bluuebunny/crossref_metadata_2025 huggingface dataset:
Disseminated coccidioidomycosis in a patient with juvenile idiopathic arthritis receiving infliximab
Authors: Trainor Megan , Henkel Emily , Diaz Lucia Z. , Carrasco Ruy
Published: May 2021

Background

Coccidioides immitis is a dimorphic fungus endemic to the arid climates of the Southwest United States, Mexico and parts of Central and South America. Human infection occurs through inhalation of spores with less than half of exposures progressing to a symptomatic state that primarily consists of pulmonary manifestations. Disseminated coccidioidomycosis is exceedingly rare, occurring in fewer than 1 % of symptomatic infections. Through hematogenous spread, the fungus can infect most organ systems and may be fatal without systemic antifungal treatment. Individuals with impaired cell-mediated immunity either from primary immunodeficiency disorders or secondary to immunosuppression with medications such as tumor necrosis factor alpha (TNF-α) inhibitors have increased risk of disseminated coccidioidomycosis and previous cases of coccidioidomycosis have been reported with biologic therapy.

Case presentation

We present a case of disseminated coccidioidomycosis in a 16-year-old female with polyarticular juvenile idiopathic arthritis (JIA) being treated with prednisone, methotrexate, and infliximab. The patient presented with symptoms of meningeal irritation, bilateral choroidal lesions, and necrotizing peripheral pneumonia. Her infection was thought to be a reactivation of coccidioidomycosis given her history of resolved pneumonia that occurred after traveling to Arizona, New Mexico, and El Paso one year prior to presentation. Following diagnosis, she improved with discontinuation of her immunosuppressive medications and two weeks of intravenous amphotericin B and fluconazole with plans for lifetime treatment with fluconazole while immunosuppressed. Due to worsening arthritis, she will begin tofacitinib and continue close monitoring of chest x-rays and coccidioides antibody.

Conclusions

Patients undergoing immunosuppressive therapy for rheumatological conditions are at increased risk of disseminated coccidioidomycosis and should be evaluated with high suspicion when presenting with atypical symptoms and history of travel to endemic regions.
Trajectories of disease courses in the inception cohort of newly diagnosed patients with JIA (ICON-JIA): the potential of serum biomarkers at baseline
Authors: Ganeva Margarita , Fuehner Sabrina , Kessel Christoph , Klotsche Jens , Niewerth Martina , Minden Kirsten , Foell Dirk , Hinze Claas H. , Wittkowski Helmut
Published: May 2021

Objective

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory joint disorders with a chronic-remitting disease course. Treat-to-target approaches have been proposed but monitoring disease activity and predicting the response to treatment remains challenging.

Methods

We analyzed biomarkers and their relationship to outcome within the first year after JIA diagnosis in the German Inception Cohort of Newly diagnosed patients with JIA (ICON-JIA). CRP, CXCL9, CXCL10, CXCL11, erythrocyte sedimentation rate, G-CSF, IL-6, IL-17A, IL-18, MCP-1, MIP-1α, MMP-3, S100A8/A9, S100A12, TNFα, and TWEAK were measured at baseline and 3 months later.

Results

Two-hundred-sixty-six JIA patients with active disease at baseline were included, with oligoarthritis and rheumatoid factor-negative polyarthritis representing the most frequent categories (72.9%). Most biomarkers were elevated in JIA compared to healthy pediatric controls. Patients with systemic JIA had higher CRP, S100A8/A9 and S100A12 levels compared to other JIA categories. Baseline levels of TWEAK, G-CSF and IL-18 were lower in oligoarthritis patients with disease extension within 1 year. Increased baseline levels of CRP, S100A8/A9, S100A12 and ESR were associated with the subsequent addition of biologic disease-modifying antirheumatic drugs (DMARDs). Higher baseline ESR, G-CSF, IL-6, IL-17A and TNF levels indicated an increased risk for ongoing disease activity after 12 months.

Conclusion

Our data demonstrate that elevated baseline levels of CRP, S100A8/A9 and S100A12 as well as increased ESR are associated with the necessity to escalate therapy during the first 12 month of follow-up. Furthermore, biomarkers related to Th17 activation may inform on future disease course in previously treatment-naïve JIA patients.
Impact of feature selection methods and subgroup factors on prognostic analysis with CT-based radiomics in non-small cell lung cancer patients
Authors: Sugai Yuto , Kadoya Noriyuki , Tanaka Shohei , Tanabe Shunpei , Umeda Mariko , Yamamoto Takaya , Takeda Kazuya , Dobashi Suguru , Ohashi Haruna , Takeda Ken , Jingu Keiichi
Published: April 2021

Background

Radiomics is a new technology to noninvasively predict survival prognosis with quantitative features extracted from medical images. Most radiomics-based prognostic studies of non-small-cell lung cancer (NSCLC) patients have used mixed datasets of different subgroups. Therefore, we investigated the radiomics-based survival prediction of NSCLC patients by focusing on subgroups with identical characteristics.

Methods

A total of 304 NSCLC (Stages I–IV) patients treated with radiotherapy in our hospital were used. We extracted 107 radiomic features (i.e., 14 shape features, 18 first-order statistical features, and 75 texture features) from the gross tumor volume drawn on the free breathing planning computed tomography image. Three feature selection methods [i.e., test–retest and multiple segmentation (FS1), Pearson's correlation analysis (FS2), and a method that combined FS1 and FS2 (FS3)] were used to clarify how they affect survival prediction performance. Subgroup analysis for each histological subtype and each T stage applied the best selection method for the analysis of All data. We used a least absolute shrinkage and selection operator Cox regression model for all analyses and evaluated prognostic performance using the concordance-index (C-index) and the Kaplan–Meier method. For subgroup analysis, fivefold cross-validation was applied to ensure model reliability.

Results

In the analysis of All data, the C-index for the test dataset is 0.62 (FS1), 0.63 (FS2), and 0.62 (FS3). The subgroup analysis indicated that the prediction model based on specific histological subtypes and T stages had a higher C-index for the test dataset than that based on All data (All data, 0.64 vs. SCCall, 060; ADCall, 0.69; T1, 0.68; T2, 0.65; T3, 0.66; T4, 0.70). In addition, the prediction models unified for each T stage in histological subtype showed a different trend in the C-index for the test dataset between ADC-related and SCC-related models (ADCT1–ADCT4, 0.72–0.83; SCCT1–SCCT4, 0.58–0.71).

Conclusions

Our results showed that feature selection methods moderately affected the survival prediction performance. In addition, prediction models based on specific subgroups may improve the prediction performance. These results may prove useful for determining the optimal radiomics-based predication model.
Implementation of second-tier tests in newborn screening for the detection of vitamin B12 related acquired and genetic disorders: results on 258,637 newborns
Authors: Pajares Sonia , Arranz Jose Antonio , Ormazabal Aida , Del Toro Mireia , García-Cazorla Ángeles , Navarro-Sastre Aleix , López Rosa María , Meavilla Silvia María , de los Santos Mariela Mercedes , García-Volpe Camila , de Aledo-Castillo Jose Manuel González , Argudo Ana , Marín Jose Luís , Carnicer Clara , Artuch Rafael , Tort Frederic , Gort Laura , Fernández Rosa , García-Villoria Judit , Ribes Antonia
Published: April 2021

Background

Alteration of vitamin B12 metabolism can be genetic or acquired, and can result in anemia, failure to thrive, developmental regression and even irreversible neurologic damage. Therefore, early diagnosis and intervention is critical. Most of the neonatal cases with acquired vitamin B12 deficiency have been detected by clinical symptoms and only few of them trough NBS programs. We aim to assess the usefulness of the second-tier test: methylmalonic acid (MMA), methylcitric acid (MCA) and homocysteine (Hcys) in our newborn screening program and explore the implications on the detection of cobalamin (vitamin B12) related disorders, both genetic and acquired conditions.

Methods

A screening strategy using the usual primary markers followed by the analysis of MMA, MCA and Hcys as second tier-test in the first dried blood spot (DBS) was developed and evaluated.

Results

During the period 2015–2018 a total of 258,637 newborns were screened resulting in 130 newborns with acquired vitamin B12 deficiency (incidence 1:1989), 19 with genetic disorders (incidence 1:13,613) and 13 were false positive. No false negatives were notified. Concerning the second-tier test, the percentage of cases with MMA above the cut-off levels, both for genetic and acquired conditions was very similar (58% and 60%, respectively). Interestingly, the percentage of cases with increased levels of Hcys was higher in acquired conditions than in genetic disorders (87% and 47%, respectively). In contrast, MCA was high only in 5% of the acquired conditions versus in 53% of the genetic disorders, and it was always very high in all patients with propionic acidemia.

Conclusions

When screening for methylmalonic acidemia and homocystinuria, differential diagnosis with acquired vitamin B12 deficiency should be done. The results of our strategy support the inclusion of this acquired condition in the NBS programs, as it is easily detectable and allows the adoption of corrective measures to avoid the consequences of its deficiency.
Quality of life and its contributors among adults with late-onset Pompe disease in China
Authors: Chen Shanquan , Wang Jingxuan , Zhu Jianfeng , Chung Roger Yat-Nork , Dong Dong
Published: May 2021

Background

Pompe disease (PD) is a rare inherited disorder caused by the deficiency of acid-α glucosidase, which leads to the impairment of organ and tissue functions and causes disabilities. As the first national survey on patients with late-onset PD (LOPD) in China, this study investigated the quality of life (QOL) of adult patients with LOPD in China and explored its contributors.

Methods

Data were derived from a nation-based, cross-sectional, self-response survey on rare diseases (RDs) in early 2018. Answers from 68 adult Chinese patients with LOPD were used for data analysis. QOL was measured using the World Health Organization Quality of Life: Brief Version. Covariates included age, gender, education, employment, reliance on assistive devices, medication history, social support, and disease economic burden. Data were analyzed using linear regression in R.

Results

For adult patients with LOPD, the average scores and standard deviations (SD) of the four dimensions of QOL were physical health = 33.77 (SD = 18.28), psychological health = 43.81 (SD = 21.70), environmental health = 39.43 (SD = 16.93), and social relationship = 46.20 (SD = 19.76); the scoring for each dimension was evaluated on a scale of 0 to 100. At the significance level of p < 0.05, with increasing age, the patients experienced a significant decrease in physical health QOL (β = − 0.75) and environmental health QOL (β = − 0.79). Those who relied heavily on assistive devices had lower perceived physical health (β = − 17.8), psychological health (β = − 22.76), environmental health (β = − 17.8), and social relationships (β = − 22.12) than those who did not. A one-unit increase in the amount of social support, as a form of social interaction, led to a significant increase in physical health (β = 0.28), psychological health (β = 0.71), environmental health (β = 0.72), and social relationships (β = 0.70).

Conclusion

Adult Chinese patients with LOPD had a lower physical health and QOL compared to their counterparts with other RDs. Being employed was found to affect the QOL of adult Chinese patients with LOPD in almost all dimensions. Encouraging adult Chinese patients with LOPD to be socially active and help them become more involved in social life might improve their QOL.
Child maltreatment, cognitive functions and the mediating role of mental health problems among maltreated children and adolescents in Uganda
Authors: Ainamani Herbert E. , Rukundo Godfrey Z. , Nduhukire Timothy , Ndyareba Eunice , Hecker Tobias
Published: May 2021

Background

Child maltreatment poses high risks to the mental health and cognitive functioning of children not only in childhood but also in later life. However, it remains unclear whether child maltreatment is directly associated with impaired cognitive functioning or whether this link is mediated by mental health problems. Our study aimed at examining this research question among children and adolescents in Uganda.

Methods

A sample of 232 school-going children and adolescents with a mean age of 14.03 (SD = 3.25) was assessed on multiple forms of maltreatment using the Maltreatment and Abuse Chronology Exposure—Pediatric Version (pediMACE). Executive functions were assessed by the Tower of London task and working memory by the Corsi Block Tapping task, while mental health problems were assessed using the Child PTSD Symptom Scale for PTSD and the Center for Epidemiological Studies Depression Scale for Children (CES-DC).

Results

In total, 232 (100%) of the participant reported to have experienced at least one type of maltreatment in their lifetime including emotional, physical, and sexual violence as well as neglect. We found a negative association between child maltreatment and executive functions (β = − 0.487, p < 0.001) and working memory (β = − 0.242, p = 0.001). Mental health problems did not mediate this relationship.

Conclusions

Child maltreatment seems to be related to lower working memory and executive functioning of affected children and adolescents even after controlling for potential cofounders. Our study indicates that child maltreatment the affects children’s cognitive functionality beyond health and well-being.
The lnc-CTSLP8 upregulates CTSL1 as a competitive endogenous RNA and promotes ovarian cancer metastasis
Authors: Wang Xinjing , Li Xiaoduan , Lin Feikai , Sun Huizhen , Lin Yingying , Wang Ziliang , Wang Xipeng
Published: May 2021

Background

Ovarian cancer is highly lethal and has a poor prognosis due to metastasis. Long non-coding RNAs (lncRNAs) are key regulators of tumor development, but their role in ovarian cancer metastasis remains unclear.

Methods

The expression of lnc-CTSLP8 in ovarian cancer was analyzed in public databases (TCGA and GEO) and validated via qRT-PCR. Lnc-CTSLP8 overexpression and knockout cell lines were constructed using a lentiviral vector and the CRISP/Cas9 system. Cell proliferation, colony formation, migration, and invasion were analyzed. An ovarian orthotopic tumor mouse model was used for the in vivo study. Changes in autophagosomes, autolysosomes, and mitochondria in ovarian cancer cells were observed via transmission electron microscopy. EMT markers were detected by immunoblotting and immunofluorescence assays. RNA immunoprecipitation, RNA pull-down, and dual luciferase reporter assays were performed to confirm the interaction between lnc-CTSLP8 and miR-199a-5p.

Results

A novel pseudogene, lnc-CTSLP8, was identified in ovarian cancer, with significantly elevated expression in metastatic tumor tissues compared to primary ovarian tumors. When overexpressed, lnc-CTSLP8 promoted ovarian cancer in vitro and in vivo by acting as a sponge for miR-199a-5p. Autophagy and EMT in ovarian cancer were also enhanced by lnc-CTSLP8. Mechanistically, lnc-CTSLP8 upregulated CTSL1 as a competitive endogenous RNA and exhibited oncogenic effects. Moreover, CTSL1 inhibitor treatment and miR-199a-5p overexpression abrogated the effects of lnc-CTSLP8 overexpression.

Conclusions

lnc-CTSLP8 acts as a ceRNA in ovarian cancer and represents a potential therapeutic target for metastatic ovarian cancer.
Machine learning approach to support taxonomic species discrimination based on helminth collections data
Authors: Borba Victor Hugo , Martin Coralie , Machado-Silva José Roberto , Xavier Samanta C. C. , de Mello Flávio L. , Iñiguez Alena Mayo
Published: May 2021

Background

There are more than 300 species of capillariids that parasitize various vertebrate groups worldwide. Species identification is hindered because of the few taxonomically informative structures available, making the task laborious and genus definition controversial. Thus, its taxonomy is one of the most complex among Nematoda. Eggs are the parasitic structures most viewed in coprological analysis in both modern and ancient samples; consequently, their presence is indicative of positive diagnosis for infection. The structure of the egg could play a role in genera or species discrimination. Institutional biological collections are taxonomic repositories of specimens described and strictly identified by systematics specialists.

Methods

The present work aims to characterize eggs of capillariid species deposited in institutional helminth collections and to process the morphological, morphometric and ecological data using machine learning (ML) as a new approach for taxonomic identification. Specimens of 28 species and 8 genera deposited at Coleção Helmintológica do Instituto Oswaldo Cruz (CHIOC, IOC/FIOCRUZ/Brazil) and Collection de Nématodes Zooparasites du Muséum National d’Histoire Naturelle de Paris (MNHN/France) were examined under light microscopy. In the morphological and morphometric analyses (MM), the total length and width of eggs as well as plugs and shell thickness were considered. In addition, eggshell ornamentations and ecological parameters of the geographical location (GL) and host (H) were included.

Results

The performance of the logistic model tree (LMT) algorithm showed the highest values in all metrics compared with the other algorithms. Algorithm J48 produced the most reliable decision tree for species identification alongside REPTree. The Majority Voting algorithm showed high metric values, but the combined classifiers did not attenuate the errors revealed in each algorithm alone. The statistical evaluation of the dataset indicated a significant difference between trees, with GL + H + MM and MM only with the best scores.

Conclusions

The present research proposed a novel procedure for taxonomic species identification, integrating data from centenary biological collections and the logic of artificial intelligence techniques. This study will support future research on taxonomic identification and diagnosis of both modern and archaeological capillariids.

Graphical abstract
Correction to: Under pressure: phenotypic divergence and convergence associated with microhabitat adaptations in Triatominae
Authors: Abad-Franch Fernando , Monteiro Fernando A. , Pavan Márcio G. , Patterson James S. , Bargues M. Dolores , Zuriaga M. Ángeles , Aguilar Marcelo , Beard Charles B. , Mas-Coma Santiago , Miles Michael A.
Published: May 2021

An amendment to this paper has been published and can be accessed via the original article.
Correction to: Emergence of the invasive Asian bush mosquito, Aedes (Finlaya) japonicus japonicus, in an urban area, Romania
Authors: Horváth Cintia , Cazan Cristina Daniela , Mihalca Andrei Daniel
Published: April 2021

An amendment to this paper has been published and can be accessed via the original article.
Proteome study of cutaneous lupus erythematosus (CLE) and dermatomyositis skin lesions reveals IL-16 is differentially upregulated in CLE
Authors: Niewold Timothy B. , Meves Alexander , Lehman Julia S. , Popovic-Silwerfeldt Karin , Häyry Aliisa , Söderlund-Matell Therese , Charlesworth Cristine M. , Madden Benjamin , Lundberg Ingrid E. , Wahren-Herlenius Marie , Svenungsson Elisabet , Oke Vilija
Published: April 2021

Background

The objective of the study was to explore the disease pathways activated in the inflammatory foci of skin lesions in cutaneous lupus erythematosus (CLE) and dermatomyositis (DM).

Methods

Skin biopsies acquired from active CLE and DM lesions, patient (PC), and also healthy controls (HC) were investigated. Biopsy sections were examined by a pathologist, inflammatory foci were laser micro-dissected and captured, and proteins within captured tissue were detected in an unbiased manner by mass spectrometry. Protein pathway analysis was performed by the string-db.org platform. Findings of interest were confirmed by immunohistochemistry (IHC).

Results

Proteome investigation identified abundant expression of interferon-regulated proteins (IRP) as a common feature of CLE and DM. Interleukin (IL)-16 was the only abundant cytokine differentially expressed in CLE compared to DM. Caspase-3, an enzyme that cleaves IL-16 into its active form, was detected in low levels. Significantly higher proportion of IL-16- and caspase-3-positive cells was identified in CLE lesions in comparison with DM, PC, and HC. Proteomic results indicate more abundant complement deposition in CLE skin lesions.

Conclusions

Using unbiased mass spectrometry investigation of CLE and DM inflammatory infiltrates, we confirmed that high IRP expression is a common feature of both CLE and DM, while IL-16 is the only differentially expressed cytokine in CLE. IHC confirmed high expression of IL-16 and caspase-3 in CLE. Our novel molecular findings indicate that IL-16 detection could be useful in differential diagnostics between the two conditions that can display similar histopathological appearance. IL-16 could be of interest as a future therapeutic target for CLE.
Increased serum asprosin is correlated with diabetic nephropathy
Authors: Wang Rui , Lin Peng , Sun Huibo , Hu Wenchao
Published: May 2021

Objective

The adipokine asprosin, which was recently discovered, facilitates hepatic glucose production. The aim of this study is to see whether serum asprosin concentrations are linked to diabetic nephropathy (DN).

Methods

We performed this investigation in a group of 212 type 2 diabetes (T2DM) patients. These patients were classified into three subgroups: DN0 group (normal to mildly increased), DN1 group (moderately increased), and DN2 group (severely increased) on the basis of urine albumin-to-creatinine ratio (ACR).

Results

When compared to the controls, T2DM patients had higher serum asprosin levels. The DN2 group had significantly higher serum asprosin than the DN0 and DN1 groups. Furthermore, the DN1 group had higher serum asprosin than the DN0 group. Serum asprosin was linked to a higher risk of T2DM and DN in a logistic regression analysis. Serum asprosin was found to be positively related with disease duration, systolic blood pressure, blood urea nitrogen, creatinine, uric acid, ACR, calcium channel blockers, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy, but negatively related with glomerular filtration rate, metformin, and acarbose therapy.

Conclusion

Serum asprosin increase with the progression of DN. Serum asprosin is correlated with renal function and ACR.
Epigenetic landscape of testis specific histone H2B variant and its influence on sperm function
Authors: Patankar Aniket , Gajbhiye Rahul , Surve Suchitra , Parte Priyanka
Published: May 2021

Background

Biological relevance of the major testis specific histone H2B variant (TH2B) in sperm is not fully understood. Studies in TH2A/TH2B double knockout male mice indicate its role in chromatin compaction and male fertility. Additionally, the presence of TH2B and TH2A reportedly generates more dynamic nucleosomes, leading to an open chromatin structure characteristic of transcriptionally active genome. Given that mature human sperm are transcriptionally and translationally inactive, the presence of TH2B in mature sperm is intriguing. To address its role in sperm, we investigated the genome-wide localization of TH2B in sperm of fertile men.

Results

We have identified the genomic loci associated with TH2B in fertile human sperm by ChIP-seq analysis. Bioinformatic analysis revealed ~ 5% sperm genome and 5527 genes to be associated with TH2B. Out of these 105 (1.9%) and 144 (2.6%) genes showed direct involvement in sperm function and early embryogenesis, respectively. Chromosome wide analysis for TH2B distribution indicated its least distribution on X and Y chromosomes and varied distribution on autosomes. TH2B showed relatively higher percentage of gene association on chromosome 4, 18, 3 and 2. TH2B enrichment was more in promoter and gene body region. Gene Ontology (GO) analysis revealed signal transduction and associated kinase activity as the most enriched biological and molecular function, respectively. We also observed the enrichment of TH2B at developmentally important loci, such as HOXA and HOXD and on genes required for normal sperm function, few of which were validated by ChIP-qPCR. The relative expression of these genes was altered in particular subgroup of infertile men showing abnormal chromatin packaging. Chromatin compaction positively correlated with sperm- motility, concentration, viability and with transcript levels of PRKAG2 and CATSPER B.

Conclusion

ChIP-seq analysis of TH2B revealed a putative role of TH2B in sperm function and embryo development. Altered expression of TH2B associated genes in infertile individuals with sperm chromatin compaction defects indicates involvement of TH2B in transcriptional regulation of these genes in post meiotic male germ cells. This altered transcriptome may be a consequence or cause of abnormal nuclear remodeling during spermiogenesis.
Artificial intelligence-based computational framework for drug-target prioritization and inference of novel repositionable drugs for Alzheimer’s disease
Authors: Tsuji Shingo , Hase Takeshi , Yachie-Kinoshita Ayako , Nishino Taiko , Ghosh Samik , Kikuchi Masataka , Shimokawa Kazuro , Aburatani Hiroyuki , Kitano Hiroaki , Tanaka Hiroshi
Published: May 2021

Background

Identifying novel therapeutic targets is crucial for the successful development of drugs. However, the cost to experimentally identify therapeutic targets is huge and only approximately 400 genes are targets for FDA-approved drugs. As a result, it is inevitable to develop powerful computational tools that can identify potential novel therapeutic targets. Fortunately, the human protein-protein interaction network (PIN) could be a useful resource to achieve this objective.

Methods

In this study, we developed a deep learning-based computational framework that extracts low-dimensional representations of high-dimensional PIN data. Our computational framework uses latent features and state-of-the-art machine learning techniques to infer potential drug target genes.

Results

We applied our computational framework to prioritize novel putative target genes for Alzheimer’s disease and successfully identified key genes that may serve as novel therapeutic targets (e.g., DLG4, EGFR, RAC1, SYK, PTK2B, SOCS1). Furthermore, based on these putative targets, we could infer repositionable candidate-compounds for the disease (e.g., tamoxifen, bosutinib, and dasatinib).

Conclusions

Our deep learning-based computational framework could be a powerful tool to efficiently prioritize new therapeutic targets and enhance the drug repositioning strategy.
Interaction between early-life pet exposure and methylation pattern of ADAM33 on allergic rhinitis among children aged 3–6 years in China
Authors: Zhang Yu , Tan Meiyu , Qian Xiaoqiong , Li Cong , Yue Lei , Liu Yuehong , Shi Song
Published: May 2021

Background

Recent research has pointed out the important roles of epigenetic modifications in the development and persistence of allergic rhinitis (AR), especially in relation to DNA methylation of disease-associated genes. We investigated whether AR susceptibility genes were epigenetically regulated, and whether methylation modulation of these genes in response to early-life environment could be a molecular mechanism underlying the risk for AR onset in a cohort of children aged 3–6 years in China.

Methods

Peripheral blood mononuclear cell (PBMC) samples were collected from 130 children patients, aged 3–6 years and diagnosed with AR; and 154 matched controls to detect promoter methylation in 25 AR susceptibility genes with the MethylTarget approach. Methylation levels were compared for each CpG site, each amplified region, and each gene. In addition, the relationship among DNA methylation, early-life environmental risk factors and AR onset were assessed.

Results

Maternal allergic history (P = 0.0390) and pet exposure (P = 0.0339) were significantly associated with increased AR risk. Differential methylation analyses were successfully performed for 507 CpG sites, 34 amplified regions and 17 genes and significant hypomethylation was observed in the promoter region of ADAM33 in AR patients [multiple test-corrected (FDR) P-value < 0.05]. Spearman correlation analysis revealed that the hypomethylation of ADAM33 was significantly associated with higher eosinophil counts (Spearman’s ρ: − 0.187, P-value = 0.037). According to the results of the multiple regression analysis, after adjusting for cofounders, the interaction of early-life pet exposure with methylation level of ADAM33 increased the risk for AR onset 1.423 times more in children (95% CI = 0.0290–4.109, P-value = 0.005).

Conclusion

This study provides evidence that early-life pet exposure and low methylation level of ADAM33 increase AR risk in children, and the interaction between pet exposure and methylation level of ADAM33 may play an important role in the development of AR.
CT facilitates improved diagnosis of adult intestinal malrotation: a 7-year retrospective study based on 332 cases
Authors: Xiong Ziman , Shen Yaqi , Morelli John N. , Li Zhen , Hu Xuemei , Hu Daoyu
Published: April 2021

Objective

To classify adult intestinal malrotation by CT.

Methods

This retrospective study enrolled adults diagnosed with intestinal malrotation who underwent abdominal CT at our institution between June 1, 2013, and August 30, 2020. All patients’ clinical information was recorded. Patients were divided into groups undergoing surgical and conservative management. The duodenum (nonrotation, partial rotation, and malrotation), jejunum, cecum, and the superior mesenteric artery/superior mesenteric vein relationship were reviewed on the CT images of each patient, and classification criteria developed based on the first three items. For each patient, each item was assessed separately by three radiologists. Consensus was required from at least two of them.

Results

A total of 332 eligible patients (218 men and 114 women; mean age 51.0 ± 15.3 years) were ultimately included and classified into ten types of malrotation. Duodenal partial rotation was present in most (73.2%, 243/332) with only 25% (83/332) demonstrating nonrotation. The jejunum was located in the right abdomen in 98.2% (326/332) of cases, and an ectopic cecum was found in only 12% (40/332, 29 cases with a left cecum, 7 pelvic, and 4 at midline). Asymptomatic patients comprised 56.6% (188/332) of cases, much higher than that in previous studies (17%, n = 82, p < .001), comprised mainly of patients with duodenal partial rotation (80.3%, 151/188). In 91 patients with detailed clinical data available (12 managed surgically and 79 conservatively), a significant difference in malrotation CT categorization was identified (p = .016).

Conclusions

CT enables greater detection of asymptomatic intestinal malrotation, enabling classification into multiple potentially clinically relevant subtypes.
Severe COVID-19 in the intensive care unit: a case series
Authors: Hariyanto Hori , Yahya Corry Quando , Aritonang Ronald Christian Agustinus
Published: May 2021

Background

Coronavirus disease 2019 (COVID-19) was first identified in Indonesia in March 2020, and the number of infections has grown exponentially. The situation is at its worst, overwhelming intensive care unit (ICU) resources and capacity.

Case presentation

This is a single-center observational case study of 21 confirmed COVID-19 patients admitted to the ICU from March 20, 2020, to April 31, 2020. Demographics, baseline comorbidities, clinical symptoms, laboratory tests, electrocardiogram (ECG) and chest imaging were obtained consecutively during patient care. We identified 21 patients with confirmed COVID-19 severe infection in our ICU. The mean (± standard deviation) age of the patients was 54 ± 10 years; 95% were men, with shortness of breath (90.6%) the most common symptom. Hypertension was identified as a comorbidity in 28.6% of patients. The most common reason for admission to the ICU was hypoxemic respiratory failure, with 80% (17 patients) requiring mechanical ventilation. Half of the patients (10) died between day 1 and day 18, with septic shock as the primary cause of death. Of the 11 surviving patients, five were discharged home, while six were discharged from the ICU but remained in the hospital ward. Even then, the median length of ICU stay amongst survivors was 18 days.

Conclusions

To date, there are no known effective antiviral agents or specific therapy to treat COVID-19. As severe systemic inflammatory response and multiple organ failure seems to be the primary cause of death, supportive care in maintaining oxygenation and hemodynamic stability remain the mainstay goals in treating critically ill COVID-19 patients.
Successful treatment of acute promyelocytic leukemia in a patient with prosthetic heart valves: a case report and review of the literature
Authors: Haghighat Shirin , Rezvani Alireza , Mokhtari Maral
Published: May 2021

Background

Although life-threatening hemorrhage is a usual manifestation of acute promyelocytic leukemia (APL), thrombotic events seem to be more common in APL compared to other subtypes of acute leukemia. The treatment and prophylaxis of thrombosis are controversial due to the high risk of bleeding caused by disseminated intravascular coagulation (DIC) and thrombocytopenia. To the best of our knowledge we report the first case of APL in a patient with prosthetic heart valves successfully treated with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). We hope this case report helps clinicians to manage different spectra of coagulopathy in APL successfully.

Case presentation

A 38-year-old Asian man presented with diagnosis of APL confirmed by bone marrow biopsy. He was on warfarin due to prosthetic mitral and aortic valves. He was at risk of both hemorrhagic events due to DIC and life-threatening valve thrombosis. Our management regimen included unfractionated heparin adjusted according to the platelet count to prevent both valve thrombosis and bleeding events. The patient tolerated treatment well without any hemorrhagic or thrombotic events, and complete molecular remission was achieved by ATRA and ATO without the need for chemotherapeutic agents.

Conclusion

Although this case is exceptional, a precise evaluation may be needed to select the appropriate dose and type of anticoagulant to treat a patient with APL.
Combined topical and systemic administration with human adipose-derived mesenchymal stem cells (hADSC) and hADSC-derived exosomes markedly promoted cutaneous wound healing and regeneration
Authors: Zhou Yang , Zhao Bo , Zhang Xin-Liao , Lu Yi-jun , Lu Shou-Tao , Cheng Jian , Fu Yu , Lin Lin , Zhang Ning-Yan , Li Pei-Xin , Zhang Jing , Zhang Jun
Published: May 2021

Background

Cutaneous wound healing and regeneration have become a recognized health challenge in the world, which causes severe damage to the mental and physical health of patients. Human adipose-derived mesenchymal stem cells (hADSC) play an essential role in wound healing via their paracrine function. Exosomes secreted by hADSC may contribute to this progress. In this study, we investigated the potential clinical application roles of hADSC and hADSC-derived exosomes (hADSC-Exo) in cutaneous wound healing.

Methods

hADSC-Exo was isolated from human hADSC by ultracentrifugation. Mice were subjected to a full-thickness skin biopsy experiment and treated with either control vehicle or hADSC or hADSC-Exo by smearing administration (sm) or subcutaneous administration (sc) or intravenous administration (iv). The efficacy of hADSC and hADSC-Exo on wound healing was evaluated by measuring wound closure rates, histological analysis.

Results

Combined application of local hADSC-Exo smearing and hADSC/hADSC-Exo intravenous administration offered the additional benefit of promoting wound healing, accelerating re-epithelialization, reducing scar widths, and enhancing angiogenesis and collagen synthesis. Either topical application of hADSC-Exo or systemic administration with hADSC/hADSC-Exo appeared more effective in stimulating cell proliferation, inhibiting cell apoptosis and inflammation, and promoting skin elasticity and barrier integrity, with increased genes expression of PCNA, VEGF, collagen III, Filaggrin, Loricrin, and AQP3, with decreased genes expression of TNF-alpha.

Conclusion

Our findings suggest that the combined administration of hADSC/hADSC-Exo can facilitate cutaneous wound healing and reduce scar formation. These data provide the first evidence for the feasibility of smearing of hADSC-Exo as a cell-free therapy in treating cutaneous wounds, and the potential clinical value of combined administration of hADSC/hADSC-Exo.
Upregulating CXCR7 accelerates endothelial progenitor cell-mediated endothelial repair by activating Akt/Keap-1/Nrf2 signaling in diabetes mellitus
Authors: Jiang Chunyu , Li Ruiting , Xiu Chaoyang , Ma Xu , Hu Hui , Wei Liming , Tang Yihan , Tao Mingyang , Zhao Jungong
Published: May 2021

Background

Endothelial progenitor cell (EPC) dysfunction contributes to vascular disease in diabetes mellitus. However, the molecular mechanism underlying EPC dysfunction and its contribution to delayed reendothelialization in diabetes mellitus remain unclear. Our study aimed to illustrate the potential molecular mechanism underlying diabetic EPC dysfunction in vivo and in vitro. Furthermore, we assessed the effect of EPC transplantation on endothelial regeneration in diabetic rats.

Methods

Late outgrowth EPCs were isolated from the bone marrow of rats for in vivo and in vitro studies. In vitro functional assays and Western blotting were conducted to reveal the association between C-X-C chemokine receptor type 7 (CXCR7) expression and diabetic EPC dysfunction. To confirm the association between cellular CXCR7 levels and EPC function, CXCR7 expression in EPCs was upregulated and downregulated via lentiviral transduction and RNA interference, respectively. Western blotting was used to reveal the potential molecular mechanism by which the Stromal-Derived Factor-1 (SDF-1)/CXCR7 axis regulates EPC function. To elucidate the role of the SDF-1/CXCR7 axis in EPC-mediated endothelial regeneration, a carotid artery injury model was established in diabetic rats. After the model was established, saline-treated, diabetic, normal, or CXCR7-primed EPCs were injected via the tail vein.

Results

Diabetic EPC dysfunction was associated with decreased CXCR7 expression. Furthermore, EPC dysfunction was mimicked by knockdown of CXCR7 in normal EPCs. However, upregulating CXCR7 expression reversed the dysfunction of diabetic EPCs. The SDF-1/CXCR7 axis positively regulated EPC function by activating the AKT-associated Kelch-like ECH-associated protein 1 (keap-1)/nuclear factor erythroid 2-related factor 2 (Nrf2) axis, which was reversed by blockade of AKT and Nrf2. Transplantation of CXCR7-EPCs accelerated endothelial repair and attenuated neointimal hyperplasia in diabetes mellitus more significantly than transplantation of diabetic or normal EPCs. However, the therapeutic effect of CXCR7-EPC transplantation on endothelial regeneration was reversed by knockdown of Nrf2 expression.

Conclusions

Dysfunction of diabetic EPCs is associated with decreased CXCR7 expression. Furthermore, the SDF-1/CXCR7 axis positively regulates EPC function by activating the AKT/keap-1/Nrf2 axis. CXCR7-primed EPCs might be useful for endothelial regeneration in diabetes-associated vascular disease.
Identification of a clinical signature predictive of differentiation fate of human bone marrow stromal cells
Authors: Kowal Justyna Magdalena , Möller Sören , Ali Dalia , Figeac Florence , Barington Torben , Schmal Hagen , Kassem Moustapha
Published: May 2021

Background

Transplantation of human bone marrow stromal cells (hBMSCs) is a promising therapy for bone regeneration due to their ability to differentiate into bone forming osteoblastic cells. However, transplanted hBMSCs exhibit variable capacity for bone formation resulting in inconsistent clinical outcome. The aim of the study was to identify a set of donor- and cell-related characteristics that detect hBMSCs with optimal osteoblastic differentiation capacity.

Methods

We collected hBMSCs from 58 patients undergoing surgery for bone fracture. Clinical profile of the donors and in vitro characteristics of cultured hBMSCs were included in uni- and multivariable analysis to determine their predictive value for osteoblastic versus adipocytic differentiation capacity assessed by quantification of mineralized matrix and mature adipocyte formation, respectively.

Results

We identified a signature that explained > 50% of variation in osteoblastic differentiation outcome which included the following positive predictors: donor sex (male), absence of osteoporosis diagnosis, intake of vitamin D supplements, higher fraction of CD146+, and alkaline phosphate (ALP+) cells. With the exception of vitamin D and ALP+ cells, these variables were also negative predictors of adipocytic differentiation.

Conclusions

Using a combination of clinical and cellular criteria, it is possible to predict differentiation outcome of hBMSCs. This signature may be helpful in selecting donor cells in clinical trials of bone regeneration.
A novel strategy for isolation of mice bone marrow endothelial cells (BMECs)
Authors: Smith Alhaji Osman , Adzraku Seyram Yao , Ju Wen , Qiao Jianlin , Xu Kailin , Zeng Lingyu
Published: May 2021

Background

In the bone marrow microenvironment (BM), endothelial cells are individual cells that form part of the sinusoidal blood vessels called the “bone marrow endothelial-vascular niche.” They account for less than 2% of the bone marrow cells. They play essential functions by generating growth and inhibitory factors that promote the hematopoietic stem cells (HSCs) regulation. In response to inflammatory stimuli, the BMECs increase in proliferation to maintain the blood vessels’ integrity within the BM. The inflammatory response releases cytokines such as tumor necrosis factor-alpha (TNF-α) that promote vascular endothelial cells’ expansion and upregulation of adhesion molecules (ICAM-1 and VCAM-1, respectively) in the BM. However, the evaluation of mouse BMECs in the bone marrow microenvironment is scared by a lack of mouse bone marrow endothelial cell primary culture

Methods

Two steps approach for isolation of bone marrow endothelial cells (BMECs) from mice. In brief, the bone marrow cells extracted from the mice long bones were cultured overnight with Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 20% fetal bovine serum (FBS) and antibiotics to separate between marrow-derived adherent and non-adherent cells. The floating cells were discarded, and the adhered section detached with accutase and BMECs selected using CD31 microbeads. The isolated BMECs were cultured in a dish pre-coated with rat-tail collagen type 1 with endothelial cells medium supplement with growth factors. The cells were verified by confocal microscopy for morphology and tube formation by matrigel assay. We validate the cells’ purity by flow cytometry, RT-qPCR, immunofluorescence staining, and immunoblotting by established BMEC markers, PECAM-1, VE-cadherin, vascular endothelial cell growth factor receptor-2 (VEGFR2), CD45, E-selectin, and endothelial selectin adhesion molecule (ESAM). Lastly, we characterize BMEC activation with recombinant TNF-α.

Results

Our method clearly defined the cells isolated have the characteristics of BMECs with the expression of CD31, VE-cadherin, E-selectin, VEGFR-2, and ESAM. The cells’ response to TNF-α indicates its inflammatory function by increasing proliferation and upregulation of adhesion molecules.

Conclusions

This study outline a simple new technique of isolating mouse BMEC primary culture and a suitable method to evaluate the function and dysregulation of BMEC in in vitro studies using mouse models.
Clinical-grade human dental pulp stem cells suppressed the activation of osteoarthritic macrophages and attenuated cartilaginous damage in a rabbit osteoarthritis model
Authors: Li Pei-Lin , Wang Yu-Xing , Zhao Zhi-Dong , Li Zhi-Ling , Liang Jia-Wu , Wang Qian , Yin Bo-Feng , Hao Rui-Cong , Han Meng-Yue , Ding Li , Wu Chu-Tse , Zhu Heng
Published: May 2021

Background

Although increasing evidence has demonstrated that human dental pulp stem cells (hDPSCs) are efficacious for the clinical treatment of skeletal disorders, the underlying mechanisms remain incompletely understood. Osteoarthritis (OA) is one of the most common degenerative disorders in joints and is characterized by gradual and irreversible cartilaginous tissue damage. Notably, immune factors were newly identified to be closely related to OA development. In this study, we explored the modulatory effects of clinical-grade hDPSCs on osteoarthritic macrophages and their protective effects on cartilaginous tissues in OA joints.

Methods

The cell morphology, immunophenotype, and inflammatory factor expression of osteoarthritic macrophages were explored by phase contrast microscope, transmission electron microscopy, immunostaining, flow cytometry, quantitative polymerase chain reaction, and enzyme linked immunosorbent assay, respectively. Additionally, the factors and signaling pathways that suppressed macrophage activation by hDPSCs were determined by enzyme-linked immunosorbent assay and western-blotting. Furthermore, hDPSCs were administered to a rabbit knee OA model via intra-articular injection. Macrophage activation in vivo and cartilaginous tissue damage were also evaluated by pathological analysis.

Results

We found that hDPSCs markedly inhibited osteoarthritic macrophage activation in vitro. The cell morphology, immunophenotype, and inflammatory factor expression of osteoarthritic macrophages changed into less inflammatory status in the presence of hDPSCs. Mechanistically, we observed that hDPSC-derived hepatocyte growth factor and transforming growth factor β1 mediated the suppressive effects on osteoarthritic macrophages. Moreover, phosphorylation of MAPK pathway proteins contributed to osteoarthritic macrophage activation, and hDPSCs suppressed their activation by partially inactivating those pathways. Most importantly, injected hDPSCs inhibited macrophage activation in osteochondral tissues in a rabbit knee OA model in vivo. Further histological analysis showed that hDPSCs alleviated cartilaginous damage to knee joints.

Conclusions

In summary, our findings reveal a novel function for hDPSCs in suppressing osteoarthritic macrophages and suggest that macrophages are efficient cellular targets of hDPSCs for alleviation of cartilaginous damage in OA.

Graphical abstract

hDPSCs treat OA via an osteoarthritic macrophages-dependent mechanisms. hDPSCs suppress the activation of osteoarthritic macrophages in vitro and in vivo and alleviate cartilaginous lesions in OA models.