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Trapping of betanin in alginate microcapsules: Stability studies under accelerated co...
Ebru Kurtulbaş
İrem Toprakçı

Ebru Kurtulbaş

and 2 more

June 11, 2022
Microcapsules including red beet extract rich in betanin was produced by ionic gelation. Sodium alginate was used as wall material. Impacts of coating amount and active material were assessed with respect to encapsulation efficiency (EE) of the capsules in terms of total phenolic content (TPC). Encapsulation of the red beet extract in alginate microbeads was satisfying with >80% under the best conditions of ionic gelation (15% calcium chloride concentration and 2% sodium alginate for 15 min of hardening time). The interaction between the active material and the alginate beads were also investigated by diffuse reflectance fourier transform (DRIFT) spectroscopy. Accelerated oxidation test was employed to measure the stability of the microcapsules against oxidation by means of Rancimat method. Stability of the produced microbeads were evaluated in terms of kinetic and thermodynamic analyzes. After the induction times were determined under different temperature conditions (110, 120, 130 and 140 ºC) by Rancimat test, kinetic and thermodynamic parameters of the product were analyzed. The findings (∆H ++>0, ∆S ++<0, and ∆G ++ >0) indicates that low entropy value is attributed to more stable microbeads with less energy (<40 kJ mol -1).
Identification of three novel variants in the UGT1A1 gene as a cause of Crigler-Najja...
Mohammad Javad Ghorbani
Seyed Mohsen Dehghani

Mohammad Javad Ghorbani

and 1 more

June 11, 2022
Crigler-Najjar syndrome type I (CN-I) is a rare inherited disorder with a frequency of one per million at birth. Patients with CN-I have severe hyperbilirubinemia and usually die due to kernicterus. CN-I occurs due to variants within the UGT1A1 gene. The present study aimed to identify genetic defects underlying CN-I.
New frontiers in CRISPR/Cas9 delivery systems delivery for gene editing
Kazem Khoshaman
Mahbobeh  Nasiri

Kazem Khoshaman

and 16 more

June 11, 2022
Since its discovery in early 1980s to date, our knowledge about CRISPR has evoloved so much. CRISPR/Cas system confers the immunization ability against phages to the bacteria and is comprised of three stages: acquisition, biogenesis, and interference. It was first in 2012 when Charpentier and Doudna proposed Cas9 enzyme as a novel gene editing tool. They opened a new gate on the way of gene editing which led to new discoveries as well as novel treatments for diseases. It must be taken into consideration that the delivery of CRISPR/Cas9 remains a great barrier on the way of mass clinical exploition. The delivery of CRISPR/Cas9 requires a cargo and a vehicle. There are three types of cargos: plasmids, mRNAs, and enzymes. There two main types of vehicles as well: viral and non-viral. Non-viral delivery can be subdivided into physical and various nanoparticle mediated delivery. In this systematic review, we aimed to give an overall insight to the all delivery methods used for the delivery of CRISPR/Cas9 used for gene editing both in-vitro and in-vivo. We conducted a thorough search from two databases: Medline and scopus. After the screening Process we found 77 eligible papers and the results are illustrated in table 1,2, and 3.
To guard the rhythm of the heart: Constructing a wall of ice with surgical endocardia...
Dimitris Tsiachris
Antonis Pitsis

Dimitris Tsiachris

and 4 more

June 11, 2022
Surgical atrial fibrillation (AF) ablation is a valid option in cases of concomitant cardiac surgery. Electroanatomical mapping before and after the procedure can assess the substrate and verify durable lesion formation. It is likely that a routine combined cardiosurgical and electrophysiological approach may yield the greatest benefit for such patients.
On certain class of IFSs and their attractors
Nicolae Adrian Secelean
Dariusz Wardowski

Nicolae Adrian Secelean

and 1 more

June 11, 2022
Our purpose in this paper is to consider a new class of iterated function systems (IFS) based on the concept of orbital condition introduced by R. Miculescu et al. (Iterated function systems consisting of continuous functions satisfying Banach’s orbital condition, Analele Universităt¸ii de Vest, Timi¸soara, Seria Matematică-Informatică LVI, 2, (2018),71-80). On the given IFS there are imposed some sufficient conditions guaranteeing the existence of an attractor. There are also established some further results which describe the nature of the attractors of the considered type. The introduced theory is supported by some examples of IFSs for which the attractors are also depicted.
The presentation of nephrotic syndrome during immunosuppressive treatment for aplasti...
Masato Yanagi
Ryoji Kobayashi

Masato Yanagi

and 6 more

June 11, 2022
Most cases of aplastic anemia (AA) complicated by nephrotic syndrome (NS) have been reported to be the effects of chronic graft-versus-host disease after hematopoietic stem cell transplantation (HSCT). We describe a 16-year-old boy with AA with monosomy 7 who developed NS during immunosuppressive treatment for AA alone without HSCT. Recently, there appeared a report of MIRAGE syndrome caused by gain-of-function mutation of SAMD9 gene on chromosome 7 who developed NS. No such mutation was detected in our patient and thus the genetic factors leading to the complication of two diseases remain unknown at this time.
Secondary pseudotumor cerebri syndrome in a child with chronic myeloid leukemia: Repo...
Annett Helleskov Rasmussen
Nina Nguyen TTN

Annett Helleskov Rasmussen

and 3 more

June 11, 2022
Chronic myeloid leukemia (CML) is a rare disease in children and adolescents and clinical presentations are variable . Symptoms are often attributable to anemia and splenomegaly. We present a case of secondary pseudotumor cerebri syndrome as the presenting feature in a pediatric patient with CML and a review of previous cases. Through these cases, we discuss this rare but important manifestation of chronic myeloid leukemia in pediatric CML, its cause and management. We conclude that pseudotumor cerebri is an important differential diagnosis in these patients as it may result in permanent visual loss if not addressed appropriately.
Allergic diseases and fungal exposome: prevention is better than cure
Jean-Pierre Gangneux
Cendrine Godet

Jean-Pierre Gangneux

and 2 more

June 11, 2022
Allergy, Editorial
Stabilization of liquid water-in-oil emulsions by modifying the interfacial interacti...
Maria Romero-Peña
Supratim Ghosh

Maria Romero-Peña

and 1 more

June 11, 2022
Glycerol monooleate (GMO)-stabilized liquid water-in-vegetable oil (W/VO) emulsions are difficult to stabilize due to the desorption of GMO from the W-VO interface towards the oil phase. This work improved the stability of GMO-stabilized liquid 20 wt% water-in-canola oil (W/CO) emulsion by modifying the dispersed aqueous phase composition with hydrogen bond-forming agents. As a control, 20 wt% water-in-mineral oil (W/MO) emulsion was also utilized. Different concentrations of hydrogen bond-forming agents (citric acid (CA), ascorbic acid (AA), low methoxyl pectin (LMP)) with and without salts (sodium chloride (S) or calcium chloride (Ca)) was added to the aqueous phase before emulsification, which enhanced emulsifier binding to the water-oil interface. The emulsions were characterized by phase separation, stability against accelerated gravitation, microstructure and rheology. W/CO emulsion without any aqueous phase additive destabilized instantly, whereas W/MO emulsion stayed stable. The addition of hydrogen bond-forming agents and salts significantly improved emulsion stability. LMP, with many hydrogen bond-forming groups, was able to provide the highest emulsion stability after 7 days in both oils compared to AA, CA and their mixtures with S. Emulsions with both oils formed weak gels with viscous and elastic characteristics due to the formation of an extensive network of water droplet aggregates. Overall, the hydrogen bond-forming agents interacted with GMO at the interface, thereby improving their presence at the water droplet surface, allowing significantly improved stability of GMO-stabilized liquid W/CO emulsions. The knowledge developed in this research can be useful in applying GMO in stabilizing liquid water-in-oil emulsion without using any crystal network.
Antisuicidal effect of ketamine as related to primary diagnosis
Krzysztof Sadko
Olga Genge

Krzysztof Sadko

and 2 more

June 10, 2022
Antisuicidal effect of ketamine as related to primary diagnosisKrzysztof Sadko¹, Olga Genge¹, Katarzyna Jakuszkowiak¹¹Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, PolandTo the Editors,We read with interest the paper “Ketamine for suicidality: An umbrella review” on antisuicidal effect of ketamine [1] . We find this text important and of clinical relevance for the understanding of the effectiveness of this therapeutic intervention.We fully agree with the opinion that ketamine is an effective and safe drug in treatment prevention of thoughts and suicidal tendencies and we understand that side effects as rise in pulse rate and blood pressure, dissociation, confusion, blurred vision, nausea and vertigo occur are mild and temporary [1] .We believe the discussion of the paper may aims to address any confusion that may still exist among the public and even among prescribers, about the relative harm and benefits related to medications and suicide prevention/risk.Ketamine causes a quick onset and a short-term improvement in depression and suicidal symptoms in treatment-resistant depression, it also reduces chronic pain after short intravenous infusions [2] . In 2020, esketamine also received FDA approval for the treatment of depressive symptoms in adults with MDD with suicidal ideation or behavior.The main problem is dissociation as an adverse event of ketamine treatment. Additionally, there is insufficient data collected on this phenomenon in depressed patients treated with ketamine. The conducted research also does not correlate dissociation with treatment results[3] . Although the pathophysiology of the mood disorder is pleomorphic, some diseases may contribute to the development of dissociation disorders [4,5] .We believe that even a single infusion of ketamine is effective and well-tolerated, and that dissociative symptoms resolve within 2 hours of ketamine administration. Single doses of ketamine may be administered to TRD patients with or without suicidal thoughts, even if the effect may be only temporary, as it will significantly improve patients’ quality of life by reducing symptoms of depression [6] .All the studies cited here suggest that the risk of side effects after administration of ketamine may not be related to the drug itself and its enantiomer, but rather is due to the underlying psychiatric diagnosis and the course of the underlying disease. We believe that this remark could contribute to discussion and research design in future research in this field. Moreover, it appears to be of particular importance for patient safety in a clinical setting.Yours faithfully,Krzysztof Sadko
Guidance for dosing and monitoring of oral antineoplastic drugs in breast cancer pati...
Jurjen Kingma
Niels Peeters

Jurjen Kingma

and 6 more

June 10, 2022
A document by Jurjen Kingma. Click on the document to view its contents.
Fortuitous detection of extensive gutta-percha extruded into the maxillary sinus duri...
Georges Aoun

Georges Aoun

June 13, 2022
Close proximity between the maxillary teeth roots and the maxillary sinus can lead to an unintentional deposition of endodontic obturation materials into the latter. Among these materials the injectable thermoplasticized gutta-percha as a consequence of overfilling. In this report a case of extensive gutta-percha extruded into the maxillary sinus following root canal treatment on the 2nd upper left molar is presented.
Environmental influences on childhood cancer risk: an umbrella review
Evangelia Ntzani
Maria Karalexi

Evangelia Ntzani

and 12 more

June 10, 2022
Aim: To explore the validity and strength of evidence on the association between environmental factors and risk of developing childhood (0-14 years) cancer. Methods: An umbrella review was conducted including systematic reviews and meta-analyses of observational epidemiological studies that examined the association of any environmental exposure of either parent or child with any type of childhood cancer. PubMed and Scopus databases were searched until April 2020. Based on predefined criteria, the evidence was graded into strong, highly suggestive, suggestive or weak. Results: 509 meta-analyses explored environmental exposures and risk of developing 10 different types of childhood cancer. Only 2.4% of the associations were considered to have highly suggestive evidence inferred by strongly statistically significant results. These associations were confined to increased risk of overall leukemia, especially acute lymphoblastic leukemia (ALL), in relation to high birthweight, paternal smoking and exposure to pesticides, particularly insecticides. By contrast, maternal multivitamin supplementation during pregnancy (summary odds ratio [OR]: 0.64, 95% confidence intervals [CI]: 0.52, 0.80) and breastfeeding for more than 6 months (summary OR: 0.76, 95%CI: 0.68, 0.84) were supported by highly suggestive evidence for decreased risk of ALL. There was also highly suggestive evidence for increased risk of central nervous system (CNS) tumors, especially astrocytoma, in relation to high birthweight, as well as increased risk of testicular cancer in relation to testicular microlithiasis and isolated cryptorchidism. Conclusions: The present findings provide evidence that exposure to seven maternal/neonatal factors significantly affects the risk of childhood leukemia, CNS tumors and testicular cancer. Further evidence from sufficiently powered studies and large consortia with uniform reporting of analyses is needed to allow firmer conclusions to be drawn.
MeStudio: crossing methylation and genomic features for comparative epigenomic analys...
Christopher Riccardi
Iacopo Passeri

Christopher Riccardi

and 5 more

June 10, 2022
DNA methylation is one of the most relevant epigenetic modifications. It is present in eukaryotes and prokaryotes and is related to several biological phenomena, including gene flow and adaptation to environmental conditions. The widespread use of third-generation sequencing technologies allows direct and easy detection of genome-wide methylation profiles, offering increasing opportunities to understand and exploit the epigenomics landscape of individuals and populations. Here, we present MeStudio, a pipeline which allows to analyse and combine genome-wide methylation profiles with genomic features. Outputs report the presence of DNA methylation in coding sequences (CDS) and noncoding sequences, including both intergenic sequences, and sequences upstream to CDS. We show the usage and performances of MeStudio on a set of single-molecule real time sequencing outputs from strains of the bacterial species Sinorhizobium meliloti. MeStudio is freely available under an open source GPLv3 license at https://github.com/combogenomics/MeStudio
SILICA APPLICATIONS IN BIOMATERIALS: TEXTUAL REVIEW
Vitoria De Godoy Saciloto
Susana Claudete Costa

Vitoria De Godoy Saciloto

and 3 more

June 10, 2022
Biomaterials are important tools for the reconstruction of organs and tissues, and silica is widely used in these reconstruction technologies. Hence, a lexical and content analysis was carried out on articles on application of silica in biomaterials, based on a search in the Capes’ Journals Portal using the keywords “silica, biomedical, application, scaffold”, between the years 2009 and 2019. The 110 selected articles were analyzed using the IRaMuTeQ software, Word Cloud and Descending Hierarchical Classification (DHC). The words: “silica, cell, nanosilica, bone, material, scaffold and application” appear prominently in the Word Cloud and DHC indicating four classes: (1) physical characterization, (2) biomedicine applications, (3) engineering applications and (4) compatibility characterization. Thus, the analysis of DHC and Word Cloud showed that the main ways of using silica are: mesoporous silica nanoparticles, amorphous silica, silica-based materials, nanofibers and silica hybrids, and the main biomaterials developed are scaffolds, grafts, aerogels, hydrogels, membranes and drug delivery systems.
A curated DNA barcode reference library for parasitoids of northern European cyclical...
Tommi Nyman
Saskia Wutke

Tommi Nyman

and 9 more

June 10, 2022
Large areas of forests are annually damaged or destroyed by outbreaking insect pests. Understanding the factors that trigger and terminate such population eruptions has become crucially important, as plants, plant-feeding insects, and their natural enemies may respond differentially to the ongoing changes in the global climate. In northernmost Europe, climate-driven range expansions of the geometrid moths Epirrita autumnata and Operophtera brumata have resulted in overlapping and increasingly severe outbreaks. Delayed density-dependent responses of parasitoids are a plausible explanation for the ten-year population cycles of these moth species, but the impact of parasitoids on geometrid outbreak dynamics is unclear due to a lack of knowledge on the host ranges and prevalences of parasitoids attacking the moths in nature. To overcome these problems, we reviewed the literature on parasitism in the focal geometrid species in their outbreak range, and then constructed a DNA barcode reference library for all relevant parasitoid species based on reared specimens and sequences obtained from public databases. The combined parasitoid community of E. autumnata and O. brumata consists of 32 hymenopteran species, all of which can be reliably identified based on their barcode sequences. The curated barcode library presented here opens up new opportunities for estimating the abundance and community composition of parasitoids across populations and ecosystems based on mass barcoding and metabarcoding approaches. Such information can be used for elucidating the role of parasitoids in moth population control, possibly also for devising methods for reducing the extent, intensity, and duration of outbreaks.
Single center, multi-surgeon experience with a sutureless rapid deployment aortic val...
Kelly Ohlrich
Michael P. Robich

Kelly Ohlrich

and 10 more

June 10, 2022
Background The Perceval S is a sutureless, rapid deployment, bovine pericardial aortic prosthesis on a nitinol stent, which has limited data on outcomes and cost from the United States. Methods We performed a retrospective review of Perceval S implantation at a single center between 2015 and 2018. After exclusion criteria, we compared 262 patients who underwent sutureless aortic valve (SLV) implantation with 394 patients who underwent standard sutured aortic valves (SAVR). Hospital cost data was reviewed, and risk adjustment, done by propensity score and inverse probability weighting, was used to compare outcomes. Results The SLV group was older, had more females, and had a higher proportion of multicomponent operations. For isolated AVR, partial upper hemisternotomy was more frequent in SLV. The median cardiopulmonary bypass and cross clamp times for isolated SLV were significantly lower than SAVR. SLV had a risk-adjusted 11.3% permanent pacemaker (PPM) rate vs 6.1% in SAVR (p=0.016). There were no differences in other postoperative complications (postoperative atrial fibrillation, stroke, renal failure, prolonged ventilation; P>.05 for all). Mortality at any time did not differ between groups. Median hospital costs were higher in the SLV group, likely due to permanent pacemaker rate leading to longer length of stay. Conclusion Sutureless tissue aortic valves can be used safely with lower cardiopulmonary bypass and clamp times than sutured prostheses and facilitate use of minimally invasive approaches with cost neutrality. This valve may be advantageous in older, higher risk patients requiring complex operations.
Methods for detection of recent population subdivisions
Gabe O'Reilly
Celine Frere

Gabe O'Reilly

and 4 more

June 10, 2022
Potential subdivision events in populations can have a wide range of causes: from natural disasters like bushfires that isolate communities, to anthropogenic disturbances like infrastructure projects cutting through a population’s habitat. Due to the unpredictability inherent in events like bushfires, or even for predictable events such as property development, populations affected by these potential subdivisions are often not studied until after the event, making it extremely hard to assess negative conservation impacts without the benefit of prior data. This paper aims to apply population genetics methods to assess whether it is possible to accurately assess the impact a potential subdivision event can have on the genetic makeup of a population, especially when one has no data prior to such an event. Differentiation measures, such as Fst, might be used for detecting whether a population has been subdivided. However, these measures often take dozens of generations to show a significant change from zero (i.e., no differentiation), especially in larger populations. In this paper we present a more sensitive method, which is suitable for detecting subdivision effects within a few generations of the event and which can be applied without prior data. We test this method using both simulated data, and genetic data from a population of koalas impacted by a railroad infrastructure development.
Noninvasive ventilation via bilevel positive airway pressure improved sleep in a chil...
Liqiang Yang
Shuyao Qiu

Liqiang Yang

and 3 more

June 10, 2022
Congenital central hypoventilation syndrome (CCHS) is rare in the world and the survival rate is low. The surviving children need lifelong ventilatory support. The sleep is closely related to nervous system development; however, there is a lack of studies on sleep in patients with CCHS.
bivariatemaps: An R Package to Create Bivariate Maps and Grid-Intersected Shapes Base...
José Hidasi Neto

José Hidasi Neto

June 10, 2022
Bivariate maps have been published in studies since the 70s, but only in the 2010s the method became more used by the general public, including scientists from low-profit universities. Here I present my new R package, bivariatemaps, capable of three things: making color matrices with different quantile numbers, making a bivariate map from two rasters and a color matrix, and making gridded shapefiles while excluding cells based on area coverage. The package basically has three functions: colmat, bivariate.map and GridFilter. I show the steps in order to generate a bivariate map and show how this method can be used in the most distinct scientific areas. The package is available in both Github and CRAN (R repository) and is freely available and customizable by anyone who wants to use it.
A simple solution for the general fractional Ambartsumian equation
Manuel Ortigueira
Gabriel Bengochea

Manuel Ortigueira

and 1 more

June 10, 2022
The Ambartsumian equation is studied and solved. A simple solution expressed in terms of a linear combination of Mittag-Leffler functions is deduced and implemented. A fast algorithm for its numerical realization is described and examplified.
Research on the Stock Correlation Network and Its Influencing Factors in China's Gree...
Qianting Ma
Jiaxin Zhao

Qianting Ma

and 4 more

June 10, 2022
Green finance is a significant step to achieving environmentally sustainable development in the context of carbon neutrality. Based on the perspective of the stock correlation network, we select 51 green and environmental protection enterprises and construct the stock correlation network model in China’s green financial market according to the correlation of their stock price fluctuations. On this basis, it discusses its network topologies and its dynamic evolution characteristics. After that, it deeply studies its impact mechanism of systemically importance in China’s green financial market and introduces the major green financial policies for comparative analysis. In the light of empirical research, we can obtain the following results. First, the stock size distribution in China’s green financial market has a power-law tail. Second, a sharp drop in the market index will increase the aggregation of the stock correlation network in the green financial market. Third, the variables about corporate social responsibility, corporate R&D investment intensity, and corporate green innovation output play significant roles in promoting the individual companies’ systemically importance ranking in the stock correlation networks of China’s green financial market. Fourth, the implementation of major green financial policies has promoted the improvement of the systematic importance of state-owned enterprises. Finally, the research enriches the application research of complex network theory in the green financial market and provides practical guidance for regulators to strengthen the risk monitoring of the green financial market.
Improving sustainable crop protection using population genetics concepts
Méline Saubin
Clémentine Louet

Méline Saubin

and 12 more

June 10, 2022
Growing genetically resistant plants allows pathogen populations to be controlled and reduces the use of chemicals. However, pathogens can quickly overcome such resistance. In this context, how can we achieve sustainable crop protection? This crucial question has remained largely unanswered despite decades of intense debate and research effort. In this study, we used a bibliographic analysis to show that the research field of resistance durability has evolved into three subfields: (i) ‘plant breeding’ (generating new genetic material), (ii) ‘molecular interactions’ (exploring the molecular dialogue governing plant–pathogen interactions) and (iii) ‘epidemiology and evolution’ (explaining and forecasting of pathogen population dynamics resulting from selection pressure(s) exerted by resistant plants). We argue that this triple split of the field impedes integrated research progress and ultimately compromises the sustainable management of genetic resistance. After identifying a gap among the three subfields, we argue that the theoretical framework of population genetics could bridge this gap. Indeed, population genetics formally explains the evolution of all heritable traits, and allows genetic changes to be tracked along with variation in population dynamics. This provides an integrated view of pathogen adaptation, notably via evolutionary–epidemiological feedbacks. In this Opinion Note, we detail examples illustrating how such a framework can better inform best practice for developing and managing genetically resistant cultivars.
Juxtaglomerular cell tumor with pulmonary metastases: A case report and review of the...
Hideki Sakiyama
Satoru Hamada

Hideki Sakiyama

and 12 more

June 10, 2022
Juxtaglomerular cell tumor with pulmonary metastases: A case report and review of the literatureHideki Sakiyama1, Satoru Hamada1,2, Tokiko Oshiro1,2, Nobuyuki Hyakuna1,2 Masaaki Kuda3, Tomoro Hishiki4, Hajime Aoyama5, Naoto Kuroda6, Kenji Yorita7, Naoki Wada8, Takako Yoshioka9, Yuhki Koga10, Koichi Nakanishi1,21) Department of Pediatrics, University of the Ryukyus Hospital, Uehara, Nishihara, Okinawa, Japan2) Department of Child Health and Welfare, Graduate School of Medicine, University of the Ryukyus, Uehara, Nishihara, Okinawa, Japan3) Department of Digestive and General Surgery Graduate School of Medicine, University of the Ryukyus, Uehara, Nishihara, Okinawa, Japan4) Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan5) Department of Pathology, Heartlife Hospital, Okinawa, Japan6) Department of Internal Medicine, Kinro Hospital, Kochi, Japan7) Department of Diagnostic Pathology, Japanese Red Cross Kochi Hospital, Kochi, Japan8) Department of Pathology and Oncology, Graduate School of Medicine, University of Ryukyus, Uehara, Nishihara, Okinawa, Japan9) Department of Pathology, National Center for Child Health and Development, Tokyo, Japan10) Department of Pediatrics, Graduate School of Medical Science, Kyusyu University, Fukuoka, JapanCorrespondence: Satoru Hamada,Department of Pediatrics, Faculty of Medicine, University of Ryukyus, 207 Uehara, Nishihara-cho, Okinawa 903-0125, Japanshamada@med.u-ryukyu.ac.jpTo the Editor: Juxtaglomerular cell tumor (JGT) is a relatively rare, benign renin-producing tumor that causes hypertension, hyperaldosteronism, and hypokalemia due to excessive renin secretion. Here, we report a case of malignant JGT with pulmonary metastases. A 7-year-old male patient was referred to the hospital for proteinuria found during a school medical checkup. An ultrasound examination revealed a tumor on the right kidney. His blood pressure was 170/120 mmHg, and plasma renin activity was high at 30 ng/mL/hr. Computed tomography (CT) revealed a mass of 3.4 cm diameter on the right kidney with multiple pulmonary metastases, which was suggestive of nephroblastoma. He underwent right nephrectomy, resulting in a return of blood pressure and plasma renin activity to normal levels (reference range, 0.2–2.3 ng/mL/hr). Gross examination of the tumor revealed a 3.2 × 3.2 × 10-cm yellowish-white mass with necrosis in the mid pole of the kidney. Most of the tumor was covered with a fibrous membrane that partially extended into the normal tissue. Histology revealed a mesenchymal neoplasm with a blastemal component that was suggestive of nephroblastoma. No vascular invasion was observed within the analyzed area (Supplemental Figures S1, S2). Subsequently, he received chemotherapy according to the DD-4A regimen of the National Wilms Tumor Study Group. The immunophenotype demonstrated renin and CD34 positivity (Supplemental Figures S3, S4). This led to a definitive diagnosis of JGT, which was consistent with the clinical feature of hypertension. Chemotherapy was stopped at week 6, at which point CT revealed unchanged metastatic lung lesions. He then underwent a two-stage surgical resection for bilateral lung metastases, and total resection was achieved. Pathologically, the metastatic lung lesions were consistent with the resected renal tumor. Because no reports of effective chemotherapy for malignant JGT were found, we followed-up this patient without administering adjuvant chemotherapy. He showed no evidence of disease after a 2-year follow-up. Targeted DNA sequencing using FoundationOne® CDx detected six genetic mutations:NOTCH3 T272M, BRAF D22N, MAP3K1 L78P, CDKN2BA56D, DAXX E451del, and ERBB4 P3L in the primary tumor.JGT is a rare benign tumor that is more common in relatively young adults. JGT causes various clinical symptoms, such as headache, nausea, dizziness, weakness, hypertension, and proteinuria.1,2JGT is generally curable by surgical resection, and tumor removal results in the improvement of hyperreninemia and clinical symptoms.1 Immunohistochemically, the diagnosis is confirmed by renin positivity in the cytoplasm. In addition, CD34, CD117, vimentin, and ACTA2 are often positive.2,3Although JGT is generally considered benign, eight malignant or pathologically atypical cases have been reported in the literature (Table).3–10 Six were adult cases, and one was a pediatric case. In all cases, the tumor diameter was relatively large (>5 cm). Pathologically, seven of eight showed either vascular invasion or mitotic figures, and among these cases, four had distant metastasis: case 1 demonstrated bilateral lung metastases 6 years after nephrectomy,4 case 4 demonstrated bilateral lung metastases at initial diagnosis,9 case 6 demonstrated multicentric synchronous disease in the liver and spleen,7 case 8 succumbed to hepatic and bone metastases 10 months after nephrectomy.3 In our case, complete metastasectomy of the bilateral pulmonary nodules was achieved after nephrectomy. Thus, he was in remission at 2 years without adjuvant chemotherapy.Ours is the first reported case of pediatric malignant JGT with multiple pulmonary metastases. Although most patients with malignant JGT present with a large tumor that is pathologically characterized by vascular invasion, our case had a relatively small-sized tumor with no vascular invasion or nuclear atypia. Few reports have described genetic abnormalities in JGT. Targeted DNA sequences in our case revealed six gene mutations although the significance of these mutations in the pathogenesis of malignant JGT is unclear. A previous study reported that the NOTCH3 receptor is highly expressed in reninoma in mice.11 Dysregulation of NOTCH3 signaling plays a role in soft tissue tumor pathogenesis.12 Therefore, the NOTCH3 mutation in our case might have been involved in this malignant transformation. In addition, NOTCH3 signaling has shown to contributed to chemoresistance to doxorubicin13, which was consistence with the clinical feature of an ineffective for metastatic lung lesions after chemotherapy including doxorubicin. JGT is generally considered to be a benign tumor, but malignant cases have recently been reported. Our patient was successfully treated with complete pulmonary metastasectomy after primary tumor resection without adjuvant chemotherapy. Pulmonary metastasectomy represents an effective approach in the treatment of JGT-related lung metastases alone. However, no established reports on the prognosis and treatment of malignant JGT exist; thus, additional case reports are needed.Conflict of Interest StatementThe authors declare that there is no conflict of interest.1. McVicar M, Carman C, Chandra M, Abbi RJ, Teichberg S, Kahn E. Hypertension secondary to renin-secreting juxtaglomerular cell tumor: case report and review of 38 cases. Pediatr Nephrol 1993;7:404-412.2. Kuroda N, Gotoda H, Ohe C, et al. Review of juxtaglomerular cell tumor with focus on pathobiological aspect. Diagn Pathol 2011;6:80.3. Zhou J, Zheng S, Zhang Y, et al. Juxtaglomerular cell tumor: clinicopathologic evaluation in a large series emphasizing its broad histologic spectrum. Pathol Int 2020;70:844-856.4. Duan X, Bruneval P, Hammadeh R, et al. Metastatic juxtaglomerular cell tumor in a 52-year-old man. Am J Surg Pathol 2004;28:1098-1102.5. Beaudoin J, Périgny M, Têtu B, Lebel M. A patient with a juxtaglomerular cell tumor with histological vascular invasion. Nat Clin Pract Nephrol 2008;4:458-462.6. Shera AH, Baba AA, Bakshi IH, Lone IA. Recurrent malignant juxtaglomerular cell tumor: a rare cause of malignant hypertension in a child. J Indian Assoc Pediatr Surg 2011;16:152-154.7. Cucchiari D, Bertuzzi A, Colombo P, et al. Juxtaglomerular cell tumor: multicentric synchronous disease associated with paraneoplastic syndrome. J Clin Oncol 2013;31:e240-e242.8. Munakata S, Tomiyama E, Takayama H. Case report of atypical juxtaglomerular cell tumor. Case Rep Pathol 2018;2018:6407360.9. Huang PW, Lin YC, Wu KF, Sheng TW, Su PJ. Juxtaglomerular cell tumor with lung metastases in a young male patient. J Cancer Surviv . 2019;6(3):128.10. Hagiya A, Zhou M, Hung A, Aron M. Juxtaglomerular cell tumor with atypical pathological features: report of a case and review of literature. Int J Surg Pathol 2020;28:87-91.11. Martini AG, Xa LK, Lacombe M-J, et al. Transcriptome analysis of human reninomas as an approach to understanding juxtaglomerular cell biology. Hypertension 2017;69:1145-1155.12. Raimondi L, Ciarapica R, De Salvo M. Inhibition of Notch3 signalling induces rhabdomyosarcoma cell differentiation promoting p38 phosphorylation and p21(Cip1) expression and hampers tumour cell growth in vitro and in vivo. Cell Death Differ 2012;19:871-881.13. Xiu M, Wang Y, Li B, et al. The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies. Front Mol Biosci. 2021;14:694141.Figure legendsFigure S1. Neoplastic cells with an ovoid shape proliferate in a solid sheet growth pattern, 40×.Figure S2. Neoplastic cells display rare mitotic activity and mild nuclear atypia, 200×.Figure S3. Neoplastic cells show CD34 labeling, 200×.Figure S4. Renin is diffusely distributed in the tumor cytoplasm, 200×.
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