bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunological Response to Exercise in Athletes with Disabilities: A Narrative Review of the Literature
Authors: Sellami Maha , Puce Luca , Bragazzi Nicola Luigi
Published: June 2023

For a person with a disability, participating in sports activities and/or competitions can be a challenge for the immune system. The relationship between exercise and immunity response in disabled athletes is, indeed, extremely complex for several reasons, including (1) the chronic low-grade inflammatory and immunodepression—“secondary immune deficiency”—state imposed by the disability/impairment; (2) the impact of the disability on an array of variables, spanning from physical fitness to well-being, quality of life, sleep, and nutritional aspects, among others, which are known to mediate/modulate the effects of exercise on human health; (3) the variability of the parameters related to the exercise/physical activity (modality, frequency, intensity, duration, training versus competition, etc.); and (4) the intra- and inter-individual variability of the immunological response to exercise. In able-bodied athletes, previously published data described several exercise-induced changes affecting various immunological subsets and subpopulations, ranging from neutrophils to lymphocytes, and monocytes. Broadly, moderate intensity workout is accompanied by optimal immunity and resistance to infections such as upper respiratory tract infections (URTI) in athletes. Periods of intense training with insufficient recovery can cause a temporary state of immunosuppression, which should end with a few days of rest/recovery from exercise. Disabled athletes are relatively overlooked and understudied with respect to their able-bodied counterparts. Findings from the few studies available on paralympic and disabled athletes are here summarized and analyzed utilizing a narrative approach to review and determine the major features of the immunological and inflammatory responses to exercise in this specific population. Moreover, a few studies have reported behavioral, dietary, and training strategies that can be adopted to limit exercise-induced immunosuppression and reduce the risk of infection in people with disabilities. However, given the paucity of data and contrasting findings, future high-quality investigations on paralympic and disabled athletes are urgently needed.
Variability in Grading Diabetic Retinopathy Using Retinal Photography and Its Comparison with an Automated Deep Learning Diabetic Retinopathy Screening Software
Authors: Teoh Chin Sheng , Wong Kah Hie , Xiao Di , Wong Hung Chew , Zhao Paul , Chan Hwei Wuen , Yuen Yew Sen , Naing Thet , Yogesan Kanagasingam , Koh Victor Teck Chang
Published: June 2023

Background: Diabetic retinopathy (DR) screening using colour retinal photographs is cost-effective and time-efficient. In real-world clinical settings, DR severity is frequently graded by individuals of different expertise levels. We aim to determine the agreement in DR severity grading between human graders of varying expertise and an automated deep learning DR screening software (ADLS). Methods: Using the International Clinical DR Disease Severity Scale, two hundred macula-centred fundus photographs were graded by retinal specialists, ophthalmology residents, family medicine physicians, medical students, and the ADLS. Based on referral urgency, referral grading was divided into no referral, non-urgent referral, and urgent referral to an ophthalmologist. Inter-observer and intra-group variations were analysed using Gwet’s agreement coefficient, and the performance of ADLS was evaluated using sensitivity and specificity. Results: The agreement coefficient for inter-observer and intra-group variability ranged from fair to very good, and moderate to good, respectively. The ADLS showed a high area under curve of 0.879, 0.714, and 0.836 for non-referable DR, non-urgent referable DR, and urgent referable DR, respectively, with varying sensitivity and specificity values. Conclusion: Inter-observer and intra-group agreements among human graders vary widely, but ADLS is a reliable and reasonably sensitive tool for mass screening to detect referable DR and urgent referable DR.
Consumer Preferences of Jalapeño Pepper in the Mexican Market
Authors: Sánchez Toledano Blanca Isabel , Camarena Gómez Dena María Jesús , López Santiago Marco Andrés , Cuevas Reyes Venancio
Published: June 2023

The jalapeño pepper is one of the best-known and most commonly consumed chili peppers in Mexico; its consumption is a tradition that dates to the first migrations of Europeans to the country. With time, its demand has increased, although in recent years its consumption presented a stabilization and stagnation. This work aimed to determine the preferences of Mexican consumers for jalapeño pepper, taking as a reference quality attributes and motivations that influence their purchasing and consumption habits, under the hypothesis that consumers in each region seek a certain type of jalapeño pepper based on specific quality attributes. In total, 1200 surveys were carried out in five regions of the country. The analysis of the information was performed using the ANOVA test, correspondence analysis, and multidimensional scaling. The main results of this study show that although there is a tendency towards frequent consumption, each purchase weighs less than 500 g. In the same way, the physical appearance of the product is fundamental at the time of purchase, in addition to other attributes such as flavor, color, and size, which are highly valued by consumers. Although there are similar consumption patterns, purchasing behaviors change by region, which can serve as a basis and spearhead for the development of differentiated strategies in the production and marketing of the product.
Selected Biotopes of Juniperus communis L. in Slovakia and Their Chemotype Determination
Authors: Salamon Ivan , Otepka Pavol , Kryvtsova Maryna , Kolesnyk Oleh , Hrytsyna Myroslava
Published: June 2023

The objective of this work was to map population of common juniper (Juniperus communis L.) in the territory of Slovak Republic. Common juniper is not protected by Slovakian law or the authorities; therefore, there is no law to preserve these plant populations. Biotopes of common juniper consist of light- to heavy-density trees and shrubs. The expansion of its habitat is also connected to human involvement. The loss of juniper naturally in observed plants is caused by a change in land use, loss of feeding pastures for cattle and sheep, and eutrophication of the environment. The current study was focused on monitoring the population of this plant species in the years of 2018–2020, the isolation of essential oils, and the identification of qualitative and quantitative characteristics. It was confirmed that juniper berries usually contain from 0.5 ± 0.05 to 1.8 ± 0.06%, usually 1.2 ± 0.16%, volatile oil depending on geography, altitude, ripeness, and other factors. Volatile oil is made up mostly of monoterpenes, mainly α-pinene (from 37.60 ± 2.23 to 61.00 ± 0.60%), β-myrcene (from 8.03 ± 2.02 to 10.56 ± 0.05%), and sabinene (from 3.50 ± 0.30 to 22.0 ± 0.96%). The dendrogram was constructed after a hierarchical cluster analysis based on the essential oil substances, which showed four different confirmed chemotypes. The essential oil is widely used in medicines, perfumes, insect repellents, insecticides, shoe polish, and in microscopy as a clearing agent of an immersion oil. The quality and chemotypes of juniper berries are very important for the Slovak national beverage “Borovicka” and the distillery industry on a whole in this country.
Nanobiochar Application in Combination with Mulching Improves Metabolites and Curd Quality Traits in Cauliflower
Authors: Xue Naiwen , Anwar Sumera , Shafiq Fahad , Gul-e-Kainat  , Ullah Kaleem , Zulqarnain Muhammad , Haider Imtiaz , Ashraf Muhammad
Published: June 2023

Sustainable nutrient management approaches could improve production and quality without affecting soil health. We conducted a field experiment to investigate the interactive effects of mulching (no mulch, plastic mulch, and straw mulch) and nanobiochar (NBC) foliar application on biomass, nutrient contents, and metabolites in the leaf and curd of cauliflower (Brassica oleracea var. botrytis). After 20 days of transplantation, NBC (0.1% w/v) was applied as a foliar spray for four consecutive weeks (one spray per week). At the curd initiation stage, changes in chlorophyll, carotenoids, and metabolite concentrations in leaves and curd were determined. The application of nanobiochar significantly enhanced the curd weight and improved curd morphology. Yield traits including curd weight, curd diameter, basal diameter, and stalk length were increased by 30, 13, 16, and 20% by NBC application compared to control. Plastic mulching also increased the aboveground biomass by 32% when compared to no mulching. Moreover, plastic mulching and nanobiochar prominently enhanced root dry weight, curd weight, rough solidity index, total soluble sugar in leaf and curd, calcium in curd, and potassium in leaf and curd of cauliflower. Overall, this study revealed the potential of the foliar application of NBC in promoting the biomass and nutritional properties of cauliflower.
German GPs’ Self-Perceived Role in the COVID-19 Pandemic: Leadership, Participation in Regional Services and Preferences for Future Pandemic Preparedness
Authors: Kugai Simon , Wild Dorothea , Krumpholtz Yelda , Schmidt Manuela , Balzer Katrin , Mayerböck Astrid , Weltermann Birgitta
Published: June 2023

General practitioners (GPs) played a vital role during the COVID-19 pandemic. Little is known about GPs’ view of their role, leadership, participation in regional services and preferences for future pandemic preparedness. This representative study of German GPs comprised a web-based survey and computer-assisted telephone interviewing (CATI). It addressed GPs’ satisfaction with their role, self-perceived leadership (validated C-LEAD scale), participation in newly established health services, and preferences for future pandemic preparedness (net promotor score; NPS; range −100 to +100%). Statistical analyses were conducted using Spearman’s correlation and Kruskal–Wallis tests. In total, 630 GPs completed the questionnaire and 102 GPs the CATI. In addition to their practice duties, most GPs (72.5%) participated in at least one regional health service, mainly vaccination centres/teams (52.7%). Self-perceived leadership was high with a C-LEAD score of 47.4 (max. 63; SD ± 8.5). Overall, 58.8% were not satisfied with their role which correlated with the feeling of being left alone (r = −0.349, p < 0.001). 77.5 % of respondents believed that political leaders underestimated GPs’ potential contribution to pandemic control. Regarding regional pandemic services, GPs preferred COVID-19 focus practices (NPS +43.7) over diagnostic centres (NPS −31). Many GPs, though highly engaged regionally, were dissatisfied with their role but had clear preferences for future regional services. Future pandemic planning should integrate GPs’ perspectives.
Clinical Challenges in the Management of Malignant Ovarian Germ Cell Tumours
Authors: Saani Iqra , Raj Nitish , Sood Raja , Ansari Shahbaz , Mandviwala Haider Abbas , Sanchez Elisabet , Boussios Stergios
Published: June 2023

Nonepithelial ovarian cancers (NEOC) are a group of rare malignancies, including germ cell tumours (GCT) and sex cord-stromal tumours (SCST), along with small-cell carcinomas and sarcomas. GCTs represent 2–5% of ovarian cancers, with a yearly incidence of 4:100,000, and they usually affect young women and adolescents. Precursory germ cells of the ovary form the basis of GCT. They are histologically classified into primitive GCT, teratomas, and monodermal and somatic-type tumours associated with dermoid cysts. A primitive GCT can be either a yolk sac tumour (YST), dysgerminoma, or mixed germ cell neoplasm. Teratomas are either mature (benign) or immature (malignant). Given that malignant GCTs occur rarely compared to epithelial ovarian tumours (EOC), greater focus is required in their diagnosis and treatment. In this article, we review the epidemiology, clinical manifestations, diagnosis, and molecular biology, along with the management and therapeutic challenges.
Molecules Inducing Dental Stem Cells Differentiation and Bone Regeneration: State of the Art
Authors: Ariano Anastasia , Posa Francesca , Storlino Giuseppina , Mori Giorgio
Published: June 2023

Teeth include mesenchymal stem cells (MSCs), which are multipotent cells that promote tooth growth and repair. Dental tissues, specifically the dental pulp and the dental bud, constitute a relevant source of multipotent stem cells, known as dental-derived stem cells (d-DSCs): dental pulp stem cells (DPSCs) and dental bud stem cells (DBSCs). Cell treatment with bone-associated factors and stimulation with small molecule compounds are, among the available methods, the ones who show excellent advantages promoting stem cell differentiation and osteogenesis. Recently, attention has been paid to studies on natural and non-natural compounds. Many fruits, vegetables, and some drugs contain molecules that can enhance MSC osteogenic differentiation and therefore bone formation. The purpose of this review is to examine research work over the past 10 years that has investigated two different types of MSCs from dental tissues that are attractive targets for bone tissue engineering: DPSCs and DBSCs. The reconstruction of bone defects, in fact, is still a challenge and therefore more research is needed; the articles reviewed are meant to identify compounds useful to stimulate d-DSC proliferation and osteogenic differentiation. We only consider the results of the research which is encouraging, assuming that the mentioned compounds are of some importance for bone regeneration.
Chitosomes Loaded with Docetaxel as a Promising Drug Delivery System to Laryngeal Cancer Cells: An In Vitro Cytotoxic Study
Authors: Moya-Garcia Christian R. , Li-Jessen Nicole Y. K. , Tabrizian Maryam
Published: June 2023

Current delivery of chemotherapy, either intra-venous or intra-arterial, remains suboptimal for patients with head and neck tumors. The free form of chemotherapy drugs, such as docetaxel, has non-specific tissue targeting and poor solubility in blood that deters treatment efficacy. Upon reaching the tumors, these drugs can also be easily washed away by the interstitial fluids. Liposomes have been used as nanocarriers to enhance docetaxel bioavailability. However, they are affected by potential interstitial dislodging due to insufficient intratumoral permeability and retention capabilities. Here, we developed and characterized docetaxel-loaded anionic nanoliposomes coated with a layer of mucoadhesive chitosan (chitosomes) for the application of chemotherapy drug delivery. The anionic liposomes were 99.4 ± 1.5 nm in diameter with a zeta potential of −26 ± 2.0 mV. The chitosan coating increased the liposome size to 120 ± 2.2 nm and the surface charge to 24.8 ± 2.6 mV. Chitosome formation was confirmed via FTIR spectroscopy and mucoadhesive analysis with anionic mucin dispersions. Blank liposomes and chitosomes showed no cytotoxic effect on human laryngeal stromal and cancer cells. Chitosomes were also internalized into the cytoplasm of human laryngeal cancer cells, indicating effective nanocarrier delivery. A higher cytotoxicity (p < 0.05) of docetaxel-loaded chitosomes towards human laryngeal cancer cells was observed compared to human stromal cells and control treatments. No hemolytic effect was observed on human red blood cells after a 3 h exposure, proving the proposed intra-arterial administration. Our in vitro results supported the potential of docetaxel-loaded chitosomes for locoregional chemotherapy delivery to laryngeal cancer cells.
Microglia and Astroglia—The Potential Role in Neuroinflammation Induced by Pre- and Neonatal Exposure to Lead (Pb)
Authors: Gąssowska-Dobrowolska Magdalena , Chlubek Mikołaj , Kolasa Agnieszka , Tomasiak Patrycja , Korbecki Jan , Skowrońska Katarzyna , Tarnowski Maciej , Masztalewicz Marta , Baranowska-Bosiacka Irena
Published: June 2023

Neuroinflammation is one of the postulated mechanisms for Pb neurotoxicity. However, the exact molecular mechanisms responsible for its pro-inflammatory effect are not fully elucidated. In this study, we examined the role of glial cells in neuroinflammation induced by Pb exposure. We investigated how microglia, a type of glial cell, responded to the changes caused by perinatal exposure to Pb by measuring the expression of Iba1 at the mRNA and protein levels. To assess the state of microglia, we analyzed the mRNA levels of specific markers associated with the cytotoxic M1 phenotype (Il1b, Il6, and Tnfa) and the cytoprotective M2 phenotype (Arg1, Chi3l1, Mrc1, Fcgr1a, Sphk1, and Tgfb1). Additionally, we measured the concentration of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). To assess the reactivity and functionality status of astrocytes, we analyzed the GFAP (mRNA expression and protein concentration) as well as glutamine synthase (GS) protein level and activity. Using an electron microscope, we assessed ultrastructural abnormalities in the examined brain structures (forebrain cortex, cerebellum, and hippocampus). In addition, we measured the mRNA levels of Cxcl1 and Cxcl2, and their receptor, Cxcr2. Our data showed that perinatal exposure to Pb at low doses affected both microglia and astrocyte cells’ status (their mobilization, activation, function, and changes in gene expression profile) in a brain-structure-specific manner. The results suggest that both microglia and astrocytes represent a potential target for Pb neurotoxicity, thus being key mediators of neuroinflammation and further neuropathology evoked by Pb poisoning during perinatal brain development.
Investigating the Effects of NaCl on the Formation of AFs from Gluten in Cooked Wheat Noodles
Authors: Liang Ying , Song Jiayang , Wang Jiayi , Liu Hao , Wu Xingquan , He Baoshan , Zhang Xia , Wang Jinshui
Published: June 2023

To clarify the effect of NaCl concentration (0–2.0%) on the formation of amyloid fibrils (AFs) in cooked wheat noodles, the morphology, surface hydrophobicity, secondary structure, molecular weight distribution, microstructure, and crystal structure of AFs were investigated in this paper. Fluorescence data and Congo red stain images confirmed the presence of AFs and revealed that the 0.4% NaCl concentration promoted the production of AFs. The surface hydrophobicity results showed that the hydrophobicity of AFs increased significantly from 3942.05 to 6117.57 when the salt concentration increased from 0 to 0.4%, indicating that hydrophobic interactions were critical for the formation of AFs. Size exclusion chromatography combined with gel electrophoresis plots showed that the effect of NaCl on the molecular weight of AFs was small and mainly distributed in the range of 5–7.1 KDa (equivalent to 40–56 amino acid residues). X-ray diffraction and AFM images showed that the 0.4% NaCl concentration promoted the formation and longitudinal growth of AFs, while higher NaCl concentrations inhibited the formation and expansion of AFs. This study contributes to the understanding of the mechanism of AF formation in wheat flour processing and provides new insight into wheat gluten aggregation behavior.
In Silico Identification of a BRCA1:miR-29:DNMT3 Axis Involved in the Control of Hormone Receptors in BRCA1-Associated Breast Cancers
Authors: Santarosa Manuela , Baldazzi Davide , Armellin Michela , Maestro Roberta
Published: June 2023

Germline inactivating mutations in the BRCA1 gene lead to an increased lifetime risk of ovarian and breast cancer (BC). Most BRCA1-associated BC are triple-negative tumors (TNBC), aggressive forms of BC characterized by a lack of expression of estrogen and progesterone hormone receptors (HR) and HER2. How BRCA1 inactivation may favor the development of such a specific BC phenotype remains to be elucidated. To address this question, we focused on the role of miRNAs and their networks in mediating BRCA1 functions. miRNA, mRNA, and methylation data were retrieved from the BRCA cohort of the TCGA project. The cohort was divided into a discovery set (Hi-TCGA) and a validation set (GA-TCGA) based on the platform used for miRNA analyses. The METABRIC, GSE81002, and GSE59248 studies were used as additional validation data sets. BCs were differentiated into BRCA1-like and non-BRCA1-like based on an established signature of BRCA1 pathway inactivation. Differential expression of miRNAs, gene enrichment analysis, functional annotation, and methylation correlation analyses were performed. The miRNAs downregulated in BRCA1-associated BC were identified by comparing the miRNome of BRCA1-like with non-BRCA1-like tumors from the Hi-TCGA discovery cohort. miRNAs:gene-target anticorrelation analyses were then performed. The target genes of miRNAs downregulated in the Hi-TCGA series were enriched in the BRCA1-like tumors from the GA-TCGA and METABRIC validation data sets. Functional annotation of these genes revealed an over-representation of several biological processes ascribable to BRCA1 activity. The enrichment of genes related to DNA methylation was particularly intriguing, as this is an aspect of BRCA1 functions that has been poorly explored. We then focused on the miR-29:DNA methyltransferase network and showed that the miR-29 family, which was downregulated in BRCA1-like tumors, was associated with poor prognosis in these BCs and inversely correlated with the expression of the DNA methyltransferases DNMT3A and DNMT3B. This, in turn, correlated with the methylation extent of the promoter of HR genes. These results suggest that BRCA1 may control the expression of HR via a miR-29:DNMT3:HR axis and that disruption of this network may contribute to the receptor negative phenotype of tumors with dysfunctional BRCA1.
Meta-CF3-Substituted Analogues of the GFP Chromophore with Remarkable Solvatochromism
Authors: Perfilov Maxim , Zaitseva Elvira , Baleeva Nadezhda , Kublitski Vadim , Smirnov Alexander , Bogdanova Yulia , Krasnova Svetlana , Myasnyanko Ivan , Mishin Alexander , Baranov Mikhail
Published: June 2023

In this work, we have shown that the introduction of a trifluoromethyl group into the me-ta-position of arylidene imidazolones (GFP chromophore core) leads to a dramatic increase in their fluorescence in nonpolar and aprotic media. The presence of a pronounced solvent-dependent gradation of fluorescence intensity makes it possible to use these substances as fluorescent polarity sensors. In particular, we showed that one of the created compounds could be used for selective labeling of the endoplasmic reticulum of living cells.
Synthesis and hLDH Inhibitory Activity of Analogues to Natural Products with 2,8-Dioxabicyclo[3.3.1]nonane Scaffold
Authors: Salido Sofía , Alejo-Armijo Alfonso , Altarejos Joaquín
Published: June 2023

Human lactate dehydrogenase (hLDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, hLDHA and hLDHB are the predominant ones. In the last few years, hLDHA has emerged as a therapeutic target for the treatment of several kinds of disorders, including cancer and primary hyperoxaluria. hLDHA inhibition has been clinically validated as a safe therapeutic method and clinical trials using biotechnological approaches are currently being evaluated. Despite the well-known advantages of pharmacological treatments based on small-molecule drugs, few compounds are currently in preclinical stage. We have recently reported the detection of some 2,8-dioxabicyclo[3.3.1]nonane core derivatives as new hLDHA inhibitors. Here, we extended our work synthesizing a large number of derivatives (42–70) by reaction between flavylium salts (27–35) and several nucleophiles (36–41). Nine 2,8-dioxabicyclo[3.3.1]nonane derivatives showed IC50 values lower than 10 µM against hLDHA and better activity than our previously reported compound 2. In order to know the selectivity of the synthesized compounds against hLDHA, their hLDHB inhibitory activities were also measured. In particular, compounds 58, 62a, 65b, and 68a have shown the lowest IC50 values against hLDHA (3.6–12.0 µM) and the highest selectivity rate (>25). Structure–activity relationships have been deduced. Kinetic studies using a Lineweaver–Burk double-reciprocal plot have indicated that both enantiomers of 68a and 68b behave as noncompetitive inhibitors on hLDHA enzyme.
Synthesis and Anticancer Evaluation of Novel 7-Aza-Coumarine-3-Carboxamides
Authors: Trifonov Alexey V. , Gazizov Almir S. , Tapalova Anipa S. , Kibardina Lyudmila K. , Appazov Nurbol O. , Voloshina Alexandra D. , Sapunova Anastasiia S. , Luybina Anna P. , Abyzbekova Gulmira M. , Dobrynin Alexey B. , Litvinov Igor A. , Tauekel Akerke K. , Yespenbetova Sholpan O. , Burilov Alexander R. , Pudovik Michail A.
Published: June 2023

Herein, we report the design and synthesis of novel 7-aza-coumarine-3-carboxamides via scaffold-hopping strategy and evaluation of their in vitro anticancer activity. Additionally, the improved non-catalytic synthesis of 7-azacoumarin-3-carboxylic acid is reported, which features water as the reaction medium and provides a convenient alternative to the known methods. The anticancer activity of the most potent 7-aza-coumarine-3-carboxamides against the HuTu 80 cell line is equal to that of reference Doxorubicin, while the selectivity towards the normal cell line is 9–14 fold higher.
Neurobiology of Parkinson’s Disease
Authors: Morelli Micaela , Pinna Annalisa
Published: June 2023

Parkinson’s disease (PD) is one of the most rapidly growing neurological disorders [...]
Inflammatory Bowel Disease: Crosstalk between Histamine, Immunity, and Disease
Authors: Dvornikova Kristina A. , Platonova Olga N. , Bystrova Elena Y.
Published: June 2023

Inflammatory bowel disease (IBD) is increasingly recognized as a serious, worldwide public health concern. It is generally acknowledged that a variety of factors play a role in the pathogenesis of this group of chronic inflammatory diseases. The diversity of molecular actors involved in IBD does not allow us to fully assess the causal relationships existing in such interactions. Given the high immunomodulatory activity of histamine and the complex immune-mediated nature of inflammatory bowel disease, the role of histamine and its receptors in the gut may be significant. This paper has been prepared to provide a schematic of the most important and possible molecular signaling pathways related to histamine and its receptors and to assess their relevance for the development of therapeutic approaches.
Clinical Trials with Mesenchymal Stem Cell Therapies for Osteoarthritis: Challenges in the Regeneration of Articular Cartilage
Authors: Carneiro Diego de Carvalho , Araújo Lila Teixeira de , Santos Girlaine Café , Damasceno Patrícia Kauanna Fonseca , Vieira Jaqueline Leite , Santos Ricardo Ribeiro dos , Barbosa Josiane Dantas Viana , Soares Milena Botelho Pereira
Published: June 2023

Osteoarthritis (OA) is a whole-joint disease primarily characterized by the deterioration of hyaline cartilage. Current treatments include microfracture and chondrocyte implantation as early surgical strategies that can be combined with scaffolds to repair osteochondral lesions; however, intra-articular (IA) injections or implantations of mesenchymal stem cells (MSCs) are new approaches that have presented encouraging therapeutic results in animal models and humans. We critically reviewed clinical trials with MSC therapies for OA, focusing on their effectiveness, quality, and outcomes in the regeneration of articular cartilage. Several sources of autologous or allogeneic MSCs were used in the clinical trials. Minor adverse events were generally reported, indicating that IA applications of MSCs are potentially safe. The evaluation of articular cartilage regeneration in human clinical trials is challenging, particularly in the inflammatory environment of osteoarthritic joints. Our findings indicate that IA injections of MSCs are efficacious in the treatment of OA and the regeneration of cartilage, but that they may be insufficient for the full repair of articular cartilage defects. The possible interference of clinical and quality variables in the outcomes suggests that robust clinical trials are still necessary for generating reliable evidence with which to support these treatments. We suggest that the administration of just-sufficient doses of viable cells in appropriate regimens is critical to achieve effective and durable effects. In terms of future perspectives, genetic modification, complex products with extracellular vesicles derived from MSCs, cell encapsulation in hydrogels, and 3D bioprinted tissue engineering are promising approaches with which to improve MSC therapies for OA.
New Insights into Adipose Tissue Metabolic Function and Dysfunction
Authors: Pallio Giovanni
Published: June 2023

Currently, one-third of people worldwide are overweight or obese, with a higher prevalence in women than in men and in the elderly than in the young [...]
PTEN Inhibitor Treatment Lowers Muscle Plasma Membrane Damage and Enhances Muscle ECM Homeostasis after High-Intensity Eccentric Exercise in Mice
Authors: Wu Baile , Shi Lijun , Wu Ying
Published: June 2023

Exercise-induced muscle damage (EIMD) is a common occurrence in athletes and can lead to delayed onset muscle soreness, reduced athletic performance, and an increased risk of secondary injury. EIMD is a complex process involving oxidative stress, inflammation, and various cellular signaling pathways. Timely and effective repair of the extracellular matrix (ECM) and plasma membrane (PM) damage is critical for recovery from EIMD. Recent studies have shown that the targeted inhibition of phosphatase and tension homolog (PTEN) in skeletal muscles can enhance the ECM environment and reduce membrane damage in Duchenne muscular dystrophy (DMD) mice. However, the effects of PTEN inhibition on EIMD are unknown. Therefore, the present study aimed to investigate the potential therapeutic effects of VO-OHpic (VO), a PTEN inhibitor, on EIMD symptoms and underlying mechanisms. Our findings indicate that VO treatment effectively enhances skeletal muscle function and reduces strength loss during EIMD by upregulating membrane repair signals related to MG53 and ECM repair signals related to the tissue inhibitor of metalloproteinases (TIMPs) and matrix metalloproteinase (MMPs). These results highlight the potential of pharmacological PTEN inhibition as a promising therapeutic approach for EIMD.
Renal Oxygen Demand and Nephron Function: Is Glucose a Friend or Foe?
Authors: Gronda Edoardo , Palazzuoli Alberto , Iacoviello Massimo , Benevenuto Manuela , Gabrielli Domenico , Arduini Arduino
Published: June 2023

The kidneys and heart work together to balance the body’s circulation, and although their physiology is based on strict inter dependence, their performance fulfills different aims. While the heart can rapidly increase its own oxygen consumption to comply with the wide changes in metabolic demand linked to body function, the kidneys physiology are primarily designed to maintain a stable metabolic rate and have a limited capacity to cope with any steep increase in renal metabolism. In the kidneys, glomerular population filters a large amount of blood and the tubular system has been programmed to reabsorb 99% of filtrate by reabsorbing sodium together with other filtered substances, including all glucose molecules. Glucose reabsorption involves the sodium–glucose cotransporters SGLT2 and SGLT1 on the apical membrane in the proximal tubular section; it also enhances bicarbonate formation so as to preserve the acid–base balance. The complex work of reabsorption in the kidney is the main factor in renal oxygen consumption; analysis of the renal glucose transport in disease states provides a better understanding of the renal physiology changes that occur when clinical conditions alter the neurohormonal response leading to an increase in glomerular filtration pressure. In this circumstance, glomerular hyperfiltration occurs, imposing a higher metabolic demand on kidney physiology and causing progressive renal impairment. Albumin urination is the warning signal of renal engagement over exertion and most frequently heralds heart failure development, regardless of disease etiology. The review analyzes the mechanisms linked to renal oxygen consumption, focusing on sodium–glucose management.
Neuropeptide Y Peptide Family and Cancer: Antitumor Therapeutic Strategies
Authors: Sánchez Manuel Lisardo , Rodríguez Francisco D. , Coveñas Rafael
Published: June 2023

Currently available data on the involvement of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) and their receptors (YRs) in cancer are updated. The structure and dynamics of YRs and their intracellular signaling pathways are also studied. The roles played by these peptides in 22 different cancer types are reviewed (e.g., breast cancer, colorectal cancer, Ewing sarcoma, liver cancer, melanoma, neuroblastoma, pancreatic cancer, pheochromocytoma, and prostate cancer). YRs could be used as cancer diagnostic markers and therapeutic targets. A high Y1R expression has been correlated with lymph node metastasis, advanced stages, and perineural invasion; an increased Y5R expression with survival and tumor growth; and a high serum NPY level with relapse, metastasis, and poor survival. YRs mediate tumor cell proliferation, migration, invasion, metastasis, and angiogenesis; YR antagonists block the previous actions and promote the death of cancer cells. NPY favors tumor cell growth, migration, and metastasis and promotes angiogenesis in some tumors (e.g., breast cancer, colorectal cancer, neuroblastoma, pancreatic cancer), whereas in others it exerts an antitumor effect (e.g., cholangiocarcinoma, Ewing sarcoma, liver cancer). PYY or its fragments block tumor cell growth, migration, and invasion in breast, colorectal, esophageal, liver, pancreatic, and prostate cancer. Current data show the peptidergic system’s high potential for cancer diagnosis, treatment, and support using Y2R/Y5R antagonists and NPY or PYY agonists as promising antitumor therapeutic strategies. Some important research lines to be developed in the future will also be suggested.
Human Ad19a/64 HERV-W Vaccines Uncover Immunosuppression Domain-Dependent T-Cell Response Differences in Inbred Mice
Authors: Skandorff Isabella , Ragonnaud Emeline , Gille Jasmin , Andersson Anne-Marie , Schrödel Silke , Duvnjak Lara , Turner Louise , Thirion Christian , Wagner Ralf , Holst Peter Johannes
Published: June 2023

Expression of human endogenous retrovirus type W (HERV-W) has been linked to cancer, making HERV-W antigens potential targets for therapeutic cancer vaccines. In a previous study, we effectively treated established tumours in mice by using adenoviral-vectored vaccines targeting the murine endogenous retrovirus envelope and group-specific antigen (Gag) of melanoma-associated retrovirus (MelARV) in combination with anti-PD-1. To break the immunological tolerance to MelARV, we mutated the immunosuppressive domain (ISD) of the MelARV envelope. However, reports on the immunogenicity of the HERV-W envelope, Syncytin-1, and its ISD are conflicting. To identify the most effective HERV-W cancer vaccine candidate, we evaluated the immunogenicity of vaccines encoding either the wild-type or mutated HERV-W envelope ISD in vitro and in vivo. Here, we show that the wild-type HERV-W vaccine generated higher activation of murine antigen-presenting cells and higher specific T-cell responses than the ISD-mutated counterpart. We also found that the wild-type HERV-W vaccine was sufficient to increase the probability of survival in mice subjected to HERV-W envelope-expressing tumours compared to a control vaccine. These findings provide the foundation for developing a therapeutic cancer vaccine targeting HERV-W-positive cancers in humans.
Multiplexing Iduronate-2-Sulphatase (MPS-II) into a 7-Plex Lysosomal Storage Disorder MS/MS Assay Using Cold-Induced Phase Separation
Authors: Courtney Elya , Pickens C. Austin , Cuthbert Carla , Petritis Konstantinos
Published: June 2023

Mucopolysaccharidosis type II (MPS-II, Hunter syndrome, OMIM:30990) is a lysosomal storage disorder (LSD) that results in iduronate 2-sulphatase (I2S) enzyme deficiency. MPS-II was added to the Recommended Uniform Screening Panel (RUSP) in August 2022; thus, there is an increased demand for multiplexing I2S into existing LSD screening assays. After incubation with LSD synthetic substrates, extracts are cleaned using liquid–liquid extraction with ethyl acetate or protein precipitation using acetonitrile (ACN). We investigated cold-induced water ACN phase separation (CIPS) to improve the combination of 6-plex and I2S extracts to create a 7-plex assay, and compared it to room temperature ACN and ethyl acetate liquid–liquid extraction. The extracts were dried and resuspended in the mobile phase, and then analyzed using an optimized 1.9 min injection-to-injection liquid chromatography method coupled with tandem mass spectrometry (LC-MS/MS). The combination of ACN and CIPS improved the detection for I2S products without significant detriment to other analytes, which is attributable to a more complete coagulation and separation of heme, proteins, and extracted residual salts. Using CIPS for sample cleanup in dried blood spots (DBS) appears to represent a promising and straightforward way of achieving cleaner sample extracts in a new 7-plex LSD screening panel.
The Use of the Cryopreserved Aortic Homograft for Aortic Valve Replacement: Is It Still an Option?
Authors: Nappi Francesco , Nenna Antonio , Spadaccio Cristiano , Avtaar Singh Sanjeet Singh , Almazil Almothana , Acar Christophe
Published: June 2023

The indications for cryopreserved allografts in aortic valve replacement are still debatable. We aim to identify factors influencing early and long-term durability of the aortic homograft and to define subgroups of patients with an improved long-term quality of life, survival, and freedom from structural valve degeneration (SVD). We evaluated our series of 210 patients who underwent allograft implantation with a retrospective cohort study design over a period of 20 years. Endpoints were overall mortality, cardiac mortality related to SVD, the incidence of SVD, reoperation, and a composite endpoint comprising major adverse cardiac and cerebrovascular events (MACCEs), which includes cardiac death both related and not related to SVD, subsequent aortic valve surgery, new or recurrent infection of implanted allograft, recurrent aortic regurgitation, rehospitalization for heart failure, an increase in New York Heart Association (NYHA) class of ≥1, or cerebrovascular events. The primary indication for surgery was endocarditis (48%), which was also a predisposing factor for increased cardiac mortality. Overall mortality was 32.4% with a 27% incidence of SVD and mortality associated with SVD of 13.8%. Reoperation occurred in 33.8% and MACCEs in 54.8%. Long-term NYHA functional class and echocardiographic parameters improved over time. Statistical analysis demonstrated that root replacement technique and adult age were protective factors for SVD. We found no statistically significant difference in the clinical outcomes analyzed between women of childbearing age who had children after surgery and the rest of the women. The cryopreserved allograft is still a valid option in aortic valve replacement, providing acceptable durability and clinical outcomes with optimal hemodynamic performance. SVD is influenced by the implantation technique. Women of childbearing age might have additional benefits from this procedure.
Risk Factors of Secondary Cardiovascular Events in a Multi-Ethnic Asian Population with Acute Myocardial Infarction: A Retrospective Cohort Study from Malaysia
Authors: Ismail Sophia Rasheeqa , Mohammad Mohd Shawal Faizal , Butterworth Adam S. , Chowdhury Rajiv , Danesh John , Di Angelantonio Emanuele , Griffin Simon J. , Pennells Lisa , Wood Angela M. , Md Noh Mohd Fairulnizal , Shah Shamsul Azhar
Published: June 2023

This retrospective cohort study investigated the incidence and risk factors of major adverse cardiovascular events (MACE) after 1 year of first-documented myocardial infarctions (MIs) in a multi-ethnic Asian population. Secondary MACE were observed in 231 (14.3%) individuals, including 92 (5.7%) cardiovascular-related deaths. Both histories of hypertension and diabetes were associated with secondary MACE after adjustment for age, sex, and ethnicity (HR 1.60 [95%CI 1.22–2.12] and 1.46 [95%CI 1.09–1.97], respectively). With further adjustments for traditional risk factors, individuals with conduction disturbances demonstrated higher risks of MACE: new left-bundle branch block (HR 2.86 [95%CI 1.15–6.55]), right-bundle branch block (HR 2.09 [95%CI 1.02–4.29]), and second-degree heart block (HR 2.45 [95%CI 0.59–10.16]). These associations were broadly similar across different age, sex, and ethnicity groups, although somewhat greater for history of hypertension and BMI among women versus men, for HbA1c control in individuals aged >50 years, and for LVEF ≤ 40% in those with Indian versus Chinese or Bumiputera ethnicities. Several traditional and cardiac risk factors are associated with a higher risk of secondary major adverse cardiovascular events. In addition to hypertension and diabetes, the identification of conduction disturbances in individuals with first-onset MI may be useful for the risk stratification of high-risk individuals.
Clinical Use of Blood Flow Analysis through 4D-Flow Imaging in Aortic Valve Disease
Authors: Mansoor Omer , Garcia Julio
Published: June 2023

Bicuspid aortic valve (BAV), which affects 1% of the general population, results from the abnormal fusion of the cusps of the aortic valve. BAV can lead to the dilatation of the aorta, aortic coarctation, development of aortic stenosis (AS), and aortic regurgitation. Surgical intervention is usually recommended for patients with BAV and bicuspid aortopathy. This review aims to examine 4D-flow imaging as a tool in cardiac magnetic resonance imaging for assessing abnormal blood flow and its clinical application in BAV and AS. We present a historical clinical approach summarizing evidence of abnormal blood flow in aortic valve disease. We highlight how abnormal flow patterns can contribute to the development of aortic dilatation and novel flow-based biomarkers that can be used for a better understanding of the disease progression.
Surgical Strategy for the Repair of Acute Type A Aortic Dissection: A Multicenter Study
Authors: Nappi Francesco , Avtaar Singh Sanjeet Singh , Gambardella Ivancarmine , Alzamil Almothana , Salsano Antonio , Santini Francesco , Biancari Fausto , Schoell Thibaut , Bonnet Nicolas , Folliguet Thierry , Fiore Antonio
Published: June 2023

Type A acute aortic dissection is associated with significant morbidity and mortality, with prompt referral imaging and management to tertiary referral centers needed urgently. Surgery is usually needed emergently, but the choice of surgery often varies depending on the patient and the presentation. Staff and center expertise also play a major role in determining the surgical strategy employed. The aim of this study was to compare the early- and medium-term outcomes of patients undergoing a conservative approach extended only to the ascending aorta and the hemiarch to those of patients subjected to extensive surgery (total arch reconstruction and root replacement) across three European referral centers. A retrospective study was conducted across three sites between January 2008 and December 2021. In total, 601 patients were included within the study, of which 30% were female, and the median age was 64.4 years. The most common operation was ascending aorta replacement (n = 246, 40.9%). The aortic repair was extended proximally (i.e., root n = 105; 17.5%) and distally (i.e., arch n = 250; 41.6%). A more extensive approach, extending from the root to the arch, was employed in 24 patients (4.0%). Operative mortality occurred in 146 patients (24.3%), and the most common morbidity was stroke (75, 12.6%). An increased length of ICU admission was noted in the extensive surgery group, which comprised younger and more frequently male patients. No significant differences were noted in surgical mortality between patients managed with extensive surgery and those managed conservatively. However, age, arterial lactate levels, “intubated/sedated” status on arrival, and “emergency or salvage” status at presentation were independent predictors of mortality both within the index hospitalization and during the follow-up. The overall survival was similar between the groups.
Nausea Predicts Bacteremia in Immunocompetent Patients with Pneumococcal Community-Acquired Pneumonia: Secondary Data Analysis from a Prospective Cohort
Authors: Floeystad Hans Kristian , Holter Jan Cato , Husebye Einar , Siljan William Ward , Berild Dag , Holm Are Martin , Heggelund Lars
Published: June 2023

Background: In pneumococcal community-acquired pneumonia (CAP), bacteremia is associated with increased mortality, but initial clinical severity scores frequently fail to identify bacteremic patients at risk. We have previously shown that gastrointestinal symptoms are common among patients admitted to the hospital with pneumococcal bacteremia. The aim of this study was to examine gastrointestinal symptoms and inflammatory responses in bacteremic and non-bacteremic pneumococcal CAP in a prospective cohort of immunocompromised and immunocompetent patients hospitalized with CAP. Methods: Logistic regression analysis was used to estimate the predictive value of gastrointestinal symptoms for pneumococcal bacteremia in patients with CAP. The Mann–Whitney test was used to compare inflammatory responses in patients with bacteremic vs. non-bacteremic pneumococcal CAP. Results: Eighty-one patients with pneumococcal CAP were included, of whom 21 (26%) had bacteremia. Immunocompetent patients with pneumococcal CAP had an odds ratio of 16.5 (95% CI 3.0–90.9, p = 0.001) for bacteremia if nausea was present, whereas no such association was found in the immunocompromised patients (OR 0.22, 95% CI 0.02–2.05, p = 0.18). The serum levels of C-reactive protein, procalcitonin and interleukin 6 were significantly higher in the patients with bacteremic pneumococcal CAP compared to non-bacteremic pneumococcal CAP patients (p < 0.001, p = 0.005, and p = 0.019, respectively). Conclusions: In immunocompetent patients hospitalized with pneumococcal CAP, nausea may be a predictor of bacteremia. Bacteremic pneumococcal CAP patients display an increased inflammatory response compared to non-bacteremic pneumococcal CAP patients.
Remimazolam as an Adjunct to General Anesthesia in Children: Adverse Events and Outcomes in a Large Cohort of 418 Cases
Authors: Kimoto Yoshitaka , Hirano Tatsuya , Kuratani Norifumi , Cavanaugh David , Mason Keira P.
Published: June 2023

Remimazolam was first approved in 2020 as a general anesthetic for adults and still does not have pediatric labeling. Our study will be the first pilot program that administers remimazolam as an adjunct to a general endotracheal anesthetic in children. Between August 2020 and December 2022, electronic medical records were collected for all children who received remimazolam during anesthesia. The remimazolam dosing regimen was extrapolated from the adult package insert, with intravenous induction doses of 12 mg/kg/h administered until the desired effect was achieved. Subsequent infusions were given at a rate of 1–2 mg/kg/h, accompanied by intermittent boluses of 0.2 mg/kg, with all dosing adjustments made according to the anesthesiologist’s clinical discretion. A total of 418 children (mean 4.6 yrs, 68.7% ASA 1 and 2) underwent surgeries which averaged 81.2 min. A total of 75.2% of patients had greater than a 20% change (increase or decrease) in MAP (lowest or highest) from baseline, and 203 (49.3%) patients had greater than a 30% change (increase or decrease) in MAP (lowest or highest) from baseline. A total of 5% received ephedrine to treat unanticipated hemodynamic variability. Discharge criteria were met within an average of 13.8 min after arrival at the post-anesthesia care unit. Remimazolam may offer the benefits of rapid recovery following general endotracheal anesthesia. The risk of hemodynamic variability which necessitates and responds to ephedrine should be anticipated.