bluuebunny/crossref_metadata_2025 huggingface dataset:
Date Seeds: A Promising Source of Oil with Functional Properties
Authors: Mrabet Abdessalem , Jiménez-Araujo Ana , Guillén-Bejarano Rafael , Rodríguez-Arcos Rocío , Sindic Marianne
Published: June 2020

The cultivation of the date palm (Phoenix dactylifera L.) is the main activity and source of livelihood for people from arid and semiarid regions of the world. Date production is increasing every year. In addition, pitted date exportation is rising and great amounts of date seeds are produced. This biomass represents a problem for manufacturing companies. At the moment, date seeds are normally discarded or used as animal feed ingredients. However, this co-product can be used for many other applications due to its valuable chemical composition. Oil is one of the most interesting components of the date seed. In fact, date seeds contain 5–13% oil. Date seed oil contains saturated and unsaturated fatty acids with lauric and oleic as the main ones, respectively. Tocopherols, tocotrienols, phytosterols, and phenolic compounds are also present in significant amounts. These phytochemicals confer added value to date seed oil, which could be used for many applications, such as food product formulations, cosmetics, and pharmaceuticals. This review provides up-to-date data on the different extraction techniques and the chemical composition of date seed oils. The applications of date seed oil have also been reviewed.
Packaging Design Using Mustard Seeds as a Natural Antimicrobial: A Study on Inhibition of Pseudomonas fragi in Liquid Medium
Authors: Bahmid Nur Alim , Heising Jenneke , Fogliano Vincenzo , Dekker Matthijs
Published: June 2020

Pseudomonas fragi is the dominant spoilage organism in various foods, especially in spoiled milk, fish, and meats. Its growth can be inhibited by releasing allyl isothiocyanate (AITC) from ground mustard seeds in food packages. This paper aims to investigate the antimicrobial potential of ground mustard seeds against P. fragi growth and the effectiveness of released AITC concentration from mustard seeds on microbial inhibition of the spoilage bacteria growing in the liquid medium. The AITC concentration in the headspace and the liquid medium was measured and the growth of P. fragi in the liquid medium was monitored. Depending on the concentration of AITC, not only growth was inhibited but a reduction of the total count of P. fragi was even observed. The inactivation rate (k) of P. fragi was estimated using first-order inactivation kinetics and the minimum gaseous-released AITC to inactivate P. fragi was determined. Higher AITC concentration in the headspace and liquid medium was observed when using a higher amount of ground mustard seeds and a lower food to headspace ratio. Increasing the amount of ground mustard seeds (>100 mg per 10 mL liquid medium) led to full inactivation of P. fragi in 48 hours. By using an inhibition sigmoid Emax model, the minimum gaseous-released AITC for inactivation of P. fragi in 48 hours was observed around 15 µg/L headspace. These results indicate that inhibition of the spoilage bacteria and extending the shelf life using ground mustard seeds is only possible by applying a careful design of the packaging system.
First Results from a Panchromatic HST/WFC3 Imaging Study of the Young, Rapidly Evolving Planetary Nebulae NGC 7027 and NGC 6302
Authors: Kastner Joel H. , Bublitz Jesse , Balick Bruce , Montez Rodolfo , Frank Adam , Blackman Eric
Published: June 2020

We present the first results from comprehensive, near-UV-to-near-IR Hubble Space Telescope Wide Field Camera 3 (WFC3) emission-line imaging studies of two young planetary nebulae (PNe), NGC 7027 and NGC 6302. These two objects represent key sources for purposes of understanding PNe shaping processes. Both nebulae feature axisymmetric and point-symmetric (bipolar) structures and, despite hot central stars and high nebular excitation states, both harbor large masses of molecular gas and dust. The sweeping wavelength coverage of our Cycle 27 Hubble Space Telescope (HST)/WFC3 imaging surveys targeting these two rapidly evolving PNe will provide a battery of essential tests for theories describing the structural and chemical evolution of evolved star ejecta. Here, we present initial color overlays for selected images, and we highlight some of the first results gleaned from the surveys.
Long-Term Socioeconomic Impact of Informal Care Provided to Patients with Pacemakers: Remote vs. Conventional Monitoring
Authors: Leal-Costa Cesar , Lopez-Villegas Antonio , Catalan-Matamoros Daniel , Robles-Musso Emilio , Lappegård Knut Tore , Bautista-Mesa Rafael Jesus , Peiró Salvador , Lopez-Liria Remedios
Published: June 2020

The impact of informal care immediately after pacemaker (PM) implantation has been well established; however, not much is known about its long-term effects. The present study compared personal characteristics, associated problems, workloads, time, and costs related to informal care provided to patients with PM under remote monitoring (RM) vs. conventional monitoring (CM) in the hospital, five years after implantation. The PONIENTE study was a controlled, non-randomized or masked clinical trial conducted with information obtained from the perspective of informal caregivers. Data were collected at 12 and 60 months after PM implantation. The patients in the study were assigned to two different groups: remote monitoring (RM) and conventional monitoring (CM). The “Disability, personal autonomy, and dependency situations survey” (EDAD) was administered to collect information on sociodemographic characteristics, time, care difficulties, health status, professional aspects, and impact on economic, family, or leisure aspects of the main caregivers providing care to patients with pacemakers. After five years, 55 patients completed the study (RM = 21; CM = 34). The average age was 63.14 years (SD = 14.90), 96% of them were women, and the most predominant marital status was married (72%). Informal caregivers lived in the homes of the patients in 70% of cases, and 88% indicated that they had to provide care six to seven days a week. The average cost per patient during the monitoring period studied was 13.17% lower in the RM group than in the CM group, and these differences were not statistically significant (p = 0.35). This study found similar results in the two groups under study with respect to sociodemographic characteristics, workload, time, and problems associated with health, leisure and family members. The costs associated with care were higher in the CM group; however, these differences were not statistically significant.
Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling
Authors: Juárez-Saldivar Alfredo , Schroeder Michael , Salentin Sebastian , Haupt V. Joachim , Saavedra Emma , Vázquez Citlali , Reyes-Espinosa Francisco , Herrera-Mayorga Verónica , Villalobos-Rocha Juan Carlos , García-Pérez Carlos A. , Campillo Nuria E. , Rivera Gildardo
Published: June 2020

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (HsDHFR) inhibitors such as trimetrexate also inhibit T. cruzi DHFR-TS (TcDHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new TcDHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities against T. cruzi infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to TcDHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative TcDHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested on T. cruzi epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.
Overexpression of Isoprene Synthase Affects ABA- and Drought-Related Gene Expression and Enhances Tolerance to Abiotic Stress
Authors: Xu Jia , Trainotti Livio , Li Mingai , Varotto Claudio
Published: June 2020

Isoprene is the most abundant single biogenic volatile compound emitted by plants. Despite the relevance of this molecule to plant abiotic resistance and its impact on global atmospheric chemistry, little is known about the details of its mechanism of action. Here, we characterized through both physiological and molecular methods the mechanisms of action of isoprene using model transgenic arabidopsis lines overexpressing a monocot isoprene synthase gene. Our results demonstrated the effect that isoprene had on ABA signaling at different tissue-specific, spatial, and temporal scales. In particular, we found that isoprene enhanced stomatal sensitivity to ABA through upregulation of RD29B signaling gene. By contrast, isoprene decreased sensitivity to ABA in germinating seeds and roots, suggesting tissue-specific mechanisms of action. In leaves, isoprene caused the downregulation of COR15A and P5CS genes, suggesting that the enhanced tolerance to water-deprivation stress observed in isoprene-emitting plants may be mediated chiefly by an enhanced membrane integrity and tolerance to osmotic stress.
Hydrogen Sulfide Treatment Improves Post-Infarct Remodeling and Long-Term Cardiac Function in CSE Knockout and Wild-Type Mice
Authors: Ellmers Leigh J. , Templeton Evelyn M. , Pilbrow Anna P. , Frampton Chris , Ishii Isao , Moore Philip K. , Bhatia Madhav , Richards A. Mark , Cameron Vicky A.
Published: June 2020

Hydrogen sulfide (H2S) is recognized as an endogenous gaseous signaling molecule generated by cystathionine γ-lyase (CSE) in cardiovascular tissues. H2S up-regulation has been shown to reduce ischemic injury, and H2S donors are cardioprotective in rodent models when administered concurrent with myocardial ischemia. We evaluated the potential utility of H2S therapy in ameliorating cardiac remodeling with administration delayed until 2 h post-infarction in mice with or without cystathionine γ-lyase gene deletion (CSE−/−). The slow-release H2S donor, GYY4137, was administered from 2 h after surgery and daily for 28 days following myocardial infarction (MI) induced by coronary artery ligation, comparing responses in CSE−/− with wild-type (WT) mice (n = 5–10/group/genotype). Measures of cardiac function and expression of key genes associated with cardiac hypertrophy, fibrosis, and apoptosis were documented in atria, ventricle, and kidney tissues. Post-MI GYY4137 administration reduced infarct area and restored cardiac function, accompanied by reduction of the elevated ventricular expression of genes mediating cardiac remodeling to near-normal levels. Few differences between WT and CSE−/− mice were observed, except CSE−/− mice had higher blood pressures, and higher atrial Mir21a expression across all treatment groups. These findings suggest endogenous CSE gene deletion does not substantially exacerbate the long-term response to MI. Moreover, the H2S donor GYY4137 administered after onset of MI preserves cardiac function and protects against adverse cardiac remodeling in both WT and CSE-deficient mice.
Multiple Roles of Transforming Growth Factor Beta in Amyotrophic Lateral Sclerosis
Authors: Galbiati Mariarita , Crippa Valeria , Rusmini Paola , Cristofani Riccardo , Messi Elio , Piccolella Margherita , Tedesco Barbara , Ferrari Veronica , Casarotto Elena , Chierichetti Marta , Poletti Angelo
Published: June 2020

Transforming growth factor beta (TGFB) is a pleiotropic cytokine known to be dysregulated in many neurodegenerative disorders and particularly in amyotrophic lateral sclerosis (ALS). This motor neuronal disease is non-cell autonomous, as it affects not only motor neurons but also the surrounding glial cells, and the target skeletal muscle fibers. Here, we analyze the multiple roles of TGFB in these cell types, and how TGFB signaling is altered in ALS tissues. Data reported support a crucial involvement of TGFB in the etiology and progression of ALS, leading us to hypothesize that an imbalance of TGFB signaling, diminished at the pre-symptomatic stage and then increased with time, could be linked to ALS progression. A reduced stimulation of the TGFB pathway at the beginning of disease blocks its neuroprotective effects and promotes glutamate excitotoxicity. At later disease stages, the persistent activation of the TGFB pathway promotes an excessive microglial activation and strengthens muscular dysfunction. The therapeutic potential of TGFB is discussed, in order to foster new approaches to treat ALS.
N-Acetylcysteine Reduces Skeletal Muscles Oxidative Stress and Improves Grip Strength in Dysferlin-Deficient Bla/J Mice
Authors: García-Campos Paz , Báez-Matus Ximena , Jara-Gutiérrez Carlos , Paz-Araos Marilyn , Astorga César , Cea Luis A. , Rodríguez Viviana , Bevilacqua Jorge A. , Caviedes Pablo , Cárdenas Ana M.
Published: June 2020

Dysferlinopathy is an autosomal recessive muscular dystrophy resulting from mutations in the dysferlin gene. Absence of dysferlin in the sarcolemma and progressive muscle wasting are hallmarks of this disease. Signs of oxidative stress have been observed in skeletal muscles of dysferlinopathy patients, as well as in dysferlin-deficient mice. However, the contribution of the redox imbalance to this pathology and the efficacy of antioxidant therapy remain unclear. Here, we evaluated the effect of 10 weeks diet supplementation with the antioxidant agent N-acetylcysteine (NAC, 1%) on measurements of oxidative damage, antioxidant enzymes, grip strength and body mass in 6 months-old dysferlin-deficient Bla/J mice and wild-type (WT) C57 BL/6 mice. We found that quadriceps and gastrocnemius muscles of Bla/J mice exhibit high levels of lipid peroxidation, protein carbonyls and superoxide dismutase and catalase activities, which were significantly reduced by NAC supplementation. By using the Kondziela’s inverted screen test, we further demonstrated that NAC improved grip strength in dysferlin deficient animals, as compared with non-treated Bla/J mice, without affecting body mass. Together, these results indicate that this antioxidant agent improves skeletal muscle oxidative balance, as well as muscle strength and/or resistance to fatigue in dysferlin-deficient animals.
A Dynamic Hanging-Drop System for Mesenchymal Stem Cell Culture
Authors: Huang Shu-Wei , Tzeng Shian-Chiuan , Chen Jem-Kun , Sun Jui-Sheng , Lin Feng-Huei
Published: June 2020

There have been many microfluid technologies combined with hanging-drop for cell culture gotten developed in the past decade. A common problem within these devices is that the cell suspension introduced at the central inlet could cause a number of cells in each microwell to not regularize. Also, the instability of droplets during the spheroid formation remains an unsolved ordeal. In this study, we designed a microfluidic-based hanging-drop culture system with the design of taper-tube that can increase the stability of droplets while enhancing the rate of liquid exchange. A ring is surrounding the taper-tube. The ring can hold the cells to enable us to seed an adequate amount of cells before perfusion. Moreover, during the period of cell culture, the mechanical force around the cell is relatively low to prevent stem cells from differentiate and maintain the phenotype. As a result of our hanging system design, cells are designed to accumulate at the bottom of the droplet. This method enhances convenience for observation activities and analysis of experiments. Thus, this microfluid chip can be used as an in vitro platform representing in vivo physiological conditions, and can be useful in regenerative therapy.
Low Ejection Fraction Predisposes to Contrast-Induced Nephropathy after the Second Step of Staged Coronary Revascularization for Acute Myocardial Infarction: A Retrospective Observational Study
Authors: Chyrchel Michał , Hałubiec Przemysław , Łazarczyk Agnieszka , Duchnevič Olgerd , Okarski Michał , Gębska Monika , Surdacki Andrzej
Published: June 2020

Patients who develop contrast-induced nephropathy (CIN) are at an increased short-term and long-term risk of adverse cardiovascular (CV) events. Our aim was to search for patient characteristics associated with changes in serum creatinine and CIN incidence after each step of two-stage coronary revascularization in patients with acute myocardial infarction (AMI) and multivessel coronary artery disease undergoing staged coronary angioplasty during hospitalization for AMI. We retrospectively analyzed medical records of 138 patients with acute myocardial infarction without hemodynamic instability, in whom two-stage coronary angioplasty was performed during the initial hospital stay. In-hospital serum creatinine levels were recorded before the 1st intervention (at admission), within 72 h after the 1st intervention (before the 2nd intervention), and within 72 h after the 2nd intervention. The incidence of CIN was 2% after the 1st intervention (i.e., primary angioplasty) and 8% after the 2nd intervention. Patients with significant left ventricular systolic dysfunction after the 1st intervention (ejection fraction (EF) ≤35%) exhibited higher relative rises in creatinine levels after the 2nd intervention (18 ± 29% vs. 2 ± 16% for EF ≤35% and >35%, respectively, p = 0.03), while respective creatinine changes after the 1st revascularization procedure were comparable (−1 ± 14% vs. 2 ± 13%, p = 0.4). CIN after the 2nd intervention was over five-fold more frequent in subjects with low EF (28% vs. 5%, p = 0.007). The association between low EF and CIN incidence or relative creatinine changes after the 2nd intervention was maintained upon adjustment for baseline renal function, major CV risk factors, and the use of renin-angiotensin axis antagonists prior to admission. In conclusion, low EF predisposes to CIN after second contrast exposure in patients undergoing two-stage coronary angioplasty during the initial hospitalization for AMI. Our findings suggest a need of extended preventive measures against CIN or even postponement of second coronary intervention in patients with significant left ventricular dysfunction scheduled for the second step of staged angioplasty.
Gene Expression Profiling in Fibromyalgia Indicates an Autoimmune Origin of the Disease and Opens New Avenues for Targeted Therapy
Authors: Dolcino Marzia , Tinazzi Elisa , Puccetti Antonio , Lunardi Claudio
Published: June 2020

Fibromyalgia is a chronic disorder characterized by widespread pain and by several non-pain symptoms. Autoimmunity, small fiber neuropathy and neuroinflammation have been suggested to be involved in the pathogenesis of the disease. We have investigated the gene expression profile in peripheral blood mononuclear cells obtained from ten patients and ten healthy subjects. Of the 545,500 transcripts analyzed, 1673 resulted modulated in fibromyalgic patients. The majority of these genes are involved in biological processes and pathways linked to the clinical manifestations of the disease. Moreover, genes involved in immunological pathways connected to interleukin-17 and to Type I interferon signatures were also modulated, suggesting that autoimmunity plays a role in the disease. We then aimed at identifying differentially expressed Long non-coding RNAs (LncRNAs) functionally connected to modulated genes both directly and via microRNA targeting. Only two LncRNAs of the 298 found modulated in patients, were able to target the most highly connected genes in the fibromyalgia interactome, suggesting their involvement in crucial gene regulation. Our gene expression data were confirmed by real time PCR, by autoantibody testing, detection of soluble mediators and Th-17 polarization in a validation cohort of 50 patients. Our results indicate that genetic and epigenetic mechanisms as well as autoimmunity play a pivotal role in the pathogenesis of fibromyalgia.
Implementing Lung Cancer Screening and Prevention in Academic Centers, Affiliated Network Offices and Collaborating Care Sites
Authors: Presant Cary A. , Salgia Ravi , Kulkarni Prakash , Tiep Brian L. , Sanani Shamel , Leach Benjamin , Ashing Kimlin , Sandoval Jossie , Sedrak Mina S. , Landau Shana , Yeung Sophia , Raz Dan , Subbiah Shanmugga
Published: June 2020

Lung cancer is one of the deadliest and yet largely preventable neoplasms. Smoking cessation and lung cancer screening are effective yet underutilized lung cancer interventions. City of Hope Medical Center, a National Cancer Institute (NCI)- designated comprehensive cancer center, has 27 community cancer centers and has prioritized tobacco control and lung cancer screening throughout its network. Despite challenges, we are implementing and monitoring the City of Hope Tobacco Control Initiative including (1) a Planning and Implementation Committee; (2) integration of IT, e.g., medical records and clinician notification/prompts to facilitate screening, cessation referral, and digital health, e.g., telehealth and social media; (3) clinician training and endorsing national guidelines; (4) providing clinical champions at all sites for site leadership; (5) Coverage and Payment reform and aids to facilitate patient access and reduce cost barriers; (6) increasing tobacco exposure screening for all patients; (7) smoking cessation intervention and evaluation—patient-centered recommendations for smoking cessation for all current and recent quitters along with including QuitLine referral for current smokers and smoking care-givers; and (8) establishing a Tobacco Registry for advancing science and discoveries including team science for basic, translation and clinical studies. These strategies are intended to inform screening, prevention and treatment research and patient-centered care.
Frailty Parameters, Morbidity and Mortality in Older Adults with Cancer: A Structural Equation Modelling Approach Based on the Fried Phenotype
Authors: Pamoukdjian Frederic , Laurent Marie , Martinez-Tapia Claudia , Rolland Yves , Paillaud Elena , Canoui-Poitrine Florence
Published: June 2020

Background: to distinguish direct and indirect pathways to frailty phenotype, and quantify associations between two frailty components (i.e., sarcopenia and cachexia) regarding mortality and morbidity in older adults with cancer. Methods: all consecutive older outpatients with cancer were included in a prospective two-centre cohort study between 2013 and 2017 and had geriatric assessment. We used the frailty phenotype. Sarcopenia and cachexia were built as latent variables by including observed variables related to physical performances and related to nutrition and inflammation respectively. Structural equation modelling was used to distinguish between direct and indirect effects of the frailty parameters on the risk of death (Model 1) and the risk of morbidity (defined by unplanned hospitalization and/or disability and/or a fall; Model 2). The root mean square error of approximation (RMSEA) and the comparative fit index (CFI) were used to assess the model fit. Results: 603 older outpatients were included (mean age: 81.2 ± 6.1; women: 54%; frailty phenotype: 58%). The 6-month mortality and morbidity rates were 18% and 64%, respectively. The fit was good for both models (RMSEA and CFI = 0.029 [0.017–0.039] and 0.99 for Model 1, and 0.028 [0.017–0.039] and 0.99 for Model 2, respectively). Sarcopenia and cachexia were both directly and significantly associated with 6-month mortality (βsarcopenia = 0.18, p = 0.01; βcachexia = 0.52, p < 0.0001) and morbidity (βsarcopenia = 0.37, p < 0.0001; βcachexia = 0.19, p < 0.02). Conclusions: sarcopenia and cachexia had a direct pathway with 6-month mortality and morbidity in older cancer patients.
The effect of Maintenance Treatment with Twice-daily or Prolonged Once-daily Tacrolimus Formulation on Visual Evoked Potentials in Stable Kidney Transplant Recipients
Authors: Kolonko Aureliusz , Jurys Małgorzata , Sirek Sebastian , Dwulit Tomasz , Pojda-Wilczek Dorota , Więcek Andrzej
Published: June 2020

In kidney transplant recipients (KTRs), uraemia-induced central nervous system damage partly subsides, while the long-lasting exposure to tacrolimus may cause pathologic visual evoked potentials (VEP) findings, which have not been investigated yet. Thus, the aim of the present study was to assess the effect of tacrolimus maintenance treatment on bioelectrical function of optic nerves in stable KTRs. Sixty-five stable KTRs were enrolled, including 30 patients treated with twice-daily (Prograf) and 35 patients treated with prolonged once-daily (Advagraf) tacrolimus formulation. In all patients, pattern and flash VEP measurements were performed. Tacrolimus dosing and exposure were also analyzed. Overall, 129 eyes were analyzed. In pattern VEP, both (1°) and (15′) latencies of P100 waves were significantly longer, whereas (1°) and (15′) amplitudes were lower in the Advagraf group as compared with the Prograf group. Multivariate regression analyses revealed that the use of Advagraf (vs. Prograf) was independently associated with longer (1°) and (15′) P100 latencies and lower corresponding amplitudes, whereas log tacrolimus daily dose was only related to amplitudes in a whole study group. In flash VEP, log tacrolimus trough level was associated with negative changes in P2 wave amplitude irrespective of tacrolimus formulation, whereas its association with P2 latency was observed only in the Prograf group. Both the type of tacrolimus formulation and drug exposure influenced the VEP parameters in stable KTRs.
A Minimal PKPD Interaction Model for Evaluating Synergy Effects of Combined NSCLC Therapies
Authors: Ionescu Clara Mihaela , Ghita Maria , Copot Dana , Derom Eric , Verellen Dirk
Published: June 2020

This paper introduces a mathematical compartmental formulation of dose-effect synergy modelling for multiple therapies in non small cell lung cancer (NSCLC): antiangiogenic, immuno- and radiotherapy. The model formulates the dose-effect relationship in a unified context, with tumor proliferating rates and necrotic tissue volume progression as a function of therapy management profiles. The model accounts for inter- and intra-response variability by using surface model response terms. Slow acting peripheral compartments such as fat and muscle for drug distribution are not modelled. This minimal pharmacokinetic-pharmacodynamic (PKPD) model is evaluated with reported data in mice from literature. A systematic analysis is performed by varying only radiotherapy profiles, while antiangiogenesis and immunotherapy are fixed to their initial profiles. Three radiotherapy protocols are selected from literature: (1) a single dose 5 Gy once weekly; (2) a dose of 5 Gy × 3 days followed by a 2 Gy × 3 days after two weeks and (3) a dose of 5 Gy + 2 × 0.075 Gy followed after two weeks by a 2 Gy + 2 × 0.075 Gy dose. A reduction of 28% in tumor end-volume after 30 days was observed in Protocol 2 when compared to Protocol 1. No changes in end-volume were observed between Protocol 2 and Protocol 3, this in agreement with other literature studies. Additional analysis on drug interaction suggested that higher synergy among drugs affects up to three-fold the tumor volume (increased synergy leads to significantly lower growth ratio and lower total tumor volume). Similarly, changes in patient response indicated that increased drug resistance leads to lower reduction rates of tumor volumes, with end-volume increased up to 25–30%. In conclusion, the proposed minimal PKPD model has physiological value and can be used to study therapy management protocols and is an aiding tool in the clinical decision making process. Although developed with data from mice studies, the model is scalable to NSCLC patients.
Recommendations for Dental Care during COVID-19 Pandemic
Authors: Gurzawska-Comis Katarzyna , Becker Kathrin , Brunello Giulia , Gurzawska Agata , Schwarz Frank
Published: June 2020

Dental clinics were suspected to be a hotspot for nosocomial transmission of coronavirus disease 19 (COVID-19), yet there has been no clear recommendation about emergency dental care and appropriate personal protective equipment during pandemics. In this paper, we aim to summarize recommendations for (i) patient risk assessment, (ii) patient triage, and (iii) measures to prevent infection of health professionals and nosocomial transmission in dental clinics. The available evidence was collected by performing searches on PubMed, Embase, and Cochrane databases. We reviewed papers on COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), influenza, and related respiratory viral diseases. Legal and ethical frameworks, as well as international (e.g., World Health Organization (WHO)) and national (e.g., public health institutes, dental associations) guidelines were screened to summarize recommendations related to dental emergency care. To assess the patient risk, a questionnaire was developed to classify patients at unknown, high, and very high risk. Patient triage recommendations were summarized in a flow chart that graded the emergency level of treatments (i.e., urgent, as soon as possible, and postpone). Measures to prevent disease transmission based on current evidence were grouped for dental health professionals, dental clinics, and patients. The present recommendations may support health professionals implement preventative measures during the pandemic.
Feasibility of Gynaecologist Led Lynch Syndrome Testing in Women with Endometrial Cancer
Authors: Ryan Neil A. J. , Donnelly Louise , Stocking Katie , Evans D. Gareth , Crosbie Emma J.
Published: June 2020

A barrier to Lynch syndrome testing is the need for prior genetic counselling, a resource demanding process for both patients and healthcare services. We explored the impact of gynaecologist led Lynch syndrome testing in women with endometrial cancer. Women were approached before surgery, on the day of surgery or during routine follow up. Lynch syndrome testing was offered irrespective of age, family history or tumour characteristics. Women’s reasons for being tested were explored using the Motivations and Concerns for GeNEtic Testing (MACGNET) instrument. The short form State-Trait Anxiety Inventory (STAI-6) was used to measure anxiety levels. Only 3/305 women declined Lynch syndrome testing. In total, 175/220 completed MACGNET and STAI-6 psychological instruments. The consent process took an average of 7 min 36 s (SD 5 min 16 s) to complete. The point of care at which consent was taken (before, day of surgery, during follow up) did not influence motivation for Lynch syndrome testing. Anxiety levels were significantly lower when women were consented during follow up (mean reversed STAI-6 score 32 vs. 42, p = 0.001). Anxiety levels were not affected by familial cancer history (p = 0.41). Gynaecologist led Lynch syndrome testing is feasible and may even be desirable in endometrial cancer, especially when offered during routine follow up.
Urinary Dimethylamine (DMA) and Its Precursor Asymmetric Dimethylarginine (ADMA) in Clinical Medicine, in the Context of Nitric Oxide (NO) and Beyond
Authors: Tsikas Dimitrios
Published: June 2020

Asymmetric protein-arginine dimethylation is a major post-translational modification (PTM) catalyzed by protein-arginine methyltransferase (PRMT). Regular proteolysis releases asymmetric dimethylarginine (ADMA). Of the daily produced ADMA, about 10% are excreted unchanged in the urine. The remaining 90% are hydrolyzed by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline and dimethylamine (DMA), which is readily excreted in the urine. The PRMT/DDAH pathway is almost the exclusive origin of urinary ADMA and the major source of urinary DMA. Dietary fish and seafood represent additional abundant sources of urinary DMA. The present article provides an overview of urinary ADMA and DMA reported thus far in epidemiological, clinical and pharmacological studies, in connection with the L-arginine/nitric oxide (NO) pathway and beyond, in neonates, children and adolescents, young and elderly subjects, males and females. Discussed diseases mainly include those relating to the renal and cardiovascular systems such as peripheral arterial occlusive disease, coronary artery disease, chronic kidney disease, rheumatoid arthritis, Becker muscular disease, Duchenne muscular disease (DMD), attention deficit hyperactivity disorder (ADHD), and type I diabetes. Under standardized conditions involving the abstinence of DMA-rich fresh and canned fish and seafood, urinary DMA and ADMA are useful as measures of whole-body asymmetric arginine-dimethylation in health and disease. The creatinine-corrected excretion rates of DMA range from 10 to 80 µmol/mmol in adults and up to 400 µmol/mmol in children and adolescents. The creatinine-corrected excretion rates of ADMA are on average 10 times lower. In general, diseases are associated with higher urinary DMA and ADMA excretion rates, and pharmacological treatment, such as with steroids and creatine (in DMD), decreases their excretion rates, which may be accompanied by a decreased urinary excretion of nitrate, the major metabolite of NO. In healthy subjects and in rheumatoid arthritis patients, the urinary excretion rate of DMA correlates positively with the excretion rate of dihydroxyphenylglycol (DHPG), the major urinary catecholamines metabolite, suggesting a potential interplay in the PRMT/DDAH/NO pathway.
High-Throughput MicroRNA Profiling of Vitreoretinal Lymphoma: Vitreous and Serum MicroRNA Profiles Distinct from Uveitis
Authors: Minezaki Teruumi , Usui Yoshihiko , Asakage Masaki , Takanashi Masakatsu , Shimizu Hiroyuki , Nezu Naoya , Narimatsu Akitomo , Tsubota Kinya , Umazume Kazuhiko , Yamakawa Naoyuki , Kuroda Masahiko , Goto Hiroshi
Published: June 2020

Purpose: Vitreoretinal lymphoma (VRL) is a non-Hodgkin lymphoma of the diffuse large B cell type (DLBCL), which is an aggressive cancer causing central nervous system related mortality. The pathogenesis of VRL is largely unknown. The role of microRNAs (miRNAs) has recently acquired remarkable importance in the pathogenesis of many diseases including cancers. Furthermore, miRNAs have shown promise as diagnostic and prognostic markers of cancers. In this study, we aimed to identify differentially expressed miRNAs and pathways in the vitreous and serum of patients with VRL and to investigate the pathogenesis of the disease. Materials and Methods: Vitreous and serum samples were obtained from 14 patients with VRL and from controls comprising 40 patients with uveitis, 12 with macular hole, 14 with epiretinal membrane, 12 healthy individuals. The expression levels of 2565 miRNAs in serum and vitreous samples were analyzed. Results: Expression of the miRNAs correlated significantly with the extracellular matrix (ECM) ‒receptor interaction pathway in VRL. Analyses showed that miR-326 was a key driver of B-cell proliferation, and miR-6513-3p could discriminate VRL from uveitis. MiR-1236-3p correlated with vitreous interleukin (IL)-10 concentrations. Machine learning analysis identified miR-361-3p expression as a discriminator between VRL and uveitis. Conclusions: Our findings demonstrate that aberrant microRNA expression in VRL may affect the expression of genes in a variety of cancer-related pathways. The altered serum miRNAs may discriminate VRL from uveitis, and serum miR-6513-3p has the potential to serve as an auxiliary tool for the diagnosis of VRL.
Non-Invasive Assessment of Breast Cancer Molecular Subtypes with Multiparametric Magnetic Resonance Imaging Radiomics
Authors: Leithner Doris , Mayerhoefer Marius E. , Martinez Danny F. , Jochelson Maxine S. , Morris Elizabeth A. , Thakur Sunitha B. , Pinker Katja
Published: June 2020

We evaluated the performance of radiomics and artificial intelligence (AI) from multiparametric magnetic resonance imaging (MRI) for the assessment of breast cancer molecular subtypes. Ninety-one breast cancer patients who underwent 3T dynamic contrast-enhanced (DCE) MRI and diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping were included retrospectively. Radiomic features were extracted from manually drawn regions of interest (n = 704 features per lesion) on initial DCE-MRI and ADC maps. The ten best features for subtype separation were selected using probability of error and average correlation coefficients. For pairwise comparisons with >20 patients in each group, a multi-layer perceptron feed-forward artificial neural network (MLP-ANN) was used (70% of cases for training, 30%, for validation, five times each). For all other separations, linear discriminant analysis (LDA) and leave-one-out cross-validation were applied. Histopathology served as the reference standard. MLP-ANN yielded an overall median area under the receiver-operating-characteristic curve (AUC) of 0.86 (0.77–0.92) for the separation of triple negative (TN) from other cancers. The separation of luminal A and TN cancers yielded an overall median AUC of 0.8 (0.75–0.83). Radiomics and AI from multiparametric MRI may aid in the non-invasive differentiation of TN and luminal A breast cancers from other subtypes.
Chronic Gastritis Is Associated with a Decreased High-Density Lipid Level: Histological Features of Gastritis Based on the Updated Sydney System
Authors: Kim Dong-Hoon , Son Byoung Kwan , Min Kyueng-Whan , Han Sang Kuk , Na Ji Ung , Choi Pil Cho , Kim Hack-Lyoung , Kwon Mi Jung , Oh Young Ha , Jung Woon Yong , Moon Ji-Yong , Hong Sangmo , Oh Ki-Wook , Kim Young Seo
Published: June 2020

Chronic gastritis could activate a systemic inflammatory response that could result in adverse lipid profiles. To determine the severity of chronic gastritis, Helicobacter pylori (HP), mononuclear cell (lymphocytes and plasma cells), and neutrophil scores were assessed on the basis of the updated Sydney system (USS), which is widely used for histological grading. The aim of this study was to assess the relationships between gastric histological features and lipid profile levels. This study included 15,322 males and 5929 females who underwent a health checkup and gastric biopsy at the Kangbuk Samsung Medical Center (KBSMC). We analyzed whether the HP, mononuclear cell, and neutrophil grades according to the USS were related to serum leukocyte count, unhealthy behaviors, and lipid profile levels. Gastritis with HP, neutrophils, or moderate to severe mononuclear cells was associated with an elevated serum leukocyte count. A high leukocyte count was related to increased low-density lipoproteins (LDL) and triglycerides/very-low-density lipoprotein (VLDL) and decreased high-density lipoproteins (HDL). In multivariate analyses, chronic gastritis with HP or moderate to severe mononuclear cells was significantly associated with decreased HDL in males, while mononuclear cells were significantly related to decreased HDL in females. Chronic gastritis was associated with an increased systemic inflammatory response, which was associated with unfavorable lipid profiles, especially low HDL levels.
Tryptophan Metabolism via the Kynurenine Pathway: Implications for Graft Optimization during Machine Perfusion
Authors: Zhang Anna , Carroll Cailah , Raigani Siavash , Karimian Negin , Huang Viola , Nagpal Sonal , Beijert Irene , Porte Robert J. , Yarmush Martin , Uygun Korkut , Yeh Heidi
Published: June 2020

Access to liver transplantation continues to be hindered by the severe organ shortage. Extended-criteria donor livers could be used to expand the donor pool but are prone to ischemia-reperfusion injury (IRI) and post-transplant graft dysfunction. Ex situ machine perfusion may be used as a platform to rehabilitate discarded or extended-criteria livers prior to transplantation, though there is a lack of data guiding the utilization of different perfusion modalities and therapeutics. Since amino acid derivatives involved in inflammatory and antioxidant pathways are critical in IRI, we analyzed differences in amino acid metabolism in seven discarded non-steatotic human livers during normothermic- (NMP) and subnormothermic-machine perfusion (SNMP) using data from untargeted metabolomic profiling. We found notable differences in tryptophan, histamine, and glutathione metabolism. Greater tryptophan metabolism via the kynurenine pathway during NMP was indicated by significantly higher kynurenine and kynurenate tissue concentrations compared to pre-perfusion levels. Livers undergoing SNMP demonstrated impaired glutathione synthesis indicated by depletion of reduced and oxidized glutathione tissue concentrations. Notably, ATP and energy charge ratios were greater in livers during SNMP compared to NMP. Given these findings, several targeted therapeutic interventions are proposed to mitigate IRI during liver machine perfusion and optimize marginal liver grafts during SNMP and NMP.
A Pharmacovigilance Study of Hydroxychloroquine Cardiac Safety Profile: Potential Implication in COVID-19 Mitigation
Authors: Singh Anand Prakash , Tousif Sultan , Umbarkar Prachi , Lal Hind
Published: June 2020

In light of the favorable outcomes of few small, non-randomized clinical studies, the Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to Hydroxychloroquine (HCQ) for hospitalized coronavirus disease 2019 (COVID-19) patients. In fact, subsequent clinical studies with COVID-19 and HCQ have reported limited efficacy and poor clinical benefits. Unfortunately, a robust clinical trial for its effectiveness is not feasible at this emergency. Additionally, HCQ was suspected of causing cardiovascular adverse reactions (CV-AEs), but it has never been directly investigated. The objective of this pharmacovigilance analysis was to determine and characterize HCQ-associated cardiovascular adverse events (CV-AEs). We performed a disproportionality analysis of HCQ-associated CV-AEs using the FDA adverse event reporting system (FAERS) database. The FAERS database, comprising more than 11,901,836 datasets and 10,668,655 patient records with drug-adverse reactions, was analyzed. The disproportionality analysis was used to calculate the reporting odds ratios (ROR) with 95% confidence intervals (CI) to predict HCQ-associated CV-AEs. HCQ was associated with higher reporting of right ventricular hypertrophy (ROR: 6.68; 95% CI: 4.02 to 11.17), left ventricular hypertrophy (ROR: 3.81; 95% CI: 2.57 to 5.66), diastolic dysfunction (ROR: 3.54; 95% CI: 2.19 to 5.71), pericarditis (ROR: 3.09; 95% CI: 2.27 to 4.23), torsades de pointes (TdP) (ROR: 3.05; 95% CI: 2.30 to 4.10), congestive cardiomyopathy (ROR: 2.98; 95% CI: 2.01 to 4.42), ejection fraction decreased (ROR: 2.41; 95% CI: 1.80 to 3.22), right ventricular failure (ROR: 2.40; 95% CI: 1.64 to 3.50), atrioventricular block complete (ROR: 2.30; 95% CI: 1.55 to 3.41) and QT prolongation (ROR: 2.09; 95% CI: 1.74 to 2.52). QT prolongation and TdP are most relevant to the COVID-19 treatment regimen of high doses for a comparatively short period and represent the most common HCQ-associated AEs. The patients receiving HCQ are at higher risk of various cardiac AEs, including QT prolongation and TdP. These findings highlight the urgent need for prospective, randomized, controlled studies to assess the risk/benefit ratio of HCQ in the COVID-19 setting before its widespread adoption as therapy.
Course of Adverse Events during Short Treatment Regimen in Patients with Rifampicin-Resistant Tuberculosis in Burundi
Authors: Ciza François , Gils Tinne , Sawadogo Michel , Decroo Tom , Roggi Alberto , Piubello Alberto , Ortuño-Gutiérrez Nimer
Published: June 2020

The introduction of the nine-month short-treatment regimen (STR) has drastically improved outcomes of rifampicin-resistant tuberculosis (RR-TB) treatment. Adverse events (AE) commonly occur, including injectable-induced hearing loss. In Burundi we retrospectively assessed the frequency of adverse events and treatment modifications in all patients who initiated the STR between 2013–2017. Among 225 included patients, 93% were successfully treated without relapse, 5% died, 1% was lost-to-follow-up, 0.4% had treatment failure and 0.4% relapsed after completion. AE were reported in 53%, with grade 3 or 4 AE in 4% of patients. AE occurred after a median of two months. Hepatotoxicity (31%), gastro-intestinal toxicity (22%) and ototoxicity (10%) were most commonly reported. One patient suffered severe hearing loss. Following AE, 7% of patients had a dose reduction and 1% a drug interruption. Kanamycin-induced ototoxicity led to 94% of modifications. All 18 patients with a modified regimen were cured relapse-free. In this exhaustive national RR-TB cohort, RR-TB was treated successfully with the STR. Adverse events were infrequent. To replace the present STR, all-oral regimens should be at least as effective and also less toxic. During and after transition, monitoring, management, and documentation of AE will remain essential.
Serum Metabolic Signatures of Chronic Limb-Threatening Ischemia in Patients with Peripheral Artery Disease
Authors: Azab Sandi M. , Zamzam Abdelrahman , Syed Muzammil H. , Abdin Rawand , Qadura Mohammad , Britz-McKibbin Philip
Published: June 2020

Peripheral artery disease (PAD) is characterized by the atherosclerotic narrowing of lower limb vessels, leading to ischemic muscle pain in older persons. Some patients experience progression to advanced chronic limb-threatening ischemia (CLTI) with poor long-term survivorship. Herein, we performed serum metabolomics to reveal the mechanisms of PAD pathophysiology that may improve its diagnosis and prognosis to CLTI complementary to the ankle–brachial index (ABI) and clinical presentations. Non-targeted metabolite profiling of serum was performed by multisegment injection–capillary electrophoresis–mass spectrometry (MSI–CE–MS) from age and sex-matched, non-diabetic, PAD participants who were recruited and clinically stratified based on the Rutherford classification into CLTI (n = 18) and intermittent claudication (IC, n = 20). Compared to the non-PAD controls (n = 20), PAD patients had lower serum concentrations of creatine, histidine, lysine, oxoproline, monomethylarginine, as well as higher circulating phenylacetylglutamine (p < 0.05). Importantly, CLTI cases exhibited higher serum concentrations of carnitine, creatinine, cystine and trimethylamine-N-oxide along with lower circulating fatty acids relative to well matched IC patients. Most serum metabolites associated with PAD progression were also correlated with ABI (r = ±0.24−0.59, p < 0.05), whereas the ratio of stearic acid to carnitine, and arginine to propionylcarnitine differentiated CLTI from IC with good accuracy (AUC = 0.87, p = 4.0 × 10−5). This work provides new biochemical insights into PAD progression for the early detection and surveillance of high-risk patients who may require peripheral vascular intervention to prevent amputation and premature death.