bluuebunny/crossref_metadata_2025 huggingface dataset:
Motor Skills, Heart Rate Variability, and Arterial Stiffness in Children with Autism Spectrum Disorder
Authors: Kalfiřt Luděk , Su Chia-Ting , Fu Chung-Pei , Lee Shin-Da , Yang Ai-Lun
Published: June 2023

The prevalence of autism spectrum disorder (ASD) among children has been recently increasing. The severity of symptoms greatly varies between individuals with ASD, ranging from relatively mild to extremely severe. It is important to have a clearer understanding of the possible adverse consequences resulting from this disorder, such as delayed motor development, autonomic dysregulation, and arterial stiffness. Thus, the objective of this study was to investigate differences in motor skills, heart rate variability (HRV), and arterial stiffness between children with ASD and typically developing children. In this study, the school-aged children with mild symptoms of ASD (n = 17, 11.1 ± 1.0 years old) and typically developing peers (n = 15, 11.0 ± 0.5 years old) were recruited. Motor skills, HRV, and arterial stiffness were measured in these two groups. Motor skills were evaluated by the Bruininks–Oseretsky Test of Motor Proficiency-Second Edition. Moreover, HRV was measured through a short-term recording using the Polar heart rate monitor, and arterial stiffness was assessed by non-invasive computerized oscillometry. Compared with the typically developing group, children with ASD displayed significant deficits in some areas of motor skills, including manual coordination, strength and agility, and total motor composite. Moreover, children with ASD exhibited significantly reduced HRV, including time- and frequency-domain measures. However, the results did not demonstrate any statistically significant differences in arterial stiffness between the groups. Our findings demonstrated the presence of motor skill deficits and autonomic dysregulation in children with ASD.
The Potential Role of Spa Therapy in Managing Frailty in Rheumatic Patients: A Scoping Review
Authors: Maccarone Maria Chiara , Scanu Anna , Coraci Daniele , Masiero Stefano
Published: June 2023

Frailty is not limited to the elderly, as patients with rheumatic diseases can also experience this condition. The present scoping review aimed to investigate the possibility of using the health resort setting as an alternative location for managing rheumatic patients with frailty. The research resulted in finding several in vitro, in vivo, and clinical studies, resulting in evidence supporting the effectiveness of spa treatments in reducing pain, improving function, and managing comorbidity in rheumatic diseases. Additionally, spa treatments were demonstrated to modulate the MAPK/ERK pathway and the NF-kB pathway’s activation and to reduce proinflammatory molecules’ secretion in rheumatic diseases, thus suggesting their potential effective role in the regulation of inflammaging in frailty. Moreover, the health resort setting may offer potential resources to reduce risk factors, such as drug consumption, inactivity, and disease severity, and may serve as a setting for developing prevention protocols for frailty. Future research should explore innovative approaches, such as exercise training and early diagnostics, for the overall management of frailty in rheumatic patients in the spa setting.
Internet Healthcare Policy Analysis, Evaluation, and Improvement Path: Multidimensional Perspectives
Authors: Wei Qi , Wang Xiaoyu , Zhang Gongrang , Li Xingguo , Yang Xuejie , Gu Dongxiao
Published: June 2023

Internet healthcare is a crucial component of the healthcare industry’s digital transformation and plays a vital role in achieving China’s Healthy China strategy and promoting universal health. To ensure the development of internet healthcare is guided by scientifically sound policies, this study analyzes and assesses current policy texts, aiming to identify potential issues and inadequacies. By examining 134 national-level policy documents, utilizing multiple research methods, including policy bibliometrics, content analysis, and the PMC Index Model, the study investigates policy characteristics, distribution of policy instruments, and evaluation outcomes related to internet healthcare. The study findings reveal that internet healthcare policies place emphasis on enhancing service quality, driving technological innovation, and promoting management standardization. Although policy instruments align with the current stage of internet healthcare development in China, they are plagued by imbalances in implementation. While policies are generally well-formulated, there are discernible discrepancies among them, necessitating the reinforcement and refinement of certain provisions. Hence, it is imperative to strategically optimize the amalgamation and implementation of policy instruments while concurrently endeavoring to achieve a dynamic equilibrium in policy combinations. Furthermore, policymakers should diligently refine the policy content pertaining to its nature and effectiveness in order to fully maximize policy utility.
Athletes Perceived Level of Risk Associated with Botanical Food Supplement Use and Their Sources of Information
Authors: McDaid Bridin , Wardenaar Floris , Woodside Jayne , Neville Charlotte , Tobin David , Madigan Sharon , Nugent Anne
Published: June 2023

Athletes should carefully consider the use of botanical food supplements (BFSs) given the current lack of substantiation for botanical nutrition and health claims under EU and UK food laws. In addition, athletes may be at an increased risk of doping violations and other adverse outcomes potentially associated with BFS use; however, little is known about athletes’ intake, knowledge, or perceptions in relation to BFS use. An online cross-sectional survey of n = 217 elite and amateur athletes living on the island of Ireland was conducted using Qualtrics XM to assess intake, knowledge, attitudes, and perceptions. General food supplements (FSs) were reported by approximately 60% of the study cohort, and 16% of the supplements reported were categorized as BFS. The most frequently consumed BFSs were turmeric/curcumin (14%), Ashwagandha (10%), and Beetroot extract (8%). A higher proportion of amateur athletes would source information about BFSs from less credible sources, such as fellow athletes, or from internet sources or their coach, compared to elite athletes. Those who sourced information about botanicals from fellow athletes (p = 0.03) or the internet (p = 0.02) reported a lower perceived level of risks associated with BFS use. This study therefore suggests that amateur athletes may be more likely to source information from less credible sources compared to elite athletes who may have more access to nutrition professionals and their knowledge/advice. This may have potential adverse implications for amateur athletes, e.g., Gaelic games players, who are included within the doping testing pool but who may not have access to evidence-based nutrition advice.
The Role of Social Banking in the Success and Sustainable Business Continuity of SSMEs
Authors: Stavropoulou Eirini , Spinthiropoulos Konstantinos , Garefalakis Alexandros , Ragazou Konstantina , Gonidakis Fragkiskos
Published: June 2023

The technological developments in the social economy have significant implications for social banks and are optimistically changing the way social retail banks conduct their business. Social banks can invest in social services for small- and medium-sized enterprises (SSMEs) either to acquire a strategic advantage or out of strategic necessity. With the assistance of a mathematical model, this study tries to identify SME service channels and assess potential impacts on social deposit banks’ performance. In the first stage, the proposed model estimates the predictive capacity of interpretive accounting variables (financial ratios) versus the interpreted accounting variable (future quarterly earnings before taxes (EBT)). Then, in the second stage, the SSME service channels were added to the earnings before tax model in terms of profitability measure, which informs corporate earnings before operating the business to account for the income tax attributed to it for the purpose of estimating their impact on the performance of social banks. According to our findings, the banks are investing in SME services just to validate their investments in SME services as a strategic necessity. SSMEs services do not provide any strategic advantage to any banks in terms of financial or accounting performance or efficiency since the banks are already efficient. Investing in SMEs is a tool for preserving their strategic positions. Therefore, the contribution of this study is focused on the fact that it highlights the impact of financing the social deposit banking industry on institutions, while most studies analyze the vice versa interaction.
Molecular Aspects of a Diet as a New Pathway in the Prevention and Treatment of Alzheimer’s Disease
Authors: Doroszkiewicz Julia , Mroczko Jan , Rutkowski Piotr , Mroczko Barbara
Published: June 2023

Alzheimer’s disease is the most common cause of dementia in the world. Lack of an established pathology makes it difficult to develop suitable approaches and treatment for the disease. Besides known hallmarks, including amyloid β peptides cumulating in plaques and hyperphosphorylated tau forming NFTs, inflammation also plays an important role, with known connections to the diet. In AD, adhering to reasonable nutrition according to age-related principles is recommended. The diet should be high in neuroprotective foods, such as polyunsaturated fatty acids, antioxidants, and B vitamins. In addition, foods capable of rising BDNF should be considered because of the known profitable results of this molecule in AD. Adhering to beneficial diets might result in improvements in memory, cognition, and biomarkers and might even reduce the risk of developing AD. In this review, we discuss the effects of various diets, foods, and nutrients on brain health and possible connections to Alzheimer’s disease.
A Ketogenic Diet in Combination with Gemcitabine Mitigates Pancreatic Cancer-Associated Cachexia in Male and Female KPC Mice
Authors: Cortez Natalia E. , Pathak Suraj , Rodriguez Lanzi Cecilia , Hong Brian V. , Crone Ryman , Sule Rasheed , Wang Fangyi , Chen Shuai , Gomes Aldrin V. , Baar Keith , Mackenzie Gerardo G.
Published: June 2023

Cancer-associated cachexia (CAC) is a critical contributor to pancreatic ductal adenocarcinoma (PDAC) mortality. Thus, there is an urgent need for new strategies to mitigate PDAC-associated cachexia; and the exploration of dietary interventions is a critical component. We previously observed that a ketogenic diet (KD) combined with gemcitabine enhances overall survival in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. In this study, we investigated the effect and cellular mechanisms of a KD in combination with gemcitabine on the maintenance of skeletal muscle mass in KPC mice. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD), a KD, a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. We observed that a KD or a KG-mitigated muscle strength declined over time and presented higher gastrocnemius weights compared CD-fed mice. Mechanistically, we observed sex-dependent effects of KG treatment, including the inhibition of autophagy, and increased phosphorylation levels of eIF2α in KG-treated KPC mice when compared to CG-treated mice. Our data suggest that a KG results in preservation of skeletal muscle mass. Additional research is warranted to explore whether this diet-treatment combination can be clinically effective in combating CAC in PDAC patients.
Predicting Structural Susceptibility of Proteins to Proteolytic Processing
Authors: Matveev Evgenii V. , Safronov Vyacheslav V. , Ponomarev Gennady V. , Kazanov Marat D.
Published: June 2023

The importance of 3D protein structure in proteolytic processing is well known. However, despite the plethora of existing methods for predicting proteolytic sites, only a few of them utilize the structural features of potential substrates as predictors. Moreover, to our knowledge, there is currently no method available for predicting the structural susceptibility of protein regions to proteolysis. We developed such a method using data from CutDB, a database that contains experimentally verified proteolytic events. For prediction, we utilized structural features that have been shown to influence proteolysis in earlier studies, such as solvent accessibility, secondary structure, and temperature factor. Additionally, we introduced new structural features, including length of protruded loops and flexibility of protein termini. To maximize the prediction quality of the method, we carefully curated the training set, selected an appropriate machine learning method, and sampled negative examples to determine the optimal positive-to-negative class size ratio. We demonstrated that combining our method with models of protease primary specificity can outperform existing bioinformatics methods for the prediction of proteolytic sites. We also discussed the possibility of utilizing this method for bioinformatics prediction of other post-translational modifications.
Homologous Recombination Deficiency (HRD) in Cutaneous Oncology
Authors: Akinjiyan Favour A. , Morecroft Renee , Phillipps Jordan , Adeyelu Tolulope , Elliott Andrew , Park Soo J. , Butt Omar H. , Zhou Alice Y. , Ansstas George
Published: June 2023

Skin cancers, including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (SCC), and melanoma, are the most common malignancies in the United States. Loss of DNA repair pathways in the skin plays a significant role in tumorigenesis. In recent years, targeting DNA repair pathways, particularly homologous recombination deficiency (HRD), has emerged as a potential therapeutic approach in cutaneous malignancies. This review provides an overview of DNA damage and repair pathways, with a focus on HRD, and discusses major advances in targeting these pathways in skin cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to exploit HRD in cancer cells. PARP inhibitors disrupt DNA repair mechanisms by inhibiting PARP enzymatic activity, leading to the accumulation of DNA damage and cell death. The concept of synthetic lethality has been demonstrated in HR-deficient cells, such as those with BRCA1/2 mutations, which exhibit increased sensitivity to PARP inhibitors. HRD assessment methods, including genomic scars, RAD51 foci formation, functional assays, and BRCA1/2 mutation analysis, are discussed as tools for identifying patients who may benefit from PARP inhibitor therapy. Furthermore, HRD has been implicated in the response to immunotherapy, and the combination of PARP inhibitors with immunotherapy has shown promising results. The frequency of HRD in melanoma ranges from 18% to 57%, and studies investigating the use of PARP inhibitors as monotherapy in melanoma are limited. Further research is warranted to explore the potential of PARP inhibition in melanoma treatment.
Impact of Gut Recolonization on Liver Regeneration: Hepatic Matrisome Gene Expression after Partial Hepatectomy in Mice
Authors: Amin Abdul Rahman , Hairulhisyam Ngatiman M. , Aqilah Raman Nur Fatin , Nur Fariha Mohd Manzor , Mallard Beth L. , Shanahan Fergus , Wheatley Antony M. , Marlini Muhamad
Published: June 2023

The hepatic matrisome is involved in the remodeling phase of liver regeneration. As the gut microbiota has been implicated in liver regeneration, we investigated its role in liver regeneration focusing on gene expression of the hepatic matrisome after partial hepatectomy (PHx) in germ-free (GF) mice, and in GF mice reconstituted with normal gut microbiota (XGF). Liver mass restoration, hepatocyte proliferation, and immune response were assessed following 70% PHx. Hepatic matrisome and collagen gene expression were also analyzed. Reduced liver weight/body weight ratio, mitotic count, and hepatocyte proliferative index at 72 h post PHx in GF mice were preceded by reduced expression of cytokine receptor genes Tnfrsf1a and Il6ra, and Hgf gene at 3 h post PHx. In XGF mice, these indices were significantly higher than in GF mice, and similar to that of control mice, indicating normal liver regeneration. Differentially expressed genes (DEGs) of the matrisome were lower in GF compared to XGF mice at both 3 h and 72 h post PHx. GF mice also demonstrated lower collagen expression, with significantly lower expression of Col1a1, Col1a2, Col5a1, and Col6a2 compared to WT mice at 72 h post PHx. In conclusion, enhanced liver regeneration and matrisome expression in XGF mice suggests that interaction of the gut microbiota and matrisome may play a significant role in the regulation of hepatic remodeling during the regenerative process.
Endogenous and Exogenous Regulation of Redox Homeostasis in Retinal Pigment Epithelium Cells: An Updated Antioxidant Perspective
Authors: Markitantova Yuliya , Simirskii Vladimir
Published: June 2023

The retinal pigment epithelium (RPE) performs a range of necessary functions within the neural layers of the retina and helps ensure vision. The regulation of pro-oxidative and antioxidant processes is the basis for maintaining RPE homeostasis and preventing retinal degenerative processes. Long-term stable changes in the redox balance under the influence of endogenous or exogenous factors can lead to oxidative stress (OS) and the development of a number of retinal pathologies associated with RPE dysfunction, and can eventually lead to vision loss. Reparative autophagy, ubiquitin–proteasome utilization, the repair of damaged proteins, and the maintenance of their conformational structure are important interrelated mechanisms of the endogenous defense system that protects against oxidative damage. Antioxidant protection of RPE cells is realized as a result of the activity of specific transcription factors, a large group of enzymes, chaperone proteins, etc., which form many signaling pathways in the RPE and the retina. Here, we discuss the role of the key components of the antioxidant defense system (ADS) in the cellular response of the RPE against OS. Understanding the role and interactions of OS mediators and the components of the ADS contributes to the formation of ideas about the subtle mechanisms in the regulation of RPE cellular functions and prospects for experimental approaches to restore RPE functions.
Crosstalk between 5-Aminolevulinic Acid and Abscisic Acid Adjusted Leaf Iron Accumulation and Chlorophyll Synthesis to Enhance the Cold Tolerance in Solanum lycopersicum Seedlings
Authors: Kang Zhen , Zhang Yong , Cai Xiongchun , Zhang Zhengda , Xu Zijian , Meng Xiangguang , Li Xiaojing , Hu Xiaohui
Published: June 2023

Previous studies found that 5-aminolevulinic acid (ALA) and abscisic acid (ABA) can mitigate damage from adversity by enhancing photosynthesis. However, it is not clear whether they have positive effects on iron utilization and chlorophyll synthesis of tomato seedlings under low-temperature stress. To investigate the possible functional relationship between ABA and ALA and elucidate the possible mechanisms of action of ALA to alleviate low-temperature stress in tomato seedlings, this experiment analyzed the effects of ALA and ABA on chlorophyll synthesis in tomato seedling leaves sprayed with exogenous of ALA (25 mg·L−1) or ABA (100 µM) under low-temperature stress (8–18 °C/8–12 °C, day/night). The results show that exogenous ALA increased the Fv/Fm of tomato leaves by 5.31% and increased the accumulation of iron and chlorophyll by 101.15% and 15.18%, respectively, compared to the low-temperature treatment alone, and tomato resistance of low-temperature stress was enhanced. Meanwhile, exogenous application of ALA increased the ABA content by 39.43%, and subsequent application of exogenous ABA revealed that tomato seedlings showed similar effects to exogenous ALA under low-temperature stress, with increased accumulation of iron and chlorophyll in tomato seedlings, which eventually increased the maximum photochemical efficiency of PS II. Under low-temperature stress, application of exogenous ABA significantly reduced ALA content, but the expression of key enzyme genes (PPGD, HEMB1, HEME1, and HEMF1), precursors of chlorophyll synthesis by ALA, was significantly elevated, presumably because the increased activity of these enzymes after external application of ABA accelerated ALA consumption. In conclusion, ABA may crosstalk with ALA to improve the photochemical efficiency and low temperature resistance of tomatoes by regulating chlorophyll synthesis and iron accumulation.
The Role of Sirtuins in the Pathogenesis of Psoriasis
Authors: Słuczanowska-Głabowska Sylwia , Salmanowicz Maria , Staniszewska Marzena , Pawlik Andrzej
Published: June 2023

Psoriasis is the most common chronic inflammatory skin disease with a genetic basis. It is characterised by keratinocyte hyperproliferation, parakeratosis and inflammatory cell infiltration. Psoriasis negatively affects a patient’s physical and emotional quality of life. Sirtuins (SIRTs; silent information regulators) are an evolutionarily conserved group of enzymes involved in the post-translational modification of proteins, including deacetylation, polyADP-ribosylation, demalonylation and lipoamidation. SIRTs are involved in a number of cellular pathways related to ageing, inflammation, oxidative stress, epigenetics, tumorigenesis, the cell cycle, DNA repair and cell proliferation, positioning them as an essential component in the pathogenesis of many diseases, including psoriasis. Activation of SIRT1 counteracts oxidative-stress-induced damage by inhibiting the mitogen-activated protein kinases (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways and may mitigate pathological events in psoriasis. There is a significant reduction in the expression of SIRT1, SIRT2, SIRT3, SIRT4 and SIRT5 and an increase in the expression of SIRT6 and SIRT7 in psoriasis. The aim of the review is to draw the attention of physicians and scientists to the importance of SIRTs in dermatology and to provide a basis and impetus for future discussions, research and pharmacological discoveries to modulate SIRT activity. In light of the analysis of the mode of action of SIRTs in psoriasis, SIRT1–SIRT5 agonists and SIRT6 and SIRT7 inhibitors may represent new therapeutic options for the treatment of psoriasis.
Exploring the Therapeutic Potential of trans-Chalcone: Modulation of MicroRNAs Linked to Breast Cancer Progression in MCF-7 Cells
Authors: Komoto Tatiana Takahasi , Nishimura Felipe Garcia , Evangelista Adriane Feijó , de Freitas Ana Julia Aguiar , da Silva Gabriel , Silva Wilson Araujo , Peronni Kamila , Marques Marcia Maria Chiquitelli , Marins Mozart , Fachin Ana Lucia
Published: June 2023

Breast cancer is responsible for 25% of all cancers that affect women. Due to its high heterogeneity pattern in clinical diagnosis and its molecular profile differences, researchers have been seeking new targets and therapies, with more specificity and fewer side effects. Thus, one compound that has garnered our attention is trans-chalcone, which is naturally occurring in various plants and possesses promising biological properties, including antitumor effects. MiRNA is an extensive class of non-coding small, endogenous, and single-stranded RNAs, and it is involved in post-translational gene regulation. Therefore, the objective of this study was to investigate the effects of TChal on miRNAs expression and its relationship with anticancer activity against MCF-7. Initially, the trans-chalcone IC50 value was established by MTT assay for MCF-7and HaCat (non-cancer cell), in which we found out that it was 53.73 and 44.18 μM, respectively. Subsequently, we treated MCF-7 cells with trans-chalcone at its IC50 concentration and performed Mi-seq analysis, which unveiled 23 differentially expressed miRNAs. From this set, we selected five miRNAs (miR-25-5p, miR-27a-3p, miR-891a, miR-449a, and miR-4485) for further validation using qRT-PCR, guided by in silico analysis and their known association with tumorigenesis. In conclusion, our research provides valuable insights into the potential use of TChal to reveal MicroRNAs molecular targets that can be applied in breast cancer therapy.
Nanodrugs for the Treatment of Ischemic Stroke: A Systematic Review
Authors: Ruscu Mihai , Cercel Andreea , Kilic Ertugrul , Catalin Bogdan , Gresita Andrei , Hermann Dirk M. , Albu Carmen Valeria , Popa-Wagner Aurel
Published: June 2023

Ischemic stroke, a significant neurovascular disorder, currently lacks effective restorative medication. However, recently developed nanomedicines bring renewed promise for alleviating ischemia’s effects and facilitating the healing of neurological and physical functions. The aim of this systematic review was to evaluate the efficacy of nanotherapies in animal models of stroke and their potential impact on future stroke therapies. We also assessed the scientific quality of current research focused on nanoparticle-based treatments for ischemic stroke in animal models. We summarized the effectiveness of nanotherapies in these models, considering multiple factors such as their anti-inflammatory, antioxidant, and angiogenetic properties, as well as their safety and biodistribution. We conclude that the application of nanomedicines may reduce infarct size and improve neurological function post-stroke without causing significant organ toxicity.
Talk to Me—Interplay between Mitochondria and Microbiota in Aging
Authors: Endres Kristina , Friedland Kristina
Published: June 2023

The existence of mitochondria in eukaryotic host cells as a remnant of former microbial organisms has been widely accepted, as has their fundamental role in several diseases and physiological aging. In recent years, it has become clear that the health, aging, and life span of multicellular hosts are also highly dependent on the still-residing microbiota, e.g., those within the intestinal system. Due to the common evolutionary origin of mitochondria and these microbial commensals, it is intriguing to investigate if there might be a crosstalk based on preserved common properties. In the light of rising knowledge on the gut–brain axis, such crosstalk might severely affect brain homeostasis in aging, as neuronal tissue has a high energy demand and low tolerance for according functional decline. In this review, we summarize what is known about the impact of both mitochondria and the microbiome on the host’s aging process and what is known about the aging of both entities. For a long time, bacteria were assumed to be immortal; however, recent evidence indicates their aging and similar observations have been made for mitochondria. Finally, we present pathways by which mitochondria are affected by microbiota and give information about therapeutic anti-aging approaches that are based on current knowledge.
In Silico Screening and Anticancer-Apoptotic Evaluation of Newly Synthesized Thienopyrimidine/Sulfonamide Hybrids
Authors: Elmongy Elshaymaa I. , Binjubair Faizah A. , Alshehri Ohoud Y. , Baeshen Kholoud A. , Almukhalfi Zaha A. , Henidi Hanan A.
Published: June 2023

This work describes the design and synthesis of new hybrids of thienopyrimidine and sulfonamides. The binding affinity of the prepared compounds to FGFR-1 enzyme and caspase-3 was investigated via molecular docking. The cytotoxic effect was estimated for the synthesized compounds against human breast cancer cell lines (MCF-7 and MDA-MB231) using Doxorubicin as a reference. All the tested compounds exhibited moderate to excellent anticancer efficacy against both tested cell lines, among which 3b and 4bi were the best. All the synthesized compounds exhibited distinguishing selectivity index values greater than Doxorubicin. The influence of the new hybrids under inquiry was further examined on both FGFR-1 and Caspase-3. The results revealed that compound 3b showed observed concordance between anti-proliferative activity and Caspase-3 activity. In respect to the compounds’ effect on the apoptosis, compound 3b significantly increased the population of late apoptotic cells and necrotic cells. In silico pharmacokinetic investigation revealed that compound 3b showed the best intestinal absorption, BBB permeability, and, along with 4bi and 4bii, the best CNS penetrability.
Imiquimod as Local Immunotherapy in the Management of Premalignant Cutaneous Conditions and Skin Cancer
Authors: Garcia-Mouronte Emilio , Berna-Rico Emilio , de Nicolas-Ruanes Belen , Azcarraga-Llobet Carlos , Alonso-Martinez de Salinas Luis , Bea-Ardebol Sonia
Published: June 2023

Cutaneous cancers are, by far, the most common malignant neoplasms of the human being. Due to the great array of clinical conditions, their worldwide increasing incidence and the steady ageing of the population, non-invasive treatments modalities that show a good clinical response, a proper benefit–risk ratio and cosmetic results are becoming increasingly important in the clinical setting. Imiquimod is a topically applied immunomodulator which is often used in the management of several premalignant and malignant cutaneous disorders. This article is a review of the current literature on its mechanism of action, pharmacokinetics, and therapeutical effects.
Evaluation of a Set of miRNAs in 26 Cases of Fatal Traumatic Brain Injuries
Authors: Bonin Serena , D’Errico Stefano , Medeot Caterina , Moreschi Carlo , Ciglieri Solange Sorçaburu , Peruch Michela , Concato Monica , Azzalini Eros , Previderè Carlo , Fattorini Paolo
Published: June 2023

In forensic medicine, identifying novel biomarkers for use as diagnostic tools to ascertain causes of death is challenging because of sample degradation. To that aim, a cohort (n = 26) of fatal traumatic brain injuries (TBIs) were tested for three candidate miRNAs (namely, miR-124-3p, miR-138-5p, and miR144-3p). For each case, three FFPE specimens (coup area (CA), contrecoup area (CCA), and the corpus callosum (CC)) were investigated, whereas the FFPE brain tissues of 45 subjects (deceased due to acute cardiovascular events) were used as controls. Relative quantification via the ∆∆Ct method returned significantly higher expression levels of the three candidate miRNAs (p < 0.01) in the TBI cases. No difference was detected in the expression levels of any miRNA investigated in the study among the CA, CCA, and CC. Furthermore, the analyzed miRNAs were unrelated to the TBI samples’ post-mortem intervals (PMIs). On the contrary, has-miR-124-3p ahashsa-miR-144-3p were significantly correlated (p < 0.01) with the agonal time in TBI deaths. Since the RNA was highly degraded in autoptic FFPE tissues, it was impossible to analyze the mRNA targets of the miRNAs investigated in the present study, highlighting the necessity of standardizing pre-analytical processes even for autopsy tissues.
Signal and Nutritional Effects of Mixed Diets on Reproduction of a Predatory Ladybird, Cheilomenes propinqua
Authors: Ovchinnikov Andrey N. , Ovchinnikova Antonina A. , Reznik Sergey Y. , Belyakova Natalia A.
Published: June 2023

It is known that food has a double impact on females of predatory ladybirds: qualitative signal effect (the onset of oogenesis) and quantitative nutritional effect (the increase in oogenesis intensity). We compared the patterns of these effects by feeding Cheilomenes propinqua females on mixed diets: unlimited low-quality prey (eggs of the grain moth Sitotroga cerealella) and limited high-quality prey (the green peach aphid Myzus persicae: 0, 2, 10, and 50 aphids per day). About half of the females fed only on the grain moth eggs oviposited and their fecundity was very low. Daily consumption of 2 aphids increased the proportion of egg-laying females whereas only consumption of 10 aphids increased their mean fecundity. Thus, the threshold of the signal effect was lower than that of the nutritional effect. As applied to mass rearing, we conclude that the addition of high-quality prey to low-quality food causes a substantial increase in egg production, although the economic feasibility of this method is not clear. Regarding biological control of pests by preventing colonization, we conclude that the fecundity of C. propinqua females supplied with the grain moth eggs in the absence of aphids will be low but the appearance of pests will cause a proportional increase in the mean fecundity of ladybirds.
Transcatheter Aortic Valve Replacement in Elderly Patients: Opportunities and Challenges
Authors: Huang Bing , Yan Hui , Li Yunyao , Zhou Qiping , Abudoureyimu Ayipali , Cao Guiqiu , Jiang Hong
Published: June 2023

Over the past two decades, the rapid evolution of transcatheter aortic valve replacement (TAVR) has revolutionized the management of severe aortic stenosis (AS) in the elderly. The prevalence of comorbidities in elderly AS patients presents a considerable challenge to the effectiveness and prognosis of patients after TAVR. In this article, we aim to summarize some of the clinical aspects of the current use of TAVR in elderly patients and attempt to highlight the challenges and issues that need further consideration.
Prevention of Atrial Fibrillation: Putting Proteostasis Derailment Back on Track
Authors: Kishore Preetam , Collinet Amelie C. T. , Brundel Bianca J. J. M.
Published: June 2023

Despite the many attempts to treat atrial fibrillation (AF), the most common cardiac tachyarrhythmia in the Western world, the treatment efficacy of AF is still suboptimal. A plausible reason for the suboptimal efficacy is that the current treatments are not directed at the underlying molecular mechanisms that drive AF. Recent discoveries revealed that the derailment of specific molecular proteostasis pathways drive electrical conduction disorders, contractile dysfunction and AF. The degree of this so-called ‘electropathology’ corresponds to the response to anti-AF treatment. Hence, to develop effective therapies to prevent AF, understanding the molecular mechanisms is of key importance. In this review, we highlight the key modulators of proteostasis derailment and describe the mechanisms that explain how they affect electrical and contractile function in atrial cardiomyocytes and AF. The key modulators of proteostasis derailment include (1) exhaustion of cardioprotective heat shock proteins (HSPs), (2) excessive endoplasmic reticulum (ER) stress and downstream autophagic protein degradation, (3) histone deacetylase 6 (HDAC6)-induced microtubule disruption, (4) activation of DNA damage-PARP1 activation and NAD+ axis and (5) mitochondrial dysfunction. Furthermore, we discuss druggable targets within these pathways that are involved in the prevention of proteostasis derailment, as well as the targets that aid in the recovery from AF. Finally, we will elaborate on the most favorable druggable targets for (future) testing in patients with AF, as well as drugs with potential benefits for AF recovery.
Risk Factors for Early- and Late-Onset Cholecystitis after Y-Configured Metal Stent Placement in Patients with Malignant Hilar Biliary Obstruction: A Single-Center Study
Authors: Lee Jonghyun , Han Sung Yong , Baek Donghoon , Kim Gwang Ha , Song Geun Am , Kim Dong Uk
Published: June 2023

This study evaluated the prevalence and risk factors of early- (within 7 days of placement) and late-onset (after 7 days of placement) cholecystitis after Y-configured metal stent placement. Between June 2005 and August 2020, 109 patients who had been treated with Y-configured metal stents for malignant hilar obstruction were enrolled in the study. We retrospectively analyzed the potential risk factors for post-stent cholecystitis. The presence of diabetes (p = 0.042), the length of the common part of the Y-stent (p = 0.017), filling of the gallbladder with contrast medium during the procedure (p = 0.040), and tumor invasion of the cystic duct accompanied by filling the gallbladder with contrast medium during metal stent placement (p = 0.001) were identified as important risk factors. In cases of late-onset cholecystitis, stent obstruction (p = 0.004) and repeated endoscopic procedures due to stent malfunction (p = 0.024) were significant risk factors. In the multivariate logistic regression analysis, significant risk factors were the length of the common part of the Y-stent (p = 0.032) in early-onset cholecystitis and stent obstruction (p = 0.007) in late-onset cholecystitis. This study demonstrated that early-onset cholecystitis may occur in patients according to the length of the common portion of the Y-stent. In contrast, late-onset cholecystitis may occur in patients with stent obstruction.
Intestinal Microbiota Reduction Followed by Fasting Discloses Microbial Triggering of Inflammation in Rheumatoid Arthritis
Authors: Häupl Thomas , Sörensen Till , Smiljanovic Biljana , Darcy Marine , Scheder-Bieschin Justus , Steckhan Nico , Hartmann Anika M. , Koppold Daniela A. , Stuhlmüller Bruno , Skriner Karl , Walewska Barbara M. , Hoppe Berthold , Bonin Marc , Burmester Gerd R. , Schendel Pascal , Feist Eugen , Liere Karsten , Meixner Martin , Kessler Christian , Grützkau Andreas , Michalsen Andreas
Published: June 2023

Rheumatoid arthritis (RA) synovitis is dominated by monocytes/macrophages with inflammatory patterns resembling microbial stimulation. In search of triggers, we reduced the intestinal microbiome in 20 RA patients (open label study DRKS00014097) by bowel cleansing and 7-day fasting (≤250 kcal/day) and performed immune monitoring and microbiome sequencing. Patients with metabolic syndrome (n = 10) served as a non-inflammatory control group. Scores of disease activity (DAS28/SDAI) declined within a few days and were improved in 19 of 20 RA patients after breaking the fast (median ∆DAS28 = −1.23; ∆SDAI = −43%) or even achieved remission (DAS28 < 2.6/n = 6; SDAI < 3.3/n = 3). Cytometric profiling with 46 different surface markers revealed the most pronounced phenomenon in RA to be an initially increased monocyte turnover, which improved within a few days after microbiota reduction and fasting. Serum levels of IL-6 and zonulin, an indicator of mucosal barrier disruption, decreased significantly. Endogenous cortisol levels increased during fasting but were insufficient to explain the marked improvement. Sequencing of the intestinal microbiota indicated that fasting reduced potentially arthritogenic bacteria and changed the microbial composition to species with broader metabolic capabilities. More eukaryotic, predominantly fungal colonizers were observed in RA, suggesting possible involvement. This study demonstrates a direct link between the intestinal microbiota and RA-specific inflammation that could be etiologically relevant and would support targeted nutritional interventions against gut dysbiosis as a causal therapeutic approach.
Autism Spectrum Disorder in Children with an Early History of Paediatric Acquired Brain Injury
Authors: Porter Melanie , Sugden-Lingard Sindella , Brunsdon Ruth , Benson Suzanne
Published: June 2023

Autism spectrum disorder (ASD) is a neurodevelopmental condition that arises from a combination of both genetic and environmental risk factors. There is a lack of research investigating whether early acquired brain injury (ABI) may be a risk factor for ASD. The current study comprehensively reviewed all hospital records at The Brain Injury Service, Kids Rehab at the Children’s Hospital at Westmead (Australia) from January 2000 to January 2020. Of the approximately 528 cases, 14 children with paediatric ABI were subsequently given an ASD diagnosis (2.7%). For this ASD sample, the mean age at the time of the ABI was 1.55 years, indicating a high prevalence of early ABI in this diagnostic group. The mean age of ASD diagnosis was, on average, 5 years later than the average ASD diagnosis in the general population. Furthermore, 100% of children had at least one medical comorbidity and 73% had three or more co-occurring DSM-5 diagnoses. Although based on a small data set, results highlight early paediatric ABI as a potential risk factor for ASD and the potential for a delayed ASD diagnosis following early ABI, with comorbidities possibly masking symptoms. This study was limited by its exploratory case series design and small sample size. Nonetheless, this study highlights the need for longitudinal investigation into the efficacy of early screening for ASD symptomatology in children who have sustained an early ABI to maximise potential intervention.
Benralizumab in Patients with Severe Eosinophilic Asthma: A Multicentre Real-Life Experience
Authors: Scioscia Giulia , Tondo Pasquale , Nolasco Santi , Pelaia Corrado , Carpagnano Giovanna Elisiana , Caiaffa Maria Filomena , Valenti Giuseppe , Maglio Angelantonio , Papia Francesco , Triggiani Massimo , Crimi Nunzio , Pelaia Girolamo , Vatrella Alessandro , Foschino Barbaro Maria Pia , Crimi Claudia
Published: June 2023

Background: Mepolizumab and benralizumab are monoclonal antibodies directed against anti-IL-5 and anti-IL5R, respectively, and their use reduces the exacerbation rate and maintains oral corticosteroid requirements in severe eosinophilic asthma. Previous studies have tested the therapeutic switch between two biologics with excellent results, further demonstrating the heterogeneity of asthmatic disease and the complexity of the therapeutic choice. It remains unclear if such patients may improve following a switch from mepolizumab to benralizumab. Aims: Within a multicentre real-life setting, we decided to evaluate the potential effectiveness of a therapeutic switch to benralizumab in patients with severe eosinophilic asthma initially treated with mepolizumab, who experienced sub-optimal responses. The secondary aim was to identify the clinical factors associated with a better response to benralizumab. Methods: We retrospectively assessed patients with severe eosinophilic asthma treated at six Italian specialist centres, who were switched from mepolizumab to benralizumab following a sub-optimal response, defined as a partial or total lack of clinical remission (i.e., frequent severe exacerbations and/or poorly controlled symptoms and/or higher OCS daily use in patients with a poor or moderate response in the global evaluation of treatment effectiveness scale), after at least 12 months of treatment. Results: Twenty-five patients were included in the analysis (mean age 56.76 ± 11.97 years, 65% female). At 6 months of treatment with benralizumab, the ACT score was significantly higher than the ACT score with mepolizumab (20.24 ± 3.38 vs. 16.77 ± 3.48, p < 0.0001); the mean number of daily SABA inhalations was significantly lower after 6 months and 12 months of treatment with benralizumab than that after treatment with mepolizumab; OCS intake and the prednisone median dosage at 6 months of treatment with benralizumab were significantly lower than those with mepolizumab. Benralizumab treatment resulted in a marked improvement in asthma control, suppressed blood eosinophil levels and reduction in the number of exacerbations in the subgroup of patients with severe eosinophilic asthma and nasal polyposis. Conclusions: Patients diagnosed with severe eosinophilic asthma who experience a partial response to mepolizumab could benefit from switching to benralizumab, and even more those who have nasal polyposis.
Spectrum and Outcome of Prenatally Diagnosed Fetal Primary Cardiomyopathies—A Twenty-Year Overview
Authors: Walter Adeline , Calite Elina , Geipel Annegret , Strizek Brigitte , Recker Florian , Herberg Ulrike , Berg Christoph , Gembruch Ulrich
Published: June 2023

Objective: to assess the course and outcome of fetuses affected by primary cardiomyopathy (CM). Methods: Retrospective study of 21 cases with prenatal diagnosis of a primary CM in one tertiary center over a period of 20 years. Charts were reviewed for echocardiographic findings, pregnancy outcome, and postnatal course. The utility of prenatal evaluation was discussed. Results: The mean gestational age (GA) at diagnosis was 26.7 (±5.1) weeks. A total of 33.3% (7/21) had associated anomalies. Genetic etiology was confirmed in 50.0% (10/20, with one case lost to follow up). The overall survival rate of the entire study population was 40% (8/20) including termination of pregnancy in 20% (4/20) and an intrauterine mortality rate of 5% (1/20). Of the initial survivors (n = 15), a neonatal and early infant mortality rate of 46.7% (7/15) was calculated. Prenatal isolated right ventricular involvement was the only identified significant parameter for survival (p = 0.035). Four phenotypical groups were identified: 42.9% (9/21) hypertrophic (HCM), 38.1% (8/21) dilated (DCM), 14.3% (3/21) isolated noncompaction (NCCM), and 4.8% (1/21) restrictive CM (RCM). Fetuses assigned to isolated NCCM revealed a 100% survival rate. Conclusion: Prenatal detection is feasible but needs to a introduce classification method for better consulting and management practices. A poor outcome is still observed in many cases, but an increase in examiners’ awareness may influence optimal multispecialized care.
Making Sense of Composite Endpoints in Clinical Research
Authors: Baracaldo-Santamaría Daniela , Feliciano-Alfonso John Edwin , Ramirez-Grueso Raul , Rojas-Rodríguez Luis Carlos , Dominguez-Dominguez Camilo Alberto , Calderon-Ospina Carlos Alberto
Published: June 2023

Multiple drugs currently used in clinical practice have been approved by regulatory agencies based on studies that utilize composite endpoints. Composite endpoints are appealing because they reduce sample size requirements, follow-up periods, and costs. However, interpreting composite endpoints can be challenging, and their misuse is not uncommon. Incorrect interpretation of composite outcomes can lead to misleading conclusions that impact patient care. To correctly interpret composite outcomes, several important questions should be considered. Are the individual components of the composite outcome equally important to patients? Did the more and less important endpoints occur with similar frequency? Do the component endpoints exhibit similar relative risk reductions? If these questions receive affirmative answers, the use and interpretation of the composite endpoint would be appropriate. However, if any component of the composite endpoint fails to satisfy the aforementioned criteria, interpretation can become difficult, necessitating additional steps. Regulatory agencies acknowledge these challenges and have specific considerations when approving drugs based on studies employing composite endpoints. In conclusion, composite endpoints are valuable tools for evaluating the efficacy and net clinical benefit of interventions; however, cautious interpretation is advised.