bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vitro Evaluation of the Antimicrobial and Immunomodulatory Activity of Culinary Herb Essential Oils as Potential Perioceutics
Authors: Popa Marcela , Măruțescu Luminița , Oprea Eliza , Bleotu Coralia , Kamerzan Crina , Chifiriuc Mariana Carmen , Grădișteanu Pircalabioru Grațiela
Published: July 2020

Due to their antimicrobial, immunomodulatory, antioxidant, and regenerative activities, culinary herbs have multiple medicinal uses, among which to prevent and treat oral diseases. The whole essential oils (EOs) have multiple advantages over purified components, such as a low probability to select for antimicrobial resistance, synergic effects of different components, and multi-pharmacological activities. In this study, we aimed to evaluate essential oils from Salvia officinalis (sage), Satureja hortensis (summer savory), and Anethum graveolens (dill) using an in vitro analysis of their antimicrobial activity against Gram-positive and Gram-negative bacterial strains isolated from the oral cavity of patients with periodontitis; the assays addressed both the planktonic and biofilm growth states and used culture-based approaches. Some of the tested EOs exhibited excellent bactericidal and antibiofilm activity, being active at concentrations as low as 0.08–1.36 mg/mL. Flow cytometry was used to investigate the potential mechanisms of their antibacterial activity and confirmed that the tested EOs act by permeabilizing the bacterial membrane and by inhibiting the activity of the efflux pumps. The immunomodulatory effect of the three EOs was determined by analyzing the gene expression profiles for pro- and anti-inflammatory cytokines of the THP-1 cells. The summer savory EO induced a clear proinflammatory effect, while the others did not significantly influence the cytokines profile of the tested cells. Taken together, our results indicate that summer savory EO and, to a lesser extent, sage and dill EOs could be used to inhibit bacteria involved in oral plaque formation and to reduce the expression of genes known to contribute to the inflammatory response using cell culture assessment.
Anti-Inflammatory and Antioxidant Effects of Regular Consumption of Cooked Ham Enriched with Dietary Phenolics in Diet-Induced Obese Mice
Authors: Serrano Antonio , González-Sarrías Antonio , Tomás-Barberán Francisco A. , Avellaneda Antonio , Gironés-Vilaplana Amadeo , Nieto Gema , Ros-Berruezo Gaspar
Published: July 2020

Oxidative damage and chronic inflammation have been proven as one of the major factors associated with obesity, which increases the incidence of non-communicable chronic diseases. In this sense, the development of new functional products aiming at the palliation of oxidative stress and inflammatory disruption can be a determining factor for public health as seen in previous researches. In this study, a blend of potentially bioavailable dietary phenolics was added to low sodium and low-fat cooked ham. A diet-induced obesity model in C57/BL6J mice has been used for testing the effectiveness of the phenolic blend and the new functionalized product, which bioavailability was tested by UPLC-ESI-QTOF-MS. After obesity induction, different oxidative and inflammatory biomarkers were evaluated. Results in the murine induced obesity model, demonstrate a robust statistically significant improvement in key parameters related with obesity risk in the groups feed with a phenolic-enriched diets (P) + high-fat diet (HFD) and phenolic enriched cooked ham (PECH) + HFD. In both groups there was an improvement in body composition parameters, inflammatory biomarkers and antioxidant enzymes levels. Specifically in the group feed with the phenolic enriched cooked ham (PECH + HFD) there was an improvement of total fat volume (23.08% reduction), spleen index (22.04% of reduction), plasmatic MCP-1 (18% reduction), IL-6 (38.94% reduction), IL-10 (13.28% reduction), TNF-α (21.32% reduction), gut IL-1β (10.86% reduction), gut IL-6 (13.63% reduction) and GPx (60.15% increase) and catalase (91.37% increase) enzymes. Thus, the functionalized ham could be considered an appropriate dietary polyphenol source, which might improve the oxidative and inflammatory status and could finally result in the potential decrease of the risk of certain non-communicable chronic diseases.
The Interaction between Mitochondrial Oxidative Stress and Gut Microbiota in the Cardiometabolic Consequences in Diet-Induced Obese Rats
Authors: Ortega-Hernández Adriana , Martínez-Martínez Ernesto , Gómez-Gordo Ruben , López-Andrés Natalia , Fernández-Celis Amaya , Gutiérrrez-Miranda Beatriz , Nieto María Luisa , Alarcón Teresa , Alba Claudio , Gómez-Garre Dulcenombre , Cachofeiro Victoria
Published: July 2020

Background: The objective of this study is to determine the role of mitochondrial oxidative stress in the dysbiosis associated with a high fat diet in rats. In addition, the impact of gut microbiota (GM) in the cardiometabolic consequences of diet-induced obesity in rats has been evaluated. Methods: Male Wistar rats were fed either a high fat diet (HFD) or a control (CT) one for 6 weeks. At the third week, one-half of the animals of each group were treated with the mitochondrial antioxidant MitoTempo (MT; 0.7 mgKg−1day−1 i.p). Results: Animals fed an HFD showed a lower microbiota evenness and diversity in comparison to CT rats. This dysbiosis is characterized by a decrease in Firmicutes/Bacteroidetes ratio and relevant changes at family and genera compared with the CT group. This was accompanied by a reduction in colonic mucin-secreting goblet cells. These changes were reversed by MT treatment. The abundance of certain genera could also be relevant in the metabolic consequences of obesity, as well as in the occurrence of cardiac fibrosis associated with obesity. Conclusions: These results support an interaction between GM and mitochondrial oxidative stress and its relation with development of cardiac fibrosis, suggesting new approaches in the management of obesity-related cardiometabolic consequences.
Spin-Dependent Phenomena in Semiconductor Micro-and Nanoparticles—From Fundamentals to Applications
Authors: Fomin Vladimir M. , Timoshenko Victor Yu.
Published: July 2020

The present overview of spin-dependent phenomena in nonmagnetic semiconductor microparticles (MPs) and nanoparticles (NPs) with interacting nuclear and electron spins is aimed at covering a gap between the basic properties of spin behavior in solid-state systems and a tremendous growth of the experimental results on biomedical applications of those particles. The first part of the review represents modern achievements of spin-dependent phenomena in the bulk semiconductors from the theory of optical spin orientation under indirect optical injection of carriers and spins in the bulk crystalline silicon (c-Si)—via numerous insightful findings in the realm of characterization and control through the spin polarization—to the design and verification of nuclear spin hyperpolarization in semiconductor MPs and NPs for magnetic resonance imaging (MRI) diagnostics. The second part of the review is focused on the electron spin-dependent phenomena in Si-based nanostructures, including the photosensitized generation of singlet oxygen in porous Si and design of Si NPs with unpaired electron spins as prospective contrast agents in MRI. The experimental results are analyzed by considering both the quantum mechanical approach and several phenomenological models for the spin behavior in semiconductor/molecular systems. Advancements and perspectives of the biomedical applications of spin-dependent properties of Si NPs for diagnostics and therapy of cancer are discussed.
The Value and Optimal Sizes of Energy Storage Units in Solar-Assist Cogeneration Energy Hubs
Authors: Chen Xiaotao , Si Yang , Liu Chengkui , Chen Laijun , Xue Xiaodai , Guo Yongqing , Mei Shengwei
Published: July 2020

Cogeneration is becoming increasingly popular in building and community energy systems with demands on electricity and heat, which is suitable for residential and industrial use in remote areas. This paper considers a stand-alone cogeneration energy hub. The electrical and thermal energies are produced by a combined heat and power (CHP) unit, photovoltaic panels, and a solar thermal collector. Since solar units generate no electricity and heat during the night, energy storage units which shift demands over time can promote the usage of solar energy and reduce the fuel cost of the CHP unit. This paper proposes a method to retrieve the optimal operation cost as an explicit function in the capacity parameters of electric and thermal energy storage units, reflecting the value of energy storage in the cogeneration energy hub. The capacity parameter set is divided into a collection of polyhedrons; on each polyhedron, the optimal value is an affine function in the capacity parameters. Furthermore, the optimal sizes of system components are discussed. The capacity of the CHP unit is determined from a linear program, ensuring supply adequacy; the capacities of solar generation and energy storage units are calculated based on the cost reduction and the budget. Case studies demonstrate the effectiveness of the proposed method.
Off-Design Performance Prediction of a S-CO2 Turbine Based on Field Reconstruction Using Deep-Learning Approach
Authors: Shi Dongbo , Sun Lei , Xie Yonghui
Published: July 2020

The reliable design of the supercritical carbon dioxide (S-CO2) turbine is the core of the advanced S-CO2 power generation technology. However, the traditional computational fluid dynamics (CFD) method is usually applied in the S-CO2 turbine design-optimization, which is a high computational cost, high memory requirement, and long time-consuming solver. In this research, a flexible end-to-end deep learning approach is presented for the off-design performance prediction of the S-CO2 turbine based on physical fields reconstruction. Our approach consists of three steps: firstly, an optimal design of a 60,000 rpm S-CO2 turbine is established. Secondly, five design variables for off-design analysis are selected to reconstruct the temperature and pressure fields on the blade surface through a deconvolutional neural network. Finally, the power and efficiency of the turbine is predicted by a convolutional neural network according to reconstruction fields. The results show that the prediction approach not only outperforms five classical machine learning models but also focused on the physical mechanism of turbine design. In addition, once the deep model is well-trained, the calculation with graphics processing unit (GPU)-accelerated can quickly predict the physical fields and performance. This prediction approach requires less human intervention and has the advantages of being universal, flexible, and easy to implement.
Tornado Risk Climatology in Europe
Authors: Grieser Jürgen , Haines Phil
Published: July 2020

Violent tornadoes are rare in Europe but they can have devastating effects. Damage associated with individual tornadoes can reach several billion euros and they have caused hundreds of fatalities. The tornado risk varies considerably over Europe, but so far only a few national maps of tornado risk and one Europe-wide map exist. We show several different ways to create quantitative maps of tornado occurrence rates as follows: Kernel smoothing of observations, climatologies of convective parameters from reanalysis, output of a logistic regression model to link convective parameters with observed tornadoes, orography-dependent climatologies and finally the population-bias corrected tornado occurrence rates from the Risk Management Solutions (RMS) Europe Severe Convective Storm Model. We discuss advantages and disadvantages of each approach and compare the results. While the climatologies created from the individual methods show a lot of qualitative similarities, we advocate to combine the methods to achieve the most reliable quantitative climatology.
The Spectroscopic Atomic and Molecular Databases at the Paris Observatory
Authors: Roueff Evelyne , Sahal-Bréchot Sylvie , Dimitrijević Milan S. , Moreau Nicolas , Abgrall Hervé
Published: July 2020

This paper is intended to give a comprehensive overview of the current status and developments of the Paris Observatory STARK-B, MOLAT and SESAM databases which can be interrogated thanks to interoperability tools. The STARK-B database provides shifting and broadening parameters of different atomic and ionic transitions due to impacts with charged particles (the so-called Stark broadening) for different temperatures and densities. The spectroscopic MOLAT and SESAM databases provide the wavelengths, the oscillator strengths or Einstein spontaneous emission coefficients of H 2 , CO and isotopologues molecules.
Antiplatelet Therapy for Acute Respiratory Distress Syndrome
Authors: Chen Chuan-Mu , Lu Hsiao-Ching , Tung Yu-Tang , Chen Wei
Published: July 2020

Acute respiratory distress syndrome (ARDS) is a common and devastating syndrome that contributes to serious morbidities and mortality in critically ill patients. No known pharmacologic therapy is beneficial in the treatment of ARDS, and the only effective management is through a protective lung strategy. Platelets play a crucial role in the pathogenesis of ARDS, and antiplatelet therapy may be a potential medication for ARDS. In this review, we introduce the overall pathogenesis of ARDS, and then focus on platelet-related mechanisms underlying the development of ARDS, including platelet adhesion to the injured vessel wall, platelet-leukocyte-endothelium interactions, platelet-related lipid mediators, and neutrophil extracellular traps. We further summarize antiplatelet therapy, including aspirin, glycoprotein IIb/IIIa receptor antagonists, and P2Y12 inhibitors for ARDS in experimental and clinical studies and a meta-analysis. Novel aspirin-derived agents, aspirin-triggered lipoxin, and aspirin-triggered resolvin D1 are also described here. In this narrative review, we summarize the current knowledge of the role of platelets in the pathogenesis of ARDS, and the potential benefits of antiplatelet therapy for the prevention and treatment of ARDS.
Understanding and Attitudes toward Cancer Clinical Trials among Patients with a Cancer Diagnosis: National Study through Cancer Trials Ireland
Authors: Kearns Cathriona , Feighery Ronan , Mc Caffrey John , Higgins Michaela , Smith Martina , Murphy Verena , O’Reilly Seamus , Horgan Anne M. , Walshe Janice , McDermott Ray , Morris Patrick G. , Keane Maccon , Martin Michael , Murphy Conleth , Duffy Karen , Mihai Alina , Armstrong John , O’Donnell Dearbhaile M. , Gallagher William M. , Kelly Ciara M. , Kelly Catherine M.
Published: July 2020

Cancer clinical trials (CCTs) are critical to translation and development of better therapies to improve outcomes. CCTs require adequate patient involvement but accrual rates are low globally. Several known barriers impede participation and knowing how subpopulations differ in understanding of CCTs can foster targeted approaches to aid accrual and advance cancer treatments. We conducted the first nationwide survey of 1089 patients attending 14 Irish cancer centres, assessing understanding of fundamental concepts in CCT methodology and factors that influence participation, to help tailor patient support for accrual to CCTs. Two-thirds (66%) of patients reported never having been offered a CCT and only 5% of those not offered asked to participate. Misunderstanding of clinical equipoise was prevalent. There were differences in understanding of randomisation of treatment by age (p < 0.0001), ethnicity (p = 0.035) and marital status (p = 0.013), and 58% of patients and 61% previous CCT participants thought that their doctor would ensure better treatment in CCTs. Females were slightly more risk averse. Males indicated a greater willingness to participate in novel drug trials (p = 0.001, p = 0.003). The study identified disparities in several demographics; older, widowed, living in provincial small towns and fewer years-educated patients had generally poorer understanding of CCTs, highlighting requirements for targeted support in these groups.
Lectins in Cervical Screening
Authors: Lim Anita WW , Neves André A. , Lam Shang Leen Sarah , Lao-Sirieix Pierre , Bird-Lieberman Elizabeth , Singh Naveena , Sheaff Michael , Hollingworth Tony , Brindle Kevin , Sasieni Peter
Published: July 2020

Cervical screening in low-resource settings remains an unmet need. Lectins are naturally occurring sugar-binding glycoproteins whose binding patterns change as cancer develops. Lectins discriminate between dysplasia and normal tissue in several precancerous conditions. We explored whether lectins could be developed for cervical screening via visual inspection. Discovery work comprised lectin histochemistry using a panel of candidate lectins on fixed-human cervix tissue (high-grade cervical intraepithelial neoplasia (CIN3, n = 20) or normal (n = 20)), followed by validation in a separate cohort (30 normal, 25 CIN1, 25 CIN3). Lectin binding was assessed visually according to staining intensity. To validate findings macroscopically, near-infra red fluorescence imaging was conducted on freshly-resected cervix (1 normal, 7 CIN3), incubated with topically applied fluorescently-labelled lectin. Fluorescence signal was compared for biopsies and whole specimens according to regions of interest, identified by the overlay of histopathology grids. Lectin histochemistry identified two lectins—wheat germ agglutinin (WGA) and Helix pomatia agglutinin (HPA)—with significantly decreased binding to CIN3 versus normal in both discovery and validation cohorts. Findings at the macroscopic level confirmed weaker WGA binding (lower signal intensity) in CIN3 vs. normal for biopsies (p = 0.0308) and within whole specimens (p = 0.0312). Our findings confirm proof-of-principle and indicate that WGA could potentially be developed further as a probe for high-grade cervical disease.
Economic Evaluation of Population-Based BRCA1/BRCA2 Mutation Testing across Multiple Countries and Health Systems
Authors: Manchanda Ranjit , Sun Li , Patel Shreeya , Evans Olivia , Wilschut Janneke , De Freitas Lopes Ana Carolina , Gaba Faiza , Brentnall Adam , Duffy Stephen , Cui Bin , Coelho De Soarez Patricia , Husain Zakir , Hopper John , Sadique Zia , Mukhopadhyay Asima , Yang Li , Berkhof Johannes , Legood Rosa
Published: July 2020

Clinical criteria/Family history-based BRCA testing misses a large proportion of BRCA carriers who can benefit from screening/prevention. We estimate the cost-effectiveness of population-based BRCA testing in general population women across different countries/health systems. A Markov model comparing the lifetime costs and effects of BRCA1/BRCA2 testing all general population women ≥30 years compared with clinical criteria/FH-based testing. Separate analyses are undertaken for the UK/USA/Netherlands (high-income countries/HIC), China/Brazil (upper–middle income countries/UMIC) and India (low–middle income countries/LMIC) using both health system/payer and societal perspectives. BRCA carriers undergo appropriate screening/prevention interventions to reduce breast cancer (BC) and ovarian cancer (OC) risk. Outcomes include OC, BC, and additional heart disease deaths and incremental cost-effectiveness ratio (ICER)/quality-adjusted life year (QALY). Probabilistic/one-way sensitivity analyses evaluate model uncertainty. For the base case, from a societal perspective, we found that population-based BRCA testing is cost-saving in HIC (UK-ICER = $−5639/QALY; USA-ICER = $−4018/QALY; Netherlands-ICER = $−11,433/QALY), and it appears cost-effective in UMIC (China-ICER = $18,066/QALY; Brazil-ICER = $13,579/QALY), but it is not cost-effective in LMIC (India-ICER = $23,031/QALY). From a payer perspective, population-based BRCA testing is highly cost-effective in HIC (UK-ICER = $21,191/QALY, USA-ICER = $16,552/QALY, Netherlands-ICER = $25,215/QALY), and it is cost-effective in UMIC (China-ICER = $23,485/QALY, Brazil−ICER = $20,995/QALY), but it is not cost-effective in LMIC (India-ICER = $32,217/QALY). BRCA testing costs below $172/test (ICER = $19,685/QALY), which makes it cost-effective (from a societal perspective) for LMIC/India. Population-based BRCA testing can prevent an additional 2319 to 2666 BC and 327 to 449 OC cases per million women than the current clinical strategy. Findings suggest that population-based BRCA testing for countries evaluated is extremely cost-effective across HIC/UMIC health systems, is cost-saving for HIC health systems from a societal perspective, and can prevent tens of thousands more BC/OC cases.
Immune Checkpoint Inhibitors in Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders: A Systematic Review
Authors: Kujan Omar , van Schaijik Bede , Farah Camile S.
Published: July 2020

Cancers of the oral cavity cause significant cancer-related death worldwide. While survival rates have improved in recent years, new methods of treatment are being investigated to limit disease progression and to improve outcomes, particularly in oral cavity squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMD). The emerging treatment modality of immunotherapy targets immune checkpoint molecules including PD-1 and its ligand PD-L1, CTLA-4, LAG-3, and TIM-3 to enhance the host immune response against tumours, and to limit the growth and progression of cancer cells. In this systematic review, we searched five databases for keywords pertaining to oral cancers and OPMDs, along with immune checkpoint inhibitors, in order to summarize the current status of their use and efficacy in these diseases. A total of 644 different articles were identified between 2004 and 2019, with 76 deemed suitable for inclusion in the study, providing a total of 8826 samples. Combined results show expression of PD-1 and PD-L1 in the majority of OPMD and OSCC samples, with expression correlating with increased progression and decreased survival rates. Immunotherapy agents pembrolizumab and nivolumab target PD-1 and have been shown to prolong survival rates and improve disease outcomes, especially in combination with chemotherapy or radiotherapy. Despite the equivocal nature of current evidence, there is support for the prognostic and predictive value of immune checkpoint molecules, especially PD-L1, and many studies provide support for the effective use of immune checkpoint inhibitors in the management of OSCC. Limited data is available for OPMD, therefore this should be the focus of future research.
“To Anticipate”: Neoadjuvant Therapy in Melanoma with a Focus on Predictive Biomarkers
Authors: Garutti Mattia , Buriolla Silvia , Bertoli Elisa , Vitale Maria Grazia , Rossi Ernesto , Schinzari Giovanni , Minisini Alessandro Marco , Puglisi Fabio
Published: July 2020

Despite surgical resection and adjuvant therapies, stage III melanomas still have a substantial risk of relapse. Neoadjuvant therapy is an emerging strategy that might offer superior efficacy compared to adjuvant therapy. Moreover, neoadjuvant therapy has some virtual advantages: it might allow for less demolitive surgery, permit the in vivo evaluation of drug efficacy, help tailor adjuvant treatments, and play a crucial role in innovative translational research. Herein, we review the available literature to explore the scientific background behind the neoadjuvant approach. We also discuss published clinical trials with a focus on predictive biomarkers and ongoing studies. Finally, we outline a possible framework for future neoadjuvant clinical trial development based on the International Neoadjuvant Melanoma Consortium guidelines.
Head and Neck Osteosarcoma—The Ongoing Challenge about Reconstruction and Dental Rehabilitation
Authors: Cassoni Andrea , Brauner Edoardo , Pucci Resi , Terenzi Valentina , Mangini Nicolò , Battisti Andrea , Della Monaca Marco , Ciolfi Alessandro , Laudoni Federico , Di Carlo Stefano , Valentini Valentino
Published: July 2020

Head and Neck osteosarcoma is an uncommon disease. Hitherto, the treatment is surgical resection and survival is influenced by the presence of free margins. However, the dimension of the resection may represent a hurdle for an adequate Quality of Life (QOL). Maxillofacial district is a narrow space where the function, esthetics and patient’s relational skills fit together like the gears of a clock. The functional results depend on the type of reconstruction and prosthetic rehabilitation that are both important to guarantee a good aesthetic result and finally increase the patient’s self-esteem. This study aims to report our experience about head and neck (HN) osteosarcoma focusing the attention on reconstructive and dental-rehabilitative problems. It is a retrospective study all patients were surgically treated in our department. Subjects with histological diagnosis of HN osteosarcoma, treated between 2005 and 2017 were included. The demographic characteristics, surgical treatment, eventually secondary reconstruction and prosthetic rehabilitation, performed in the same department, have been collected. The QOL was assessed through the EORTC QLQ-H&N35 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35) questionnaire. Fifteen patients were enrolled, eight received a free flap microsurgical reconstruction. Dental rehabilitation was performed in five cases and a mobile prosthesis was always delivered. Eighteen implants were inserted in fibula bones for three patients; highly porous implants were used.
New CXCR4 Antagonist Peptide R (Pep R) Improves Standard Therapy in Colorectal Cancer
Authors: D’Alterio Crescenzo , Zannetti Antonella , Trotta Anna Maria , Ieranò Caterina , Napolitano Maria , Rea Giuseppina , Greco Adelaide , Maiolino Piera , Albanese Sandra , Scognamiglio Giosuè , Tatangelo Fabiana , Tafuto Salvatore , Portella Luigi , Santagata Sara , Nasti Guglielmo , Ottaiano Alessandro , Pacelli Roberto , Delrio Paolo , Botti Gerardo , Scala Stefania
Published: July 2020

The chemokine receptor CXCR4 is overexpressed and functional in colorectal cancer. To investigate the role of CXCR4 antagonism in potentiating colon cancer standard therapy, the new peptide CXCR4 antagonist Peptide R (Pep R) was employed. Human colon cancer HCT116 xenograft-bearing mice were treated with chemotherapeutic agents (CT) 5-Fluorouracil (5FU) and oxaliplatin (OX) or 5FU and radio chemotherapy (RT-CT) in the presence of Pep R. After two weeks, CT plus Pep R reduced by 4-fold the relative tumor volume (RTV) as compared to 2- and 1.6-fold reductions induced, respectively, by CT and Pep R. In vitro Pep R addition to CT/RT-CT impaired HCT116 cell growth and further reduced HCT116 and HT29 clonal capability. Thus, the hypothesis that Pep R could target the epithelial mesenchyme transition (EMT) process was evaluated. While CT decreased ECAD and increased ZEB-1 and CD90 expression, the addition of Pep R restored the pretreatment expression. In HCT116 and HT29 cells, CT/RT-CT induced a population of CD133+CXCR4+ cells, supposedly a stem-resistant cancer cell population, while Pep R reduced it. Taken together, the results showed that targeting CXCR4 ameliorates the effect of treatment in colon cancer through inhibition of cell growth and reversal of EMT treatment-induced markers, supporting further clinical studies.
Postoperative Morbidity and Failure to Rescue in Surgery for Gastric Cancer: A Single Center Retrospective Cohort Study of 1107 Patients from 1972 to 2014
Authors: Galata Christian , Ronellenfitsch Ulrich , Blank Susanne , Reißfelder Christoph , Hardt Julia
Published: July 2020

Background: The aim of this study was to evaluate postoperative morbidity, mortality, and failure to rescue following complications after radical resection for gastric cancer. Methods: A retrospective analysis of the surgical database of patients with gastroesophageal malignancies at our institution was performed. All consecutive patients undergoing R0 gastrectomy for pT1–4 M0 gastric adenocarcinoma between October 1972 and February 2014 were eligible for this analysis. Patients were divided into two groups according to the date of surgery: an early cohort operated on from 1972–1992 and a late cohort operated on from 1993–2014. Both groups were compared regarding patient characteristics and surgical outcomes. Results: A total of 1107 patients were included. Postoperative mortality was more than twice as high in patients operated on from 1972–1992 compared to patients operated on from 1993–2014 (6.8% vs. 3.2%, p = 0.017). Between both groups, no significant difference in failure to rescue after major surgical complications was observed (20.8% vs. 20.5%, p = 1.000). Failure to rescue after other surgical and non-surgical complications was 37.8% in the early cohort compared to 3.2% in the late cohort (p < 0.001). Non-surgical complications accounted for 71.2% of lethal complications between 1972 and 1992, but only for 18.2% of lethal complications between 1993 and 2014 (p = 0.002). Conclusion: In the course of four decades, postoperative mortality after radical resection for gastric cancer has more than halved. In this cohort, the reason for this decrease was reduced mortality due to non-surgical complications. Major surgical morbidity after gastrectomy remains challenging.
CUX1—Transcriptional Master Regulator of Tumor Progression in Pancreatic Neuroendocrine Tumors
Authors: Krug Sebastian , Weissbach Julia , Blank Annika , Perren Aurel , Haybaeck Johannes , Fendrich Volker , Rinke Anja , Gress Thomas Mathias , Rosendahl Jonas , Michl Patrick
Published: July 2020

Recently, we identified the homeodomain transcription factor Cut homeobox 1 (CUX1) as mediator of tumour de-differentiation and metastatic behaviour in human insulinoma patients. In insulinomas, CUX1 enhanced tumour progression by stimulating proliferation and angiogenesis in vitro and in vivo. In patients with non-functional pancreatic neuroendocrine tumours (PanNET), however, the impact of CUX1 remains to be elucidated. Here, we analysed CUX1 expression in two large independent cohorts (n = 43 and n = 141 tissues) of non-functional treatment-naïve and pre-treated PanNET patients, as well as in the RIP1Tag2 mouse model of pancreatic neuroendocrine tumours. To further assess the functional role of CUX1, expression profiling of DNA damage-, proliferation- and apoptosis-associated genes was performed in CUX1-overexpressing Bon-1 cells. Validation of differentially regulated genes was performed in Bon-1 and QGP1 cells with knock-down and overexpression strategies. CUX1 expression assessed by a predefined immunoreactivity score (IRS) was significantly associated with shorter progression-free survival (PFS) of pre-treated PanNET patients (23 vs. 8 months; p = 0.005). In treatment-naïve patients, CUX1 was negatively correlated with grading and recurrence-free survival (mRFS of 39 versus 8 months; p = 0.022). In both groups, high CUX1 levels indicated a metastatic phenotype. Functionally, CUX1 upregulated expression of caspases and death associated protein kinase 1 (DAPK1), known as mediators of tumour progression and resistance to cytotoxic drugs. This was also confirmed in both cell lines and human tissues. In the RIP1Tag2 mouse model, CUX1 expression was associated with advanced tumour stage and resistance to apoptosis. In summary, we identified the transcription factor CUX1 as mediator of tumour progression in non-functional PanNET in vitro and in vivo, indicating that the CUX1-dependent signalling network is a promising target for future therapeutic intervention.
The Biological Context of C-Reactive Protein as a Prognostic Marker in Renal Cell Carcinoma: Studies on the Acute Phase Cytokine Profile
Authors: Aarstad Helene Hersvik , Guðbrandsdottir Gigja , Hjelle Karin M. , Bostad Leif , Bruserud Øystein , Tvedt Tor Henrik Anderson , Beisland Christian
Published: July 2020

High serum levels of the acute phase protein C-reactive protein (CRP) are associated with an adverse prognosis in renal cancer. The acute phase reaction is cytokine-driven and includes a wide range of inflammatory mediators. This overall profile of the response depends on the inducing event and can also differ between patients. We investigated an extended acute phase cytokine profile for 97 renal cancer patients. Initial studies showed that the serum CRP levels had an expected prognostic association together with tumor size, stage, nuclear grading, and Leibovich score. Interleukin (IL)6 family cytokines, IL1 subfamily mediators, and tumor necrosis factor (TNF)α can all be drivers of the acute phase response. Initial studies suggested that serum IL33Rα (the soluble IL33 receptor α chain) levels were also associated with prognosis, although the impact of IL33Rα is dependent on the overall cytokine profile, including seven IL6 family members (IL6, IL6Rα, gp130, IL27, IL31, CNTF, and OSM), two IL1 subfamily members (IL1RA and IL33Rα), and TNFα. We identified a patient subset characterized by particularly high levels of IL6, IL33Rα, and TNFα alongside an adverse prognosis. Thus, the acute phase cytokine reaction differs between renal cancer patients, and differences in the acute phase cytokine profile are associated with prognosis.
Non-Conventional Treatments for Conventional Chondrosarcoma
Authors: Monga Varun , Mani Hariharasudan , Hirbe Angela , Milhem Mohammed
Published: July 2020

Chondrosarcomas are the most common malignant tumors of the cartilage, are seen predominantly in adults, and have varied clinical behavior. The majority of them affect the medullary canal of long bones and pelvic bones. The prognosis of chondrosarcoma is closely related to histological grading; however, the grading is subject to interobserver variability. Conventional chondrosarcomas are overall considered to be chemotherapy- and radiation-resistant, resulting in limited treatment options. The majority of advanced conventional chondrosarcomas are treated with chemotherapy without any survival benefit. Recent studies have evaluated molecular genetic findings which have improved the understanding of chondrosarcoma biology. Newer therapeutic targets are desperately needed. In this review article, we explore ongoing clinical trials evaluating novel ways of treating advanced conventional chondrosarcoma.
The Multidrug Resistance-Reversing Activity of a Novel Antimicrobial Peptide
Authors: Teng Qiu-Xu , Luo Xiaofang , Lei Zi-Ning , Wang Jing-Quan , Wurpel John , Qin Zuodong , Yang Dong-Hua
Published: July 2020

The overexpression of ATP-binding cassette (ABC) transporters is a common cause of multidrug resistance (MDR) in cancers. The intracellular drug concentration of cancer cells can be decreased relative to their normal cell counterparts due to increased expression of ABC transporters acting as efflux pumps of anticancer drugs. Over the past decades, antimicrobial peptides have been investigated as a new generation of anticancer drugs and some of them were reported to have interactions with ABC transporters. In this article, we investigated several novel antimicrobial peptides to see if they could sensitize ABCB1-overexpressing cells to the anticancer drugs paclitaxel and doxorubicin, which are transported by ABCB1. It was found that peptide XH-14C increased the intracellular accumulation of ABCB1 substrate paclitaxel, which demonstrated that XH-14C could reverse ABCB1-mediated MDR. Furthermore, XH-14C could stimulate the ATPase activity of ABCB1 and the molecular dynamic simulation revealed a stable binding pose of XH-14C-ABCB1 complex. There was no change on the expression level or the location of ABCB1 transporter with the treatment of XH-14C. Our results suggest that XH-14C in combination with conventional anticancer agents could be used as a novel strategy for cancer treatment.
The Emerging Role of Extracellular Vesicles in the Glioma Microenvironment: Biogenesis and Clinical Relevance
Authors: Balakrishnan Anjali , Roy Sabrina , Fleming Taylor , Leong Hon S. , Schuurmans Carol
Published: July 2020

Gliomas are a diverse group of brain tumors comprised of malignant cells (‘tumor’ cells) and non-malignant ‘normal’ cells, including neural (neurons, glia), inflammatory (microglia, macrophage) and vascular cells. Tumor heterogeneity arises in part because, within the glioma mass, both ‘tumor’ and ‘normal’ cells secrete factors that form a unique microenvironment to influence tumor progression. Extracellular vesicles (EVs) are critical mediators of intercellular communication between immediate cellular neighbors and distantly located cells in healthy tissues/organs and in tumors, including gliomas. EVs mediate cell–cell signaling as carriers of nucleic acid, lipid and protein cargo, and their content is unique to cell types and physiological states. EVs secreted by non-malignant neural cells have important physiological roles in the healthy brain, which can be altered or co-opted to promote tumor progression and metastasis, acting in combination with glioma-secreted EVs. The cell-type specificity of EV content means that ‘vesiculome’ data can potentially be used to trace the cell of origin. EVs may also serve as biomarkers to be exploited for disease diagnosis and to assess therapeutic progress. In this review, we discuss how EVs mediate intercellular communication in glioma, and their potential role as biomarkers and readouts of a therapeutic response.
Combined C-Reactive Protein and Novel Inflammatory Parameters as a Predictor in Cancer—What Can We Learn from the Hematological Experience?
Authors: Bruserud Øystein , Aarstad Helene Hersvik , Tvedt Tor Henrik Anderson
Published: July 2020

The acute phase reaction is a systemic response to acute or chronic inflammation. The serum level of C-reactive protein (CRP) is the only acute phase biomarker widely used in routine clinical practice, including its uses for prognostics and therapy monitoring in cancer patients. Although Interleukin 6 (IL6) is a main trigger of the acute phase reactions, a series of acute phase reactants can contribute (e.g., other members in IL6 family or IL1 subfamily, and tumor necrosis factor α). However, the experience from patients receiving intensive chemotherapy for hematological malignancies has shown that, besides CRP, other biomarkers (e.g., cytokines, soluble cytokine receptors, soluble adhesion molecules) also have altered systemic levels as a part of the acute phase reaction in these immunocompromised patients. Furthermore, CRP and white blood cell counts can serve as a dual prognostic predictor in solid tumors and hematological malignancies. Recent studies also suggest that biomarker profiles as well as alternative inflammatory mediators should be further developed to optimize the predictive utility in cancer patients. Finally, the experience from allogeneic stem cell transplantation suggests that selected acute phase reactants together with specific markers of organ damages are useful for predicting or diagnosing graft versus host disease. Acute phase proteins may also be useful to identify patients (at risk of) developing severe immune-mediated toxicity after anticancer immunotherapy. To conclude, future studies of acute phase predictors in human malignancies should not only investigate the conventional inflammatory mediators (e.g., CRP, white blood cell counts) but also combinations of novel inflammatory parameters with specific markers of organ damages.
Effectiveness and Safety of Nivolumab in Child–Pugh B Patients with Hepatocellular Carcinoma: A Real-World Cohort Study
Authors: Choi Won-Mook , Lee Danbi , Shim Ju Hyun , Kim Kang Mo , Lim Young-Suk , Lee Han Chu , Yoo Changhoon , Park Sook Ryun , Ryu Min-Hee , Ryoo Baek-Yeol , Choi Jonggi
Published: July 2020

Nivolumab has shown durable response and safety in patients with hepatocellular carcinoma (HCC) in previous trials. However, real-world data of nivolumab in HCC patients, especially those with Child–Pugh class B, are limited. To investigate the effectiveness and safety of nivolumab in a real-world cohort of patients with advanced HCC, we retrospectively evaluated 203 patients with HCC who were treated with nivolumab between July 2017 and February 2019. Of 203 patients, 132 patients were classified as Child–Pugh class A and 71 patients were Child–Pugh class B. Objective response rate was lower in patients with Child–Pugh class B than A (2.8% vs. 15.9%; p = 0.010). Child–Pugh class B was an independent negative predictor for objective response. Median overall survival was shorter in Child–Pugh B patients (11.3 vs. 42.9 weeks; adjusted hazard ratio [AHR], 2.10; p < 0.001). In Child–Pugh B patients, overall survival of patients with Child–Pugh score of 8 or 9 was worse than patients with Child–Pugh score of 7 (7.4 vs. 15.3 weeks; AHR, 1.93; p < 0.020). In conclusion, considering the unsatisfactory response in Child–Pugh B patients, nivolumab may not be used in unselected Child–Pugh B patients. Further studies are needed in this patient population.
Inhibition of Methyltransferase DOT1L Sensitizes to Sorafenib Treatment AML Cells Irrespective of MLL-Rearrangements: A Novel Therapeutic Strategy for Pediatric AML
Authors: Lonetti Annalisa , Indio Valentina , Laginestra Maria Antonella , Tarantino Giuseppe , Chiarini Francesca , Astolfi Annalisa , Bertuccio Salvatore N. , Martelli Alberto M. , Locatelli Franco , Pession Andrea , Masetti Riccardo
Published: July 2020

Pediatric acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis for which there are few effective targeted approaches, despite the numerous genetic alterations, including MLL gene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting the proliferation of MLL-r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatric MLL-r leukemic patients. However, modest clinical effects have been observed. Recent studies have reported that additional leukemia subtypes lacking MLL-r are sensitive to DOT1L inhibition. Here, we report that targeting DOT1L with Pinometostat sensitizes pediatric AML cells to further treatment with the multi-kinase inhibitor Sorafenib, irrespectively of MLL-r. DOT1L pharmacologic inhibition induces AML cell differentiation and modulates the expression of genes with relevant roles in cancer development. Such modifications in the transcriptional program increase the apoptosis and growth suppression of both AML cell lines and primary pediatric AML cells with diverse genotypes. Through ChIP-seq analysis, we identified the genes regulated by DOT1L irrespective of MLL-r, including the Sorafenib target BRAF, providing mechanistic insights into the drug combination activity. Our results highlight a novel therapeutic strategy for pediatric AML patients.
Integration of Serum Metabolomics into Clinical Assessment to Improve Outcome Prediction of Metastatic Soft Tissue Sarcoma Patients Treated with Trabectedin
Authors: Miolo Gianmaria , Di Gregorio Emanuela , Saorin Asia , Lombardi Davide , Scalone Simona , Buonadonna Angela , Steffan Agostino , Corona Giuseppe
Published: July 2020

Soft tissue sarcomas (STS) are a group of rare and heterogeneous cancers with few diagnostic or prognostic biomarkers. This metabolomics study aimed to identify new serum prognostic biomarkers to improve the prediction of overall survival in patients with metastatic STS. The study enrolled 24 patients treated with the same trabectedin regimen. The baseline serum metabolomics profile, targeted to 68 metabolites encompassing amino acids and bile acids pathways, was quantified by liquid chromatography-tandem mass spectrometry. Correlations between individual metabolomics profiles and overall survival were examined and a risk model to predict survival was built by Cox multivariate regression. The median overall survival of the studied patients was 13.0 months (95% CI, 5.6–23.5). Among all the metabolites investigated, only citrulline and histidine correlated significantly with overall survival. The best Cox risk prediction model obtained integrating metabolomics and clinical data, included citrulline, hemoglobin and patients’ performance status score. It allowed to distinguish patients into a high-risk group with a low median overall survival of 2.1 months and a low- to moderate-risk group with a median overall survival of 19.1 months (p < 0.0001). The results of this metabolomics translation study indicate that citrulline, an amino acid belonging to the arginine metabolism, represents an important metabolic signature that may contribute to explain the high inter-patients overall survival variability of STS patients. The risk prediction model based on baseline serum citrulline, hemoglobin and performance status may represent a new prognostic tool for the early classification of patients with metastatic STS, according to their overall survival expectancy.
Impact of Eukaryotic Translation Initiation Factors on Breast Cancer: Still Much to Investigate
Authors: Chen Qin , Yang Bo , Nass Norbert , Schatz Christoph , Haybaeck Johannes
Published: July 2020

Breast carcinoma (BC) remains one of the most serious health problems. It is a heterogeneous entity, and mainly classified according to receptor status for estrogen (ER), progesterone (PR) and egf (HER2/Neu), as well as the proliferation marker ki67. Gene expression in eukaryotes is regulated at the level of both gene transcription and translation, where eukaryotic initiation factors (eIFs) are key regulators of protein biosynthesis. Aberrant translation results in an altered cellular proteome, and this clearly effects cell growth supporting tumorigenesis. The relationship between various eIFs and BC entities, as well as the related regulatory mechanisms, has meanwhile become a focus of scientific interest. Here, we give an overview on the current research state of eIF function, focusing on BC.
Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis
Authors: Tomko Andrea M. , Whynot Erin G. , Ellis Lee D. , Dupré Denis J.
Published: July 2020

In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings. Cannabinoids have been suggested and shown to be effective in the treatment of various conditions. In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis. However, the therapeutic use of cannabinoids is currently limited to the treatment of symptoms and pain associated with chemotherapy, while their potential use as cytotoxic drugs in chemotherapy still requires validation in patients. Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions. The potential anti-cancer effects of cannabinoids, terpenes and flavonoids, present in cannabis, are explored in this literature review.
Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders
Authors: Paul Sujay , Bravo Vázquez Luis Alberto , Pérez Uribe Samantha , Roxana Reyes-Pérez Paula , Sharma Ashutosh
Published: July 2020

MicroRNAs (miRNAs) are a key gene regulator and play essential roles in several biological and pathological mechanisms in the human system. In recent years, plenty of miRNAs have been identified to be involved in the development of neurodegenerative disorders (NDDs), thus making them an attractive option for therapeutic approaches. Hence, in this review, we provide an overview of the current research of miRNA-based therapeutics for a selected set of NDDs, either for their high prevalence or lethality, such as Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic Lateral Sclerosis, Friedreich’s Ataxia, Spinal Muscular Atrophy, and Frontotemporal Dementia. We also discuss the relevant delivery techniques, pertinent outcomes, their limitations, and their potential to become a new generation of human therapeutic drugs in the near future.