bluuebunny/crossref_metadata_2025 huggingface dataset:
Organoids for Drug Discovery and Personalized Medicine
Authors: Takahashi Toshio
Published: August 2018

A wide variety of organs are in a dynamic state, continuously undergoing renewal as a result of constant growth and differentiation. Stem cells are required during these dynamic events for continuous tissue maintenance within the organs. In a steady state of production and loss of cells within these tissues, new cells are constantly formed by differentiation from stem cells. Today, organoids derived from either adult stem cells or pluripotent stem cells can be grown to resemble various organs. As they are similar to their original organs, organoids hold great promise for use in medical research and the development of new treatments. Furthermore, they have already been utilized in the clinic, enabling personalized medicine for inflammatory bowel disease. In this review, I provide an update on current organoid technology and summarize the application of organoids in basic research, disease modeling, drug development, personalized treatment, and regenerative medicine.
Tackling the threshold concepts in physiology: what is the role of the laboratory class?
Authors: Horrigan Louise A.
Published: August 2018

Laboratory practical programs are expected to fulfill many roles in the learning process, including the development of laboratory skills and problem-solving skills. However, little is known about the role of laboratory practical classes in the conceptual learning of physiology. Therefore, the main aims of this study were to identify some of the threshold concepts in physiology and to explore the role of our laboratory practical program in helping students to tackle these concepts. An online questionnaire gathered opinions from students on the value of the laboratory classes in helping them to learn. Interviews with students and with lecturers were performed to ascertain which concepts students find particularly difficult, why they find these concepts difficult, and what their opinions are on the role of the laboratory practical classes in helping students to grasp difficult concepts. A number of threshold concepts in physiology were identified, and some possible reasons underlying the difficulties were explored. Overall, the majority of respondents found that the laboratory practical program helped them to learn physiology. While the laboratory classes were found to promote conceptual learning in a number of ways, a prominent finding was that the laboratory classes help students to grasp the theory because they allow students to visually see the physiological events, they bring the theory to life, and they allow students to experience some applications of the theory. The study also highlighted areas for further development in relation to the promotion of conceptual learning within the teaching laboratory.
Provocative decompression causes diffuse vascular injury in mice mediated by microparticles containing interleukin-1β
Authors: Thom Stephen R. , Bhopale Veena M. , Yu Kevin , Yang Ming
Published: August 2018

Inflammatory mediators are known to be elevated in association with decompression from elevated ambient pressure, but their role in tissue damage or overt decompression sickness is unclear. Circulating microparticles (MPs) are also known to increase, and because interleukin (IL)-1β is packaged within these particles, we hypothesized that IL-1β was responsible for tissue injuries. Here, we demonstrate that elevations of circulating MPs containing up to ninefold higher concentrations of IL-1β occur while mice are exposed to high air pressure (790 kPa), whereas smaller particles carrying proteins specific to exosomes are not elevated. MPs number and intra-particle IL-1β concentration increase further over 13 h post decompression. MPs also exhibit intra-particle elevations of tumor necrosis factor-α, caspase-1, inhibitor of κB kinase-β, and inhibitor of κB kinase-γ, and elevated IL-6 is adsorbed to the surface of MPs. Contrary to lymphocytes, neutrophil nucleotide-binding oligomerization domain-like receptor, pyrin domain containing 3 (NLRP3) inflammasome oligomerization and cell activation parameters occur during high pressure exposure, and additional evidence for activation is manifested post decompression. Diffuse vascular damage, although not apparent immediately post decompression, was present 2 h later and remained elevated for at least 13 h. Prophylactic administration of an IL-1β receptor inhibitor or neutralizing antibody to IL-1β inhibited MPs elevations, increases of all MPs-associated pro-inflammatory agents, and vascular damage. We conclude that an auto-activation process triggered by high pressure stimulates MPs production and concurrent inflammasome activation, and IL-1β is a proximal factor responsible for further cytokine production and decompression-associated vascular injuries.

NEW & NOTEWORTHY Elevations in circulating microparticles due to decompression have been documented in humans and animals. This report shows that intra-particle interleukin-1β causes vascular damage that can be abrogated by interventions directed against this cytokine.
Low Total Dose of Anti-Human T-Lymphocyte Globulin (ATG) Guarantees a Good Glomerular Filtration Rate after Liver Transplant in Recipients with Pretransplant Renal Dysfunction
Authors: Dopazo Cristina , Charco Ramón , Caralt Mireia , Pando Elizabeth , Lázaro José Luis , Gómez-Gavara Concepción , Castells Lluis , Bilbao Itxarone
Published: August 2018

We aimed to evaluate the safety and efficacy of low doses of anti-T-lymphocyte globulin (ATG)-based immunosuppression in preserving renal function and preventing liver rejection in liver transplant (LT) recipients with pretransplant renal dysfunction. We designed a prospective single-center cohort study analyzing patients with pre-LT renal dysfunction defined as eGFR<60 mL/min/1.73m2, who underwent induction therapy with ATG (ATG group, n=20). This group was compared with a similar retrospective cohort treated with basiliximab (BAS group, n=20). An economic analysis between both induction therapies was also undertaken. In the ATG group, 45% and 50% of patients had recovered their renal function without acute cellular rejection (ACR) episodes at day 7 and 1 month after LT, respectively, versus 40% and 55% of patients in the BAS group (p=1). Renal function improved in both groups over time and no differences between groups were observed regarding one-year eGRF and one-year probability of ACR. Cost per patient of the ATG course was 403€ (r: 126-756) versus 2,524€ of the basiliximab course (p=0.001). In conclusion, induction with low dose of ATG or basiliximab in patients with pretransplant renal dysfunction is a good strategy for preserving posttransplant renal function; however the use of low-dose ATG resulted in a substantial reduction in drug costs. This trail is registered with ClinicalTrials.gov number: NCT01453218.
Comparative Study of Nonlinear Static and Time‐History Analyses of Typical Korean STS Container Cranes
Authors: Tran Quang Huy , Huh Jungwon , Nguyen Van Bac , Haldar Achintya , Kang Choonghyun , Hwang Kyeong Min
Published: August 2018

Ship‐to‐shore (STS) container gantry cranes, used at terminals for loading and unloading containers from a ship, are an important part of harbor structures. The size and weight of modern STS container cranes are increasing to satisfy the demand for bigger ships. This is expected to result in more lateral load when excited by seismic motions. The existing Korean STS container cranes did not behave properly during several recent moderate earthquakes in South Korea. Typical Korean STS container cranes must be checked for the earthquake‐resistant capacity. In this research, two nonlinear static analyses procedures, also known as pushover analyses, commonly used for seismic design of buildings, namely, capacity spectrum method and equivalent linearization method, are comprehensively studied to check their suitability for studying seismic behavior of STS cranes. Results obtained by these two nonlinear static analysis methods are then compared with the results obtained by nonlinear time‐history analyses of the STS cranes by exciting them with nine recorded earthquake time histories around worldwide. The behaviors of the cranes are analyzed in terms of the total base shear, drift, and base uplift. The comparisons indicate that the nonlinear static methods can be appropriate for estimating the total base shear and drift of the portal frame of a container crane. The pushover analyses also provide information on performance levels as defined in ASCE/SEI 41‐13, of a typical Korean STS container crane. Furthermore, it is observed that the uplift response of the crane is strongly influenced by the duration of an earthquake.
Ferulated Arabinoxylans and Their Gels: Functional Properties and Potential Application as Antioxidant and Anticancer Agent
Authors: Mendez-Encinas Mayra Alejandra , Carvajal-Millan Elizabeth , Rascon-Chu Agustín , Astiazaran-Garcia Humberto Francisco , Valencia-Rivera Dora Edith
Published: August 2018

In the last years, biomedical research has focused its efforts in the development of new oral delivery systems for the treatment of different diseases. Ferulated arabinoxylans are polysaccharides from cereals that have been gaining attention in the pharmaceutical field due to their prebiotic, antioxidant, and anticancer properties. The antioxidant and anticancer properties of these polysaccharides make them attractive compounds for the treatment of cancer, particularly colon cancer. In addition, ferulated arabinoxylans can form covalent gels through the cross‐linking of their ferulic acids. Due to their particular characteristics, ferulated arabinoxylan gels represent an excellent alternative as colon‐targeted drug delivery systems. The aim of the present work is to review the physicochemical and functional properties of ferulated arabinoxylans and their gels and to present the future perspectives for potential application as antioxidant and anticancer agents.
Recurrent Cardiac Myxoma Treated by Orthotopic Heart Transplantation: A Case Report and Literature Review of Heart Transplantation for Primary Cardiac Tumor
Authors: Kewcharoen Jakrin , Prasongdee Klaorat , Sinphurmsukskul Supanee , Siwamogsatham Sarawut , Puwanant Sarinya , Ongcharit Pat , Benjacholamas Vichai , Ariyachaipanich Aekarach
Published: August 2018

Primary cardiac myxoma is the most common primary cardiac tumor. Tumor resection is the treatment of choice and overall long-term prognosis is good and recurrence is rare. This report presents a case of a young girl who presented with multiple recurrent cardiac myxoma. She underwent 3 sternotomy surgeries of 3 separated episodes of cardiac myxoma resection. On the fourth recurrence, the patient underwent orthotopic heart transplant. The patient tolerated the procedure well and is alive 6 months after the procedure with NYHA class I. We reviewed evidences and summarized reported cases of orthotopic heart transplant operation for primary cardiac tumor in the literature.
Alkali Solution Erodes Shale: Influencing Factors and Structural Damage Characteristics
Authors: She Jiping , Zhang Hao , Zhong Ying , Yuan Yang , You Jiachun
Published: August 2018

High-pH drilling fluids are often used for drilling shale gas wells. Alkali erosion of shale is one of the important factors of wellbore instability. Alkali erosion experiments of different kinds of minerals and shale were conducted in this paper. Experimental results show that the corrosion rate of kaolinite is the highest when the pH is 9, the corrosion rate of smectite is the highest when the pH is 10 or 11, and the corrosion rate of the quartz is the highest when the pH is 12. Both shale particle size and concentration of hydroxide ion all affect the reaction rate, and the former has a negative correlation with the reaction rate, and the latter has a positive correlation with the reaction rate. In addition, alkaline erosion can lead to the fracture propagation along the bedding planes of shale, which can easily result in wellbore instability. This study may offer some theoretical basis for wellbore instability induced by high-pH drilling fluids.
Circulating Levels of Omentin, Leptin, VEGF, and HGF and Their Clinical Relevance with PSA Marker in Prostate Cancer
Authors: Fryczkowski M. , Bułdak R. J. , Hejmo T. , Kukla M. , Żwirska-Korczala K.
Published: August 2018

Background. Prostate cancer (PCa) is the first in terms of occurrence in Europe and second in Poland. The PCa risk factors include: genetic load, obesity, diet rich in fat, hypertriglyceridemia, and exposure to androgens. The prostate-specific antigen (PSA) level may be elevated in prostate cancer or other prostate disorders. Fat tissue secretes adipocytokines, which increase the risk of cancer development and metastasis. Objectives. The aims of the study were to investigate the relationship between circulating levels of PSA, adipocytokines: omentin, leptin, hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) in serum obtained from patients with benign prostate hyperplasia (BPH) and prostate cancer (PCa). Methods. Forty patients diagnosed with BPH and forty diagnosed with PCa were assessed for the purpose of the study. The concentrations of omentin, leptin, HGF, and VEGF were determined using enzyme-linked immunosorbent assays (EIA). Results. PSA level was significantly higher in the PCa group than in BPH (18.2 versus 9 ng/mL, p<0.01), while volume of prostate gland was significantly higher in the BPH group than in PCa (39.1 versus 31.1 cm3, p=0.02). HGF, VEGF, omentin, and leptin concentrations were significantly higher in PCa group than in BPH (359.5 versus 294.9 pg/mL, p=0.04; 179.3 versus 127.3 pg/mL, p<0.01; 478.8 versus 408.3 ng/mL, p=0.01; 15.7 versus 11.2 ng/mL, p=0.02, resp.). The multiple logistic regression analysis demonstrated that only omentin and PSA levels were independent predictors of PCa in studied subjects. Conclusions. PSA level as well as the level of omentin may be valuable markers of PCa with clinical significance, when compared to PSA.
Search of Fuzzy Periods in the Works of Poetry of Different Authors
Authors: Nor Artur , Korotkov Eugene
Published: August 2018

We applied a new method for the identification of fuzzy periods and the insertion and deletion of characters were taken into consideration while studying the works of poetry. The technique employs genetic algorithm, dynamic programming, and the Monte Carlo method. In the present work, the technique was applied to poems written by the famous Russian and foreign classics. A total of 95 poems were studied; and fuzzy periods possessing high statistical significance were identified with more than half of the poems under study. The existence of correlation between the stressed vowel letters in a poem with the position of the fuzzy periods was shown. The present study shows that a work of poetry contains both semantic component and fuzzy periods of letters; hence a poem could have psychological impact on the audience.
A New Theoretical View of Rockburst and Its Engineering Application
Authors: Pan Junfeng , Liu Shaohong , Wang Shuwen , Xia Yongxue
Published: August 2018

Traditionally, rockburst is considered as a dynamic phenomenon of sudden destruction of coal/rock mass. In this study, rockburst is treated as an event process rather than a phenomenon. This paper introduces typical rockburst process, its classification, mechanism of internal and external causes, and energy criterion. Analysis indicates that rockburst is a dynamic process that includes three sequential phases: burst start‐up, burst energy transfer, and rockburst pressure behavior. Excessive static stress concentration in the strata nearby the target zone appears to be the internal cause of rockburst start‐up, while the external cause is the disturbance of the static stress concentration and additional load transfer by the concentrated dynamic load occurred at further distance. Potential burst start‐up area is the highest stress concentration zone within the region where stress is in the critical equilibrium state. With the identified internal and external factors that contribute to rockburst start‐up, it is concluded that the rockburst preventive measures should focus on the monitoring and controlling of originating source of static and dynamic stress concentrations. Field practice proves that the reunderstanding of rockburst and the derived preventive measures are feasible and successful.
Identifying the Impact Factors of the Dynamic Strength of Mudded Intercalations during Cyclic Loading
Authors: Yan Changbin , Xu Xiao , Huang Lei
Published: August 2018

Despite reports on previous research associated with the dynamic strength of mudded intercalations during cyclic loading, a systematic investigation of the impact factors of this strength is still valuable. This work aimed at experimentally revealing the impact factors of the strength along with their impacts. The potential impact factors considered in this work include (i) water content, (ii) clay mineral composition, (iii) clay content, (iv) confining pressure, and (v) cyclic failure time. Specimens of mudded intercalations were collected from China and were remolded and prepared for a dynamic triaxial test under cyclic loads. The test results showed that the dynamic strength is impacted by water content (strongly), clay mineral composition (moderately), confining pressure (moderately), and cyclic failure time (weakly); no significant impact of clay content was detected. Moreover, the dynamic cohesion is correlated with clay mineral composition (strongly), water content (moderately), and cyclic failure time (weakly); no significant correlation with clay content or confining pressure was detected. Finally, the dynamic friction angle is correlated with water content (strongly), clay content (moderately), and cyclic failure time (weakly); no significant correlation with clay mineral composition or confining pressure was detected.
Neuroprotective Activity of Sitagliptin via Reduction of Neuroinflammation beyond the Incretin Effect: Focus on Alzheimer’s Disease
Authors: Wiciński Michał , Wódkiewicz Eryk , Słupski Maciej , Walczak Maciej , Socha Maciej , Malinowski Bartosz , Pawlak-Osińska Katarzyna
Published: August 2018

Sitagliptin is a member of a class of drugs that inhibit dipeptidyl peptidase (DPP-4). It increases the levels of the active form of incretins such as GLP-1 (glucagon-like peptide-1) or GIP (gastric inhibitory polypeptide) and by their means positively affects glucose metabolism. It is successfully applied in the treatment of diabetes mellitus type 2. The most recent scientific reports suggest beneficial effect of sitagliptin on diseases in which neuron damage occurs. Result of experimental studies may indicate a reducing influence of sitagliptin on inflammatory response within encephalon area. Sitagliptin decreased the levels of proinflammatory factors: TNF-α (tumor necrosis factor-α), IL-6 (interleukin-6), IL-17 (interleukin-17), and CD-163 (cluster of differentiation 163), and contributed to an increase in levels of anti-inflammatory factors: IL-10 (interleukin-10) and TGF-β (transforming growth factor β). Moreover, sitagliptin demonstrated antioxidative and antiapoptotic properties by modifying glutamate and glutathione levels within the region of hippocampus in mice. It has been observed that sitagliptin decreases accumulation of β-amyloid within encephalon structures in experimental models of Alzheimer’s dementia. This effect may be connected with SDF-1α (stromal cell-derived factor 1α) concentration. Administration of sitagliptin caused a significant improvement in MMSE (Mini–Mental State Examination) tests used for assessment of dementias. The paper presents potential mechanisms of sitagliptin activity in conditions connected with neuroinflammation with special emphasis on Alzheimer’s disease.
Enhancement of Adiponectin Ameliorates Nonalcoholic Fatty Liver Disease via Inhibition of FoxO1 in Type I Diabetic Rats
Authors: Xie Xiang , Yan Dan , Li Haobo , Zhu Qiqi , Li Jun , Fang Yong-ping , Cheung Chi Wai , Irwin Michael G. , Xia Zhengyuan , Lian Qingquan
Published: August 2018

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease which has been previously shown to be associated with type 2 diabetes mellitus (T2DM). Recent research has indicated that type 1 diabetes mellitus (T1DM) is also involved in the development of nonalcoholic fatty liver disease, whereas the underlying mechanisms are largely unknown. Forkhead box O1 (FoxO1) and adiponectin (APN) have been proposed to play an important role in the processes in NAFLD in T1DM. We herein investigated the effects of FoxO1 and APN on the development of NAFLD and the underlying mechanism in streptozotocin-induced T1DM. Serum liver enzymes AST, ALT, and triglyceride (TG) were determined by commercially available kits. Blood glucose levels were measured by the OneTouch Ultra glucose meter. Relevant protein expression was tested by Western blot analysis. Results showed that serum AST, ALT, and TG were all significantly increased in T1DM rats, which was ameliorated by application of APN or selective inhibition of FoxO1 with AS1842856. Moreover, APN and AS1842856 both decreased the expression of liver nuclear FoxO1 which was significantly increased in diabetic rats. However, the inhibition of FoxO1 did not alter the expression of APN and its receptors. We also found that Akt1 expression was significantly declined in diabetic rat which was restored by APN and moderately and significantly increased by FoxO1 inhibition. It is concluded that APN ameliorates NAFLD via inhibition of FoxO1 through Akt1/FoxO1 signaling pathway.
On Robust Stability Analysis of Uncertain Discrete-Time Switched Nonlinear Systems with Time Varying Delays
Authors: Kermani Marwen , Sakly Anis
Published: August 2018

This paper provides new sufficient conditions on robust asymptotic stability for a class of uncertain discrete-time switched nonlinear systems with time varying delays. The main focus will be dedicated to development of new algebraic criteria to break with classical criteria in terms of linear matrix inequalities (LMIs). Firstly, by contracting a new common Lyapunov-Krasovskii functional as well as resorting to the M-matrix proprieties, a novel robust stability criterion under arbitrary switching signals is derived. Secondly, the obtained result is extended for a class of switched nonlinear systems modeled by a set of differences equations by applying the aggregation techniques, the norm vector notion, and the Borne-Gentina criterion. Furthermore, a generalization for switched nonlinear systems with multiple delays is proposed. The main contribution of this work is that the obtained stability conditions are algebraic and simple. In addition, they provide a solution of the most difficult problem in switched systems, which is stability under arbitrary switching, and enable avoiding searching a common Lyapunov function considered as a very difficult task even for some low-order linear switched systems. Finally, two examples are given, with numerical simulations, to show the merit and effectiveness of the proposed approach.
The Effects of Combined Micron‐Scale Surface and Different Nanoscale Features on Cell Response
Authors: Kang Yi , Ren Xuelei , Yuan Xin , Ma Li , Xie Youneng , Bian Zeyu , Zuo Jun , Wang Xiyang , Yu Zhiming , Zhou Kechao , Wei Qiuping
Published: August 2018

Sandblasting and acid‐etching (SLA) and anodization are the two most commonly used methods for surface modification of biomedical titanium. However, there are unavoidable problems such as residual sand particles and lack of hydrophilicity on the surface of titanium sheets treated with SLA technology. In addition, titanium implants showed only the micro/submicroscopic structure. In order to avoid the residue of sand particles in the surface of titanium, the two surface treatments etching treatment (E) and etched‐anodizing (EA) on titanium were used, and their surface topography, surface chemistry, and surface roughness were compared with those of the SLA control group. Their wettability and the biocompatibility were also compared and evaluated. The results show that both E and EA samples have the micro/nano hierarchical structure and better wettability compared with the SLA samples. Their performances, especially the E surfaces, were enhanced in terms of cell adhesion, spreading, proliferation, and differentiation abilities.
Pipeline Leak Aperture Recognition Based on Wavelet Packet Analysis and a Deep Belief Network with ICR
Authors: Lang Xianming , Hu Zhiyong , Li Ping , Li Yan , Cao Jiangtao , Ren Hong
Published: August 2018

The leakage aperture cannot be easily identified, when an oil pipeline has small leaks. To address this issue, a leak aperture recognition method based on wavelet packet analysis (WPA) and a deep belief network (DBN) with independent component regression (ICR) is proposed. WPA is used to remove the noise in the collected sound velocity of the ultrasonic signal. Next, the denoised sound velocity of the ultrasonic signal is input into the deep belief network with independent component regression (DBNICR) to recognize different leak apertures. Because the optimization of the weights of the DBN with the gradient leads to a local optimum and a slow learning rate, ICR is used to replace the gradient fine‐tuning method in conventional DBN for improving the classification accuracy, and a Lyapunov function is constructed to prove the convergence of the DBNICR learning process. By analyzing the acquired ultrasonic sound velocity of different leak apertures, the results show that the proposed method can quickly and effectively identify different leakage apertures.
From de Sitter to de Sitter: Decaying Vacuum Models as a Possible Solution to the Main Cosmological Problems
Authors: Zilioti G. J. M. , Santos R. C. , Lima J. A. S.
Published: August 2018

Decaying vacuum cosmological models evolving smoothly between two extreme (very early and late time) de Sitter phases are able to solve or at least to alleviate some cosmological puzzles; among them we have (i) the singularity, (ii) horizon, (iii) graceful-exit from inflation, and (iv) the baryogenesis problem. Our basic aim here is to discuss how the coincidence problem based on a large class of running vacuum cosmologies evolving from de Sitter to de Sitter can also be mollified. It is also argued that even the cosmological constant problem becomes less severe provided that the characteristic scales of the two limiting de Sitter manifolds are predicted from first principles.
What Makes People Actually Embrace or Shun Mobile Payment: A Cross-Culture Study
Authors: Zhang Yali , Sun Jun , Yang Zhaojun , Wang Ying
Published: August 2018

Mobile payment is becoming increasingly popular, but it encounters the resistance from certain user groups. This study examines the factors that influence both the technology acceptance and actual usage aspects of mobile payment adoption from the perspective of the general systems theory. Based on a literature review, it conceptualizes the embedding relationships among relevant behavioral processes, personal characteristics, and extrinsic factors and develops a research model. Together, the extrinsic factors in terms of culture, subjective norm, and socioeconomic status and main personal characteristics including demographics, personality traits, and past behavior are hypothesized to have direct and moderating effects on mobile payment acceptance and usage. The observations collected from China and the USA support most of the hypothesized relationships and reveal interesting cross-culture differences. Whereas users in the USA appear to be more rational and risk-averse, people in China seem more subject to social influence. The findings contribute to the mobile payment literature by deepening the understanding of adoption stages and expanding the scope of explanatory variables beyond technology acceptance.
Exploring General Equilibrium Points for Cournot Model
Authors: Gao Bingyuan , Du Yueping
Published: August 2018

In Cournot model, when there are many competitions, the competitive equilibrium becomes chaotic. It is extremely difficult to derive the general equilibrium points. There is no previous research to explore a further problem with the general equilibrium points of n-contenders in Cournot model. In this paper, a general equilibrium Cournot game is proposed based on an inverse demand function. A market spatial structure model is built. Intermediate value theorem, as a realistic method, is introduced to handle a general competitive equilibrium in Cournot model. The number and stability in general equilibrium points are detected by means of celestial motion theory and spatial agglomeration competition model. The existence of general equilibrium points and the stability of Cournot equilibrium points, which are new and future complement of previously known results. Numerical simulations are given to support the research results.
Role of Oxidative and Nitro‐Oxidative Damage in Silver Nanoparticles Cytotoxic Effect against Human Pancreatic Ductal Adenocarcinoma Cells
Authors: Barcińska Ewelina , Wierzbicka Justyna , Zauszkiewicz-Pawlak Agata , Jacewicz Dagmara , Dabrowska Aleksandra , Inkielewicz-Stepniak Iwona
Published: August 2018

Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies, where the 5‐year survival rate is less than 4% worldwide. Successful treatment of pancreatic cancer is a challenge for today’s oncology. Several studies showed that increased levels of oxidative stress may cause cancer cells damage and death. Therefore, we hypothesized that oxidative as well as nitro‐oxidative stress is one of the mechanisms inducing pancreatic cancer programmed cell death. We decided to use silver nanoparticles (AgNPs) (2.6 and 18 nm) as a key factor triggering the reactive oxygen species (ROS) and reactive nitrogen species (RNS) in pancreatic ductal adenocarcinoma cells (PANC‐1). Previously, we have found that AgNPs induced PANC‐1 cells death. Furthermore, it is known that AgNPs may induce an accumulation of ROS and alteration of antioxidant systems in different type of tumors, and they are indicated as promising agents for cancer therapy. Then, the aim of our study was to evaluate the implication of oxidative and nitro‐oxidative stress in this cytotoxic effect of AgNPs against PANC‐1 cells. We determined AgNP‐induced increase of ROS level in PANC‐1 cells and pancreatic noncancer cell (hTERT‐HPNE) for comparison purposes. We found that the increase was lower in noncancer cells. Reduction of mitochondrial membrane potential and changes in the cell cycle were also observed. Additionally, we determined the increase in RNS level: nitric oxide (NO) and nitric dioxide (NO2) in PANC‐1 cells, together with increase in family of nitric oxide synthases (iNOS, eNOS, and nNOS) at protein and mRNA level. Disturbance of antioxidant enzymes: superoxide dismutase (SOD1, SOD2, and SOD3), glutathione peroxidase (GPX‐4) and catalase (CAT) were proved at protein and mRNA level. Moreover, we showed cells ultrastructural changes, characteristic for oxidative damage. Summarizing, oxidative and nitro‐oxidative stress and mitochondrial disruption are implicated in AgNPs‐mediated death in human pancreatic ductal adenocarcinoma cells.
The Coincidence of Newly Diagnosed Type 1 Diabetes Mellitus with IgM Antibody Positivity to Enteroviruses and Respiratory Tract Viruses
Authors: Karaoglan Murat , Eksi Fahriye
Published: August 2018

Objective. Viruses trigger and promote islet cell destruction and cause type 1 diabetes mellitus (T1DM). However, the existence of a cause-and-effect relationship is under debate. The aim of this study is to investigate the sero-epidemiological and molecular evidence on enteroviruses and respiratory viruses in patients with newly diagnosed T1DM during the cold season. Design. Forty children newly diagnosed with T1DM and 30 healthy children who presented to the clinic over the course of a year were included in the study. The IgM antibodies against enteroviruses and respiratory viruses were studied using the indirect immunofluorescence assay (IFA) test, and no CBV4-specific RNA was detected in the children. The onset times of T1DM were classified into fall-winter and spring-summer seasons and separated into cold, moderate, or warm months in terms of temperature. Results. The percentages of viral IgM antibodies against most common viruses were detected in the patients as follows: influenza B (IVB) (70%), echovirus 7 (ECHO7) (45%), parainfluenza virus 4 (PIV4) (40%), coxsackievirus A7 (CAV7) (27.5%), and H3N2 (22.5%). Compared with the control group, the above viruses had a significant association with T1DM (p≤0.001, p≤0.001, p=0.035, p=0.003, and p=0.023, resp.). CBV4-specific RNA was not detected in any serum. A total of 75% and 95% patients were diagnosed with T1DM in the fall-winter seasons and cold-moderate months, respectively. Conclusion. Our study demonstrates the significant association between T1DM and the presence of IgM antibodies against IVB, ECHO7, PIV4, CAV7, and H3N2, and the majority of newly diagnosed T1DM appeared in the fall-winter season. It suggests that enteroviruses and respiratory viruses, in addition to seasonal variation, could play a role in the etiopathogenesis and clinical onset of T1DM.
Siji Antiviral Mixture Protects against CA16 Induced Brain Injury through Inhibiting PERK/STAT3/NF-κB Pathway
Authors: Xiao Huimin , Zhao Rong , He Yue , Liu Yang , He Qiaoyan , Wang Siwang , Chen Fei
Published: August 2018

Coxsackievirus 16 (CA16) causes hand, foot, and mouth disease (HFMD) in young children and infants, and it can lead to fatal neurological complications. This study investigated antiviral effects of Siji Antiviral Mixture (SAM) on CA16 in neonatal mice and the protective effects of SAM on CA16 induced brain injuries. Neonatal BALB/c mice and SH-SY5Y cells were used and injected with CA16 stains to study the efficacy. ELISA and Western blotting were used to measure the cytokines levels and proteins expression. Genes transduction was also used to verify interaction mechanism. As the results shown, SAM could reduce the clinical scores at the beginning and delay disease developmentin vivo. Treatment with SAM decreased the levels of LDH, CK-MB, caspase 3 and Bax, ER stress, and inflammatory reaction induced by CA16 infection. Further siRNA transfection results showed that CA16 induced ER stress and inflammatory reaction through PERK/STAT3/NF-κB signaling and the protective effects of SAM might be through inhibiting PERK/STAT3/NF-κB signaling. HPLC analysis showed fingerprint profiles of SAM had 42 chromatographic peaks. Collectively, our study highlighted distinct roles of SAM in inhibiting CA16 infection and brain injury. The molecular mechanism of SAM might be through inhibiting PERK/STAT3/NF-κB signaling.
Synthesis of Fluorescent Polythiophene Dots
Authors: Liu Zhen , Nahhas Alaa , Liu Li , Ada Earl , Zhang Xinyu , Manohar Sanjeev K.
Published: August 2018

Ring-functionalized semiconducting polythiophene dots (Pdots) were synthesized rapidly and in one step by the hydrazine hydrate reduction of doped parent polythiophene, obtained by conventional chemical oxidation of thiophene monomer by FeCl3 in anhydrous acetonitrile. Dispersions of these Pdots display robust (pseudo) solvatochromism and solvatofluorism. Polythiophene Pdots exhibit significant cytotoxicity towards prostate cancer cells (expected) although when injected subcutaneously in vivo in live mouse, no toxicity is observed for 24 days when monitored in real time using fluorescence imaging.
Damage Assessment of an RC Pier under Noncontact Blast Loading Based on P‐I Curves
Authors: Liu Lu , Zong Zhouhong , Tang Biao , Li Minghong
Published: August 2018

Since the 9.11 attacks in New York, terrorist attacks, military strikes, and accidental explosions have caused serious damage to various infrastructures around the world. Accidental traffic explosions in bridge engineering have occurred frequently due to the increasing firework truck on the bridge and heavy fuel oil ships under the bridge. Besides, intentional car bomb explosions in terrorist attacks and military assaults are significant threats to the bridge structure. Bridge pier is a particularly important component of the overall bridge structure due to its vertical support capacity. Therefore, the damage of reinforced concrete (RC) piers under blast loading should be studied. In this paper, the pier is simplified as a single degree of freedom (SDOF) system based on energy equality, and the blast loading distribution on the surface of the pier is simplified as a uniform distribution. Then, the P‐I curves of an RC pier are obtained based on the SDOF system and a uniform distribution blast loading to quickly evaluate the damage extent of an RC pier so that the P‐I curves and fitting formulas for different damage extents can be used for practical engineering. After a numerical simulation verification, the P‐I curves and fitting formulas based on the simplified method can supply a rapid and effective method for engineers to assess the postexplosive damage of an RC pier.
Study on Mechanical Properties and Damage Evolution Law of Secondary Destruction Induced by Simultaneous Unloading after the Peak of the Curve of Sandstone
Authors: Fukun Xiao , Gang Liu , Qianlong Cheng
Published: August 2018

The research adopts the French ROCK600‐50 three‐axis experiment instrument and SH‐II system to evaluate the acoustic emission (AE) peak of the rear axle of yellow sandstone by carrying out the confining pressure synchronous unloading experiment, and evolution of mechanical properties and characteristics of energy transformation and damage of a yellow sandstone, which is a two‐damage process, the results of which have shown the following: (1) there are two damages appearing when the confining pressure is 5 MPa, 10 MPa, and 20 MPa. In contrast, these two damages do not appear when the confining pressure is 30 MPa and 40 MPa. The fracture degree and crack number of the two fractures are larger than those without two damages. (2) A failure stress release rate showed an obvious “√” trend. With the increase of confining pressure, the stress release rate of the two failures is increasing. (3) By keeping the strain of the body constant, it is determined to be the first time to destroy the warning. The two failures of rock are predicted by the inflection point of the axial strain slope. No two failures occurred, and the strain unloading process showed two characteristics. (4) Meanwhile, with the increase of confining pressure, the energy released from the peak decreases first and then increases; the law of releasing energy from one failure and two destructions is the opposite. No damage occurred two times. As the confining pressure increases, there is a continuous decrease of the energy released from the peak. As the confining pressure increases, the release rate of the primary energy decreases at first and then increases, and the rate of energy released two times is increasing. The plasticity coefficient shows the trend of increasing first and then decreasing. (5) The damage degree of the second rupture is greater than the first rupture.
CD44-Targeting PLGA Nanoparticles Incorporating Paclitaxel and FAK siRNA Overcome Chemoresistance in Epithelial Ovarian Cancer
Authors: Byeon Yeongseon , Lee Jeong-Won , Choi Whan Soo , Won Ji Eun , Kim Ga Hee , Kim Min Gi , Wi Tae In , Lee Jae Myeong , Kang Tae Heung , Jung In Duk , Cho Young-Jae , Ahn Hyung Jun , Shin Byung Cheol , Lee Young Joo , Sood Anil K. , Han Hee Dong , Park Yeong-Min
Published: August 2018

Chemotherapy is commonly used in the treatment of ovarian cancer, yet most ovarian cancers harbor inherent resistance or develop acquired resistance. Therefore, novel therapeutic approaches to overcome chemoresistance are required. In this study, we developed a hyaluronic acid-labeled poly(d,l-lactide-co-glycolide) nanoparticle (HA-PLGA-NP) encapsulating both paclitaxel (PTX) and focal adhesion kinase (FAK) siRNA as a selective delivery system against chemoresistant ovarian cancer. The mean size and zeta potential of the HA-PLGA-NP were 220 nm and -7.3 mV, respectively. Incorporation efficiencies for PTX and FAK siRNA in the HA-PLGA-NPs were 77% and 85%, respectively. HA-PLGA-NP showed higher binding efficiency for CD44-positive tumor cells as compared with CD44-negative cells. HA-PLGA (PTX+FAK siRNA)-NP caused increased cytotoxicity and apoptosis in drug-resistant tumor cells. Treatment of human epithelial ovarian cancer tumor models HeyA8-MDR (P < 0.001) and SKOV3-TR (P < 0.001) with HA-PLGA (PTX+FAK siRNA)-NP resulted in significant inhibition of tumor growth. Moreover, in a drug-resistant, patient-derived xenograft (PDX) model, HA-PLGA (PTX+FAK siRNA)-NP significantly inhibited tumor growth compared with PTX alone (P < 0.002). Taken together, HA-PLGA-NP acts as an effective and selective delivery system for both the chemotherapeutic and the siRNA in order to overcome chemoresistance in ovarian carcinoma.

Significance: These findings demonstrate the efficacy of a novel, selective, two-in-one delivery system to overcome chemoresistance in epithelial ovarian cancer. Cancer Res; 78(21); 6247–56. ©2018 AACR.
In Vivo Estimation of Oncolytic Virus Populations within Tumors
Authors: Jung Mi-Yeon , Offord Chetan P. , Ennis Matthew K. , Kemler Iris , Neuhauser Claudia , Dingli David
Published: August 2018

The use of replication-competent viruses as oncolytic agents is rapidly expanding, with several oncolytic viruses approved for cancer therapy. As responses to therapy are highly variable, understanding the dynamics of therapy is critical for optimal application of virotherapy in practice. Although mathematical models have been developed to understand the dynamics of tumor virotherapy, a scarcity of in vivo data has made difficult parametrization of these models. To tackle this problem, we studied the in vitro and in vivo spread of two oncolytic measles viruses that induce expression of the sodium iodide symporter (NIS) in cells. NIS expression enabled infected cells to concentrate radioactive isotopes that could be reproducibly and quantitatively imaged using SPECT/CT. We observed a strong linear relationship in vitro between infectious virus particles, viral N and NIS gene expression, and radioactive isotope uptake. In vivo radioisotope uptake was highly correlated with viral N and NIS gene expression. Similar expression patterns between viral N and NIS gene expression in vitro and in vivo implied that the oncolytic virus behaved similarly in both scenarios. Significant titers of viable virus were consistently isolated from tumors explanted from mice that had been injected with oncolytic measle viruses. We observed a weaker but positive in vivo relationship between radioisotope uptake and the viable virus titer recovered from tumors; this was likely due to anisotropies in the viral distribution in vivo. These data suggest that methods that enable quantitation of in vivo anisotropies are required for continuing development of oncolytic virotherapy.

Significance: These findings address a fundamental gap in our knowledge of oncolytic virotherapy by presenting technology that gives insight into the behavior of oncolytic viruses in vivo. Cancer Res; 78(20); 5992–6000. ©2018 AACR.
ErbB3 Targeting Enhances the Effects of MEK Inhibitor in Wild-Type BRAF/NRAS Melanoma
Authors: Capparelli Claudia , Purwin Timothy J. , Heilman Shea A. , Chervoneva Inna , McCue Peter A. , Berger Adam C. , Davies Michael A. , Gershenwald Jeffrey E. , Krepler Clemens , Aplin Andrew E.
Published: August 2018

MEK–ERK1/2 signaling is elevated in melanomas that are wild-type for both BRAF and NRAS (WT/WT), but patients are insensitive to MEK inhibitors. Stromal-derived growth factors may mediate resistance to targeted inhibitors, and optimizing the use of targeted inhibitors for patients with WT/WT melanoma is a clinical unmet need. Here, we studied adaptive responses to MEK inhibition in WT/WT cutaneous melanoma. The Cancer Genome Atlas data set and tumor microarray studies of WT/WT melanomas showed that high levels of neuregulin-1 (NRG1) were associated with stromal content and ErbB3 signaling. Of growth factors implicated in resistance to targeted inhibitors, NRG1 was effective at mediating resistance to MEK inhibitors in patient-derived WT/WT melanoma cells. Furthermore, ErbB3/ErbB2 signaling was adaptively upregulated following MEK inhibition. Patient-derived cancer-associated fibroblast studies demonstrated that stromal-derived NRG1 activated ErbB3/ErbB2 signaling and enhanced resistance to a MEK inhibitor. ErbB3- and ErbB2-neutralizing antibodies blocked the protective effects of NRG1 in vitro and cooperated with the MEK inhibitor to delay tumor growth in both cell line and patient-derived xenograft models. These results highlight tumor microenvironment regulation of targeted inhibitor resistance in WT/WT melanoma and provide a rationale for combining MEK inhibitors with anti-ErbB3/ErbB2 antibodies in patients with WT/WT cutaneous melanoma, for whom there are no effective targeted therapy options.

Significance: This work suggests a mechanism by which NRG1 regulates the sensitivity of WT NRAS/BRAF melanomas to MEK inhibitors and provides a rationale for combining MEK inhibitors with anti-ErbB2/ErbB3 antibodies in these tumors. Cancer Res; 78(19); 5680–93. ©2018 AACR.
Oxygen-Enhanced and Dynamic Contrast-Enhanced Optoacoustic Tomography Provide Surrogate Biomarkers of Tumor Vascular Function, Hypoxia, and Necrosis
Authors: Tomaszewski Michal R. , Gehrung Marcel , Joseph James , Quiros-Gonzalez Isabel , Disselhorst Jonathan A. , Bohndiek Sarah E.
Published: August 2018

Measuring the functional status of tumor vasculature, including blood flow fluctuations and changes in oxygenation, is important in cancer staging and therapy monitoring. Current clinically approved imaging modalities suffer long procedure times and limited spatiotemporal resolution. Optoacoustic tomography (OT) is an emerging clinical imaging modality that may overcome these challenges. By acquiring data at multiple wavelengths, OT can interrogate hemoglobin concentration and oxygenation directly and resolve contributions from injected contrast agents. In this study, we tested whether two dynamic OT techniques, oxygen-enhanced (OE) and dynamic contrast-enhanced (DCE)-OT, could provide surrogate biomarkers of tumor vascular function, hypoxia, and necrosis. We found that vascular maturity led to changes in vascular function that affected tumor perfusion, modulating the DCE-OT signal. Perfusion in turn regulated oxygen availability, driving the OE-OT signal. In particular, we demonstrate for the first time a strong per-tumor and spatial correlation between imaging biomarkers derived from these in vivo techniques and tumor hypoxia quantified ex vivo. Our findings indicate that OT may offer a significant advantage for localized imaging of tumor response to vascular-targeted therapies when compared with existing clinical DCE methods.

Significance: Imaging biomarkers derived from optoacoustic tomography can be used as surrogate measures of tumor perfusion and hypoxia, potentially yielding rapid, multiparametric, and noninvasive cancer staging and therapeutic response monitoring in the clinic.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5980/F1.large.jpg. Cancer Res; 78(20); 5980–91. ©2018 AACR.
CDK4/6 Inhibitors: What Is the Best Cocktail?
Authors: Malumbres Marcos
Published: August 2018

CDK4/6 inhibitors have shown great potential in the new armamentarium against cancer. However, their effect as single agents is limited, and the hopes are on new combinatory strategies. Recent data suggest that inhibiting mTOR may significantly cooperate with cell-cycle arrest in a variety of cancers.

See related article by Song et al., p. 403