bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis and numerical modelling of large-scale controls on aquifer structure and hydrogeological properties in the African basement (Benin, West Africa)
Authors: Dickson Neil E. M. , Comte Jean-Christophe , Koussoube Youssouf , Ofterdinger Ulrich S. , Vouillamoz Jean-Michel 
Published: May 2018

Abstract

The metamorphic basement units of the Upper Ouémé watershed in Benin have been investigated to identify the structural controls on aquifer properties, groundwater flow and water balance at large scale. Spatial analysis of borehole and hydrogeophysical data suggests that large-scale weathering profiles, aquifer transmissivity and storage properties are better correlated to a palaeo-weathering surface. Multi-model analysis, combined with assessment of nine transient numerical groundwater models against observations, suggests the best conceptualizations are those where hydraulic conductivity and specific yield are distributed within a weathered zone determined through interpolation of weathered zone thickness. When compared to previous studies, the general groundwater balance of simulated models suggests the groundwater system contributes, on average, 49.8 m
3
s
−1
to the river flow (mostly during the rainy season). The same volumetric flow would be lost to groundwater evapo-transpiration and deep/lateral drainage of the catchment. Borehole abstraction (about 7.5 m
3
s
−1
) represents only 6% of the average groundwater recharge and 1% of the average rainfall. This suggests that despite relatively low borehole productivity, the basement aquifer system still has an important unused potential for rural to mid-scale water supply and that, at present, the main external drivers for groundwater resource sustainability are changes in climate and land use.
Alternatively-Activated Macrophages Upregulate Mesothelial Expression of P-Selectin to Enhance Adhesion of Ovarian Cancer Cells
Authors: Carroll Molly J. , Fogg Kaitlin C. , Patel Harin A. , Krause Harris B. , Mancha Anne-Sophie , Patankar Manish S. , Weisman Paul S. , Barroilhet Lisa , Kreeger Pamela K. 
Published: May 2018

Abstract
Peritoneal metastasis of high-grade serous ovarian cancer (HGSOC) occurs when tumor cells suspended in ascites adhere to mesothelial cells. Despite the strong relationship between metastatic burden and prognosis in HGSOC, there are currently no therapies specifically targeting the metastatic process. We utilized a coculture model and multivariate analysis to examine how interactions between tumor cells, mesothelial cells, and alternatively-activated macrophages (AAM) influence the adhesion of tumor cells to mesothelial cells. We found that AAM-secreted MIP-1β activates CCR5/PI3K signaling in mesothelial cells, resulting in expression of P-selectin on the mesothelial cell surface. Tumor cells attached to this de novo P-selectin through CD24, resulting in increased tumor cell adhesion in static conditions and rolling underflow. C57/BL6 mice treated with MIP-1β exhibited increased P-selectin expression on mesothelial cells lining peritoneal tissues, which enhanced CaOV3 adhesion ex vivo and ID8 adhesion in vivo. Analysis of samples from patients with HGSOC confirmed increased MIP-1β and P-selectin, suggesting that this novel multicellular mechanism could be targeted to slow or stop metastasis in HGSOC by repurposing anti-CCR5 and P-selectin therapies developed for other indications.
Significance: This study reports novel insights on the peritoneal dissemination occurring during progression of ovarian cancer and has potential for therapeutic intervention.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3560/F1.large.jpg. Cancer Res; 78(13); 3560–73. ©2018 AACR.
Evidence of Intertissue Differences in the DNA Damage Response and the Pro-oncogenic Role of NF-κB in Mice with Disengaged BRCA1–PALB2 Interaction
Authors: Mahdi Amar Hekmat , Huo Yanying , Tan Yongmei , Simhadri Srilatha , Vincelli Gabriele , Gao Jie , Ganesan Shridar , Xia Bing 
Published: May 2018

Abstract
The BRCA1–PALB2–BRCA2 axis plays an essential role in DNA homologous recombination repair, defect in which drives genome instability and cancer development. How cells with defects in this pathway respond to DNA damage in vivo and how tumors develop from these cells remain poorly defined. Here, we analyzed several aspects of the DNA damage response in multiple tissues of Palb2-mutant mice in which the interaction between PALB2 and BRCA1 is disengaged. Without any challenge, the mutant mice showed increased endogenous DNA damage. Following ionizing radiation, the mutant mice displayed higher levels of DNA breaks and stronger induction of p53 and p21, but continued DNA synthesis, reduced apoptosis, and accelerated tumor development. The differences in p21 induction, DNA synthesis, and apoptosis between wild-type and mutant mice were substantially more pronounced in the mammary gland than in the intestine, suggesting a potential contributing factor to the increased risk and the tissue specificity of BRCA/PALB2-associated tumor development. Moreover, the mutant mice showed higher levels of reactive oxygen species and constitutive activation of NF-κB, an antiapoptotic transcription factor inducible by both DNA damage and oxidative stress. Treatment of the mutant mice with an inhibitor of NF-κB reactivated apoptosis and delayed tumor development following radiation. Thus, our results also suggest a prosurvival and pro-oncogenic role of NF-κB in PALB2-mutant cells.
Significance: This study explores novel tumor suppression mechanisms of the BRCA1-PALB2 DNA damage response pathway and implicates NF-κB activation as a protumorogenic event and possible therapeutic target. Cancer Res; 78(14); 3969–81. ©2018 AACR.
ΔNp63γ/SRC/Slug Signaling Axis Promotes Epithelial-to-Mesenchymal Transition in Squamous Cancers
Authors: Srivastava Kirtiman , Pickard Adam , Craig Stephanie G. , Quinn Gerard P. , Lambe Shauna M. , James Jacqueline A. , McDade Simon S. , McCance Dennis J. 
Published: May 2018

Abstract
Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in head and neck squamous cell carcinoma (HNSCC) and its importance in tumor invasion.
Experimental Design: We use a three-dimensional invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the human papilloma virus-16, coupled with bioinformatic and IHC analysis of patient samples to investigate the role played by EMT in invasion and identify effectors and upstream regulatory pathways.
Results: We identify SNAI2 (Slug) as a critical effector of EMT-activated downstream of TP63 overexpression in HNSCC. Splice-form–specific depletion and rescue experiments further identify the ΔNp63γ isoform as both necessary and sufficient to activate the SRC signaling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in patients with HNSCC in The Cancer Genome Atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacologic inhibition of SRC.
Conclusions: Overexpression of ΔNp63γ modulates cell invasion by inducing targetable SRC-Slug–evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signaling. Clin Cancer Res; 24(16); 3917–27. ©2018 AACR.
Curation of the Pancreatic Ductal Adenocarcinoma Subset of the Cancer Genome Atlas Is Essential for Accurate Conclusions about Survival-Related Molecular Mechanisms
Authors: Peran Ivana , Madhavan Subha , Byers Stephen W. , McCoy Matthew D. 
Published: May 2018

Abstract
Purpose: Publicly available databases, for example, The Cancer Genome Atlas (TCGA), containing clinical and molecular data from many patients are useful in validating the contribution of particular genes to disease mechanisms and in forming novel hypotheses relating to clinical outcomes.
Experimental Design: The impact of key drivers of cancer progression can be assessed by segregating a patient cohort by certain molecular features and constructing survival plots using the associated clinical data. However, conclusions drawn from this straightforward analysis are highly dependent on the quality and source of tissue samples, as demonstrated through the pancreatic ductal adenocarcinoma (PDAC) subset of TCGA.
Results: Analyses of the PDAC-TCGA database, which contains mainly resectable cancer samples from patients in stage IIB, reveal a difference from widely known historic median and 5-year survival rates of PDAC. A similar discrepancy was observed in lung, stomach, and liver cancer subsets of TCGA. The whole transcriptome expression patterns of PDAC-TCGA revealed a cluster of samples derived from neuroendocrine tumors, which have a distinctive biology and better disease prognosis than PDAC. Furthermore, PDAC-TCGA contains numerous pseudo-normal samples, as well as those that arose from tumors not classified as PDAC.
Conclusions: Inclusion of misclassified samples in the bioinformatic analyses distorts the association of molecular biomarkers with clinical outcomes, altering multiple published conclusions used to support and motivate experimental research. Hence, the stringent scrutiny of type and origin of samples included in the bioinformatic analyses by researchers, databases, and web-tool developers is of crucial importance for generating accurate conclusions. Clin Cancer Res; 24(16); 3813–9. ©2018 AACR.
MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer
Authors: de Leeuw Renée , McNair Christopher , Schiewer Matthew J. , Neupane Neermala Poudel , Brand Lucas J. , Augello Michael A. , Li Zhen , Cheng Larry C. , Yoshida Akihiro , Courtney Sean M. , Hazard E. Starr , Hardiman Gary , Hussain Maha H. , Diehl J. Alan , Drake Justin M. , Kelly Wm. Kevin , Knudsen Karen E. 
Published: May 2018

Abstract
Purpose: Loss of cell-cycle control is a hallmark of cancer, which can be targeted with agents, including cyclin-dependent kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G1–S cell-cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon.
Experimental Design: In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer.
Results: This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive in vitro and in vivo phenotypes, including proliferation, migration, and invasion. Integration of RNA sequencing analysis and phosphoproteomics profiling revealed rewiring of the kinome, with a strong enrichment for enhanced MAPK signaling across all resistance models, which resulted in aggressive in vitro and in vivo phenotypes and prometastatic signaling. However, CDK4/6 inhibitor–resistant models were sensitized to MEK inhibitors, revealing reliance on active MAPK signaling to promote tumor cell growth and invasion.
Conclusions: In sum, these studies identify MAPK reliance in acquired CDK4/6 inhibitor resistance that promotes aggressive disease, while nominating MEK inhibition as putative novel therapeutic strategy to treat or prevent CDK4/6 inhibitor resistance in cancer. Clin Cancer Res; 24(17); 4201–14. ©2018 AACR.
p16 Controls p53 Protein Expression Through miR-dependent Destabilization of MDM2
Authors: Al-Khalaf Huda H. , Aboussekhra Abdelilah 
Published: May 2018

Abstract
p16INK4A and p53 are two major tumor suppressor proteins that are both upregulated in response to various cellular stresses and during senescence and aging. p53 is a well-characterized transcription factor, while p16INK4A a cyclin-dependent kinase inhibitor encoded by the CDKN2A gene, and controls the expression of several genes through protein–protein interactions and also via miRNAs. This report demonstrates a p16INK4A-dependent positive regulation of p53 expression, at the protein level, in various human cells as well as in mouse embryonic fibroblasts. p16 suppresses p53 turnover through inhibition of its MDM2-related ubiquitination. This effect occurs through p16-related promotion of the MDM2 mRNA turnover via the p16INK4A downstream effectors miR-141 and miR-146b-5p, which bind specific sites at the 3′ untranslated region of the MDM2 mRNA.
Implications: The current findings show p16INK4A-dependent stabilization of p53 through miR-141/miR-146b-5p–related posttranscriptional repression of MDM2, thus providing new insights into the complex functional link between p16INK4A and p53. Mol Cancer Res; 16(8); 1299–308. ©2018 AACR.
Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells
Authors: Rasheed Adil , Tsai Ricky , Cummins Carolyn L. 
Published: May 2018

Background

The liver X receptors (
LXRs
; α/β) are nuclear receptors known to regulate cholesterol homeostasis and the production of select hematopoietic populations. The objective of this study was to determine the importance of
LXR
s and a high‐fat high‐cholesterol diet on global hematopoiesis, with special emphasis on endothelial progenitor cells (
EPC
s), a vasoreparative cell type that is derived from bone marrow hematopoietic stem cells.

Methods and Results

Wild‐type and
LXR
double‐knockout (
Lxr
αβ

−/−

) mice were fed a Western diet (
WD
) to increase plasma cholesterol levels. In
WD
‐fed
Lxr
αβ

−/−

mice, flow cytometry and complete blood cell counts revealed that hematopoietic stem cells, a myeloid progenitor, and mature circulating myeloid cells were increased;
EPC
numbers were significantly decreased. Hematopoietic stem cells from
WD
‐fed
Lxr
αβ

−/−

mice showed increased cholesterol content, along with increased myeloid colony formation compared with chow‐fed mice. In contrast,
EPC
s from
WD
‐fed
Lxr
αβ

−/−

mice also demonstrated increased cellular cholesterol content that was associated with greater expression of the endothelial lineage markers
Cd144
and
Vegfr2
, suggesting accelerated differentiation of the
EPC
s. Treatment of human umbilical vein endothelial cells with conditioned medium collected from these
EPC
s increased
THP
‐1 monocyte adhesion. Increased monocyte adhesion to conditioned medium–treated endothelial cells was recapitulated with conditioned medium from
Lxr
αβ

−/−

EPC
s treated with cholesterol ex vivo, suggesting cholesterol is the main component of the
WD
inducing
EPC
dysfunction.

Conclusions

LXR
s are crucial for maintaining the balance of hematopoietic cells in a hypercholesterolemic environment and for mitigating the negative effects of cholesterol on
EPC
differentiation/secretome changes that promote monocyte‐endothelial adhesion.
Single‐Beat Estimation of Right Ventricular Contractility and Its Coupling to Pulmonary Arterial Load in Patients With Pulmonary Hypertension
Authors: Inuzuka Ryo , Hsu Steven , Tedford Ryan J. , Senzaki Hideaki 
Published: May 2018

Background
An accurate assessment of intrinsic right ventricular (RV) contractility and its relation to pulmonary arterial load is essential for the management of pulmonary hypertension. The pressure‐volume relationship with load manipulation is the gold standard assessment used for this purpose, but its clinical application has been hindered by the lack of a single‐beat method that is valid for the human RV. In the present study, we sought to validate a novel single‐beat method to estimate the preload recruitable stroke work (PRSW) and its derivative for ventriculoarterial coupling in the human RV.

Methods and Results

A novel single‐beat slope of the PRSW relationship (M
sw
) was derived by calculating the mean ejection pressure when the end‐systolic volume was equal to volume‐axis intercept of the PRSW relationship. In addition, by using a mathematical transformation of the equation representing the linearity of the PRSW relationship, a novel index for ventriculoarterial coupling, M
sw
/mean ejection pressure, was developed. RV pressure‐volume relationships were measured in 31 patients (including 23 patients with pulmonary hypertension) who were referred for right‐sided heart catheterization. In this cohort, the single‐beat M
sw
was strongly correlated with the multiple‐beat M
sw
(
r
=0.91,
P
<0.0001). Moreover, a significant correlation was observed between the single‐ and multiple‐beat M
sw
/mean ejection pressure (
r
=0.53,
P
=0.002), with a stronger correlation in those with greater RV systolic pressure (
r
=0.70,
P
=0.003).

Conclusions
The novel single‐beat approach provided an accurate estimation of indexes for the PRSW relationship and ventriculoarterial coupling. It may be particularly useful in assessing RV adaptation to increased pressure overload.
Effect of Wave Reflection and Arterial Stiffness on the Risk of Development of Hypertension in Japanese Men
Authors: Tomiyama Hirofumi , Komatsu Shunsuke , Shiina Kazuki , Matsumoto Chisa , Kimura Kazutaka , Fujii Masatsune , Takahashi Lisa , Chikamori Taishiro , Yamashina Akira 
Published: May 2018

Background
We conducted analyses of repeated‐measures data to examine whether pressure wave reflection acts additively or synergistically with arterial stiffness in the pathogenesis of hypertension.

Methods and Results

In 3172 middle‐aged (42±9 years) healthy Japanese men without hypertension at the study baseline, systolic and diastolic blood pressures, brachial–ankle pulse wave velocity, and radial augmentation index were measured annually during a 9‐year study period. Of these, 474 participants (15%) developed hypertension by the end of the study period. Binary logistic regression analysis demonstrated significant individual odds ratios for both baseline brachial–ankle pulse wave velocity and radial augmentation index for the development of hypertension. The rate of onset of hypertension during the study period was highest in the participant group with high values for both brachial–ankle pulse wave velocity and radial augmentation index at study baseline (262 of 965 participants: 27%). The generalized estimating equation analysis revealed that both radial augmentation index (estimate=0.06, SE=0.03,
P
=0.05) and brachial–ankle pulse wave velocity (estimate=0.07×10
−1
, SE=0.02×10
−1
,
P
<0.01) showed significant longitudinal association with new onset of hypertension, with no significant interaction.

Conclusions
In Japanese men, abnormal wave reflection and increased arterial stiffness may be additively associated with the risk of new onset of hypertension. Abnormal wave reflection and elevated central blood pressure may be longitudinally associated with increase in arterial stiffness, and this longitudinal association may be a mechanism underlying the additive effect of these 2 variables on the risk of new onset of hypertension.
Prevalence of Carotid Plaque in a 63‐ to 65‐Year‐Old Norwegian Cohort From the General Population: The ACE (Akershus Cardiac Examination) 1950 Study
Authors: Ihle‐Hansen Håkon , Vigen Thea , Ihle‐Hansen Hege , Rønning Ole Morten , Berge Trygve , Thommessen Bente , Lyngbakken Magnus Nakrem , Orstad Eivind Bjørkan , Enger Steve , Nygård Ståle , Røsjø Helge , Tveit Arnljot 
Published: May 2018

Background

New data on extracranial carotid atherosclerosis are needed, as improved ultrasound techniques may detect more atherosclerosis, the definition of plaque has changed over the years, and better cardiovascular risk control in the population may have changed patterns of carotid arterial wall disease and actual prevalence of established cardiovascular disease. We investigated the prevalence of atherosclerotic carotid plaques and carotid intima–media thickness (
cIMT
) and their relation to cardiovascular risk factors in a middle‐aged cohort from the general population.

Methods and Results

We performed carotid ultrasound in 3683 participants who were born in 1950 and included in a population‐based Norwegian study. Carotid plaque and c
IMT
were assessed according to the Mannheim Carotid Intima–Media Thickness and Plaque Consensus, and a carotid plaque score was used to calculate atherosclerotic burden. The participants were aged 63 to 65 years, and 49% were women. The prevalence of established cardiovascular disease was low (10%), but 62% had hypertension, 53% had hypercholesterolemia, 11% had diabetes mellitus, and 23% were obese. Mean
cIMT
was 0.73±0.11 mm, and atherosclerotic carotid plaques were present in 87% of the participants (median plaque score: 2; interquartile range: 3). Most of the cardiovascular risk factors, with the exception of diabetes mellitus, obesity and waist–hip ratio, were independently associated with the plaque score. In contrast, only sex, hypertension, obesity, current smoking, and cerebrovascular disease were associated with
cIMT
.

Conclusions

We found very high prevalence of carotid plaque in this middle‐aged population, and our data support a greater association between cardiovascular risk factors and plaque burden, compared with
cIMT
.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
01555411.
Longitudinal Change of Perceived Salt Intake and Stroke Risk in a Chinese Population
Authors: Li Yun , Huang Zhe , Jin Cheng , Xing Aijun , Liu Yesong , Huangfu Chunmei , Lichtenstein Alice H. , Tucker Katherine L. , Wu Shouling , Gao Xiang 
Published: May 2018

Background and Purpose—
Data for a relationship between salt intake and stroke have been inconsistent. This inconstancy could be because of the majority of studies evaluated salt intake at a single time point, which may be insufficient to accurately characterize salt intake throughout the observation period.

Methods—
Included were 77 605 participants from the Kailuan study. We assessed perceived salt intake via questionnaire in 2006, 2008, and 2010. Salt intake trajectories from 2006 to 2010 were identified using latent mixture models. Incident stroke cases were identified from 2010 to 2015 and confirmed by review of medical records. Cox proportional hazards model was used to examine the association between salt intake trajectories and stroke risk after adjusting for possible confounders, including age, sex, lifestyle, social economic status, body mass index, use of medicines, blood pressure, and lipoprotein profiles.

Results—

Identified were 5 distinct salt intake trajectories: moderate-stable (n=59 241), moderate-decreasing (n=9268), moderate-increasing (n=2975), low-increasing (n=2879), and high-decreasing (n=3242). During the 5-year follow-up period, there were 1564 incident strokes cases. Compared with individuals with the moderate-stable salt intake trajectory, individuals with moderate-decreasing salt intake trajectory had significantly lower cerebral infarction stroke risk (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63–0.92) but not intracerebral hemorrhage risk (adjusted hazard ratio, 0.84; 95% confidence interval, 0.55–1.29). Further adjustment for 2006 or 2010 perceived salt intakes generated similar results. When baseline perceived salt intake only was used as the exposure, a significant dose–response relationship between higher perceived salt intake and higher stroke risk was observed (
P
trend=0.006).

Conclusions—
Change in salt intake was associated with the stroke risk. These data support the dietary recommendation to the reduction of salt intake.