bluuebunny/crossref_metadata_2025 huggingface dataset:
The Antioxidant Role of a Taurine-Enriched Diet in Combating the Immunotoxic and Inflammatory Effects of Pyrethroids and/or Carbamates in Oreochromis niloticus
Authors: Abdel-Rahman Mohamed Amany , Abdel Rahman Afaf N. , Salem Gamal A. , Deib Maha M.El , Nassan Mohamed A. , Rhouma Nasreddin R. , Khater Safaa I.
Published: May 2021

Indiscriminate use of insecticides is a major concern due to its ubiquitous occurrence and potential toxicity to aquatic animals. This study investigated the adverse effects of lambda-cyhalothrin (LCT; C23H19ClF3NO3) and methomyl (MTM; C5H10N2O2S) on immune system modulations and growth performance of juvenile fishes. The supportive role of a taurine (TUR; C2H7NO3S)-supplemented diet was also evaluated. Juvenile O. niloticus fishes were exposed to LCT (0.079 µg/L), MTM (20.39 µg/L), or both in water and were fed on a basal diet only or taurine-supplemented basal diet. Exposure to LCT and MTM retarded growth and increased mortality rate. LCT and MTM reduced antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase) and innate and humoral immunity but upregulated interleukin and chemokine expressions. Moreover, exposure to LCT and MTM elevated 8-OHdG levels and increased the mortality of Oreochromis niloticus after the experimental bacterial challenge. The TUR-enriched diet enhanced antioxidant enzymes and acted as a growth promoter and anti-inflammatory agent. TUR can modify innate and adaptive immune responses. Furthermore, TUR supplementation is a beneficial additive candidate for mitigating LCT and MTM toxicities mixed with O. niloticus aquafeed.
Genetic Analysis of Major Production and Reproduction Traits of Korean Duroc, Landrace and Yorkshire Pigs
Authors: Alam Mahboob , Chang Hyuk-Kee , Lee Seung-Soo , Choi Tae-Jeong
Published: May 2021

The study aimed to investigate the genetic parameters of the production and reproduction traits of Korean Duroc, Landrace, and Yorkshire pigs. Three production traits, namely average daily gain (ADG), age at 105 kg body weight (DAYS105) and backfat thickness (BFT), and three reproduction traits, namely age at first farrowing (AFF), total number of piglets born (TNB) and number of piglets born alive (NBA), were analyzed. The reproduction dataset was based on first-parity gilts only. However, the production dataset comprised pigs of both sexes. Genetic parameters were estimated from individual datasets using a multiple-trait animal model in AIREMLF90 software. The heritability values of ADG, DAYS105 and BFT were 0.34–0.36, 0.41–0.44 and 0.38–0.48, respectively, across breeds. Heritability values for AFF, TNB and NBA were 0.07–0.14, 0.09–0.11 and 0.09–0.10, respectively. Strong genetic correlations existed between ADG and DAYS105 (−0.97) and between TNB and NBA (0.90 to 0.96). In line with breeding goals, all productive traits in Duroc pigs, and all reproduction traits except AFF in Landrace and Yorkshire pigs, also showed noticeable improvements in recent years. In conclusion, we believe that our findings on economic traits would greatly assist future pig breeding decisions in Korea.
Exploring the One Health Perspective in Sweden’s Policies for Containing Antibiotic Resistance
Authors: Eriksen Jaran , Björkman Ingeborg , Röing Marta , Essack Sabiha Y. , Stålsby Lundborg Cecilia
Published: May 2021

Antibiotic resistance is considered to be a major threat to global health. The main driver of antibiotic resistance is antibiotic use. Antibiotics are used in humans, animals, and food production and are released into the environment. Therefore, it is imperative to include all relevant sectors in the work to contain antibiotic resistance, i.e., a One Health approach. In this study, we aimed to describe and analyse Sweden’s policies related to containing antibiotic resistance, from a One Health perspective. Twenty-three key policy documents related to containment of antibiotic resistance in Sweden were selected and analysed according to the policy triangle framework. Sweden started early to introduce policies for containing antibiotic resistance from an international perspective. Systematic measures against antibiotic resistance were implemented in the 1980s, strengthened by the creation of Strama in 1995. The policies involve agencies and organisations from human and veterinary medicine, the environment, and food production. All actors have clear responsibilities in the work to contain antibiotic resistance with a focus on international collaboration, research, and innovation. Sweden aims to be a model country in the work to contain antibiotic resistance and has a strategy for achieving this through international cooperation through various fora, such as the EU, the UN system, and OECD.
Point Prevalence Survey of Antimicrobial Use in a Malaysian Tertiary Care University Hospital
Authors: Jamaluddin Nurul Adilla Hayat , Periyasamy Petrick , Lau Chee Lan , Ponnampalavanar Sasheela , Lai Pauline Siew Mei , Ramli Ramliza , Tan Toh Leong , Kori Najma , Yin Mei Kuen , Azman Nur Jannah , James Rodney , Thursky Karin , Naina-Mohamed Isa
Published: May 2021

Antimicrobial resistance remains a significant public health issue, and to a greater extent, caused by the misuse of antimicrobials. Monitoring and benchmarking antimicrobial use is critical for the antimicrobial stewardship team to enhance prudent use of antimicrobial and curb antimicrobial resistance in healthcare settings. Employing a comprehensive and established tool, this study investigated the trends and compliance of antimicrobial prescribing in a tertiary care teaching hospital in Malaysia to identify potential target areas for quality improvement. A point prevalence survey method following the National Antimicrobial Prescribing Survey (NAPS) was used to collect detailed data on antimicrobial prescribing and assessed a set of quality indicators associated with antimicrobial use. The paper-based survey was conducted across 37 adult wards, which included all adult in-patients on the day of the survey to form the study population. Of 478 patients surveyed, 234 (49%) patients received at least one antimicrobial agent, with 357 antimicrobial prescriptions. The highest prevalence of antimicrobial use was within the ICU (80%). Agents used were mainly amoxicillin/β-lactamase inhibitor (14.8%), piperacillin/β-lactamase inhibitor (10.6%) and third-generation cephalosporin (ceftriaxone, 9.5%). Intravenous administration was ordered in 62.7% of prescriptions. Many antimicrobials were prescribed empirically (65.5%) and commonly prescribed for pneumonia (19.6%). The indications for antimicrobials were documented in the patients’ notes for 80% of the prescriptions; however, the rate of review/stop date recorded must be improved (33.3%). One-half of surgical antimicrobial prophylaxis was administered for more than 24 h. From 280 assessable prescriptions, 141 (50.4%) were compliant with guidelines. Treating specialties, administration route, class of antimicrobial, and the number of prescriptions per patient were contributing factors associated with compliance. On multivariate analysis, administering non-oral routes of antimicrobial administration, and single antimicrobial prescription prescribed per patient was independently associated with non-compliance. NAPS can produce robust baseline information and identifying targets for improvement in antimicrobial prescribing in reference to current AMS initiatives within the tertiary care teaching hospital. The findings underscore the necessity to expand the AMS efforts towards reinforcing compliance, documentation, improving surgical prophylaxis prescribing practices, and updating local antibiotic guidelines.
Spinach Methanolic Extract Attenuates the Retinal Degeneration in Diabetic Rats
Authors: Bautista-Pérez Rocio , Cano-Martínez Agustina , Gutiérrez-Velázquez Elisa , Martínez-Rosas Martín , Pérez-Gutiérrez Rosa M. , Jiménez-Gómez Francisco , Flores-Estrada Javier
Published: May 2021

It has been suggested that spinach methanolic extract (SME) inhibits the formation of advanced glycation end products (AGEs), which are increased during diabetes progression, so it is important to know if SME has beneficial effects in the diabetic retina. In this study, in vitro assays showed that SME inhibits glycation, carbonyl groups formation, and reduced-thiol groups depletion in bovine serum albumin incubated either reducing sugars or methylglyoxal. The SME effect in retinas of streptozotocin-induced diabetic rats (STZ) was also studied (n = 10) in the normoglycemic group, STZ, STZ rats treated with SME, and STZ rats treated with aminoguanidine (anti-AGEs reference group) during 12 weeks. The retina was sectioned and immunostained for Nε-carboxymethyl lysine (CML), receptor RAGE, NADPH-Nox4, inducible nitric oxide synthase (iNOS), 3-nitrotyrosine (NT), nuclear NF-κB, vascular endothelial growth factor (VEGF), glial fibrillary acidic protein (GFAP), S100B protein, and TUNEL assay. Lipid peroxidation was determined in the whole retina by malondialdehyde (MDA) levels. The results showed that in the diabetic retina, SME reduced the CML-RAGE co-localization, oxidative stress (NOX4, iNOS, NT, MDA), inflammation (NF-κB, VEGF, S100B, GFAP), and apoptosis (p < 0.05). Therefore, SME could attenuate the retinal degeneration by inhibition of CML–RAGE interaction.
Hidrox® and Endometriosis: Biochemical Evaluation of Oxidative Stress and Pain
Authors: Cordaro Marika , Trovato Salinaro Angela , Siracusa Rosalba , D'Amico Ramona , Impellizzeri Daniela , Scuto Maria , Ontario Maria Laura , Interdonato Livia , Crea Roberto , Fusco Roberta , Cuzzocrea Salvatore , Di Paola Rosanna , Calabrese Vittorio
Published: May 2021

Endometriosis is a gynecological and painful condition affecting women of reproductive age. It is characterized by dysfunctional endometrium-like implants outside of the uterine cavity. The purpose of this study was to evaluate the effects of Hidrox®, an aqueous extract of olive pulp containing hydroxytyrosol, on endometriotic lesions associated with pro-oxidative alterations and pain-like behaviors. Endometriosis was induced by intraperitoneal injection of uterine fragments, and Hidrox® was administered daily. At the end of the 14-day treatment, behavioral alterations were assessed and hippocampal tissues were collected. Laparotomy was performed, and the endometrial implants were harvested for histological and biochemical analysis. Hidrox® treatment reduced endometriotic implant area, diameter and volumes. Vehicle-treated rats showed lesional fibrosis, epithelial–mesenchymal transition and fibroblast–myofibroblast transdifferentiation, angiogenesis and pro-oxidative alterations in the peritoneal cavity. Hidrox® treatment reduced the aniline blue-stained area, α-smooth muscle actin (α-sma) and CD34 positive expressions. Moreover, it reduced mast cell recruitment into the lesions, myeloperoxidase activity and lipid peroxidation and increased superoxide dismutase (SOD) activity and glutathione levels in the endometrial explants. In the peritoneal fluid, Hidrox® treatment reduced interleukin (IL)-1β, IL2, IL6, tumor necrosis factor-α (TNF-α) and vascular endothelial grow factor (VEGF) levels increased by the disease. Hidrox® administration also reduced peripheral and visceral sensibility as shown by the behavioral tests (open field test, hot plate test, elevated plus maze test and acetic-acid-induced abdominal contractions). Animals treated with Hidrox® also showed reduced blood–brain barrier permeability and mast cell infiltration in the hippocampus, as well as astrocyte and microglia activation and brain oxidative status restoring brain-derived neurotrophic factor (BDNF) protein expression and increasing Nuclear factor erythroid 2-related factor 2 (Nfr2) nuclear translocation. In conclusion, Hidrox® displayed potential ameliorative effects on endometriotic implants and related pain-induced behaviors due to its potent antioxidative properties.
Understanding Balance Control in the Context of Riding a Personal Mobility Device
Authors: Park Donggun , Lee Yushin , Yun Myunghwan
Published: May 2021

This study aimed at investigating the human ability to shift weight and maintain balance when driving a self-balancing personal mobility device (SPMD). In the experiment, participants performed a weight-shifting task, which is moving the center of pressure (COP) toward 15 targets comprising three distances and five directions. They were also given a maintaining balance task, which is holding the COP as close as possible to the same targets. The results showed that during the weight-shifting task, the target distance significantly increased the movement time and decreased the movement fluency and accuracy. In the balance control task, while the target distance significantly affected the postural stability, the target direction had no major effect, although there were interaction effects with the direction on the postural sway along the medial–lateral direction. It is expected that this study can help in understanding the balance control of humans and design safer SPMDs.
Efficacy of Joint Mobilization Apparatus in Treating Frozen Shoulder
Authors: Wu Cheng-Ju , Ting Hua , Lin Chuan-Chao , Chen Yi-Chung , Chao Ming-Che , Lee Shin-Da
Published: May 2021

This purpose of this study is to investigate the efficacy of shoulder joint mobilization generated by an innovative servomotor joint mobilization apparatus that was developed in this research for patients suffering from frozen shoulder. Forty-eight patients with frozen shoulder were recruited and stratified randomly assigned into one of two groups: joint mobilization apparatus (posterior and inferior gliding, 80 N, 5 Hz, 30 min) combined with regular therapy (experimental group; EG) versus a regular therapy alone group (control group; CG), three times a week for eight weeks. The visual analogue scale (VAS) for pain and shoulder range of motion (ROM) were measured before, during, and the end of the treatment. Results showed that the shoulder flexion, abduction, internal rotation, and external rotation of the EG improved by 36%, 51%, 81%, and 88%, respectively, while VAS pain scores decreased by 62% when compared with the baseline. Furthermore, the shoulder flexion, abduction, internal rotation, external rotation, and pain score of the EG was 11%, 25%, 41%, 24%, and 34% better than those of the CG, respectively. No complaint as well as no side effects were found during or after usage of the joint mobilization apparatus in EG. This study suggests that the joint mobilization apparatus operated by a very small amount of professional manpower and combined with physical therapy further improves shoulder ROM and pain in patients with frozen shoulder compared to regular physical therapy alone and could be one of the new therapeutic regimens in the future.
An Integrated Model of Production, Maintenance, and Quality Control with Statistical Process Control Chart of a Supply Chain
Authors: Hajej Zied , Nyoungue Aime C. , Abubakar Aminu S. , Mohamed Ali Kammoun
Published: May 2021

This article investigates integrated maintenance, production, and product quality control policy for a supply chain consisting of a single machine producing only one type of product, a main storage warehouse, and multi-purchases warehouses. The variation of the production rate and its use over time impact the manufacturing system’s degradation degree. Hence, the machine is subject to a random failure that directly affects the quality of the products. The goal of this study is to establish an optimal production and delivery planning with inventory management considering the production, holding, and delivery costs, and then an appropriate maintenance strategy, considering the influence of the production rate on the system degradation. Also, we provide a quality control policy to reduce the proportion of non-compliant products by using the statistical process control chart to forecast production. Forecasting the production aims to satisfy the varying demands during a finite horizon under service and quality levels. Numerical examples are presented to justify the effectiveness of the suggested strategy.
Effects of Water-to-Cement Ratios on the Properties of Magnesium Potassium Phosphate Cement Prepared with Lithium-Extracted Magnesium Residue
Authors: Zheng Weixin , Dong Jinmei , Wen Jing , Chang Chenggong , Xiao Xueying
Published: May 2021

Salt lake magnesium phosphate cement (SLMKPC) was prepared by mixing potassium dihydrogen phosphate (KH2PO4) with lithium-extracted magnesium residue (MR). The hydration-hardening process and the variation in the phase composition and microstructure of hydration products with the change of the water-cement-ratio (W/C) were studied by measuring the setting time, hydration exothermic temperature, and compressive strength of the hardened slurry. It was found that W/C ratios had significant effects on the setting time, hydration exothermal temperature curve, and compressive strength of SLMKPC. With the increase of W/C, the setting time was prolonged significantly. The exothermic hydration peak temperature first increased and then decreased, and the number of exothermic peaks gradually changed from one to two. The optimal compressive strength was obtained when W/C = 0.2–0.3. Hydration products changed significantly with the increase of W/C, the MgKPO4·6H2O (MKP) in the matrix was more stable when W/C = 0.2 and 0.3 than when W/C = 0.25, 0.35, and 0.4. When W/C = 0.3, SLMKPC had a compact structure with a certain operating space and better mechanical properties.
Biomechanical Effect of 3D-Printed Foot Orthoses in Patients with Knee Osteoarthritis
Authors: Lin Kuang-Wei , Chou Li-Wei , Su Yi-Tien , Wei Shun-Hwa , Chen Chen-Shen
Published: May 2021

Lateral wedges are a common conservative treatment for medial knee osteoarthritis (OA). However, use of lateral wedges might increase the ankle eversion moment. To minimize the risk of ankle symptoms, lateral wedges with custom arch support are suggested. However, the manufacturing process of a custom foot orthosis (FO) is complicated, labor-intensive, and time-consuming. The technology of 3D printing is an ideal method for mass customization. Therefore, the purpose of this study was to develop custom FOs using 3D-printing techniques and to evaluate the effects of 3D-printed FOs in patients with knee OA. Fifteen patients with medial knee OA were enrolled into this study. Kinematic and kinetic data were collected during walking by using an optical motion capture system. A paired-sample t-test was conducted to compare biomechanical variables under two conditions: walking in standard shoes (Shoe) and walking in shoes embedded with 3D-printed FOs (Shoe + FO). The results show that the first and second peak knee adduction moments were significantly reduced by 4.08% and 9.09% under the Shoe + FO condition. The FOs alter the biomechanical environment in a way that reduces the variables used to infer abnormal loads at the knee and ankle that could result in painful symptoms.
Speeding up Statistical Tolerance Analysis to Real Time
Authors: Grohmann Peter , Walter Michael S. J.
Published: May 2021

Statistical tolerance analysis based on Monte Carlo simulation can be applied to obtain a cost-optimized tolerance specification that satisfies both the cost and quality requirements associated with manufacturing. However, this process requires time-consuming computations. We found that an implementation that uses the graphics processing unit (GPU) for vector-chain-based statistical tolerance analysis scales better with increasing sample size than a similar implementation on the central processing unit (CPU). Furthermore, we identified a significant potential for reducing runtime by using array vectorization with NumPy, the proper selection of row- and column- major order, and the use of single precision floating-point numbers for the GPU implementation. In conclusion, we present open source statistical tolerance analysis and statistical tolerance synthesis approaches with Python that can be used to improve existing workflows to real time on regular desktop computers.
Synovial Fluid Fatty Acid Profiles Are Differently Altered by Inflammatory Joint Pathologies in the Shoulder and Knee Joints
Authors: Mustonen Anne-Mari , Käkelä Reijo , Joukainen Antti , Lehenkari Petri , Jaroma Antti , Kääriäinen Tommi , Kröger Heikki , Paakkonen Tommi , Sihvo Sanna P. , Nieminen Petteri
Published: May 2021

Anomalies of fatty acid (FA) metabolism characterize osteoarthritis (OA) and rheumatoid arthritis (RA) in the knee joint. No previous study has investigated the synovial fluid (SF) FA manifestations in these aging-related inflammatory diseases in the shoulder. The present experiment compared the FA alterations between the shoulder and knee joints in patients with end-stage OA or end-stage RA. SF samples were collected during glenohumeral or knee joint surgery from trauma controls and from OA and RA patients (n = 42). The FA composition of SF total lipids was analyzed by gas chromatography with flame ionization and mass spectrometric detection and compared across cohorts. The FA signatures of trauma controls were mostly uniform in both anatomical locations. RA shoulders were characterized by elevated percentages of 20:4n-6 and 22:6n-3 and with reduced proportions of 18:1n-9. The FA profiles of OA and RA knees were relatively uniform and displayed lower proportions of 18:2n-6, 22:6n-3 and total n-6 polyunsaturated FAs (PUFAs). The results indicate location- and disease-dependent differences in the SF FA composition. These alterations in FA profiles and their potential implications for the production of PUFA-derived lipid mediators may affect joint lubrication, synovial inflammation and pannus formation as well as cartilage and bone degradation and contribute to the pathogeneses of inflammatory joint diseases.
Hair Testing for Classic Drugs of Abuse to Monitor Cocaine Use Disorder in Patients Following Transcranial Magnetic Stimulation Protocol Treatment
Authors: Rotolo Maria Concetta , Pacifici Roberta , Pellegrini Manuela , Cardullo Stefano , Pérez Luis J. Gómez , Cuppone Diego , Gallimberti Luigi , Madeo Graziella
Published: May 2021

In recent years, hair has become an alternative biological specimen for drug testing in the fields of forensic and clinical toxicology. The advantages of hair testing include larger detection windows (months/years), depending on the length of the hair shaft, compared to those of urine/blood (hours to 2–4 days for most drugs). Segmental hair analysis can disclose a month-to-month (considering 1 cm segment cuts) information of drug exposure (single or repeated) and potentially identify patterns of drug use/administration. Repetitive transcranial magnetic stimulation (rTMS) was recently proposed as a valid tool for therapeutic purposes in addictions, including cocaine use disorder (CocUD). Here, we proposed hair testing analyses of classic drugs of abuse in a clinical setting to monitor the clinical changes in treatment-seeker CocUD patients undergoing protocol treatments with rTMS stimulating the left dorsolateral prefrontal cortex (l-DLPFC). We collected hair samples from nine CocUD patients at different stages from the beginning of treatments. Hair sample analyses revealed significant changes in the patterns of cocaine use, according to the negativity of urine screening tests and the clinical reductions of craving. These data, albeit preliminary, suggest that hair testing analysis of classic drugs of abuse could be extended to clinical settings to monitor the clinical efficacy of innovative therapeutic interventions, such as rTMS.
Human Endogenous Retroviruses (HERVs) and Mammalian Apparent LTRs Retrotransposons (MaLRs) Are Dynamically Modulated in Different Stages of Immunity
Authors: Pisano Maria Paola , Grandi Nicole , Tramontano Enzo
Published: May 2021

Human Endogenous retroviruses (HERVs) and Mammalian Apparent LTRs Retrotransposons (MaLRs) are remnants of ancient retroviral infections that represent a large fraction of our genome. The HERV and MaLR transcriptional activity is regulated in developmental stages, adult tissues, and pathological conditions. In this work, we used a bioinformatics approach based on RNA-sequencing (RNA-seq) to study the expression and modulation of HERVs and MaLR in a scenario of activation of the immune response. We analyzed transcriptome data from subjects before and after the administration of an inactivated vaccine against the Hantaan orthohantavirus, the causative agent of Korean hemorrhagic fever, to investigate the HERV and MaLR expression and differential expression in response to the administration of the vaccine. Specifically, we described the HERV transcriptome in PBMCs and identified HERV and MaLR loci differentially expressed after the 2nd, 3rd, and 4th inactivated vaccine administrations. We found that the expression of 545 HERV and MaLR elements increased in response to the vaccine and that the activation of several individual HERV and MaLR loci is specific for each vaccine administration and correlated to different genes and immune-related pathways.
Early Life Exposure to Food Contaminants and Social Stress as Risk Factor for Metabolic Disorders Occurrence?—An Overview
Authors: Guzylack-Piriou Laurence , Ménard Sandrine
Published: May 2021

The global prevalence of obesity has been increasing in recent years and is now the major public health challenge worldwide. While the risks of developing metabolic disorders (MD) including obesity and type 2 diabetes (T2D) have been historically thought to be essentially driven by increased caloric intake and lack of exercise, this is insufficient to account for the observed changes in disease trends. Based on human epidemiological and pre-clinical experimental studies, this overview questioned the role of non-nutritional components as contributors to the epidemic of MD with a special emphasis on food contaminants and social stress. This overview examines the impact of early life adverse events (ELAE) focusing on exposures to food contaminants or social stress on weight gain and T2D occurrence in the offspring and explores potential mechanisms leading to MD in adulthood. Indeed, summing up data on both ELAE models in parallel allowed us to identify common patterns that appear worthwhile to study in MD etiology. This overview provides some evidence of a link between ELAE-induced intestinal barrier disruption, inflammation, epigenetic modifications, and the occurrence of MD. This overview sums up evidence that MD could have developmental origins and that ELAE are risk factors for MD at adulthood independently of nutritional status.
Trace Element and Mineral Levels in Serum, Hair, and Urine of Obese Women in Relation to Body Composition, Blood Pressure, Lipid Profile, and Insulin Resistance
Authors: Tinkov Alexey A. , Bogdański Paweł , Skrypnik Damian , Skrypnik Katarzyna , Skalny Anatoly V. , Aaseth Jan , Skalnaya Margarita G. , Suliburska Joanna
Published: May 2021

The objective of this study was to evaluate serum, hair, and urinary trace element and mineral content in normal-weight and obese women in relation to metabolic risk factors. A total of 80 women aged 30–70 y.o. were enrolled in the obese group (n = 40) and normal-weight group (n = 40). Serum, hair, and urinary trace element and mineral levels were assessed using inductively coupled plasma spectrometry. Body fat percentage was evaluated using bioimpedance. Obese subjects were characterized by significantly higher body fat percentage, blood pressure, serum triglyceride concentration, and insulin resistance. Serum Ca, Fe, Mg, Se, V, Zn levels, hair Fe, Mg, V content, and urinary Se and V concentrations were found to be lower in obese subjects as compared to lean controls. In turn, serum Cu and urinary Fe levels in obese women were characterized by a significant increase. In multiple regression models serum Cu, Se, and Zn levels were significantly associated with BMI even after adjustment for blood biochemistry, body composition, and blood pressure. Serum trace element and mineral levels also significantly contributed to group discrimination. These findings allow to propose that obesity-associated disturbances in trace element and mineral status may at least partially contribute to metabolic risk in obese subjects.
Antimicrobial Photodynamic Inactivation Affects the Antibiotic Susceptibility of Enterococcus spp. Clinical Isolates in Biofilm and Planktonic Cultures
Authors: Woźniak Agata , Kruszewska Beata , Pierański Michał Karol , Rychłowski Michał , Grinholc Mariusz
Published: May 2021

Enterococcus faecium and Enterococcus faecalis are opportunistic pathogens that can cause a vast variety of nosocomial infections. Moreover, E. faecium belongs to the group of ESKAPE microbes, which are the main cause of hospital-acquired infections and are especially difficult to treat because of their resistance to many antibiotics. Antimicrobial photodynamic inactivation (aPDI) represents an alternative to overcome multidrug resistance problems. This process requires the simultaneous presence of oxygen, visible light, and photosensitizing compounds. In this work, aPDI was used to resensitize Enterococcus spp. isolates to antibiotics. Antibiotic susceptibility testing according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations was combined with synergy testing methods recommended by the American Society for Microbiology. Two clinical isolates, E. faecalis and E. faecium, were treated with a combination of aPDI utilizing rose bengal (RB) or fullerene (FL) derivative as photosensitizers, antimicrobial blue light (aBL), and 10 recommended antibiotics. aPDI appeared to significantly impact the survival rate of both isolates, while aBL had no significant effect. The synergy testing results differed between strains and utilized methods. Synergy was observed for RB aPDI in combination with gentamycin, ciprofloxacin and daptomycin against E. faecalis. For E. faecium, synergy was observed between RB aPDI and gentamycin or ciprofloxacin, while for RB aPDI with vancomycin or daptomycin, antagonism was observed. A combination of FL aPDI gives a synergistic effect against E. faecalis only with imipenem. Postantibiotic effect tests for E. faecium demonstrated that this isolate exposed to aPDI in combination with gentamycin, streptomycin, tigecycline, doxycycline, or daptomycin exhibits delayed growth in comparison to untreated bacteria. The results of synergy testing confirmed the effectiveness of aPDI in resensitization of the bacteria to antibiotics, which presents great potential in the treatment of infections caused by multidrug-resistant strains.
Strategies for the Improvement of Metal-Based Chemotherapeutic Treatments
Authors: Cirri Damiano , Bartoli Francesco , Pratesi Alessandro , Baglini Emma , Barresi Elisabetta , Marzo Tiziano
Published: May 2021

This article provides an overview of the various research approaches we have explored in recent years to improve metal-based agents for cancer or infection treatments. Although cisplatin, carboplatin, and oxaliplatin remain the cornerstones in tumor chemotherapy, the discovery and approval of novel inorganic anticancer drugs is a very slow process. Analogously, although a few promising inorganic drugs have found clinical application against parasitic or bacterial infections, their use remains relatively limited. Moreover, the discovery process is often affected by small therapeutic enhancements that are not attractive for the pharmaceutical industry. However, the availability of increasing mechanistic information for the modes of action of established inorganic drugs is fueling the exploration of various approaches for developing effective inorganic chemotherapy agents. Through a series of examples, some from our own research experience, we focus our attention on a number of promising strategies, including (1) drug repurposing, (2) the simple modification of the chemical structures of approved metal-based drugs, (3) testing novel drug combinations, and (4) newly synthesized complexes coupling different anticancer drugs. Accordingly, we aim to suggest and summarize a series of reliable approaches that are exploitable for the development of improved and innovative treatments.
Early Dysfunction of Substantia Nigra Dopamine Neurons in the ParkinQ311X Mouse
Authors: Regoni Maria , Zanetti Letizia , Comai Stefano , Mercatelli Daniela , Novello Salvatore , Albanese Federica , Croci Laura , Consalez Gian Giacomo , Ciammola Andrea , Valtorta Flavia , Morari Michele , Sassone Jenny
Published: May 2021

Mutations in the PARK2 gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP), a neurodegenerative disease characterized by early dysfunction and loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). No therapy is currently available to prevent or slow down the neurodegeneration in ARJP patients. Preclinical models are key to clarifying the early events that lead to neurodegeneration and reveal the potential of novel neuroprotective strategies. ParkinQ311X is a transgenic mouse model expressing in DA neurons a mutant parkin variant found in ARJP patients. This model was previously reported to show the neuropathological hallmark of the disease, i.e., the progressive loss of DA neurons. However, the early dysfunctions that precede neurodegeneration have never been investigated. Here, we analyzed SNc DA neurons in parkinQ311X mice and found early features of mitochondrial dysfunction, extensive cytoplasmic vacuolization, and dysregulation of spontaneous in vivo firing activity. These data suggest that the parkinQ311X mouse recapitulates key features of ARJP and provides a useful tool for studying the neurodegenerative mechanisms underlying the human disease and for screening potential neuroprotective drugs.
Psychological and Physiological Signatures of Music Listening in Different Listening Environments—An Exploratory Study
Authors: Tervaniemi Mari , Makkonen Tommi , Nie Peixin
Published: May 2021

We compared music emotion ratings and their physiological correlates when the participants listened to music at home and in the laboratory. We hypothesized that music emotions are stronger in a familiar environment, that is, at home. Participants listened to their self-selected favorite and neutral music excerpts at home and in the laboratory for 10 min in each environment. They completed the questionnaires about their emotional states and gave saliva samples for the analyses of the stress hormone cortisol. We found that in the context of music listening, the participants’ emotion ratings differed between home and the laboratory. Furthermore, the cortisol levels were generally lower at home than in the laboratory and decreased after music listening at home and in the laboratory. However, the modulatory effects of music listening on cortisol levels did not differ between the home and the laboratory. Our exploratory multimethodological data offer novel insight about the psychological and physiological consequences of music listening. These data reveal the sensitivity of the current research methods to investigate human emotions in various contexts without excluding the use of laboratory environment in investigating them.
Using Process Indicators to Monitor Documentation of Patient-Centred Variables in an Integrated Oncology and Palliative Care Pathway—Results from a Cluster Randomized Trial
Authors: Hjermstad Marianne Jensen , Hamfjord Julian , Aass Nina , Dajani Olav , Lundeby Tonje , Wester Torunn , Kaasa Stein
Published: May 2021

Background. Despite robust evidence from randomized controlled trials (RCTs) demonstrating clinical and patient-reported benefits of integrated oncology and palliative care, the tumour-centred focus is predominant. This single–centre process evaluation monitors documentation of required patient-centred variables during an RCT. Methods. Performance status, patient self-reported symptoms, weight and summaries to general practitioners were assessed from June 2017 to July 2020 in three consultation types: first oncological after study inclusion and palliative and oncological consultations during chemotherapy. Descriptive statistics were used to monitor if the pre-defined program fulfilment of ≥85% documentation was reached. Results. 435 consultations were monitored in 76 patients; 60.5% males, 86.8% with GI cancers; 76 (17.5%) were from the first oncological consultations, 87 (20.0%) and 272 (62.5%) from palliative or subsequent oncological consultations. Program fulfilment differed across consultation types with 94.8% in the palliative consultations (83.3–100%), relative to 65.8% (62.5–75.0%) and 69.2% (57.0–84.3%) for first and subsequent oncological consultations over time, respectively. Use of self-reported symptoms was consistently lower in the oncological consultations. Conclusions. The documentation level of required core variables was not satisfactory, notwithstanding their high clinical relevance and continuous reminders during study. Pre-trial optimization strategies are paramount to promote integration and reduce professional and personal barriers towards a more patient-centred focus.
Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1–AKT–p53 Interactions
Authors: Lynch Katherine N. , Liu Joyce F. , Kesten Nikolas , Chow Kin-Hoe , Shetty Aniket , He Ruiyang , Afreen Mosammat Faria , Yuan Liping , Matulonis Ursula A. , Growdon Whitfield B. , Muto Michael G. , Horowitz Neil S. , Feltmate Colleen M. , Worley Michael J. , Berkowitz Ross S. , Crum Christopher P. , Rueda Bo R. , Hill Sarah J.
Published: May 2021

Uterine carcinoma (UC) is the most common gynecologic malignancy in the United States. TP53 mutant UCs cause a disproportionate number of deaths due to limited therapies for these tumors and the lack of mechanistic understanding of their fundamental vulnerabilities. Here we sought to understand the functional and therapeutic relevance of TP53 mutations in UC. We functionally profiled targetable TP53 dependent DNA damage repair and cell cycle control pathways in a panel of TP53 mutant UC cell lines and patient-derived organoids. There were no consistent defects in DNA damage repair pathways. Rather, most models demonstrated dependence on defective G2/M cell cycle checkpoints and subsequent upregulation of Aurora kinase-LKB1-p53-AKT signaling in the setting of baseline mitotic defects. This combination makes them sensitive to Aurora kinase inhibition. Resistant lines demonstrated an intact G2/M checkpoint, and combining Aurora kinase and WEE1 inhibitors, which then push these cells through mitosis with Aurora kinase inhibitor-induced spindle defects, led to apoptosis in these cases. Overall, this work presents Aurora kinase inhibitors alone or in combination with WEE1 inhibitors as relevant mechanism driven therapies for TP53 mutant UCs. Context specific functional assessment of the G2/M checkpoint may serve as a biomarker in identifying Aurora kinase inhibitor sensitive tumors.
JNK in Tumor Microenvironment: Present Findings and Challenges in Clinical Translation
Authors: Tam Shing Yau , Law Helen Ka-Wai
Published: May 2021

The c-Jun N-terminal kinases (JNKs) are a group of mitogen-activated protein kinases (MAPKs). JNK is mainly activated under stressful conditions or by inflammatory cytokines and has multiple downstream targets for mediating cell proliferation, differentiation, survival, apoptosis, and immune responses. JNK has been demonstrated to have both tumor promoting and tumor suppressing roles in different cancers depending on the focused pathway in each study. JNK also plays complex roles in the heterogeneous tumor microenvironment (TME). JNK is involved in different tumorigenesis pathways. TME closely relates with tumor development and consists of various stressful and chronic inflammatory conditions along with different cell populations, in which the JNK pathway may have various mediating roles. In this review, we aim to summarize the present knowledge of JNK-mediated processes in TME, including hypoxia, reactive oxygen species, inflammation, immune responses, angiogenesis, as well as the regulation of various cell populations within TME. This review also suggests future research directions for translating JNK modulation in pre-clinical findings to clinical benefits.
Perioperative Management of Complex Hepatectomy for Colorectal Liver Metastases: The Alliance between the Surgeon and the Anesthetist
Authors: Giustiniano Enrico , Nisi Fulvio , Rocchi Laura , Zito Paola C. , Ruggieri Nadia , Cimino Matteo M. , Torzilli Guido , Cecconi Maurizio
Published: May 2021

Hepatic resection has been widely accepted as the first choice for the treatment of colorectal metastases. Liver surgery has been recognized as a major abdominal procedure; it exposes patients to a high risk of perioperative adverse events. Decision sharing and the multimodal approach to the patients’ management are the two key items for a safe outcome, even in such a high-risk surgery. This review aims at addressing the main perioperative issues (preoperative evaluation; general anesthesia and intraoperative fluid management and hemodynamic monitoring; intraoperative metabolism; administration policy for blood-derivative products; postoperative pain control; postoperative complications), in particular, from the anesthetist’s point of view; however, only an alliance with the surgery team may be successful in case of adverse events to accomplish a good final outcome.
De-Escalation Strategies of (Chemo)Radiation for Head-and-Neck Squamous Cell Cancers—HPV and Beyond
Authors: Rühle Alexander , Grosu Anca-Ligia , Nicolay Nils H.
Published: May 2021

Oncological outcomes for head-and-neck squamous cell carcinoma (HNSCC) patients are still unsatisfactory, especially for advanced tumor stages. Besides the moderate survival rates, the prevalence of severe treatment-induced normal tissue toxicities is high after multimodal cancer treatments, both causing significant morbidity and decreasing quality of life of surviving patients. Therefore, risk-adapted and individualized treatment approaches are urgently needed for HNSCC patients to optimize the therapeutic gain. It has been a well-known fact that especially HPV-positive oropharyngeal squamous cell carcinoma (OSCC) patients exhibit an excellent prognosis and may therefore be subject to overtreatment, resulting in long-term treatment-related toxicities. Regarding the superior prognosis of HPV-positive OSCC patients, treatment de-escalation strategies are currently investigated in several clinical trials, and HPV-positive OSCC may potentially serve as a model for treatment de-escalation also for other types of HNSCC. We performed a literature search for both published and ongoing clinical trials and critically discussed the presented concepts and results. Radiotherapy dose or volume reduction, omission or modification of concomitant chemotherapy, and usage of induction chemotherapy are common treatment de-escalation strategies that are pursued in clinical trials for biologically selected subgroups of HNSCC patients. While promising data have been reported from various Phase II trials, evidence from Phase III de-escalation trials is either lacking or has failed to demonstrate comparable outcomes for de-escalated treatments. Therefore, further data and a refinement of biological HNSCC stratification are required before deescalated radiation treatments can be recommended outside of clinical trials.
Lymph Node Yield and Ratio in Selective and Modified Radical Neck Dissection in Head and Neck Cancer—Impact on Oncological Outcome
Authors: Sheppard Sean C. , Frech Lukas , Giger Roland , Nisa Lluís
Published: May 2021

Background: Lymph node metastases are associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). Neck dissection (ND) is often performed prior to or after (chemo)radiation (CRT) and is an integral part of HNSCC treatment strategies. The impact of CRT delivered prior to ND on lymph node yield (LNY) and lymph node ratio (LNR) has not been comprehensively investigated. Material and methods: A retrospective cohort study was conducted from January 2014 to 30 June 2019 at the University Hospital of Bern, Switzerland. We included 252 patients with primary HNSCC who underwent NDs either before or after CRT. LNY and LNR were compared in patients undergoing ND prior to or after CRT. A total of 137 and 115 patients underwent modified radical ND (levels I to V) and selective ND, respectively. The impact of several features on survival and disease control was assessed. Results: Of the included patients, 170 were male and 82 were females. There were 141 primaries from the oral cavity, 55 from the oropharynx, and 28 from the larynx. ND specimens showed a pN0 stage in 105 patients and pN+ in 147. LNY, but LNR was not significantly higher in patients undergoing upfront ND than in those after CRT (median: 38 vs. 22, p < 0.0001). Cox hazard ratio regression showed that an LNR ≥ 6.5% correlated with poor overall (HR 2.42, CI 1.12-4.89, p = 0.014) and disease-free survival (HR 3.416, CI 1.54-754, p = 0.003) in MRND. Conclusion: ND after CRT leads to significantly reduced LNY. An LNR ≥6.5% is an independent risk factor for decreased overall, disease-free, and distant metastasis-free survival for MRND.
TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation
Authors: Shen Yinghui , Liu Lu , Wang Mengyuan , Xu Bo , Lyu Ruitu , Shi Yujiang Geno , Tan Li
Published: May 2021

Activation of PD-1/PD-L1 checkpoint is a critical step for the immune evasion of malignant tumors including breast cancer. However, the epigenetic mechanism underlying the aberrant expression of PD-L1 in breast cancer cells remains poorly understood. To investigate the role of TET2 in the regulation of PD-L1 gene expression, quantitative reverse transcription PCR (RT-qPCR), Western blotting, chromatin immunoprecipitation (ChIP) assay and MeDIP/hMeDIP-qPCR were performed on MCF7 and MDA-MB-231 human breast cancer cells. Here, we reported that TET2 depletion upregulated PD-L1 gene expression in MCF7 cells. Conversely, ectopic expression of TET2 inhibited PD-L1 gene expression in MDA-MB-231 cells. Mechanistically, TET2 protein recruits histone deacetylases (HDACs) to PD-L1 gene promoter and orchestrates a repressive chromatin structure to suppress PD-L1 gene transcription, which is likely independent of DNA demethylation. Consistently, treatment with HDAC inhibitors upregulated PD-L1 gene expression in wild-type (WT) but not TET2 KO MCF7 cells. Furthermore, analysis of the CCLE and TCGA data showed a negative correlation between TET2 and PD-L1 expression in breast cancer. Taken together, our results identify a new epigenetic regulatory mechanism of PD-L1 gene transcription, linking the catalytic activity-independent role of TET2 to the anti-tumor immunity in breast cancer.