bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanism of MCP-1 in Acute Lung Injury and Advanced Therapy by Drug-Loaded Dextrin Nanoparticle
Authors: Cao Zheng , Liu Jing-Lan , Wu Shen , Wang Qiao
Published: September 2018

Objective. To observe the expression of monocyte chemotactic protein 1 (MCP-1) in acute lung injury (ALI) rat model, to characterize its effect on the development and progression of ALI, and to identify the potential new drug delivery approach during in vivo experiment. Method. The effects of different doses of lipopolysaccharide (LPS) on human pulmonary artery endothelial cells (HPAEC) were tested. For the animal experiments, thirty Sprague-Dawley (SD) rats were divided into physiological saline control group (NC group), the LPS model group (L group), the antagonist RS102895 combined with LPS group (R + L group), and the antagonist RS102895-loaded polyaldehyde dextran nanoparticles combined with LPS group (DNPR + L group). The blood gas analysis and dry/wet weight ratio were detected 24 hours after interventions. The levels of inflammatory factors, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), were tested by ELISA. The expression of monocyte chemoattractant protein-1 (MCP-1) in lung tissues was examined through Western blot, and the change of MCP-1 mRNA expression level was detected by performing RT-PCR. Result. LPS was responsible for inducing ALI in rats, and the degree of cell damage was dose-dependent. Blood gas analysis of L group showed that PaO2 and PaO2/FiO2 levels were significantly lower than those of the NC group (P<0.05), while the dry/wet weight ratio of lung tissues in L group increased (P<0.05). Inflammatory factors including TNF-α and IL-1β and the expression of MCP-1 in both protein and mRNA levels were higher in L group than in the NC group (P<0.05). The inhibition of the interaction between MCP-1 and chemokines receptor 2 (CCR2) by antagonist RS102895 can significantly alleviate the ALI in rats, which is accompanied by a significant decrease of inflammatory factors and MCP-1 expression (P<0.05). Compared with R + L group, treatment with DNPR and LPS combination significantly improved the condition of rats and decreased the level of TNF-α, IL-1β, and MCP-1 expression (P<0.05). Conclusion. In ALI, RS102895 can inhibit the MCP-1/CCR2 interaction, therefore, retarding the progress of ALI. Because of the high transfection efficiency of inhibitor RS102895packgaed by polyaldehyde dextran nanoparticles, this phenomenon particularly reached a significant level. The results imply new insights for the treatment of ALI.
Acupuncture Treatment for Chronic Pelvic Pain in Women: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials
Authors: Sung Soo-Hyun , Sung Angela-Dong-Min , Sung Hyun-Kyung , An Tteul-E-Bom , Kim Kyeong Han , Park Jang-Kyung
Published: September 2018

Aim of the Study. This systematic review and meta‐analysis aims to evaluate the current evidence from randomized controlled trials (RCTs) related to the effectiveness and safety of acupuncture treatment (AT), including electroacupuncture or thread‐embedding therapy in combination with modern technology, for chronic pelvic pain (CPP) in women. Materials and Methods. We searched 12 electronic databases up to December 2017. All randomized controlled trials evaluating the effect of AT for CPP were considered. Results. Four RCTs with 474 participants were included. The methodological quality of included studies was generally low. The results of meta‐analysis of two studies showed that AT combined with conventional treatment (CT) was associated with significantly reduced CPP, based on the total effectiveness rate (n=277, mean difference = 1.29, confidence interval = 1.13 to 1.47, P=0.0001, I2 = 0%). Conclusions. This review suggests the potential of AT combined with CT compared to CT alone for treating female CPP. However, there is insufficient evidence to conclude that AT can be recommended as a complementary and alternative (CAM) treatment for women with CPP. To draw a firm conclusion, future studies should require not only lager, more rigorously designed RCTs but also research on different AT types. Protocol Registration Number. This study is registered with PROSPERO 2018 (CRD42018088627).
Effects of Pioglitazone on Nonalcoholic Fatty Liver Disease in the Absence of Constitutive Androstane Receptor Expression
Authors: Ahn Hwa Young , Kim Hwan Hee , Hwang Ji-Yeon , Park Changhun , Cho Bo Youn , Park Young Joo
Published: September 2018

Nonalcoholic fatty liver disease or steatohepatitis (NAFLD/NASH) is a fatty liver disease that is closely related to obesity, diabetes, and dyslipidemia. Pioglitazone, which was developed as an antidiabetic drug, is known to improve NALFD. Pioglitazone is metabolized by multiple cytochrome P450 (CYP) enzymes, which are regulated by the xenobiotic receptor constitutive androstane receptor (CAR). In this study, we investigated the effects of pioglitazone on NAFLD by absence of CAR activity under high-fat (HF)-fed conditions. CAR-/- mice showed significant improvement in NALFD after 12 weeks of pioglitazone treatment compared to wild-type mice. This improvement in NAFLD persisted in CAR-/- mice regardless of blood pioglitazone concentration. The expression of lipogenesis genes in the liver, sterol-regulatory element binding protein-1c (SREBP-1c), and stearoyl-CoA desaturase (SCD)-1 was decreased after pioglitazone treatment in HF-fed CAR-/- mice. In addition, the expression of peroxisome proliferator-activated receptor gamma 2 (PPARγ2) was decreased by pioglitazone in HF-fed CAR-/- mice. Changes in SREBP-1c and PPAR γ2 remained constant over short-term (6 h) pioglitazone and lipid injection. Our results showed that NAFLD was improved significantly by pioglitazone in a CAR deletion state. These results might be valuable because they suggest that interaction with CAR and pioglitazone/PPARγ2 may be important in regulating gene expression associated with NAFLD.
Childhood Overweight, Tallness, and Growth Increase Risks of Ovarian Cancer
Authors: Aarestrup Julie , Trabert Britton , Ulrich Lian G. , Wentzensen Nicolas , Sørensen Thorkild I.A. , Baker Jennifer L.
Published: September 2018

Background:

Adult body size is related to ovarian cancer risks, but size in childhood may also influence risks. We investigated if childhood body mass index (kg/m2), height, and growth patterns were associated with ovarian cancer overall and by histologic subtypes, including effects of birthweight.

Methods:

A cohort of 155,958 girls from the Copenhagen School Health Records Register, born 1930 to 1989 with measured weights and heights from 7 to 13 years, were included. During follow-up, 1,041 ovarian cancers were recorded. Overweight was defined using International Obesity Task Force criteria. Cox regressions were performed.

Results:

Compared with non-overweight girls, at most ages girls with overweight had increased risks of ovarian cancer overall (HR range: 1.24–1.34), mucinous, endometrioid, and clear cell ovarian cancers, but not serous and other ovarian cancers. Childhood height had positive and significant associations with ovarian cancer overall (HR range: 1.07–1.10 per z-score) and the endometrioid subtype but not with the other subtypes. Adjusting for birthweight minimally altered the associations with childhood body size. In growth analyses, girls with overweight or who were tall at 7 and 13 years had increased risks of ovarian cancer overall compared with average-sized girls at both ages.

Conclusions:

Ovarian carcinogenesis is linked to childhood overweight, tallness, and growth, with variations across histological subtypes, suggesting that early life plays a role in the origins of this disease.

Impact:

These findings emphasize that healthy body size and growth during childhood are important as they may contribute to reducing ovarian cancer risks.
A Designer Cross-reactive DNA Immunotherapeutic Vaccine that Targets Multiple MAGE-A Family Members Simultaneously for Cancer Therapy
Authors: Duperret Elizabeth K. , Liu Shujing , Paik Megan , Trautz Aspen , Stoltz Regina , Liu Xiaoming , Ze Kan , Perales-Puchalt Alfredo , Reed Charles , Yan Jian , Xu Xiaowei , Weiner David B.
Published: September 2018

Purpose:

Cancer/testis antigens have emerged as attractive targets for cancer immunotherapy. Clinical studies have targeted MAGE-A3, a prototype antigen that is a member of the MAGE-A family of antigens, in melanoma and lung carcinoma. However, these studies have not yet had a significant impact due to poor CD8+ T-cell immunogenicity, platform toxicity, or perhaps limited target antigen availability. In this study, we develop an improved MAGE-A immunogen with cross-reactivity to multiple family members.

Experimental Design:

In this study, we analyzed MAGE-A expression in The Cancer Genome Atlas and observed that many patients express multiple MAGE-A isoforms, not limited to MAGE-A3, simultaneously in diverse tumors. On the basis of this, we designed an optimized consensus MAGE-A DNA vaccine capable of cross-reacting with many MAGE-A isoforms, and tested immunogenicity and antitumor activity of this vaccine in a relevant autochthonous melanoma model.

Results:

Immunization of this MAGE-A vaccine by electroporation in C57Bl/6 mice generated robust IFNγ and TNFα CD8+ T-cell responses as well as cytotoxic CD107a/IFNγ/T-bet triple-positive responses against multiple isoforms. Furthermore, this MAGE-A DNA immunogen generated a cross-reactive immune response in 14 of 15 genetically diverse, outbred mice. We tested the antitumor activity of this MAGE-A DNA vaccine in Tyr::CreER;BRAFCa/+;Ptenlox/lox transgenic mice that develop melanoma upon tamoxifen induction. The MAGE-A DNA therapeutic vaccine significantly slowed tumor growth and doubled median mouse survival.

Conclusions:

These results support the clinical use of consensus MAGE-A immunogens with the capacity to target multiple MAGE-A family members to prevent tumor immune escape.
MORAb-202, an Antibody–Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity
Authors: Cheng Xin , Li Jing , Tanaka Keigo , Majumder Utpal , Milinichik Andrew Z. , Verdi Arielle C. , Maddage Christopher J. , Rybinski Katherine A. , Fernando Shawn , Fernando Danielle , Kuc Megan , Furuuchi Keiji , Fang Frank , Uenaka Toshimitsu , Grasso Luigi , Albone Earl F.
Published: September 2018

Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody–drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload.
Selective Inhibition of the Lactate Transporter MCT4 Reduces Growth of Invasive Bladder Cancer
Authors: Todenhöfer Tilman , Seiler Roland , Stewart Craig , Moskalev Igor , Gao Jian , Ladhar Simroop , Kamjabi Alireza , Al Nakouzi Nader , Hayashi Tetsuharo , Choi Stephen , Wang Yuzhuo , Frees Sebastian , Daugaard Mads , Oo Htoo Zarni , Fisel Pascale , Schwab Matthias , Schaeffeler Elke , Douglas James , Hennenlotter Jörg , Bedke Jens , Gibb Ewan A. , Fazli Ladan , Stenzl Arnulf , Black Peter C.
Published: September 2018

The significance of lactate transporters has been recognized in various cancer types, but their role in urothelial carcinoma remains mostly unknown. The aim of this study was to investigate the functional importance of the monocarboxylate transporter (MCT) 4 in preclinical models of urothelial carcinoma and to assess its relevance in patient tumors. The association of MCT4 expression with molecular subtypes and outcome was determined in The Cancer Genome Atlas (TCGA) cohort and two independent cohorts of patients with urothelial carcinoma. Silencing of MCT4 was performed using siRNAs in urothelial carcinoma cell lines. Effects of MCT4 inhibition on cell growth, apoptosis, and production of reactive oxygen species (ROS) were assessed. Moreover, effects on lactate efflux were determined. The in vivo effects of MCT4 silencing were assessed in an orthotopic xenograft model. MCT4 expression was higher in the basal subtype. Decreased MCT4 methylation and increased RNA and protein expression were associated with worse overall survival (OS). Inhibition of MCT4 led to a reduction in cell growth, induction of apoptosis, and an increased synthesis of ROS. MCT4 inhibition resulted in intracellular accumulation of lactate. In vivo, stable knockdown of MCT4 reduced tumor growth. The expression of MCT4 in urothelial carcinoma is associated with features of aggressive tumor biology and portends a poor prognosis. Inhibition of MCT4 results in decreased tumor growth in vitro and in vivo. Targeting lactate metabolism via MCT4 therefore provides a promising therapeutic approach for invasive urothelial carcinoma, especially in the basal subtype.
Incidence and Outcomes of Pituitary Microadenomas in Children with Short Stature/Growth Hormone Deficiency
Authors: Derrick Kristina M. , Gomes William A. , Gensure Robert C.
Published: September 2018

Background/Aims: Patients with short stature (SS)/growth hormone deficiency (GHD) and precocious puberty (PP) undergo brain MRI to evaluate for structural brain abnormalities or pituitary lesions, and pituitary microadenomas are a common finding. Theoretically, a mass effect from these lesions could cause GHD and growth hormone treatment could cause them to enlarge, but they should not cause PP, at least in females. Methods: We investigated if pituitary microadenomas cause GHD by comparing their incidence in patients with SS/GHD to that in females with PP. We performed a retrospective chart review of patients with these disorders who had a brain MRI between 2000 and 2013. Results: The incidence of microadenoma was high in both groups, 18.5% for SS (n = 346) and 21.1% for PP females (n = 194), but did not differ between groups (p = 0.46). In patients with microadenomas, repeat imaging showed resolution in 58% (SS, n = 33) and 67% (PP females, n = 21). Importantly, none of the lesions grew, even in patients treated with growth hormone. Conclusions: Pituitary microadenomas are common in children with GHD/SS and PP, but it does not appear that they are a cause of GHD. They appear to be of limited clinical significance and should not be considered a contraindication to growth hormone therapy.
Sleep Disordered Breathing Is Highly Prevalent in Patients with Lung Cancer: Results of the Sleep Apnea in Lung Cancer Study
Authors: Cabezas Elena , Pérez-Warnisher M. Teresa , Troncoso Maria Fernanda , Gómez Teresa , Melchor Rosario , Pinillos Erwin Javier , El Hachem Abdul , Gotera Carolina , Rodríguez Paula , Mahillo Fernández Ignacio , Martínez-García Miguel Ángel ,   González-Mangado, Peces-Barba German , Seijo Luis M.
Published: September 2018

Background: Obstructive sleep apnea (OSA) has been linked to tumorigenesis and tumor progression. Objectives: The Sleep Apnea in Lung Cancer (SAIL) study (NCT02764866) was designed to determine the prevalence of OSA in patients with lung cancer. Methods: Cross-sectional study including consecutive patients with newly diagnosed lung cancer. All patients were offered home sleep apnea testing (HSAT) and administered a sleep-specific questionnaire prior to initiating oncologic treatment. Sleep study-related variables, symptoms, and epidemiologic data as well as cancer related variables were recorded. Results: Eighty-three patients were enrolled in the SAIL study. Sixty-six completed HSAT. The mean age was 68 ± 11 years and 58% were male with a mean body mass index of 28.1 ± 5.4. Forty-seven percent were current smokers, 42% former smokers, and 11% never smokers with a median tobacco consumption of 51 pack-years. Fifty percent had COPD with a mean FEV1 of 83 ± 22.6% of predicted and a mean DLCO of 85.5 ± 20.1%. Adenocarcinoma was the most common histologic type (46.7%), followed by squamous cell (16.7%) and small cell (16.7%). Most patients were diagnosed at an advanced stage (65% in stages III–IV). The vast majority (80%) had OSA (apnea-hypopnea index [AHI] > 5), and 50% had moderate to severe OSA (AHI > 15) with a mean Epworth Sleepiness Score of 7.43 ± 3.85. Significant nocturnal hypoxemia was common (Median T90: 10.9% interquartile range 2.4–42.2). Conclusions: Sleep apnea and nocturnal hypoxemia are highly prevalent in patients with lung cancer.
Waterpipe Smoking Is Associated with Changes in Fibrinogen, FVII, and FVIII Levels
Authors: Muddathir Abdel Rahim Mahmoud , Abd Alla Mozfar Idrees , Khabour Omar F.
Published: September 2018

Cigarette smoking has been shown to be associated with changes in coagulation factors in the circulation and the subsequent thrombosis development. In this study, the impact of waterpipe smoking on the levels of fibrinogen, factor VII (FVII), and factor VIII (FVIII) was investigated. In addition, the effects of waterpipe smoking were compared to those of cigarette smoking and never smokers. A total of 80 male smokers (40 cigarette smokers and 40 waterpipe smokers) and 40 apparently healthy never smokers were recruited in the study. Both waterpipe smoking and cigarette smoking induced significant increases in the plasma levels of fibrinogen, factor VII, and factor VIII (p < 0.01). The magnitude of the increase in fibrinogen levels induced by waterpipe smoking was higher than that induced by cigarette smoking (p < 0.01), while similar increases were observed in other factors (p > 0.05). In addition, in the waterpipe group, the magnitude of the increase in fibrinogen and factor VIII was higher in the smokers with more than 3 years of use (p < 0.05). In conclusion, similar to cigarette smoking, waterpipe smoking modulates the levels of coagulation factors, suggesting its thrombotic potential.
Inosine – a Multifunctional Treatment for Complications of Neurologic Injury
Authors: Doyle Claire , Cristofaro Vivian , Sullivan Maryrose P. , Adam Rosalyn M.
Published: September 2018

Spinal cord injury (SCI) caused by trauma or disease leads to motor and sensory abnormalities that depend on the level, severity and duration of the lesion. The most obvious consequence of SCI is paralysis affecting lower and upper limbs. SCI also leads to loss of bladder and bowel control, both of which have a deleterious, life-long impact on the social, psychological, functional, medical and economic well being of affected individuals. Currently, there is neither a cure for SCI nor is there adequate management of its consequences. Although medications provide symptomatic relief for the complications of SCI including muscle spasms, lower urinary tract dysfunction and hyperreflexic bowel, strategies for repair of spinal injuries and recovery of normal limb and organ function are still to be realized. In this review, we discuss experimental evidence supporting the use of the naturally occurring purine nucleoside inosine to improve the devastating sequelae of SCI. Evidence suggests inosine is a safe, novel agent with multifunctional properties that is effective in treating complications of SCI and other neuropathies.
Interference with NTSR1 Expression Exerts an Anti-Invasion Effect via the Jun/miR-494/SOCS6 Axis of Glioblastoma Cells
Authors: Ou-yang Qing , He Xuzhi , Yang Anqi , Li Bing , Xu Minhui
Published: September 2018

Background/Aims: Glioblastoma is the most common and aggressive brain tumor and carries a poor prognosis. Previously, we found that neurotensin receptor 1 (NTSR1) contributes to glioma progression, but the underlying mechanisms of NTSR1 in glioblastoma invasion remain to be clarified. The aim of this study was to investigate the molecular mechanisms of NTSR1 in glioblastoma invasion. Methods: Cell migration and invasion were evaluated using wound-healing and transwell assays. Cell proliferation was detected using CCK-8. The expression of NTSR1, Jun, and suppressor of cytokine signaling 6 (SOCS6) was detected using western blotting. The expression of miR-494 was detected by Quantitative real-time PCR. Chromatin immunoprecipitation assay was performed to examine the interaction between Jun and miR-494 promoter. Dual-luciferase reporter assay and western blotting were performed to identify the direct regulation of SOCS6 by miR-494. An orthotopic xenograft mouse model was conducted to assess tumor growth and invasion. Results: NTSR1 knockdown attenuated the invasion of glioblastoma cells. Jun was positively regulated by NTSR1, which promoted miR-494 expression through binding to miR-494 promoter. SOCS6 was confirmed as a direct target of miR-494, thus, NTSR1-induced miR-494 upregulation resulted in SOCS6 downregulation. Both miR-494 and SOCS6 were involved in the NTSR1-induced invasion of glioblastoma cells. In vivo, tumor invasion and growth were inhibited by NTSR1 knockdown, but were restored with miR-494 overexpression. Conclusion: NTSR1 knockdown inhibited glioblastoma invasion via the Jun/miR-494/SOCS6 axis.
Propofol Alters Long Non-Coding RNA Profiles in the Neonatal Mouse Hippocampus: Implication of Novel Mechanisms in Anesthetic-Induced Developmental Neurotoxicity
Authors: Logan Sarah , Jiang Congshan , Yan Yasheng , Inagaki Yasuyoshi , Arzua Thiago , Bai Xiaowen
Published: September 2018

Background: Propofol induces acute neurotoxicity (e.g., neuroapoptosis) followed by impairment of long-term memory and learning in animals. However, underlying mechanisms remain largely unknown. Long non-coding RNAs (lncRNAs) are found to participate in various pathological processes. We hypothesized that lncRNA profile and the associated signaling pathways were altered, and these changes might be related to the neurotoxicity observed in the neonatal mouse hippocampus following propofol exposure. Methods: In this laboratory experiment, 7-day-old mice were exposed to a subanesthetic dose of propofol for 3 hours, with 4 animals per group. Hippocampal tissues were harvested 3 hours after propofol administration. Neuroapoptosis was analyzed based on caspase 3 activity using a colorimetric assay. A microarray was performed to investigate the profiles of 35,923 lncRNAs and 24,881 messenger RNAs (mRNAs). Representative differentially expressed lncRNAs and mRNAs were validated using reverse transcription quantitative polymerase chain reaction. All mRNAs dysregulated by propofol and the 50 top-ranked, significantly dysregulated lncRNAs were subject to bioinformatics analysis for exploring the potential mechanisms and signaling network of propofol-induced neurotoxicity. Results: Propofol induced neuroapoptosis in the hippocampus, with differential expression of 159 lncRNAs and 100 mRNAs (fold change ± 2.0, P< 0.05). Bioinformatics analysis demonstrated that these lncRNAs and their associated mRNAs might participate in neurodegenerative pathways (e.g., calcium handling, apoptosis, autophagy, and synaptogenesis). Conclusion: This novel report emphasizes that propofol alters profiles of lncRNAs, mRNAs, and their cooperative signaling network, which provides novel insights into molecular mechanisms of anesthetic-induced developmental neurodegeneration and preventive targets against the neurotoxicity.
The Long Noncoding RNA TUG1 Promotes Laryngeal Cancer Proliferation and Migration
Authors: Zhang Zhonghua , Wang Xuehai , Cao Shengda , Han Xiao , Wang Zhanwang , Zhao Xiaoyan , Liu Xuejun , Li Guojun , Pan Xinliang , Lei Dapeng
Published: September 2018

Background/Aims: Researchers have shown that long noncoding RNAs are closely associated with the pathogenesis of laryngeal squamous cell carcinoma (LSCC). However, the role of the long noncoding RNA taurine-upregulated gene 1 (TUG1) in the pathogenesis of LSCC remains unclear, although it is recognized as an oncogenic regulator for several types of squamous cell carcinoma. Methods: qRT-PCR was performed to measure the expression of TUG1 in LSCC tissues and cell lines. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) was used to measure the effect of TUG1 on cell proliferation. Transwell assay and flow cytometry were employed to determine the effect of TUG1 on cell migration and invasion. Western-blot were performed to explore the relation of TUG1 and p53 mRNA. Results: Higher TUG1 expression in LSCC than in paired normal tumor-adjacent tissue specimens (N = 64) was observed using quantitative real-time polymerase chain reaction. Also, high TUG1 expression was positively associated with advanced T category, worse lymph node metastasis and late clinical stage. Furthermore, in vitro experiments demonstrated that silencing of TUG1 markedly inhibited proliferation, cell-cycle progression, migration, and invasion of LSCC cells, whereas depletion of TUG1 led to increased apoptosis. Conclusion: These findings demonstrated that upregulated TUG1 expression exerted oncogenic effects by promoting proliferation, migration, and invasion, and inhibiting apoptosis in LSCC cells.
Haploinsufficiency of Homeodomain Proteins Six3, Vax1, and Otx2 Causes Subfertility in Mice via Distinct Mechanisms
Authors: Hoffmann Hanne M. , Pandolfi Erica C. , Larder Rachel , Mellon Pamela L.
Published: September 2018

Haploinsufficiency occurs when loss of one copy of a diploid gene (hemizygosity) causes a phenotype. It is relatively rare, in that most genes can produce sufficient mRNA and protein from a single copy to prevent any loss of normal activity and function. Reproduction is a complex process relying on migration of GnRH neurons from the olfactory placode to the hypothalamus during development. We have studied 3 different homeodomain genes Otx2, Vax1, and Six3 and found that the deletion of one allele for any of these genes in mice produces subfertility or infertility in one or both sexes, despite the presence of one intact allele. All 3 heterozygous mice have reduced numbers of GnRH neurons, but the mechanisms of subfertility differ significantly. This review compares the subfertility phenotypes and their mechanisms.
Lipid Raft Clustering and Redox Signaling Platform Formation in Coronary Arterial Endothelial Cells
Authors: Zhang Andrew Y. , Yi Fan , Zhang Guo , Gulbins Erich , Li Pin-Lan
Published: September 2018

Recent studies have indicated that lipid rafts (LRs) in the cell membrane are clustered in response to different stimuli to form signaling platforms for transmembrane transduction. It remains unknown whether this LR clustering participates in redox signaling in endothelial cells. The present study tested a hypothesis that clustering of LRs on the membrane of coronary endothelial cells produces aggregation and activation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, thereby forming a redox signaling platform. By confocal microscopic analysis of agonist-stimulated rafts patch formation, we found that several death receptor ligands or apoptotic factors, including tumor necrosis factor α, Fas ligand, or endostatin, stimulated the clustering and trafficking of individual LRs on the plasma membrane of coronary endothelial cells. Interestingly, double labeling of a membrane-bound NADPH oxidase subunit, gp91

phox

, and LRs showed that gp91

phox

colocalized within the LR patches when endothelial cells were stimulated by Fas ligand. In isolated LR fractions from Fas-stimulated endothelial cells, gp91

phox

, p47

phox

(a crucial cytosolic regulatory subunit of NADPH oxidase), and Rac GTPase were markedly increased and blocked by nystatin, a compound that disrupts LRs. These clustered LRs contained high NADPH oxidase activity, which increased in response to Fas stimulation. Functionally, Fas ligand–induced inhibition of endothelium-dependent vasorelaxation was reduced if LRs were disrupted or NADPH oxidase was inhibited. These results suggest that LR clustering occurs in coronary endothelial cells. The formation of redox signaling platforms on the cell membrane mediates transmembrane signaling of death receptors, resulting in endothelial dysfunction.
Effects of Aging and Hypertension on the Microcirculation
Authors: James Martin A. , Tullett Jayne , Hemsley Anthony G. , Shore Angela C.
Published: September 2018

Alterations of structure and function of the microcirculation in hypertension in the elderly and changes with normotensive aging have not been fully clarified. We studied capillary pressure, density, and skin microvascular function in 46 subjects in 3 groups: elderly subjects (aged >60 years) with untreated hypertension (n=16), elderly normotensive subjects (n=16), and young normotensive subjects (age <45 years, n=14). In a subgroup of 19 subjects, we also studied resistance artery function in the isometric myograph. Capillary pressure was higher in both elderly groups (elderly hypertensives: 18.6±4.7 mm Hg, elderly normotensives: 17.6±4.0 mm Hg) compared with young normotensives (13.9±2.6 mm Hg,
P
<0.05), but capillary density did not differ between the groups. Skin vasodilating responses to acetylcholine were greater in young normotensives compared with both elderly groups (
P
<0.05). In isolated resistance arteries, there was a greater inhibitory effect from blockade of the
l
-arginine-NO pathway in elderly normotensives (
P
<0.05) and a reduction in the maximal inhibitory effect of combined blockade of NO, prostanoids, and endothelium-derived hyperpolarizing factor in elderly hypertensives (
P
<0.05). This study has demonstrated a significant effect of aging but no additional effect of hypertension on capillary pressure and no effect of either on capillary density. Our findings with both in vivo and in vitro methods suggest that normotensive aging may depend on relative preservation of NO-dependent vasodilatation in resistance arteries at the expense of a rise in capillary pressure.
Aging Modulates the Influence of Arginase on Endothelial Dysfunction in Obesity
Authors: Masi Stefano , Colucci Rocchina , Duranti Emiliano , Nannipieri Monica , Anselmino Marco , Ippolito Chiara , Tirotta Erika , Georgiopoulos Georgios , Garelli Francesca , Nericcio Anna , Segnani Cristina , Bernardini Nunzia , Blandizzi Corrado , Taddei Stefano , Virdis Agostino
Published: September 2018

Objective—

Arginase can reduce NO availability. In this study, we explored arginase as a determinant of endothelial dysfunction in small arteries from obese patients and its relationship with aging and microvascular remodeling.

Approach and Results—

Small arteries were dissected after subcutaneous fat biopsies and evaluated on a pressurized micromyograph. Endothelium-dependent vasodilation was assessed by acetylcholine, repeated under L-NAME (
N
 
G
-nitro-L-arginine-methyl ester), N(ω)-hydroxy-nor-
l
-arginine (arginase inhibitor) and gp91ds-tat (NADPH [nicotinamide adenine dinucleotide phosphate oxidase] oxidase inhibitor) in vessels from young (age <30 years) control and obese and old (>30 years) control and obese subjects. Media-lumen ratio and amount of vascular wall fibrosis were used as markers of vascular remodeling. Amount of vascular superoxide anions and NO production were determined with immunofluorescence, whereas arginase expression was quantified using Western blot and quantitative polymerase chain reaction. Obese and older age groups had lower vascular NO, as well as higher media-lumen ratio, wall fibrosis, intravascular superoxide, and blunted inhibitory effect of L-NAME on acetylcholine versus controls and younger age groups. N(ω)-hydroxy-nor-
l
-arginine restored the acetylcholine-induced vasodilation in young and, to a lesser extent, in old obese subjects. This effect was abolished by addition of L-NAME. Gp91ds-tat increased the vasodilatory response to N(ω)-hydroxy-nor-
l
-arginine in old obese. Superoxide anions and arginase I/II levels were higher in the vascular wall of obese versus controls.

Conclusions—

Arginase contributes to microvascular endothelial dysfunction in obesity. Its impact is reduced by aging because of higher levels of vascular oxidative stress. Obesity is accompanied by accelerated microvascular remodeling, the extent of which is related to the amount of arginase in the vascular wall.
Loss of EMILIN-1 Enhances Arteriolar Myogenic Tone Through TGF-β (Transforming Growth Factor-β)–Dependent Transactivation of EGFR (Epidermal Growth Factor Receptor) and Is Relevant for Hypertension in Mice and Humans
Authors: Carnevale Daniela , Facchinello Nicola , Iodice Daniele , Bizzotto Dario , Perrotta Marialuisa , De Stefani Diego , Pallante Fabio , Carnevale Lorenzo , Ricciardi Franco , Cifelli Giuseppe , Da Ros Francesco , Casaburo Manuel , Fardella Stefania , Bonaldo Paolo , Innocenzi Gualtiero , Rizzuto Rosario , Braghetta Paola , Lembo Giuseppe , Bressan Giorgio M.
Published: September 2018

Objective—

EMILIN-1 (elastin microfibrils interface located protein-1) protein inhibits pro–TGF-β (transforming growth factor-β) proteolysis and limits TGF-β bioavailability in vascular extracellular matrix.
Emilin1
−/−
null mice display increased vascular TGF-β signaling and are hypertensive. Because EMILIN-1 is expressed in vessels from embryonic life to adulthood, we aimed at unravelling whether the hypertensive phenotype of
Emilin1
−/−
null mice results from a developmental defect or lack of homeostatic role in the adult.

Approach and Results—

By using a conditional gene targeting inactivating EMILIN-1 in smooth muscle cells of adult mice, we show that increased blood pressure in mice with selective smooth muscle cell ablation of EMILIN-1 depends on enhanced myogenic tone. Mechanistically, we unveil that higher TGF-β signaling in smooth muscle cells stimulates HB-EGF (heparin-binding epidermal growth factor) expression and subsequent transactivation of EGFR (epidermal growth factor receptor). With increasing intraluminal pressure in resistance arteries, the cross talk established by TGF-β and EGFR signals recruits TRPC6 (TRP [transient receptor potential] classical type 6) and TRPM4 (TRP melastatin type 4) channels, lastly stimulating voltage-dependent calcium channels and potentiating myogenic tone. We found reduced EMILIN-1 and enhanced myogenic tone, dependent on increased TGF-β-EGFR signaling, in resistance arteries from hypertensive patients.

Conclusions—

Taken together, our findings implicate an unexpected role of the TGF-β-EGFR pathway in hypertension with current translational perspectives.
SM22α (Smooth Muscle Protein 22-α) Promoter-Driven IGF1R (Insulin-Like Growth Factor 1 Receptor) Deficiency Promotes Atherosclerosis
Authors: Sukhanov Sergiy , Higashi Yusuke , Shai Shaw-Yung , Snarski Patricia , Danchuk Svitlana , D’Ambra Veronica , Tabony Michael , Woods T. Cooper , Hou Xuwei , Li Zhaohui , Ozoe Atsufumi , Chandrasekar Bysani , Takahashi Shin-Ichiro , Delafontaine Patrice
Published: September 2018

Objective—

IGF-1 (insulin-like growth factor 1) is a major autocrine/paracrine growth factor, which promotes cell proliferation, migration, and survival. We have shown previously that IGF-1 reduced atherosclerosis and promoted features of stable atherosclerotic plaque in Apoe
−/
−
mice—an animal model of atherosclerosis. The aim of this study was to assess effects of smooth muscle cell (SMC) IGF-1 signaling on the atherosclerotic plaque.

Approach and Results—

We generated Apoe
−/−
mice with IGF1R (IGF-1 receptor) deficiency in SMC and fibroblasts (SM22α [smooth muscle protein 22 α]-CreKI/IGF1R-flox mice). IGF1R was decreased in the aorta and adventitia of SM22α-CreKI/IGF1R-flox mice and also in aortic SMC, embryonic, skin, and lung fibroblasts isolated from SM22α-CreKI/IGF1R-flox mice. IGF1R deficiency downregulated collagen mRNA-binding protein LARP6 (La ribonucleoprotein domain family, member 6) and vascular collagen, and mice exhibited growth retardation. The high-fat diet–fed SM22α-CreKI/IGF1R-flox mice had increased atherosclerotic burden and inflammatory responses. α-SMA (α-smooth muscle actin)–positive plaque cells had reduced proliferation and elevated apoptosis. SMC/fibroblast-targeted decline in IGF-1 signaling decreased atherosclerotic plaque SMC, markedly depleted collagen, reduced plaque fibrous cap, and increased plaque necrotic cores. Aortic SMC isolated from SM22α-CreKI/IGF1R-flox mice had decreased cell proliferation, migration, increased sensitivity to apoptosis, and these effects were associated with disruption of IGF-1–induced Akt signaling.

Conclusions—

IGF-1 signaling in SMC and in fibroblast is a critical determinant of normal vascular wall development and atheroprotection.
Lp(a) [Lipoprotein(a)]-Related Risk of Heart Failure Is Evident in Whites but Not in Other Racial/Ethnic Groups
Authors: Steffen Brian T. , Duprez Daniel , Bertoni Alain G. , Guan Weihua , Tsai Michael Y.
Published: September 2018

Objective—

Lp(a) [lipoprotein(a)] levels vary by race/ethnicity and were recently found to be associated with risk of heart failure (HF). We aimed to determine whether Lp(a)-related risk of HF is similar across different races and whether Lp(a) may further be related to HF with reduced ejection fraction or HF with preserved ejection fraction (HFpEF).

Approach and Results—

In 6809 participants of the MESA (Multi-Ethnic Study of Atherosclerosis), aged 45 to 84 years and free of cardiovascular disease, 308 incident HF events occurred during a median 13-year follow-up. Baseline Lp(a) concentrations were determined by immunoassay. Incident HF was adjudicated, distinguishing HF with reduced ejection fraction (ejection fraction, <45%) from HFpEF (ejection fraction, ≥45%). Cox regression assessed relations between Lp(a) and HF risk among 4 races/ethnicities. Lp(a) was examined as a continuous variable (per log unit) and using clinical cutoff values, 30 and 50 mg/dL. Lp(a) was related to greater risk of HF in whites alone: per log unit Lp(a) (hazard ratio [HR], 1.20;
P
=0.02); Lp(a) ≥30 mg/dL (HR, 1.69;
P
=0.01), Lp(a) ≥50 mg/dL (HR, 1.87;
P
=0.006). No significant relations were found in black, Hispanic, or Chinese participants, and significant race interactions were observed. Lp(a) was additionally related to greater risk of HFpEF in white participants: per log unit Lp(a) (HR, 1.48;
P
=0.001), Lp(a) ≥30 mg/dL (HR, 2.15;
P
=0.01), Lp(a) ≥50 mg/dL (HR, 2.60;
P
=0.004). Lp(a)-related risk of HF and HFpEF in whites was independent of aortic valve disease.

Conclusions—

In a multiethnic sample, Lp(a)-related risks of HF and HFpEF were only evident in white participants. If confirmed, these findings have implications in further Lp(a) research and clinical practice.
Associations of Circulating Protein Levels With Lipid Fractions in the General Population
Authors: Figarska Sylwia M. , Gustafsson Stefan , Sundström Johan , Ärnlöv Johan , Mälarstig Anders , Elmståhl Sölve , Fall Tove , Lind Lars , Ingelsson Erik
Published: September 2018

Objective—

Revealing patterns of associations between circulating protein and lipid levels could improve biological understanding of cardiovascular disease (CVD). In this study, we investigated the associations between proteins related to CVD and triglyceride (TG), total cholesterol, LDL (low-density lipoprotein), and HDL (high-density lipoprotein) cholesterol levels in individuals from the general population.

Approach and Results—

We measured plasma protein levels using the Olink ProSeek CVD I or II+III arrays and analyzed 57 proteins available in 3 population-based cohorts: EpiHealth (n=2029; 52% women; median age, 61 years), PIVUS (Prospective Study of the Vasculature in Uppsala Seniors; n=790; 51% women; all aged 70 years), and ULSAM (Uppsala Longitudinal Study of Adult Men; n=551; all men aged 77 years). A discovery analysis was performed in EpiHealth in a regression framework (adjusted for sex, age, body mass index, smoking, glucose levels, systolic blood pressure, blood pressure medication, diabetes mellitus medication, and CVD history), and associations with false discovery rate <0.05 were further tested in PIVUS and ULSAM, where a
P
value of 0.05 was considered a successful replication (validation false discovery rate of 0.1%). We used summary statistics from a genome-wide association study on each protein biomarker (meta-analysis of EpiHealth, PIVUS, ULSAM, and IMPROVE [Carotid Intima–Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population]) and publicly available data from Global Lipids Genetics Consortium to perform Mendelian randomization analyses to address possible causality of protein levels. Of 57 tested proteins, 42 demonstrated an association with at least 1 lipid fraction; 35 were associated with TG, 15 with total cholesterol, 9 with LDL cholesterol, and 24 with HDL cholesterol. Among these associations, we found KIM-1 (kidney injury molecule-1), TNFR (TNF [tumor necrosis factor] receptor) 1 and 2, TRAIL-R2 (TRAIL [TNF-related apoptosis-inducing ligand] receptor 2), and RETN (resistin) to be associated with all 4 lipid fractions. Further, 15 proteins were related to both TG and HDL cholesterol in a consistent and biologically expected manner, that is, higher TG and lower HDL cholesterol or vice versa. Another common pattern of associations was concomitantly higher TG, total cholesterol, and LDL cholesterol, which is associated with higher CVD risk. We did not find evidence of causal links for protein levels.

Conclusions—

Our comprehensive analysis of plasma proteins and lipid fractions of 3370 individuals from the general population provides new information about lipid metabolism.
Childhood Fat and Lean Mass
Authors: Sletner Line , Mahon Pamela , Crozier Sarah R. , Inskip Hazel M. , Godfrey Keith M. , Chiesa Scott , Bhowruth Devina J. , Charakida Marietta , Deanfield John , Cooper Cyrus , Hanson Mark
Published: September 2018

Objective—

Childhood body mass index (BMI) has been related to vascular structure and function. However, little is known about the differing contributions of fat and lean mass to this relationship. Our objectives were to relate the fat and lean mass (bone excluded) components of BMI (fat mass index and lean mass index; mass [kg]/height [m]
2
) to vascular measures in prepubertal children.

Approach and Results—

In the UK Southampton Women’s Survey mother-offspring cohort, 983 children had dual x-ray absorptiometry and vascular measurements at 8 to 9 years. Using linear regression analyses, we found that most vascular measures were related to BMI, but fat and lean mass contributed differently. Systolic blood pressure was positively associated with both fat mass index (β=0.91 [95% CI, 0.52–1.30] mm Hg) and lean mass index (β=2.16 [95% CI, 1.47–2.85] mm Hg), whereas pulse rate was positively associated with fat mass index (β=0.93 [95% CI, 0.48–1.38] b/min) but negatively associated with lean mass index (β=−1.79 [95% CI, −2.59 to −0.99] b/min). The positive relation between BMI and carotid intima-media thickness was mainly due to a positive association with lean mass index (β=0.013 [95% CI, 0.008–0.019] mm). Carotid-femoral pulse wave velocity, but not carotid-radial pulse wave velocity, was positively associated with fat mass index (β=0.06 [95% CI, 0.03–0.09] m/s). For systolic blood pressure, carotid-femoral pulse wave velocity and reactive hyperemia significant interactions indicated that the association with fat mass depended on the amount of lean mass.

Conclusions—

In prepubertal children, differences in vascular structure and function in relation to BMI probably represent combinations of adverse effects of fat mass, adaptive effects of body size, and relatively protective effects of lean mass.
Inhibition of Vascular Calcification
Authors: Liu Lipei , Zeng Peng , Yang Xiaoxiao , Duan Yajun , Zhang Wenwen , Ma Chuanrui , Zhang Xiaomeng , Yang Shu , Li Xiaoju , Yang Jie , Liang Yu , Han Hao , Zhu Yan , Han Jihong , Chen Yuanli
Published: September 2018

Objective—

Vascular calcification is a major risk factor for rupture of atherosclerotic plaques. High expression of BMP2 (bone morphogenetic protein 2) in lesions suggests its importance in vascular calcification during atherosclerosis. Teniposide is a Topo II (DNA topoisomerase II) inhibitor and is used for cancer treatment. Previously, we reported that teniposide activated macrophage ABCA1 (ATP-binding cassette transporter A1) expression and free cholesterol efflux indicating Topo II inhibitors may demonstrate antiatherogenic properties. Herein, we investigated the effects of teniposide on the development of atherosclerosis and vascular calcification in apoE
−/−
(apoE deficient) mice.

Approach and Results—

apoE
−/−
mice were fed high-fat diet containing teniposide for 16 weeks, or prefed high-fat diet for 12 weeks followed by high-fat diet containing teniposide for 4 weeks. Atherosclerosis and vascular calcification were determined. Human aortic smooth muscle cells were used to determine the mechanisms for teniposide-inhibited vascular calcification. Teniposide reduced atherosclerotic lesions. It also substantially reduced vascular calcification without affecting bone structure. Mechanistically, teniposide reduced vascular calcification by inactivating BMP2/(pi-Smad1/5/8 [mothers against decapentaplegic homolog 1, 5, and 8])/RUNX2 (runt-related transcription factor 2) axis in a p53-dependent manner. Furthermore, activated miR-203-3p by teniposide functioned as a link between activated p53 expression and inhibited BMP2 expression in inhibition of calcification.

Conclusions—

Our study demonstrates that teniposide reduces vascular calcification by regulating p53-(miR-203-3p)-BMP2 signaling pathway, which contributes to the antiatherogenic properties of Topo II inhibitors.
Coronary Artery Anomalies
Authors: Angelini Paolo
Published: September 2018

Coronary artery anomalies (CAAs) are a diverse group of congenital disorders whose manifestations and pathophysiological mechanisms are highly variable. The subject of CAAs is undergoing profound evolutionary changes related to the definition, morphogenesis, clinical presentation, diagnostic workup, prognosis, and treatment of these anomalies. To understand the clinical impact of CAAs, the fundamental challenge is the firm establishment, for a particular type of CAA, of a mechanism capable of interference with the coronary artery’s function, which is to provide adequate blood flow to the dependent myocardium. The present review focuses on anomalous origination of a coronary artery from the opposite sinus—the subgroup of CAAs that has the most potential for clinical repercussions, specifically sudden death in the young. For this subgroup, solid diagnostic screening protocols should be established, especially for athletes and other young individuals subjected to extreme exertion. Intravascular ultrasonography is the preferred means to evaluate the mechanisms responsible for ischemia in anomalous origination of a coronary artery from the opposite sinus and other potentially significant CAAs. Patients symptomatic of anomalous origination of a coronary artery from the opposite sinus may undergo medical treatment/observation, coronary angioplasty with stent deployment, or surgical repair. To be competent to advise CAA carriers, especially in the context of sporting or military activities, cardiologists should undergo specific training in these disorders. Only multicenter collaboration on protocols dedicated to CAAs can give rise to the large-scale studies needed to define the prognosis and optimal treatment of these disorders.