bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired DNA damage response promotes atherosclerosis by enhancing cellular senescence and proinflammatory activation
Authors: Sakai C , Ishida M.I , Tashiro S.T , Yoshizumi M.Y , Ishida T.I 
Published: November 2020

Abstract

Background
DNA damage likely contributes to the pathogenesis and progression of atherosclerosis. Chemotherapy, radiotherapy and some DNA damage response (DDR) syndromes are known to increase atherosclerosis. However, causative links between DNA damage and atherosclerosis are yet to be established.

Purpose
The aim of this study was to investigate the role of impaired DDR in atherosclerosis.

Methods and results
Ku80, a DNA repair protein, -deficient apolipoprotein E knockout mice (Ku80+/− ApoE−/−) and ApoE−/m- mice were fed on high-fat diet for 4 weeks, and then oil red O staining was performed on their isolated aortas. Plaque area was significantly increased in Ku80+/− ApoE−/− mice. Immunohistochemical analysis of lesions from Ku80+/− ApoE−/− mice revealed enhanced accumulation of DNA double-strand breaks (DSBs). Similar results were obtained from Ku80+/− ApoE−/− mice fed on high-fat diet for 2 weeks which was considered as the early stages of atherosclerosis. mRNA levels of inflammatory cytokines such as IL-6 and MCP-1 in the aorta were significantly elevated in Ku80+/− ApoE−/− mice compared with those of ApoE−/− mice. To investigate whether impaired DDR is associated with the increased expression of inflammatory cytokines, vascular smooth muscle cells were isolated from Ku80 WT and Ku80+/− mice and subjected to quantitative RT-PCR analysis. mRNA levels of IL-6 and MCP-1 were significantly elevated in Ku80+/− cells. In addition, IκBα protein expression was significantly decreased in Ku80+/− cells, which suggested enhanced NF-κB activation in those cells. Immunofluorescent analysis revealed accumulation of DSBs and persistent DDR in Ku80+/− cells. In addition, elevated p16 mRNA level and senescence-associated β-gal activity were observed in Ku80+/− cells.

Conclusion
These results suggested that impaired DDR promoted atherosclerosis partly through cellular senescence and enhanced proinflammatory activation. Therefore, therapies targeting enhancing DDR may be beneficial in the prevention of DNA damage-induced atherosclerosis.

Funding Acknowledgement
Type of funding source: Public Institution(s). Main funding source(s): KAKENHI
Different tryptophan-kynurenine metabolism profiles in human pulmonary arterial hypertension and animal models of pulmonary hypertension
Authors: Cai Z , Klein T , Tu L , Geenen L.W , Tian S , Van Der Ley C , Van Faassen M , Kema I , Van Den Bosch A.E , De Rijke J.B , Reiss I.K.M , Duncker D.J , Boomars K.A , Guignabert C , Merkus D 
Published: November 2020

Abstract

Background
De novo NAD+ synthesis through the tryptophan-kynurenine (TK) metabolism was recognized as an important pathway in improving mitochondrial function and survival of injury or apoptotic cells, which are key processes involved in the pathogenesis of pulmonary arterial hypertension (PAH). Although abnormal TK metabolism has been reported in human PAH, the difference between human and animal models of pulmonary hypertension (PH) are currently unknown.

Objective
Determine and compare TK metabolism profiles in plasma from human PAH and 3 animal models of PH.

Methods
Human plasma was collected from treatment naïve patients with PAH (n=43) and healthy controls (n=111). Animal plasma was collected from 3 animal models of PH and corresponding controls, including monocrotaline (MCT) induced PH in rat (n=7, control n=6), Sugen + hypoxia (SuHx) induced PH in rat (n=5, control n=6), and pulmonary vein banding (PVB) induced PH in swine (n=7, control n=6). TK metabolites were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results
TK metabolism was altered in the plasma from of PAH compared to healthy controls (Figure 1A). Lower tryptophan (0.8 fold vs Control, p&lt;0.0001), maintained 3-hydroxyanthranilic acid, and higher kynurenine, 3-hydroxykynurenine, anthranilic acid, and quinolinic acid (1.5, 2.6, 2.0, 2.6 fold vs Control, respectively, p all&lt;0.0001) were seen in the plasma from human PAH. In the rat SuHx-PH model, kynurenine (0.7 fold, p&lt;0.01) and quinolinic acid (0.5 fold, p&lt;0.001) were lower, while 3-hydroxyanthranilic acid (4.3 fold, p&lt;0.001) was higher in PH compared to control (Figure 1B). However, the TK metabolism was unaltered in MCT-PH model in rat (Figure 1C), and PVB-PH model in swine (Figure 1D).

Conclusions
TK metabolism was altered in the plasma from human PAH. The TK metabolism profiles were different among 3 animal models of PH, but did not mimic the profile in human PAH. Further research is required to determine the mechanism(s) behind the abnormal TK metabolism in human PAH as well as whether these mechanisms relate to disease onset or progression.
Figure 1

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): This work was supported by the China Scholarship Council (201606230252) as well as the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-11, RECONNECT), and German Center for Cardiovascular Research (DZHK81Z0600207). Instrumentation support was received from AB Sciex, ltd. for LC-MS/MS analyses performed in this study.
Ponatinib induces vascular toxicity through the Notch-1 signaling pathway
Authors: Madonna R , Pieragostino D , Cufaro M , Doria V , Del Boccio P , Deidda M , Pierdomenico S , Cadeddu Dessalvi C , De Caterina R , Mercuro G 
Published: November 2020

Abstract

Background
Ponatinib, a third-generation tyrosine kinase inhibitor (TKI), is the only approved TKI that is effective against T315I mutations in patients with chronic myeloid leukemia (CML). Specific activation of Notch signaling in CML cells by ponatinib can be considered as the “on-target effect” on the tumor and represents a therapeutic approach for CML. Nevertheless, ponatinib-induced vascular toxicity remains a serious concern, with underlying mechanisms poorly understood.

Aims
We aimed at determining mechanisms of ponatinib-induced vascular toxicity, defining associated signaling pathways and identifying potential rescue strategies.

Methods and results
We exposed human umbilical endothelial cells (HUVECs) to ponatinib or vehicle in the presence or absence of the neutralizing factor anti-Notch-1 antibody for exposure times of 0–72 hours. Label-free proteomics and network analysis showed that protein cargo of HUVECs treated with ponatinib triggered apoptosis, and inhibited vasculature development (Fig. 1). We validated the proteomic data showing the inhibition of matrigel tube formation, an upregulation of cleaved caspase-3 and a downregulation of phosphorylated AKT and phosphorylated eNOS. We delineated the signaling of ponatinib-induced vascular toxicity demonstrating that ponatinib inhibits endothelial survival, reduces angiogenesis and induces endothelial senescence and apoptosis via Notch-1 pathway.

Conclusion
Ponatinib induced endothelial toxicity in vitro. Hyperactivation of Notch-1 in the vessels can lead to abnormal vascular development and vascular dysfunction. By hyperactivating Notch-1 in the vessels, ponatinib exerts an “on-target off turmor effect”, which leads to deleterious effects and may explain the drug's vasculotoxicity. Selective blockade of Notch-1 prevented ponatinib-induced vascular toxicity.
Figure 1

Funding Acknowledgement
Type of funding source: None
A case report on the successful interventional treatment of a rare cause of left heart failure in a 69-year-old woman
Authors: Podnar Tomaz , Plank Fabian , Müller Silvana , Mair Johannes 
Published: November 2020

Abstract

Background
Dyspnoea is very common in elderly patients and can be caused by a variety of different diseases. However, the initial diagnosis of patent ductus arteriosus (PDA) as a cause of left heart failure is very rare in this patient population.

Case summary
A 69-year-old physically active woman with known hypertension presented with worsening exertional dyspnoea. Echocardiography showed a dilated left ventricle with moderately reduced left ventricular ejection fraction, and evidence for PDA. The PDA was confirmed by computed tomography angiography and successfully closed by implantation of an Amplatzer PDA occluder II 06-06 mm. As a result, the heart failure symptoms receded completely.

Discussion
Congenital heart diseases should be considered as heart failure causes even in older adults. In addition to the standard medical therapy, there may be effective interventional treatment options to reverse the symptoms of heart failure in such patients.
Case report: isolated pulmonary valve endocarditis in a 39-year-old patient with intravenous drug abuse
Authors: Platz Martin Richard , Stöbe Stephan , Baum Paul , Metze Michael 
Published: November 2020

Abstract

Background
Isolated pulmonary valve endocarditis is a very rare form of right-sided infective endocarditis. Due to the anatomy, in most cases, just the tricuspid valve is involved. Diagnosis can be challenging because of non-specific symptoms (fever, dyspnoea, haemoptysis, and pleuritic chest pain) and difficulty of detection by echocardiography. Risk factors include intravenous drug abuse, congenital heart disorders, alcohol abuse, male sex and central venous catheters, or pacemaker leads.

Case summary
A 39-year-old homeless male patient, who was a current intravenous drug user, presented with fever, dyspnoea, and haemoptysis. The chest X-ray showed bilateral infiltrates. Empiric antibiotic treatment was initiated. Blood cultures showed the presence of Streptococcus dysgalactiae. Atypical causes of pneumonia were excluded. Systemic embolism was suspected, and a computed tomography scan of brain, thorax, and abdomen was performed. Multiple septic embolic lesions were detected in both lungs. Echocardiography revealed an isolated pulmonary valve endocarditis. Penicillin G and gentamycin were administered intravenously for a duration of 6 and 2 weeks, respectively. The patient was discharged in stable condition but did not return for outpatient clinical appointments.

Discussion
To detect rare causes of right-sided infective endocarditis, repeated echocardiograms with special focus on the pulmonary valve may be required. Usually, antibiotic treatment alone leads to recovery. In special situations (heart failure, septic shock, or large vegetation size) surgery is required. Due to the high risk of postoperative complications, surgery in intravenous drug users should be avoided if possible.
Efforts needed for preventing breast and colorectal cancer through changes in dietary patterns
Authors: Mullie Patrick , Guillot Gilles , Pizot Cécile , Autier Philippe , Boyle Peter 
Published: November 2020

Abstract

Background
Prospective cohort studies on diet and cancer report risk associations as hazard ratios. But hazard ratios do not inform on the number of people who need to alter their dietary behaviours for preventing cancer. The objective of this study is to estimate the number of people that need to alter their diet for preventing one additional case of female breast or colorectal cancer.

Methods
Based on the largest prospective studies done in the USA and in Europe, we computed the number of subjects who need to alter their diet.

Results
For preventing one case of breast cancer, European women should increase their fruit consumption by 100 g/day during 33 000 person-years, and US women by 60 g/day during 10 600 person-years. For vegetables, European women should increase their consumption by 160 g/day during 26 900 person-years and US women by 100 g/day during 19 000 person-years. For preventing one case of colorectal cancer, European subjects should decrease their red meat consumption by 20 g/day during 26 100 person-years, and US subjects by 30 g/day during 8170 person-years. For processed meat, European subjects should decrease their consumption by 20 g/day during 17 400 person-years, and US subjects by 10 g/day during 7940 person-years.

Conclusions
Large number of subjects would need to alter their intake of fruits, vegetables, red and processed meat during many years in order to prevent one additional breast or colorectal cancer.
Judicial Dialogue Between National Courts and the Inter-American Court of Human Rights: A Comparative Study of Argentina, Brazil, Colombia and Mexico
Authors: Maués Antonio Moreira , Magalhães Breno Baía , Nassar Paulo André , Sena Rafaela 
Published: November 2020

ABSTRACT
This article discusses the dialogue between the Supreme Courts of Argentina, Brazil and Mexico and the Constitutional Court of Colombia with the Inter-American Court of Human Rights. It assesses the impact of the following variables on this judicial dialogue: the hierarchy and direct effect of human rights treaties, consistent interpretation with international law and judicial postures related to international law. The article develops an analysis of each court’s leading cases and discusses whether and how these variables have contributed to dialogue and whether it is possible to identify common patterns in these four countries’ relations with the Inter-American Court of Human Rights (IACtHR). We argue that the constitutional status of human rights treaties, the use of the American Convention on Human Rights to control the conventionality of domestic law, the application of the principle of consistent interpretation and a posture of convergence or engagement with international law lead domestic courts to acknowledge an obligation to follow or, at least, consider IACtHR jurisprudence.
The Law and Its Limits: Land Grievances, Wicked Problems, and Transitional Justice in Timor-Leste
Authors: Almeida Bernardo 
Published: November 2020

Abstract
This article discusses the inherent limitations of law in transitional justice processes regarding land grievances. Through analysis of the case of Timor-Leste (East Timor), a country marked by post-colonialism, post-authoritarianism, and post-conflict. The article shows how complex transitional justice regarding land grievances can be, and argues that a legalist perspective gives a limited view of these grievances, both for studying and finding solutions to them. The article employs the concept of ‘wicked problems’ to overcome the limitations of law. First, it shows how these grievances should be studied through a multi-disciplinary approach instead of a purely legal one. Second, it argues that transitional justice regarding land grievances is primarily a political issue, and creating adequate arenas for political negotiation should be prioritized. Finally, the article shows that, due to its complexity and political nature, transitional justice for land grievances is ultimately a search for acceptable, rather than optimal, solutions.
Low Barometric Pressure Enhances Tethered-Flight Performance and Reproductive of the Oriental Armyworm, Mythimna separata (Lepidoptera: Noctuidae)
Authors: Miao Jin , Guo Pei , Li Huiling , Wei Changshuan , Liu Qihang , Gong Zhongjun , Duan Yun , Li Tong , Jiang Yueli , Feng Hongqiang , Wu Yuqing 
Published: November 2020

Abstract
Barometric pressure is an important factor influencing several insect traits. Most studies have been conducted on the behavior of insects in relation to rapid and slight changes in pressure magnitudes or short-term pressure trends, but there is little information on the effect of long-term and large pressure variations on insect traits. Here, we assessed the effects of static low barometric pressure on the tethered flight, lifespan and reproductive performance of Mythimna separata (Walker), a long-distance migratory insect, using an apparatus simulating low barometric pressure at altitudes of 500 m above sea level. We found that both the flight distance and flight duration of M. separata moths were significantly longer under low barometric pressure conditions. Exposure to low barometric pressure conditions for 24 and 48 h significantly shortened the lifespan of female moths but had no influence on male moths. The ovaries of female moths developed earlier, and the preoviposition and oviposition periods were significantly shortened under low atmospheric pressure. Moreover, low atmospheric pressure reduced the respiration rate of female moths. However, there was an increase in the respiration rate of female moths after being returned to standard barometric pressure conditions. Our results show that the behavior and physiological traits of insects are affected by the low-pressure environment during migration. The low barometric pressure conditions at high altitudes is one of important factors accelerating reproductive behavior of M. separata after migration.
Geographical variation in germination traits of the salt-marsh cordgrassSpartina alterniflorain its invasive and native ranges
Authors: Liu Wen-Wen , Zhang Yi-Hui 
Published: November 2020

AbstractAimsGermination is the earliest life-history transition of a plant species. It determines the ecological breadth and geographic ranges of a species and has major effects on its invasion potential. The largest spread of the invasive salt-marsh cordgrass Spartina alterniflora in China, where it extends to latitudes lower than its native range in North America, provides an opportunity to examine germination trait variation across latitudes within and among its invasive and native ranges.MethodsWe studied seed germination traits of S. alterniflora using seeds collected from 10 locations across latitudes in its invasive range (China, 20°–40° N) and 16 locations across latitudes in its native range (USA, 27°–43° N) in growth chambers with 0 PSU sterilized distilled water. We further evaluated how climate and tide range in the original locations influenced germination traits.Important FindingsNative populations showed higher (~10%) germination percentage and significantly higher (~20%) germination index than invasive populations did, but invasive populations germinated significantly earlier (~3 days) than native populations. Germination percentage and germination index increased with latitude in the invasive range but decreased with latitude in the native range. The mean germination time decreased with latitude in the invasive range and paralleled that in the native range. Germination percentage and germination index were negatively correlated with mean daily temperature (Tmean), mean daily maximum temperature (Tmax) and mean daily minimum temperature (Tmin), and inversely correlated with Tmean, Tmax and Tmin in the native range. However, the mean germination time was positively correlated with Tmean, Tmax and Tmean in both ranges. Our results demonstrate that invasive and native populations have evolved different latitudinal clines in germination percentage and index, but the mean germination time of the invasive population mirrored the latitudinal cline observed in the native range, suggesting that germination strategy across latitudes may change during invasion process.
Hardiness Predicts Post-Traumatic Growth and Well-Being in Severely Wounded Servicemen and Their Spouses
Authors: Bartone Paul T , Bowles Stephen V 
Published: November 2020

ABSTRACT

Introduction
Thousands of military personnel have suffered severe wounds and traumatic amputations in recent overseas conflicts. They face multiple surgeries and long, painful rehabilitation. Despite the tremendous stress for these servicemen and families, many appear to cope quite well and even thrive despite their devastating wounds. Hardiness is a world view or mindset marked by high levels of commitment and engagement in the world, a strong sense of control, and the tendency to see change as a challenge and opportunity to learn and improve. Previous research has shown that military personnel high in hardiness are at lower risk for post-traumatic stress disorder, depression, and other psychiatric symptoms following combat exposure. This study evaluated the impact of personality hardiness on post-traumatic growth (PTG) and psychological well-being in severely wounded service members and their spouses.

Materials and Methods
Male volunteers were surveyed while in hospital for severe battle wounds including loss of limbs. All were married, and all spouses also agreed to participate. Participants (N = 44) completed measures of hardiness, PTG, well-being, and neuroticism, and answered a question regarding potential benefits of their experience.

Results
Hierarchical multiple regression showed that hardiness significantly predicted both PTG and well-being, while controlling for age, education, family income, and neuroticism. Both service members and spouses indicated they experienced benefits in the following areas: strengthened family ties and connections; greater appreciation for and perspective on life; new career and educational opportunities; stronger, more resilient as a person; and formed new relationships, friends, and connections.

Conclusion
These results suggest that seriously wounded military members and their spouses who are high in hardiness are more likely to experience PTG and psychological well-being following extremely stressful experiences. Hardiness entails positive reframing of negative experiences as opportunities and challenges to overcome, and taking action to solve problems. Training programs to increase hardiness attitudes and related coping skills may thus be beneficial in facilitating healthy adaptation for severely injured patients.
Validation of the 3D reconstructed human skin micronucleus (RSMN) assay: an animal-free alternative for following-up positive results from standardin vitrogenotoxicity assays
Authors: Pfuhler Stefan , Downs Thomas R , Hewitt Nicola J , Hoffmann Sebastian , Mun Greg C , Ouedraogo Gladys , Roy Shambhu , Curren Rodger D , Aardema Marilyn J 
Published: November 2020

AbstractIn vitro test batteries have become the standard approach to determine the genotoxic potential of substances of interest across industry sectors. While useful for hazard identification, standard in vitro genotoxicity assays in 2D cell cultures have limited capability to predict in vivo outcomes and may trigger unnecessary follow-up animal studies or the loss of promising substances where animal tests are prohibited or not desired. To address this problem, a team of regulatory, academia and industry scientists was established to develop and validate 3D in vitro human skin-based genotoxicity assays for use in testing substances with primarily topical exposure. Validation of the reconstructed human skin micronucleus (RSMN) assay in MatTek Epi-200™ skin models involved testing 43 coded chemicals selected by independent experts, in four US/European laboratories. The results were analysed by an independent statistician according to predefined criteria. The RSMN assay showed a reproducibly low background micronucleus frequency and exhibited sufficient capacity to metabolise pro-mutagens. The overall RSMN accuracy when compared to in vivo genotoxicity outcomes was 80%, with a sensitivity of 75% and a specificity of 84%, and the between- and within-laboratory reproducibility was 77 and 84%, respectively. A protocol involving a 72-h exposure showed increased sensitivity in detecting true positive chemicals compared to a 48-h exposure. An analysis of a test strategy using the RSMN assay as a follow-up test for substances positive in standard in vitro clastogenicity/aneugenicity assays and a reconstructed skin Comet assay for substances with positive results in standard gene mutation assays results in a sensitivity of 89%. Based on these results, the RSMN assay is considered sufficiently validated to establish it as a ‘tier 2’ assay for dermally exposed compounds and was recently accepted into the OECD’s test guideline development program.