bluuebunny/crossref_metadata_2025_split huggingface dataset:
How to demonstrate the role of geology in a modern society: the case of Lithuania, where geology is not visible
Authors: Satkūnas Jonas 
Published: November 2019

Abstract

Lithuania is a comparatively small country (65 000 km
2
) with prevailing flat, glacial and post glacial relief composed of soft sediments without any rocky formations visible on the surface. There are no underground mines, but rather only pits for sand and gravel and few quarries of dolomite and limestone. Oil is produced from 15 oil fields in the west of the country. All potable water is taken from aquifers, with negligible if any concern. Most people, therefore, know very little about the geology of Lithuania and hardly realize what the Geological Survey is doing. Only in rare cases of hazardous events, like the Kaliningrad earthquake in 2004, or landslides devastating Gediminas Hill in 2016–17, or the largest karst sinkholes, is the name of the Geological Survey visible in the mass media. Nevertheless, the Geological Survey operates with several duties, private sector geological companies are generating business, and geosciences are on the agenda of scientific institutions. The aim of this study is to take a deeper look into the current factors that are determining the role of the Geological Survey of Lithuania at present, and to outline circumstances which could influence the role of the Survey in the future.
Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer
Authors: Patel Rachana , Brzezinska Elspeth A. , Repiscak Peter , Ahmad Imran , Mui Ernest , Gao Meiling , Blomme Arnaud , Harle Victoria , Tan Ee Hong , Malviya Gaurav , Mrowinska Agata , Loveridge Carolyn J. , Rushworth Linda K. , Edwards Joanne , Ntala Chara , Nixon Colin , Hedley Ann , Mackay Gillian , Tardito Saverio , Sansom Owen J. , Leung Hing Y. 
Published: November 2019

Abstract

Inhibition of the androgen receptor (AR) is the main strategy to treat advanced prostate cancers. AR-independent treatment-resistant prostate cancer is a major unresolved clinical problem. Patients with prostate cancer with alterations in canonical WNT pathway genes, which lead to β-catenin activation, are refractory to AR-targeted therapies. Here, using clinically relevant murine prostate cancer models, we investigated the significance of β-catenin activation in prostate cancer progression and treatment resistance. β-Catenin activation, independent of the cell of origin, cooperated with Pten loss to drive AR-independent castration-resistant prostate cancer. Prostate tumors with β-catenin activation relied on the noncanonical WNT ligand WNT5a for sustained growth. WNT5a repressed AR expression and maintained the expression of c-Myc, an oncogenic effector of β-catenin activation, by mediating nuclear localization of NFκBp65 and β-catenin. Overall, WNT/β-catenin and AR signaling are reciprocally inhibited. Therefore, inhibiting WNT/β-catenin signaling by limiting WNT secretion in concert with AR inhibition may be useful for treating prostate cancers with alterations in WNT pathway genes.

Significance:
Targeting of both AR and WNT/β-catenin signaling may be required to treat prostate cancers that exhibit alterations of the WNT pathway.
Prediagnostic Allostatic Load as a Predictor of Poorly Differentiated and Larger Sized Breast Cancers among Black Women in the Women's Circle of Health Follow-Up Study
Authors: Xing Cathleen Y. , Doose Michelle , Qin Bo , Lin Yong , Plascak Jesse J. , Omene Coral , He Chunyan , Demissie Kitaw , Hong Chi-Chen , Bandera Elisa V. , Llanos Adana A.M. 
Published: November 2019

Abstract

Background:
Few studies have empirically tested the association of allostatic load (AL) with breast cancer clinicopathology. The aim of this study was to examine the association of AL, measured using relevant biomarkers recorded in medical records before breast cancer diagnosis, with unfavorable tumor clinicopathologic features among Black women.

Methods:
In a sample of 409 Black women with nonmetastatic breast cancer who are enrolled in the Women's Circle of Health Follow-Up Study, we estimated prediagnostic AL using two measures: AL measure 1 [lipid profile–based—assessed by systolic and diastolic blood pressure (SBP, DBP), high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides, and glucose levels; waist circumference; and use of diabetes, hypertension, or hypercholesterolemia medication] and AL measure 2 (inflammatory index–based—assessed by SBP, DBP, glucose, and albumin levels; estimated glomerular filtration rate; body mass index; waist circumference; and use of medications previously described). We used Cohen's statistic to assess agreement between the two AL measures and multivariable logistic models to assess the associations of interest.

Results:
AL measures 1 and 2 moderately agreed (κ = 0.504). Higher prediagnostic AL predicted higher grade (poorly differentiated vs. well/moderately differentiated) using AL measure 1 [OR = 2.16; 95% confidence interval (CI), 1.18–3.94] and AL measure 2 (OR = 1.60; 95% CI, 1.02–2.51), and larger tumor size (≥2 cm vs. &lt;2 cm; OR = 1.58; 95% CI, 1.01–2.46) using AL measure 2 only.

Conclusions:
Elevated prediagnostic AL might contribute to more unfavorable breast cancer clinicopathology.

Impact:
Addressing elevated prediagnostic levels of AL has potentially important clinical implications.
Reproductive and Hormonal Factors and Risk of Ovarian Cancer by Tumor Dominance: Results from the Ovarian Cancer Cohort Consortium (OC3)
Authors: Huang Tianyi , Townsend Mary K. , Wentzensen Nicolas , Trabert Britton , White Emily , Arslan Alan A. , Weiderpass Elisabete , Buring Julie E. , Clendenen Tess V. , Giles Graham G. , Lee I-Min , Milne Roger L. , Onland-Moret N. Charlotte , Peters Ulrike , Sandler Dale P. , Schouten Leo J. , van den Brandt Piet A. , Wolk Alicja , Zeleniuch-Jacquotte Anne , Tworoger Shelley S. 
Published: November 2019

Abstract

Background:
Laterality of epithelial ovarian tumors may reflect the underlying carcinogenic pathways and origins of tumor cells.

Methods:
We pooled data from 9 prospective studies participating in the Ovarian Cancer Cohort Consortium. Information on measures of tumor size or tumor dominance was extracted from surgical pathology reports or obtained through cancer registries. We defined dominant tumors as those restricted to one ovary or where the dimension of one ovary was at least twice as large as the other, and nondominant tumors as those with similar dimensions across the two ovaries or peritoneal tumors. Competing risks Cox models were used to examine whether associations with reproductive and hormonal risk factors differed by ovarian tumor dominance.

Results:
Of 1,058 ovarian cancer cases with tumor dominance information, 401 were left-dominant, 363 were right-dominant, and 294 were nondominant. Parity was more strongly inversely associated with risk of dominant than nondominant ovarian cancer (Pheterogeneity = 0.004). Ever use of oral contraceptives (OC) was associated with lower risk of dominant tumors, but was not associated with nondominant tumors (Pheterogeneity = 0.01). Higher body mass index was associated with higher risk of left-dominant tumors, but not significantly associated with risk of right-dominant or nondominant tumors (Pheterogeneity = 0.08).

Conclusions:
These data suggest that reproductive and hormonal risk factors appear to have a stronger impact on dominant tumors, which may have an ovarian or endometriosis origin.

Impact:
Examining the associations of ovarian cancer risk factors by tumor dominance may help elucidate the mechanisms through which these factors influence ovarian cancer risk.
Hepatitis C Virus Infection and the Temporal Trends in the Risk of Liver Cancer: A National Register-Based Cohort Study in Sweden
Authors: Batyrbekova Nurgul , Aleman Soo , Lybeck Charlotte , Montgomery Scott , Duberg Ann-Sofi 
Published: November 2019

Abstract

Background:
In many countries, including Sweden, the birth cohorts with the highest prevalence of hepatitis C virus (HCV) infection have now reached the ages with high risk of primary liver cancer (PLC). The aims of this study were to investigate the temporal trends in PLC incidence and the relative risks of PLC among people diagnosed with HCV infection between 1990 and 2015.

Methods:
The HCV cohort (n = 52,853) was compared with a matched non-HCV comparison cohort (n = 523,649). Both the national Cancer Register (CR) and Cause of Death Register (DR) were used for follow-up. The crude and age-standardized PLC incidence rates were calculated. The relative risk was estimated as standardized incidence ratios (SIR) and as HRs using stratified Cox hazards regression.

Results:
There were 1,609 with PLC diagnosis in the HCV cohort; the annual number increased continuously with the crude incidence rate reaching 4.56 per 1,000 person-years in 2013 while remaining low and stable in the comparison cohort. In the HCV cohort, the age-standardized PLC incidence rates per 1,000 person-years remained relatively constant at 2.64 [95% confidence interval (CI), 1.54–3.75] in 2000 and 3.31 (2.51–4.12) in 2014. The highest SIR was 73 (65.9–79.5) among those infected for 35 to 40 years; and the highest HR was 65.9 (55.9–77.6) for men and 62.2 (31.9–121.1) for women.

Conclusions:
There was a considerable increase in PLC incidence over time and an extremely high relative risk in the population with HCV infection for more than 35 years.

Impact:
The national HCV-associated PLC incidence should be monitored in future studies to evaluate the effect of direct-acting antiviral (DAA) treatment.
Comprehensive Transcriptome Profiling of Cryptic CBFA2T3–GLIS2 Fusion–Positive AML Defines Novel Therapeutic Options: A COG and TARGET Pediatric AML Study
Authors: Smith Jenny L. , Ries Rhonda E. , Hylkema Tiffany , Alonzo Todd A. , Gerbing Robert B. , Santaguida Marianne T. , Eidenschink Brodersen Lisa , Pardo Laura , Cummings Carrie L. , Loeb Keith R. , Le Quy , Imren Suzan , Leonti Amanda R. , Gamis Alan S. , Aplenc Richard , Kolb E. Anders , Farrar Jason E. , Triche Timothy J. , Nguyen Cu , Meerzaman Daoud , Loken Michael R. , Oehler Vivian G. , Bolouri Hamid , Meshinchi Soheil 
Published: November 2019

Abstract

Purpose:
A cryptic inv(16)(p13.3q24.3) encoding the CBFA2T3–GLIS2 fusion is associated with poor outcome in infants with acute megakaryocytic leukemia. We aimed to broaden our understanding of the pathogenesis of this fusion through transcriptome profiling.

Experimental Design:
Available RNA from children and young adults with de novo acute myeloid leukemia (AML; N = 1,049) underwent transcriptome sequencing (mRNA and miRNA). Transcriptome profiles for those with the CBFA2T3–GLIS2 fusion (N = 24) and without (N = 1,025) were contrasted to define fusion-specific miRNAs, genes, and pathways. Clinical annotations defined distinct fusion-associated disease characteristics and outcomes.

Results:
The CBFA2T3–GLIS2 fusion was restricted to infants &lt;3 years old (P &lt; 0.001), and the presence of this fusion was highly associated with adverse outcome (P &lt; 0.001) across all morphologic classifications. Further, there was a striking paucity of recurrent cooperating mutations, and transduction of cord blood stem cells with this fusion was sufficient for malignant transformation. CBFA2T3–GLIS2 positive cases displayed marked upregulation of genes with cell membrane/extracellular matrix localization potential, including NCAM1 and GABRE. Additionally, miRNA profiling revealed significant overexpression of mature miR-224 and miR-452, which are intronic miRNAs transcribed from the GABRE locus. Gene-set enrichment identified dysregulated Hippo, TGFβ, and hedgehog signaling, as well as NCAM1 (CD56) interaction pathways. Therapeutic targeting of fusion-positive leukemic cells with CD56-directed antibody–drug conjugate caused significant cytotoxicity in leukemic blasts.

Conclusions:
The CBFA2T3–GLIS2 fusion defines a highly refractory entity limited to infants that appears to be sufficient for malignant transformation. Transcriptome profiling elucidated several highly targetable genes and pathways, including the identification of CD56, providing a highly plausible target for therapeutic intervention.
Coaltered Ras/B-raf and TP53 Is Associated with Extremes of Survivorship and Distinct Patterns of Metastasis in Patients with Metastatic Colorectal Cancer
Authors: Datta Jashodeep , Smith J. Joshua , Chatila Walid K. , McAuliffe John C. , Kandoth Cyriac , Vakiani Efsevia , Frankel Timothy L. , Ganesh Karuna , Wasserman Isaac , Lipsyc-Sharf Marla , Guillem Jose , Nash Garrett M. , Paty Philip B. , Weiser Martin R. , Saltz Leonard B. , Berger Michael F. , Jarnagin William R. , Balachandran Vinod , Kingham T. Peter , Kemeny Nancy E. , Cercek Andrea , Garcia-Aguilar Julio , Taylor Barry S. , Viale Agnes , Yaeger Rona , Solit David B. , Schultz Nikolaus , D'Angelica Michael I. 
Published: November 2019

Abstract

Purpose:
We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer and their applicability in informing survival in distinct subsets of patients with metastatic colorectal cancer.

Experimental Design:
We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: ≤2-year (n = 17) and ≥10-year (n = 18) survivors. Relevant genomic findings, and their association with overall survival (OS), were validated in two independent datasets of 935 stage IV and 443 resected stage I–IV patients.

Results:
In the extremes-of-survivorship cohort, significant co-occurrence of KRAS hotspot mutations and TP53 alterations was observed in ≤2-year survivors (P &lt; 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic Ras/B-raf (i.e., either KRAS, NRAS, or BRAF) and TP53 alteration generated three prognostic clusters: (i) TP53-altered alone (median OS, 132 months); (ii) Ras/B-raf–altered alone (65 months) or Ras/B-raf- and TP53 pan-wild-type (60 months); and (iii) coaltered Ras/B-raf–TP53 (40 months; P &lt; 0.0001). Coaltered Ras/B-raf–TP53 was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91–3.21; P &lt; 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I–IV patients. Coaltered Ras/B-raf–TP53 was associated with worse OS in patients with liver (n = 490) and lung (n = 172) but not peritoneal surface (n = 149) metastases. Moreover, coaltered Ras/B-raf–TP53 tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options.

Conclusions:
Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered Ras/B-raf–TP53 and its association with distinct patterns of colorectal cancer metastasis.
TCR Repertoire Diversity of Peripheral PD-1+CD8+ T Cells Predicts Clinical Outcomes after Immunotherapy in Patients with Non–Small Cell Lung Cancer
Authors: Han Jiefei , Duan Jianchun , Bai Hua , Wang Yuqi , Wan Rui , Wang Xin , Chen Si , Tian Yanhua , Wang Di , Fei Kailun , Yao Zhuoran , Wang Shuhang , Lu Zhimin , Wang Zhijie , Wang Jie 
Published: November 2019

Abstract
T-cell receptor (TCR)–based biomarkers might predict patient response to immune checkpoint blockade (ICB) but need further exploration and validation for that use. We sequenced complementarity-determining region 3 of TCRβ chains isolated from PD-1+ CD8+ T cells to investigate its value for predicting the response to anti–programmed cell death 1 (PD-1)/PD-ligand 1 (PD-L1) therapy in patients with non–small cell lung cancer (NSCLC). Two independent patient cohorts (cohort A, n = 25; cohort B, n = 15) were used as discovery and validation sets, respectively. Pre- and post-ICB peripheral blood samples were collected. In cohort A, patients with high PD-1+ CD8+ TCR diversity before ICB treatment showed better response to ICB and progression-free survival (PFS) compared with patients with low diversity [6.4 months vs. 2.5 months, HR, 0.39; 95% confidence interval (CI), 0.17–0.94; P = 0.021]. The results were validated in cohort B. Pre-ICB PD-1+ CD8+ TCR diversity achieved an optimal Youden's index of 0.81 (sensitivity = 0.87 and specificity = 0.94) for differentiating the ICB response in the merged dataset (cohort A plus cohort B). Patients with increased PD-1+ CD8+ TCR clonality after ICB treatment had longer PFS (7.3 months vs. 2.6 months, HR, 0.26; 95% CI, 0.08–0.86; P = 0.002) than those with decreased clonality. Thus, TCR diversity and clonality in peripheral blood PD-1+ CD8+ T cells may serve as noninvasive predictors of patient response to ICB and survival outcomes in NSCLC.
Serial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway and Total Mortality, Cause‐Specific Mortality, and Cardiovascular Diseases in the Cardiovascular Health Study
Authors: Lai Heidi T.M. , de Oliveira Otto Marcia C. , Lee Yujin , Wu Jason H.Y. , Song Xiaoling , King Irena B. , Psaty Bruce M. , Lemaitre Rozenn N. , McKnight Barbara , Siscovick David S. , Mozaffarian Dariush 
Published: November 2019

Background

Synthesized fatty acids (
FA
s) from de novo lipogenesis may affect cardiometabolic health, but longitudinal associations between serially measured de novo lipogenesis–related fatty acid biomarkers and mortality or cardiovascular disease (
CVD)
are not well established.

Methods and Results

We investigated longitudinal associations between de novo lipogenesis–related fatty acids with all‐cause mortality, cause‐specific mortality, and incident
CVD
among 3869 older US adults, mean (
SD
) age 75 (5) years and free of prevalent
CVD
at baseline. Levels of plasma phospholipid palmitic (16:0), palmitoleic (16:1n‐7), stearic (18:0), oleic acid (18:1n‐9), and other risk factors were serially measured at baseline, 6 years, and 13 years. All‐cause mortality, cause‐specific mortality, and incident fatal and nonfatal
CVD
were centrally adjudicated. Risk was assessed in multivariable‐adjusted Cox models with time‐varying
FA
s and covariates. During 13 years, median follow‐up (maximum 22.4 years), participants experienced 3227 deaths (1131
CVD
, 2096 non‐
CVD
) and 1753 incident
CVD
events. After multivariable adjustment, higher cumulative levels of 16:0, 16:1n‐7, and 18:1n‐9 were associated with higher all‐cause mortality, with extreme‐quintile hazard ratios (95%
CI
s) of 1.35 (1.17–1.56), 1.40 (1.21–1.62), and 1.56 (1.35–1.80), respectively, whereas higher levels of 18:0 were associated with lower mortality (hazard ratio=0.76; 95%
CI
=0.66–0.88). Associations were generally similar for
CVD
mortality versus non‐
CVD
mortality, as well as total incident
CVD
. Changes in levels of 16:0 were positively, and 18:0 inversely, associated with all‐cause mortality (hazard ratio=1.23, 95%
CI
=1.08–1.41; and hazard ratio=0.78, 95%
CI
=0.68–0.90).

Conclusions
Higher long‐term levels of 16:0, 16:1n‐7, and 18:1n‐9 and changes in 16:0 were positively, whereas long‐term levels and changes in 18:0 were inversely, associated with all‐cause mortality in older adults.
Pigment Epithelial‐Derived Factor Deficiency Accelerates Atherosclerosis Development via Promoting Endothelial Fatty Acid Uptake in Mice With Hyperlipidemia
Authors: Wang Haiping , Yang Yanfang , Yang Ming , Li Xinghui , Tan Jing , Wu Yandi , Zhang Yuling , Li Yuanlong , Hu Bo , Deng Shijie , Yang Fengmin , Gao Saifei , Li Hui , Yang Zhenyu , Chen Hui , Cai Weibin 
Published: November 2019

Background

Endothelial cell injury, induced by dyslipidemia, is the initiation of atherosclerosis, resulting in an imbalance in endothelial fatty acid (
FA
) transport. Pigment epithelial‐derived factor (
PEDF
) is an important regulator in lipid metabolism. We hypothesized that
PEDF
is involved in endothelium‐mediated
FA
uptake under hyperlipidemic conditions.

Methods and Results

Circulating
PEDF
levels were higher in patients with atherosclerotic cardiovascular disease than in normal individuals. However, decreasing trends of serum
PEDF
levels were confirmed in both wild‐type and apolipoprotein E–deficient mice fed a long‐term high‐fat diet. Apolipoprotein E–deficient/PEDF‐deficient mice were generated by crossing PEDF‐deficient mice with apolipoprotein E–deficient mice, and then mice were fed with 24, 36, or 48 weeks of high‐fat diet. Greater increases in body fat and plasma lipids were displayed in
PEDF
‐deficient mice. In addition,
PEDF
deficiency in mice accelerated atherosclerosis, as evidenced by increased atherosclerotic plaques, pronounced vascular dysfunction, and increased lipid accumulation in peripheral tissues, whereas injection of adeno‐associated virus encoding
PEDF
exerted opposite effects. Mechanistically,
PEDF
inhibited the vascular endothelial growth factor B paracrine signaling by reducing secretion of protein vascular endothelial growth factor B in peripheral tissue cells and decreasing expression of its downstream targets in endothelial cells, including its receptors (namely, vascular endothelial growth factor receptor‐1 and neuropilin‐1), and FA transport proteins 3 and 4, to suppress endothelial
FA
uptake, whereas
PEDF
deletion in mice activated the vascular endothelial growth factor B signaling pathway, thus causing markedly increased lipid accumulation.

Conclusions

Decreasing expression of
PEDF
aggravates atherosclerosis by significantly impaired vascular function and enhanced endothelial
FA
uptake, thus exacerbating ectopic lipid deposition in peripheral tissues.