and implementation in the first 2 years are described. Learner outcome measures include pre- and postintervention Likert scale measures of knowledge and confidence. Statistical assessment of curriculum efficacy includes Wilcoxon sign rank test and effect size (Cohen’s d). Results: The described rotation was successfully implemented for 8 entering PGY-1 residents in the 2016-2017 and 2017-1018 academic years. Learners reported significant improvement in knowledge and confidence (5-point Likert scale, all P < .0001) in each of the following grouped domains following the intervention: anesthesia skills (pre 2.79, post 4.02), anesthesia knowledge (pre 2.31, post 3.50), anesthesia overall preparedness (pre 2.75, post 4.04), otolaryngology skills (pre 2.90, post 4.19), otolaryngology scenarios (pre 2.80, post 4.00), and otolaryngology overall preparedness (pre 2.38, post 3.75). Very large effect sizes (Cohen’s d, range = 1.6-2.9) were observed. Conclusion: Changing rotation structure in ORL-HNS training programs provides an opportunity to develop novel rotations with high educational impact. Early outcome data suggest that the described clinical skills rotation is practically feasible and was perceived to have measurable value as part of the PGY-1 curriculum.
Surgical Site Infection in Head and Neck Surgery: A National Perspective
Authors: Al‐Qurayshi Zaid , Walsh Jarrett , Owen Scott , Kandil Emad 
Published: April 2019

ObjectivesTo examine trend, prevalence, and outcomes of surgical site infection (SSI) in head and neck surgery.Study DesignRetrospective cross‐sectional analysis.SettingThe Nationwide Readmissions Database (2010‐2014), which represents 56.6% of all US hospitalization.SubjectsAdult patients (≥18 years) who underwent head and neck surgery. Patients with SSI were compared with controls.MethodsAnalysis included chi‐square test and multivariate logistic and linear regression models.ResultsA total of 427 cases and 116,921 controls were identified. SSI prevalence among patients who underwent head and neck surgery was 0.37%, of which 41.0% was reported within the initial admission while the remaining 59.0% was reported on readmission within 30 days of first surgery. SSI was associated with a higher mortality risk (odds ratio, 3.95; 95% CI, 1.25‐12.50; P =. 019). Multivariate analysis demonstrated that a higher risk of SSI was associated with major surgery of the ear, nose and paranasal sinuses, mouth and tonsil, salivary glands and ducts, maxillofacial bones and mandible, and pharynx and larynx (P <. 05 each). However, a lower risk of SSI was reported in thyroid and parathyroid and nonmajor procedures (P <. 05 each). Other factors associated with a higher risk of SSI included multiple comorbidities, smoking, cancer diagnosis, concomitant neck dissection, and tracheostomy (P <. 05 each). SSI was associated with a mean ± SE additional hospital stay of 8.1 ± 0.8 days per case (P <. 001) and an additional cost on the health system of $20,953.00 ± $186.3 per case (P <. 001).ConclusionsSSI is associated with a significant mortality risk and burden on the health system. More than half of SSI cases were identified on readmission.
Periostin and Inflammatory Disease: Implications for Chronic Rhinosinusitis
Authors: Lehmann Ashton E. , Scangas George A. , Bergmark Regan W. , El Rassi Edward , Stankovic Konstantina M. , Metson Ralph 
Published: April 2019

ObjectiveTo provide a comprehensive overview of the emerging role of periostin, an extracellular matrix protein, as a key component in the development, diagnosis, and treatment of patients with chronic rhinosinusitis.Data SourcesMedline database.Review MethodsA state of the art review was performed targeting English‐language studies investigating the role of periostin in cardiopulmonary, neoplastic, and inflammatory diseases, with emphasis on recent advances in the study of periostin in chronic rhinosinusitis.ConclusionsPeriostin has emerged as a novel biomarker and therapeutic target for numerous human pathologies, including cardiac, pulmonary, and neoplastic disease. The upregulation of periostin in chronic rhinosinusitis suggests the potential for similar roles among patients with sinonasal disease.Implications for PracticeChronic rhinosinusitis is a widespread disease with major clinical and societal impact. A critical limitation in the current treatment of patients with chronic rhinosinusitis is the absence of clinically relevant biomarkers to guide diagnosis and treatment selection. A review of the literature supports a likely role of periostin as a biomarker of chronic rhinosinusitis, as well as a novel therapeutic target in the future treatment of patients with sinonasal disease.
Clinical Prediction Model for Obstructive Sleep Apnea among Adult Patients with Habitual Snoring
Authors: Lin Hsin‐Ching , Lai Chi‐Chih , Lin Pei‐Wen , Friedman Michael , Salapatas Anna M. , Chang Hsueh‐Wen , Lin Meng‐Chih , Chin Chien‐Hung 
Published: April 2019

ObjectiveTo identify standard clinical parameters that may predict the presence and severity of obstructive sleep apnea/hypopnea syndrome (OSA).DesignCase series with chart review.SettingTertiary academic medical center.Subjects and MethodsA total of 325 adult patients (274 men and 51 women; mean age, 44.2 years) with habitual snoring completed comprehensive polysomnography and anthropometric measurements, including modified Mallampati grade (also known as updated Friedman's tongue position [uFTP]), tonsil size grading, uvular length, neck circumference, waist circumference, hip circumference, and body mass index (BMI).ResultsWhen the aforementioned physical parameters were correlated singly with the apnea/hypopnea index (AHI), we found that sex, uFTP, tonsil size grading, neck circumference, waist circumference, hip circumference, thyroid‐mental distance, and BMI grade were reliable predictors of OSA. When all important factors were considered in a multiple stepwise regression analysis, an estimated AHI can be formulated by factoring sex, uFTP, tonsil size grading, and BMI grade as follows: –43.0 + 14.1 × sex + 12.8 × uFTP + 5.0 × tonsil size + 8.9 × BMI grade. Severity of OSA can be predicted with a receiver operating characteristic curve. Predictors of OSA can be further obtained by the “OSA score.”ConclusionThis study has distinguished the correlations between sex, uFTP, tonsil size, and BMI grade and the presence and severity of OSA. An OSA score might be beneficial in identifying patients who should have a full sleep evaluation.
Cost-effectiveness and screening performance of ECG handheld machine in a population screening programme: The Belgian Heart Rhythm Week screening programme
Authors: Proietti Marco , Farcomeni Alessio , Goethals Peter , Scavee Christophe , Vijgen Johan , Blankoff Ivan , Vandekerckhove Yves , Lip Gregory YH , Mairesse Georges H ,   on behalf of Belgian Heart Rhythm Week Investigators
Published: April 2019

Aims Overall, 40% of patients with atrial fibrillation are asymptomatic. The usefulness and cost-effectiveness of atrial fibrillation screening programmes are debated. We evaluated whether an atrial fibrillation screening programme with a handheld electrocardiogram (ECG) machine in a population-wide cohort has a high screening yield and is cost-effective. Methods We used a Markov-model based modelling analysis on 1000 hypothetical individuals who matched the Belgian Heart Rhythm Week screening programme. Subgroup analyses of subjects ≥65 and ≥75 years old were performed. Screening was performed with one-lead ECG handheld machine Omron® HeartScan HCG-801. Results In both overall population and subgroups, the use of the screening procedure diagnosed a consistently higher number of diagnosed atrial fibrillation than not screening. In the base-case scenario, the screening procedure resulted in 106.6 more atrial fibrillation patient-years, resulting in three fewer strokes, 10 more life years and five more quality-adjusted life years (QALYs). The number needed-to-screen (NNS) to avoid one stroke was 361. In subjects ≥65 years old, we found 80.8 more atrial fibrillation patient-years, resulting in three fewer strokes, four more life-years and five more QALYs. The NNS to avoid one stroke was 354. Similar results were obtained in subjects ≥75 years old, with a NNS to avoid one stroke of 371. In the overall population, the incremental cost-effectiveness ratio for any gained QALY showed that the screening procedure was cost-effective in all groups. Conclusions In a population-wide screening cohort, the use of a handheld ECG machine to identify subjects with newly diagnosed atrial fibrillation was cost-effective in the general population, as well as in subjects ≥65 and subjects ≥75 years old.