bluuebunny/crossref_metadata_2025 huggingface dataset:
Tribbles Pseudokinases in Colorectal Cancer
Authors: Ferreira Bibiana I. , Santos Bruno , Link Wolfgang , De Sousa-Coelho Ana Luísa
Published: June 2021

The Tribbles family of pseudokinases controls a wide number of processes during cancer on-set and progression. However, the exact contribution of each of the three family members is still to be defined. Their function appears to be context-dependent as they can act as oncogenes or tumor suppressor genes. They act as scaffolds modulating the activity of several signaling pathways involved in different cellular processes. In this review, we discuss the state-of-knowledge for TRIB1, TRIB2 and TRIB3 in the development and progression of colorectal cancer. We take a perspective look at the role of Tribbles proteins as potential biomarkers and therapeutic targets. Specifically, we chronologically systematized all available articles since 2003 until 2020, for which Tribbles were associated with colorectal cancer human samples or cell lines. Herein, we discuss: (1) Tribbles amplification and overexpression; (2) the clinical significance of Tribbles overexpression; (3) upstream Tribbles gene and protein expression regulation; (4) Tribbles pharmacological modulation; (5) genetic modulation of Tribbles; and (6) downstream mechanisms regulated by Tribbles; establishing a comprehensive timeline, essential to better consolidate the current knowledge of Tribbles’ role in colorectal cancer.
Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential
Authors: Fermaintt Charles S. , Peramuna Thilini , Cai Shengxin , Takahashi-Ruiz Leila , Essif Jacob Nathaniel , Grant Corena V. , O’Keefe Barry R. , Mooberry Susan L. , Cichewicz Robert H. , Risinger April L.
Published: June 2021

The heterogeneity of triple negative breast cancer (TNBC) has led to efforts to further subtype this disease with the hope of identifying new molecular liabilities and drug targets. Furthermore, the finding that TNBC is the most inherently immunogenic type of breast cancer provides the potential for effective treatment with immune checkpoint inhibitors and immune adjuvants. Thus, we devised a dual screen to identify compounds from natural product extracts with TNBC subtype selectivity that also promote the expression of cytokines associated with antitumor immunity. These efforts led to the identification of yuanhuacine (1) as a potent and highly selective inhibitor of the basal-like 2 (BL2) subtype of TNBC that also promoted an antitumor associated cytokine signature in immune cells. The mechanism of action of yuanhuacine for both phenotypes depends on activation of protein kinase C (PKC), defining a novel target for the treatment of this clinical TNBC subtype. Yuanhuacine showed potent antitumor efficacy in animals bearing BL2 tumors further demonstrating that PKC could function as a potential pharmacological target for the treatment of the BL2 subtype of TNBC.
Sinonasal Squamous Cell Carcinoma, a Narrative Reappraisal of the Current Evidence
Authors: Ferrari Marco , Taboni Stefano , Carobbio Andrea Luigi Camillo , Emanuelli Enzo , Maroldi Roberto , Bossi Paolo , Nicolai Piero
Published: June 2021

Sinonasal squamous cell carcinoma is a rare tumor affecting the nasal cavity and paranasal sinuses. Several aspects of this disease, ranging from epidemiology to biology, pathology, diagnosis, staging, treatment, and post-treatment surveillance are controversial, and consensus on how to manage this sinonasal cancer is lacking. A narrative literature review was performed to summarize the current evidence and provide the reader with available data supporting the decision-making process in patients affected by sinonasal squamous cell carcinoma, alongside the authors’ personal opinion on the unsolved issues of this tumor. The review has highlighted several advances in molecular definition of epithelial cancers of the sinonasal tract. Surgery represents the pivot of treatment and is performed through an endoscopic transnasal approach whenever feasible. Open surgery is required for a large proportion of cases. Reconstruction of the defect follows principles of skull base and cranio-maxillo-facial reconstruction. Chemotherapy is given as neoadjuvant treatment or concomitantly to radiotherapy. Photon-based radiation therapy has a crucial role in the adjuvant setting. Particle therapy is providing promising results. Management of the neck should be planned based on the presence of clinically appreciable metastases, primary tumor extension, and need for recipient vessels. Biotherapy and immunotherapy are still underexplored therapeutical modalities.
Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies
Authors: Taylor Zachary L. , Vang Jesper , Lopez-Lopez Elixabet , Oosterom Natanja , Mikkelsen Torben , Ramsey Laura B.
Published: June 2021

Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX clearance can lead to prolonged, elevated exposure, causing increased risks for nephrotoxicity, mucositis, seizures, and neutropenia. Numerous pharmacogenetic studies have investigated the effects of several genes and polymorphisms on MTX clearance in an attempt to better understand the pharmacokinetic variability and improve patient outcomes. To date, several genes and polymorphisms that affect MTX clearance have been identified. However, evidence for select genes have conflicting results or lack the necessary replication and validation needed to confirm their effects on MTX clearance. Therefore, we performed a systematic review to identify and then summarize the pharmacogenetic factors that influence high-dose MTX pharmacokinetics in pediatric malignancies. Using the PRISMA guidelines, we analyzed 58 articles and 24 different genes that were associated with transporter pharmacology or the folate transport pathway. We conclude that there is only one gene that reliably demonstrates an effect on MTX pharmacokinetics: SLCO1B1.
TremelImumab and Durvalumab Combination for the Non-OperatIve Management (NOM) of Microsatellite InstabiliTY (MSI)-High Resectable Gastric or Gastroesophageal Junction Cancer: The Multicentre, Single-Arm, Multi-Cohort, Phase II INFINITY Study
Authors: Raimondi Alessandra , Palermo Federica , Prisciandaro Michele , Aglietta Massimo , Antonuzzo Lorenzo , Aprile Giuseppe , Berardi Rossana , Cardellino Giovanni G. , De Manzoni Giovanni , De Vita Ferdinando , Di Maio Massimo , Fornaro Lorenzo , Frassineti Giovanni L. , Granetto Cristina , Iachetta Francesco , Lonardi Sara , Murialdo Roberto , Ongaro Elena , Pucci Francesca , Ratti Margherita , Silvestris Nicola , Smiroldo Valeria , Spallanzani Andrea , Strippoli Antonia , Tamberi Stefano , Tamburini Emiliano , Zaniboni Alberto , Di Bartolomeo Maria , Cremolini Chiara , Sposito Carlo , Mazzaferro Vincenzo , Pietrantonio Filippo
Published: June 2021

In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection.
A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways
Authors: Zaher Dana M. , Ramadan Wafaa S. , El-Awady Raafat , Omar Hany A. , Hersi Fatema , Srinivasulu Vunnam , Hachim Ibrahim Y. , Al-Marzooq Farah I. , Vazhappilly Cijo G. , Merali Salim , Merali Carmen , Soares Nelson C. , Schilf Paul , Ibrahim Saleh M. , Al-Tel Taleb H.
Published: June 2021

(1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of benzopyranes to identify an anticancer lead drug candidate. Here, we aim to characterize the anticancer effect of a novel benzopyrane derivative, aiming to develop a promising clinical anticancer candidate. (2) Methods: The anticancer effect of SIMR1281 against a panel of cancer cell lines was tested. In vitro assays were performed to determine the effect of SIMR1281 on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and the induction of apoptosis. Additionally, SIMR1281 was evaluated in vivo for its safety and in a xenograft mice model. (3) Results: SIMR1281 strongly inhibits GSHR while it moderately inhibits TrxR and modulates the mitochondrial metabolism. SIMR1281 inhibits the cell proliferation of various cancers. The antiproliferative activity of SIMR1281 was mediated through the induction of DNA damage, perturbations in the cell cycle, and the inactivation of Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induced apoptosis and attenuated cell survival machinery. In addition, SIMR1281 reduced the tumor volume in a xenograft model while maintaining a high in vivo safety profile at a high dose. (4) Conclusions: Our findings demonstrate the anticancer multitarget effect of SIMR1281, including the dual inhibition of glutathione and thioredoxin reductases. These findings support the development of SIMR1281 in preclinical and clinical settings, as it represents a potential lead compound for the treatment of cancer.
Targeting Tissue Factor to Tumor Vasculature to Induce Tumor Infarction
Authors: Berdel Andrew F. , Schwöppe Christian , Brand Caroline , Harrach Saliha , Brömmel Kathrin , Hintelmann Heike , Lenz Georg , Liersch Ruediger , Heinzow Hauke , Schliemann Christoph , Mesters Rolf M. , Berdel Wolfgang E. , Kessler Torsten
Published: June 2021

Besides its central functional role in coagulation, TF has been described as being operational in the development of malignancies and is currently being studied as a possible therapeutic tool against cancer. One of the avenues being explored is retargeting TF or its truncated extracellular part (tTF) to the tumor vasculature to induce tumor vessel occlusion and tumor infarction. To this end, multiple structures on tumor vascular wall cells have been studied at which tTF has been aimed via antibodies, derivatives, or as bifunctional fusion protein through targeting peptides. Among these targets were vascular adhesion molecules, oncofetal variants of fibronectin, prostate-specific membrane antigens, vascular endothelial growth factor receptors and co-receptors, integrins, fibroblast activation proteins, NG2 proteoglycan, microthrombus-associated fibrin-fibronectin, and aminopeptidase N. Targeting was also attempted toward cellular membranes within an acidic milieu or toward necrotic tumor areas. tTF-NGR, targeting tTF primarily at aminopeptidase N on angiogenic endothelial cells, was the first drug candidate from this emerging class of coaguligands translated to clinical studies in cancer patients. Upon completion of a phase I study, tTF-NGR entered randomized studies in oncology to test the therapeutic impact of this novel therapeutic modality.
Prognostic Association between Common Laboratory Tests and Overall Survival in Elderly Men with De Novo Metastatic Castration Sensitive Prostate Cancer: A Population-Based Study in Canada
Authors: Wallis Christopher J. D. , Shayegan Bobby , Morgan Scott C. , Hamilton Robert J. , Cagiannos Ilias , Basappa Naveen S. , Ferrario Cristiano , Gotto Geoffrey T. , Fernandes Ricardo , Roy Soumyajit , Noonan Krista L. , Niazi Tamim , Hotte Sebastien J. , Saad Fred , Hew Huong , Chan Katherine F. Y. , Park-Wyllie Laura , Malone Shawn
Published: June 2021

De novo cases of metastatic prostate cancer (mCSPC) are associated with poorer prognosis. To assist in clinical decision-making, we aimed to determine the prognostic utility of commonly available laboratory-based markers with overall survival (OS). In a retrospective population-based study, a cohort of 3556 men aged ≥66 years diagnosed with de novo mCSPC between 2014 and 2019 was identified in Ontario (Canada) administrative database. OS was assessed by using the Kaplan–Meier method. Multivariate Cox regression analysis was performed to evaluate the association between laboratory markers and OS adjusting for patient and disease characteristics. Laboratory markers that were assessed include neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), albumin, hemoglobin, serum testosterone and PSA kinetics. Among the 3556 older men with de novo mCSPC, their median age was 77 years (IQR: 71–83). The median survival was 18 months (IQR: 10–31). In multivariate analysis, a statistically significant association with OS was observed with all the markers (NLR, PLR, albumin, hemoglobin, PSA decrease, reaching PSA nadir and a 50% PSA decline), except for testosterone levels. Our findings support the use of markers of systemic inflammation (NLR, PLR and albumin), hemoglobin and PSA metrics as prognostic indicators for OS in de novo mCSPC.
Hyperspectral Imaging (HSI)—A New Tool to Estimate the Perfusion of Upper Abdominal Organs during Pancreatoduodenectomy
Authors: Moulla Yusef , Buchloh Dorina Christin , Köhler Hannes , Rademacher Sebastian , Denecke Timm , Meyer Hans-Jonas , Mehdorn Matthias , Lange Undine Gabriele , Sucher Robert , Seehofer Daniel , Jansen-Winkeln Boris , Gockel Ines
Published: June 2021

Hyperspectral imaging (HSI) in abdominal surgery is a new non-invasive tool for the assessment of the perfusion and oxygenation of various tissues and organs. Its benefit in pancreatic surgery is still unknown. The aim of this study was to evaluate the key impact of using HSI during pancreatoduodenectomy (PD). In total, 20 consecutive patients were included. HSI was recorded during surgery as part of a pilot study approved by the local Ethics Committee. Data were collected prospectively with the TIVITA® Tissue System. Intraoperative HS images were recorded before and after gastroduodenal artery (GDA) clamping. We detected four patients with celiac artery stenosis (CAS) caused by a median arcuate ligament (MAL). In two of these patients, a reduction in liver oxygenation (StO2) was discovered 15 and 30 min after GDA clamping. The MAL was divided in these patients. HSI showed an improvement of liver StO2 after MAL division (from 61% to 73%) in one of these two patients. There was no obvious decrease in liver StO2 in the other two patients with CAS. HSI, as a non-invasive procedure, could be helpful in evaluating liver and gastric perfusion during PD, which might assist surgeons in choosing the best surgical approach and in improving patients’ outcomes.
Circulating Levels of the Interferon-γ-Regulated Chemokines CXCL10/CXCL11, IL-6 and HGF Predict Outcome in Metastatic Renal Cell Carcinoma Patients Treated with Antiangiogenic Therapy
Authors: Esteban Emilio , Exposito Francisco , Crespo Guillermo , Lambea Julio , Pinto Alvaro , Puente Javier , Arranz Jose A. , Redrado Miriam , Rodriguez-Antona Cristina , de Andrea Carlos , Lopez-Brea Marta , Redin Esther , Rodriguez Angel , Serrano Diego , Garcia Jorge , Grande Enrique , Castellano Daniel , Calvo Alfonso
Published: June 2021

Sunitinib and pazopanib are standard first-line treatments for patients with metastatic renal cell carcinoma (mRCC). Nonetheless, as the number of treatment options increases, there is a need to identify biomarkers that can predict drug efficacy and toxicity. In this prospective study we evaluated a set of biomarkers that had been previously identified within a secretory signature in mRCC patients. This set includes tumor expression of c-Met and serum levels of HGF, IL-6, IL-8, CXCL9, CXCL10 and CXCL11. Our cohort included 60 patients with mRCC from 10 different Spanish hospitals who received sunitinib (n = 51), pazopanib (n = 4) or both (n = 5). Levels of biomarkers were studied in relation to response rate, progression-free survival (PFS) and overall survival (OS). High tumor expression of c-Met and high basal serum levels of HGF, IL-6, CXCL11 and CXCL10 were significantly associated with reduced PFS and/or OS. In multivariable Cox regression analysis, CXCL11 was identified as an independent biomarker predictive of shorter PFS and OS, and HGF was an independent predictor of reduced PFS. Correlation analyses using our cohort of patients and patients from TCGA showed that HGF levels were significantly correlated with those of IL-6, CXCL11 and CXCL10. Bioinformatic protein–protein network analysis revealed a significant interaction between these proteins, all this suggesting a coordinated expression and secretion. We also developed a prognostic index that considers this group of biomarkers, where high values in mRCC patients can predict higher risk of relapse (HR 5.28 [2.32–12.0], p < 0.0001). In conclusion, high plasma HGF, CXCL11, CXCL10 and IL-6 levels are associated with worse outcome in mRCC patients treated with sunitinib or pazopanib. Our findings also suggest that these factors may constitute a secretory cluster that acts coordinately to promote tumor growth and resistance to antiangiogenic therapy.
Cancer Metabolism as a New Real Target in Tumor Therapy
Authors: Chiaradonna Ferdinando , Scumaci Domenica
Published: June 2021

Cancer cells exhibit common hallmarks consisting of specific competencies acquired during the tumorigenesis process, including stimulation of cancer cell proliferation, insensitivity to growth signal inhibition, apoptosis evasion, enhancement of replicative potential, induction of angiogenesis, and tissue invasion and metastasis [...]
Venlafaxine and L-Thyroxine Treatment Combination: Impact on Metabolic and Synaptic Plasticity Changes in an Animal Model of Coexisting Depression and Hypothyroidism
Authors: Głombik Katarzyna , Detka Jan , Budziszewska Bogusława
Published: June 2021

The clinical effectiveness of supportive therapy with thyroid hormones in drug-resistant depression is well-known; however, the mechanisms of action of these hormones in the adult brain have not been fully elucidated to date. We determined the effects of venlafaxine and/or L-thyroxine on metabolic parameters and markers involved in the regulation of synaptic plasticity and cell damage in an animal model of coexisting depression and hypothyroidism, namely, Wistar Kyoto rats treated with propylthiouracil. In this model, in relation to the depression model itself, the glycolysis process in the brain was weakened, and a reduction in pyruvate dehydrogenase in the frontal cortex was normalized only by the combined treatment with L-thyroxine and venlafaxine, whereas changes in pyruvate and lactate levels were affected by all applied therapies. None of the drugs improved the decrease in the expression of mitochondrial respiratory chain enzymes. No intensification of glucocorticoid action was shown, while an unfavorable change caused by the lack of thyroid hormones was an increase in the caspase-1 level, which was not reversed by venlafaxine alone. The results indicated that the combined administration of drugs was more effective in normalizing glycolysis and the transition to the Krebs cycle than the use of venlafaxine or L-thyroxine alone.
Revisiting the Karyotypes of Alligators and Caimans (Crocodylia, Alligatoridae) after a Half-Century Delay: Bridging the Gap in the Chromosomal Evolution of Reptiles
Authors: Oliveira Vanessa C. S. , Altmanová Marie , Viana Patrik F. , Ezaz Tariq , Bertollo Luiz A. C. , Ráb Petr , Liehr Thomas , Al-Rikabi Ahmed , Feldberg Eliana , Hatanaka Terumi , Scholz Sebastian , Meurer Alexander , de Bello Cioffi Marcelo
Published: June 2021

Although crocodilians have attracted enormous attention in other research fields, from the cytogenetic point of view, this group remains understudied. Here, we analyzed the karyotypes of eight species formally described from the Alligatoridae family using differential staining, fluorescence in situ hybridization with rDNA and repetitive motifs as a probe, whole chromosome painting (WCP), and comparative genome hybridization. All Caimaninae species have a diploid chromosome number (2n) 42 and karyotypes dominated by acrocentric chromosomes, in contrast to both species of Alligatorinae, which have 2n = 32 and karyotypes that are predominantly metacentric, suggesting fusion/fission rearrangements. Our WCP results supported this scenario by revealing the homeology of the largest metacentric pair present in both Alligator spp. with two smaller pairs of acrocentrics in Caimaninae species. The clusters of 18S rDNA were found on one chromosome pair in all species, except for Paleosuchus spp., which possessed three chromosome pairs bearing these sites. Similarly, comparative genomic hybridization demonstrated an advanced stage of sequence divergence among the caiman genomes, with Paleosuchus standing out as the most divergent. Thus, although Alligatoridae exhibited rather low species diversity and some level of karyotype stasis, their genomic content indicates that they are not as conserved as previously thought. These new data deepen the discussion of cytotaxonomy in this family.
Functional Characterization of the Photosynthetic Machinery in Smicronix Galls on the Parasitic Plant Cuscuta campestris by JIP-Test
Authors: Zagorchev Lyuben , Atanasova Alexandra , Albanova Ivanela , Traianova Anelia , Mladenov Petko , Kouzmanova Margarita , Goltsev Vasilij , Kalaji Hazem M. , Teofanova Denitsa
Published: June 2021

Members of the genus Cuscuta are generally considered to be non-photosynthetic, stem-holoparasitic flowering plants. Under certain circumstances, at least some members of the genus are capable of limited photosynthesis. The galls of the Smicronyx weevils formed on Cuscuta campestris are particularly rich in chlorophylls compared to the stem of the parasitic plant. In the present study, we aimed to characterize the photosynthetic activity in the inner and outer gall cortices in comparison to the non-photosynthetic stems and a reference plant (Arabidopsis thaliana). The recorded prompt chlorophyll fluorescence transients were analyzed using JIP test. Detailed analysis of the chlorophyll fluorescence confirmed the presence of actively functioning photosynthetic machinery, especially in the inner cortex of the galls. This photosynthesis, induced by the insect larvae, did not reach the levels of the photosynthetic activity in Arabidopsis thaliana plants. Thylakoid protein complexes were identified by separation with two-dimensional Blue Native/SDS PAGE. It appeared that some of the complexes presented in A. thaliana are missing in C. campestris. We hypothesize that the insect-triggered transition from non-photosynthetic to photosynthetic tissue in the gall is driven by the increased requirements for nutrients related to the larval nutrition.
Role of Intermediate Filaments in Blood–Brain Barrier in Health and Disease
Authors: Bayir Ece , Sendemir Aylin
Published: June 2021

The blood–brain barrier (BBB) is a highly selective cellular monolayer unique to the microvasculature of the central nervous system (CNS), and it mediates the communication of the CNS with the rest of the body by regulating the passage of molecules into the CNS microenvironment. Limitation of passage of substances through the BBB is mainly due to tight junctions (TJ) and adherens junctions (AJ) between brain microvascular endothelial cells. The importance of actin filaments and microtubules in establishing and maintaining TJs and AJs has been indicated; however, recent studies have shown that intermediate filaments are also important in the formation and function of cell–cell junctions. The most common intermediate filament protein in endothelial cells is vimentin. Vimentin plays a role in blood–brain barrier permeability in both cell–cell and cell–matrix interactions by affecting the actin and microtubule reorganization and by binding directly to VE-cadherin or integrin proteins. The BBB permeability increases due to the formation of stress fibers and the disruption of VE–cadherin interactions between two neighboring cells in various diseases, disrupting the fiber network of intermediate filament vimentin in different ways. Intermediate filaments may be long ignored key targets in regulation of BBB permeability in health and disease.
A Simple, Accurate and Cost-Effective Capillary Electrophoresis Test with Computational Methods to Aid in Universal Microsatellite Instability Testing
Authors: Toh James Wei Tatt , Singh Puneet , Tangirala Venkata A. A. S. K. , Limmer Alex , Spring Kevin J.
Published: June 2021

Background: Microsatellite instability (MSI) testing is important for the classification of Lynch syndrome, as a prognostic marker and as a guide for adjuvant chemotherapy in colorectal cancer (CRC). The gold standard for determining MSI status has traditionally been fluorescent multiplex polymerase chain reaction (PCR) and capillary gel electrophoresis (CGE). However, its use in the clinical setting has diminished and has been replaced by immunohistochemical (IHC) detection of loss of mismatch repair protein expression due to practicability and cost. The aim of this study was to develop a simple, cost-effective and accurate MSI assay based on CGE. Method: After amplification of microsatellites by polymerase chain reaction (PCR) using the National Cancer Institute (NCI) panel (BAT 25, BAT26, D5S346, D2S123, D17S250) of MSI markers, parallel CGE was utilized to classify colorectal cancers as MSI-H, MSI-L and MSS using the 5200 Fragment Analyzer System. Cell lines and patient cancer specimens were tested. DNA from 56 formalin-fixed paraffin-embedded cancer specimens and matched normal tissue were extracted and CGE was performed. An automated computational algorithm for MSI status determination was also developed. Results: Using the fragment analyser, MSI status was found to be 100% concordant with the known MSI status of cell lines and was 86% and 87% concordant with immunohistochemistry (IHC) from patient cancer specimens using traditional assessment and our MSI scoring system, respectively, for MSI determination. The misclassification rate was mainly attributed to IHC, with only one (1.8%) sampling error attributed to CGE testing. CGE was also able to distinguish MSI-L from MSI-H and MSS, which is not possible with IHC. An MSI score based on total allelic variability that can accurately determine MSI status was also successfully developed. A significant reduction in cost compared with traditional fluorescent multiplex PCR and CGE was achieved with this technique. Conclusions: A simple, cost-effective and reliable method of determining MSI status and an MSI scoring system based on an automatic computational algorithm to determine MSI status, as well as degree of allelic instability in colorectal cancer, has been developed using the 5200 Fragment Analyzer System.
Know How to Regrow—Axon Regeneration in the Zebrafish Spinal Cord
Authors: Tsata Vasiliki , Wehner Daniel
Published: June 2021

The capacity for long-distance axon regeneration and functional recovery after spinal cord injury is poor in mammals but remarkable in some vertebrates, including fish and salamanders. The cellular and molecular basis of this interspecies difference is beginning to emerge. This includes the identification of target cells that react to the injury and the cues directing their pro-regenerative responses. Among existing models of successful spinal cord regeneration, the zebrafish is arguably the most understood at a mechanistic level to date. Here, we review the spinal cord injury paradigms used in zebrafish, and summarize the breadth of neuron-intrinsic and -extrinsic factors that have been identified to play pivotal roles in the ability of zebrafish to regenerate central nervous system axons and recover function.
Urine-Derived Epithelial Cells as Models for Genetic Kidney Diseases
Authors: Bondue Tjessa , Arcolino Fanny O. , Veys Koenraad R. P. , Adebayo Oyindamola C. , Levtchenko Elena , van den Heuvel Lambertus P. , Elmonem Mohamed A.
Published: June 2021

Epithelial cells exfoliated in human urine can include cells anywhere from the urinary tract and kidneys; however, podocytes and proximal tubular epithelial cells (PTECs) are by far the most relevant cell types for the study of genetic kidney diseases. When maintained in vitro, they have been proven extremely valuable for discovering disease mechanisms and for the development of new therapies. Furthermore, cultured patient cells can individually represent their human sources and their specific variants for personalized medicine studies, which are recently gaining much interest. In this review, we summarize the methodology for establishing human podocyte and PTEC cell lines from urine and highlight their importance as kidney disease cell models. We explore the well-established and recent techniques of cell isolation, quantification, immortalization and characterization, and we describe their current and future applications.
Inhibition of the Heat Shock Protein A (HSPA) Family Potentiates the Anticancer Effects of Manumycin A
Authors: Sojka Damian Robert , Hasterok Sylwia , Vydra Natalia , Toma-Jonik Agnieszka , Wieczorek Anna , Gogler-Pigłowska Agnieszka , Scieglinska Dorota
Published: June 2021

Manumycin A (MA) is a well-tolerated natural antibiotic showing pleiotropic anticancer effects in various preclinical in vitro and in vivo models. Anticancer drugs may themselves act as stressors to induce the cellular adaptive mechanism that can minimize their cytotoxicity. Heat shock proteins (HSPs) as cytoprotective factors can counteract the deleterious effects of various stressful stimuli. In this study, we examined whether the anticancer effects of MA can be counteracted by the mechanism related to HSPs belonging to the HSPA (HSP70) family. We found that MA caused cell type-specific alterations in the levels of HSPAs. These changes included concomitant upregulation of the stress-inducible (HSPA1 and HSPA6) and downregulation of the non-stress-inducible (HSPA2) paralogs. However, neither HSPA1 nor HSPA2 were necessary to provide protection against MA in lung cancer cells. Conversely, the simultaneous repression of several HSPA paralogs using pan-HSPA inhibitors (VER-155008 or JG-98) sensitized cancer cells to MA. We also observed that genetic ablation of the heat shock factor 1 (HSF1) transcription factor, a main transactivator of HSPAs expression, sensitized MCF7 cells to MA treatment. Our study reveals that inhibition of HSF1-mediated heat shock response (HSR) can improve the anticancer effect of MA. These observations suggest that targeting the HSR- or HSPA-mediated adaptive mechanisms may be a promising strategy for further preclinical developments.
The Multiple Functions of Rho GTPases in Fission Yeasts
Authors: Vicente-Soler Jero , Soto Teresa , Franco Alejandro , Cansado José , Madrid Marisa
Published: June 2021

The Rho family of GTPases represents highly conserved molecular switches involved in a plethora of physiological processes. Fission yeast Schizosaccharomyces pombe has become a fundamental model organism to study the functions of Rho GTPases over the past few decades. In recent years, another fission yeast species, Schizosaccharomyces japonicus, has come into focus offering insight into evolutionary changes within the genus. Both fission yeasts contain only six Rho-type GTPases that are spatiotemporally controlled by multiple guanine–nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and whose intricate regulation in response to external cues is starting to be uncovered. In the present review, we will outline and discuss the current knowledge and recent advances on how the fission yeasts Rho family GTPases regulate essential physiological processes such as morphogenesis and polarity, cellular integrity, cytokinesis and cellular differentiation.
Increased Serum Concentrations of High Mobility Group Box 1 (HMGB1) Protein in Children with Autism Spectrum Disorder
Authors: Makris Gerasimos , Chouliaras Giorgos , Apostolakou Filia , Papageorgiou Charalabos , Chrousos George P. , Papassotiriou Ioannis , Pervanidou Panagiota
Published: June 2021

High mobility group box 1 protein (HMGB1) has been suggested to be involved in the immune dysfunction and inflammation reported in autism spectrum disorder (ASD). We aimed to assess HMGB1 serum concentrations (SCs) in high-functioning ASD children compared to typically developing (TD) controls and to explore their associations with the autism spectrum quotient (AQ), the empathy quotient (EQ), and the systemizing quotient (SQ). The study involved 42 ASD children and 38 TD children, all-male, aged between 6.1 and 13.3 years old. HMGB1 SCs were measured by enzyme-linked immunosorbent assay (ELISA). Groups were comparable regarding age, general IQ, birth weight, and maternal age at birth. ASD children showed significantly higher HMGB1 SCs compared to TD children (1.25 ± 0.84 ng/mL versus 1.13 ± 0.79 ng/mL, respectively, p = 0.039). The Spearman’s rho revealed that HMGB1 SCs were positively correlated with the AQ attention to detail subscale (rs = 0.46, p = 0.045) and with the SQ total score (rs = 0.42, p = 0.04) in the ASD group. These results show that HMGB1 serum concentrations are altered in ASD children, and suggest that inflammatory processes mediated by HMGB1 may be associated with specific cognitive features observed in ASD.
Exploring the Perspectives of South African Parents and Primary Caregivers Living in Low-Income Communities on What Children Need to Thrive within the First 1000 Days of Life
Authors: Adebiyi Babatope O. , Goldschmidt Tessa , Benjamin Fatiema , Sonn Inge K. , Roman Nicolette V.
Published: June 2021

The first 1000 days is recognised as a critical period for the development of children. What children need to thrive in this particular phase of development may be different from any other phase. In South Africa, parents’ perception of children’s needs within the first 1000 days of life could be considered as emerging. Therefore, this study aims to explore the perspectives of South African parents and primary caregivers on what children need to thrive within the first 1000 days. An exploratory qualitative study design was used to explore the parents’ understanding of what children need to thrive in the first 1000 days. A purposive sampling approach was employed to select parents and primary caregivers in low-income communities. In all, thirty respondents participated in the study. The data were analysed using thematic analysis. During the analysis, four themes emerged. The themes included (1) the importance of parenting, care and support; (2) children’s need for holistic development; (3) parental roles; and (4) sharing responsibilities. Parents and primary caregivers living in low-income communities understand what children need to thrive within the first thousand days of life. The study could assist policymakers and service providers to design appropriate interventions for parents within these communities.
The Association between Education Outside the Classroom and Physical Activity: Differences Attributable to the Type of Space?
Authors: Bølling Mads , Mygind Erik , Mygind Lærke , Bentsen Peter , Elsborg Peter
Published: June 2021

Education outside the classroom (EOtC) has become an attractive approach, not only for learning but also for health. This explorative, cross-sectional study investigated children’s sedentary behaviours (SED), light physical activity (LPA) and moderate-to-vigorous PA (MVPA) on school days with an EOtC session in green space compared to school days with EOtC in other environments and without EOtC. Teachers from 17 Danish school classes practised EOtC for one school year on a weekly basis and self-reported the characteristics of the EOtC environment. The pupils’ PA was device-measured for seven consecutive days in a random period during the school year with AX3 accelerometers. Across 617 pupils (age 9–13 years), PA intensity cases (N = 2264) on school days (8:10–14:00 h) with (n = 317) or without (n = 1947) EOtC were included in a mixed-effects regression analysis. Mean exposure to EOtC was 262 min per session. School days with green EOtC (e.g., parks, forests and nature schools) were associated with (mean, [95% CI]) −24.3 [−41.8, −7.7] min SED and +21.3 [7.7, 36.4] min LPA compared to school days with non-green EOtC (e.g., cultural and societal institutions or companies) and with +6.2 [−0.11, 11.48] min MVPA compared to school days with a school-ground EOtC. No sex differences were found. In conclusion, school days with green EOtC must be considered promising to counteract children’s sedentary behaviours during school hours.
RETRACTED: Safety of Commercially Available Beef Burger in Saudi Arabia
Authors: Al-Thubaiti Eman , Shaikh Omar Abdulkader , El-Omri Abdelfatteh , Al-Matary Mohammed , Al-Mwallad Ali , Eldeeb Seham
Published: June 2021

The safety of meat has been at the forefront of societal concerns in recent years, and indications exist that challenges to meat safety will continue in the future. Major meat safety issues and related challenges include the need to control traditional and emerging pathogenic microorganisms, such as increased virulence and low infectious doses or resistance to antibiotics or food-related stresses. This study aimed to recognize microbial contamination and heavy metals content. Thirty-eight frozen and freshly prepared burger (local and imported) samples were collected from randomly selected supermarkets and fast-food restaurants in Jeddah. Yeasts/Molds had the highest count (204.3 CFU/mL) followed by total aerobic mesophiles (69.5 CFU/mL), total coliforms (16.2 CFU/mL) and Escherichia coli (10.0 CFU/mL). Salmonella species were positive in 39.5% of samples. Fresh burgers had more counts of TVC, total coliforms, Escherichia coli, and Bacillus cereus. Amoxicillin-clavulanate and Ampicillin had a high frequency of resistance in the studied sample. None of the studied samples had detectable traces of heavy metals’ elements. This research provides valid data to protect consumers from different health risks related to burgers in Saudi Arabia.
1D–2D Numerical Model for Wave Attenuation by Mangroves as a Porous Structure
Authors: Magdalena Ikha , Kusnowo Vivianne , Azis Moh. Ivan , Widowati
Published: June 2021

In this paper, we investigate wave attenuation caused by mangroves as a porous media. A 1-D mathematical model is derived by modifying the shallow water equations (SWEs). Two approaches are used to involve the existing of mangrove: friction term and diffusion term. The model will be solved analytically using the separation of variables method and numerically using a staggered finite volume method. From both methods, wave transmission coefficient will be obtained and used to observe the damping effect induced by the porous media. Several comparisons are shown to examine the accuracy and robustness of the derived numerical scheme. The results show that the friction coefficient, diffusion coefficient and vegetation’s length have a significant effect on the transmission coefficient. Moreover, numerical observation is extended to a 2-D SWEs, where we conduct a numerical simulation over a real bathymetry profile. The results from the 2-D numerical scheme will be validated using the data obtained from the field measurement which took place in Demak, Central Java, Indonesia. The results from this research will be beneficial to determine the characteristics of porous structures used for coastal protection.
A Phononic Crystal with Differently Configured Double Defects for Broadband Elastic Wave Energy Localization and Harvesting
Authors: Jo Soo-Ho , Youn Byeng D.
Published: June 2021

Several previous studies have been dedicated to incorporating double defect modes of a phononic crystal (PnC) into piezoelectric energy harvesting (PEH) systems to broaden the bandwidth. However, these prior studies are limited to examining an identical configuration of the double defects. Therefore, this paper aims to propose a new design concept for PnCs that examines differently configured double defects for broadband elastic wave energy localization and harvesting. For example, a square-pillar-type unit cell is considered and a defect is considered to be a structure where one piezoelectric patch is bonded to a host square lattice in the absence of a pillar. When the double defects introduced in a PnC are sufficiently distant from each other to implement decoupling behaviors, each defect oscillates like a single independent defect. Here, by differentiating the geometric dimensions of two piezoelectric patches, the defects’ dissimilar equivalent inertia and stiffness contribute to individually manipulating defect bands that correspond to each defect. Hence, with adequately designed piezoelectric patches that consider both the piezoelectric effects on shift patterns of defect bands and the characteristics for the output electric power obtained from a single-defect case, we can successfully localize and harvest the elastic wave energy transferred in broadband frequencies.
Properties and Applications of Flexible Poly(Vinylidene Fluoride)-Based Piezoelectric Materials
Authors: Xie Linfang , Wang Guoliang , Jiang Chao , Yu Fapeng , Zhao Xian
Published: June 2021

Poly (vinylidene fluoride) (PVDF) is a kind of semicrystalline organic polymer piezoelectric material. Adopting processes such as melting crystallization and solution casting, and undergoing post-treatment processes such as annealing, stretching, and polarization, PVDF films with high crystallinity and high piezoelectric response level can be realized. As a polymer material, PVDF shows excellent mechanical properties, chemical stability and biocompatibility, and is light in weight, easily prepared, which can be designed into miniaturized, chip-shaped and integrated devices. It has a wide range of applications in self-powered equipment such as sensors, nanogenerators and currently is a research hotspot for use as flexible wearable or implantable materials. This article mainly introduces the crystal structures, piezoelectric properties and their applications in flexible piezoelectric devices of PVDF materials.
Influencing Factors on the Oncuria™ Urinalysis Assay: An Experimental Model
Authors: Murakami Kaoru , Pagano Ian , Chen Runpu , Sun Yijun , Goodison Steve , Rosser Charles J. , Furuya Hideki
Published: June 2021

Background: The Oncuria™ urine test for the detection of bladder cancer measures a multiplex protein signature. In this study, we investigated the influence of urinary cellularity, protein, and hematuria on the performance of the Oncuria™ test in an ex vivo experimental model. Materials and Methods: Pooled urine from healthy subjects was spiked with cultured benign (UROtsa) or malignant cells (T24), cellular proteins, or whole blood. The resulting samples were analyzed using the Oncuria™ test following the manufacturer’s instructions. Results: Urine samples obtained from healthy subjects were negative for bladder cancer by Oncuria™ test criteria. The majority of the manipulated conditions did not result in a false-positive test. The addition of whole blood (high concentration) did result in a false-positive result, but this was abrogated by sample centrifugation prior to analysis. The addition of cellular proteins (high concentration) resulted in a positive Oncuria™ test, and this was unaffected by pre-analysis sample centrifugation. Conclusions: The Oncuria™ multiplex test performed well in the ex vivo experimental model and shows promise for clinical application. The identification of patients who require additional clinical evaluation could reduce the need to subject patients who do not have bladder cancer to frequent, uncomfortable and expensive cystoscopic examinations, thus benefiting both patients and the healthcare system.
Differential Diagnosis of Intraplaque Hemorrhage and Dissection on High-Resolution MR Imaging in Patients with Focal High Signal of the Vertebrobasilar Artery on TOF Imaging
Authors: Kim Jung Hwan , Kwak Hyo Sung , Hwang Seung Bae , Chung Gyung Ho
Published: June 2021

Purpose: Intraplaque hemorrhage (IPH) and dissection in the vertebrobasilar artery (VBA) on time of flight (TOF) source imaging are seen as focal eccentric high-signal intensity. The purpose of this study is to identify IPH and dissection in the VBA using high-resolution magnetic resonance imaging (HR-MRI). Methods: A total of 78 patients (VBA IPH: 55; dissection: 23) with focal high-signal intensity in the VBA on simultaneous non-contrast angiography and intraplaque hemorrhage (SNAP) of HR-MRI were included in this study. The focal high-signal intensity in the VBA on SNAP was defined as >200% than that of the adjacent muscle. We analyzed the signal intensity ratio (area of focal high signal intensity area/lumen) on TOF imaging and black blood (BB) T2-weighted imaging. Results: The VBA IPH group was older than the dissection group and had more hypertension. Signal intensity of a false lumen in patients with dissection on TOF imaging was significantly higher than that of VBA IPH (p < 0.001). The signal intensity ratio between lumen and lesion on TOF imaging was significantly higher in the dissection group (p < 0.001). The signal intensity of a false lumen in patients with dissection on BB T2-weighted imaging was significantly lower than that of VBA IPH (p < 0.001). The signal intensity ratio between lumen and lesion on BB T2–weighted imaging was significantly higher in the VBA IPH group (p < 0.001). Conclusions: TOF imaging and BB T2-weighted imaging on HR-MRI in patients with focal eccentric high-signal intensity on TOF imaging can distinguish between VBA IPH and dissection.