bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Existing Legal Assessment Values for Heavy Metal Deposition in Western Europe and Calculation of Assessment Values for Luxembourg
Authors: Schlutow Angela , Schröder Winfried
Published: November 2021

The protection against eco- and human-toxicological impairments caused by atmospheric deposition of heavy metals requires legally defined assessment values. Since such values are missing for Luxembourg, the aim of this investigation was to evaluate different approaches to derive assessment values for the regulation of heavy metals that are in accordance with scientific and legal standards. To this end, assessment values for heavy metals were derived from the compilation of respective values implemented in European countries. In addition, (1) precipitation-related assessment values for the protection of soil for Cr, Zn, and Cu and (2) precautionary assessment values (critical loads for Cr, Zn, and Cu, as well as As, Cd, Ni, and Pb) for the protection of human health and ecosystems were calculated. The calculation of the regionally differentiated precipitation-related assessment values resulted in ranges of 17–272 g Cu ha−1 a−1, 167–2672 g Zn ha−1 a−1 and 17–272 g Crtotal ha−1 a−1. The critical loads for drinking water protection vary in the ranges from 1.23 to 2.14 g Cd ha−1 a−1, from 4.05 to 8.63 g Pb ha−1 a−1, from 2.6 to 5.9 g As ha−1 a−1, from 258 to 564 g Cu ha−1 a−1, from 1292 to 2944 g Zn ha−1 a−1, and from 12.9 to 29.9 g Crtotal ha−1 a−1. Ecosystems are significantly more sensitive to Pb, Cu, and Zn inputs than humans. For As and Cr, humans react much more sensitively than ecosystems. For Cd, the critical loads for drinking water, ecosystems, and wheat products are about the same.
Certain Subclasses of Analytic Multivalent Functions Associated with Petal-Shape Domain
Authors: Shi Lei , Srivastava Hari M. , Khan Muhammad Ghaffar , Khan Nazar , Ahmad Bakhtiar , Khan Bilal , Mashwani Wali Khan
Published: November 2021

In this article, we introduce a new class of multivalent analytic functions associated with petal-shape region. Furthermore, some useful properties, such as the Fekete–Szegö inequality, and their consequences for some special cases are discussed. For some specific value of function f, we obtain sufficient conditions for multivalent starlike functions connected with petal-shape domain. Finally, in the concluding section, we draw the attention of the interested readers toward the prospect of studying the basic or quantum (or q-) generalizations of the results, which are presented in this paper. However, the (p,q)-variations of the suggested q-results will provide a relatively minor and inconsequential development because the additional (rather forced-in) parameter p is obviously redundant.
Association between Sleep, Alzheimer’s, and Parkinson’s Disease
Authors: Matsumoto Sumire , Tsunematsu Tomomi
Published: November 2021

The majority of neurodegenerative diseases are pathologically associated with protein misfolding and aggregation. Alzheimer’s disease (AD) is a type of dementia that slowly affects memory and cognitive function, and is characterized by the aggregation of the β-amyloid protein and tau neurofibrillary tangles in the brain. Parkinson’s disease (PD) is a movement disorder typically resulting in rigidity and tremor, which is pathologically linked to the aggregation of α-synuclein, particularly in dopaminergic neurons in the midbrain. Sleep disorders commonly occur in AD and PD patients, and it can precede the onset of these diseases. For example, cognitively normal older individuals who have highly fragmented sleep had a 1.5-fold increased risk of subsequently developing AD. This suggests that sleep abnormalities may be a potential biomarker of these diseases. In this review, we describe the alterations of sleep in AD and PD, and discuss their potential in the early diagnosis of these diseases. We further discuss whether sleep disturbance could be a target for the treatment of these diseases.
A Cross-Sectional Observation on Maximal Eccentric Hamstring Strength in 7- to 15-Year-Old Competitive Alpine Skiers
Authors: Kiers Kirsten , Ellenberger Lynn , Javet Marie , Bruhin Björn , Frey Walter O. , Spörri Jörg
Published: November 2021

Severe knee injuries are common in alpine skiing and the hamstring muscles are known to counteract the anterior tibial displacement that typically accompanies major injury mechanisms. This study aimed to assess the Maximal Eccentric Hamstring Strength (MEHS) of youth competitive alpine skiers during Nordic Hamstring Exercise (NHE) in terms of dependence of sex, age and biological maturation. A total of 246 7- to 15-year-old skiers were tested with respect to their MEHS using an NHE-based measurement device (Vald Performance, Newstead, Australia). Significantly greater absolute MEHS was observed in skiers of the under 15 years (U15) category compared to skiers under 10 years old (U10) (227.9 ± 61.1 N vs. 142.6 ± 28.9 N; p < 0.001), also when grouped by sex. Absolute MEHS was revealed to be lower in U15 females compared to males (213.5 ± 49.0 N vs. 241.9 ± 68.4 N; p = 0.001); in U10 skiers there was no sex difference. For all age groups and sexes, absolute MEHS values were significantly correlated with age and biological maturation (p < 0.001). However, when normalized to body weight such associations disappeared, which is why this is strongly recommended when testing around their growth spurt. Overall, this study established sport-specific normative reference data that may be of interest to researchers and sport practitioners alike.
Complement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model
Authors: Armento Angela , Murali Aparna , Marzi Julia , Almansa-Garcia Ana C , Arango-Gonzalez Blanca , Kilger Ellen , Clark Simon J , Schenke-Layland Katja , Ramlogan-Steel Charmaine A , Steel Jason C , Ueffing Marius
Published: November 2021

Age-related Macular degeneration (AMD) is a degenerative disease of the macula affecting the elderly population. Treatment options are limited, partly due to the lack of understanding of AMD pathology and the lack of suitable research models that replicate the complexity of the human macula and the intricate interplay of the genetic, aging and lifestyle risk factors contributing to AMD. One of the main genetic risks associated with AMD is located on the Complement Factor H (CFH) gene, leading to an amino acid substitution in the Factor H (FH) protein (Y402H). However, the mechanism of how this FH variant promotes the onset of AMD remains unclear. Previously, we have shown that FH deprivation in RPE cells, via CFH silencing, leads to increased inflammation, metabolic impairment and vulnerability toward oxidative stress. In this study, we established a novel co-culture model comprising CFH silenced RPE cells and porcine retinal explants derived from the visual streak of porcine eyes, which closely resemble the human macula. We show that retinae exposed to FH-deprived RPE cells show signs of retinal degeneration, with rod cells being the first cells to undergo degeneration. Moreover, via Raman analyses, we observed changes involving the mitochondria and lipid composition of the co-cultured retinae upon FH loss. Interestingly, the detrimental effects of FH loss in RPE cells on the neuroretina were independent of glial cell activation and external complement sources. Moreover, we show that the co-culture model is also suitable for human retinal explants, and we observed a similar trend when RPE cells deprived of FH were co-cultured with human retinal explants from a single donor eye. Our findings highlight the importance of RPE-derived FH for retinal homeostasis and provide a valuable model for AMD research.
Editorial of Special Issue “Multiple Sclerosis: Diagnosis and Treatment II”
Authors: Rivera Victor M.
Published: November 2021

The special issue on Multiple Sclerosis: Diagnosis and Treatment II, reflects advances and discoveries in the molecular and cellular mechanisms of disease, and novel laboratory techniques providing more sensitivity to diagnostic techninques and the understanding of neuroinflammation. Mitochondrial-mediated apoptosis in isolated peripheral blood mononuclear cells and the role of reactive oxygen species are studied as indicators of activity of MS. In these cells, downregulation of circular and linera RNAs are reported as markers of highly active disease in MS. Progress and importance of Neurofilaments determinations in early diagnosis and as a marker of disease activity, and the analysis of the complex mechanisms and therapeutic potential of Sphingosine-1-phosphate receptor modulator are discussed. Epidemiologic observations from a highly diversified area of the world provide more insights into this important aspect of MS; discussions on the clinical challenges posed by spinal cord involvement in demyelinatind disorders and the latest aspects of pediatric onset MS, complement this fine collection of scientific papers.
Renal Hypouricemia 1: Rare Disorder as Common Disease in Eastern Slovakia Roma Population
Authors: Stiburkova Blanka , Bohatá Jana , Pavelcová Kateřina , Tasic Velibor , Plaseska-Karanfilska Dijana , Cho Sung-Kweon , Potočnaková Ludmila , Šaligová Jana
Published: November 2021

Renal hypouricemia (RHUC) is caused by an inherited defect in the main reabsorption system of uric acid, SLC22A12 (URAT1) and SLC2A9 (GLUT9). RHUC is characterized by a decreased serum uric acid concentration and an increase in its excreted fraction. Patients suffer from hypouricemia, hyperuricosuria, urolithiasis, and even acute kidney injury. We report clinical, biochemical, and genetic findings in a cohort recruited from the Košice region of Slovakia consisting of 27 subjects with hypouricemia and relatives from 11 families, 10 of whom were of Roma ethnicity. We amplified, directly sequenced, and analyzed all coding regions and exon–intron boundaries of the SLC22A12 and SLC2A9 genes. Sequence analysis identified dysfunctional variants c.1245_1253del and c.1400C>T in the SLC22A12 gene, but no other causal allelic variants were found. One heterozygote and one homozygote for c.1245_1253del, nine heterozygotes and one homozygote for c.1400C>T, and two compound heterozygotes for c.1400C>T and c.1245_1253del were found in a total of 14 subjects. Our result confirms the prevalence of dysfunctional URAT1 variants in Roma subjects based on analyses in Slovak, Czech, and Spanish cohorts, and for the first time in a Macedonian Roma cohort. Although RHUC1 is a rare inherited disease, the frequency of URAT1-associated variants indicates that this disease is underdiagnosed. Our findings illustrate that there are common dysfunctional URAT1 allelic variants in the general Roma population that should be routinely considered in clinical practice as part of the diagnosis of Roma patients with hypouricemia and hyperuricosuria exhibiting clinical signs such as urolithiasis, nephrolithiasis, and acute kidney injury.
Circularly Permuted Far-Red Fluorescent Proteins
Authors: Wu Tianchen , Pang Yu , Ai Hui-wang
Published: November 2021

The color palette of genetically encoded fluorescent protein indicators (GEFPIs) has expanded rapidly in recent years. GEFPIs with excitation and emission within the “optical window” above 600 nm are expected to be superior in many aspects, such as enhanced tissue penetration, reduced autofluorescence and scattering, and lower phototoxicity. Circular permutation of fluorescent proteins (FPs) is often the first step in the process of developing single-FP-based GEFPIs. This study explored the tolerance of two far-red FPs, mMaroon1 and mCarmine, towards circular permutation. Several initial constructs were built according to previously reported circularly permuted topologies for other FP analogs. Mutagenesis was then performed on these constructs and screened for fluorescent variants. As a result, five circularly permuted far-red FPs (cpFrFPs) with excitation and emission maxima longer than 600 nm were identified. Some displayed appreciable brightness and efficient chromophore maturation. These cpFrFPs variants could be intriguing starting points to further engineer far-red GEFPIs for in vivo tissue imaging.
Short- and Long-Term Effect of Parkinson’s Disease Multimodal Complex Treatment
Authors: Heimrich Konstantin G. , Prell Tino
Published: November 2021

Parkinson´s disease multimodal complex treatment (PD-MCT) is a multidisciplinary inpatient treatment option increasingly applied in Germany. However, data on its effectiveness are rare. Data were collected at the Department of Neurology of the University Hospital Jena, Germany. In 2019, 159 patients were admitted to our neurology ward for PD-MCT. Patients were followed for up to 12 months, and their data were retrospectively analyzed to assess the short- and long-term treatment effects. The treatment led to an improvement in motor function assessed by Movement Disorder Society sponsored revision of the unified Parkinson´s disease rating scale part III (MDS-UPDRS III) and motor performance (Tinetti test). Improvement of MDS-UPDRS III was associated with lower age, higher MDS-UPDRS III at admission, and less depression (assessed by Hospital Anxiety and Depression Scale and Beck-Depression Inventory II). One month after the hospital stay, 36.8% of the patients reported feeling better, while 32.6% reported feeling worse. If the patients were not depressed, they were more likely to have reported feeling better. PD-MCT is an effective inpatient treatment option. However, to improve patients’ satisfaction, screening and treatment for depression is essential. The effectiveness of different treatment durations has to be elucidated in further studies.
Behavioral Sciences in the Optimization of Pharmacological and Non-Pharmacological Therapy for Type 2 Diabetes
Authors: Lopes António , Roque Fátima , Morgado Sandra , Dinis Cristina , Herdeiro Maria Teresa , Morgado Manuel
Published: November 2021

Type 2 diabetes mellitus is one of the main chronic diseases worldwide, with a significant impact on public health. Behavioral changes are an important step in disease prevention and management, so the way in which individuals adapt their lifestyle to new circumstances will undoubtedly be a predictor of the success of the treatments instituted, contributing to a reduction in the morbidity and mortality that may be associated with them. It is essential to prepare and educate all diabetic patients on the importance of changing behavioral patterns in relation to the disease, with health professionals assuming an extremely important role in this area, both from a pharmacological and non-pharmacological point of view, and also ensuring the monitoring of the progress of these measures. Diabetes is a chronic disease that requires a high self-management capacity on the part of patients in order to achieve success in treating the disease, and non-adherence to therapy or non-compliance with the previously defined plan, together with an erratic lifestyle, will contribute to failure in controlling the disease. The lower adherence to pharmacological and non-pharmacological treatment in diabetes is mainly correlated to socio-economic aspects, lower health literacy, the side effects associated with the use of antidiabetic therapy or even the concomitant use of several drugs. This article consists of a narrative review that aims to synthesize the findings published in the literature, retrieved by searching databases, manuals, previously published scientific articles and official texts, following the methodology of the Scale for Assessment of Narrative Review Articles (SANRA). We aim to address the importance of behavioral sciences in the treatment of diabetes, in order to assess behavior factors and barriers for behavior changes that have an impact on the therapeutic and non-therapeutic optimization in patients with type 2 diabetes mellitus control.
Comparative Study of Key Supply Chain Management Elements in Sustainability Reports
Authors: Lee Veronika , Marasini Durga , Dong Wenye , Lee Hyun-Jung , Lee DonHee
Published: November 2021

During the COVID-19 pandemic, several issues have emerged as important in evaluating firm value and investment-oriented decision making. These issues include supply chain management, human rights, climate change, safety, and environmental risks. This study analyzed the sustainability reports of four business firms, each in four different countries, covering 2005/2006, 2013, and 2020. The analysis revealed similar factors and their dimensions that are critical for effective supply chain management: environmental and public sector issues, collaboration and cooperation with partner organizations, environmentally friendly production and development systems, human-centered operation plans, and risk management. While the study results delineated several key categories, there were variations among the four firms’ sustainability reports, indicating a need for global standards for comparative analysis. This study highlights the importance of sustainability, its effective measurement, and global standards for sustainability reports. As governments put pressure on businesses to demonstrate their commitments to environmental issues, many firms have embraced the concept of corporate social responsibility by practicing socially responsible codes of conduct throughout their supply chains.
Correction: Sioud et al. Evaluation of In Vitro Phototoxicity of a Minibody-IR700 Conjugate Using Monolayer and Multicellular Tumor Spheroid Models. Cancers 2021, 13, 3356
Authors: Sioud Mouldy , Juzenas Petras , Zhang Qindong , Kleinauskas Andrius , Peng Qian
Published: November 2021

The authors wish to make the following corrections to this paper [...]
Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading
Authors: Hanaoka Hirofumi , Ohshima Yasuhiro , Suzuki Hiroyuki , Sasaki Ichiro , Watabe Tadashi , Ooe Kazuhiro , Watanabe Shigeki , Ishioka Noriko S.
Published: November 2021

L-type amino acid transporter 1 (LAT1) might be a useful target for tumor therapy since it is highly expressed in various types of cancers. We previously developed an astatine-211 (211At)-labeled amino acid derivative, 2-211At-astato-α-methyl-L-phenylalanine (2-211At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-211At-AAMP was insufficient, probably due to its low tumor retention. The preloading of probenecid, an organic anion transporter inhibitor, can delay the clearance of some amino acid tracers from the blood and consequently increase their accumulation in tumors. In this study, we evaluated the effect of probenecid preloading on the biodistribution and therapeutic effect of 2-211At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-211At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-211At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-211At-AAMP with probenecid, and the tumor volume was significantly lower in the treatment group than in the untreated control group from day 2 to day 30 (end of the follow-up period) after treatment. These results indicate that probenecid loading could improve the therapeutic effect of 2-211At-AAMP by increasing its accumulation in tumors.
WNT/β-Catenin Pathway in Soft Tissue Sarcomas: New Therapeutic Opportunities?
Authors: Martinez-Font Esther , Pérez-Capó Marina , Vögler Oliver , Martín-Broto Javier , Alemany Regina , Obrador-Hevia Antònia
Published: November 2021

Soft tissue sarcomas (STS) are a very heterogeneous group of rare tumors, comprising more than 50 different histological subtypes that originate from mesenchymal tissue. Despite their heterogeneity, chemotherapy based on doxorubicin (DXR) has been in use for forty years now and remains the standard first-line treatment for locally advanced unresectable or metastatic STS, although overall survival could not be improved by combination with other chemotherapeutics. In this sense, the development of new therapeutic approaches continues to be a largely unmatched goal. The WNT/β-catenin signaling pathway is involved in various fundamental processes for embryogenic development, including the proliferation and differentiation of mesenchymal stem cells. Although the role of this pathway has been widely researched in neoplasms of epithelial origin, little is known about its relevance for mesenchymal neoplasms. This review covers the most important molecular alterations of the WNT signaling pathway in STS. The detection of these alterations and the understanding of their functional consequences for those pathways controlling sarcomagenesis development and progression are crucial to broaden the current knowledge about STS as well as to identify novel drug targets. In this regard, the current therapeutic options and drug candidates to modulate WNT signaling, which are usually classified by their interaction site upstream or downstream of β-catenin, and their presumable clinical impact on STS are also discussed.
Machine Learning Based Prediction of Squamous Cell Carcinoma in Ex Vivo Confocal Laser Scanning Microscopy
Authors: Ruini Cristel , Schlingmann Sophia , Jonke Žan , Avci Pinar , Padrón-Laso Víctor , Neumeier Florian , Koveshazi Istvan , Ikeliani Ikenna U. , Patzer Kathrin , Kunrad Elena , Kendziora Benjamin , Sattler Elke , French Lars E. , Hartmann Daniela
Published: November 2021

Image classification with convolutional neural networks (CNN) offers an unprecedented opportunity to medical imaging. Regulatory agencies in the USA and Europe have already cleared numerous deep learning/machine learning based medical devices and algorithms. While the field of radiology is on the forefront of artificial intelligence (AI) revolution, conventional pathology, which commonly relies on examination of tissue samples on a glass slide, is falling behind in leveraging this technology. On the other hand, ex vivo confocal laser scanning microscopy (ex vivo CLSM), owing to its digital workflow features, has a high potential to benefit from integrating AI tools into the assessment and decision-making process. Aim of this work was to explore a preliminary application of CNN in digitally stained ex vivo CLSM images of cutaneous squamous cell carcinoma (cSCC) for automated detection of tumor tissue. Thirty-four freshly excised tissue samples were prospectively collected and examined immediately after resection. After the histologically confirmed ex vivo CLSM diagnosis, the tumor tissue was annotated for segmentation by experts, in order to train the MobileNet CNN. The model was then trained and evaluated using cross validation. The overall sensitivity and specificity of the deep neural network for detecting cSCC and tumor free areas on ex vivo CLSM slides compared to expert evaluation were 0.76 and 0.91, respectively. The area under the ROC curve was equal to 0.90 and the area under the precision-recall curve was 0.85. The results demonstrate a high potential of deep learning models to detect cSCC regions on digitally stained ex vivo CLSM slides and to distinguish them from tumor-free skin.
Heart Failure Therapies for the Prevention of HER2-Monoclonal Antibody-Mediated Cardiotoxicity: A Systematic Review and Meta-Analysis of Randomized Trials
Authors: Brown Lauren , Meredith Thomas , Yu Jie , Patel Anushka , Neal Bruce , Arnott Clare , Lim Elgene
Published: November 2021

Monoclonal antibodies including trastuzumab, pertuzumab, and antibody-drug conjugates, form the backbone of HER2-positive breast cancer therapy. Unfortunately, an important adverse effect of these agents is cardiotoxicity, occurring in approximately 10% of patients. There is increasing published data regarding prevention strategies for cardiotoxicity, though seldom used in clinical practice. We performed a systematic review and meta-analysis of randomized-controlled trials to evaluate pharmacotherapy for the prevention of monoclonal HER2-directed antibody-induced cardiotoxicity in patients with breast cancer. Online databases were queried from their inception until October 2021. Effects were determined by calculating risk ratios (RRs) and 95% confidence intervals (CI) or mean differences (MD) using random-effects models. We identified five eligible trials. In the three trials (n = 952) reporting data on the primary outcome of cardiotoxicity, there was no clear effect for patients assigned active treatment compared to control (RR = 0.90, 95% CI 0.63 to 1.29, p = 0.57). Effects were similar for ACE-I/ARB and beta-blockers (p homogeneity = 0.50). Active treatment reduced the risk of HER2 therapy interruptions (RR = 0.57, 95% CI 0.43 to 0.77, p < 0.001) with similar findings for ACE-I/ARB and beta-blockers (p homogeneity = 0.97). Prophylactic treatment with ACE-I/ARB or beta-blocker therapy may be of value for cardio-protection in patients with breast cancer prescribed monoclonal antibodies. Further, adequately powered randomized trials are required to define the role of routine prophylactic treatment in this patient group.
Roles of G Protein-Coupled Receptors (GPCRs) in Gastrointestinal Cancers: Focus on Sphingosine 1-Shosphate Receptors, Angiotensin II Receptors, and Estrogen-Related GPCRs
Authors: Zeng Zhen , Ma Chunxiang , Chen Kexin , Jiang Mingshan , Vasu Reshma , Liu Rui , Zhao Yinglan , Zhang Hu
Published: November 2021

It is well established that gastrointestinal (GI) cancers are common and devastating diseases around the world. Despite the significant progress that has been made in the treatment of GI cancers, the mortality rates remain high, indicating a real need to explore the complex pathogenesis and develop more effective therapeutics for GI cancers. G protein-coupled receptors (GPCRs) are critical signaling molecules involved in various biological processes including cell growth, proliferation, and death, as well as immune responses and inflammation regulation. Substantial evidence has demonstrated crucial roles of GPCRs in the development of GI cancers, which provided an impetus for further research regarding the pathophysiological mechanisms and drug discovery of GI cancers. In this review, we mainly discuss the roles of sphingosine 1-phosphate receptors (S1PRs), angiotensin II receptors, estrogen-related GPCRs, and some other important GPCRs in the development of colorectal, gastric, and esophageal cancer, and explore the potential of GPCRs as therapeutic targets.
Craniofacial Bone Tissue Engineering: Current Approaches and Potential Therapy
Authors: Aghali Arbi
Published: November 2021

Craniofacial bone defects can result from various disorders, including congenital malformations, tumor resection, infection, severe trauma, and accidents. Successfully regenerating cranial defects is an integral step to restore craniofacial function. However, challenges managing and controlling new bone tissue formation remain. Current advances in tissue engineering and regenerative medicine use innovative techniques to address these challenges. The use of biomaterials, stromal cells, and growth factors have demonstrated promising outcomes in vitro and in vivo. Natural and synthetic bone grafts combined with Mesenchymal Stromal Cells (MSCs) and growth factors have shown encouraging results in regenerating critical-size cranial defects. One of prevalent growth factors is Bone Morphogenetic Protein-2 (BMP-2). BMP-2 is defined as a gold standard growth factor that enhances new bone formation in vitro and in vivo. Recently, emerging evidence suggested that Megakaryocytes (MKs), induced by Thrombopoietin (TPO), show an increase in osteoblast proliferation in vitro and bone mass in vivo. Furthermore, a co-culture study shows mature MKs enhance MSC survival rate while maintaining their phenotype. Therefore, MKs can provide an insight as a potential therapy offering a safe and effective approach to regenerating critical-size cranial defects.
Similarities and Differences of Hsp70, hsc70, Grp78 and Mortalin as Cancer Biomarkers and Drug Targets
Authors: Rai Rajani , Kennedy Amy L. , Isingizwe Zitha Redempta , Javadian Pouya , Benbrook Doris Mangiaracina
Published: November 2021

Background: Upregulation of Heath Shock Protein 70 (HSP70) chaperones supports cancer cell survival. Their high homology causes a challenge to differentiate them in experimental or prevention and treatment strategies. The objective of this investigation was to determine similarities and differences of Hsp70, hsc70, Grp78 and Mortalin members of the HSP70 family encoded by HSPA1, HSPA8, HSPA5 and HSPA9 genes, respectively. Methods: Literature reviews were conducted using HSPA1, HSPA5, HSPA8 and HSPA9 gene or protein names or synonyms combined with biological or cancer-relevant terms. Ingenuity Pathway Analysis was used to identify and compare profiles of proteins that directly bind individual chaperones and their associated pathways. TCGA data was probed to identify associations of hsc70 with cancer patient survival. ClinicalTrials.gov was used to identify HSP70 family studies. Results: The chaperones have similar protein folding functions. Their different cellular effects are determined by co-chaperones and client proteins combined with their intra- and extra-cellular localizations. Their upregulation is associated with worse patient prognosis in multiple cancers and can stimulate tumor immune responses or drug resistance. Their inhibition selectively kills cancer over healthy cells. Conclusions: Differences in Hsp70, hsc70, Grp78 and mortalin provide opportunities to calibrate HSP70 inhibitors for individual cancers and combination therapies.
Cell Therapy of Stroke: Do the Intra-Arterially Transplanted Mesenchymal Stem Cells Cross the Blood–Brain Barrier?
Authors: Yarygin Konstantin N. , Namestnikova Daria D. , Sukhinich Kirill K. , Gubskiy Ilya L. , Majouga Alexander G. , Kholodenko Irina V.
Published: November 2021

Animal model studies and first clinical trials have demonstrated the safety and efficacy of the mesenchymal stem cells’ (MSCs) transplantation in stroke. Intra-arterial (IA) administration looks especially promising, since it provides targeted cell delivery to the ischemic brain, is highly effective, and can be safe as long as the infusion is conducted appropriately. However, wider clinical application of the IA MSCs transplantation will only be possible after a better understanding of the mechanism of their therapeutic action is achieved. On the way to achieve this goal, the study of transplanted cells’ fate and their interactions with the blood–brain barrier (BBB) structures could be one of the key factors. In this review, we analyze the available data concerning one of the most important aspects of the transplanted MSCs’ action—the ability of cells to cross the blood–brain barrier (BBB) in vitro and in vivo after IA administration into animals with experimental stroke. The collected data show that some of the transplanted MSCs temporarily attach to the walls of the cerebral vessels and then return to the bloodstream or penetrate the BBB and either undergo homing in the perivascular space or penetrate deeper into the parenchyma. Transmigration across the BBB is not necessary for the induction of therapeutic effects, which can be incited through a paracrine mechanism even by cells located inside the blood vessels.
Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers
Authors: Masi Mirco , Racchi Marco , Travelli Cristina , Corsini Emanuela , Buoso Erica
Published: November 2021

Cancer is one of the most common causes of death worldwide, and its development is a result of the complex interaction of genetic factors, environmental cues, and aging. Hormone-sensitive cancers depend on the action of one or more hormones for their development and progression. Sex steroids and corticosteroids can regulate different physiological functions, including metabolism, growth, and proliferation, through their interaction with specific nuclear receptors, that can transcriptionally regulate target genes via their genomic actions. Therefore, interference with hormones’ activities, e.g., deregulation of their production and downstream pathways or the exposition to exogenous hormone-active substances such as endocrine-disrupting chemicals (EDCs), can affect the regulation of their correlated pathways and trigger the neoplastic transformation. Although nuclear receptors account for most hormone-related biologic effects and their slow genomic responses are well-studied, less-known membrane receptors are emerging for their ability to mediate steroid hormones effects through the activation of rapid non-genomic responses also involved in the development of hormone-sensitive cancers. This review aims to collect pre-clinical and clinical data on these extranuclear receptors not only to draw attention to their emerging role in cancer development and progression but also to highlight their dual role as tumor microenvironment players and potential candidate drug targets.
Arabidopsis SUMO E3 Ligase SIZ1 Interacts with HDA6 and Negatively Regulates HDA6 Function during Flowering
Authors: Gao Sujuan , Zeng Xueqin , Wang Jianhao , Xu Yingchao , Yu Chunwei , Huang Yishui , Wang Feng , Wu Keqiang , Yang Songguang
Published: November 2021

The changes in histone acetylation mediated by histone deacetylases (HDAC) play a crucial role in plant development and response to environmental changes. Mammalian HDACs are regulated by post-translational modifications (PTM), such as phosphorylation, acetylation, ubiquitination and small ubiquitin-like modifier (SUMO) modification (SUMOylation), which affect enzymatic activity and transcriptional repression. Whether PTMs of plant HDACs alter their functions are largely unknown. In this study, we demonstrated that the Arabidopsis SUMO E3 ligase SAP AND MIZ1 DOMAIN-CONTAINING LIGASE1 (SIZ1) interacts with HISTONE DEACETYLASE 6 (HDA6) both in vitro and in vivo. Biochemical analyses indicated that HDA6 is not modified by SUMO1. Overexpression of HDA6 in siz1-3 background results in a decreased level of histone H3 acetylation, indicating that the activity of HDA6 is increased in siz1-3 plants. Chromatin immunoprecipitation (ChIP) assays showed that SIZ1 represses HDA6 binding to its target genes FLOWERING LOCUS C (FLC) and MADS AFFECTING FLOWERING 4 (MAF4), resulting in the upregulation of FLC and MAF4 by increasing the level of histone H3 acetylation. Together, these findings indicate that the Arabidopsis SUMO E3 ligase SIZ1 interacts with HDA6 and negatively regulates HDA6 function.
Response to Electrostimulation Is Impaired in Muscle Cells from Patients with Chronic Obstructive Pulmonary Disease
Authors: Catteau Matthias , Passerieux Emilie , Blervaque Léo , Gouzi Farés , Ayoub Bronia , Hayot Maurice , Pomiès Pascal
Published: November 2021

Among the comorbidities associated with chronic obstructive pulmonary disease (COPD), skeletal muscle weakness and atrophy are known to affect patient survival rate. In addition to muscle deconditioning, various systemic and intrinsic factors have been implicated in COPD muscle dysfunction but an impaired COPD muscle adaptation to contraction has never been extensively studied. We submitted cultured myotubes from nine healthy subjects and nine patients with COPD to an endurance-type protocol of electrical pulse stimulation (EPS). EPS induced a decrease in the diameter, covered surface and expression of MHC1 in COPD myotubes. Although the expression of protein degradation markers was not affected, expression of the protein synthesis marker mTOR was not induced in COPD compared to healthy myotubes after EPS. The expression of the differentiation markers p16INK4a and p21 was impaired, while expression of Myf5 and MyoD tended to be affected in COPD muscle cells in response to EPS. The expression of mitochondrial biogenesis markers PGC1α and MFN2 was affected and expression of TFAM and COX1 tended to be reduced in COPD compared to healthy myotubes upon EPS. Lipid peroxidation was increased and the expression of the antioxidant enzymes SOD2 and GPx4 was affected in COPD compared to healthy myotubes in response to EPS. Thus, we provide evidence of an impaired response of COPD muscle cells to contraction, which might be involved in the muscle weakness observed in patients with COPD.
Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence
Authors: Lee Yun Haeng , Park Ji Yun , Lee Haneur , Song Eun Seon , Kuk Myeong Uk , Joo Junghyun , Oh Sekyung , Kwon Hyung Wook , Park Joon Tae , Park Sang Chul
Published: November 2021

Mitochondria are one of organelles that undergo significant changes associated with senescence. An increase in mitochondrial size is observed in senescent cells, and this increase is ascribed to the accumulation of dysfunctional mitochondria that generate excessive reactive oxygen species (ROS). Such dysfunctional mitochondria are prime targets for ROS-induced damage, which leads to the deterioration of oxidative phosphorylation and increased dependence on glycolysis as an energy source. Based on findings indicating that senescent cells exhibit mitochondrial metabolic alterations, a strategy to induce mitochondrial metabolic reprogramming has been proposed to treat aging and age-related diseases. In this review, we discuss senescence-related mitochondrial changes and consequent mitochondrial metabolic alterations. We assess the significance of mitochondrial metabolic reprogramming for senescence regulation and propose the appropriate control of mitochondrial metabolism to ameliorate senescence. Learning how to regulate mitochondrial metabolism will provide knowledge for the control of aging and age-related pathologies. Further research focusing on mitochondrial metabolic reprogramming will be an important guide for the development of anti-aging therapies, and will provide novel strategies for anti-aging interventions.
Effect of Fiber Content and Silane Treatment on the Mechanical Properties of Recycled Acrylonitrile-Butadiene-Styrene Fiber Composites
Authors: Chauhan Vardaan , Kärki Timo , Varis Juha
Published: November 2021

The aim of the present study was to investigate the effects of fiber content and then silane treatment on the mechanical performance of the natural fiber composites of recycled acrylonitrile–butadiene–styrene (ABS) provided by the automotive sector. Wood and palmyra fibers were used as fillers in 10% and 20% fiber content composites. The fibers were treated with N-(2-Aminoethyl)-3-aminopropyltrimethoxysilane to improve the interfacial adhesion between fibers and polymer matrices. The mechanical properties of the composites were determined by tensile and impact tests. Morphological analysis was later performed using a scanning electron microscope (SEM). According to the experiment results, the tensile and impact strength of both wood and palmyra fibers increase after silane treatment. However, for the low-wood-fiber-content composite, the tensile and impact strength decrease after silane treatment due to the presence of an excess amount of silane relative to fiber content. The addition of wood and palmyra fibers significantly improved the tensile modulus of composite material and further increases slightly after silane treatment. Finally, SEM analysis shows a homogenous mix of fibers and polymer matrices with fewer voids after silane treatment, thereby improving interfacial adhesion.
Associations between Physical Activity Patterns, Screen Time and Cardiovascular Fitness Levels in Swedish Adolescents
Authors: Kjellenberg Karin , Ekblom Örjan , Stålman Cecilia , Helgadóttir Björg , Nyberg Gisela
Published: November 2021

Cardiovascular fitness (CVF) has been associated with cardiovascular risk factors in adolescents. CVF levels are determined by non-modifiable and modifiable factors; one modifiable factor is physical activity (PA). There is a lack of studies investigating the associations between PA patterns and CVF and how gender, parental education, BMI status and country of birth are associated with CVF. The aim of this study was to explore the cross-sectional associations between PA patterns and CVF in Swedish 13–14-year-old adolescents. CVF was estimated using the Ekblom-Bak submaximal test, data on PA patterns were collected using hip-worn accelerometers and a questionnaire. The mean CVF was 44.8 mL/kg/min in girls (n = 569) and 55.5 mL/kg/min in boys (n = 451) p < 0.01. The results showed a significant association between participation in organised sports (β = 3.32 CI: 2.14, 4.51, β = 4.38, CI: 2.80, 5.96), MVPA (β = 0.07, CI: 0.04, 0.11, β = 0.07, CI: 0.03, 0.11), a high proportion of SED (β = −0.47, CI: −0.70, −0.25, β = −0.41, CI: −0.64, −0.18) and CVF in girls and boys, respectively. More than five hours of screen time on weekdays was associated with lower CVF (β = −2.32 CI: −3.92, −0.71 in girls and boys β = −2.82, CI: −5.14, −0.50). While causal relations remain unknown, these findings could be relevant when designing future interventions with the aim to improve CVF.
Effects of Gender and Age in Mandibular Leeway Space for Taiwanese Children
Authors: Sun Kuo-Ting , Wu Yun-Zhen , Hsu Jui-Ting , Tsai Min-Chia , Huang Heng-Li
Published: November 2021

Purpose: Leeway space is clinically crucial in pediatric dentistry because it is utilized to resolve tooth crowding and allow the first molars to drift mesially to establish a Class I molar relationship in the later stages of mixed dentition. This study investigated leeway space in the mixed dentition of Taiwanese children of different sexes and ages. Materials and Methods: The digital panoramic dental films of 182 lower arches of 119 boys and 63 girls aged 5–10 years were analyzed in this retrospective study. The mesiodistal crown widths of the primary canines and first and second molars and the permanent canines and first and second premolars were measured using medical imaging software. Differences in leeway space were statistically analyzed. Results: The average leeway space was 1.29 ± 1.48 mm on each side of the lower arch. The leeway space of children aged 5–6 years was significantly greater than that of children aged 7–8 years. No gender difference in crown width was discovered, except with regard to the primary first molar. Although no gender difference in leeway space was observed, permanent teeth affected leeway space more for girls than for boys. Conclusion: In Taiwanese children, although leeway space does not differ by sex, age affects leeway space. However, permanent tooth size has an influence on the leeway space of girls.
Limited Utility of SIRS Criteria for Identifying Serious Infections in Febrile Young Infants
Authors: Nomura Osamu , Morikawa Yoshihiko , Mori Takaaki , Hagiwara Yusuke , Sakakibara Hiroshi , Horikoshi Yuho , Inoue Nobuaki
Published: November 2021

(1) Background: Young infants have a high risk of serious infection. The Systematic Inflammatory Response Syndrome (SIRS) criteria can be useful to identify both serious bacterial and viral infections. The aims of this study were to evaluate the diagnostic performance of the SIRS criteria for identifying serious infections in febrile young infants and to identify potential clinical predictors of such infections. (2) Methods: We conducted this prospective cohort study including febrile young infants (aged < 90 days) seen at the emergency department with a body temperature of 38.0 °C or higher. We calculated the diagnostic performance parameters and conducted the logistic regression analysis to identify the predictors of serious infection. (3) Results: Of 311 enrolled patients, 36.7% (n = 114) met the SIRS criteria and 28.6% (n = 89) had a serious infection. The sensitivity, specificity, positive predictive value, and positive likelihood ratio of the SIRS criteria for serious infection was 45.9%, 69.4%, 43.5%, 71.4%, 1.5, and 0.8, respectively. Logistic regression showed that male gender, body temperature ≥ 38.5 °C, heart rate ≥ 178 bpm, and age ≤ 50 days were significant predictors. (4) Conclusions: The performance of the SIRS criteria for predicting serious infections among febrile young infants was poor.
SIRT1 Promotes Osteogenic Differentiation in Human Dental Pulp Stem Cells through Counteracting the Activation of STAT3
Authors: Zhao Dan , Kang Wen , Wang Yiwen , Ge Jiuyu , Huang Jianfeng , Yang Jie , Yang Weidong , Tang Xuna , Xie Sijing
Published: November 2021

Human dental pulp stem cells (hDPSCs), which are characterized by self-renewal capacity and the ability of multilineage differentiation, have gained increased attention in regenerative medicine recently. Histone acetylation modulator proteins (HAMPs) are a protein family that mediates the modification and identification of histone acetylation and participates in various critical cellular processes. Here, we comprehensively surveyed the expression profile of HAMPs during osteoblast differentiation of hDPSCs and found that the HDAC class III pathway was upregulated, whereas the signal transducer and activator of transcription 3 (STAT3) signaling was downregulated during osteogenesis. Further laboratory research demonstrated that Sirtuin-1 (SIRT1), a class III HDAC, was upregulated and STAT3 activation was downregulated during osteogenic differentiation. SIRT1 counteracted the activation of STAT3 to promote osteogenic differentiation of hDPSCs at 7 and 21 days in both Western blot assay and chemical staining, which highlights the promising utility of SIRT1 activators in hDPSCs-based therapies for bone augmentation strategies and provides clinical insights that may lead to the development of osteogenic agents.
Electrochemical Perspective on Hematite–Malonate Interactions
Authors: Kędra Karolina , Łazarczyk Marzena , Begović Tajana , Namjesnik Danijel , Lament Karolina , Piasecki Wojciech , Zarzycki Piotr
Published: November 2021

Organic matter (OM) interactions with minerals are essential in OM preservation against decomposition in the environment. Here, by combining potentiometric and electrophoretic measurements, we probed the mode of coordination and the role of pH-dependent electrostatic interactions between organic acids and an iron oxide surface. Specifically, we show that malonate ions adsorbed to a hematite surface in a wide pH window between 3 and 8.7 (point of zero charge). The mode of interactions varied with this pH range and depended on the acid and surface acidity constants. In the acidic environment, hematite surface potential was highly positive (+47 mV, pH 3). At pH < 4 malonate adsorption reduced the surface potential (+30 mV at pH 3) but had a negligible effect on the diffuse layer potential, consistent with the inner-sphere malonate complexation. Here, the specific and electrostatic interactions were responsible for the malonate partial dehydration and surface accumulation. These interactions weakened with an increasing pH and near PZC, the hematite surface charge was neutral on average. Adsorbed malonates started to desorb from the surface with less pronounced accumulation in the diffuse layer, which was reflected in zeta potential values. The transition between specific and non-specific sorption regimes was smooth, suggesting the coexistence of the inner- and outer-sphere complexes with a relative ratio that varied with pH.