bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of dietary inorganic nitrate on blood pressure and vascular function in hypertension: prospective implications for adjunctive treatment
Authors: Broxterman Ryan M. , La Salle D. Taylor , Zhao Jia , Reese Van R. , Richardson Russell S. , Trinity Joel D. 
Published: August 2019

Dietary inorganic nitrate (nitrate) is a promising adjunctive treatment to reduce blood pressure and improve vascular function in hypertension. However, it remains unknown if the efficacy of nitrate is dependent upon an elevated blood pressure or altered by medication in patients with hypertension. Therefore, blood pressure and vascular function, measured by passive leg movement (PLM) and flow-mediated dilation (FMD), were assessed following 3 days of placebo (nitrate-free beetroot juice) and nitrate (nitrate-rich beetroot juice) administration in 13 patients (age: 53 ± 12 yr) with hypertension taking antihypertensive medications ( study 1) and in 14 patients (49 ± 13 yr) with hypertension not taking antihypertensive medications ( study 2). In study 1, plasma nitrite concentration was greater for nitrate than placebo (341 ± 118 vs. 308 ± 123 nmol/L, P < 0.05), yet blood pressure and vascular function were unaltered. In study 2, plasma nitrite concentration was greater for nitrate than placebo (340 ± 102 vs. 295 ± 93 nmol/L, P < 0.01). Systolic (136 ± 16 vs. 141 ± 19 mmHg), diastolic (84 ± 13 vs. 88 ± 12 mmHg), and mean (101 ± 12 vs. 106 ± 13 mmHg) blood pressures were lower ( P < 0.05), whereas the PLM change in leg vascular conductance (6.0 ± 3.0 vs. 5.1 ± 2.6 mL·min−1·mmHg−1) and FMD (6.1 ± 2.4% vs. 4.1 ± 2.7%) were greater ( P < 0.05) for nitrate than placebo. The changes in systolic blood pressure ( r = −0.60) and FMD ( r = −0.48) induced by nitrate were inversely correlated ( P < 0.05) to the respective baseline values obtained in the placebo condition. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive medication status, per se. NEW & NOTEWORTHY Dietary nitrate (nitrate) is a promising intervention to improve blood pressure and vascular function in hypertension. We demonstrate that these beneficial effects of nitrate are inversely related to the baseline value in a continuous manner with no distinction between antihypertensive medication status. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive mediation status.
Thermal behavior alleviates thermal discomfort during steady-state exercise without affecting whole body heat loss
Authors: Vargas Nicole T. , Chapman Christopher L. , Johnson Blair D. , Gathercole Rob , Cramer Matthew N. , Schlader Zachary J. 
Published: August 2019

We tested the hypothesis that thermal behavior resulting in reductions in mean skin temperature alleviates thermal discomfort and mitigates the rise in core temperature during light-intensity exercise. In a 27 ± 0°C, 48 ± 6% relative humidity environment, 12 healthy subjects (6 men, 6 women) completed 60 min of recumbent cycling. In both trials, subjects wore a water-perfused suit top continually perfusing 34 ± 0°C water. In the behavior trial, subjects maintained their upper body thermally comfortable by pressing a button to perfuse cool water (2.2 ± 0.5°C) through the top for 2 min per button press. Metabolic heat production (control: 404 ± 52 W, behavior: 397 ± 65 W; P = 0.44) was similar between trials. Mean skin temperature was reduced in the behavior trial (by −2.1 ± 1.8°C, P < 0.01) because of voluntary reductions in water-perfused top temperature ( P < 0.01). Whole body ( P = 0.02) and local sweat rates were lower in the behavior trial ( P ≤ 0.05). Absolute core temperature was similar ( P ≥ 0.30); however, the change in core temperature was greater in the behavior trial after 40 min of exercise ( P ≤ 0.03). Partitional calorimetry did not reveal any differences in cumulative heat storage (control: 554 ± 229, behavior: 544 ± 283 kJ; P = 0.90). Thermal behavior alleviated whole body thermal discomfort during exercise (by −1.17 ± 0.40 arbitrary units, P < 0.01). Despite lower evaporative cooling in the behavior trial, similar heat loss was achieved by voluntarily employing convective cooling. Therefore, thermal behavior resulting in large reductions in skin temperature is effective at alleviating thermal discomfort during exercise without affecting whole body heat loss. NEW & NOTEWORTHY This study aimed to determine the effectiveness of thermal behavior in maintaining thermal comfort during exercise by allowing subjects to voluntarily cool their torso and upper limbs with 2°C water throughout a light-intensity exercise protocol. We show that voluntary cooling of the upper body alleviates thermal discomfort while maintaining heat balance through convective rather than evaporative means of heat loss.
miR-221 Targets QKI to Enhance the Tumorigenic Capacity of Human Colorectal Cancer Stem Cells
Authors: Mukohyama Junko , Isobe Taichi , Hu Qingjiang , Hayashi Takanori , Watanabe Takashi , Maeda Masao , Yanagi Hisano , Qian Xin , Yamashita Kimihiro , Minami Hironobu , Mimori Koshi , Sahoo Debashis , Kakeji Yoshihiro , Suzuki Akira , Dalerba Piero , Shimono Yohei 
Published: August 2019

Abstract

miRNAs are key players in the integrated regulation of cellular processes and shape many of the functional properties that define the “cancer stem cell” (CSC) phenotype. Little is known, however, about miRNAs that regulate such properties in human colorectal carcinoma. In this study, we compared the expression levels of 754 miRNAs between paired samples of EpCAM+/CD44+ cancer cells (enriched in CSCs) and EpCAM+/CD44neg cancer cells (with CSC depletion) sorted in parallel from human primary colorectal carcinomas and identified miR-221 as the miRNA that displayed the highest level of preferential expression in EpCAM+/CD44+ cancer cells. High levels of miR-221 expression were associated with Lgr5+ cells in mouse colon crypts and reduced survival in patients with colorectal carcinoma. Constitutive overexpression of miR-221 enhanced organoid-forming capacity of both conventional colorectal carcinoma cell lines and patient-derived xenografts (PDX) in vitro. Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity in vitro and substantially reduced the tumorigenic capacity of CSC populations from PDX lines in vivo. Finally, the most abundant splicing isoform of the human Quaking (QKI) gene, QKI-5, was identified as a functional target of miR-221; overexpression of miR-221–reduced QKI-5 protein levels in human colorectal carcinoma cells. As expected, overexpression of QKI-5 suppressed organoid-forming capacity in vitro and tumorigenic capacity of colorectal carcinoma PDX cells in vivo. Our study reveals a mechanistic link between miR-221 and QKI and highlights their key role in regulating CSC properties in human colorectal cancer.

Significance:
These findings uncover molecular mechanisms underlying the maintenance of cancer stem cell properties in colon cancer.
Curatopes Melanoma: A Database of Predicted T-cell Epitopes from Overly Expressed Proteins in Metastatic Cutaneous Melanoma
Authors: Lischer Christopher , Eberhardt Martin , Jaitly Tanushree , Schinzel Cornelia , Schaft Niels , Dörrie Jan , Schuler Gerold , Vera Julio 
Published: August 2019

Abstract

Therapeutic anticancer vaccination has been adapted as an immunotherapy in several solid tumors. However, the selection of promising candidates from the total quantity of possible epitopes poses a challenge to clinicians and bioinformaticians alike, and very few epitopes have been tested in experimental or clinical settings to validate their efficacy. Here, we present a comprehensive database of predicted nonmutated peptide epitopes derived from genes that are overly expressed in a group of 32 melanoma biopsies compared with healthy tissues and that were filtered against expression in a curated list of survival-critical tissues. We hypothesize that these "self-tolerant" epitopes have two desirable properties: they do not depend on mutations, being immediately applicable to a large patient collective, and they potentially cause fewer autoimmune reactions. To support epitope selection, we provide an aggregated score of expected therapeutic efficiency as a shortlist mechanism. The database has applications in facilitating epitope selection and trial design and is freely accessible at https://www.curatopes.com.

Significance:
A database is presented that predicts and scores antitumor T-cell epitopes, with a focus on tolerability and avoidance of severe autoimmunity, offering a supplementary epitope set for further investigation in immunotherapy.
Tie2–FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma
Authors: Li Xiaolong , Martinez-Ledesma Emmanuel , Zhang Chen , Gao Feng , Zheng Siyuan , Ding Jie , Wu Shaofang , Nguyen Nghi , Clifford Stephan C. , Wen Patrick Y. , Ligon Keith L. , Yung W.K. Alfred , Koul Dimpy 
Published: August 2019

AbstractPI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere–forming cell (GSC) xenograft model resistant to the PI3K-specific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) signaling pathway was the main driver of PI3K inhibitor resistance in the resistant xenografts. Aurora kinase was upregulated and pCDK1 was downregulated in resistant tumors from both xenografts and tumor tissues from patients treated with the PI3K inhibitor. Mechanistically, the tyrosine kinase receptor Tie2 physically interacted with FGFR1, promoting STAT3 phosphorylation and binding to the AURKA promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor–induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy.Significance:These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma.
Arming Tumor-Associated Macrophages to Reverse Epithelial Cancer Progression
Authors: Wettersten Hiromi I. , Weis Sara M. , Pathria Paulina , Von Schalscha Tami , Minami Toshiyuki , Varner Judith A. , Cheresh David A. 
Published: August 2019

Abstract

Tumor-associated macrophages (TAM) are highly expressed within the tumor microenvironment of a wide range of cancers, where they exert a protumor phenotype by promoting tumor cell growth and suppressing antitumor immune function. Here, we show that TAM accumulation in human and mouse tumors correlates with tumor cell expression of integrin αvβ3, a known driver of epithelial cancer progression and drug resistance. A monoclonal antibody targeting αvβ3 (LM609) exploited the coenrichment of αvβ3 and TAMs to not only eradicate highly aggressive drug-resistant human lung and pancreas cancers in mice, but also to prevent the emergence of circulating tumor cells. Importantly, this antitumor activity in mice was eliminated following macrophage depletion. Although LM609 had no direct effect on tumor cell viability, it engaged macrophages but not natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC) of αvβ3-expressing tumor cells despite their expression of the CD47 “don't eat me” signal. In contrast to strategies designed to eliminate TAMs, these findings suggest that anti-αvβ3 represents a promising immunotherapeutic approach to redirect TAMs to serve as tumor killers for late-stage or drug-resistant cancers.

Significance:
Therapeutic antibodies are commonly engineered to optimize engagement of NK cells as effectors. In contrast, LM609 targets αvβ3 to suppress tumor progression and enhance drug sensitivity by exploiting TAMs to trigger ADCC.
Precision Therapy for Aggressive Endometrial Cancer by Reactivation of Protein Phosphatase 2A
Authors: Haines Kaitlin , Huang Gloria S. 
Published: August 2019

Abstract
Critically important to reducing uterine cancer mortality is the development of more effective therapy for aggressive endometrial cancers, including uterine serous cancer and uterine carcinosarcoma, which together account for over half of deaths due to endometrial cancer. About one-third of these aggressive endometrial cancers harbor mutations in the protein phosphatase 2A (PP2A) Aα scaffold subunit encoded by PPP2R1A. In this issue, the study by Taylor and colleagues elucidates the role of a highly recurrent PP2A-Aα–subunit mutation PPP2R1A P179R as a biological driver of aggressive endometrial cancer. Compelling data demonstrate that the P179R mutation alters PP2A-Aα protein conformation, impairing holoenzyme formation and reducing PP2A phosphatase activity to promote endometrial cancer progression. Restoration of wild-type PPP2R1A in P179R-mutant endometrial cancer cells increases phosphatase activity and inhibits tumor growth in vivo. Furthermore, a small-molecule activator of PP2A (SMAP) phenocopies restoration of wild-type PPP2R1A to suppress tumor growth. These promising results are an important advance toward effective precision therapy for aggressive endometrial cancer.
See related article by Taylor et al., p. 4242
Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer
Authors: Farago Anna F. , Yeap Beow Y. , Stanzione Marcello , Hung Yin P. , Heist Rebecca S. , Marcoux J. Paul , Zhong Jun , Rangachari Deepa , Barbie David A. , Phat Sarah , Myers David T. , Morris Robert , Kem Marina , Dubash Taronish D. , Kennedy Elizabeth A. , Digumarthy Subba R. , Sequist Lecia V. , Hata Aaron N. , Maheswaran Shyamala , Haber Daniel A. , Lawrence Michael S. , Shaw Alice T. , Mino-Kenudson Mari , Dyson Nicholas J. , Drapkin Benjamin J. 
Published: August 2019

Abstract

Small-cell lung cancer (SCLC) is an aggressive malignancy in which inhibitors of PARP have modest single-agent activity. We performed a phase I/II trial of combination olaparib tablets and temozolomide (OT) in patients with previously treated SCLC. We established a recommended phase II dose of olaparib 200 mg orally twice daily with temozolomide 75 mg/m2 daily, both on days 1 to 7 of a 21-day cycle, and expanded to a total of 50 patients. The confirmed overall response rate was 41.7% (20/48 evaluable); median progression-free survival was 4.2 months [95% confidence interval (CI), 2.8–5.7]; and median overall survival was 8.5 months (95% CI, 5.1–11.3). Patient-derived xenografts (PDX) from trial patients recapitulated clinical OT responses, enabling a 32-PDX coclinical trial. This revealed a correlation between low basal expression of inflammatory-response genes and cross-resistance to both OT and standard first-line chemotherapy (etoposide/platinum). These results demonstrate a promising new therapeutic strategy in SCLC and uncover a molecular signature of those tumors most likely to respond.

Significance:
We demonstrate substantial clinical activity of combination olaparib/temozolomide in relapsed SCLC, revealing a promising new therapeutic strategy for this highly recalcitrant malignancy. Through an integrated coclinical trial in PDXs, we then identify a molecular signature predictive of response to OT, and describe the common molecular features of cross-resistant SCLC.
See related commentary by Pacheco and Byers, p. 1340.
This article is highlighted in the In This Issue feature, p. 1325
ApoER2 (Apolipoprotein E Receptor-2) Deficiency Accelerates Smooth Muscle Cell Senescence via Cytokinesis Impairment and Promotes Fibrotic Neointima After Vascular Injury
Authors: Komaravolu Ravi K. , Waltmann Meaghan D. , Konaniah Eddy , Jaeschke Anja , Hui David Y. 
Published: August 2019

Objective:

Genome-wide studies showed that mutation in apoER2 (apolipoprotein E receptor-2) is additive with ε4 polymorphism in the
APOE
gene on cardiovascular disease risk in humans. ApoE or apoER2 deficiency also accelerates atherosclerosis lesion necrosis in hypercholesterolemic mice and promotes neointima formation after vascular injury. This study tests the hypothesis that apoE and apoER2 modulate vascular occlusive diseases through distinct mechanisms.

Approach and Results:

Carotid endothelial denudation induced robust neointima formation in both
apoE
−/−
and apoER2-deficient
Lrp8
−/−
mice. The intima in
apoE
−/−
mice was rich in smooth muscle cells, but the intima in
Lrp8
−/−
mice was cell-poor and rich in extracellular matrix. Vascular smooth muscle cells isolated from
apoE
−/−
mice were hyperplastic whereas
Lrp8
−/−
smooth muscle cells showed reduced proliferation but responded robustly to TGF (transforming growth factor)-β–induced fibronectin synthesis indicative of a senescence-associated secretory phenotype, which was confirmed by increased β-galactosidase activity, p16
INK4a
immunofluorescence, and number of multinucleated cells. Western blot analysis of cell cycle-associated proteins showed that apoER2 deficiency promotes cell cycle arrest at the metaphase/anaphase. Coimmunoprecipitation experiments revealed that apoER2 interacts with the catalytic subunit of protein phosphatase 2A. In the absence of apoER2, PP2A-C (protein phosphatase 2A catalytic subunit) failed to interact with CDC20 (cell-division cycle protein 20) thus resulting in inactive anaphase-promoting complex and impaired cell cycle exit.

Conclusions:
This study showed that apoER2 participates in APC (anaphase-promoting complex)/CDC20 complex formation during mitosis, and its absence impedes cytokinesis abscission thereby accelerating premature cell senescence and vascular disease. This mechanism is distinct from apoE deficiency, which causes smooth muscle cell hyperplasia to accelerate vascular disease.
Serum apoA1 (Apolipoprotein A-1), Insulin Resistance, and the Risk of Gestational Diabetes Mellitus in Human Pregnancy—Brief Report
Authors: Retnakaran Ravi , Ye Chang , Connelly Philip W. , Hanley Anthony J. , Sermer Mathew , Zinman Bernard 
Published: August 2019

Objective:
apoA1 (apolipoprotein A-1) is the main lipoprotein associated with HDL (high-density lipoprotein) cholesterol. It was recently reported that intravenous infusion of apoA1 could lower insulin resistance in pregnant rats, leading to the suggestion that apoA1 could provide a target for reducing pregnancy-induced insulin resistance and the risk of gestational diabetes mellitus (GDM) in humans. However, the effects of apoA1 on insulin resistance and risk of GDM in human pregnancy are not known. Thus, we sought to systematically evaluate the relationships of apoA1 with glucose homeostasis and metabolic function in pregnant women.

Approach and Results:

In this study, 870 pregnant women were recruited in late second trimester and underwent metabolic characterization, including an oral glucose tolerance test on which 214 were diagnosed with GDM. Metabolic characterization included assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, homeostasis model assessment of insulin resistance), pancreatic β-cell function, lipids (LDL [low-density lipoprotein] cholesterol, HDL cholesterol, triglycerides, apoB [apolipoprotein B], and apoA1), CRP (C-reactive protein), and adiponectin. Serum apoA1 was strongly correlated with HDL (r=0.79,
P
<0.0001) and weakly so with adiponectin (r=0.12,
P
=0.0004) but showed no association with measures of insulin sensitivity/resistance, β-cell function, glycemia, or CRP. There were no significant differences across apoA1 tertiles in mean adjusted Matsuda index (
P
=0.24), homeostasis model assessment of insulin resistance (
P
=0.08), or area under the glucose curve on the oral glucose tolerance test (
P
=0.96). Moreover, there were no differences in risk of GDM across tertiles of apoA1, both before (
P
=0.67) and after covariate adjustment (
P
=0.78).

Conclusions:
Serum apoA1 is not associated with insulin resistance or the risk of GDM in human pregnancy.
Regional Variability in Longitudinal Strain Across Vendors in Patients With Cardiomyopathy Due to Increased Left Ventricular Wall Thickness
Authors: Sperry Brett W. , Sato Kimi , Phelan Dermot , Grimm Richard , Desai Milind Y. , Hanna Mazen , Jaber Wael A. , Popović Zoran B 
Published: August 2019

Background:
Cardiomyopathies with increased left ventricular wall thickness such as cardiac amyloidosis, septal hypertrophic cardiomyopathy (HCM), and apical HCM exhibit characteristic regional longitudinal strain (LS) patterns. However, between-vendor agreement of segmental and regional LS has not been tested in these diseases. We sought to assess LS values among vendors in specific cardiomyopathies that exhibit regional strain variation: cardiac amyloidosis, septal HCM, and apical HCM.

Methods:
This was a prospective, cross-sectional study of 69 patients (18 amyloidosis, 30 septal HCM, 6 apical HCM, and 15 controls) who underwent clinically indicated outpatient echocardiography at the Cleveland Clinic. Peak systolic segmental, regional (basal, mid, and apical), and global LS were evaluated using GE (EchoPAC), Siemens (Velocity Vector Imaging), and Phillips (QLab) systems in the same imaging session. Between-vendor, differences were analyzed using correlation coefficients, Bland Altman plots, and a mixed model.

Results:

Global LS was highly correlated among the 3 software packages and most abnormal in patients with amyloidosis (
P
<0.001). Regional LS analysis demonstrated that QLab software tended to produce more negative LS values, driven by differences in apical strains. EchoPAC had the greatest ability to discriminate patients with amyloidosis using regional strain values (area under the curve, 0.932) as compared with Velocity Vector Imaging and QLab (
P
<0.001).

Conclusions:
Global and regional variations in LS exist between-vendors in patients with cardiomyopathies with increased left ventricular wall thickness (amyloidosis, septal HCM, and apical HCM). It is important to be aware of these differences for diagnosis, prognosis, and serial examinations in these conditions.