bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatic stellate cells retain retinoid-laden lipid droplets after cellular transdifferentiation into activated myofibroblasts
Authors: Jophlin Loretta L. , Koutalos Yiannis , Chen Chunhe , Shah Vijay , Rockey Don C. 
Published: July 2018

Loss of retinyl ester (RE)-rich lipid droplets (LDs) from hepatic stellate cells (HSCs) is cited as a key event in their cellular transdifferentiation to activated, pro-fibrotic myofibroblasts; however, it remains unclear if changes in LD morphology or RE content are causal for transdifferentiation. To better understand LD dynamics in vitro within a common model of HSC activation, we used novel approaches preserving LD morphology and allowing for quantitation of RE. The size and quantity of LDs within in vitro and in vivo bile duct ligation (BDL)-activated HSCs were quantitated using adipocyte differentiation-related protein (ADRP) labeling and oil red o (ORO) staining (gold standard), and RE content was determined using fluorescence microscopy. We found during HSC activation in vitro that LD number differed significantly when measured by ADRP and ORO, respectively ( day 1: 56 vs. 5, P = 0.03; day 4: 101 vs. 39, P = 0.03; day 14: 241 vs. 12, P = 0.02). Ex vivo HSCs activated in vivo contained the same number of LDs as day 4 in vitro activated HSCs (118 vs. 101, P = 0.54). Decline in LD RE occurred beyond day 4 in vitro and day 1 ex vivo , after HSC transdifferentiation was underway. Lastly, in situ HSCs examined using electron microscopy show LDs tend to be smaller but are ultimately retained in BDL injured livers. Therefore, we conclude that during HSC transdifferentiation, LDs are not lost but are retained, decreasing in size. Additionally, RE content declines after transdifferentiation is underway. These data suggest that these LD changes are not causal for HSC transdifferentiation.NEW & NOTEWORTHY Loss of retinoid-laden lipid droplets from hepatic stellate cells has long been held as a hallmark of their transdifferentiation into activated myofibroblasts, the dominant cells that drive hepatic fibrosis. This study demonstrates that stellate cells activated in culture and after liver injury in vivo retain their lipid droplets and that these droplets become smaller and more numerous, with decreases in droplet retinoid concentration occurring only after cellular transdifferentiation is underway.
Cabozantinib Exhibits Potent Antitumor Activity in Colorectal Cancer Patient-Derived Tumor Xenograft Models via Autophagy and Signaling Mechanisms
Authors: Scott Aaron J. , Arcaroli John J. , Bagby Stacey M. , Yahn Rachel , Huber Kendra M. , Serkova Natalie J. , Nguyen Anna , Kim Jihye , Thorburn Andrew , Vogel Jon , Quackenbush Kevin S. , Capasso Anna , Schreiber Anna , Blatchford Patrick , Klauck Peter J. , Pitts Todd M. , Eckhardt S. Gail , Messersmith Wells A. 
Published: July 2018

Abstract
Antiangiogenic therapy used in treatment of metastatic colorectal cancer (mCRC) inevitably succumbs to treatment resistance. Upregulation of MET may play an essential role to acquired anti-VEGF resistance. We previously reported that cabozantinib (XL184), an inhibitor of receptor tyrosine kinases (RTK) including MET, AXL, and VEGFR2, had potent antitumor effects in mCRC patient-derived tumor explant models. In this study, we examined the mechanisms of cabozantinib sensitivity, using regorafenib as a control. The tumor growth inhibition index (TGII) was used to compare treatment effects of cabozantinib 30 mg/kg daily versus regorafenib 10 mg/kg daily for a maximum of 28 days in 10 PDX mouse models. In vivo angiogenesis and glucose uptake were assessed using dynamic contrast-enhanced (DCE)-MRI and [18F]-FDG-PET imaging, respectively. RNA-Seq, RTK assay, and immunoblotting analysis were used to evaluate gene pathway regulation in vivo and in vitro. Analysis of TGII demonstrated significant antitumor effects with cabozantinib compared with regorafenib (average TGII 3.202 vs. 48.48, respectively; P = 0.007). Cabozantinib significantly reduced vascularity and glucose uptake compared with baseline. Gene pathway analysis showed that cabozantinib significantly decreased protein activity involved in glycolysis and upregulated proteins involved in autophagy compared with control, whereas regorafenib did not. The combination of two separate antiautophagy agents, SBI-0206965 and chloroquine, plus cabozantinib increased apoptosis in vitro. Cabozantinib demonstrated significant antitumor activity, reduction in tumor vascularity, increased autophagy, and altered cell metabolism compared with regorafenib. Our findings support further evaluation of cabozantinib and combinational approaches targeting autophagy in colorectal cancer. Mol Cancer Ther; 17(10); 2112–22. ©2018 AACR.
Inhibition of BMI1, a Therapeutic Approach in Endometrial Cancer
Authors: Buechel Megan , Dey Anindya , Dwivedi Shailendra Kumar Dhar , Crim Aleia , Ding Kai , Zhang Roy , Mukherjee Priyabrata , Moore Kathleen N. , Cao Liangxian , Branstrom Arthur , Weetall Marla , Baird John , Bhattacharya Resham 
Published: July 2018

Abstract
With rising incidence rates, endometrial cancer is one of the most common gynecologic malignancies in the United States. Although surgery provides significant survival benefit to early-stage patients, those with advanced or recurrent metastatic disease have a dismal prognosis. Limited treatment options include chemotherapy and radiotherapy. Hence, there is a compelling need for developing molecularly targeted therapy. Here, we show that the polycomb ring finger protein BMI1, also known as a stem cell factor, is significantly overexpressed in endometrial cancer cell lines, endometrial cancer patient tissues as well as in nonendometrioid histologies and associated with poor overall survival. PTC-028, a second-generation inhibitor of BMI1 function, decreases invasion of endometrial cancer cells and potentiates caspase-dependent apoptosis, while normal cells with minimal expression of BMI1 remain unaffected. In an aggressive uterine carcinosarcoma xenograft model, single-agent PTC-028 significantly delayed tumor growth and increased tumor doubling time compared with the standard carboplatin/paclitaxel therapy. Therefore, anti-BMI1 strategies may represent a promising targeted approach in patients with advanced or recurrent endometrial cancer, a population where treatment options are limited. Mol Cancer Ther; 17(10); 2136–43. ©2018 AACR.
Chemoprevention with Enalapril and Aspirin in <b><i>Men1</i></b><sup><i>(+/T)</i></sup> Knockout Mouse Model
Authors: Manoharan Jerena , Fendrich Volker , Di Fazio Pietro , Bollmann Carmen , Roth Silvia , Joos Barbara , Mintziras Ioannis , Albers Max B. , Ramaswamy Annette , Bertolino  Philippe , Zhang Chang X. , Slater Emily P. , Bartsch Detlef K. , Lopez-Lopez Caroline L. 
Published: July 2018

Pancreatic neuroendocrine neoplasias (pNEN) are the most common cause of death in adult patients with multiple endocrine neoplasia type 1 (MEN1). So far, only few chemopreventive strategies (e.g., with somatostatin analogues) have been evaluated for MEN1 associated pNENs. In this experimental study on 75 <i>Men1</i><sup><i>(+/T)</i></sup> knockout mice, the effect of aspirin (<i>n</i> = 25) and an inhibitor of angiotensin-I converting enzyme (enalapril, <i>n</i> = 25) compared to controls (<i>n</i> = 25) were evaluated as single chemopreventive strategies for pNENs after 6, 9, 12, 15, and 18 months. After each study period, mice were sacrificed and the resected pancreata were evaluated by histopathological analysis, immunostaining, and real-time PCR. PNEN size and number was measured. Aspirin and enalapril lead to a pNEN size reduction of 80% (167,518 vs. 838,876 µm<sup>2</sup>, <i>p</i> &#x3c; 0.001) and 79% (174,758 vs. 838,876 µm<sup>2</sup>, <i>p</i> &#x3c; 0.001) compared to controls. Furthermore, aspirin and enalapril treatment resulted in a significant reduction of the number of pNENs by 33%, (<i>p</i> = 0.04) and 41% (<i>p</i> = 0.002) respectively. The apoptosis marker caspase 3 revealed a higher positive expression in pNEN of treated <i>Men1</i><sup><i>(+/T)</i></sup> mice. Immunostaining of VEGF in pNEN detected a downregulation of its expression in treated <i>Men1</i><sup><i>(+/T)</i></sup> mice compared to the control group. REL A transcript was significantly downregulated in 18-months treated enalapril <i>Men1</i><sup><i>(+/T)</i></sup> mice, but not in aspirin-treated <i>Men1</i><sup><i>(+/T)</i></sup> mice. There was no significant difference in the Ki-67 index. Using a transgenic mouse model that imitates human MEN1, this study provides first evidence that aspirin and enalapril are effective chemopreventive agents that aid in the progression of pNENs.
Liraglutide Reduces Postprandial Hyperlipidemia by Increasing ApoB48 (Apolipoprotein B48) Catabolism and by Reducing ApoB48 Production in Patients With Type 2 Diabetes Mellitus
Authors: Vergès Bruno , Duvillard Laurence , Pais de Barros Jean Paul , Bouillet Benjamin , Baillot-Rudoni Sabine , Rouland Alexia , Sberna Anne-Laure , Petit Jean-Michel , Degrace Pascal , Demizieux Laurent 
Published: July 2018

Objective—
Treatment with liraglutide, a GLP-1 (glucagon-like peptide-1) agonist, has been shown to reduce postprandial lipidemia, an important feature of diabetic dyslipidemia. However, the underlying mechanisms for this effect remain unknown. This prompted us to study the effect of liraglutide on the metabolism of ApoB48 (apolipoprotein B48).

Approach and Results—

We performed an in vivo kinetic study with stable isotopes (D
8
-valine) in the fed state in 10 patients with type 2 diabetes mellitus before treatment and 6 months after the initiation of treatment with liraglutide (1.2 mg/d). We also evaluated, in mice, the effect of a 1-week liraglutide treatment on postload triglycerides and analysed in vitro on jejunum, the direct effect of liraglutide on the expression of genes involved in the biosynthesis of chylomicron. In diabetic patients, liraglutide treatment induced a dramatic reduction of ApoB48 pool (65±38 versus 162±87 mg;
P
=0.005) because of a significant decrease in ApoB48 production rate (3.02±1.33 versus 6.14±4.27 mg kg
-1
d
-1
;
P
=0.009) and a significant increase in ApoB48 fractional catabolic rate (5.12±1.35 versus 3.69±0.75 pool d
-1
;
P
=0.005). One-week treatment with liraglutide significantly reduced postload plasma triglycerides in mice and liraglutide, in vitro, reduced the expression of ApoB48, DGAT1 (diacylglycerol O-acyltransferase 1), and MTP (microsomal transfer protein) genes.

Conclusions—
We show that treatment with liraglutide induces a significant reduction of the ApoB48 pool because of both a reduction of ApoB48 production and an increase in ApoB48 catabolism. In vitro, liraglutide reduces the expression of genes involved in chylomicron synthesis. These effects might benefit cardiovascular health.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02721888.
HDL (High-Density Lipoprotein) Metrics and Atherosclerotic Risk in Women
Authors: El Khoudary Samar R. , Ceponiene Indre , Samargandy Saad , Stein James H. , Li Dong , Tattersall Matthew C. , Budoff Matthew J. 
Published: July 2018

Objective—
HDL-C (high-density lipoprotein cholesterol) may not always be cardioprotective in postmenopausal women. HDL particles (HDL-P) via ion-mobility may better reflect the antiatherogenicity of HDL. Objectives were (1) to evaluate associations of HDL-C and ion-mobility HDL-P with carotid intima-media thickness (cIMT) and carotid plaque separately and jointly in women; and (2) to assess interactions by age at and time since menopause.

Approach and Results—

Analysis included 1380 females from the MESA (Multi-Ethnic Study of Atherosclerosis; age: 61.8±10.3; 61% natural-, 21% surgical-, and 18% peri-menopause). Women with unknown or early menopause (age at nonsurgical menopause ≤45 years) were excluded. Adjusting for each other, higher HDL-P but not HDL-C was associated with lower cIMT (
P
=0.001), whereas higher HDL-C but not HDL-P was associated with greater risk of carotid plaque presence (
P
=0.04). Time since menopause significantly modified the association of large but not small HDL-P with cIMT; higher large HDL-P was associated with higher cIMT close to menopause but with lower cIMT later in life. The proatherogenic association reported for HDL-C with carotid plaque was most evident in women with later age at menopause who were >10 years postmenopausal.

Conclusions—
Elevated HDL-C may not always be cardioprotective in postmenopausal women. The cardioprotective capacity of large HDL-P may adversely compromise close to menopause supporting the importance of assessing how the menopause transition might impact HDL quality and related cardiovascular disease risk later in life.
Transcription Factor
Zhx2
Deficiency Reduces Atherosclerosis and Promotes Macrophage Apoptosis in Mice
Authors: Erbilgin Ayca , Seldin Marcus M. , Wu Xiuju , Mehrabian Margarete , Zhou Zhiqiang , Qi Hongxiu , Dabirian Keeyon S. , Sevag Packard René R. , Hsieh Wei , Bensinger Steven J. , Sinha Satyesh , Lusis Aldons J. 
Published: July 2018

Objective—
The objective of this study was to determine the basis of resistance to atherosclerosis of inbred mouse strain BALB/cJ.

Approach and Results—

BALB/cJ mice carry a naturally occurring null mutation of the gene encoding the transcription factor
Zhx2
, and genetic analyses suggested that this may confer resistance to atherosclerosis. On a hyperlipidemic low-density lipoprotein receptor null background, BALB/cJ mice carrying the mutant allele for
Zhx2
exhibited up to a 10-fold reduction in lesion size as compared with an isogenic strain carrying the wild-type allele. Several lines of evidence, including bone marrow transplantation studies, indicate that this effect of
Zhx2
is mediated, in part, by monocytes/macrophages although nonbone marrow–derived pathways are clearly involved as well. Both in culture and in atherosclerotic lesions, macrophages from
Zhx2
null mice exhibited substantially increased apoptosis.
Zhx2
null macrophages were also enriched for M2 markers. Effects of
Zhx2
on proliferation and other bone marrow–derived cells, such as lymphocytes, were at most modest. Expression microarray analyses identified >1000 differentially expressed transcripts between
Zhx2
wild-type and null macrophages. To identify the global targets of
Zhx2
, we performed ChIP-seq (chromatin immunoprecipitation sequencing) studies with the macrophage cell line RAW264.7. The ChIP-seq peaks overlapped significantly with gene expression and together suggested roles for transcriptional repression and apoptosis.

Conclusions—

A mutation of
Zhx2
carried in BALB/cJ mice is responsible in large part for its relative resistance to atherosclerosis. Our results indicate that
Zhx2
promotes macrophage survival and proinflammatory functions in atherosclerotic lesions, thereby contributing to lesion growth.
Mild Hypothermia in Cardiogenic Shock Complicating Myocardial Infarction
Authors: Fuernau Georg , Beck Johannes , Desch Steffen , Eitel Ingo , Jung Christian , Erbs Sandra , Mangner Norman , Lurz Philipp , Fengler Karl , Jobs Alexander , Vonthein Reinhard , de Waha-Thiele Suzanne , Sandri Marcus , Schuler Gerhard , Thiele Holger 
Published: July 2018

Background:
Experimental trials suggest improved outcome by mild therapeutic hypothermia for cardiogenic shock after acute myocardial infarction. The objective of this study was to investigate the hemodynamic effects of mild therapeutic hypothermia in patients with cardiogenic shock complicating acute myocardial infarction.

Methods:
Patients (n=40) with cardiogenic shock undergoing primary percutaneous coronary intervention without classic indications for mild therapeutic hypothermia underwent randomization in a 1:1 fashion to mild therapeutic hypothermia for 24 hours or control. The primary end point was cardiac power index at 24 hours; secondary end points included other hemodynamic parameters and serial measurements of arterial lactate.

Results:

No relevant differences were observed for the primary end point of cardiac power index at 24 hours (mild therapeutic hypothermia versus control: 0.41 [interquartile range, 0.31–0.52] versus 0.36 [interquartile range, 0.31–0.48] W/m
2
;
P
=0.50; median difference, −0.025 W/m
2
; 95% CI, −0.12 to 0.06). Similarly, all other hemodynamic measurements were not statistically different. Arterial lactate levels at 6, 8, and 10 hours were significantly higher in patients in the mild therapeutic hypothermia group with a slower decline (
P
for interaction=0.03). There were no differences in 30-day mortality (60% versus 50%; hazard ratio, 1.27; 95% CI, 0.55–2.94;
P
=0.55).

Conclusions:
In this randomized trial, mild therapeutic hypothermia failed to show a substantial beneficial effect on cardiac power index at 24 hours in patients with cardiogenic shock after acute myocardial infarction.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01890317.
Hox gene expression profiles during embryonic development of common sole
Authors: Kavouras Menelaos , Malandrakis Emmanouil E. , Golomazou Eleni , Konstantinidis Ioannis , Blom Ewout , Palstra Arjan P. , Anastassiadis Konstantinos , Panagiotaki Panagiota , Exadactylos Athanasios 
Published: July 2018

AbstractCommon sole (Solea solea) aquaculture production is based mostly on wild-caught breeders. Recently, the successful reproduction of first-generation fish that were reared in captivity was accomplished. A consistent good quality and quantity of produced eggs throughout the year, and of next-generation broodstock, is important for reducing the overall cost of production.Hoxgenes play a pivotal role in normal embryonic development and alterations of their temporal expression level may be important for egg viability. Expression profile analysis of fivehoxgenes (hoxa1a,hoxa2a,hoxa2b,hoxb1aandhoxb1b) involved in early embryonic development and ofhoxa13a, which is involved in late stages, was carried out. Results revealed a premature and/or maternal expression ofhoxa13ain sole embryos, and the detection ofhoxa2aandhoxa2bgenes as members of paralog group 2. Principal Component Analysis ofhoxgene expression in 54 ± 6 hours post fertilization embryos coming from wild-caught broodstock and a first-generation one reared in the hatchery, unveiled that these broodstocks are clearly distinct. In addition, their pairwise comparison revealed significant differences in the expression levels ofhoxb1aandhoxb1bgenes.Hoxgene regulation during embryonic development could give valuable insight into rearing sole broodstocks with different origin in concert, and also into gaining a steady mass production of eggs, either in quality or quantity, all year round.
“She Has Them Coming to Judaism”: Tradition and Jewish Affinity in Jewish Wills of Seventeenthcentury Livorno
Authors: Melcer-Padon Nourit 
Published: July 2018

Abstract
From its inception, the Jewish community in Livorno enjoyed a unique status, encouraging former conversos to settle there. In Livorno they could live openly as Jews. Thus, it is most interesting to study their attitude to their cultural heritage, according to the wills left by several of the Sephardi community’s prominent members. A linguistic analysis of phrases used by three testators is particularly revealing in assessing their positions regarding Judaism. Their words reflect anxiety and determination: a realization of hardships encountered by New Christians on their way to Judaism, and a further realization that only few will adhere to it.
Middle Stone Age Technologies in Mozambique: A Preliminary Study of the Niassa and Massingir Regions
Authors: Bicho Nuno , Cascalheira João , Haws Jonathan , Gonçalves Célia 
Published: July 2018

Abstract
Southeast Africa has become an important region for understanding the development of the Middle Stone Age (MSA) and Anatomically Modern Humans. Due to its location between east and southern Africa, Mozambique is a key region for evaluating the development of Homo sapiens and the MSA across Africa. Here, we present the first results of lithic analyses of MSA assemblages collected during survey and testing in the Niassa and Massingir regions of Mozambique in 2014-2016. We were able to locate close to 200 new Stone Age surface sites. Data show that raw material use is different in the two areas. The lithic assemblages from both areas show the use of centripetal technology, but in Massingir, Levallois points, the respective cores and blade technology are frequent, they are almost absent in the northern region.
Effect of Process- and Outcome-Based Financial Incentives on Weight Loss Among Prediabetic New York Medicaid Patients: A Randomized Clinical Trial
Authors: VanEpps Eric M. , Troxel Andrea B. , Villamil Elizabeth , Saulsgiver Kathryn A. , Zhu Jingsan , Chin Jo-Yu , Matson Jacqueline , Anarella Joseph , Roohan Patrick , Gesten Foster , Volpp Kevin G. 
Published: July 2018

Purpose: To determine whether different financial incentives are effective in promoting weight loss among prediabetic Medicaid recipients. Design: Four-group, multicenter, randomized clinical trial. Setting and Participants: Medicaid managed care enrollees residing in New York, aged 18 to 64 years, and diagnosed as prediabetic or high risk for diabetes (N = 703). Intervention: In a 16-week program, participants were randomly assigned to one of 4 arms: (1) control (no incentives), (2) process incentives for attending weekly Diabetes Prevention Program sessions, (3) outcome incentives for achieving weekly weight loss goals, and (4) combined process and outcome incentives. Measures: Weight loss over a 16-week period; proportion who completed educational sessions; proportion who met weight loss goals. Analysis and Results: No intervention arm achieved greater reduction in weight than control (outcome incentive −6.6 lb [−9.1 to −4.1 lb], process incentive −7.3 lb [−9.5 to −5.1 lb], combined incentive −5.8 lb [−8.8 to −2.8 lb], control −7.9 lb [−11.1 to −4.7 lb]; all P > .29). Session attendance in the process incentive arm (50%) was significantly higher than control (31%; P < .0001) and combined incentive arms (28%; P < .0001), but not significantly higher than the outcome incentive arm (38%). Conclusion: Process incentives increased session attendance, but when combined at half strength with outcome incentives did not achieve that effect. There were no significant effects of either process or outcomes incentives on weight loss.
Association of Platelet to Lymphocyte Ratio and Risk of 30-Day Postoperative Complications in Patients Undergoing Abdominal Aortic Surgical Repair
Authors: Lareyre Fabien , Carboni Joseph , Chikande Julien , Massiot Nicolas , Voury-Pons Audrey , Umbdenstock Emilien , Jean-Baptiste Elixène , Hassen-Khodja Réda , Raffort Juliette 
Published: July 2018

Introduction: The predictive value of the platelet to lymphocyte ratio (PLR) has been demonstrated in several cardiovascular diseases. The aim of this study was to investigate the interest of the preoperative PLR as a predictor of 30-day postoperative outcome in patients with abdominal aortic aneurysm (AAA) undergoing open or endovascular surgical repair. Material and Methods: Two hundred twenty-four consecutive patients with infrarenal AAA were retrospectively included and divided into 4 quartiles according to the value of the preoperative PLR: PLR < 91.5 (group I), 91.5 < PLR < 120.8 (group II), 120.8 < PLR < 163.3 (group III), and PLR > 163.3 (group IV). Results: The AAA diameter was similar among the groups (54.9 mm vs 58.6, 57.5, and 58.7 mm; P = .4655). The proportion of symptomatic AAA and the procedural characteristics did not differ. Patients from group I and IV had significantly higher rates of all-cause postoperative complications compared to group II and III (55.4% and 64.3% vs 39.3% and 46.4%, respectively; P = .0478). The all-cause mortality tended to be higher in group I and IV (7.1% and 8.9% vs 0% and 3.6%, respectively; P = .1305). Conclusion: Extreme values of PLR are associated with a higher risk of complications following AAA surgical repair, suggesting its interest as a biomarker to evaluate the surgical risk.