bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of denosumab switched from bisphosphonates in preventing joint destruction in postmenopausal rheumatoid arthritis patients with anti-cyclic citrullinated peptide antibodies
Authors: Mori Yu , Izumiyama Takuya , Kurishima Hiroaki , Kamimura Masayuki , Baba Kazuyoshi , Mori Naoko , Itoi Eiji
Published: February 2021

Introduction

This study aimed to determine the effects of denosumab treatment on the joint destruction of Japanese females with rheumatoid arthritis (RA) and anti-cyclic citrullinated peptide (CCP) antibodies.

Materials and methods

This retrospective longitudinal study included 56 patients treated with denosumab and 50 patients treated with bisphosphonate. All participants were positive for anti-CCP antibodies. All patients also had a history of osteoporosis treatment with bisphosphonate, which was either continued or switched to 60 mg of subcutaneous denosumab injection every 6 months. To assess the progression of joint destruction, hand and foot radiographs were taken, and changes in modified total Sharp score (mTSS), erosion score (ERO), and joint space narrowing score (JSN) were evaluated at 12 months and 24 months. The changes in BMD of the lumbar spine and hip were also assessed at 12 months.

Results

At 12 months, there were significant differences in the change of ERO (p = 0.015) and mTSS (p = 0.01). Similarly, there were significant differences in the change of ERO (p = 0.013) and mTSS (p = 0.003) at 24 months. In contrast, no significant difference was observed in the changes of JSN and clinical parameters. There were significant differences in the changes in BMD in the femoral neck (p = 0.011) and total hip (p = 0.012).

Conclusion

Denosumab treatment might be effective for the inhibition of bone erosion progression in the patients with RA, and it potentially contributes to the treatment of osteoporosis and prevention of destructive arthritis in patients with switching treatment from bisphosphonate.
Bi-allelic amplification of ATM gene in blastoid variant of mantle cell lymphoma: a novel mechanism of inactivation due to chromoanagenesis?
Authors: Ortega Veronica , Mendiola Christina , Rodriguez Juana , Ehman William , Qian You-Wen , Velagaleti Gopalrao
Published: February 2021

Background

Mantle cell lymphoma (MCL) is derived from naïve CD5+ B-cells with the cytogenetic hallmark translocation 11;14. The presence of additional abnormalities is associated with blastoid variants in MCL (BMCL) and confers a poor prognosis. Many of these tumors also show deletion or loss of heterozygosity (LOH) of the ATM gene and biallelic ATM inactivation show significantly higher chromosomal imbalances.

Case presentation

Here we report a 52 year-old male who presented to the clinic with worsening dyspnea, fever, chills, diffuse lymphadenopathy, splenomegaly and leukocytosis with blastoid cells circulating in blood. The bone marrow aspirate showed about 40% abnormal blast-looking cells and biopsy revealed a remarkable lymphoid infiltrate. The patient was diagnosed with blastoid variant mantle cell lymphoma (BMCL). Chromosome analysis on bone marrow showed a complex karyotype. FISH analysis from B-cell lymphoma panel showed bi-allelic amplification of ATM gene. Other abnormalities were present including CCND1/IGH fusion, confirming the MCL diagnosis, in addition to RB1 and p53 deletion. High resolution SNP-microarray studies showed complex copy number changes, especially on chromosomes 7 and 11, consistent with chromoanagenesis. Microarray studies also showed LOH at the ATM locus indicating the amplification seen on FISH is not biallelic.

Conclusion

To the best of our knowledge, ATM gene amplification is not previously reported in BMCL and our case suggests a novel mechanism of ATM inactivation caused by chromoanagenesis resulting in mutant allele specific imbalance with copy number gain.
Retraction Note: LncRNA TUG1 promoted KIAA1199 expression via miR-600 to accelerate cell metastasis and epithelial-mesenchymal transition in colorectal cancer
Authors: Sun Junfeng , Hu Jiyi , Wang Guojun , Yang Zhen , Zhao Chunlin , Zhang Xiefu , Wang Jiaxiang
Published: February 2021

An amendment to this paper has been published and can be accessed via the original article.
Actin-like protein 6A/MYC/CDK2 axis confers high proliferative activity in triple-negative breast cancer
Authors: Jian Yunting , Huang Xinjian , Fang Lishan , Wang Meng , Liu Qinghua , Xu Hongyi , Kong Lingzhi , Chen Xiangfu , Ouyang Ying , Wang Xi , Wei Weidong , Song Libing
Published: February 2021

Background

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high proliferative activity. TNBC tumors exhibit elevated MYC expression and altered expression of MYC regulatory genes, which are associated with tumor progression and poor prognosis; however, the underlying mechanisms by which MYC retains its high expression and mediates TNBC tumorigenesis require further exploration.

Methods

ACTL6A regulation of MYC and its target gene, CDK2, was defined using Co-IP, mass spectrometry and ChIP assays. To study the role of ACTL6A in TNBC, we performed soft-agar, colony formation, flow cytometry and tumor formation in nude mice. CDK2 inhibitor and paclitaxel were used in testing combination therapy in vitro and in vivo.

Results

ACTL6A bound MYC to suppress glycogen synthase kinase 3 beta (GSK3β)-induced phosphorylation on MYC T58, which inhibited ubiquitination of MYC and stabilized it. Moreover, ACTL6A promoted the recruitment of MYC and histone acetyltransferase KAT5 on CDK2 promoters, leading to hyperactivation of CDK2 transcription. ACTL6A overexpression promoted, while silencing ACTL6A suppressed cell proliferation and tumor growth in TNBC cells in vitro and in vivo, which was dependent on MYC signaling. Furthermore, co-therapy with paclitaxel and CDK2 inhibitor showed synergistic effects in tumor suppression. Notably, ACTL6A/MYC/CDK2 axis was specifically up-regulated in TNBC and high expression of ACTL6A was correlated to shorter survival in patients with TNBC.

Conclusions

These findings reveal a novel mechanism by which ACTL6A prolongs the retention of MYC in TNBC and suggest that pharmacological targeting ACTL6A/MYC/CDK2 axis might have therapeutic potential in patients with TNBC.
Long non-coding RNA CCDC183-AS1 acts AS a miR-589-5p sponge to promote the progression of hepatocellular carcinoma through regulating SKP1 expression
Authors: Zhu He , Zhang Hongwei , Pei Youliang , Liao Zhibin , Liu Furong , Su Chen , Liu Yachong , Dong Renshun , Song Jia , Zhang Xuewu , Fan Yawei , Liang Huifang , Zhang Bixiang , Chen Xiaoping
Published: February 2021

Background

Hepatocellular carcinoma (HCC) is a common type of malignant human cancer with high morbidity and poor prognosis, causing numerous deaths per year worldwide. Growing evidence has been demonstrated that long non-coding RNAs (lncRNAs) are closely associated with hepatocarcinogenesis and metastasis. However, the roles, functions, and working mechanisms of most lncRNAs in HCC remain poorly defined.

Methods

Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression level of CCDC183-AS1 in HCC tissues and cell lines. Cell proliferation, migration and invasion ability were evaluated by CCK-8 and transwell assay, respectively. Animal experiments were used to explore the role of CCDC183-AS1 and miR-589-5p in vivo. Bioinformatic analysis, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to confirm the regulatory relationship between CCDC183-AS1, miR-589-5p and SKP1.

Results

Significantly upregulated expression of CCDC183-AS1 was observed in both HCC tissues and cell lines. HCC patients with higher expression of CCDC183-AS1 had a poorer overall survival rate. Functionally, overexpression of CCDC183-AS1 markedly promoted HCC cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo, whereas the downregulation of CCDC183-AS1 exerted opposite effects. MiR-589-5p inhibitor counteracted the proliferation, migration and invasion inhibitory effects induced by CCDC183-AS1 silencing. Mechanistically, CCDC183-AS1 acted as a ceRNA through sponging miR-589-5p to offset its inhibitory effect on the target gene SKP1, then promoted the tumorigenesis of HCC.

Conclusions

CCDC183-AS1 functions as an oncogene to promote HCC progression through the CCDC183-AS1/miR-589-5p/SKP1 axis. Our study provided a novel potential therapeutic target for HCC patients.
Angiopoietin-2 outperforms other endothelial biomarkers associated with severe acute kidney injury in patients with severe sepsis and respiratory failure
Authors: Yu Wen-Kuang , McNeil J. Brennan , Wickersham Nancy E. , Shaver Ciara M. , Bastarache Julie A. , Ware Lorraine B.
Published: February 2021

Background

Endothelial dysfunction and injury is a major pathophysiologic feature of sepsis. Sepsis is also the most frequent cause of acute kidney injury (AKI) in critically ill patients. Though most studies of AKI in sepsis have focused on tubular epithelial injury, the role of endothelial dysfunction and injury is less well studied. The goal of this study was first to investigate whether endothelial dysfunction and injury biomarkers were associated with severe AKI in sepsis patients. The second goal was to determine the best performing biomarker for severe AKI and whether this biomarker was associated with severe AKI across different etiologies of sepsis and clinical outcomes.

Methods

We studied adults with severe sepsis and acute respiratory failure (ARF) enrolled in the prospective observational Validating Acute Lung Injury markers for Diagnosis (VALID) study. Plasma endothelial dysfunction and injury biomarkers, including angiopoietin-2, soluble vascular endothelial cadherin (sVE-cadherin), endocan and syndecan-1, were measured at study enrollment. Primary analysis focused on the association between endothelial biomarker levels with severe AKI (defined as Kidney Disease: Improving Global Outcomes [KDIGO] AKI stage 2 or 3), other organ dysfunctions (defined by Brussels organ failure scores), and comparison of pulmonary versus non-pulmonary sepsis.

Results

Among 228 sepsis patients enrolled, 141 developed severe AKI. Plasma levels of angiopoietin-2, endocan, sVE-cadherin, and syndecan-1 were significantly higher in sepsis patients with severe AKI compared to those without severe AKI. Among four endothelial biomarkers, only angiopoietin-2 was independently associated with severe AKI (odds ratio 6.07 per log increase, 95% CI 2.34–15.78, p < 0.001). Plasma angiopoietin-2 levels by quartile were significantly higher in sepsis patients with hepatic, coagulation, and circulatory failure. Plasma angiopoietin-2 levels were also significantly higher in patients with non-pulmonary sepsis compared to subjects with pulmonary sepsis.

Conclusion

Among four biomarkers of endothelial dysfunction and injury, angiopoietin-2 had the most robust independent association with development of severe AKI in patients with severe sepsis and ARF. Plasma angiopoietin-2 levels were also associated with other organ dysfunctions, non-pulmonary sepsis, and death. These findings highlight the importance of early endothelial dysfunction and injury in the pathogenesis of sepsis-induced AKI.
Age-dependent VDR peak DNA methylation as a mechanism for latitude-dependent multiple sclerosis risk
Authors: Ong Lawrence T. C. , Schibeci Stephen D. , Fewings Nicole L. , Booth David R. , Parnell Grant P.
Published: February 2021

Background

The mechanisms linking UV radiation and vitamin D exposure to the risk of acquiring the latitude and critical period-dependent autoimmune disease, multiple sclerosis, is unclear. We examined the effect of vitamin D on DNA methylation and DNA methylation at vitamin D receptor binding sites in adult and paediatric myeloid cells. This was accomplished through differentiating CD34+ haematopoietic progenitors into CD14+ mononuclear phagocytes, in the presence and absence of calcitriol.

Results

Few DNA methylation changes occurred in cells treated with calcitriol. However, several VDR-binding sites demonstrated increased DNA methylation in cells of adult origin when compared to cells of paediatric origin. This phenomenon was not observed at other transcription factor binding sites. Genes associated with these sites were enriched for intracellular signalling and cell activation pathways involved in myeloid cell differentiation and adaptive immune system regulation.

Conclusion

These results suggest vitamin D exposure at critical periods during development may contribute to latitude-related differences in autoimmune disease incidence.
The role of point-of-care ultrasound in the diagnosis of pericardial effusion: a single academic center retrospective study
Authors: Hanson Matthew G. , Chan Barry
Published: February 2021

Background

Symptomatic pericardial effusion (PCE) presents with non-specific features and are often missed on the initial physical exam, chest X-ray (CXR), and electrocardiogram (ECG). In extreme cases, misdiagnosis can evolve into decompensated cardiac tamponade, a life-threatening obstructive shock. The purpose of this study is to evaluate the impact of point-of-care ultrasound (POCUS) on the diagnosis and therapeutic intervention of clinically significant PCE.

Methods

In a retrospective chart review, we looked at all patients between 2002 and 2018 at a major Canadian academic hospital who had a pericardiocentesis for clinically significant PCE. We extracted the rate of presenting complaints, physical exam findings, X-ray findings, ECG findings, time-to-diagnosis, and time-to-pericardiocentesis and how these were impacted by POCUS.

Results

The most common presenting symptom was dyspnea (64%) and the average systolic blood pressure (SBP) was 120 mmHg. 86% of people presenting had an effusion > 1 cm, and 89% were circumferential on departmental echocardiogram (ECHO) with 64% having evidence of right atrial systolic collapse and 58% with early diastolic right ventricular collapse. The average time-to-diagnosis with POCUS was 5.9 h compared to > 12 h with other imaging including departmental ECHO. Those who had the PCE identified by POCUS had an average time-to-pericardiocentesis of 28.1 h compared to > 48 h with other diagnostic modalities.

Conclusion

POCUS expedites the diagnosis of symptomatic PCE given its non-specific clinical findings which, in turn, may accelerate the time-to-intervention.
Toxoplasma gondii in Sheep and Goats from Central Iran
Authors: Bahreh Mojtaba , Hajimohammadi Bahador , Eslami Gilda
Published: February 2021

Objective

Toxoplasmosis, caused by Toxoplasma gondii, infects humans by consuming infected raw or undercooked meat and foods harboring mature oocysts. In this study, we assessed the prevalence of T. gondii in sheep and goats coming from central Iran. After completing the questionnaire, about one gram of liver or diaphragm tissue was taken as a sample from 90 sheep and 90 goats slaughtered in Yazd Province and stored at – 20 ºC. DNA extraction was done, and then T. gondii was detected using nested PCR.

Results

This study indicated that the prevalence of T. gondii in all slaughtered animals was 11.6% (21 of 180), including 14.4% (13/90) in sheep and 8.8% (8/90) in goats. The infection rates in liver and diaphragm samples were 12.2% (11/90) and 11.1% (10/90), respectively (p = 0.8163). The infection rate in animals older than one was 16.3% (15/92), and it was 6.8% (6/88) in animals under one year of age. Therefore, no significant differences were found (p = 0.475). Infection rates were 19.5% (18/92) in males and 3.4% (3/88) in females (p = 0.0007). In conclusion, the infection rates of toxoplasmosis in livestock in this area are almost high, and therefore, it is necessary to design appropriate prevention programs to control the disease.
Genome-wide DNA methylation profiling is able to identify prefibrotic PMF cases at risk for progression to myelofibrosis
Authors: Lehmann Ulrich , Stark Helge , Bartels Stephan , Schlue Jerome , Büsche Guntram , Kreipe Hans
Published: February 2021

Background

Patients suffering from the BCR-ABL1-negative myeloproliferative disease prefibrotic primary myelofibrosis (pre-PMF) have a certain risk for progression to myelofibrosis. Accurate risk estimation for this fibrotic progression is of prognostic importance and clinically relevant. Commonly applied risk scores are based on clinical, cytogenetic, and genetic data but do not include epigenetic modifications. Therefore, we evaluated the assessment of genome-wide DNA methylation patterns for their ability to predict fibrotic progression in PMF patients.

Results

For this purpose, the DNA methylation profile was analyzed genome-wide in a training set of 22 bone marrow trephines from patients with either fibrotic progression (n = 12) or stable disease over several years (n = 10) using the 850 k EPIC array from Illumina. The DNA methylation classifier constructed from this data set was validated in an independently measured test set of additional 11 bone marrow trephines (7 with stable disease, 4 with fibrotic progress). Hierarchical clustering of methylation β-values and linear discriminant classification yielded very good discrimination between both patient groups. By gene ontology analysis, the most differentially methylated CpG sites are primarily associated with genes involved in cell–cell and cell–matrix interactions.

Conclusions

In conclusion, we could show that genome-wide DNA methylation profiling of bone marrow trephines is feasible under routine diagnostic conditions and, more importantly, is able to predict fibrotic progression in pre-fibrotic primary myelofibrosis with high accuracy.
Unusual deletion of the maternal 11p15 allele in Beckwith–Wiedemann syndrome with an impact on both imprinting domains
Authors: Eggermann Thomas , Begemann Matthias , Pfeiffer Lutz
Published: February 2021

Background

Whereas duplications in 11p15.5 covering both imprinting centers (ICs) and their subordinated genes account for up to 1% of Beckwith–Wiedemann and Silver–Russell syndrome patients (BWS, SRS), the deletions in 11p15.5 reported so far only affect one of the ICs. In these cases, not only the size and gene content had an impact on the phenotype, but also the sex of the contributing parent influences the clinical signs of the deletion carrier.

Results

We here report on the first case with a heterozygous deletion within the maternal allele affecting genes which are regulated by both ICs in 11p15.5 in a BWS patient, and describe the molecular and clinical consequences in case of its maternal or paternal inheritance.

Conclusions

The identification of a unique deletion affecting both 11p15.5 imprinting domains in a BWS patient illustrates the complexity of the regulation mechanisms in these key imprinting regions.
Comprehensive analysis of allergen-specific IgE in COPD: mite-specific IgE specifically related to the diagnosis of asthma-COPD overlap
Authors: Toyota Hikaru , Sugimoto Naoya , Kobayashi Konomi , Suzuki Yuki , Takeshita Yuri , Ito Ayaka , Ujino Mariko , Tomyo Fuminori , Sakasegawa Hirokazu , Koizumi Yuta , Kuramochi Michio , Yamaguchi Masao , Nagase Hiroyuki
Published: February 2021

Background

Although the relationship between allergic sensitization and increased respiratory symptoms of chronic obstructive pulmonary disease (COPD) has been suggested, which allergen has a significant effect on COPD pathology is unclear. This study aimed to identify the specific IgE related to clinical features of COPD and the diagnosis of asthma-COPD overlap (ACO).

Methods

We recruited 76 patients with COPD and analyzed 39 IgE using panel IgE test (View Allergy 39®). ACO was diagnosed according to the Japanese Respiratory Society Guidelines.

Results

As for perennial aeroallergens, the positivity for moth (31.5%), Candida (23.7%), Dermatophagoides pteronyssinus (22.4%) and house dust (22.4%), and concerning pollen, Japanese cedar (35.5%) and Japanese cypress (22.2%) exceeded 20%. Only the positivity of IgE for Dermatophagoides pteronyssinus and house dust was significantly higher in ACO compared with that in non-ACO COPD. Moreover, it contributed to the diagnosis of ACO in an IgE class-dependent manner. Patients with cockroach IgE exhibited higher residual volume, whereas those with Japanese cedar IgE exhibited better diffusion capacity than negative patients. The contribution for ACO diagnosis by the receiver operating characteristic curve analysis was comparable among total IgE (cutoff value: 158 IU/mL), blood eosinophil count (234/μL), and fraction of exhaled nitric oxide (31.0 ppb).

Conclusions

The prominent role of mite-specific IgE in the diagnosis and pathology of ACO and the potentially detrimental effect of cockroach sensitization on air trapping in COPD were suggested. The finding highlights the future development of a treatment targeting IgE as a treatable trait in COPD.
Klebsiella brain abscess in an immunocompetent patient: a case report
Authors: Wu Clay , Han Semi , Baydur Ahmet , Lindgren Brett
Published: February 2021

Background

Klebsiella pneumoniae brain abscesses are a rare entity and typically present in immunocompromised patients. We present a case of an overall healthy patient who developed a Klebsiella pneumoniae brain abscess in the absence of liver pathology.

Case presentation

A 46-year-old Vietnamese man with past medical history significant for hypertension presented to the hospital with acute on chronic worsening of altered mental status, personality changes, and gait dysfunction. Initial vitals revealed temperature of 37.1 °C, heart rate 87 beats/minute, blood pressure 150/87 mmHg, respiratory rate 18/minute, and oxygen saturation 99% on room air. Physical exam was notable for altered mental status, Glasgow Coma Scale (GCS) score of 14, and right lower facial droop. Cardiopulmonary exam was within normal limits. Head computed tomography (CT) showed a left frontotemporal mass, with subsequent brain magnetic resonance imaging (MRI) revealing a ring-enhancing lesion concerning for a brain abscess. The abscess was urgently drained; however, there was intraoperative spillage into the ventricles. Intraoperative cultures grew Klebsiella pneumoniae, and the patient was maintained on appropriate antibiotics. He developed worsening mental status, septic shock, and cerebral edema requiring decompressive left hemicraniectomy. Computed tomography of the abdomen and pelvis revealed no hepatic lesions. The patient did not improve, and the family elected for comfort measures.

Conclusion

High mortality is associated with Klebsiella pneumoniae (as opposed to Klebsiella oxytoca) brain abscesses, especially in the setting of intraventricular spread. This case illustrates the need for early detection, and an aggressive medical and surgical treatment approach is required for a potential favorable outcome.
The therapeutic applications of mesenchymal stromal cells from human perinatal tissues in autoimmune diseases
Authors: Yang Chao , Wu Mingjun , You Min , Chen Yu , Luo Maowen , Chen Qiang
Published: February 2021

The autoimmune diseases are characterized by overactivation of immune cells, chronic inflammation, and immune response to self-antigens, leading to the damage and dysfunction of multiple organs. Patients still do not receive desired clinical outcomes while suffer from various adverse effects imparted by current therapies. The therapeutic strategies based on mesenchymal stromal cell (MSC) transplantation have become the promising approach for the treatment of autoimmune diseases due to the immunomodulation property of MSCs. MSCs derived from perinatal tissues are collectively known as perinatal MSCs (PMSCs), which can be obtained via painless procedures from donors with lower risk of being contaminated by viruses than those MSCs from adult tissue sources. Therefore, PMSCs may be the ideal cell source for the treatment of autoimmune diseases. This article summarizes recent progress and possible mechanisms of PMSCs in treating autoimmune diseases in animal experiments and clinical studies. This review also presents existing challenges and proposes solutions, which may provide new hints on PMSC transplantation as a therapeutic strategy for the treatment of autoimmune diseases.
KAT6A regulates stemness of aging bone marrow-derived mesenchymal stem cells through Nrf2/ARE signaling pathway
Authors: Fei Dongdong , Wang Yazheng , Zhai Qiming , Zhang Xige , Zhang Yang , Wang Yang , Li Bei , Wang Qintao
Published: February 2021

Background

This study aimed to explore the effect of KAT6A on the decreased stemness of aging bone marrow-derived mesenchymal stem cells (BMSCs) and its potential mechanism.

Methods

The acetylation level and KAT6A expression of BMSCs from the young (YBMSCs) and the old (OBMSCs) were examined. Gain- and loss-of-function experiments were performed to determine the effect of KAT6A on BMSC proliferation, colony formation, and osteogenic differentiation. The effect of KAT6A on Nrf2/ARE signaling pathway was investigated after KAT6A inhibition in YBMSCs or overexpression in OBMSCs, and the role of Nrf2/ARE signaling pathway on stemness was examined by investigating proliferation, colony formation, and osteogenic differentiation. Further in vivo study was performed to explore osteogenesis ability of OBMSCs after modulation of KAT6A and Nrf2/ARE pathway through cell sheet technology.

Results

The acetylation level and KAT6A expression of OBMSCs were decreased, and KAT6A downregulation resulted in decreased proliferation, colony formation, and osteogenic differentiation of OBMSCs. Mechanically, KAT6A was found to regulate Nrf2/ARE signaling pathway and inhibit ROS accumulation in OBMSCs, thus promoting proliferation, colony formation, and osteogenic differentiation of OBMSCs. Further study demonstrated that KAT6A could promote osteogenesis of OBMSCs by regulating Nrf2/ARE signaling pathway.

Conclusions

Downregulation of KAT6A resulted in the decreased stemness of OBMSCs by inhibiting the Nrf2/ARE signaling pathway.

Graphical abstract

KAT6A was downregulated in aging bone marrow-derived mesenchymal stem cells (BMSCs), and downregulation of KAT6A resulted in Nrf2/ARE signaling pathway inhibition and ROS accumulation, thus leading to decreased stemness of aging BMSCs.
Mesenchymal stromal cells as prophylaxis for graft-versus-host disease in haplo-identical hematopoietic stem cell transplantation recipients with severe aplastic anemia?—a systematic review and meta-analysis
Authors: Li Ruonan , Tu Jingke , Zhao Jingyu , Pan Hong , Fang Liwei , Shi Jun
Published: February 2021

Background

Mesenchymal stromal cells (MSCs) are an emerging prophylaxis option for graft-versus-host disease (GVHD) in haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) recipients with severe aplastic anemia (SAA), but studies have reported inconsistent results. This systematic review and meta-analysis evaluates the efficacy of MSCs as prophylaxis for GVHD in SAA patients with haplo-HSCT.

Methods

Studies were retrieved from PubMed, EMBASE, Cochrane, Web of Science, and http://clinicaltrials.gov from establishment to February 2020. Twenty-nine single-arm studies (n = 1456) were included, in which eight (n = 241) studies combined with MSCs and eleven (n = 1215) reports without MSCs in haplo-HSCT for SAA patients. The primary outcomes were the incidences of GVHD. Other outcomes included 2-year overall survival (OS) and the incidence of cytomegalovirus (CMV) infection. Odds ratios (ORs) were calculated to compare the results pooled through random or fixed effects models.

Results

Between MSCs and no MSCs groups, no significant differences were found in the pooled incidences of acute GVHD (56.0%, 95% CI 48.6–63.5% vs. 47.2%, 95% CI 29.0–65.4%; OR 1.43, 95% CI 0.91–2.25; p = 0.123), grade II–IV acute GVHD (29.8%, 95% CI 24.1–35.5% vs. 30.6%, 95% CI 26.6–34.6%; OR 0.97, 95% CI 0.70–1.32; p = 0.889), and chronic GVHD (25.4%, 95% CI 19.8–31.0% vs. 30.0%, 95% CI 23.3–36.6%; OR 0.79, 95% CI 0.56–1.11; p = 0.187). Furtherly, there was no obvious difference in 2-year OS (OR 0.98, 95% CI 0.60–1.61; p = 1.000) and incidence of CMV infection (OR 0.61, 95% CI 0.40–1.92; p = 0.018).

Conclusions

Our meta-analysis indicates that the prophylactic use of MSC co-transplantation is not an effective option for SAA patients undergoing haplo-HSCT. Hence, the general co-transplantation of MSCs for SAA haplo-HSCT recipients may lack evidence-based practice.
Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation
Authors: Fan Xiaoqing , Yang Haoran , Zhao Chenggang , Hu Lizhu , Wang Delong , Wang Ruiting , Fang Zhiyou , Chen Xueran
Published: February 2021

Background

A large number of preclinical studies have shown that local anesthetics have a direct inhibitory effect on tumor biological activities, including cell survival, proliferation, migration, and invasion. There are few studies on the role of local anesthetics in cancer stem cells. This study aimed to determine the possible role of local anesthetics in glioblastoma stem cell (GSC) self-renewal and the underlying molecular mechanisms.

Methods

The effects of local anesthetics in GSCs were investigated through in vitro and in vivo assays (i.e., Cell Counting Kit 8, spheroidal formation assay, double immunofluorescence, western blot, and xenograft model). The acyl-biotin exchange method (ABE) assay was identified proteins that are S-acylated by zinc finger Asp-His-His-Cys-type palmitoyltransferase 15 (ZDHHC15). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to explore the mechanisms of ZDHHC15 in effects of local anesthetics in GSCs.

Results

In this study, we identified a novel mechanism through which local anesthetics can damage the malignant phenotype of glioma. We found that local anesthetics prilocaine, lidocaine, procaine, and ropivacaine can impair the survival and self-renewal of GSCs, especially the classic glioblastoma subtype. These findings suggest that local anesthetics may weaken ZDHHC15 transcripts and decrease GP130 palmitoylation levels and membrane localization, thus inhibiting the activation of IL-6/STAT3 signaling.

Conclusions

In conclusion, our work emphasizes that ZDHHC15 is a candidate therapeutic target, and local anesthetics are potential therapeutic options for glioblastoma.
STAT3 activation by catalpol promotes osteogenesis-angiogenesis coupling, thus accelerating osteoporotic bone repair
Authors: Chen Liang , Zhang Ri-Yan , Xie Jun , Yang Jia-Yi , Fang Kang-Hao , Hong Chen-Xuan , Yang Rong-Bo , Bsoul Najeeb , Yang Lei
Published: February 2021

Background

Bone fracture repair has gained a lot of attention due to the high incidence of delayed union or even nonunion especially in osteoporotic patients, resulting in a dreadful impact on the quality of life. However, current therapies involve the costly expense and hence become unaffordable strategies for fracture recovery. Herein, developing new strategies for better bone repair is essential and urgent. Catalpol treatment has been reported to attenuate bone loss and promote bone formation. However, the mechanisms underlying its effects remain unraveled.

Methods

Rat bone marrow mesenchymal stem cells (BMSCs) were isolated from rat femurs. BMSC osteogenic ability was assessed using ALP and ARS staining, immunofluorescence, and western blot analysis. BMSC-mediated angiogenic potentials were determined using the western blot analysis, ELISA testing, scratch wound assay, transwell migration assay, and tube formation assay. To investigate the molecular mechanism, the lentivirus transfection was used. Ovariectomized and sham-operated rats with calvaria defect were analyzed using micro-CT, H&E staining, Masson’s trichrome staining, microfil perfusion, sequential fluorescent labeling, and immunohistochemistry assessment after administrated with/without catalpol.

Results

Our results manifested that catalpol enhanced BMSC osteoblastic differentiation and promoted BMSC-mediated angiogenesis in vitro. More importantly, this was conducted via the JAK2/STAT3 pathway, as knockdown of STAT3 partially abolished beneficial effects in BMSCs. Besides, catalpol administration facilitated bone regeneration as well as vessel formation in an OVX-induced osteoporosis calvarial defect rat model.

Conclusions

The data above showed that catalpol could promote osteogenic ability of BMSC and BMSC-dependent angiogenesis through activation of the JAK2/STAT3 axis, suggesting it may be an ideal therapeutic agent for clinical medication of osteoporotic bone fracture.
ASFP (Artificial Intelligence based Scoring Function Platform): a web server for the development of customized scoring functions
Authors: Zhang Xujun , Shen Chao , Guo Xueying , Wang Zhe , Weng Gaoqi , Ye Qing , Wang Gaoang , He Qiaojun , Yang Bo , Cao Dongsheng , Hou Tingjun
Published: February 2021

Virtual screening (VS) based on molecular docking has emerged as one of the mainstream technologies of drug discovery due to its low cost and high efficiency. However, the scoring functions (SFs) implemented in most docking programs are not always accurate enough and how to improve their prediction accuracy is still a big challenge. Here, we propose an integrated platform called ASFP, a web server for the development of customized SFs for structure-based VS. There are three main modules in ASFP: (1) the descriptor generation module that can generate up to 3437 descriptors for the modelling of protein–ligand interactions; (2) the AI-based SF construction module that can establish target-specific SFs based on the pre-generated descriptors through three machine learning (ML) techniques; (3) the online prediction module that provides some well-constructed target-specific SFs for VS and an additional generic SF for binding affinity prediction. Our methodology has been validated on several benchmark datasets. The target-specific SFs can achieve an average ROC AUC of 0.973 towards 32 targets and the generic SF can achieve the Pearson correlation coefficient of 0.81 on the PDBbind version 2016 core set. To sum up, the ASFP server is a powerful tool for structure-based VS.
Inverse ray mapping in phase space for two-dimensional reflective optical systems
Authors: Filosa Carmela , ten Thije Boonkkamp Jan , IJzerman Wilbert
Published: February 2021

A new method to compute the target photometric variables of non-imaging optical systems is presented. The method is based on the phase space representation of each surface that forms the optical system. All surfaces can be modeled as detectors of the incident light and emitters of the reflected light. Moreover, we assume that the source can only emit light and the target can only receive light. Therefore, one phase space is taken into account for the source and one for the target. For the other surfaces both the source and target phase spaces are considered. The output intensity is computed from the rays that leave the source and hit the target. We implement the method for two-dimensional optical systems, and we compare the new method with Monte Carlo (MC) ray tracing. This paper is a proof of principle. Therefore, we present the results for systems formed by straight lines which are all located in the same medium. Numerical results show that the intensity found with the ray mapping method equals the exact intensity. Accuracy and speed advantages of several orders are observed with the new method.
Pulse radar randomly interrupted transmitting and receiving optimization based on genetic algorithm in radio frequency simulation
Authors: Liu Xiaobin , Zhao Feng , Ai Xiaofeng , Wu Qihua
Published: February 2021

The interrupted transmitting and receiving (ITR) can be used in anechoic chamber to solve the coupling between the transmitted and reflected signals. When the ITR periods are random, the fake peaks in high-resolution range profile (HRRP) of ITR echo can be reduced. Then, by utilizing the piecewise sparse property of ITR echo, the HRRP is reconstructed based on compressive sensing (CS). However, the periods of ITR determine the restricted isometry property (RIP) condition and the HRRP reconstruction performance. In order to improve the HRRP reconstruction performance, the ITR period sequence optimization method based on a genetic algorithm (GA) is proposed in this paper. The correlation coefficient of the sensing matrix columns is minimized after optimization so that the RIP of the sensing matrix can be well satisfied. Simulation and comparison results illustrate that the optimization method converges fast and the HRRP reconstruction performance is improved with the optimized ITR periods.
Mean-square stability of Riemann–Liouville fractional Hopfield’s graded response neural networks with random impulses
Authors: Agarwal R. , Hristova S. , O’Regan D. , Kopanov P.
Published: February 2021

In this paper a model of Hopfield’s graded response neural network is investigated. A network whose neurons are subject to a certain impulsive state displacement at random times is considered. The model is set up and studied. The presence of random moments of impulses in the model leads to a change of the solutions to stochastic processes. Also, we use the Riemann–Liouville fractional derivative to model adequately the long-term memory and the nonlocality in the neural networks. We set up in an appropriate way both the initial conditions and the impulsive conditions at random moments. The application of the Riemann–Liouville fractional derivative leads to a new definition of the equilibrium point. We define mean-square Mittag-Leffler stability in time of the equilibrium point of the model and study this type of stability. Some sufficient conditions for this type of stability are obtained. The general case with time varying self-regulating parameters of all units and time varying functions of the connection between two neurons is studied.
Efficacy of a coordinated strategy for containment of multidrug-resistant Gram-negative bacteria carriage in a Neonatal Intensive Care Unit in the context of an active surveillance program
Authors: Saporito Laura , Graziano Giorgio , Mescolo Federica , Amodio Emanuele , Insinga Vincenzo , Rinaudo Grazia , Aleo Aurora , Bonura Celestino , Vitaliti Marcello , Corsello Giovanni , Vitale Francesco , Maida Carmelo Massimo , Giuffrè Mario
Published: February 2021

Background

Antimicrobial resistance in neonatal intensive care unit (NICU) patients is a threat, due to the frequent use of antimicrobial treatment and invasive devices in fragile babies. Since 2014 an active surveillance program of multidrug-resistant Gram-negative bacteria (MDR-GNB) carriage has been in place in the five NICUs of Palermo, Italy. In 2017 an increase in the prevalence of MDR-GNB, and in particular of extended-spectrum β-lactamases-producingKlebsiella pneumoniae(ESBL-KP), was observed in “Civico” hospital NICU.

Aim

To assess the impact of a coordinated intervention strategy in achieving long-lasting reduction of MDR-GNB prevalence in the NICU.

Methods

Rectal swabs were obtained monthly and processed to detect MDR-GNB using standard methods. MDR-GNB were characterized by pulsed-field gel electrophoresis (PFGE). Since November 2017 the following intervention measures were applied: (a) two-months intensification of sample collection; (b) stakeholders meetings; (c) improvement of prevention measures and antimicrobial policies.

Findings

During the intensified microbiological surveillance MDR-GNB and ESBL-KP were detected in rectal swabs (34.8%; 23.2%), nasal swabs (24.6%; 14.5%), oral swabs (14.5%; 5.4%), milk samples (32.1%; 17.9%), pacifiers swabs (30.8%; 17.9%) and from sub-intensive room surfaces. Thirteen ESBL-KP strains isolated from clinical and environmental samples showed identical PFGE patterns. The prevalence of MDR-GNB and ESBL-KP carriage significantly decreased in the year after intervention compared to the previous year (20.6% vs 62.2%;p < 0.001 and 11.1% vs 57.8%;p < 0.001). MDR-GNB were not detected at all for three months and ESBL-KP for five months. Multivariate analysis of the principal exposure variables showed that admission in the post-intervention period significantly reduced the risk of MDR-GNB carriage (adj-OR = 0.21, 95% CI = 0.076–0.629;p < 0.001).

Conclusions

MDR-GNB broadly circulate in NICU setting, they can colonize different body sites and spread through various vehicles. A coordinated strategy of multiple interventions with active cooperation between epidemiologists and clinicians in the NICU can effectively reduce their circulation and in particular the carriage of the most dangerous ESBL-KP strains.
Sustainable genomic research for food security in sub-Saharan Africa
Authors: Aryee Sethlina Naa Dodua , Owusu-Adjei Dennis , Osei-Amponsah Richard , Skinner Benjamin , Sowatey Emmanuel , Sargent Carole Anne
Published: February 2021

Although traditional selective breeding has had a tremendous impact on both livestock and crop production in Africa, this has not kept pace with the high demand for animal and plant products on account of increasing urbanization, improved livelihoods and a rapidly growing human population. These challenges justify the need for more innovative and sustainable ways of improving animal and crop production to meet this demand. Over the last two decades the potential of genomics as a key tool to achieve improvement in desirable phenotypic traits has revolutionized the field of applied animal and plant biology. However, well informed use of such techniques has yet to be fully exploited within the context of local resources and capacity-building. The objective of this review is to highlight the rich agricultural biodiversity of sub-Saharan Africa, the potential of genomics in their sustainable use for food security, the challenges of genomic research and the strategies that can be adopted to overcome them in the implementation of agricultural genomic research in Africa. The lack of state-of-the-art laboratory research facilities, skilled human resources, poor funding and non-availability of scientific research resources, paucity of collaborative links between African researchers and a lack of engagement between key stakeholders in the agricultural value chain were identified as major barriers that affect agricultural genomic research in Africa. Finally, the recommended strategies to overcome these challenges will guide policy-makers, researchers, development partners and key stakeholders in the smooth advancement of sustainable agricultural genomic research for improved food security in Africa.
Estimating a Seismic Wave Velocity for Exciting the Greatest Anticipated Vertical Deck Displacement of a Cable-Stayed Bridge Subjected to Asynchronous Excitation
Authors: Hariri Bashar , Lin Lan
Published: February 2021

The purpose of this study is to examine the effects of the seismic wave velocity on vertical displacement of a cable-stayed bridge’s deck under asynchronous excitation. The Quincy Bayview Bridge located in Illinois, USA, and four other generic bridges are selected for the study. Ten records obtained from earthquakes in US, Japan, and Taiwan are used as input for the seismic excitation in the time-history analysis. Two equations are proposed in this study to determine a critical seismic wave velocity that would produce the greatest vertical deck displacement. The critical wave velocity depends on the total length of the bridge, the fundamental period of the bridge, and the C-factor. The C-factor in this study is 0.72, which is based on analyzed results from the five selected bridges. The two equations and the C-factor are verified through application on two 3-span cable-stayed bridges studied previously by Nazmy and Abdel-Ghaffar. The proposed C-factor of 0.72 is recommended for use for typical 3-span cable-stayed bridges with a side-to-main span ratio of about 0.48. The methodology developed in the study, however, can be applied to any specific bridge to examine the excitation of the deck vertical displacement under the longitudinal seismic ground motion.
Low expression of ZHX1 and ZHX2 impacts on the prognosis of chronic lymphocytic leukemia
Authors: Maciel Natália Ioseph Gladistone , Filiú-Braga Luma Dayane Carvalho , Neves Francisco Assis Rocha , Rego Eduardo Magalhaes , Lucena-Araujo Antonio Roberto , Saldanha-Araujo Felipe
Published: February 2021

Experimental evidence points to the role of Zinc fingers and homeoboxes protein 1 and 2 (ZHX1 and ZHX2) in the development and progression of several types of cancer, including hematological malignancies. Here, we determined whether the altered expression of ZHX1 and ZHX2 has clinical implications in patients with CLL. Interestingly, CLL patients with low expression ZHX1 and ZHX2 presented higher WBC counts. Importantly, our data showed that CLL patients with cytogenetic alterations presented reduced transcriptional levels of ZHX1 and ZHX2 in comparison with patients with normal karyotype. Moreover, when stratifying CLL patients according to the karyotype prognosis value, we observed that the expression of ZHX1 and ZHX2 was significantly reduced in CLL patients presenting adverse karyotypes. Finally, we stratified patients according to the number of chromosomal aberrations and observed a negative association between ZHX1 and ZHX2 expression and the accumulation of chromosomal abnormalities in CLL patients. Our data showed that the low expression of ZHX1 and ZHX2 is associated with a worse prognosis in CLL, followed by a greater number of leukemic cells and unfavorable cytogenetics findings in the diagnosis. Further studies will be important to confirm the prognostic value of ZHX1 and ZHX2 in independent CLL cohorts.
Article 4: Impact assessment of supervision performance assessment and recognition strategy (SPARS) to improve supply chain management in health facilities in Uganda: a national pre and post study
Authors: Ladwar Denis Okidi , Sembatya Moses Nixon , Amony Nancy Miriam , Seru Morries , Ross-Degnan Dennis , Garabedian Laura , Trap Birna
Published: February 2021

Background

To strengthen medicines management capacity, including supply chain management, at public sector health facilities in Uganda, the Ministry of Health introduced a multipronged supervision, performance assessment, and recognition strategy (SPARS). The aim of this study was to assess the impact of SPARS on improving supply chain management. A series of four papers on SPARS described the SPARS concept, its impact on overall and domain practices and appropriate medicines use, and now in the fourth paper describing the effect on supply chain management.

Methods

District-based health workers trained as supervisors build facility-level capacity in medicines management using an indicator-based performance assessment followed by targeted supervisory visits. From 2010 to 2013, 1222 SPARS visits were implemented, and the SPARS performance indicator scores determined. This article assesses impact on 13 indicators in three of the five SPARS domains—stock management, storage management, and ordering and reporting quality—using a pre–post design. We also explored factors that may have influenced these outcomes.

Results

Between the first and last visit within one year of SPARS implementation, we found an average improvement of 16 percentage points (p < 0.001) in supply chain management measures across all levels of care. The improvement in scores for stock management, storage management, and ordering and reporting was 22 (ns), 16 (p < 0.001), and 11 (p = 0.032) percentage points, respectively. The study identified the key predictors of positive change as a low initial indicator score, frequent supervisory visits, and engagement of the district health officer.

Conclusions

The multipronged SPARS approach was effective in building supply chain management capacity in lower-level health care facilities with statistically significant improvements in supply chain management overall and in almost all stock and storage- management and ordering and reporting measures after one year of implementation. We recommend broad dissemination of the SPARS approach as an effective strategy to strengthen supply chain management in low-income countries.

Trial registration: The study did not involve or use human participants or identifiable personal data, human tissue, or animals and thus did not require ethical approval or a waiver. It is a study implemented in collaboration with the Ministry of Health and does not require trial registration.