bluuebunny/crossref_metadata_2025 huggingface dataset:
Extending Thrombolysis in Acute Ischemic Stroke to Primary Care: Early Experiences with a Network-Based Teleneurology Approach
Authors: Corea Francesco , Acciarresi Monica , Bernetti Laura , Brustenghi Pierluigi , Guidubaldi Arianna , Maiotti Mariangela , Micheli Sara , Pierini Vilma , Gamboni Alessio , Calabrò Giuseppe , Busti Chiara , Magistrato Cesare , Proietti-Silvestri Gianluca , Bracaccia Massimo , Caso Valeria , Zampolini Mauro
Published: January 2022

Background and Purpose—Systemic thrombolysis represents the main proven therapy for acute ischemic stroke, but safe treatment is reported only in well-established stroke units. To extend the use of tissue plasminogen activator (tPA) treatment in primary care hospitals on isolated areas through telemedic was the purpose of specific initiatives in southern Umbria, Italy. Methods—The stroke center of Foligno established a telestroke network to provide consultations for three local hospitals in southern Umbria. The telemedic system consists of a digital network that includes a two-way video conference system and imaging sharing. The main network hospital established specialized stroke wards/teams in which qualified teams treat acute stroke patients. Physicians in these hospitals are able to contact the stroke centers 24 h per day. Quality data are available to support the safe implementation of the stroke procedures. Those available from governmental authorities and local datasets are volume of hospitalization, in-hospital mortality, 30-days mortality, and discharge setting. Objective of the study was to assess the annual hospitalization volume in both the hub and spoke hospitals for ischemic stroke and appraise the performance of the network after the introduction of the telestroke system. Results—A total of 225 systemic thrombolyses were performed in time period indicated above all hospitals. In the main spoke hospital, 41 procedures were performed after teleconsultations were made available. The thrombolysis rate in the hub hospital ranged between 10% in 2016 and 20% in 2019, while in the spoke hospital was below 5% in 2016 and raised to 15% in 2019. The statistically significant difference, in the number of procedures, between hub and spoke in the beginning of the observation time disappeared after introduction of the telestroke network. No increase of the mortality was found. Conclusions—The present data suggest that systemic thrombolysis indicated via stroke experts in the setting of teleconsultation shows similar complication rates to those reported in the National Institute of Neurological Disorders and Stroke trial. Therefore, tPA treatment is also safe in this context and can be extended to primary hospitals.
COVID-19 Mortality in Europe, by Latitude and Obesity Status: A Geo-Spatial Analysis in 40 Countries
Authors: Tyrovolas Stefanos , Tsiampalis Thomas , Morena Marianthi , Leung Angela Y. M. , Faka Antigoni , Chalkias Christos , Tsiodras Sotirios , Panagiotakos Dimosthenes
Published: January 2022

On 30 January 2020, the World Health Organization (WHO) declared the current novel coronavirus disease 2019 (COVID-19) as a public health emergency of international concern and later characterized it as a pandemic. New data show that excess body mass and vitamin D deficiency might be related to the disease severity and mortality. The aim of this study was to evaluate whether latitude, as a proxy of sunlight exposure and Vitamin D synthesis, and prevalent obesity among European populations, is related to COVID-19 spread and severity. European COVID-19 data (incidence and fatality), including information on the prevalence of obesity, social distancing, and others were obtained by the “Our World in Data” website on 17 April 2021. Adjusted analysis showed that higher COVID-19 incidence and fatality were pictured in countries being in higher latitude, both during the whole period, as well as, during the time period 1 November 2020–31 March 2021. Higher incidence and fatality of COVID-19 were observed where the prevalence of overweight/obesity was higher during the whole time period, whereas during the time period 1 November 2020–31 March 2021, only COVID-19 incidence was higher but not a fatality. The present results provide insights for targeted interventions and preventive strategies against COVID-19.
Investigating the Postprandial Metabolome after Challenge Tests to Assess Metabolic Flexibility and Dysregulations Associated with Cardiometabolic Diseases
Authors: Lépine Gaïa , Tremblay-Franco Marie , Bouder Sabrine , Dimina Laurianne , Fouillet Hélène , Mariotti François , Polakof Sergio
Published: January 2022

This review focuses on the added value provided by a research strategy applying metabolomics analyses to assess phenotypic flexibility in response to different nutritional challenge tests in the framework of metabolic clinical studies. We discuss findings related to the Oral Glucose Tolerance Test (OGTT) and to mixed meals with varying fat contents and food matrix complexities. Overall, the use of challenge tests combined with metabolomics revealed subtle metabolic dysregulations exacerbated during the postprandial period when comparing healthy and at cardiometabolic risk subjects. In healthy subjects, consistent postprandial metabolic shifts driven by insulin action were reported (e.g., a switch from lipid to glucose oxidation for energy fueling) with similarities between OGTT and mixed meals, especially during the first hours following meal ingestion while differences appeared in a wider timeframe. In populations with expected reduced phenotypic flexibility, often associated with increased cardiometabolic risk, a blunted response on most key postprandial pathways was reported. We also discuss the most suitable statistical tools to analyze the dynamic alterations of the postprandial metabolome while accounting for complexity in study designs and data structure. Overall, the in-depth characterization of the postprandial metabolism and associated phenotypic flexibility appears highly promising for a better understanding of the onset of cardiometabolic diseases.
The Immunologic Profile of Vitamin D and Its Role in Different Immune-Mediated Diseases: An Expert Opinion
Authors: Giannini Sandro , Giusti Andrea , Minisola Salvatore , Napoli Nicola , Passeri Giovanni , Rossini Maurizio , Sinigaglia Luigi
Published: January 2022

Historically, vitamin D is recognized as an essential component for the maintenance of the musculoskeletal system. The immunomodulatory role of vitamin D in health and disease has gained much interest in recent years due to the many pathologies that share underlying immunological features where vitamin D has been shown to exert a potential role. Evidence from pre-clinical studies show that vitamin D elicits biological effects on both the innate and adaptive immune systems. Furthermore, in vivo studies have shown that administration of vitamin D can lead to changes in or the development of a range of immune-related diseases. This encourages the hypothesis that data derived from clinical and epidemiological studies connect vitamin D with the incidence and severity of many immune-mediated disorders such as rheumatoid arthritis, diabetes, and infectious diseases. Since some other immune-mediated diseases share similar features to that of viral infection such as COVID-19, in this review, we examined these other areas and the role of vitamin D in these diseases.
Association of Food Allergy, Respiratory Allergy, and Skin Allergy with Attention Deficit/Hyperactivity Disorder among Children
Authors: Xu Guifeng , Liu Buyun , Yang Wenhan , Snetselaar Linda G. , Chen Mingwu , Bao Wei , Strathearn Lane
Published: January 2022

Background: Previous studies have predominately examined associations of respiratory allergy and skin allergy with ADHD, but little is known about the association between food allergy and ADHD. Methods: We included 192,573 children aged 4–17 years from the National Health Interview Survey (NHIS), a leading health survey in a nationally representative sample of the US population. Allergy conditions and ADHD were defined based on an affirmative response in the NHIS questionnaire. We used weighted logistic regression to estimate the odds ratio (OR) of ADHD. Results: Among the 192,573 children, 15,376 reported ADHD diagnosis. The prevalence of ADHD was higher among children with allergic conditions: 12.66% vs. 7.99% among children with and without food allergy; 12.16% vs. 7.63% among children with and without respiratory allergy; and 11.46% vs. 7.83% among children with and without skin allergy. After adjusting for covariates, the OR of ADHD was 1.72 (95% CI, 1.55–1.91) comparing children with and without food allergy, 1.50 (95% CI, 1.41–1.59) comparing children with and without respiratory allergy, and 1.65 (95% CI, 1.55–1.75) comparing children with and without skin allergy. The observed associations remained significant after mutual adjustment for other allergic conditions. Conclusions: In a nationally representative sample of US children, we found a significant association of common allergic conditions (food allergy, respiratory allergy, and skin allergy) with ADHD.
Homemade Food Allergen Extracts for Use in Skin Prick Tests in the Diagnosis of IgE-Mediated Food Allergy: A Good Alternative in the Absence of Commercially Available Extracts?
Authors: Terlouw Severina , van Boven Frank E. , Borsboom-van Zonneveld Monika , de Graaf-in ‘t Veld Catharina , van Splunter Marloes E. , van Daele Paul L. A. , van Maaren Maurits S. , Schreurs Marco W. J. , de Jong Nicolette W.
Published: January 2022

Introduction: The skin prick test (SPT) is the first step in the diagnosis of an immunoglobulin E (IgE)-mediated food allergy. The availability of commercial food allergen extracts is very limited, resulting in a need for alternative extraction methods of food allergens. The objective of this study was to compare the SPT results of homemade food allergen extracts with commercially available extracts. Methods: Adult patients with a suspected food allergy were included. Food allergen-specific symptoms were scored using a questionnaire. SPTs were performed with homemade and commercially available extracts (ALK-Abelló, Kopenhagen, Denmark) from almond, apple, hazelnut, peach, peanut, and walnut. Serum-specific IgE was measured with ISAC or ImmunoCAP™. Intra-class correlation coefficients (ICC) between the SPT results of both extract methods were calculated. The proportion of agreement with food allergen-specific symptoms was analyzed. Results: Fifty-four patients (mean age 36; range 19–69 years; female/male: 42/12) were included. The intra-class correlation coefficient (ICC) between the SPT results of both extract methods were strong for hazelnut 0.79 (n = 44) and walnut 0.78 (n = 31), moderate for apple 0.74 (n = 21) and peanut 0.66 (n = 28), and weak for almond 0.36 (n = 27) and peach 0.17 (n = 23). The proportion of agreement between SPT results and food allergen-specific symptoms was comparable for homemade and commercially available extracts, except for peach; 0.77 versus 0.36, respectively. Conclusion: In the diagnostic procedures to identify an IgE-mediated food allergy, homemade extracts from hazelnut and walnut appear to be a good alternative in the absence of commercially available food allergen extracts.
Breast Cancer Diet “BCD”: A Review of Healthy Dietary Patterns to Prevent Breast Cancer Recurrence and Reduce Mortality
Authors: Cava Edda , Marzullo Paolo , Farinelli Deborah , Gennari Alessandra , Saggia Chiara , Riso Sergio , Prodam Flavia
Published: January 2022

Breast cancer (BC) represents the most common cancer in women, while overweight and obesity are the second preventable cause of cancer. Weight gain and fat accumulation are common after BC diagnosis; moreover, weight gain during the treatment decreases the survival rate and increases the risk of recurrence in breast cancer survivors (BCS). To reduce the risk of second primary cancer or BC recurrence, and all-cause mortality in BCS, multiple interventions have been investigated to obtain reduction in weight, BMI and/or waist circumference. The aim of this narrative review is to analyze evidence on BCS for their risk of recurrence or mortality related to increased weight or fat deposition, and the effects of interventions with healthy dietary patterns to achieve a proper weight and to reduce fat-related risk. The primary focus was on dietary patterns instead of single nutrients and supplements, as the purpose was to investigate on secondary prevention in women free from disease at the end of their cancer treatment. In addition, BC relation with insulin resistance, dietary carbohydrate, and glycemic index/glycemic load is discussed. In conclusion, obesity and overweight, low rates of physical activity, and hormone receptor-status are associated with poorer BC-treatment outcomes. To date, there is a lack of evidence to suggest which dietary pattern is the best approach for weight management in BCS. In the future, multimodal lifestyle interventions with dietary, physical activity and psychological support after BC diagnosis should be studied with the aim of reducing the risk of BC recurrence or mortality.
Modulatory Properties of Food and Nutraceutical Components Targeting NLRP3 Inflammasome Activation
Authors: Spano Mattia , Di Matteo Giacomo , Ingallina Cinzia , Ambroselli Donatella , Carradori Simone , Gallorini Marialucia , Giusti Anna Maria , Salvo Andrea , Grosso Michela , Mannina Luisa
Published: January 2022

Inflammasomes are key intracellular multimeric proteins able to initiate the cellular inflammatory signaling pathway. NLRP3 inflammasome represents one of the main protein complexes involved in the development of inflammatory events, and its activity has been largely demonstrated to be connected with inflammatory or autoinflammatory disorders, including diabetes, gouty arthritis, liver fibrosis, Alzheimer’s disease, respiratory syndromes, atherosclerosis, and cancer initiation. In recent years, it has been demonstrated how dietary intake and nutritional status represent important environmental elements that can modulate metabolic inflammation, since food matrices are an important source of several bioactive compounds. In this review, an updated status of knowledge regarding food bioactive compounds as NLRP3 inflammasome modulators is discussed. Several chemical classes, namely polyphenols, organosulfurs, terpenes, fatty acids, proteins, amino acids, saponins, sterols, polysaccharides, carotenoids, vitamins, and probiotics, have been shown to possess NLRP3 inflammasome-modulating activity through in vitro and in vivo assays, mainly demonstrating an anti-NLRP3 inflammasome activity. Plant foods are particularly rich in important bioactive compounds, each of them can have different effects on the pathway of inflammatory response, confirming the importance of the nutritional pattern (food model) as a whole rather than any single nutrient or functional compound.
Clinical Manifestation and Diagnostic Process of Celiac Disease in Poland—Comparison of Pediatric and Adult Patients in Retrospective Study
Authors: Majsiak Emilia , Choina Magdalena , Gray Alastair M. , Wysokiński Mariusz , Cukrowska Bożena
Published: January 2022

The diagnosis of celiac disease (CD) may be delayed due to non-specific clinical symptoms. The aim of the study was to evaluate the clinical manifestation and diagnostic process of CD in Polish children and adults. Methods: The members of the Polish Coeliac Society (n = 2500) were asked to complete a questionnaire on socio-demographic factors, clinical and diagnostic aspects of CD. The analysis was based on 796 responses from patients with confirmed CD diagnosis, and included 224 (28.1%) children and 572 (71.9%) adults. Results: The mean duration of symptoms prior to CD diagnosis in children was significantly shorter than in adults (p < 0.001), and amounted to 3.1 and 9 years respectively. The most frequent symptoms before CD diagnosis were abdominal pain and bloating in children (70.4%), and chronic fatigue in adults (74.5%). Although almost all CD patients claimed to strictly avoid gluten after CD diagnosis, symptoms were still present in the majority of these respondents. No comorbid diseases were reported by 29.8% of children and by 11.7% of adults (p < 0.001). Conclusions: the results indicate that CD diagnosis is delayed in Poland, especially in adults, and clinicians should be aware of the diversity in CD presentation.
Nutrition in Abrupt Sunlight Reduction Scenarios: Envisioning Feasible Balanced Diets on Resilient Foods
Authors: Pham Alix , García Martínez Juan B. , Brynych Vojtech , Stormbjorne Ratheka , Pearce Joshua M. , Denkenberger David C.
Published: January 2022

Abrupt sunlight reduction scenarios (ASRS) following catastrophic events, such as a nuclear war, a large volcanic eruption or an asteroid strike, could prompt global agricultural collapse. There are low-cost foods that could be made available in an ASRS: resilient foods. Nutritionally adequate combinations of these resilient foods are investigated for different stages of a scenario with an effective response, based on existing technology. While macro- and micronutrient requirements were overall met, some—potentially chronic—deficiencies were identified (e.g., vitamins D, E and K). Resilient sources of micronutrients for mitigating these and other potential deficiencies are presented. The results of this analysis suggest that no life-threatening micronutrient deficiencies or excesses would necessarily be present given preparation to deploy resilient foods and an effective response. Careful preparedness and planning—such as stock management and resilient food production ramp-up—is indispensable for an effective response that not only allows for fulfilling people’s energy requirements, but also prevents severe malnutrition.
Assessment of the Cholesterol-Lowering Effect of MOMAST®: Biochemical and Cellular Studies
Authors: Bartolomei Martina , Bollati Carlotta , Li Jianqiang , Arnoldi Anna , Lammi Carmen
Published: January 2022

MOMAST® is a patented phenolic complex derived from the olive oil vegetation water, a by-product of the olive oil supply chain, in which hydroxytyrosol (OH-Tyr) and tyrosol (Tyr) and verbascoside are the main compounds. This study was aimed at investigating its hypocholesterolemic effect by assessing the ability to modulate the low-density lipoprotein (LDL) receptor (LDLR)/sterol regulatory element-binding protein 2 (SREBP-2), and proprotein convertase subtilisin/kexin type 9 (PCSK9) pathways. MOMAST® inhibits the in vitro activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCOAR) with a dose-response trend. After the treatment of HepG2 cells, MOMAST® increases the SREBP-2, LDLR, and HMGCoAR protein levels leading, from a functional point of view to an improved ability of hepatic cells to up-take LDL from the extracellular environment with a final cholesterol-lowering effect. Furthermore, MOMAST® decreased the PCSK9 protein levels and its secretion in the extracellular environment, presumably via the reduction of the hepatic nuclear factor 1-α (HNF1-α). The experiments were performed in parallel, using pravastatin as a reference compound. Results demonstrated that MOMAST® may be exploited as a new ingredient for the development of functional foods and/or nutraceuticals for cardiovascular disease prevention.
Predictive Factors for Oral Immune Modulation in Cow Milk Allergy
Authors: Muntean Ioana Adriana , Bocsan Ioana Corina , Wiest Lena Katharina , Pintea Irena , Dobrican Carmen Teodora , Duca Emanuela , Ureche Corina , Buzoianu Anca Dana , Deleanu Diana
Published: January 2022

Aim: The present study analyzed clinical and biological factors that might predict achievement of tolerance in patients with IgE-mediated cow milk allergy (CMA). Method: Seventy patients with IgE-mediated CMA (44.24 ± 24.16 months) were included in the study. The patients were evaluated clinically through skin prick test and sIgE to whole milk, casein, beta-lactoglobulin and alpha-lactalbumin. An eviction diet of 6 months was established, followed by oral food challenge test (OFC) and oral immunotherapy (OIT) with baked milk for 6 months. The tolerance was assessed after 2 years follow up. Results: Thirty percent of patients presented anaphylaxis of different degrees of severity as first manifestation of CMA. Sixty-two patients followed OIT or an accelerated reintroduction of milk. Ten patients (14.28%) did not obtain tolerance to milk within 2 years. A larger wheal in SPT and higher sIgE to milk, casein and betalactoglobulin were noted in patients with positive OFC. A basal level of <2.5 kU/l for sIgE to milk and <11.73 kU/l for sIgE to caseins predicted the occurrence of tolerance in patients with all types of clinical manifestations, including anaphylaxis. Conclusion: Basal levels of sIgE to milk and casein may help to identify patients that could become tolerant to milk.
Evaluation of Serological Methods and a New Real-Time Nested PCR for Small Ruminant Lentiviruses
Authors: Schaer Jessica , Cvetnic Zeljko , Sukalic Tomislav , Dörig Sven , Grisiger Martin , Iscaro Carmen , Feliziani Francesco , Pfeifer Folke , Origgi Francesco , Zanoni Reto Giacomo , Abril Carlos Eduardo
Published: January 2022

Small ruminant lentiviruses (SRLVs), i.e., CAEV and MVV, cause insidious infections with life-long persistence and a slowly progressive disease, impairing both animal welfare and productivity in affected herds. The complex diagnosis of SRLVs currently combines serological methods including whole-virus and peptide-based ELISAs and Immunoblot. To improve the current diagnostic protocol, we analyzed 290 sera of animals originating from different European countries in parallel with three commercial screening ELISAs, Immunoblot as a confirmatory assay and five SU5 peptide ELISAs for genotype differentiation. A newly developed nested real-time PCR was carried out for the detection and genotype differentiation of the virus. Using a heat-map display of the combined results, the drawbacks of the current techniques were graphically visualized and quantified. The immunoblot and the SU5-ELISAs exhibited either unsatisfactory sensitivity or insufficient reliability in the differentiation of the causative viral genotype, respectively. The new truth standard was the concordance of the results of two out of three screening ELISAs and the PCR results for serologically false negative samples along with genotype differentiation. Whole-virus antigen-based ELISA showed the highest sensitivity (92.2%) and specificity (98.9%) among the screening tests, whereas PCR exhibited a sensitivity of 75%.
Epstein–Barr Virus Infection in Lung Cancer: Insights and Perspectives
Authors: Osorio Julio C. , Blanco Rancés , Corvalán Alejandro H. , Muñoz Juan P. , Calaf Gloria M. , Aguayo Francisco
Published: January 2022

Lung cancer (LC) is the leading cause of cancer death worldwide. Tobacco smoke is the most frequent risk factor etiologically associated with LC, although exposures to other environmental factors such as arsenic, radon or asbestos are also involved. Additionally, the involvement of some viral infections such as high-risk human papillomaviruses (HR-HPVs), Merkel cell polyomavirus (MCPyV), Jaagsiekte Sheep Retrovirus (JSRV), John Cunningham Virus (JCV), and Epstein–Barr virus (EBV) has been suggested in LC, though an etiological relationship has not yet been established. EBV is a ubiquitous gamma herpesvirus causing persistent infections and some lymphoid and epithelial tumors. Since EBV is heterogeneously detected in LCs from different parts of the world, in this review we address the epidemiological and experimental evidence of a potential role of EBV. Considering this evidence, we propose mechanisms potentially involved in EBV-associated lung carcinogenesis. Additional studies are warranted to dissect the role of EBV in this very frequent malignancy.
The Relevance of TLR8 in Viral Infections
Authors: Martínez-Espinoza Iván , Guerrero-Plata Antonieta
Published: January 2022

Toll-like receptors (TLRs) are the largest pattern recognition receptors responsible for activating the innate and adaptive immune response against viruses through the release of inflammatory cytokines and antiviral mediators. Viruses are recognized by several TLRs, including TLR8, which is known to bind ssRNA structures. However, the similarities between TLR8 and TLR7 have obscured the distinctive characteristics of TLR8 activation and its importance in the immune system. Here we discuss the activation and regulation of TLR8 by viruses and its importance in therapeutical options such as vaccine adjuvants and antiviral stimulators.
Prioritisation of Provinces for African Swine Fever Intervention in South Africa through Decision Matrix Analysis
Authors: Janse van Rensburg Leana , Penrith Mary-Louise , Etter Eric M. C.
Published: January 2022

South Africa has experienced an increase in the number of African swine fever (ASF) outbreaks in domestic pigs in the last ten years. Intervention will be needed in the form of control and prevention strategies to minimise the impact of this disease in the country. The aim of this study is to prioritise which provinces resources should be allocated to for ASF intervention strategies, based on the risk factors identified as pertinent in South Africa. A multi-criteria decision analysis approach was followed using an analytic hierarchy process (AHP) method to determine the perceived risk of ASF outbreaks in domestic pigs per province. Nine risk factors applicable to the South African context were identified from literature. Data on the presence of these risk factors per province were collected from records and by means of a questionnaire. The risk factors were weighted by means of an AHP. The decision matrix determined that ASF intervention and prevention resources should be focused on Mpumalanga, Free State and Gauteng provinces in South Africa. Specific intervention strategies should be focused on the confinement of pigs, swill-feeding of pigs and buying/selling of pigs at auctions through a participatory approach with stakeholders.
Development of Cathepsin L-like Real-Time PCR Assays for the Detection of African Animal Trypanosomosis (AAT) in South Africa
Authors: Mnkandla Samantha , Neves Luis , Vorster Ilse , Bhoora Raksha Vasantrai
Published: January 2022

African animal trypanosomosis (AAT), is an infectious parasitic disease of wildlife and livestock caused by multiple species and strains of Trypanosoma. In South Africa, it is restricted to northern KwaZulu-Natal (NKZN) and caused by Trypanosoma congolense and Trypanosoma vivax. A cross-sectional study was done to determine AAT prevalence in 384 goat samples and identify trypanosome species circulating in 60 cattle at dip tanks that are on the interface with the Hluhluwe-uMfolozi game reserve in NKZN. Both cattle and goat samples were analyzed using the buffy coat technique (BCT) and a polymerase chain reaction (PCR) assay targeting the internal transcribed spacer 1 (ITS) region. Cattle samples were further analyzed using an ITS quantitative real-time PCR (qPCR) assays designed for the detection of T. congolense, T. vivax, and T. brucei. None of the goat samples tested positive for Trypanosoma infections. The ITS qPCR assay detected Trypanosoma DNA in 30% of the cattle samples, while only 8.3% were positive with the ITS PCR and 11.7% were positive using BCT. Quantitative real-time PCR assays were designed to amplify a 98 bp, 137 bp, and 116 bp fragment of the cathepsin L-like (CATL) gene from T. brucei, T. theileri, and T. congolense, respectively. Each assay was shown to be efficient (>94%) and specific (109 to 102/101 copies/reaction) in the detection of Trypanosoma species. The CATL qPCR assays detected T. congolense and T. theileri infections in 33.3% of the cattle samples. The CATL qPCR assays also detected T. congolense infections in goats (23.1%) that were neither detected by BCT nor the ITS PCR. The CATL qPCR assays provide an additional, sensitive, and specific tool for Trypanosoma diagnostics. The presence of trypanosomes in goats suggests they might be potential reservoirs of infections to other livestock.
Response Predictive Markers and Synergistic Agents for Drug Repositioning of Statins in Ovarian Cancer
Authors: Kobayashi Yusuke , Takeda Takashi , Kunitomi Haruko , Chiwaki Fumiko , Komatsu Masayuki , Nagai Shimpei , Nogami Yuya , Tsuji Kosuke , Masuda Kenta , Ogiwara Hideaki , Sasaki Hiroki , Banno Kouji , Aoki Daisuke
Published: January 2022

In the field of drug repurposing, the use of statins for treating dyslipidemia is considered promising in ovarian cancer treatment based on epidemiological studies and basic research findings. Biomarkers should be established to identify patients who will respond to statin treatment to achieve clinical application. In the present study, we demonstrated that statins have a multifaceted mode of action in ovarian cancer and involve pathways other than protein prenylation. To identify biomarkers that predict the response to statins, we subjected ovarian cancer cells to microarray analysis and calculated Pearson’s correlation coefficients between gene expression and cell survival after statin treatment. The results showed that VDAC1 and LDLRAP1 were positively and negatively correlated with the response to statins, respectively. Histoculture drug response assays revealed that statins were effective in clinical samples. We also confirmed the synergistic effects of statins with paclitaxel and panobinostat and determined that statins are hematologically safe to administer to statin-treated mice. Future clinical trials based on the expression of the biomarkers identified in this study for repurposing statins for ovarian cancer treatment are warranted.
Combined Administration of (R)-Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Induces Rapid and Sustained Effects in the CUMS Model of Depression via a TrkB/BDNF-Dependent Mechanism
Authors: Rafało-Ulińska Anna , Brański Piotr , Pałucha-Poniewiera Agnieszka
Published: January 2022

Ketamine is an effective, rapid-acting antidepressant drug (RAAD), but it induces side effects. To overcome these challenges, attempts have been made to use safer enantiomer ((R)-ketamine) or mGlu2/3 receptor antagonists, which induce ketamine-like effects and enhance its action. Here, we propose combining these two strategies to investigate the antidepressant-like effects of low doses of two ketamine enantiomers in combination with a low dose of the mGlu2/3 receptor antagonist LY341495. Rapid and sustained antidepressant-like effects were assessed in C57BL/6J mice using the tail suspension test (TST) and the chronic unpredictable mild stress (CUMS) model of depression in stress-naïve mice. ELISA was used to measure BDNF levels. In the TST, low doses of both (S)-ketamine and (R)-ketamine were potentiated by a subeffective dose of LY341495. However, in the CUMS model, only (R)-ketamine was able to induce long-lasting anti-apathetic and anti-anhedonic effects when coadministered with low-dose LY341495. The mechanism of this drug combination was dependent on BDNF and AMPA receptor activity. ELISA results suggest that the hippocampus might be the site of this action. MGlu2/3 receptor antagonists, in combination with (R)-ketamine, may serve as potential RAADs, with a high efficiency and low risk of side effects.
Development and Validation of Open-Source R Package HMCtdm for Therapeutic Drug Monitoring
Authors: Lee Sooyoung , Song Moonsik , Lim Woojae , Song Eunjung , Han Jongdae , Kim Bo-Hyung
Published: January 2022

Most therapeutic drug monitoring (TDM) packages are based on the maximum a posteriori (MAP) estimation. In this study, HMCtdm, a new TDM package, was developed using a Hamiltonian Monte Carlo (HMC) simulation. The estimation process of HMCtdm for the drugs amikacin, vancomycin, theophylline, and phenytoin was based on the R package Torsten. The prior pharmacokinetic (PK) models of the drugs were derived from the Abbottbase® pharmacokinetics systems (PKS) program. The performance of HMCtdm for each drug was assessed through internal and external validations. The internal validation results of the HMCtdm were compared with those of a MAP-based estimation. The developed open-source HMCtdm package is user friendly. The validation results were reviewed and interpreted using the mean percentage error and root mean squared error. The successful transplantation of the prior PK structures (used in PKS) was confirmed by comparing the validation results with a MAP estimation. An open-source HMC-based TDM package was also successfully developed in this study, and its performance was evaluated. This package can be operated by users unfamiliar with C++ and can be further developed for various applications.
The Effects of Statins on Prostate Cancer Patients Receiving Androgen Deprivation Therapy or Definitive Therapy: A Systematic Review and Meta-Analysis
Authors: Hou Yu-Chen , Shao Yu-Hsuan
Published: January 2022

Mortality associated with statin use has been reported in prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) or definitive therapy in several observational studies, although the results have varied. This study aimed to analyze the association of statin use with all-cause mortality and cancer-specific mortality among PCa patients receiving ADT or definitive therapy as their primary treatment and to examine the effect of statin initiation (pre-ADT) timing on outcomes. A systematic literature search of PubMed, the Cochrane library, and Embase was conducted from database inception to 4 October 2021. In total, 12 eligible studies from 976 references were included in the final analysis. The results showed that statin use was associated with a significant reduction in the risks of all-cause mortality (hazard ratio (HR) = 0.73, 95% confidence interval (CI) = 0.64–0.84, p < 0.0001) and cancer-specific mortality (HR = 0.61, 95% CI = 0.49–0.77, p < 0.0001) in PCa patients receiving ADT. However, statin use before ADT initiation did not significantly lower the risk of all-cause mortality (HR = 0.87, 95% CI = 0.66–1.16, p = 0.35) or cancer-specific mortality (HR = 0.84, 95% CI = 0.62–1.13, p = 0.25) in advanced PCa patients receiving ADT. In contrast, statin use was not associated with a significantly reduced risk of all-cause mortality (HR = 0.69, 95% CI = 0.39–1.21, p = 0.20), but it was associated with a reduced risk of cancer-specific mortality (HR = 0.82, 95% CI = 0.68–0.98, p = 0.03) in PCa patients receiving definitive therapy. This review indicated that statin use in combination with ADT was correlated with better all-cause and cancer-specific mortality in PCa patients. However, the beneficial effect might not come from statin use before ADT initiation. In addition, statin use in combination with definitive therapy was correlated with a reduced risk of cancer-specific mortality in PCa patients. In the future, randomized controlled trials are needed to validate the efficacy of statin use in combination with primary treatment for PCa among PCa patients.
Evaluation of Docking Machine Learning and Molecular Dynamics Methodologies for DNA-Ligand Systems
Authors: de Oliveira Tiago Alves , Medaglia Lucas Rolim , Maia Eduardo Habib Bechelane , Assis Letícia Cristina , de Carvalho Paulo Batista , da Silva Alisson Marques , Taranto Alex Gutterres
Published: January 2022

DNA is a molecular target for the treatment of several diseases, including cancer, but there are few docking methodologies exploring the interactions between nucleic acids with DNA intercalating agents. Different docking methodologies, such as AutoDock Vina, DOCK 6, and Consensus, implemented into Molecular Architect (MolAr), were evaluated for their ability to analyze those interactions, considering visual inspection, redocking, and ROC curve. Ligands were refined by Parametric Method 7 (PM7), and ligands and decoys were docked into the minor DNA groove (PDB code: 1VZK). As a result, the area under the ROC curve (AUC-ROC) was 0.98, 0.88, and 0.99 for AutoDock Vina, DOCK 6, and Consensus methodologies, respectively. In addition, we proposed a machine learning model to determine the experimental ∆Tm value, which found a 0.84 R2 score. Finally, the selected ligands mono imidazole lexitropsin (42), netropsin (45), and N,N′-(1H-pyrrole-2,5-diyldi-4,1-phenylene)dibenzenecarboximidamide (51) were submitted to Molecular Dynamic Simulations (MD) through NAMD software to evaluate their equilibrium binding pose into the groove. In conclusion, the use of MolAr improves the docking results obtained with other methodologies, is a suitable methodology to use in the DNA system and was proven to be a valuable tool to estimate the ∆Tm experimental values of DNA intercalating agents.
Methylomic Biomarkers of Lithium Response in Bipolar Disorder: A Proof of Transferability Study
Authors: Marie-Claire Cynthia , Courtin Cindie , Bellivier Frank , Scott Jan , Etain Bruno
Published: January 2022

Response to lithium (Li) is highly variable in bipolar disorders (BD) and no clinical or biological predictors of long-term response have been validated to date. Using a genome-wide methylomic approach (SeqCapEpi), we previously identified seven differentially methylated regions (DMRs) that discriminated good from non-responders (prophylactic response phenotype defined using the “Alda” scale). This study is a proof of transferability from bench to bedside of this epigenetic signature. For this purpose, we used Methylation Specific High-Resolution Melting (MS-HRM), a PCR based method that can be implemented in any medical laboratory at low cost and with minimal equipment. In 23 individuals with BD, MS-HRM measures of three out of seven DMRs were technically feasible and consistencies between SeqCapEpi and MS-HRM-measures were moderate to high. In an extended sample of individuals with BD (n = 70), the three MS-HRM-measured DMRs mainly predicted nonresponse, with AUC between 0.70–0.80 according to different definitions of the phenotype (Alda- or machine-learning-based definitions). Classification tree analyses further suggested that the MS-HRM-measured DMRs correctly classified up to 84% of individuals as good or non-responders. This study suggested that epigenetic biomarkers, identified in a retrospective sample, accurately discriminate non-responders from responders to Li and may be transferrable to routine practice.
Smartcrystals for Efficient Dissolution of Poorly Water-Soluble Meloxicam
Authors: Ambrus Rita , Alshweiat Areen , Szabó-Révész Piroska , Bartos Csilla , Csóka Ildikó
Published: January 2022

Nanocrystal is widely applied to improve the dissolution of poorly water-soluble drugs. We aimed to prepare meloxicam (MLX) nanocrystals using the bead mill method, followed by high-pressure homogenization (HPH). Simple drying at room temperature (RD), vacuum-drying (VD), and freeze-drying (FD) using mannitol or trehalose as a cryoprotectant were applied to obtain dry nanocrystals. The nanocrystals were fully characterized. The MLX nanosuspension containing 5% w/v MLX and 1% w/v of Pluronic F68 showing a mean particle size (MPS) of 242 nm and a polydispersity index (PDI) of 0.36 was prepared after 40 min of premilling and 30 min of HPH. The dried nanocrystals were spherical within the nano range. DSC and XRPD confirmed the absence of MLX amorphization. The smartcrystals showed enhanced MLX release. Approximately 100% release was achieved with phosphate buffer (PB), pH 5.6, and 80% was released with PB, pH 7.4, from the freeze-dried samples. The results revealed the effects of the drying method and cryoprotectant type on the properties of dry nanocrystals. The freeze-dried samples showed the smallest particle size, in particular trehalose-based samples. On the other hand, mannitol-based dried samples showed the highest crystallinity index among all nanocrystals (77.8%), whereas trehalose showed the lowest (59.2%). These factors explained the dissolution differences among the samples.
Technology of Processing Plant Extracts Using an Aluminometasilicate Porous Carrier into a Solid Dosage Form
Authors: Kostelanská Klára , Kurhajec Slavomír , Pavloková Sylvie , Vetchý David , Gajdziok Jan , Franc Aleš
Published: January 2022

A method of preparing tablets called liquisolid technique is currently emerging. In these formulations, an important role is played by porous carriers, which are the basic building blocks of liquisolid systems (LSSs). The most common are microcrystalline cellulose (MCC), magnesium aluminometasilicates, silica aerogels, mesoporous silicates, clays, etc. In this study, magnesium aluminometasilicate is used to prepare modified LSS formulations with plant extracts as model drugs dissolved in water (W) or ethanol (E). The modification involves drying tablets in a microwave (MW) and hot air dryer (HA) for a specified period. Powder blends and tablets were evaluated for physical properties, and their antioxidant activity (AA) was measured in a modified dissolution by ferric reducing antioxidant power assay (FRAP). PLS and ANOVA were used to compare tablets properties depending on the composition and technology. The experiment is based on a previous one, in which the plant extracts were processed into tablets using a similar method. Therefore, extending the study to include more plants and the robust statistical evaluation and comparison of the products was a procedure to justify the suitability of the presented method for a wide range of liquid plant extracts. As a result, we obtained tablets with excellent physical properties, including a short disintegration and dissolution, which is problematic in tableted extracts.
A New Calcium(II)-Based Substitute for Enrofloxacin with Improved Medicinal Potential
Authors: Yan Hou-Tian , Liu Rui-Xue , Yang Qi-Zhen , Liu Yan-Cheng , Li Hong-Chang , Guo Rui-Feng , Wu Lin-Hua , Liu Li-Min , Liang Hong
Published: January 2022

Enrofloxacin (EFX) reacting with Ca(II) afforded a new complex, [Ca(EFX)2(H2O)4] (EFX-Ca), which was structurally characterized both in solid and solution chemistry. E. coli and S. typhi were tested to be the most sensitive strains for EFX-Ca. The LD50 value of EFX-Ca in mice was 7736 mg/kg, implying the coordination of EFX to Ca(II) effectively reduced its acute toxicity. EFX-Ca also decreased the plasma-binding rate and enhanced the drug distribution in rats along with longer elimination half-life. EFX-Ca also showed similar low in vivo acute toxicity and higher anti-inflammation induced by H2O2 or CuSO4 in zebrafish, with reactive oxygen species (ROS)-related elimination. The therapeutic effects of EFX-Ca on two types (AA and 817) of E. coli-infected broilers were also better than those of EFX, with cure rates of 78% and 88%, respectively. EFX-Ca showed promise as a bio-safe metal-based veterinary drug with good efficacy and lower toxicity.
Effects of Various Drying Times on the Properties of 3D Printed Orodispersible Films
Authors: Janigová Natália , Elbl Jan , Pavloková Sylvie , Gajdziok Jan
Published: January 2022

Orodispersible films are an innovative dosage form. Their main advantages are the application comfort and the possibility of personalization. This work aimed to evaluate the influence of different drying times on the properties of orodispersible films of various thicknesses, prepared in two different semisolid extrusion 3D printing setups. In the first experiment, drying times were dependent on the overall print time of each batch. In the second setup, the drying time was set equal according to the longest one. The evaluated parameters were films’ weight uniformity, thickness, moisture content, surface pH, disintegration time, hardness, and tensile strength. Upon statistical comparison, significant differences in the moisture content were found, subsequently affecting the disintegration time. Moreover, statistically significant differences in films’ mechanical properties (hardness, tensile strength) were also described, proving that moisture content simultaneously affects film plasticity and related properties. In conclusion, a mutual comparison of the manufactured orodispersible films showed that the drying time affects their physical and mechanical properties. The in-process drying setup was proved to be sufficient while allowing quicker manufacturing.
Pharmacophore-Based Discovery of Substrates of a Novel Drug/Proton-Antiporter in the Human Brain Endothelial hCMEC/D3 Cell Line
Authors: Smirnova Maria , Goracci Laura , Cruciani Gabriele , Federici Laetitia , Declèves Xavier , Chapy Hélène , Cisternino Salvatore
Published: January 2022

A drug/proton-antiporter, whose the molecular structure is still unknown, was previously evidenced at the blood-brain barrier (BBB) by functional experiments. The computational method could help in the identification of substrates of this solute carrier (SLC) transporter. Two pharmacophore models for substrates of this transporter using the FLAPpharm approach were developed. The trans-stimulation potency of 40 selected compounds for already known specific substrates ([3H]-clonidine) were determined and compared in the human brain endothelial cell line hCMEC/D3. Results. The two pharmacophore models obtained were used as templates to screen xenobiotic and endogenous compounds from four databases (e.g., Specs), and 45 hypothetical new candidates were tested to determine their substrate capacity. Psychoactive drugs such as antidepressants (e.g., imipramine, desipramine), antipsychotics/neuroleptics such as phenothiazine derivatives (chlorpromazine), sedatives anti-histamine-H1 drugs (promazine, promethazine, triprolidine, pheniramine), opiates/opioids (e.g., hydrocodone), trihexyphenidyl and sibutramine were correctly predicted as proton-antiporter substrates. The best performing pharmacophore model for the proton-antiporter substrates appeared as a good predictor of known substrates and allowed the identification of new substrate compounds. This model marks a new step in the characterization of this drug/proton-antiporter and will be of great use in uncovering its substrates and designing chemical entities with an improved influx capability to cross the BBB.
Angioprevention of Urologic Cancers by Plant-Derived Foods
Authors: García-Caballero Melissa , Torres-Vargas José Antonio , Marrero Ana Dácil , Martínez-Poveda Beatriz , Medina Miguel Ángel , Quesada Ana R.
Published: January 2022

The number of cancer cases worldwide keeps growing unstoppably, despite the undeniable advances achieved by basic research and clinical practice. Urologic tumors, including some as prevalent as prostate, bladder or kidney tumors, are no exceptions to this rule. Moreover, the fact that many of these tumors are detected in early stages lengthens the duration of their treatment, with a significant increase in health care costs. In this scenario, prevention offers the most cost-effective long-term strategy for the global control of these diseases. Although specialized diets are not the only way to decrease the chances to develop cancer, epidemiological evidence support the role of certain plant-derived foods in the prevention of urologic cancer. In many cases, these plants are rich in antiangiogenic phytochemicals, which could be responsible for their protective or angiopreventive properties. Angiogenesis inhibition may contribute to slow down the progression of the tumor at very different stages and, for this reason, angiopreventive strategies could be implemented at different levels of chemoprevention, depending on the targeted population. In this review, epidemiological evidence supporting the role of certain plant-derived foods in urologic cancer prevention are presented, with particular emphasis on their content in bioactive phytochemicals that could be used in the angioprevention of cancer.