bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer
Authors: Zhang Hanwen , Zhang Ning , Liu Ying , Su Peng , Liang Yiran , Li Yaming , Wang Xiaolong , Chen Tong , Song Xiaojin , Sang Yuting , Duan Yi , Zhang Jiashu , Wang Lijuan , Chen Bing , Zhao Wenjing , Guo Haiyang , Liu Zhaojian , Hu Guohong , Yang Qifeng 
Published: April 2019

Abstract

Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS. NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway in vitro and in vivo. In a cohort of 480 breast cancer patients, NAMPT was associated with breast cancer–specific survival and overall survival. These results demonstrate that NAMPT-AS is an oncogenic lncRNA in TNBC that epigenetically activates NAMPT to promote tumor progression and metastasis. Furthermore, these data identify NAMPT-AS/NAMPT as promising therapeutic targets in patients with TNBC.

Significance:
Upregulation of the long noncoding antisense RNA of NAMPT gene (NAMPT-AS) is associated with metastasis and poor prognosis in TNBC.
Auranofin Protects Intestine against Radiation Injury by Modulating p53/p21 Pathway and Radiosensitizes Human Colon Tumor
Authors: Nag Dhrubajyoti , Bhanja Payel , Riha Randal , Sanchez-Guerrero Giselle , Kimler Bruce F. , Tsue Terance T. , Lominska Chris , Saha Subhrajit 
Published: April 2019

Abstract

Purpose:
The radiosensitivity of the normal intestinal epithelium is the major limiting factor for definitive radiotherapy against abdominal malignancies. Radiosensitizers, which can be used without augmenting radiation toxicity to normal tissue, are still an unmet need. Inhibition of proteosomal degradation is being developed as a major therapeutic strategy for anticancer therapy as cancer cells are more susceptible to proteasomal inhibition–induced cytotoxicity compared with normal cells. Auranofin, a gold-containing antirheumatoid drug, blocks proteosomal degradation by inhibiting deubiquitinase inhibitors. In this study, we have examined whether auranofin selectively radiosensitizes colon tumors without promoting radiation toxicity in normal intestine.

Experimental Design:
The effect of auranofin (10 mg/kg i.p.) on the radiation response of subcutaneous CT26 colon tumors and the normal gastrointestinal epithelium was determined using a mouse model of abdominal radiation. The effect of auranofin was also examined in a paired human colonic organoid system using malignant and nonmalignant tissues from the same patient.

Results:
Both in the mouse model of intestinal injury and in the human nonmalignant colon organoid culture, auranofin pretreatment prevented radiation toxicity and improved survival with the activation of p53/p21–mediated reversible cell-cycle arrest. However, in a mouse model of abdominal tumor and in human malignant colonic organoids, auranofin inhibited malignant tissue growth with inhibition of proteosomal degradation, induction of endoplasmic reticulum stress/unfolded protein response, and apoptosis.

Conclusions:
Our data suggest that auranofin is a potential candidate to be considered as a combination therapy with radiation to improve therapeutic efficacy against abdominal malignancies.
Combination of Trastuzumab Emtansine and Stereotactic Radiosurgery Results in High Rates of Clinically Significant Radionecrosis and Dysregulation of Aquaporin-4
Authors: Stumpf Priscilla K. , Cittelly Diana M. , Robin Tyler P. , Carlson Julie A. , Stuhr Kelly A. , Contreras-Zarate Maria Jose , Lai Steven , Ormond D. Ryan , Rusthoven Chad G. , Gaspar Laurie E. , Rabinovitch Rachel , Kavanagh Brian D. , Liu Arthur , Diamond Jennifer R. , Kabos Peter , Fisher Christine M. 
Published: April 2019

Abstract

Purpose:
Patients with human EGFR2-positive (HER2+) breast cancer have a high incidence of brain metastases, and trastuzumab emtansine (T-DM1) is often employed. Stereotactic radiosurgery (SRS) is frequently utilized, and case series report increased toxicity with combination SRS and T-DM1. We provide an update of our experience of T-DM1 and SRS evaluating risk of clinically significant radionecrosis (CSRN) and propose a mechanism for this toxicity.

Experimental Design:
Patients with breast cancer who were ≤45 years regardless of HER2 status or had HER2+ disease regardless of age and underwent SRS for brain metastases were included. Rates of CSRN, SRS data, and details of T-DM1 administration were recorded. Proliferation and astrocytic swelling studies were performed to elucidate mechanisms of toxicity.

Results:
A total of 45 patients were identified; 66.7% were HER2+, and 60.0% were ≤ 45 years old. Of the entire cohort, 10 patients (22.2%) developed CSRN, 9 of whom received T-DM1. CSRN was observed in 39.1% of patients who received T-DM1 versus 4.5% of patients who did not. Receipt of T-DM1 was associated with a 13.5-fold (P = 0.02) increase in CSRN. Mechanistically, T-DM1 targeted reactive astrocytes and increased radiation-induced cytotoxicity and astrocytic swelling via upregulation of Aquaporin-4 (Aqp4).

Conclusions:
The strong correlation between development of CSRN after SRS and T-DM1 warrants prospective studies controlling for variations in timing of T-DM1 and radiation dosing to further stratify risk of CSRN and mitigate toxicity. Until such studies are completed, we advise caution in the combination of SRS and T-DM1.
Targeting Glutamine Metabolism and Redox State for Leukemia Therapy
Authors: Gregory Mark A. , Nemkov Travis , Park Hae J. , Zaberezhnyy Vadym , Gehrke Sarah , Adane Biniam , Jordan Craig T. , Hansen Kirk C. , D’Alessandro Angelo , DeGregori James 
Published: April 2019

Abstract

Purpose:
Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. These studies were directed at determining the effects of glutaminase inhibition on metabolism in AML and identifying general weaknesses that can be exploited therapeutically.

Experimental Design:
AML cancer cell lines, primary AML cells, and mouse models of AML and acute lymphoblastic leukemia (ALL) were utilized.

Results:
We show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples, and in vivo using mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating ALL cells in vitro and in vivo.

Conclusions:
Targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.
Targeting CD38 Enhances the Antileukemic Activity of Ibrutinib in Chronic Lymphocytic Leukemia
Authors: Manna Alak , Aulakh Sonikpreet , Jani Prachi , Ahmed Salman , Akhtar Sharoon , Coignet Marie , Heckman Michael , Meghji Zahara , Bhatia Kirtipal , Sharma Aarushi , Sher Taimur , Alegria Victoria , Malavasi Fabio , Chini Eduardo N. , Chanan-Khan Asher , Ailawadhi Sikander , Paulus Aneel 
Published: April 2019

AbstractPurpose:CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 mAb). The clinical importance of CD38 in patients with chronic lymphocytic leukemia (CLL) has been known for over 2 decades, although it's relevance as a therapeutic target in CLL remains understudied.Experimental Design:We investigated the biological effects and antitumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector mechanisms (antibody-dependent cell-mediated cytotoxicity, complement-dependent death, and antibody-dependent cellular phagocytosis), we also measured direct apoptotic effects of daratumumab alone or in combination with ibrutinib. In vivo antileukemic activity was assessed in a partially humanized xenograft model. The influence of CD38 on B-cell receptor (BCR) signaling was measured via immunoblotting of Lyn, Syk, BTK, PLCγ2, ERK1/2, and AKT.Results:In addition to immune-effector mechanisms; daratumumab also induced direct apoptosis of primary CLL cells, which was partially dependent on FcγR cross-linking. For the first time, we demonstrated the influence of CD38 on BCR signaling where interference of CD38 downregulated Syk, BTK, PLCγ2, ERK1/2, and AKT; effects that were further enhanced by addition of ibrutinib. In comparison to single-agent treatment, the combination of ibrutinib and daratumumab resulted in significantly enhanced anti-CLL activity in vitro and significantly decreased tumor growth and prolonged survival in the in vivo CLL xenograft model.Conclusions:Overall, our data demonstrate the antitumor mechanisms of daratumumab in CLL; furthermore, we show how cotargeting BTK and CD38 lead to a robust anti-CLL effect, which has clinical implications.
Urinary Biomarkers of Tubular Damage Are Associated with Mortality but Not Cardiovascular Risk among Systolic Blood Pressure Intervention Trial Participants with Chronic Kidney Disease
Authors: Jotwani Vasantha K. , Lee Alexandra K. , Estrella Michelle M. , Katz Ronit , Garimella Pranav S. , Malhotra Rakesh , Rifkin Dena E. , Ambrosius Walter , Freedman Barry I. , Cheung Alfred K. , Raphael Kalani L. , Drawz Paul , Neyra Javier A. , Oparil Suzanne , Punzi Henry , Shlipak Michael G. , Ix Joachim H. ,   for the SPRINT Research Group
Published: April 2019

<b><i>Background:</i></b> Kidney tubulointerstitial fibrosis on biopsy is a strong predictor of chronic kidney disease (CKD) progression, and CKD is associated with elevated risk of cardiovascular disease (CVD). Tubular health is poorly quantified by traditional kidney function measures, including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of tubular injury, inflammation, and repair would be associated with higher risk of CVD and mortality in persons with CKD. <b><i>Methods:</i></b> We measured urinary concentrations of interleukin-18 (IL-18), kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and chitinase-3-like protein-1 (YKL-40) at baseline among 2,377 participants of the Systolic Blood Pressure Intervention Trial who had an eGFR &#x3c; 60 mL/min/1.73 m<sup>2</sup>. We used Cox proportional hazards models to evaluate biomarker associations with CVD events and all-cause mortality. <b><i>Results:</i></b> At baseline, the mean age of participants was 72 ± 9 years, and eGFR was 48 ± 11 mL/min/1.73 m<sup>2</sup>. Over a median follow-up of 3.8 years, 305 CVD events (3.6% per year) and 233 all-cause deaths (2.6% per year) occurred. After multivariable adjustment including eGFR, albuminuria, and urinary creatinine, none of the biomarkers showed statistically significant associations with CVD risk. Urinary IL-18 (hazard ratio [HR] per 2-fold higher value, 1.14; 95% CI 1.01–1.29) and YKL-40 (HR per 2-fold higher value, 1.08; 95% CI 1.02–1.14) concentrations were each incrementally associated with higher mortality risk. Associations were similar when stratified by randomized blood pressure arm. <b><i>Conclusions:</i></b> Among hypertensive trial participants with CKD, higher urinary IL-18 and YKL-40 were associated with higher risk of mortality, but not CVD.
Clinical Role of Microembolic Signals in Adult Moyamoya Disease With Ischemic Stroke
Authors: Jeon Chiman , Yeon Je Young , Jo Kyung Il , Hong Seung-Chyul , Kim Jong-Soo 
Published: April 2019

Background and Purpose—
Hemodynamic compromise has been implicated in moyamoya disease (MMD) with transient ischemic attacks or ischemic stroke. However, increasing evidence supports the notion that artery-to-artery embolism may also contribute to ischemic events based on microembolic signal (MES) monitoring.

Methods—
A total of 48 patients aged between 20 and 60 years with newly diagnosed MMD were enrolled and angiographically classified according to the Suzuki staging system. For detection of MESs, transcranial Doppler was performed at the middle cerebral artery bilaterally for a 30-minute period. Mean flow velocities in the middle cerebral artery were also evaluated and categorized into low (<40 cm/s), normal (40–80 cm/s), and high (>80 cm/s). Clinical characteristics, cerebral angiography findings, recent ischemic events within 3 months, and antiplatelet medication were correlated with transcranial Doppler findings.

Results—

MESs were detected in 11 of the 48 patients (23%), with a frequency of 11 of 89 (12%) examined hemispheres. The mean number of MESs was 2 (range, 1–6). Six of the 11 hemispheres (55%) presented with ischemic strokes or transient ischemic attacks, and 2 (18%) presented with hemorrhagic strokes. The presence of MESs was associated with recent ischemic events (
P
=0.024) and high mean flow velocities (
P
=0.016), which was usually observed in Suzuki stage I and II (early-stage MMD). After controlling for age, sex, and antiplatelet medication, both recent ischemic events (odds ratio, 6.294; 95% CI, 1.345–29.457;
P
=0.019) and high mean flow velocities (odds ratio, 6.172; 95% CI, 1.235–31.25;
P
=0.027) were found to be independent predictors of MESs.

Conclusions—
MESs were observed in patients with high mean flow velocities, particularly early-stage MMD, and clinically associated with recent ischemic events. A randomized controlled study is necessary to determine the efficacy of antiplatelet agents in the treatment of MES-positive MMD.
Antiepileptic Drugs to Prevent Seizures After Spontaneous Intracerebral Hemorrhage
Authors: Angriman Federico , Tirupakuzhi Vijayaraghavan Bharath Kumar , Dragoi Laura , Lopez Soto Carmen , Chapman Martin , Scales Damon C. 
Published: April 2019

Background and Purpose—
We sought to evaluate the available literature to determine whether primary seizure prevention with antiepileptic drugs reduces the risk of poor outcomes and clinically relevant seizures among adult patients with spontaneous intracerebral hemorrhage.

Methods—
Meta-analysis of observational studies and randomized controlled trials evaluating the use of any antiepileptic drug for primary seizure prevention among adult (≥18 years) patients with spontaneous intracerebral hemorrhage. The primary end point was poor clinical outcome at the longest recorded follow-up, defined as either a high (>3) modified Rankin Scale score or all-cause mortality during follow-up if the modified Rankin Scale score was not recorded. Early and late seizures were secondary outcomes. A random mixed effects model was used to estimate the pooled odds ratio of outcomes and associated 95% CI.

Results—
We identified 7 studies with a total of 3241 patients for analysis of the primary outcome and 4 studies with a total of 1861 patients for analysis of the secondary outcomes. Overall, the use of antiepileptic drugs was not associated with a high Rankin Scale or all-cause mortality (odds ratio: 0.99; 95% CI, 0.66–1.49) or incident seizures (odds ratio: 0.89; 95% CI, 0.52–1.51) at the longest recorded follow-up time.

Conclusions—
The use of antiepileptic drugs as primary prevention among adult patients with spontaneous intracerebral hemorrhage is not associated with improved neurological function during long-term follow-up. Future studies should focus on the preventive use of distinct antiepileptic agents among patients at high risk of both seizures and poor outcomes.
Changes in Vegetation Cover of the Arctic National Wildlife Refuge Estimated from MODIS Greenness Trends, 2000–18
Authors: Potter Christopher 
Published: April 2019

Abstract
Trends and transitions in the growing-season normalized difference vegetation index (NDVI) from the Moderate Resolution Imaging Spectroradiometer (MODIS) satellite sensor at 250-m resolution were analyzed for the period from 2000 to 2018 to understand recent patterns of vegetation change in ecosystems of the Arctic National Wildlife Refuge (ANWR) in Alaska. Statistical analysis of changes in the NDVI time series was conducted using the breaks for additive seasonal and trend method (BFAST). This structural change analysis indicated that NDVI breakpoints and negative 18-yr trends in vegetation greenness over the years since 2000 could be explained in large part by the impacts of severe wildfires. At least one NDVI breakpoint was detected in around 20% of the MODIS pixels within both the Porcupine River and Coleen River basins of the study area. The vast majority of vegetation cover in the ANWR Brooks Range and coastal plain ecoregions was detected with no (positive or negative) growing-season NDVI trends since the year 2000. Results suggested that most negative NDVI anomalies in the 18-yr MODIS record have been associated with early spring thawing and elevated levels of surface moisture in low-elevation drainages of the northern ANWR ecoregions.
Summer Temperature over the Tibetan Plateau Modulated by Atlantic Multidecadal Variability
Authors: Shi Chunming , Sun Cheng , Wu Guocan , Wu Xiuchen , Chen Deliang , Masson-Delmotte Valérie , Li Jianping , Xue Jiaqing , Li Zongshan , Ji Duoying , Zhang Jing , Fan Zexin , Shen Miaogen , Shu Lifu , Ciais Philippe 
Published: April 2019

Abstract
Rapid warming has led to an aggregated environmental degradation over the Tibetan Plateau (TP) in the last few decades, including accelerated glacier retreat, early snowmelt, permafrost degradation, and forest fire occurrence. Attribution of this warming in recent decades has mainly been focused on anthropogenic forcing. Yet, linkages to the Atlantic multidecadal variability (AMV), an essential part of the climate system causing decadal to centennial fluctuations of temperature, remains poorly understood for the TP, especially at long time scales. Using well-replicated tree-ring width records, we reconstructed 358 years of summer minimum temperature (MinT) of the whole TP. This reconstruction matches the recent warming signal recorded since the 1980s, and captures 63% of the variance in 1950–2005 instrumental records. A teleconnection from the North Atlantic to the TP is further identified based in observations and simulations with an atmospheric general circulation model (AGCM). We propose that half of the multidecadal variability of TP summer MinT can be explained by the AMV over the past three and a half centuries. Both observations and AGCM simulations indicate that the AMV warm phase induces a zonal dipole response in sea level pressure across the Atlantic–Eurasia region, with anomalously high surface pressure and corresponding downward atmospheric motion over the TP. We propose that the descending motion during warm AMV phases causes negative rainfall and positive temperature anomalies over the TP. Our findings highlight that the AMV plays a role in the multidecadal temperature variability over the TP.
Triggering Global Climate Transitions through Volcanic Eruptions
Authors: Gupta Mukund , Marshall John , Ferreira David 
Published: April 2019

AbstractA coupled climate model with idealized representations of atmosphere, ocean, sea ice, and land is used to investigate transitions between global climate equilibria. The model supports the presence of climates with limited ice cover (Warm), a continuum of climates in which sea ice extends down into the midlatitudes and the tropics (Cold), together with a completely ice-covered earth (Snowball). Transitions between these states are triggered through volcanic eruptions, where the radiative effect of stratospheric sulfur emissions is idealized as an impulse reduction in incoming solar radiation. Snowball transitions starting from the Cold state are more favorable than from the Warm state, because less energy must be extracted from the system. However, even when starting from a Cold climate, Toba-like volcanic events (cooling of order −100 W m−2) must be sustained continuously for several decades to glaciate the entire planet. When the deep ocean is involved, the volcanic response is characterized by relaxation time scales spanning hundreds to thousands of years. If the interval between successive eruptions is significantly shorter (years to decades) than the ocean’s characteristic time scales, the cumulative cooling can build over time and initiate a state transition. The model exhibits a single hysteresis loop that connects all three climate equilibria. When starting from a Snowball, the model cannot access the Cold branch without first transitioning to an ice-free climate and completing the hysteresis loop. By contrast, a Cold state, when warmed, transitions to the Warm equilibrium without any hysteresis.
Downslope Winds and Dust Storms in the Salton Basin
Authors: Evan Amato T. 
Published: April 2019

Abstract
The Salton basin is a closed, subsea level basin located in extreme southeastern California. At the center of the basin lies the Salton Sea, the state’s largest inland lake, which is surrounded by a desert landscape characterized by paleo lakebed surfaces, dry washes, alluvial fans, and interdunes. Dust storms are common occurrence in this region. However, despite the regularity of dust outbreaks here, little is known about the meteorological processes responsible for these storms. Here I use observations and output from reanalysis to elucidate the meteorological controls on dust emission events in the Salton basin during 2015–18. Analysis of surface and upper-air observations, satellite data, and reanalysis, suggest that the largest dust storms in the region are associated with an upper-level low centered near the coastline of western Canada, which directs a zonal low-level jet over the region. Flow blocking by a coastal mountain range results in isentropic drawdown of air in the lee of these mountains. Once surface warming at the floor of the Salton basin is sufficient such that the density of the descending air is greater than that of the ambient air at the surface, the downslope windstorm reaches the desert floor and initiates dust emission. This process may also be accompanied by a downwind propagating hydraulic jump. These processes appear to be similar to those responsible for the strongest dust events in the Owens Valley, and may represent the main mechanisms for emission from other closed basins.