bluuebunny/crossref_metadata_2025 huggingface dataset:
Impairments in the reproductive axis of female mice lacking estrogen receptor β in GnRH neurons
Authors: Novaira Horacio J. , Negron Ariel L. , Graceli Jones B. , Capellino Silvia , Schoeffield Andrew , Hoffman Gloria E. , Levine Jon E. , Wolfe Andrew , Wondisford Fredric E. , Radovick Sally
Published: July 2018

The effect of estrogen on the differentiation and maintenance of reproductive tissues is mediated by two nuclear estrogen receptors (ERs), ERα, and ERβ. Lack of functional ERα and ERβ genes in vivo significantly affects reproductive function; however, the target tissues and signaling pathways in the hypothalamus are not clearly defined. Here, we describe the generation and reproductive characterization of a complete-ERβ KO (CERβKO) and a GnRH neuron-specific ERβKO (GERβKO) mouse models. Both ERβKO mouse models displayed a delay in vaginal opening and first estrus. Hypothalamic gonadotropin-releasing hormone (GnRH) mRNA expression levels in both ERβKO mice were similar to control mice; however female CERβKO and GERβKO mice had lower basal and surge serum gonadotropin levels. Although a GnRH stimulation test in both female ERβKO models showed preserved gonadotropic function in the same animals, a kisspeptin stimulation test revealed an attenuated response by GnRH neurons, suggesting a role for ERβ in normal GnRH neuron function. No alteration in estrogen-negative feedback was observed in either ERβKO mouse models after ovariectomy and estrogen replacement. Further, abnormal development of ovarian follicles with low serum estradiol levels and impairment of fertility were observed in both ERβKO mouse models. In male ERβKO mice, no differences in the timing of pubertal onset or serum luteinizing hormone and follicle-stimulating hormone levels were observed as compared with controls. Taken together, these data provide in vivo evidence for a role of ERβ in GnRH neurons in modulating puberty and reproduction, specifically through kisspeptin responsiveness in the female hypothalamic-pituitary-gonadal axis.
Changes in blood glucose as a function of body temperature in laboratory mice: implications for daily torpor
Authors: Lo Martire Viviana , Valli Alice , Bingaman Mark J. , Zoccoli Giovanna , Silvani Alessandro , Swoap Steven J.
Published: July 2018

Many small mammals, such as the laboratory mouse, utilize the hypometabolic state of torpor in response to caloric restriction. The signals that relay the lack of fuel to initiate a bout of torpor are not known. Because the mouse will only enter a torpid state when calorically challenged, it may be that one of the inputs for initiation into a bout of torpor is the lack of the primary fuel (glucose) used to power brain metabolism in the mouse. Using glucose telemetry in mice, we tested the hypotheses that 1) circulating glucose (GLC), core body temperature (Tb), and activity are significantly interrelated; and 2) that the level of GLC at the onset of torpor differs from both GLC during arousal from torpor and during feeding when there is no torpor. To test these hypotheses, six C57Bl/6J mice were implanted with glucose telemeters and exposed to different feeding conditions (ad libitum, fasting, limited food intake, and refeeding) to create different levels of GLC and Tb. We found a strong positive and linear correlation between GLC and Tb during ad libitum feeding. Furthermore, mice that were calorically restricted entered torpor bouts readily. GLC was low during torpor entry but did not drop precipitously as Tb did at the onset of a torpor bout. GLC significantly increased during arousal from torpor, indicating the presence of endogenous glucose production. While low GLC itself was not predictive of a bout of torpor, hyperactivity and low GLC preceded the onset of torpor, suggesting that this may be involved in triggering torpor.
Complex Analyses of Short Inverted Repeats in All Sequenced Chloroplast DNAs
Authors: Brázda Václav , Lýsek Jiří , Bartas Martin , Fojta Miroslav
Published: July 2018

Chloroplasts are key organelles in the management of oxygen in algae and plants and are therefore crucial for all living beings that consume oxygen. Chloroplasts typically contain a circular DNA molecule with nucleus-independent replication and heredity. Using “palindrome analyser” we performed complete analyses of short inverted repeats (S-IRs) in all chloroplast DNAs (cpDNAs) available from the NCBI genome database. Our results provide basic parameters of cpDNAs including comparative information on localization, frequency, and differences in S-IR presence. In a total of 2,565 cpDNA sequences available, the average frequency of S-IRs in cpDNA genomes is 45 S-IRs/per kbp, significantly higher than that found in mitochondrial DNA sequences. The frequency of S-IRs in cpDNAs generally decreased with S-IR length, but not for S-IRs 15, 22, 24, or 27 bp long, which are significantly more abundant than S-IRs with other lengths. These results point to the importance of specific S-IRs in cpDNA genomes. Moreover, comparison by Levenshtein distance of S-IR similarities showed that a limited number of S-IR sequences are shared in the majority of cpDNAs. S-IRs are not located randomly in cpDNAs, but are length-dependently enriched in specific locations, including the repeat region, stem, introns, and tRNA regions. The highest enrichment was found for 12 bp and longer S-IRs in the stem-loop region followed by 12 bp and longer S-IRs located before the repeat region. On the other hand, S-IRs are relatively rare in rRNA sequences and around introns. These data show nonrandom and conserved arrangements of S-IRs in chloroplast genomes.
Surgical Treatment for Malunion of the Lateral Humeral Epicondyle with Posterior Subluxation of the Radial Head: A Case Report and Literature Review
Authors: Yano Koichi , Kaneshiro Yasunori , Sakanaka Hideki
Published: July 2018

A 24-year-old right-handed man suffered right olecranon and lateral epicondylar fracture from high energy trauma. Fixation of olecranon was performed by a previous doctor. Three months after operation, he presented with limited range of motion (ROM) of the right elbow caused by malunion of the lateral epicondylar fracture and subluxation of the radiohumeral joint. Preoperative ROM of the right elbow was flexion 110° and extension −75°. Forearm rotation was pronation 85° and supination 65°. Fragment excision of the lateral epicondyle, which was 27 mm in length, and lateral collateral ligament repair using anchors were performed. Fourteen months postoperatively, contracture release of the elbow was performed. Twenty-four months postoperatively, radiograph of the elbow showed normal congruence without osteoarthritic changes and the ROM of the right elbow was flexion 120° and extension −35°. Forearm rotation was pronation 90° and supination 70°. In the surgical setting, in case of the size of the lateral epicondylar fragment is relatively large, the fragment should be fixed or lateral collateral ligament should be repaired when the instability of the elbow is found.
Variations in the Temperature-Humidity Index and Dorsal Fat Thickness during the Last Trimester of Gestation and Early Postpartum Period Affect Fertility ofBos indicusCows in the Tropics
Authors: Díaz Ramiro F. , Galina Carlos S. , Estrada Sandra , Montiel Felipe , Castillo Gloriana , Romero-Zúñiga Juan José
Published: July 2018

In order to measure the influence of the temperature-humidity index (THI) and the variation of fat thickness on reproductive performance, ninety-twoBos indicuscows kept under grazing conditions were used in two farms in Veracruz (Mexico) and Puntarenas (Costa Rica). THI was calculated with the average environmental temperature and relative humidity. Measurements of fat thickness (FAT) were taken two weeks apart from the last trimester of gestation to approximately 80 days postpartum (dpp). Natural breeding was used in both farms. Time to conception was calculated based on the interval from days at risk to conception (DRC), which had to be at least 28 dpp. THI was between65.4±2.9and73.2±1.5in Veracruz and75.4±0.26and76.5±0.55in Puntarenas. Variations in THI were observed in Puntarenas whereas in Veracruz THI variations were more prominent. In Veracruz, loss of fat during the last trimester of gestation was on average 8.5%, whereas in the postpartum period it was 18.4% (P = 0.042). In Puntarenas, the variation in the last trimester of gestation was on average 18.7% and in the postpartum period was 10.5% (P = 0.012). The relative change in FAT in Veracruz was 36.7%, and in Puntarenas it was 29.3%. Overall, 60% of the cows became pregnant. FAT decreased the interval of DRC (R2=0.06; P=0.033) with a high relationship (R2=0.76; P< 0.0001) between THI and time to conception, in both farms. In conclusion, THI levels influence the reproductive performance in early postpartum period affecting DRC.
Surface Characteristic Effect of Ag/TiO2 Nanoarray Composite Structure on Supercapacitor Electrode Properties
Authors: Cui Jie , Cao Lin , Zeng Dahai , Wang Xiaojian , Li Wei , Lin Zhidan , Zhang Peng
Published: July 2018

Ag-ion-modified titanium nanotube (Ag/TiO2-NT) arrays were designed and fabricated as the electrode material of supercapacitors for electrochemical energy storage. TiO2 nanotube (NT) arrays were prepared by electrochemical anodic oxidation and then treated by Ag metal vapor vacuum arc (MEVVA) implantation. The Ag amount was controlled via adjusting ion implantation parameters. The morphology, crystallinity, and electrochemistry properties of as-obtained Ag/TiO2-NT electrodes were distinguished based on various characterizations. Compared with different doses of Ag/TiO2-NTs, the electrode with the dose of 5.0 × 1017 ions·cm−2 exhibited much higher electrode capacity and greatly enhanced activity in comparison to the pure TiO2-NTs. The modified electrode showed a high capacitance of 9324.6 mF·cm−3 (86.9 mF·g, 1.2 mF·cm−2), energy density of 82.8 μWh·cm−3 (0.8 μWh·g, 0.0103 μWh·cm−2), and power density of 161.0 mW·cm−3 (150.4 μW·g, 2.00 μW·cm−2) at the current density of 0.05 mA. Therefore, Ag/TiO2-NTs could act as a feasible electrode material of supercapacitors.
Robust Optimization for Integrated Construction Scheduling and Multiscale Resource Allocation
Authors: Li Qian , Tao Sha , Chong Heap-Yih , Dong Zhijie Sasha
Published: July 2018

This research investigates an integrated problem of construction scheduling and resource allocation. Inspired by complex construction practices, multi‐time scale resources are considered for different length of terms, such as permanent staff and temporary workers. Differing from the common stochastic optimization problems, the resource price is supposed to be an uncertain parameter of which probability distribution is unknown, but observed data is given. Hence, the problem here is called Data‐Driven Construction Scheduling and Multiscale Resource Allocation Problem (DD‐CS&MRAP). Based on likelihood robust optimization, a multiobjective programming is developed where project completion time and expected resource cost are minimized simultaneously. To solve the problem efficiently, a double‐layer metaheuristic comprised of Multiple Objective Particle Swarm Optimization (MOPSO) and interior point method named MOPSO‐interior point algorithm is designed. The new solution presentation scheme and decoding process are developed. Finally, a construction case is used to validate the proposed method. The experimental results indicate that the MOPSO‐interior point algorithm can reduce resource cost and improve the efficiency of resource utilization.
The Volume-Outcome Relationship in Retroperitoneal Soft Tissue Sarcoma: Evidence of Improved Short- and Long-Term Outcomes at High-Volume Institutions
Authors: Bagaria Sanjay P. , Neville Matthew , Gray Richard J. , Gabriel Emmanuel , Ashman Jonathan B. , Attia Steven , Wasif Nabil
Published: July 2018

Background. We sought to study the association between RPS case volume and outcomes. Although a relationship has been demonstrated between case volume and patient outcomes in some cancers, such a relationship has not been established for retroperitoneal sarcomas (RPSs). Study Design. The National Cancer Database (NCDB) was queried for patients undergoing treatment for primary RPS diagnosed between 2004 and 2013. Mean annual patient volume for RPS resection was calculated for all hospitals and divided into low volume (<5 cases/year), medium volume (5–10 cases/year), and high volume (>10 cases/year). Risk-adjusted regression analyses were performed to identify predictors of 30-day surgical mortality, R0 margin status, and overall survival (OS). Results. Our study population consisted of 5,407 patients with a median age of 61 years, of whom 47% were male and 3,803 (70%) underwent surgical resection. Absolute 30-day surgical mortality and R0 margin rate following surgery for low-, medium-, and high-volume institutions were 2.4%, 1.3%, and 0.5% (p=0.027) and 68%, 65%, and 82%, (p<0.001), respectively. Five-year overall survival rates for low, medium, and high-volume institutions were 56%, 57%, and 66%, respectively (p<0.001). Patients treated at low-volume institutions had a significantly higher risk of 30-day mortality (adjusted OR = 4.66, 95% CI 2.26–9.63) and long-term mortality (adjusted HR = 1.56, 95% CI 1.16–2.11) compared to high-volume institutions. Conclusion. We demonstrate the existence of a hospital sarcoma service line volume-oncologic outcome relationship for RPS at the national level and provide benchmark data for cancer care delivery systems and policy makers.
Analytical Model for the Flow in Progressing Cavity Pump with the Metallic Stator and Rotor in Clearance Fit
Authors: Zheng Lei , Wu Xiaodong , Han Guoqing , Li Huachang , Zuo Yi , Zhou Dake
Published: July 2018

As the metallic stator progressing cavity pump (PCP) operates with the stator and rotor in clearance fit, the slippage between cavities has a significant influence on the pump performance. In this paper, an analytical model is developed for the flow in the metallic stator PCP. Based on the analyses of the meshing movement and the clearance geometry inside the pump, the slippage through the transversal and longitudinal sealing regions is calculated considering different slippage mechanisms. Then the flow rate is obtained by subtracting the total slippage from the theoretical volumetric rate. This model is validated against results obtained from the performance experiments of commercial metallic stator PCP products from Shihong Petroleum Equipment Company. The model results show that the metallic stator PCP with smaller clearance or more stages is more capable of achieving good performance at high differential pressure. It is suitable for pumping the fluid with certain viscosity, and the influence of the slippage can be compensated by adopting appropriate high rotational speed. Furthermore, the model can be used to predict the pump performance and provide guidance for the pump design and performance optimization in field applications.
Changes in Immunoreactivity of Sensory Substances within the Enteric Nervous System of the Porcine Stomach during Experimentally Induced Diabetes
Authors: Bulc Michał , Palus Katarzyna , Całka Jarosław , Zielonka Łukasz
Published: July 2018

One of the most frequently reported disorders associated with diabetes is gastrointestinal (GI) disturbance. Although pathogenesis of these complications is multifactorial, the complicity of the enteric nervous system (ENS) in this respect has significant importance. Therefore, this paper analysed changes in substance P- (SP-), calcitonin gene-related peptide- (CGRP-), and leu5-enkephalin- (L-ENK-) like immunoreactivity (LI) in enteric stomach neurons caused by chemically induced diabetes in a porcine model. Using double immunofluorescent labelling, it was found that acute hyperglycaemia led to significant changes in the chemical coding of stomach enteric neurons. Generally, the response to artificially inducted diabetes depended on the “kind” of enteric plexus as well as the stomach region studied. A clear increase in the percentage of neurons immunoreactive to SP and CGRP was visible in the myenteric plexus (MP) in the antrum, corpus, and pylorus as well as in the submucosal plexus (SmP) in the corpus. For L-ENK, an increase in the number of L-ENK-LI neurons was observed in the MP of the antrum and SmP in the corpus, while in the MP of the corpus and pylorus, a decrease in the percentage of L-ENK-LI neurons was noted.
Lactate Gap: A Diagnostic Support in Severe Metabolic Acidosis of Unknown Origin
Authors: Hauvik Linn E. , Varghese Mercy , Nielsen Erik W.
Published: July 2018

Ethylene glycol poisoning is a medical emergency. The metabolites glycolate and glyoxylate give metabolic acidosis. Because of similar structure, these metabolites are misinterpreted as lactate by many point-of-care blood gas analyzers. The falsely high lactate values can lead to misdiagnosis, inappropriate laparotomies, and delayed antidotal therapy. As laboratory analyzers measure plasma lactate only, the difference or the “lactate gap” aids in early diagnosis. We present a patient with severe metabolic acidosis and elevated lactate levels on the point-of-care analyzer. A lactate gap supported the diagnosis of ethylene glycol poisoning. Hemodialysis and fomepizole treatment could be started immediately.
Microgrids as Flexible and Network-Connected Grid Assets in Active Distribution Systems
Authors: Shao Lei , Zhou Xu , Li Ji , Liu Hongli , Chen Xiaoqi
Published: July 2018

The functionalities of microgrids are detailed and thereby expanded in active distribution systems. A versatile and coordinated operation among multiple microgrids is proposed to facilitate the integration of renewable energy sources (RES) in modern distribution grids. Particularly, to meet the requirements of high penetration level of renewables (e.g., photovoltaics and small hydro), more than one networked controlled microgrids are deployed simultaneously in different locations of a distribution system. Therefore, local RES can be aggregated in each microgrids. In order to satisfy the latest standards in terms of renewable energy integration (i.e., IEEE Std. 1547 Rev), an optimal operation strategy is designed to coordinate the operation of multiple microgrids. A simulation model is implemented in MATLAB to validate the proposed networked microgrids and the corresponding operation strategy.
The Correlation between miR-122 and Lipoprotein Lipase Expression in Chronic Hepatitis C Patients
Authors: Sidorkiewicz Malgorzata , Grek-Kowalinska Martyna , Piekarska Anna
Published: July 2018

Chronic HCV infection is strictly associated with host lipid/lipoprotein metabolism disorders. The study aimed to analyze the relationship between viral load, lipid profile, IFNγ, and the expression of miR-122 and LPL in the liver and PBMCs. Sera, PBMCs, and matching liver biopsies from 17 chronic hepatitis C patients were enrolled in this study. Collected data shows that liver (not PBMCs) miR-122 expression is positively correlated with HCV RNA load and IFNγ and reversely with LPL expression in CHC patients. Presented, for the first time, in this study, the reverse correlation of miR-122 and LPL expression in liver; miR-122 and LPL seem to be important factors of CHC infection.
Effective Treatment of Chronic Proliferative Cholangitis by Local Gentamicin Infusion in Rabbits
Authors: Yang Qin , Wu Zhenru , Liu Fei , Wang Junke , Ma Wenjie , Hu Haijie , Li Fuyu , Pan Qiuwei
Published: July 2018

Background. Hepatolithiasis is highly prevalent in East Asia characterized by the presence of gallstones in the biliary ducts of the liver. Surgical resection is the potentially curative treatment but bears a high risk of stone recurrence and biliary restenosis. This is closely related to the universal presence of chronic proliferative cholangitis (CPC) in the majority of patients. Recent evidence has indicated the association of bacterial infection with the development of CPC in hepatolithiasis. Thus, this study aims to investigate the feasibility and efficacy of local infusion of gentamicin (an antibiotic) for the treatment of CPC in a rabbit model. Methods. The rabbit CPC model was established based on previously published protocols. Bile duct samples were collected from gentamicin-treated or control animals for pathological and molecular characterization. Results. Histologically, the hyperplasia of biliary epithelium and submucosal glands were inhibited and the thickness of the bile duct wall was significantly decreased after gentamicin therapy. Consistently, the percentage of proliferating cells marked by ki67 was significantly reduced by the treatment. More importantly, this treatment inhibited interleukin 2 production, an essential inflammatory cytokine, and the enzyme activity of endogenous β-Glucuronidase, a key factor in the formation of bile pigment. Conclusions. Local gentamicin infusion effectively inhibits the inflammation, cell proliferation, and lithogenesis in a rabbit model of CPC. This approach represents a potential treatment for CPC and thus prevents recurrent hepatolithiasis.
Alpha-Tocopherol Serum Levels Are Increased in Caucasian Women with Uterine Fibroids: A Pilot Study
Authors: Ciebiera Michał , Szymańska-Majchrzak Jolanta , Sentkowska Aleksandra , Kilian Krzysztof , Rogulski Zbigniew , Nowicka Grażyna , Jakiel Grzegorz , Tomaszewski Piotr , Włodarczyk Marta
Published: July 2018

Uterine fibroids (UFs) are benign tumors of the reproductive tract, arising from smooth muscle cells of the uterus. Steroid hormones, estrogen, and progesterone are considered to be the most important links in the pathophysiology of UFs. Alpha-tocopherol (AT) is the most active form of vitamin E. What is important as far as UFs are concerned is that ATs contain structural determinants, which makes them possible ligands for estrogen receptors (ERs). We present a retrospective cohort study performed in a university teaching hospital. We included a total of 162 patients divided into 2 groups: with UFs and controls. The effects of age, body mass index (BMI), positive medical history, parity, and AT serum concentrations on the risk for the development of UFs were investigated. Mean AT serum concentrations were 11.66 ± 4.97 μg/ml and 7.83 ± 3.13 μg/ml (medians 10.56 μg/ml and 7.42 μg/ml) in patients with UFs confirmed on ultrasound and controls, respectively. The presented difference was statistically significant. Higher BMI, positive family history, and low parity were found to be major risk factors for UFs. In our study, we confirmed that elevated serum AT concentration might be an important risk factor for UFs in Caucasian women. Further research in this area is necessary.
Probing the Catalytic Efficiency of Supported Heteropoly Acids for Esterification: Effect of Weak Catalyst Support Interactions
Authors: Alsalme Ali , Alsharif Aliyah A. , Al-Enizi Hamda , Khan Mujeeb , Alshammari Saad G. , Alotaibi Mshari A. , Khan Rais Ahmad , Siddiqui Mohammed Rafiq H.
Published: July 2018

Supported heteropoly acids are an interesting class of solid acid catalysts which possess flexible structure and super acidic properties essentially required for the oil-based biodiesel production. In this study, a series of catalysts containing 25 wt.% of heteropolytungstate (HPW) supported on various clays or SiO2 were prepared, and their catalytic efficiency was evaluated for esterification of acetic acid with heptanol. The as-prepared catalysts were characterized by various techniques including FT-IR spectroscopy, thermogravimetric analysis, X-ray diffraction, scanning electron microscopy, and BET. The catalytic efficiency of both bulk and supported HPW catalysts for the esterification activity strongly depends on the type of support and amount of catalyst; the bulk HPW catalyst and the catalyst supported by kaolinite with 25 wt.% of HPW exhibited highest activity. In order to study the effect of temperature on conversion, all the catalysts were subjected to different reaction temperatures. It was revealed that esterification activity of both bulk and supported HPW catalysts strongly depends upon the temperature variations of the reaction. Besides, the effect of leaching of active sites on the catalysts performance for biodiesel production was also evaluated by inductively coupled plasma studies (ICP). The kaolinite-supported catalyst (25% HPW/kaolinite) demonstrated higher amount of leaching which is also confirmed by the significant decrease in its catalytic activity when it is used for the second time. However, the higher activity demonstrated by HPW/kaolinite maybe because of some homogeneous reaction indicating a weak catalyst support interaction (WCSI) resulting in the leaching of the catalyst during the test. Furthermore, the effects of other reaction variables such as catalyst loading and reaction time on the conversion of acetic acid were also studied.
The Usefulness of the Forced Oscillation Technique in the Diagnosis of Bronchial Asthma in Children
Authors: Starczewska-Dymek L. , Bozek A. , Jakalski M.
Published: July 2018

The forced oscillation technique (FOT) requires minimal patient cooperation and is useful for children. However, comprehensive values of respiratory impedance at baseline and after the reversibility test have not been definitively confirmed. The aim of this study was to evaluate the basic parameters of FOT reactance (Xrs) and resistance (Rrs) in groups of healthy children and children with controlled and uncontrolled asthma. The second aim was the assessment of the reversibility bronchial test using the forced oscillation method in children with bronchial asthma. Materials and Methods. One hundred and six children aged from 2 to 6 years diagnosed with early-onset controlled or uncontrolled asthma and healthy controls were included in this single-center, prospective, randomized study. All asthmatic patients and healthy controls underwent basic FOT as one measurement according to the recommendation of Resmon Pro FOT. The reversibility test was then performed 15 min after the administration of 200 mcg salbutamol by MDI in all patients. Results. Basic Rrs showed significantly higher mean values in patients with uncontrolled asthma compared to patients with controlled asthma, which were in turn higher than the values for patients in the control group (11.14 ± 1.29 versus 15.71 ± 2.6 versus 9.21 ± 0.98, resp.; p<0.05). The data analysis showed similar relationships in terms of the Xrs between the studied groups (−4.76 ± 1.19 versus −7.31 ± 2.33 versus −2.11 ± 0.48, resp.; p<0.05). According to the changes in the Rrs values, 35 (66%) positive bronchial reversibility tests were obtained in 53 subjects with controlled asthma and in 39 (74%) subjects with uncontrolled asthma. Conclusions. Rrs and Xrs obtained by FOT well-discriminate patients with asthma from healthy children. A bronchial reversibility test involving the use of FOT is valuable for the diagnosis of bronchial asthma.
Public Acceptance as a Driver for Repository Design
Authors: McKinley Ian G. , Masuda Sumio , Hardie Susie M. L. , Umeki Hiroyuki , Naito Morimasa , Takase Hiroyasu
Published: July 2018

The Japanese geological disposal programme for radioactive waste is based on a volunteering approach to siting, which places particular emphasis on the need for public acceptance. This, as established in law, emphasises the development of a repository project as a partnership with local communities and involves stakeholders in important decisions associated with key milestones in the selection of repository sites and subsequent construction, operation, and closure. To date, however, repository concept development has proceeded in a more traditional manner, focusing particularly on ease of developing a post-closure safety case. In the current project, we have attempted to go further by assessing what requirements stakeholders would place on a repository and assessing how these could be used to rethink repository designs so that they meet the desires of the public without compromising critical operational or long-term safety.
Drug-Eluting Balloons versus Second-Generation Drug-Eluting Stents for Treating In-Stent Restenosis in Coronary Heart Disease after PCI: A Meta-Analysis
Authors: Xiu Wen-Juan , Yang Hai-Tao , Zheng Ying-Ying , Ma Yi-Tong , Xie Xiang
Published: July 2018

Background. In-stent restenosis (ISR) remains a common problem following percutaneous coronary intervention (PCI). However, the best treatment strategy remains uncertain. There is some controversy over the efficacy of drug-eluting balloons (DEBs) and second-generation drug-eluting stents (DESs) for treating ISR. Methods. A meta-analysis was used to compare the efficacy of the DEB and second-generation DES in the treatment of ISR. The primary endpoint is the incidence of target lesion revascularization (TLR). The secondary endpoint is the occurrence of target vessel revascularization (TVR), myocardial infarction (MI), all-cause death (ACM), cardiac death (CD), major adverse cardiac events (MACEs), minimum luminal diameter (MLD), late luminal loss (LLL), binary restenosis (BR), and percent diameter stenosis (DS%). Results. A total of 12 studies (4 randomized controlled trials and 8 observational studies) including 2020 patients with a follow-up of 6–25 months were included in the present study. There was a significant difference in the MLD between the two groups during follow-up (P=0.007, RR = 0.23, and 95% CI: 0.06–0.4 mm). There was no significant difference in LLL, BR, or DS% and the overall incidence of MACEs between the two groups. Subgroup analysis showed no significant difference in the incidence of primary and secondary endpoints when considering RCTs or observational studies only. Conclusions. The efficacy of the DEB and second-generation DES in the treatment of ISR is comparable. However, our results need further verification through multicenter randomized controlled trials.
A Third-Order Consensus Approach for Vehicle Platoon with Intervehicle Communication
Authors: Chen Jianzhong , Bai Dongyang , Liang Huan , Zhou Yang
Published: July 2018

A third-order consensus approach is proposed for the vehicle platoon. For addressing the platoon problem, a realistic, third-order vehicle dynamics model is used, and the spacing policy and the vehicle acceleration error are embedded into the consensus protocol. A sufficient and necessary condition of asymptotically stability is obtained for the vehicle platooning system. Numerical simulations for several traffic scenarios are carried out. The results demonstrate the effectiveness and the robustness of the presented approach.
IGF-1-Overexpressing Mesenchymal Stem/Stromal Cells Promote Immunomodulatory and Proregenerative Effects in Chronic Experimental Chagas Disease
Authors: Silva Daniela N. , Souza Bruno S. F. , Azevedo Carine M. , Vasconcelos Juliana F. , de Jesus Paloma G. , Feitoza Malena S. , Meira Cassio S. , Carvalho Gisele B. , Cavalcante Bruno Raphael , Ribeiro-dos-Santos Ricardo , Soares Milena B. P.
Published: July 2018

Mesenchymal stem/stromal cells (MSCs) have been investigated for the treatment of diseases that affect the cardiovascular system, including Chagas disease. MSCs are able to promote their beneficial actions through the secretion of proregenerative and immunomodulatory factors, including insulin-like growth factor-1 (IGF-1), which has proregenerative actions in the heart and skeletal muscle. Here, we evaluated the therapeutic potential of IGF-1-overexpressing MSCs (MSC_IGF-1) in a mouse model of chronic Chagas disease. C57BL/6 mice were infected with Colombian strain Trypanosoma cruzi and treated with MSCs, MSC_IGF-1, or vehicle (saline) six months after infection. RT-qPCR analysis confirmed the presence of transplanted cells in both the heart and skeletal muscle tissues. Transplantation of either MSCs or MSC_IGF-1 reduced the number of inflammatory cells in the heart when compared to saline controls. Moreover, treatment with MSCs or MSC_IGF-1 significantly reduced TNF-α, but only MSC treatment reduced IFN-γ production compared to the saline group. Skeletal muscle sections of both MSC- and MSC_IGF-1-treated mice showed a reduction in fibrosis compared to saline controls. Importantly, the myofiber area was reduced in T. cruzi-infected mice, and this was recovered after treatment with MSC_IGF-1. Gene expression analysis in the skeletal muscle showed a higher expression of pro- and anti-inflammatory molecules in MSC_IGF-1-treated mice compared to MSCs alone, which significantly reduced the expression of TNF-α and IL-1β. In conclusion, our results indicate the therapeutic potential of MSC_IGF-1, with combined immunomodulatory and proregenerative actions to the cardiac and skeletal muscles.
Autophagy Is Independent of the Chondroprotection Induced by Platelet-Rich Plasma Releasate
Authors: Yang Fan , Hu Haoran , Yin Wenjing , Li Guangyi , Yuan Ting , Xie Xuetao , Zhang Changqing
Published: July 2018

Background. Platelet-rich plasma (PRP) has been shown to be a promising therapeutic agent against osteoarthritis (OA), whereas its chondroprotection mechanism is not fully elucidated. Autophagy is considered an important biological process throughout the development of OA. Therefore, the objective of the present study is to investigate the role of autophagy in the chondroprotection and compare the effects of releasate between L-PRP and P-PRP. Methods. PRP were prepared from rat blood. Rat chondrocytes pretreated in the presence or absence of interleukin-1 beta (IL-1β) were incubated with PRP releasate. The expressions of OA-related genes and autophagy-related genes were determined by RT-PCR and western blot, respectively. Autophagic bodies were assessed by transmission electron microscopy and the autophagy flux was monitored under the confocal microscopy. The effect of PRP on autophagy was further investigated in the milieu of autophagy activator, rapamycin, or autophagy inhibition by downregulation of Atg5. The effect of PRP on cartilage repair and autophagy was also evaluated in an OA rat model. Results. In vitro, PRP releasate increased the expression of the anabolic genes, COL2 and Aggrecan, and decreased the expression of the catabolic genes, whereas the expression of autophage markers, Atg5 and Beclin-1, as well as the ratio of LC3 II/LC3 I, was not significantly altered in normal or IL-1β-treated chondrocytes. Similar expression pattern was found following the activation (rapamycin) or inhibition (Atg5 silencing) of autophagy. In vivo, PRP releasate ameliorated posttraumatic cartilage degeneration while the expression of LC3 was comparable to that in the vehicle treatment group. Conclusions. PRP releasate promoted the anabolic gene expression, relieved inflammatory stress in chondrocytes, and ameliorated cartilage degeneration, but autophagy was independent of these processes.
miRNA-30 Family Members Inhibit Breast Cancer Invasion, Osteomimicry, and Bone Destruction by Directly Targeting Multiple Bone Metastasis–Associated Genes
Authors: Croset Martine , Pantano Francesco , Kan Casina W.S. , Bonnelye Edith , Descotes Françoise , Alix-Panabières Catherine , Lecellier Charles-Henri , Bachelier Richard , Allioli Nathalie , Hong Saw-See , Bartkowiak Kai , Pantel Klaus , Clézardin Philippe
Published: July 2018

miRNAs are master regulators of gene expression that play key roles in cancer metastasis. During bone metastasis, metastatic tumor cells must rewire their biology and express genes that are normally expressed by bone cells (a process called osteomimicry), which endow tumor cells with full competence for outgrowth in the bone marrow. Here, we establish miR-30 family members miR-30a, miR-30b, miR-30c, miR-30d, and miR-30e as suppressors of breast cancer bone metastasis that regulate multiple pathways, including osteomimicry. Low expression of miR-30 in primary tumors from patients with breast cancer were associated with poor relapse-free survival. In addition, estrogen receptor (ER)-negative/progesterone receptor (PR)-negative breast cancer cells expressed lower miR-30 levels than their ER/PR-positive counterparts. Overexpression of miR-30 in ER/PR-negative breast cancer cells resulted in the reduction of bone metastasis burden in vivo. In vitro, miR-30 did not affect tumor cell proliferation, but did inhibit tumor cell invasion. Furthermore, overexpression of miR-30 restored bone homeostasis by reversing the effects of tumor cell–conditioned medium on osteoclastogenesis and osteoblastogenesis. A number of genes associated with osteoclastogenesis stimulation (IL8, IL11), osteoblastogenesis inhibition (DKK-1), tumor cell osteomimicry (RUNX2, CDH11), and invasiveness (CTGF, ITGA5, ITGB3) were identified as targets for repression by miR-30. Among these genes, silencing CDH11 or ITGA5 in ER-/PR-negative breast cancer cells recapitulated inhibitory effects of miR-30 on skeletal tumor burden in vivo. Overall, our findings provide evidence that miR-30 family members employ multiple mechanisms to impede breast cancer bone metastasis and may represent attractive targets for therapeutic intervention.

Significance: These findings suggest miR-30 family members may serve as an effective means to therapeutically attenuate metastasis in triple-negative breast cancer. Cancer Res; 78(18); 5259–73. ©2018 AACR.
Phase Ib Results of the Rational Combination of Selumetinib and Cyclosporin A in Advanced Solid Tumors with an Expansion Cohort in Metastatic Colorectal Cancer
Authors: Krishnamurthy Anuradha , Dasari Arvind , Noonan Anne M. , Mehnert Janice M. , Lockhart Albert C. , Leong Stephen , Capasso Anna , Stein Mark N. , Sanoff Hanna K. , Lee James J. , Hansen Aaron , Malhotra Usha , Rippke Sarah , Gustafson Daniel L. , Pitts Todd M. , Ellison Kim , Davis S. Lindsey , Messersmith Wells A. , Eckhardt S. Gail , Lieu Christopher H.
Published: July 2018

MEK inhibition is of interest in cancer drug development, but clinical activity in metastatic colorectal cancer (mCRC) has been limited. Preclinical studies demonstrated Wnt pathway overexpression in KRAS-mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A, a noncanonical Wnt pathway modulator, demonstrated antitumor activity in mCRC patient-derived xenografts. To translate these results, we conducted a NCI Cancer Therapy Evaluation Program–approved multicenter phase I/IB trial (NCT02188264) of the combination of selumetinib and cyclosporin A. Patients with advanced solid malignancies were treated with the combination of oral selumetinib and cyclosporin A in the dose escalation phase, followed by an expansion cohort of irinotecan and oxaliplatin-refractory mCRC. The expansion cohort utilized a single-agent selumetinib “run-in” to evaluate FZD2 biomarker upregulation and KRAS-WT and KRAS-MT stratification to identify any potential predictors of efficacy. Twenty and 19 patients were enrolled in dose escalation and expansion phases, respectively. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three dose-limiting toxicities (grade 3 hypertension, rash, and increased creatinine) were reported. The MTD was selumetinib 75 mg twice daily and cyclosporin A 2 mg/kg twice daily on a 28-day cycle. KRAS stratification did not identify any differences in response between KRAS-WT and KRAS-MT cancers. Two partial responses, 18 stable disease, and 10 progressive disease responses were observed. Combination selumetinib and cyclosporin A is well tolerated, with evidence of activity in mCRC. Future strategies for concept development include identifying better predictors of efficacy and improved Wnt pathway modulation.

Significance: These findings translate preclinical studies combining selumetinib and cyclosporin into a phase I first-in-human clinical trial of such a combination in patients with advanced solid malignancies. Cancer Res; 78(18); 5398–407. ©2018 AACR.
The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications
Authors: Iglesias-Gato Diego , Thysell Elin , Tyanova Stefka , Crnalic Sead , Santos Alberto , Lima Thiago S. , Geiger Tamar , Cox Jürgen , Widmark Anders , Bergh Anders , Mann Matthias , Flores-Morales Amilcar , Wikström Pernilla
Published: July 2018

Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage.

Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation.

Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid β-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair–related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies.

Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. Clin Cancer Res; 24(21); 5433–44. ©2018 AACR.
R1 Regulates Prostate Tumor Growth and Progression By Transcriptional Suppression of the E3 Ligase HUWE1 to Stabilize c-Myc
Authors: Lin Tzu-Ping , Li Jingjing , Li Qinlong , Li Xiangyan , Liu Chunyan , Zeng Ni , Huang Jen-Ming , Chu Gina Chia-Yi , Lin Chi-Hung , Zhau Haiyen E. , Chung Leland W.K. , Wu Boyang Jason , Shih Jean C.
Published: July 2018

Prostate cancer is a prevalent public health problem, especially because noncutaneous advanced malignant forms significantly affect the lifespan and quality of life of men worldwide. New therapeutic targets and approaches are urgently needed. The current study reports elevated expression of R1 (CDCA7L/RAM2/JPO2), a c-Myc–interacting protein and transcription factor, in human prostate cancer tissue specimens. In a clinical cohort, high R1 expression is associated with disease recurrence and decreased patient survival. Overexpression and knockdown of R1 in human prostate cancer cells indicate that R1 induces cell proliferation and colony formation. Moreover, silencing R1 dramatically reduces the growth of prostate tumor xenografts in mice. Mechanistically, R1 increases c-Myc protein stability by inhibiting ubiquitination and proteolysis through transcriptional suppression of HUWE1, a c-Myc–targeting E3 ligase, via direct interaction with a binding element in the promoter. Moreover, transcriptional repression is supported by a negative coexpression correlation between R1 and HUWE1 in a prostate cancer clinical dataset. Collectively, these findings, for the first time, characterize the contribution of R1 to prostate cancer pathogenesis.

Implications:

These findings provide evidence that R1 is a novel regulator of prostate tumor growth by stabilizing c-Myc protein, meriting further investigation of its therapeutic and prognostic potential.
Long-term Tumor Adaptation after Radiotherapy: Therapeutic Implications for Targeting Integrins in Prostate Cancer
Authors: Eke Iris , Makinde Adeola Y. , Aryankalayil Molykutty J. , Reedy Jessica L. , Citrin Deborah E. , Chopra Sunita , Ahmed Mansoor M. , Coleman C. Norman
Published: July 2018

Adaptation of tumor cells to radiotherapy induces changes that are actionable by molecular targeted agents and immunotherapy. This report demonstrates that radiation-induced changes in integrin expression can be targeted 2 months later. Integrins are transmembrane cell adhesion molecules that are essential for cancer cell survival and proliferation. To analyze the short- and long-term effects of radiation on the integrin expression, prostate cancer cells (DU145, PC3, and LNCaP) were cultured in a 3D extracellular matrix and irradiated with either a single dose of radiation (2–10 Gy) or a multifractionated regimen (2–10 fractions of 1 Gy). Whole human genome microarrays, immunoblotting, immunoprecipitation assays, and immunofluorescence staining of integrins were performed. The results were confirmed in a prostate cancer xenograft model system. Interestingly, β1 and β4 integrins (ITGB1 and ITGB4) were upregulated after radiation in vitro and in vivo. This overexpression lasted for more than 2 months and was dose dependent. Moreover, radiation-induced upregulation of β1 and β4 integrin resulted in significantly increased tumor cell death after treatment with inhibitory antibodies. Combined, these findings indicate that long-term tumor adaptation to radiation can result in an increased susceptibility of surviving cancer cells to molecular targeted therapy due to a radiation-induced overexpression of the target.

Implications:

Radiation induces dose- and schedule-dependent adaptive changes that are targetable for an extended time; thus suggesting radiotherapy as a unique strategy to orchestrate molecular processes, thereby providing new radiation-drug treatment options within precision cancer medicine.
The Impact of Age on the Prognosis of Vulvar Cancer
Authors: Hami Louisa T. , Lampe Bjoern , Mallmann Peter , Forner Dirk M.
Published: July 2018

Introduction: Younger women are particularly affected by the increase in the incidence of vulvar cancer. The purpose of this study was to investigate how clinical characteristics differ depending on the patient´s age and what role the age of initial diagnosis plays in the prognosis. Patients andMethods: Included patients were divided into groups aged below or above 50 years. The disease-free survival (DFS) was calculated and a multivariate discriminant analysis was conducted. Results: Of the 300 patients, 79 were ≤50 years and 221 were >50 years. The median age was 64 years (19-96 years). There were no differences between the groups regarding lymph node (LN) status and distant metastasis, but T1 tumours were more frequent in patients ≤50 years (77% vs. 62%, p = 0.02). The DFS only differed between the groups when there were no LN metastases. The nodal status was the predominant prognostic factor for the DFS regardless of age. In node-free patients, the 5-year DFS was 49% for the ≤50 years group and 89% for the >50 years group (p = 0.008), whereas there was no difference if a LN was involved. Conclusion: In node-free patients, the risk for recurrence is lower for patients older than 50 years.
Activity of Eribulin Mesylate in Brain Metastasis from Breast Cancer: A Stone in a Pond?
Authors: Catania Giovanna , Malaguti Paola , Gasparro Simona , Cognetti Francesco , Vidiri Antonello , Fabi Alessandra
Published: July 2018

Background: Brain metastases develop in approximately 10–25% of patients with metastatic breast cancer (MBC) and are associated with a very poor prognosis. Case Report: We report the case of a 40-year-old woman with MBC and associated lung, bone, liver, and brain metastases, who experienced a time to progression of several months with eribulin after whole-brain radiotherapy (WBRT), 2 lines of chemotherapy, and 1 line of hormonal therapy, maintaining a good toxicity profile. Discussion: Eribulin, in association with local treatment such as WBRT, can be well tolerated and effective in achieving a long progression-free survival and a good control of brain metastases in patients with MBC who have received multiple lines of treatment. The vascular remodeling properties of eribulin, combined with brain radiotherapy, might facilitate the passage of eribulin across the blood brain barrier, improving brain response. Conclusion: Our anecdotal experience suggests that eribulin may have a potentially beneficial effect on brain metastases while maintaining a good systemic control of the disease in patients with MBC.