bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of NF-κB–Dependent Signaling Enhances Sensitivity and Overcomes Resistance to BET Inhibition in Uveal Melanoma
Authors: Ambrosini Grazia , Do Catherine , Tycko Benjamin , Realubit Ronald B. , Karan Charles , Musi Elgilda , Carvajal Richard D. , Chua Vivian , Aplin Andrew E. , Schwartz Gary K. 
Published: March 2019

Abstract

Bromodomain and extraterminal protein inhibitors (BETi) are epigenetic therapies aimed to target dysregulated gene expression in cancer cells. Despite early successes of BETi in a range of malignancies, the development of drug resistance may limit their clinical application. Here, we evaluated the mechanisms of BETi resistance in uveal melanoma, a disease with little treatment options, using two approaches: a high-throughput combinatorial drug screen with the clinical BET inhibitor PLX51107 and RNA sequencing of BETi-resistant cells. NF-κB inhibitors synergistically sensitized uveal melanoma cells to PLX51107 treatment. Furthermore, genes involved in NF-κB signaling were upregulated in BETi-resistant cells, and the transcription factor CEBPD contributed to the mechanism of resistance. These findings suggest that inhibitors of NF-κB signaling may improve the efficacy of BET inhibition in patients with advanced uveal melanoma.

Significance:
These findings provide evidence that inhibitors of NF-κB signaling synergize with BET inhibition in in vitro and in vivo models, suggesting a clinical utility of these targeted therapies in patients with uveal melanoma.
Long Noncoding RNA MPRL Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via Disruption of Pre-miRNA Processing
Authors: Tian Tian , Lv Xiaobin , Pan Guokai , Lu Yingjuan , Chen Weixiong , He Wang , Lei Xinyuan , Zhang Hanqing , Liu Mo , Sun Sheng , Ou Zhanpeng , Lin Xinyu , Cai Lei , He Lile , Tu Zhiming , Wang Xinhui , Tannous Bakhos A. , Ferrone Soldano , Li Jinsong , Fan Song 
Published: March 2019

Abstract

Purpose:
The overall biological roles and clinical significance of most long noncoding RNAs (lncRNA) in chemosensitivity are not fully understood. We investigated the biological function, mechanism, and clinical significance of lncRNA NR_034085, which we termed miRNA processing–related lncRNA (MPRL), in tongue squamous cell carcinoma (TSCC).

Experimental Design:
LncRNA expression in TSCC cell lines with cisplatin treatment was measured by lncRNA microarray and confirmed in TSCC tissues. The functional roles of MPRL were demonstrated by a series of in vitro and in vivo experiments. The miRNA profiles, RNA pull-down, RNA immunoprecipitation, serial deletion analysis, and luciferase analyses were used to investigate the potential mechanisms of MPRL.

Results:
We found that MPRL expression was significantly upregulated in TSCC cell lines treated with cisplatin and transactivated by E2F1. MPRL controlled mitochondrial fission and cisplatin sensitivity through miR–483-5p. In exploring the underlying interaction between MPRL and miR–483-5p, we identified that cytoplasmic MPRL directly binds to pre–miR–483 within the loop region and blocks pre–miR–483 recognition and cleavage by TRBP–DICER-complex, thereby inhibiting miR–483-5p generation and upregulating miR–483-5p downstream target-FIS1 expression. Furthermore, overexpression or knockdown MPRL altered tumor apoptosis and growth in mouse xenografts. Importantly, we found that high expression of MPRL and pre–miR–483, and low expression of miR–483-5p were significantly associated with neoadjuvant chemosensitivity and better TSCC patients’ prognosis.

Conclusions:
We propose a model in which lncRNAs impair microprocessor recognition and are efficient of pre-miRNA cropping. In addition, our study reveals a novel regulatory network for mitochondrial fission and chemosensitivity and new biomarkers for prediction of neoadjuvant chemosensitivity in TSCC.
These findings uncover a novel mechanism by which lncRNA determines mitochondrial fission and cisplatin chemosensitivity by inhibition of pre-miRNA processing and provide for the first time the rationale for lncRNA and miRNA biogenesis for predicting chemosensitivity and patient clinical prognosis.
CD47-Targeted Near-Infrared Photoimmunotherapy for Human Bladder Cancer
Authors: Kiss Bernhard , van den Berg Nynke S. , Ertsey Robert , McKenna Kelly , Mach Kathleen E. , Zhang Chiyuan Amy , Volkmer Jens-Peter , Weissman Irving L. , Rosenthal Eben L. , Liao Joseph C. 
Published: March 2019

Abstract

Purpose:
Near-infrared photoimmunotherapy (NIR-PIT) is a localized molecular cancer therapy combining a photosensitizer-conjugated mAb and light energy. CD47 is an innate immune checkpoint widely expressed on bladder cancer cells, but absent from luminal normal urothelium. Targeting CD47 for NIR-PIT has the potential to selectively induce cancer cell death and minimize damage to normal urothelium.

Experimental Design:
The cytotoxic effect of NIR-PIT with anti-CD47-IR700 was investigated in human bladder cancer cell lines and primary human bladder cancer cells derived from fresh surgical samples. Phagocytosis assays were performed to evaluate macrophage activity after NIR-PIT. Anti-CD47-IR700 was administered to murine xenograft tumor models of human bladder cancer for in vivo molecular imaging and NIR-PIT.

Results:
Cytotoxicity in cell lines and primary bladder cancer cells significantly increased in a light-dose–dependent manner with CD47-targeted NIR-PIT. Phagocytosis of cancer cells significantly increased with NIR-PIT compared with antibody alone (P = 0.0002). In vivo fluorescence intensity of anti-CD47-IR700 in tumors reached a peak 24-hour postinjection and was detectable for at least 14 days. After a single round of CD47-targeted NIR-PIT, treated animals showed significantly slower tumor growth compared with controls (P &lt; 0.0001). Repeated CD47-targeted NIR-PIT treatment further slowed tumor growth (P = 0.0104) and improved survival compared with controls.

Conclusions:
CD47-targeted NIR-PIT increased direct cancer cell death and phagocytosis resulting in inhibited tumor growth and improved survival in a murine xenograft model of human bladder cancer.
Sex Hormones and Anticancer Immunity
Authors: Özdemir Berna C. , Dotto Gian-Paolo 
Published: March 2019

Abstract
The impact of sex hormones on anticancer immunity deserves attention due to the importance of the immune system in cancer therapy and the recognition of sex differences in immunity. Cancer is ultimately the result of failed immune surveillance, and the diverging effects of male and female sex hormones on anticancer immunity could contribute to the higher cancer incidence and poorer outcome in men. Estrogens and androgens affect the number and function of immune cells, an effect that depends on cell type, tumor microenvironment, and the age and reproductive status of the individual. Despite the recent progress in immuno-oncology, our current understanding of the interplay between sex hormones and anticancer immune responses is in its infancy. In this review, we will focus on the impact of sex hormones on anticancer immunity and immunotherapy. We will discuss the potential role of the changing hormone levels in anticancer immunity during aging and in the context of menopausal hormone therapies and oral contraception. We will review emerging data on sex differences in PD-L1 expression and potential biomarkers predictive for the efficacy of immune checkpoint inhibitors such as the microbiome and consider ongoing clinical trials evaluating the potential impact of hormone deprivation therapies to increase response to immune checkpoint inhibitors in breast and prostate cancer. Finally, we will point to areas of future research.
Longitudinal Adherence to Immunochemical Fecal Occult Blood Testing vs Guaiac-based FOBT in an Organized Colorectal Cancer Screening Program
Authors: Benito Llucia , Travier Noemie , Binefa Gemma , Vidal Carmen , Espinosa Jose , Milà Núria , Garcia Montse 
Published: March 2019

Abstract
Longitudinal adherence is a critical component of the efficacy of stool-based screening programs because they should be repeated every 1–2 years. Few data have been published on the uptake in multiple rounds of fecal occult blood test-based (FOBT) colorectal cancer (CRC) screening. We calculated two measures of longitudinal adherence to biennial FOBT (guaiac fecal occult blood test:gFOBT or fecal immunochemical test:FIT) to better understand its impact on the programmatic effectiveness of a population-based CRC screening program (2000–2017). Ongoing population-based CRC program of men and women aged 50–69 years. Variables: Age at first CRC screening invitation, sex, number of screening invitations, number of screens, deprivation score, and uptake rate. Logistic regression models were used to assess the independent effect of sex, age at first invitation, deprivation, and the type of screening test offered on adherence. The uptake rate for guaiac fecal occult blood test (gFOBT) was 23.9%, and for the fecal immunochemical test (FIT), it was 37.4%. The overall rate of consistently screened invitees after seven rounds of screening was 14.2%, being 20.6% for those individuals who used FIT and 14.3% for those who used gFOBT. Factors associated with continued participation (consistent vs. inconsistent screenees) showed that the longitudinal adherence was associated with age, screening test used, and number of invitations. Continued participation was lower in individuals who were screened using FIT than among those screened using gFOBT [OR, 0.68; 95% confidence interval (CI), 0.57–0.81]. The overall rate of consistently screened invitees for colorectal cancer screening was higher with FIT than gFOBT. Studying the rate of individuals being current for screening may help to anticipate potential benefits before the long-term outcome data are available.
Influence of lactose intolerance and physical activity level on bone mineral density in young women
Authors: Salomão Najoua Adriana , Geraldes Amandio Aristides Rihan , Lima-Silva Adriano Eduardo 
Published: March 2019

The aim of this study was to verify the effect of physical activity level on bone mineral density (BMD) in pre-menopausal women with lactose intolerance. Sixty women was engaged in this study (age: 31.9±6.9 years) and were initially separated into two groups: 30 women with lactose intolerance (LI) and 30 controls (C). The groups were further subdivided into less and more active using the median of weekly total energy expenditure, estimated by the International Physical Activity Questionnaire (IPAQ-long version). The LI diagnosis was confirmed by lactose intolerance test (oral lactose overload with monitoring of blood glucose and associated clinical manifestations). BMD was assessed by dual energy X-ray absorptiometry (DXA). As expected, physical activity score was higher in both groups for women classified as more active (p>0.05). The BMD at hip and pelvis was lower in LI than in C group (p<0.05). In addition, there was a tendency for a lower BMD in L2, L4, femoral neck and total hip for LI compared to C group (p<0.10). However, there was no main effect of physical activity level or interaction for the BMD at any other bone sites (p<0.10). The LI group had lower (p<0.05) absolute free-fat mass, independently of physical activity level. Therefore, the results of the present study suggest that LI reduces BMD in pre-menopausal women and this reduction is independent of physical activity level.
Prophylactic Use of Implantable Cardioverter-Defibrillators in the Prevention of Sudden Cardiac Death in Dialysis Patients
Authors: Jukema J. Wouter , Timal Rohit J. , Rotmans Joris I. , Hensen Liselotte C. R. , Buiten Maurits S. , de Bie Mihaly K. , Putter Hein , Zwinderman Aeilko H. , van Erven Lieselot , Krol-van Straaten M. Jacqueline , Hommes Nienke , Gabreëls Bas , van Dorp Wim , van Dam Bastiaan , Herzog Charles A. , Schalij Martin J. , Rabelink Ton J. ,   For the ICD2 Trial Investigators
Published: March 2019

Background:
Patients with end-stage renal disease who are undergoing dialysis are reported to be at high risk of sudden cardiac death (SCD), and to date, no therapy has been shown to be effective in reducing this risk. The feasibility and value of prophylactic implantable cardioverter-defibrillator (ICD) implantation to prevent SCD is uncertain.

Methods:
We conducted the ICD2 trial (Implantable Cardioverter-Defibrillator in Dialysis Patients), a prospective, randomized, controlled study investigating the value and safety of ICD implantation to prevent SCD in 200 patients on dialysis with a left ventricular ejection fraction ≥35%, after adequate screening and optimization of other treatments. The primary end point was SCD. Secondary end points were all-cause mortality and ICD-related complications.

Results:

The trial was stopped as per the recommendation of the data and safety monitoring board for futility reasons after inclusion of 188 patients, 97 in the ICD group and 91 in the control group. The median duration of follow-up was 6.8 years (interquartile range, 3.8–8.8 years). SCD occurred in 19 of 188 cases (10.1%), 11 of 97 in the ICD group and 8 of 91 in the control group. The cumulative SCD incidence at 5 years was 9.7% (95% CI, 3.3%–16.2%) in the ICD group and 7.9% (95% CI, 1.7–14.0%) in the control group, resulting in a hazard ratio of 1.32 (95% CI, 0.53–3.29;
P
=0.55). Overall, 99 of 188 patients died (52.7%), 52 in the ICD group and 47 in the control group. Five-year survival probability was 50.6% (95% CI, 39.8%–61.5%) in the ICD group and 54.5% (95% CI, 43.0–66.0%) in the control group, resulting in a hazard ratio of 1.02 (95% CI, 0.69–1.52;
P
=0.92). Among 80 patients who received an ICD, 25 adverse events related to ICD implantation occurred.

Conclusions:
In a well-screened and well-treated population undergoing dialysis, prophylactic ICD therapy did not reduce the rate of SCD or all-cause mortality, which remained high.

Clinical Trial Registration:

URL:
http://www.controlled-trials.com
. Unique identifier: ISRCTN20479861.
Endothelial Insulin Resistance of Freshly Isolated Arterial Endothelial Cells From Radial Sheaths in Patients With Suspected Coronary Artery Disease
Authors: Masaki Nobuyuki , Ido Yasuo , Yamada Toshiyuki , Yamashita Youhei , Toya Takumi , Takase Bonpei , Hamburg Naomi M. , Adachi Takeshi 
Published: March 2019

Background
Endothelial insulin resistance is insulin‐insensitivity in the vascular endothelium and can be observed in experimental models. This study aimed to investigate endothelial insulin resistance in patients with suspected coronary artery disease. To this end, a novel method of obtaining freshly isolated arterial endothelial cells from a radial catheter sheath was developed.

Methods and Results

Freshly isolated arterial endothelial cells were retrieved from catheter sheaths placed in radial arteries for coronary angiography (n=69, patient age 64±12 years). The endothelial cells were divided into groups for incubation with or without insulin, vascular endothelial growth factor, or acetylcholine. The intensity of phosphorylated endothelial nitric oxide synthase at Ser1177 (p‐
eNOS
) was quantified by immunofluorescence microscopy. The percentage increase of insulin‐induced phosphorylated endothelial nitric oxide synthase correlated negatively with derivatives of reactive oxygen metabolites, an oxidative stress test (
r
=−0.348, n=53,
P
=0.011), E/E′, an index of left ventricular diastolic dysfunction in Doppler echocardiography (ρ=−0.374, n=49,
P
=0.008), and log‐transformed brain natriuretic peptide (
r
=−0.266, n=62,
P
=0.037). Furthermore, percentage increase of insulin‐induced p‐
eNOS
was an independent factor for the cardio‐ankle vascular index (standardized coefficient β=−0.293, n=42,
P
=0.021) in the multivariate regression analysis of adaptive least absolute shrinkage and selection operator.

Conclusions
Our results suggested that endothelial insulin resistance is associated with oxidative stress, left ventricular diastolic dysfunction, heart failure, and arterial stiffness.
Emphysema
Authors: Mahta Ali , Merkler Alexander E. , Reznik Michael E. , Burch Jaclyn E. , Yaghi Shadi , Sellke Frank W. , Furie Karen L. , Kamel Hooman 
Published: March 2019

Background and Purpose—
Protease/antiprotease imbalance is implicated in the pathogenesis of emphysema and may also lead to vessel wall weakening, aneurysm development, and rupture. However, it is unclear whether emphysema is associated with cerebral and aortic aneurysm rupture.

Methods—

We performed a retrospective cohort study using outpatient and inpatient claims data from 2008 to 2014 from a nationally representative sample of Medicare beneficiaries ≥66 years of age. Our predictor variable was emphysema, and our outcome was hospitalization for either aneurysmal subarachnoid hemorrhage or a ruptured aortic aneurysm. All predictors and outcomes were defined using previously reported
International Classification of Diseases, Ninth Revision, Clinical Modification
diagnosis code algorithms. Survival statistics and Cox regression were used to compare risk between patients with and without emphysema.

Results—
We identified 1 670 915 patients, of whom 133 972 had a diagnosis of emphysema. During a mean follow-up period of 4.3 (±1.9) years, we identified 4835 cases of aneurysm rupture, 433 of which occurred in patients with emphysema. The annual incidence of aneurysm rupture was 6.5 (95% CI, 6.4–6.8) per 10 000 in patients without emphysema and 14.6 (95% CI, 13.3–16.0) per 10 000 in patients with emphysema. After adjustment for demographics and known risk factors for aneurysmal disease, emphysema was independently associated with aneurysm rupture (hazard ratio, 1.7; 95% CI, 1.5–1.9). Emphysema was associated with both aneurysmal subarachnoid hemorrhage (hazard ratio, 1.5; 95% CI, 1.3–1.7) and ruptured aortic aneurysm (hazard ratio, 2.3; 95% CI, 1.9–2.8).

Conclusions—
Patients with emphysema face an increased risk of developing subarachnoid hemorrhage and aortic aneurysm rupture, potentially consistent with shared pathways in pathogenesis.
Sorting out Lalos: description of new species and additional taxonomic data on megophryid frogs from northern Indochina (genus Leptolalax, Megophryidae, Anura)
Authors: OHLER ANNEMARIE , WOLLENBERG KATHARINA C. , GROSJEAN STÉPHANE , HENDRIX RALF , VENCES MIGUEL , ZIEGLER THOMAS , DUBOIS ALAIN 
Published: March 2019

Frogs in the subgenus Lalos of the genus Leptolalax (Megophryidae) are highly diversified in continental Asia and consist of about 17 nominal species. These frogs are small, inconspicuous, and of high superficial morphological similarity. We here formulate a hypothesis of phylogenetic relationships and assess the amount of genetic variation among genealogical lineages on the basis of 536bp of mitochondrial 16S rDNA sequences. Combining molecular data with a study of morpho-logy, morphometric divergence and geographical proximity, we tested hypotheses of species identity. We (1) used character-based and morphometric analyses to assign the onymophoronts (type specimens) of species in Lalos available to us to respectively one of the main clades, in order to propose the best potential correct taxonomic and nomenclatural allocation for the individuals included in the molecular study, and (2) tried to also assign the historical museum specimens to these molecular taxonomic units and to reclassify them whenever necessary. We also used the molecular data to match tadpoles with adults and provide tadpole descriptions for species the larvae of which were previously unknown. Specimens, that could neither be allocated to a molecularly characterised species (on the basis of their DNA “barcode”) nor to a morphologically defined species named on the basis of a type specimen, are described here as new species. Based on this integrative set of data and analyses we describe two new species, Leptolalax eos n. sp. and Leptolalax nyx n. sp., we resurrect Leptolalax minimus, and reassess the distribution of the species studied. We propose changes in the Red List status of L. pelodytoides and L. ventripunctatus and suggest a conservation status for the new species described herein.
Application of the Cell Perturbation Method to Large-Eddy Simulations of a Real Urban Area
Authors: Lee Gwang-Jin , Muñoz-Esparza Domingo , Yi Chaeyeon , Choe Hi Jun 
Published: March 2019

AbstractWith the continuous increase in computing capabilities, large-eddy simulation (LES) has recently gained popularity in applications related to flow, turbulence, and dispersion in the urban atmospheric boundary layer (ABL). Herein, we perform high-resolution building-scale LES over the Seoul, South Korea, city area to investigate the impact of inflow turbulence on the resulting turbulent flow field in the urban ABL. To that end, LES using the cell perturbation method for inflow turbulence generation is compared to a case where no turbulence fluctuations in the incoming ABL are present (unperturbed case). Validation of the model results using wind speed and wind direction observations at 3 m above ground level reveals minimal differences irrespective of the presence of incoming ABL turbulence. This is due to the high density of building structures present at the surface level that create shear instabilities in the flow field and therefore induce local turbulence production. In the unperturbed case, turbulent fluctuations are found to slowly propagate in the vertical direction with increasing fetch from the inflow boundaries, creating an internal boundary layer that separates the turbulent region near the building structures and the nonturbulent flow aloft that occupies the rest of the ABL. Analysis of turbulence quantities including energy spectra, velocity correlations, and passive scalar fluxes reveals significant underpredictions that rapidly grow with increasing height within the ABL. These results demonstrate the need for realistic inflow turbulence in building-resolving LES modeling to ensure proper interactions within the ABL.
Modulation of the Impacts of the Indian Ocean Basin Mode on Tropical Cyclones over the Northwest Pacific during the Boreal Summer by La Niña Modoki
Authors: Huangfu Jingliang , Chen Wen , Huang Ronghui , Feng Juan 
Published: March 2019

AbstractThis paper investigates how La Niña Modoki modulates the impacts of the warm Indian Ocean basin mode (IOBM) on the boreal summer climate and the genesis of tropical cyclones (TCs) over the northwest Pacific (NWP). The results showed that the influence of the Indian Ocean sea surface temperature (SST) on TC genesis is the primary mechanism during the boreal summer, while La Niña Modoki exerts a secondary influence. However, although the summertime index of the IOBM shows a high negative correlation with the number of TCs generated over the NWP, warm IOBM events without La Niña Modoki have only limited influences on the boreal summertime circulations and TC genesis. The present study showed that when warm IOBM events and La Niña Modoki coexisted, the average location of TC genesis shifted westward, and the annual number of generated TCs substantially decreased. La Niña Modoki–related cold sea surface temperature anomalies over the central Pacific further suppressed convective activities over the eastern NWP compared with warm IOBM events without La Niña Modoki. Upper-level convergence and enlarged tropospheric vertical wind shears both contributed to the weakening of the low-level relative vorticity in the coupled cases, leading to a suppressed NWP monsoon trough. Additionally, together with the weaker moisture supply, the impacts of warm IOBM cases were significantly enhanced under the modulation of La Niña Modoki, leading to poorer TC genesis conditions over the eastern NWP. In addition, the energy conversion processes in the aforementioned modulation showed that joint cases will provide fewer initial disturbance seedlings for TC genesis. These results are useful for further understanding the role of warm IOBM cases in TC genesis over the NWP.