bluuebunny/crossref_metadata_2025 huggingface dataset:
In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy
Authors: Petővári Gábor , Dankó Titanilla , Tőkés Anna-Mária , Vetlényi Enikő , Krencz Ildikó , Raffay Regina , Hajdu Melinda , Sztankovics Dániel , Németh Krisztina , Vellai-Takács Krisztina , Jeney András , Kulka Janina , Sebestyén Anna
Published: September 2020

In spite of tremendous developments in breast cancer treatment, the relatively high incidence of relapsing cases indicates a great need to find new therapeutic strategies in recurrent, metastatic and advanced cases. The bioenergetic needs of growing tumours at the primary site or in metastases—accumulating genomic alterations and further heterogeneity—are supported by metabolic rewiring, an important hallmark of cancer. Adaptation mechanisms as well as altered anabolic and catabolic processes balance according to available nutrients, energy, oxygen demand and overgrowth or therapeutic resistance. Mammalian target of rapamycin (mTOR) hyperactivity may contribute to this metabolic plasticity and progression in breast carcinomas. We set out to assess the metabolic complexity in breast cancer cell lines and primary breast cancer cases. Cellular metabolism and mTOR-related protein expression were characterised in ten cell lines, along with their sensitivity to specific mTOR and other metabolic inhibitors. Selected immunohistochemical reactions were performed on ~100 surgically removed breast cancer specimens. The obtained protein expression scores were correlated with survival and other clinicopathological data. Metabolic and mTOR inhibitor mono-treatments had moderate antiproliferative effects in the studied cell lines in a subtype-independent manner, revealing their high adaptive capacity and survival/growth potential. Immunohistochemical analysis of p-S6, Rictor, lactate dehydrogenase A, glutaminase, fatty acid synthase and carnitine palmitoyltransferase 1A in human samples identified high mTOR activity and potential metabolic plasticity as negative prognostic factors for breast cancer patients, even in subtypes generally considered as low-risk. According to our results, breast cancer is characterised by considerable metabolic diversity, which can be targeted by combining antimetabolic treatments and recent therapies. Alterations in these pathways may provide novel targets for future drug development in breast cancer. We also propose a set of immunostainings for scoring metabolic heterogeneity in individual cases in order to select patients who may benefit from more accurate follow-up and specific therapies.
Translational Considerations to Improve Response and Overcome Therapy Resistance in Immunotherapy for Hepatocellular Carcinoma
Authors: Heinrich Sophia , Castven Darko , Galle Peter R. , Marquardt Jens U.
Published: September 2020

Over the last decade, progress in systemic therapies significantly improved the outcome of primary liver cancer. More recently, precision oncological and immunotherapeutic approaches became the focus of intense scientific and clinical research. Herein, preclinical studies showed promising results with high response rates and improvement of overall survival. However, results of phase III clinical trials revealed that only a subfraction of hepatocellular carcinoma (HCC) patients respond to therapy and display only moderate objective response rates. Further, predictive molecular characteristics are largely missing. In consequence, suitable trial design has emerged as a crucial factor for the success of a novel compound. In addition, increasing knowledge from translational studies indicate the importance of targeting the tumor immune environment to overcome resistance to immunotherapy. Thus, combination of different immunotherapies with other treatment modalities including antibodies, tyrosine kinase inhibitors, or local therapies is highly promising. However, the mechanisms of failure to respond to immunotherapy in liver cancer are still not fully understood and the modulation of the immune system and cellular tumor composition is particularly relevant in this context. Altogether, it is increasingly clear that tailoring of immunotherapy and individualized approaches are required to improve efficacy and patient outcome in liver cancer. This review provides an overview of the current knowledge as well as translational considerations to overcome therapy resistance in immunotherapy of primary liver cancer.
Role of Natural Bioactive Compounds in the Rise and Fall of Cancers
Authors: Luparello Claudio
Published: September 2020

Recent years have seen the idea of a close association between nutrition and the modulation of cancer development/progression reinforced [...]
BMS-599626, a Highly Selective Pan-HER Kinase Inhibitor, Antagonizes ABCG2-Mediated Drug Resistance
Authors: Ashar Yunali V. , Zhou Jingchun , Gupta Pranav , Teng Qiu-Xu , Lei Zi-Ning , Reznik Sandra E. , Lusvarghi Sabrina , Wurpel John , Ambudkar Suresh V. , Chen Zhe-Sheng
Published: September 2020

Multidrug resistance (MDR) associated with the overexpression of ABC transporters is one of the key causes of chemotherapy failure. Various compounds blocking the function and/or downregulating the expression of these transporters have been developed over the last few decades. However, their potency and toxicity have always been a concern. In this report, we found that BMS-599626 is a highly potent inhibitor of the ABCG2 transporter, inhibiting its efflux function at 300 nM. Our study repositioned BMS-599626, a highly selective pan-HER kinase inhibitor, as a chemosensitizer in ABCG2-overexpressing cell lines. As shown by the cytotoxicity assay results, BMS-599626, at noncytotoxic concentrations, sensitizes ABCG2-overexpressing cells to topotecan and mitoxantrone, two well-known substrates of ABCG2. The results of our radioactive drug accumulation experiment show that the ABCG2-overexpressing cells, treated with BMS-599626, had an increase in the accumulation of substrate chemotherapeutic drugs, as compared to their parental subline cells. Moreover, BMS-599626 did not change the protein expression or cell surface localization of ABCG2 and inhibited its ATPase activity. Our in-silico docking study also supports the interaction of BMS-599626 with the substrate-binding site of ABCG2. Taken together, these results suggest that administration of chemotherapeutic drugs, along with nanomolar concentrations (300 nM) of BMS-599626, may be effective against ABCG2-mediated MDR in clinical settings.
The Optimal Duration of Adjuvant Chemotherapy in Colon Cancer
Authors: Collienne Maike , Arnold Dirk
Published: September 2020

Adjuvant chemotherapy for colon cancer (UICC stage II and III) has been under investigation over the last 30 years, regarding treatment duration and regimens. In this review, choice of regimen, its duration, possible limitations and future perspectives are discussed. Monotherapy with 5-fluorouracil was followed by addition of oxaliplatin, resulting in improved 3-yr disease free survival (DFS) and overall survival (OS) rates, but also increased peripheral sensory neurotoxicity (PSN). The International Duration Evaluation of Adjuvant therapy (IDEA) collaboration demonstrated less toxicity, especially PSN, when shortening treatment duration to 3 months. However, formally, the anticipated non-inferiority of 3 months with fluoropyrimidine (FP)/oxaliplatin over 6 months (at 3-yr DFS) was not met for all patients groups, although subgroup analyses showed non-inferiority with capecitabine/oxaliplatin (CAPOX) rather than with FOLFOX, and also in relation to the prognostic information (e.g., clinical low-risk group, pT1-3 N0). In addition, first data of newer parameters like Immunoscore® and ctDNA show promising results as stratification parameters. Further investigations to better define clinical risk groups and prognostic factors are mandatory. Besides this, individual decision-making of treatment intensity (FP or FP/oxaliplatin) and duration should always consider patient characteristics and preferences, also given the absolute relatively small differences and their clinical relevance.
Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers
Authors: Kaps Leonard , Schuppan Detlef
Published: September 2020

Cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) produced by them have been recognized as key players in cancer biology and emerged as important targets for cancer treatment and drug discovery. Apart from their presence in stroma rich tumors, such as biliary, pancreatic and subtypes of hepatocellular cancer (HCC), both CAF and certain ECM components are also present in cancers without an overt intra-tumoral desmoplastic reaction. They support cancer development, growth, metastasis and resistance to chemo- or checkpoint inhibitor therapy by a multitude of mechanisms, including angiogenesis, ECM remodeling and active immunosuppression by secretion of tumor promoting and immune suppressive cytokines, chemokines and growth factors. CAF resemble activated hepatic stellate cells (HSC)/myofibroblasts, expressing α-smooth muscle actin and especially fibroblast activation protein (FAP). Apart from FAP, CAF also upregulate other functional cell surface proteins like platelet-derived growth factor receptor β (PDGFRβ) or the insulin-like growth factor receptor II (IGFRII). Notably, if formulated with adequate size and zeta potential, injected nanoparticles home preferentially to the liver. Several nanoparticular formulations were tested successfully to deliver dugs to activated HSC/myofibroblasts. Thus, surface modified nanocarriers with a cyclic peptide binding to the PDGFRβ or with mannose-6-phosphate binding to the IGFRII, effectively directed drug delivery to activated HSC/CAF in vivo. Even unguided nanohydrogel particles and lipoplexes loaded with siRNA demonstrated a high in vivo uptake and functional siRNA delivery in activated HSC, indicating that liver CAF/HSC are also addressed specifically by well-devised nanocarriers with optimized physicochemical properties. Therefore, CAF have become an attractive target for the development of stroma-based cancer therapies, especially in the liver.
Membrane Transporters for Amino Acids as Players of Cancer Metabolic Rewiring
Authors: Scalise Mariafrancesca , Console Lara , Rovella Filomena , Galluccio Michele , Pochini Lorena , Indiveri Cesare
Published: September 2020

Cancer cells perform a metabolic rewiring to sustain an increased growth rate and compensate for the redox stress caused by augmented energy metabolism. The metabolic changes are not the same in all cancers. Some features, however, are considered hallmarks of this disease. As an example, all cancer cells rewire the amino acid metabolism for fulfilling both the energy demand and the changed signaling routes. In these altered conditions, some amino acids are more frequently used than others. In any case, the prerequisite for amino acid utilization is the presence of specific transporters in the cell membrane that can guarantee the absorption and the traffic of amino acids among tissues. Tumor cells preferentially use some of these transporters for satisfying their needs. The evidence for this phenomenon is the over-expression of selected transporters, associated with specific cancer types. The knowledge of the link between the over-expression and the metabolic rewiring is crucial for understanding the molecular mechanism of reprogramming in cancer cells. The continuous growth of information on structure–function relationships and the regulation of transporters will open novel perspectives in the fight against human cancers.
Psychogastroenterology: A Cure, Band-Aid, or Prevention?
Authors: van Tilburg Miranda A. L.
Published: September 2020

Psychogastroenterology is a field that focuses on the brain–gut connection. Many children with gut disorders also struggle with psychological and social factors that affect their disease outcomes. Psychological factors have been suggested to be a cure, a band-aid, or a prevention. This article examines the underlying models of disease and health that determine how we understand and treat psychosocial factors in gut diseases. The biomedical and biopsychosocial models are presented and applied to pediatric gut disorders. This article should familiarize clinicians as well as children and their families to the challenges and opportunities for addressing psychosocial factors in gut disease. Psychogastroenterology is best thought of as a cog in a complex treatment machine.
A Model for a Standardized and Sustainable Pediatric Anesthesia-Intensive Care Unit Hand-Off Process
Authors: Dalal Priti G. , Cios Theodore J. , DeMartini Theodore K. M. , Prasad Amit A. , Whitley Meghan C. , Clark Joseph B. , Lin Leon , Mujsce Dennis J. , Cilley Robert E.
Published: September 2020

Background and Objectives: The hand-off process between pediatric anesthesia and intensive care unit (ICU) teams involves the exchange of patient health information and plays a major role in reducing errors and increasing staff satisfaction. Our objectives were to (1) standardize the hand-off process in children’s ICUs, and (2) evaluate the provider satisfaction, efficiency and sustainability of the improved hand-off process. Methods: Following multidisciplinary discussions, the hand-off process was standardized for transfers of care between anesthesia-ICU teams. A pre-implementation and two post-implementation (6 months, >2 years) staff satisfaction surveys and audits were conducted to evaluate the success, quality and sustainability of the hand-off process. Results: There was no difference in the time spent during the sign out process following standardization—median 5 min for pre-implementation versus 5 and 6 min for post-implementation at six months and >2 years, respectively. There was a significant decrease in the number of missed items (airway/ventilation, venous access, medications, and laboratory values pertinent events) post-implementation compared to pre-implementation (p ≤ 0.001). In the >2 years follow-up survey, 49.2% of providers felt that the hand-off could be improved versus 78.4% in pre-implementation and 54.2% in the six-month survey (p < 0.001). Conclusion: A standardized interactive hand-off improves the efficiency and staff satisfaction, with a decreased rate of missed information at the cost of no additional time.
Entropy Analysis of a Flexible Markovian Queue with Server Breakdowns
Authors: Bounkhel Messaoud , Tadj Lotfi , Hedjar Ramdane
Published: September 2020

In this paper, a versatile Markovian queueing system is considered. Given a fixed threshold level c, the server serves customers one a time when the queue length is less than c, and in batches of fixed size c when the queue length is greater than or equal to c. The server is subject to failure when serving either a single or a batch of customers. Service rates, failure rates, and repair rates, depend on whether the server is serving a single customer or a batch of customers. While the analytical method provides the initial probability vector, we use the entropy principle to obtain both the initial probability vector (for comparison) and the tail probability vector. The comparison shows the results obtained analytically and approximately are in good agreement, especially when the first two moments are used in the entropy approach.
Minimal Products of Coordinate and Momentum Uncertainties of High Orders: Significant and Weak High-Order Squeezing
Authors: Citeli de Freitas Miguel , Dantas Meireles Vitor , Dodonov Viktor V.
Published: September 2020

We consider the problem of minimization of products of mean values of the high powers of operators x and p. From this point of view, we study several two-term superpositions of the Fock states, as well as three popular families of infinite superpositions: squeezed states, even/odd coherent states, and orthogonal even coherent states (or compass states). The new element is the analysis of products of the corresponding (co)variances and the related generalized (Robertson–Schrödinger) intelligent states (RSIS). In particular, we show that both Fock and pure Gaussian homogeneous states are RSIS for the fourth powers (but not for the sixth ones). We show that lower bounds of the high-order uncertainty products can be significantly below the vacuum values. In this connection, the concept of significant and weak high-order squeezing is introduced.
A Generalized Approach to the Steady-State Efficiency Analysis of Torque-Adding Transmissions Used in Renewable Energy Systems
Authors: Neagoe Mircea , Saulescu Radu , Jaliu Codruta , Simionescu Petru A.
Published: September 2020

The paper presents a general approach to the steady-state efficiency analysis of one degree of freedom (1-DOF) speed increasers with one or two inputs, and one or two outputs, applicable to wind, hydro and marine-current power generating systems. The mechanical power flow, and the efficiency of this type of complex speed increasers, are important issues in the design and development of new power-generating systems. It is revealed that speed increases, with in-parallel transmission of the mechanical power from the wind or water rotors to the electric generator, have better efficiency than serial transmissions, but their efficiency calculus is still a challenging problem, solved in the paper by applying the decomposition method of complex speed increasers into simpler component planetary gear sets. Therefore, kinematic, steady-state torque and efficiency equations are derived for a generic 1-DOF speed increasers with two inputs and two outputs, obtained by connecting in parallel two gear mechanisms. These equations allow any speed increaser to be analysed with two inputs and one output, with one input and two outputs, and with one input and one output. We discuss a novel design of a patent-pending planetary-gear speed increaser, equipped with a two-way clutch, which can operate (in combination with the pitch adjustment of the rotors blades) in four distinct configurations. It was found that the mechanical efficiency of this speed increaser in the steady-state regime is influenced by the interior kinematic ratios, the input-torque ratio and by the meshing efficiency of its individual gear pairs. The efficiency of counter-rotating dual-rotor systems was found to be the highest, followed by systems with counter-rotating electric generator, and both have higher efficiency than conventional systems with one rotor and one electric generator with fixed-stator.
Energy Analyses of Serbian Buildings with Horizontal Overhangs: A Case Study
Authors: Nikolic Danijela , Djordjevic Slobodan , Skerlic Jasmina , Radulovic Jasna
Published: September 2020

It is well known that nowadays a significant part of the total energy consumption is related to buildings, so research for improving building energy efficiency is very important. This paper presents our investigations about the dimensioning of horizontal overhangs in order to determine the minimum annual consumption of building primary energy for heating, cooling and lighting. In this investigation, embodied energy for horizontal roof overhangs was taken into account. The annual simulation was carried out for a residential building located in the city of Belgrade (Serbia). Horizontal overhangs (roof and balcony) are positioned to provide shading of all exterior of the building. The building is simulated in the EnergyPlus software environment. The optimization of the overhang size was performed by using the Hooke Jeeves algorithm and plug-in GenOpt program. The objective function minimizes the annual consumption of primary energy for heating, cooling and lighting of the building and energy spent to build overhangs. The simulation results show that the building with optimally sized roof and balcony overhangs consumed 7.12% lessprimary energy for heating, cooling and lighting, compared to the house without overhangs. A 44.15% reduction in cooling energy consumption is also achieved.
Characterization of Tissue Engineered Endothelial Cell Networks in Composite Collagen-Agarose Hydrogels
Authors: Ichanti Houda , Sladic Sanja , Kalies Stefan , Haverich Axel , Andrée Birgit , Hilfiker Andres
Published: September 2020

Scaffolds constitute an important element in vascularized tissues and are therefore investigated for providing the desired mechanical stability and enabling vasculogenesis and angiogenesis. In this study, supplementation of hydrogels containing either MatrigelTM and rat tail collagen I (MatrigelTM/rCOL) or human collagen (hCOL) with SeaPlaqueTM agarose were analyzed with regard to construct thickness and formation and characteristics of endothelial cell (EC) networks compared to constructs without agarose. Additionally, the effect of increased rCOL content in MatrigelTM/rCOL constructs was studied. An increase of rCOL content from 1 mg/mL to 3 mg/mL resulted in an increase of construct thickness by approximately 160%. The high rCOL content, however, impaired the formation of an EC network. The supplementation of MatrigelTM/rCOL with agarose increased the thickness of the hydrogel construct by approximately 100% while supporting the formation of a stable EC network. The use of hCOL/agarose composite hydrogels led to a slight increase in the thickness of the 3D hydrogel construct and supported the formation of a multi-layered EC network compared to control constructs. Our findings suggest that agarose/collagen-based composite hydrogels are promising candidates for tissue engineering of vascularized constructs as cell viability is maintained and the formation of a stable and multi-layered EC network is supported.
Newly Emerged Serotype 1c of Shigella flexneri: Multiple Origins and Changing Drug Resistance Landscape
Authors: Parajuli Pawan , Minh Bui Quang , Verma Naresh K.
Published: September 2020

Bacillary dysentery caused by Shigella flexneri is a major cause of under-five mortality in developing countries, where a novel S. flexneri serotype 1c has become very common since the 1980s. However, the origin and diversification of serotype 1c remain poorly understood. To understand the evolution of serotype 1c and their antimicrobial resistance, we sequenced and analyzed the whole-genome of 85 clinical isolates from the United Kingdom, Egypt, Bangladesh, Vietnam, and Japan belonging to serotype 1c and related serotypes of 1a, 1b and Y/Yv. We identified up to three distinct O-antigen modifying genes in S. flexneri 1c strains, which were acquired from three different bacteriophages. Our analysis shows that S. flexneri 1c strains have originated from serotype 1a and serotype 1b strains after the acquisition of bacteriophage-encoding gtrIc operon. The maximum-likelihood phylogenetic analysis using core genes suggests two distinct S. flexneri 1c lineages, one specific to Bangladesh, which originated from ancestral serotype 1a strains and the other from the United Kingdom, Egypt, and Vietnam originated from ancestral serotype 1b strains. We also identified 63 isolates containing multiple drug-resistant genes in them conferring resistance against streptomycin, sulfonamide, quinolone, trimethoprim, tetracycline, chloramphenicol, and beta-lactamase. Furthermore, antibiotic susceptibility assays showed 83 (97.6%) isolates as either complete or intermediate resistance to the WHO-recommended first- and second-line drugs. This changing drug resistance pattern demonstrates the urgent need for drug resistance surveillance and renewed treatment guidelines.
The Relationship between Just World Beliefs and Life Satisfaction
Authors: Harding Warren G. , McConatha Jasmin Tahmaseb , Kumar V. K.
Published: September 2020

An important and often unexplored factor shaping life satisfaction is one’s perception of the world as a “just” place. The “just world hypothesis” is predicated on the idea that the world works as a place where people get what they merit, an idea that often serves as a means for people to rationalize injustices. The research addressing just world beliefs has expanded into a four-factor model that categorizes just world beliefs for self and others into subcategories of distributive and procedural justice. Distributive justice involves evaluations of the fairness of outcomes, allocations, or distribution of resources, while procedural concerns evaluations of the fairness of decision processes, rules, or interpersonal treatment. This study explored the relationship between the four just world beliefs subscales and overall satisfaction with life and examined their associations with demographic variables including ethnicity, age, gender, religion, and social class. The relationships of demographic factors with justice beliefs and life satisfaction generally yielded very small effect sizes. However, respondents who identified themselves as middle and upper class reported higher levels of life satisfaction than those who identified themselves as lower class, with a medium effect size. Consistent with the results of earlier research, regressing life satisfaction on the four justice beliefs subscales indicated that the two self-subscales (distributive and procedural) were significantly predictive of life satisfaction, but the two other subscales (distributive and procedural) were not.
The Impact of Expanded National Health Insurance Coverage of Dentures and Dental Implants on Dental Care Utilization among Older Adults in South Korea: A Study Based on the Korean Health Panel Survey
Authors: Choi Jin-Sun , Jung Se-Hwan
Published: September 2020

In South Korea, the National Health Insurance Service (NHIS) began its coverage of dentures and dental implants for older people in 2012 and 2014, respectively. This study aimed to investigate the impact of these policies on dental care utilization among people aged 65 years or older according to their sociodemographic characteristics. Data were collected from the Korea Health Panel Survey (KHP; years 2012 and 2015). The statistical significance of the relationships between sociodemographic characteristics and the use of outpatient dental care, denture, and dental implant were analyzed. Results showed an increase of 5.7%, 1.4%, and 2.8% in the use of outpatient dental care, denture, and dental implant, respectively, over the course of three years. Including dentures increased its use by 2.5–3.7 times among people aged 70 years or older. Including dental implants alleviated the disparities among older adults based on age groups and duration of education, except those among uneducated people; however, it caused inequity according to household income. Some Korean older adults remain neglected from the benefits of the expanded NHIS. Therefore, older adults’ access to dental care should be enhanced by the implementation of policies to promote oral health care utilization, dental prosthetic services, and older adults’ insurance coverage.
Application of the Safe-by-Design Concept in Crop Breeding Innovation
Authors: van der Berg Jan Pieter , Kleter Gijs A. , Battaglia Evy , Bouwman Lianne M. S. , Kok Esther J.
Published: September 2020

The present paper proposes the application of the safe-by-design concept to crop breeding innovation with the aim to accommodate safety considerations for new agricultural food and feed products. Safe-by-design can be implemented in all stages of the innovation cycle of agricultural products, from the early stages of research and development towards the post-market stage. Our proposed application of safe-by-design can be part of “responsible research and innovation” concepts, because they share features such as risk prevention strategies and a participatory approach. Early awareness of potential safety issues can guide the development of agricultural products towards safe options, both at the process and product level, and thus may help to reduce extensive pre-market assessment studies that might otherwise be needed further downstream for regulatory product approval. Here, it is discussed how the proposed safe-by-design approach can be introduced into the development of safe food crops using emerging technologies, such as gene editing and synthetic biology, and how this may help to safeguard the safety of our food and feed supply in the light of the ongoing global innovations in agricultural crop breeding.
Risk Perception of Air Pollution: A Systematic Review Focused on Particulate Matter Exposure
Authors: Cori Liliana , Donzelli Gabriele , Gorini Francesca , Bianchi Fabrizio , Curzio Olivia
Published: September 2020

The adverse health effects of exposure to air pollutants, notably to particulate matter (PM), are well-known, as well as the association with measured or estimated concentration levels. The role of perception can be relevant in exploring effects and pollution control actions. The purpose of this study was to explore studies that analyse people’s perception, together with the measurement of air pollution, in order to elucidate the relationship between them. We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In March 2020, PubMed, EMBASE, and Scopus databases were explored in an attempt to search for studies published from 2000 to 2020. The review included 38 studies, most of which were conducted in China (n = 13) and the United States (n = 11) and published over the last four years (n = 26). Three studies were multicenter investigations, while five articles were based on a national-level survey. The air quality (AQ) was assessed by monitoring stations (n = 24) or dispersion models (n = 7). Many studies were population questionnaire-based, air monitoring and time-series studies, and web-based investigations. A direct association between exposure and perception emerged in 20 studies. This systematic review has shown that most of the studies establish a relationship between risk perception measurement. A broad spectrum of concepts and notions related to perception also emerged, which is undoubtedly an indicator of the wealth of available knowledge and is promising for future research.
Opioid Pain Medication Prescription for Chronic Pain in Primary Care Centers: The Roles of Pain Acceptance, Pain Intensity, Depressive Symptoms, Pain Catastrophizing, Sex, and Age
Authors: Ramírez-Maestre Carmen , Reyes-Pérez Ángela , Esteve Rosa , López-Martínez Alicia E. , Bernardes Sonia , Jensen Mark P.
Published: September 2020

Background: Psychological factors of patients may influence physicians’ decisions on prescribing opioid analgesics. However, few studies have sought to identify these factors. The present study had a double objective: (1) To identify the individual factors that differentiate patients who had been prescribed opioids for the management of chronic back pain from those who had not been prescribed opioids and (2) to determine which factors make significant and independent contributions to the prediction of opioid prescribing. Methods: A total of 675 patients from four primary care centers were included in the sample. Variables included sex, age, pain intensity, depressive symptoms, pain catastrophizing, and pain acceptance. Results: Although no differences were found between men and women, participants with chronic noncancer pain who were prescribed opioids were older, reported higher levels of pain intensity and depressive symptoms, and reported lower levels of pain-acceptance. An independent association was found between pain intensity and depressive symptoms and opioid prescribing. Conclusions: The findings suggest that patient factors influence physicians’ decisions on prescribing opioids. It may be useful for primary care physicians to be aware of the potential of these factors to bias their treatment decisions.
The Effect of Wearing a Customized Mouthguard on Body Alignment and Balance Performance in Professional Basketball Players
Authors: Nam Hae Joo , Lee Joon-Hee , Hong Dae-Seok , Jung Hyun Chul
Published: September 2020

The present study examined the influence of a customized mouthguard on body alignment and balance performance in professional basketball players. Twenty-three professional male basketball players, aged 25.8 ± 8.6 years old, were voluntarily assigned to participate in three treatments, including no treatment (no mouthguard), acute treatment (wearing a mouthguard), and repeated treatments (8 weeks follow-up). Body alignment status, such as spinal and pelvic posture and balance performance, were measured at each time point using a 3D Formetric III (Germany) and a postural control device (Posturomed 202, Germany), respectively. A repeated MANOVA analysis with a Bonferroni post hoc test was applied, and the adjusted p-value was set at 0.02. No significant treatment effect was observed in body alignment (p = 0.302). However, univariate analysis showed a significant difference in pelvic torsion, where it was decreased after acute and repeated mouthguard treatments compared to no treatment (p < 0.001). Kyphotic angle also increased significantly following 8 weeks of treatment compared to no treatment (p < 0.001) and acute treatment (p < 0.002). There was a significant treatment effect on balance performance (p < 0.001). Both static and dynamic balance performance improved following 8 weeks of treatment (p < 0.001). Our study revealed that a customized mouthguard provides a benefit to balance performance. Notably, repeated treatment impacts on balance performance more than acute treatment. Although our findings did not show a significant effect on body alignment, some positive results, such as pelvic torsion and kyphotic angle, may provide substantial information for developing future longitudinal studies with large sample sizes.
Ceramic Scaffolds in a Vacuum Suction Handle for Intraoperative Stromal Cell Enrichment
Authors: Busch André , Herten Monika , Haversath Marcel , Kaiser Christel , Brandau Sven , Jäger Marcus
Published: September 2020

During total joint replacement, high concentrations of mesenchymal stromal cells (MSCs) are released at the implantation site. They can be found in cell–tissue composites (CTC) that are regularly removed by surgical suction. A surgical vacuum suction handle was filled with bone substitute granules, acting as a filter allowing us to harvest CTC. The purpose of this study was to investigate the osteopromotive potential of CTC trapped in the bone substitute filter material during surgical suction. In the course of 10 elective total hip and knee replacement surgeries, β-tricalcium-phosphate (TCP) and cancellous allograft (Allo) were enriched with CTC by vacuum suction. Mononuclear cells (MNC) were isolated from the CTC and investigated towards cell proliferation and colony forming unit (CFU) formation. Furthermore, MSC surface markers, trilineage differentiation potential and the presence of defined cytokines were examined. Comparable amounts of MNC and CFUs were detected in both CTCs and characterized as MSC‰ of MNC with 9.8 ± 10.7‰ for the TCP and 12.8 ± 10.2‰ for the Allo (p = 0.550). CTCs in both filter materials contain cytokines for stimulation of cell proliferation and differentiation (EGF, PDGF-AA, angiogenin, osteopontin). CTC trapped in synthetic (TCP) and natural (Allo) bone substitute filters during surgical suction in the course of a joint replacement procedure include relevant numbers of MSCs and cytokines qualified for bone regeneration.
Oxidative Stress, Kinase Activity and Inflammatory Implications in Right Ventricular Hypertrophy and Heart Failure under Hypobaric Hypoxia
Authors: Pena Eduardo , Brito Julio , El Alam Samia , Siques Patricia
Published: September 2020

High altitude (hypobaric hypoxia) triggers several mechanisms to compensate for the decrease in oxygen bioavailability. One of them is pulmonary artery vasoconstriction and its subsequent pulmonary arterial remodeling. These changes can lead to pulmonary hypertension and the development of right ventricular hypertrophy (RVH), right heart failure (RHF) and, ultimately to death. The aim of this review is to describe the most recent molecular pathways involved in the above conditions under this type of hypobaric hypoxia, including oxidative stress, inflammation, protein kinases activation and fibrosis, and the current therapeutic approaches for these conditions. This review also includes the current knowledge of long-term chronic intermittent hypobaric hypoxia. Furthermore, this review highlights the signaling pathways related to oxidative stress (Nox-derived O2.- and H2O2), protein kinase (ERK5, p38α and PKCα) activation, inflammatory molecules (IL-1β, IL-6, TNF-α and NF-kB) and hypoxia condition (HIF-1α). On the other hand, recent therapeutic approaches have focused on abolishing hypoxia-induced RVH and RHF via attenuation of oxidative stress and inflammatory (IL-1β, MCP-1, SDF-1 and CXCR-4) pathways through phytotherapy and pharmacological trials. Nevertheless, further studies are necessary.
Modulatory Roles of ATP and Adenosine in Cholinergic Neuromuscular Transmission
Authors: Ziganshin Ayrat U. , Khairullin Adel E. , Hoyle Charles H. V. , Grishin Sergey N.
Published: September 2020

A review of the data on the modulatory action of adenosine 5’-triphosphate (ATP), the main co-transmitter with acetylcholine, and adenosine, the final ATP metabolite in the synaptic cleft, on neuromuscular transmission is presented. The effects of these endogenous modulators on pre- and post-synaptic processes are discussed. The contribution of purines to the processes of quantal and non-quantal secretion of acetylcholine into the synaptic cleft, as well as the influence of the postsynaptic effects of ATP and adenosine on the functioning of cholinergic receptors, are evaluated. As usual, the P2-receptor-mediated influence is minimal under physiological conditions, but it becomes very important in some pathophysiological situations such as hypothermia, stress, or ischemia. There are some data demonstrating the same in neuromuscular transmission. It is suggested that the role of endogenous purines is primarily to provide a safety factor for the efficiency of cholinergic neuromuscular transmission.
Seminal Plasma Analysis of Oxidative Stress in Different Genitourinary Topographical Regions Involved in Reproductive Tract Disorders Associated with Genital Heat Stress
Authors: Fraczek Monika , Wojnar Lukasz , Kamieniczna Marzena , Piasecka Malgorzata , Gill Kamil , Kups Michal , Chopyak Valentina , Havrylyuk Anna , Nakonechnyy Jozef , Nakonechnyy Andrij , Wozniak Tomasz , Kurpisz Maciej
Published: September 2020

The pathophysiological mechanisms responsible for male subfertility/infertility caused by or complicated by genital heat stress remains unclear in many respects. Because seminal plasma creates the environment for the proper functioning of spermatozoa, in this study, we verified the associations among standard spermiograms, seminal biochemical parameters (neutral alpha-glucosidase, fructose, and citric acid) and oxidative stress markers (total antioxidant capacity, catalase activity, superoxide dismutase activity, and malondialdehyde concentration) in distinct entities associated with male infertility with and without long-time exposure to local hyperthermia. We demonstrated that men exposed to prolonged environmental or clinically recognized local heat stress in adulthood may suffer from dysregulation of seminal antioxidant components, which can be directly associated with epididymal and prostate function. The comparative analysis of the studied parameters showed numerous correlations among all biochemical parameters (particularly neutral alpha-glucosidase) with low standard semen quality in almost all the investigated infertile groups. In light of the data obtained in this originally designed study, we conclude that more attention should be paid to the epididymis and accessory gland function in subfertile and infertile men exposed to genital heat stress, especially in the context of novel treatment algorithms (targeted therapies).
The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement
Authors: Bachiller Sara , Alonso-Bellido Isabel M. , Real Luis Miguel , Pérez-Villegas Eva María , Venero José Luis , Deierborg Tomas , Armengol José Ángel , Ruiz Rocío
Published: September 2020

Neuromuscular disorders (NMDs) affect 1 in 3000 people worldwide. There are more than 150 different types of NMDs, where the common feature is the loss of muscle strength. These disorders are classified according to their neuroanatomical location, as motor neuron diseases, peripheral nerve diseases, neuromuscular junction diseases, and muscle diseases. Over the years, numerous studies have pointed to protein homeostasis as a crucial factor in the development of these fatal diseases. The ubiquitin–proteasome system (UPS) plays a fundamental role in maintaining protein homeostasis, being involved in protein degradation, among other cellular functions. Through a cascade of enzymatic reactions, proteins are ubiquitinated, tagged, and translocated to the proteasome to be degraded. Within the ubiquitin system, we can find three main groups of enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin–protein ligases). Only the ubiquitinated proteins with specific chain linkages (such as K48) will be degraded by the UPS. In this review, we describe the relevance of this system in NMDs, summarizing the UPS proteins that have been involved in pathological conditions and neuromuscular disorders, such as Spinal Muscular Atrophy (SMA), Charcot–Marie–Tooth disease (CMT), or Duchenne Muscular Dystrophy (DMD), among others. A better knowledge of the processes involved in the maintenance of proteostasis may pave the way for future progress in neuromuscular disorder studies and treatments.
GO Nanosheets: Promising Nano Carrier for the S29, 1-(2-Chloro-2-(4-chlorophenyl-ethyl)-N-(4-fluorobenzyl)-1H-pyrazolo[3,4-d] pyrimidin-4-amine, Therapeutic Agent in Neuroblastoma
Authors: Mardente Stefania , Aventaggiato Michele , Mari Emanuela , Francioso Antonio , Tafani Marco , Mosca Luciana , Zicari Alessandra , Malyshev Igor , Kuznetsova Larisa , Valentini Federica
Published: September 2020

Graphene oxide (GO) derivatives are reported as a valid alternative to conventional carriers of therapeutic agents, because they have a large surface area, an excellent electrical and thermal conductivity and a great capacity for selective binding of drugs and therapeutics, due to the functionalization of their surfaces, edges and sides. In this work GO nanosheets, synthesized by electrochemical exfoliation of graphite (patent N 102015000023739, Tor Vergata University), were investigated as possible carriers of an anticancer drug, the S29, an inhibitor of a cytoplasmic tyrosine kinase (c-SRC) on a neuroblastoma cell line (SK N BE 2 cells). Neuroblastoma is a heterogenous tumor whose characteristics range from spontaneous regression to aggressive phenotypes that are due to different mutations that often occur in SRC family kinases. Inhibitors of tyrosine kinases are currently investigated for their anti-tumoral effects on aggressive neuroblastomas, but their uptake in cells and pharmacokinetics needs to be improved. In this work S29 was stably conjugated with highly water-dispersible GO nanoparticles. S29/GO complex formation was induced by 1h sonication and its stability was analyzed by chromatography coupled with spectrophotometry and mass spectrometry. The synthesized composite (GO-S29) was delivered into SK N BE 2 cells and its effects on cell viability, production of reactive oxygen species (ROS) and migration were studied. The results show that the compound GO-S29 exerts anti-tumoral effects on the neuroblastoma cell line, higher than both GO and S29 do alone and that GO has an additive effect on S29.
Molecular Profile of Barrett’s Esophagus and Gastroesophageal Reflux Disease in the Development of Translational Physiological and Pharmacological Studies
Authors: Korbut Edyta , Janmaat Vincent T , Wierdak Mateusz , Hankus Jerzy , Wójcik Dagmara , Surmiak Marcin , Magierowska Katarzyna , Brzozowski Tomasz , Peppelenbosch Maikel P , Magierowski Marcin
Published: September 2020

Barrett’s esophagus (BE) is a premalignant condition caused by gastroesophageal reflux disease (GERD), where physiological squamous epithelium is replaced by columnar epithelium. Several in vivo and in vitro BE models were developed with questionable translational relevance when implemented separately. Therefore, we aimed to screen Gene Expression Omnibus 2R (GEO2R) databases to establish whether clinical BE molecular profile was comparable with animal and optimized human esophageal squamous cell lines-based in vitro models. The GEO2R tool and selected databases were used to establish human BE molecular profile. BE-specific mRNAs in human esophageal cell lines (Het-1A and EPC2) were determined after one, three and/or six-day treatment with acidified medium (pH 5.0) and/or 50 and 100 µM bile mixture (BM). Wistar rats underwent microsurgical procedures to generate esophagogastroduodenal anastomosis (EGDA) leading to BE. BE-specific genes (keratin (KRT)1, KRT4, KRT5, KRT6A, KRT13, KRT14, KRT15, KRT16, KRT23, KRT24, KRT7, KRT8, KRT18, KRT20, trefoil factor (TFF)1, TFF2, TFF3, villin (VIL)1, mucin (MUC)2, MUC3A/B, MUC5B, MUC6 and MUC13) mRNA expression was assessed by real-time PCR. Pro/anti-inflammatory factors (interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, tumor necrosis factor α, interferon γ, granulocyte-macrophage colony-stimulating factor) serum concentration was assessed by a Luminex assay. Expression profile in vivo reflected about 45% of clinical BE with accompanied inflammatory response. Six-day treatment with 100 µM BM (pH 5.0) altered gene expression in vitro reflecting in 73% human BE profile and making this the most reliable in vitro tool taking into account two tested cell lines. Our optimized and established combined in vitro and in vivo BE models can improve further physiological and pharmacological studies testing pathomechanisms and novel therapeutic targets of this disorder.
FRUITFULL Is a Repressor of Apical Hook Opening in Arabidopsis thaliana
Authors: Führer Miriam , Gaidora Angelika , Venhuizen Peter , Dobrogojski Jedrzej , Béziat Chloé , Feraru Mugurel I , Kleine-Vehn Jürgen , Kalyna Maria , Barbez Elke
Published: September 2020

Plants adjust their architecture to a constantly changing environment, requiring adaptation of differential growth. Despite their importance, molecular switches, which define growth transitions, are largely unknown. Apical hook development in dark grown Arabidopsis thaliana (A. thaliana) seedlings serves as a suitable model for differential growth transition in plants. Here, we show that the phytohormone auxin counteracts the light-induced growth transition during apical hook opening. We, subsequently, identified genes which are inversely regulated by light and auxin. We used in silico analysis of the regulatory elements in this set of genes and subsequently used natural variation in gene expression to uncover correlations between underlying transcription factors and the in silico predicted target genes. This approach uncovered that MADS box transcription factor AGAMOUS-LIKE 8 (AGL8)/FRUITFULL (FUL) modulates apical hook opening. Our data shows that transient FUL expression represses the expression of growth stimulating genes during early phases of apical hook development and therewith guards the transition to growth promotion for apical hook opening. Here, we propose a role for FUL in setting tissue identity, thereby regulating differential growth during apical hook development.