bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomics Associates Molecular Features with 18F-Fluorocholine PET/CT Imaging Phenotype and Its Potential Relationship to Survival in Hepatocellular Carcinoma
Authors: Kwee Sandi A. , Tiirikainen Maarit , Sato Miles M. , Acoba Jared D. , Wei Runmin , Jia Wei , Le Marchand Loic , Wong Linda L. 
Published: February 2019

Abstract

Studies involving transcriptomics have revealed multiple molecular subtypes of hepatocellular carcinoma (HCC). Positron emission tomography/computed tomography (PET/CT) has also identified distinct molecular imaging subtypes, including those with increased and decreased choline metabolism as measured by the tissue uptake of the radiopharmaceutical 18F-fluorocholine. Gene signatures reflecting the molecular heterogeneity of HCC may identify the biological and clinical significance of these imaging subtypes. In this study, 41 patients underwent 18F-fluorocholine PET/CT, followed by tumor resection and gene expression profiling. Over- and underexpressed components of previously published gene signatures were evaluated for enrichment between tumors with high and low 18F-fluorocholine uptake using gene set analysis. Significant gene sets were enumerated by FDR based on phenotype permutation. Associations with overall survival were analyzed by univariate and multivariate proportional hazards regression. Ten gene sets related to HCC were significantly associated with high tumor 18F-fluorocholine uptake at FDR q &lt; 0.05, including those from three different clinical molecular classification systems and two prognostic signatures for HCC that showed predictive value in the study cohort. Tumor avidity for 18F-fluorocholine was associated with favorable characteristics based on these signatures with lower mortality based on survival analysis (HR 0.36; 95% confidence interval, 0.14–0.95). Tumors demonstrating high 18F-fluorocholine uptake were also enriched for genes involved in oxidative phosphorylation, fatty acid metabolism, peroxisome, bile acid metabolism, xenobiotic metabolism, and adipogenesis. These results provide a pathobiological framework to further evaluate 18F-fluorocholine PET/CT as a molecular and prognostic classifier in HCC.

Significance:
A pathobiological framework for HCC brings together multiple prognostically relevant gene signatures via convergence with 18F-fluorocholine PET/CT imaging phenotype.
PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers
Authors: Pilié Patrick G. , Gay Carl M. , Byers Lauren A. , O'Connor Mark J. , Yap Timothy A. 
Published: February 2019

Abstract
A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. Although PARP inhibitors as a class display many similarities, critical differences in structure can translate into differences in tolerability and antitumor activity that have important implications for the clinic. Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small-cell lung cancer. In this article, we highlight the key similarities and differences between individual PARP inhibitors and their implications for the clinic. We discuss data that currently support clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers, toward broader populations of patients through the use of novel biomarkers of homologous recombination repair deficiency (HRD), as well as predictive biomarkers rooted in mechanisms of sensitivity outside of HRD. We also explore the potential application of PARP inhibitors in earlier treatment settings, including neoadjuvant, adjuvant, and even chemoprevention approaches. Finally, we focus on promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non–DDR-targeted agents that induce “chemical BRCAness.”
LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway
Authors: Dalvi Priya S. , Macheleidt Iris F. , Lim So-Young , Meemboor Sonja , Müller Marion , Eischeid-Scholz Hannah , Schaefer Stephan C. , Buettner Reinhard , Klein Sebastian , Odenthal Margarete 
Published: February 2019

Abstract

Lysine-specific demethylase 1 (LSD1) is a histone modifier that is highly overexpressed in lung adenocarcinoma, which results in aggressive tumor biology. Tumor cell proliferation and migration analysis after LSD1 inhibition in the lung adenocarcinoma cell line PC9, using the LSD1 inhibitor HCI-2509 and siRNA, demonstrated that LSD1 activity was essential for proliferation and migration capacities of tumor cells. Moreover, reduced proliferation rates after LSD1 inhibition were shown to be associated with a cell-cycle arrest of the tumor cells in the G2–M-phase. Expression profiling followed by functional classification and pathway analysis indicated prominent repression of the polo-like kinase 1 (PLK1) pathway upon LSD1 inhibition. In contrast, transient overexpression of exogenous PLK1 plasmid rescued the LSD1 inhibition–mediated downregulation of PLK1 pathway genes. Mechanistically, LSD1 directly regulates expression of PLK1 by binding to its promoter region that subsequently affects expression of its downstream target genes. Notably, using lung adenocarcinoma TCGA datasets a significant correlation between LSD1 and PLK1 along with its downstream targets was observed. Furthermore, the LSD1/PLK1 linkage was confirmed by IHC analysis in a clinical lung adenocarcinoma cohort (n = 43). Conclusively, this is the first study showing a direct transcriptional link between LSD1 and PLK1.

Implications:
These findings point to a role of LSD1 in regulating PLK1 and thus efficient G2–M-transition–mediating proliferation of tumor cells and suggest targeting the LSD1/PLK1 axis as a novel therapeutic approach for lung adenocarcinoma treatment.
Calcium Intake and Risk of Colorectal Cancer According to Tumor-infiltrating T Cells
Authors: Yang Wanshui , Liu Li , Keum NaNa , Qian Zhi Rong , Nowak Jonathan A. , Hamada Tsuyoshi , Song Mingyang , Cao Yin , Nosho Katsuhiko , Smith-Warner Stephanie A. , Zhang Sui , Masugi Yohei , Ng Kimmie , Kosumi Keisuke , Ma Yanan , Garrett Wendy S. , Wang Molin , Nan Hongmei , Giannakis Marios , Meyerhardt Jeffrey A. , Chan Andrew T. , Fuchs Charles S. , Nishihara Reiko , Wu Kana , Giovannucci Edward L. , Ogino Shuji , Zhang Xuehong 
Published: February 2019

Abstract
Calcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell–mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs. &lt;600 mg/day; 95% CI, 0.36–0.84; Ptrend = 0.002) for CD8+ T-cell–low but not for CD8+ T-cell–high tumors (HR = 1.02; 95% CI, 0.67–1.55; Ptrend = 0.47). Similarly, the corresponding HRs (95% CIs) for calcium for low versus high T-cell–infiltrated tumors were 0.63 (0.42–0.94; Ptrend = 0.01) and 0.89 (0.58–1.35; Ptrend = 0.20) for CD3+; 0.58 (0.39–0.87; Ptrend = 0.006) and 1.04 (0.69–1.58; Ptrend = 0.54) for CD45RO+; and 0.56 (0.36–0.85; Ptrend = 0.006) and 1.10 (0.72–1.67; Ptrend = 0.47) for FOXP3+, although the differences by subtypes defined by T-cell density were not statistically significant. These potential differential associations generally appeared consistent regardless of sex, source of calcium intake, tumor location, and tumor microsatellite instability status. Our findings suggest a possible role of calcium in cancer immunoprevention via modulation of T-cell function.
Testing Novel Pyrimidinyl Rexinoids: A New Paradigm for Evaluating Rexinoids for Cancer Prevention
Authors: Zhang Di , Leal Ana S. , Carapellucci Sarah , Shahani Pritika H. , Bhogal Jaskaran S. , Ibrahim Samir , Raban San , Jurutka Peter W. , Marshall Pamela A. , Sporn Michael B. , Wagner Carl E. , Liby Karen T. 
Published: February 2019

Abstract
Rexinoids, selective ligands for retinoid X receptors (RXR), have shown promise in preventing many types of cancer. However, the limited efficacy and undesirable lipidemic side-effects of the only clinically approved rexinoid, bexarotene, drive the search for new and better rexinoids. Here we report the evaluation of novel pyrimidinyl (Py) analogues of two known chemopreventive rexinoids, bexarotene (Bex) and LG100268 (LG268) in a new paradigm. We show that these novel derivatives were more effective agents than bexarotene for preventing lung carcinogenesis induced by a carcinogen. In addition, these new analogues have an improved safety profile. PyBex caused less elevation of plasma triglyceride levels than bexarotene, while PyLG268 reduced plasma cholesterol levels and hepatomegaly compared with LG100268. Notably, this new paradigm mechanistically emphasizes the immunomodulatory and anti-inflammatory activities of rexinoids. We reveal new immunomodulatory actions of the above rexinoids, especially their ability to diminish the percentage of macrophages and myeloid-derived suppressor cells in the lung and to redirect activation of M2 macrophages. The rexinoids also potently inhibit critical inflammatory mediators including IL6, IL1β, CCL9, and nitric oxide synthase (iNOS) induced by lipopolysaccharide. Moreover, in vitro iNOS and SREBP (sterol regulatory element-binding protein) induction assays correlate with in vivo efficacy and toxicity, respectively. Our results not only report novel pyrimidine derivatives of existing rexinoids, but also describe a series of biological screening assays that will guide the synthesis of additional rexinoids. Further progress in rexinoid synthesis, potency, and safety should eventually lead to a clinically acceptable and useful new drug for patients with cancer.
Health-Related Quality of Life at 30 Days Among Indian Patients With Acute Myocardial Infarction
Authors: Huffman Mark D. , Mohanan Padinhare P. , Devarajan Raji , Baldridge Abigail S. , Kondal Dimple , Zhao Lihui , Ali Mumtaj , Spertus John A. , Chan Paul S. , Natesan Syam , Abdullakutty Jabir , Krishnan Mangalath N. , TP Abhilash , Renga Sujay , Punnoose Eapen , Unni Govindan , Prabhakaran Dorairaj , Lloyd-Jones Donald M. ,   on behalf of the ACS QUIK Investigators
Published: February 2019

Background:
Despite a high cardiovascular disease burden, data on patient-reported health status outcomes among individuals with cardiovascular disease in India are limited.

Methods and Results:

Between November 2014 and November 2016, we collected health-related quality of life data among 1261 participants in the ACS QUIK trial (Acute Coronary Syndrome Quality Improvement in Kerala). We used a translated, validated version of the Seattle Angina Questionnaire administered 30 days after discharge for acute myocardial infarction, wherein higher scores represent better health status. We compared results across sex, myocardial infarction type, and randomization status using regression models that account for clustering and temporal trends. Mean (SD) age was 60.8 (13.7) years, 62% were men, and 63% presented with ST-segment–elevation myocardial infarction. More than 2 out of 5 respondents (44%) experienced angina 30 days after hospitalization, but most (68% of respondents with angina; 27% of the total sample) experienced it less than once per week (Seattle Angina Questionnaire angina frequency score 60). Respondents rated high median (interquartile range [IQR]) scores for angina frequency (100.0 [80.0–100.0]) overall with similar unadjusted scores by sex, but between-hospitality variability was high. Median (IQR) physical limitation scale response was 58.3 (41.7–77.8), which is consistent with limitations in moderate- and high-intensity activities at 30-day follow-up. Older respondents had more angina frequency and physical limitations and lower treatment satisfaction and quality of life. Women had greater physical limitations (median [IQR], 52.8 [38.9–72.2] for women versus median [IQR], 61.1 [44.4–80.6] for men;
P
<0.01). Overall treatment satisfaction was high with median (IQR) score, 81.3 (75.0–93.8), but overall quality of life was lower with median (IQR) score, 66.7 (50.0–83.3). Allocation to the quality improvement intervention group had the strongest direct association with higher quality of life (difference, 4.2;
P
=0.03), but overall effects were modest.

Conclusions:
This study represents the largest report of quality of life among myocardial infarction survivors in India with variability across age, sex, and quality improvement intervention status. Wide variability demonstrated across hospitals warrants further study.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02256657.
β‐Blockers and 1‐Year Postdischarge Mortality for Heart Failure and Reduced Ejection Fraction and Slow Discharge Heart Rate
Authors: Park Jin Joo , Park Hyun‐Ah , Cho Hyun‐Jai , Lee Hae‐Young , Kim Kye Hun , Yoo Byung‐Su , Kang Seok‐Min , Baek Sang Hong , Jeon Eun‐Seok , Kim Jae‐Joong , Cho Myeong‐Chan , Chae Shung Chull , Oh Byung‐Hee , Choi Dong‐Ju 
Published: February 2019

Background

Many hospitalized patients with heart failure and reduced ejection fraction (
HF
r
EF
) have a slow heart rate at discharge, and the effect of β‐blockers may be reduced in those patients. We sought to examine the variable effect of β‐blockers on clinical outcomes according to the discharge heart rate of hospitalized
HF
r
EF
patients.

Methods and Results

The KorAHF (Korean Acute Heart Failure) registry consecutively enrolled 5625 patients hospitalized for acute heart failure. In this analysis, we included patients with
HF
r
EF
(left ventricular ejection fraction ≤40%).
Slow heart rate
was defined as <70 beats per minute regardless of the use of β‐blockers. The primary outcome was 1‐year all‐cause postdischarge death according to heart rate. Among 2932 patients with
HF
r
EF
, 840 (29%) had a slow heart rate and 56% received β‐blockers at discharge. Patients with slow heart rates were older and had lower 1‐year mortality than those with high heart rates (
P
<0.001). A significant interaction between discharge heart rate and β‐blocker use was observed (
P
<0.001 for interaction). When stratified, only patients without a β‐blocker prescription and with a high heart rate showed higher 1‐year mortality. In a Cox‐proportional hazards regression analysis, β‐blocker prescription at discharge was associated with 24% reduced risk for 1‐year mortality in patients with high heart rates (hazard ratio: 0.76; 95% CI, 0.61–0.95) but not in those with slow heart rates (hazard ratio: 1.02; 95% CI, 0.68–1.55).

Conclusions

Many patients with acute heart failure have slow discharge heart rates, and β‐blockers may have a limited effect on
HF
r
EF
and slow discharge heart rate.

Clinical Trial Registration

URL
:
http://www.clinicaltrial.gov
. Unique identifier:
NCT
01389843.
The occurrence and development of intraxylary phloem in young Aquilaria sinensis shoots
Authors: Luo Bei , Imai Tomoya , Sugiyama Junji , Qiu Jian 
Published: February 2019

ABSTRACT
Agarwoods such as Aquilaria spp. and Gyrinops spp. (Thymelaeaceae) produce interxylary phloem in their secondary xylem and intraxylary phloem at the periphery of the pith, facing the primary xylem. We studied young shoots of Aquilaria sinensis and characterized the development of its intraxylary phloem. It was initiated by the division of parenchyma cells localized in the outer parts of the ground meristem immediately following the maturation of first-formed primary xylem. Its nascent sieve plates bore donut-like structures, the individual pores of which were so small (less than 0.1 μm) that they were hardly visible under FE-SEM. Intraxylary phloem developed into mature tissue by means of the division and proliferation of parenchyma cells. During the shoots’ active growth period, the sieve pore sizes were 0.1–0.5 μm, with tubular elements passing through them. In the maturation stage, large clusters of sieve tubes continued to be differentiated in the intraxylary phloem. In the partial senescence stage observed in a three-centimeter-diameter branch, intraxylary phloem cells in the adaxial part became crushed, and sieve plates had pores over 1–2 μm in diameter without any callose deposition. Before and after the differentiation of interxylary phloem in the first and second internodes, callose staining detected more than twice as many sieve tubes in intraxylary phloem than in external phloem. However, after differentiation of interxylary phloem in the eleventh internode, more sieve tubes were found in interxylary phloem than in intraxylary and external phloem. This suggests that prior to the initiation of interxylary phloem intraxylary phloem acts as the principal phloem. After its differentiation, however, interxylary phloem takes over the role of principal phloem. Interxylary phloem thus acts as the predominant phloem in the translocation of photosynthates in Aquilaria sinensis.
An Analytical Derivation of Ice-Shelf Basal Melt Based on the Dynamics of Meltwater Plumes
Authors: Lazeroms Werner M. J. , Jenkins Adrian , Rienstra Sjoerd W. , van de Wal Roderik S. W. 
Published: February 2019

AbstractThe interaction between ice shelves and the ocean is an important process for the development of marine ice sheets. However, it is difficult to model in full detail due to the high computational cost of coupled ice–ocean simulations, so that simplified basal-melt parameterizations are required. In this work, a new analytical expression for basal melt is derived from the theory of buoyant meltwater plumes moving upward under the ice shelf and driving the overturning circulation within the ice-shelf cavity. The governing equations are nondimensionalized in the case of an ice shelf with constant basal slope and uniform ambient ocean conditions. An asymptotic analysis of these equations in terms of small slopes and small thermal driving, assumed typical for Antarctic ice shelves, leads to an equation that can be solved analytically for the dimensionless melt rate. This analytical expression describes a universal melt-rate curve onto which the scaled results of the original plume model collapse. Its key features are a positive melt peak close to the grounding line and a transition to refreezing further away. Comparing the analytical expression with numerical solutions of the plume model generally shows a close agreement between the two, even for more general cases than the idealized geometry considered in the derivation. The results show how the melt rates adapt naturally to changes in the geometry and ambient ocean temperature. The new expression can readily be used for improving ice-sheet models that currently still lack a sufficiently realistic description of basal melt.
Sociodemographic, environmental characteristics and comorbidities of older adults with schizophrenia who access community health service support: A national cross-sectional study
Authors: Lacey Cameron , Manuel Jenni , Schluter Philip J , Porter Richard J , Pitama Suzanne , Jamieson Hamish A 
Published: February 2019

Objectives: Schizophrenia is a serious and chronic mental illness known to have broad ranging impacts for individuals across the lifespan, yet research on the disease in older adults is sparse. This study provides a profile of the sociodemographic, environmental and diagnostic characteristics of older community residents with schizophrenia using a national database. Methods: A cross-sectional sample of individuals who underwent community needs assessment using the standardised Home Care International Residential Assessment Instrument between 1 September 2012 and 31 January 2016 was utilised. Sociodemographic, diagnostic, and social and environmental variables were measured for individuals with a diagnosis of schizophrenia and compared to those without a diagnosis of schizophrenia. Statistical investigations employed bivariable and multivariable logistic regression models. Results: A total sample of 71,859 was eligible and 517 (0.7%) had a diagnosis of schizophrenia. The majority of the sociodemographic variables were statistically associated with schizophrenia in the adjusted analysis, except for ethnicity ( p = 0.35). Nearly all the measured social and environmental variables were adversely associated with having a diagnosis of schizophrenia, such as living in squalid conditions (adjusted odds ratio = 2.16; 95% confidence interval = [1.42, 3.28]). Participants with schizophrenia were significantly more likely to be diagnosed with all assessed psychiatric comorbidities ( p < 0.001) and diabetes mellitus ( p  = 0.002), whereas coronary heart disease ( p = 0.001) and other physical comorbidities ( p = 0.001) were found at significantly lower rates. Conclusion: The profile of schizophrenia found here suggests some subtle differences in the demographic profile and distribution of medical comorbidities in the older population with schizophrenia. The results also suggest that this group continues to experience social disadvantage into old age. This requires the attention of policy-makers to ensure that services are tailored to the high social needs of these individuals.
Current Smoking: An Independent Predictor of Elevated A1C in Persons With Type 2 Diabetes
Authors: Dinardo Monica M. , Sereika Susan M. , Korytkowski Mary , Baniak Lynn M. , Weinzierl Valarie A. , Hoenstine Amy L. , Chasens Eileen R. 
Published: February 2019

Purpose The purpose of this study is to examine the association of current smoking as one of several potential predictors of elevated A1C in adults with type 2 diabetes (T2D). Methods Using a cross-sectional design, baseline data (N = 282) were analyzed from a randomized clinical trial examining treatment of obstructive sleep apnea in persons with T2D. Sociodemographic, clinical, and behavioral data were collected using questionnaires and physical examinations. Physical activity (mean daily steps walked) was measured with the BodyMedia Armband. Participants were asked if they never smoked, had previously smoked, or currently smoke. The sample distributions of demographic and clinical characteristics were examined using descriptive statistics. Continuous variables were described using means and standard deviations; categorical variables were described as numbers and percentages. Multiple linear regression analysis with backward selection was conducted to develop a parsimonious predictive model for the dependent variable A1C. Results Participants were generally middle-aged and, on average, obese with suboptimal blood glucose control; almost 1 of every 5 participants currently smoked. After controlling for age, race, education, financial difficulty, diabetes education, physical activity, and diabetes knowledge, 4 variables were found in the final model to be independently associated with higher A1C: (1) current smoking status, (2) younger age, (3) longer diabetes duration, and (4) higher diabetes-related distress. Conclusions The study found that not only is smoking prevalent among persons with T2D with self-reported sleep problems but smoking is also an independent predictor of elevated A1C. The results highlight the vital role diabetes educators have in promoting risk reduction through education and support for smoking cessation.