bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptomic Profiles in Children With Septic Shock With or Without Immunoparalysis
Authors: Snyder Andrew , Jedreski Kathleen , Fitch James , Wijeratne Saranga , Wetzel Amy , Hensley Josey , Flowers Margaret , Bline Katherine , Hall Mark W. , Muszynski Jennifer A.
Published: October 2021

Background

Severe innate immune suppression, termed immunoparalysis, is associated with increased risks of nosocomial infection and mortality in children with septic shock. Currently, immunoparalysis cannot be clinically diagnosed in children, and mechanisms remain unclear. Transcriptomic studies identify subsets of septic children with downregulation of genes within adaptive immune pathways, but assays of immune function have not been performed as part of these studies, and little is known about transcriptomic profiles of children with immunoparalysis.

Methods

We performed a nested case-control study to identify differences in RNA expression patterns between children with septic shock with immunoparalysis (defined as lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)α response < 200 pg/ml) vs those with normal LPS-induced TNFα response. Children were enrolled within 48 hours of the onset of septic shock and divided into two groups based on LPS-induced TNFα response. RNA was extracted from whole blood for RNAseq, differential expression analyses using DESeq2 software, and pathway analyses using Ingenuity Pathway Analysis.

Results

32 children were included in analyses. Comparing those with immunoparalysis (n =19) to those with normal TNFα response (n = 13), 2,303 transcripts were differentially expressed with absolute value fold change ≥ 1.5 and false discovery rate ≤ 0.05. The majority of downregulated pathways in children with immunoparalysis were pathways that involved interactions between innate and adaptive immune cells necessary for cell-mediated immunity, crosstalk between dendritic cells and natural killer cells, and natural killer cell signaling pathways. Upregulated pathways included those involved in humoral immunity (T helper cell type 2), corticotropin signaling, platelet activation (GP6 signaling), and leukocyte migration and extravasation.

Conclusions

Our study suggests that gene expression data might be useful to identify children with immunoparalysis and identifies several key differentially regulated pathways involved in both innate and adaptive immunity. Our ongoing work in this area aims to dissect interactions between innate and adaptive immunity in septic children and to more fully elucidate patient-specific immunologic pathophysiology to guide individualized immunotherapeutic targets.
Pro-Inflammatory and B Cell Regulating Capacities of TWEAK in Rainbow Trout (Oncorhynchus mykiss)
Authors: Abós Beatriz , Pérez-Fernández Elena , Morel Esther , Perdiguero Pedro , Tafalla Carolina
Published: October 2021

Tumor necrosis factor (TNF)-like weak inducer of apoptosis or TWEAK is a member of the TNF superfamily involved in the regulation of many biological processes. In mammals, TWEAK has been shown to play a role in some autoimmune or inflammatory conditions, but its immune role is not yet clearly defined. In teleost fish, although a few studies have identified homologues to mammalian TWEAK, their biological effects have never been investigated. In the current study, we have studied the transcriptional regulation of two TWEAK homologues (TWEAK 1 and 2) identified in rainbow trout (Oncorhynchus mykiss) throughout different tissues, in response to parasitic or viral infections, or in head kidney (HK) leukocytes stimulated with different stimuli. Although the transcription of both homologues was modulated when HK leukocytes were exposed to several immune stimuli, only TWEAK 1 was significantly modulated upon pathogenic exposure. Thus, we performed a characterization of the functions exerted by this cytokine in HK leukocytes. Recombinant TWEAK 1 strongly up-regulated the transcription of pro-inflammatory genes and antimicrobial peptides in HK leukocytes, with differential transcriptional effects in IgM+ B cells, IgM- lymphocytes and myeloid cells. TWEAK 1 also increased the survival and promoted the differentiation of B cells in HK leukocyte cultures. Our results demonstrate that in teleost fish, TWEAK 1 is involved in the response to different types of pathogens, through the modulation of antimicrobial and pro-inflammatory genes in different leukocytes subsets. Furthermore, a role for TWEAK as a B cell differentiation factor has also been established in rainbow trout.
Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics
Authors: Kumar Sriram , Çalışkan Duygu Merve , Janowski Josua , Faist Aileen , Conrad Beate Claudine Gisela , Lange Julius , Ludwig Stephan , Brunotte Linda
Published: October 2021

Since November 2019 the SARS-CoV-2 pandemic has caused nearly 200 million infection and more than 4 million deaths globally (Updated information from the World Health Organization, as on 2ndAug 2021). Within only one year into the pandemic, several vaccines were designed and reached approval for the immunization of the world population. The remarkable protective effects of the manufactured vaccines are demonstrated in countries with high vaccination rates, such as Israel and UK. However, limited production capacities, poor distribution infrastructures and political hesitations still hamper the availability of vaccines in many countries. In addition, due to the emergency of SARS-CoV-2 variants with immune escape properties towards the vaccines the global numbers of new infections as well as patients developing severe COVID-19, remains high. New studies reported that about 8% of infected individuals develop long term symptoms with strong personal restrictions on private as well as professional level, which contributes to the long socioeconomic problems caused by this pandemic. Until today, emergency use-approved treatment options for COVID-19 are limited to the antiviral Remdesivir, a nucleoside analogue targeting the viral polymerase, the glucocorticosteroide Dexamethasone as well as neutralizing antibodies. The therapeutic benefits of these treatments are under ongoing debate and clinical studies assessing the efficiency of these treatments are still underway. To identify new therapeutic treatments for COVID-19, now and by the post-pandemic era, diverse experimental approaches are under scientific evaluation in companies and scientific research teams all over the world. To accelerate clinical translation of promising candidates, repurposing approaches of known approved drugs are specifically fostered but also novel technologies are being developed and are under investigation. This review summarizes the recent developments from the lab bench as well as the clinical status of emerging therapeutic candidates and discusses possible therapeutic entry points for the treatment strategies with regard to the biology of SARS-CoV-2 and the clinical course of COVID-19.
Four Types of ST11 Novel Mutations From Increasing Carbapenem-Resistant Klebsiella pneumoniae in Guangdong, 2016–2020
Authors: Zhao Yunhu , Liao Yalong , Zhang Ni , Liu Suling , Zhang Jiao , Hu Xuejiao , Zhou Dianrong , Deng Qianyun , Shi Yanping , Gu Bing , Hou Tieying
Published: October 2021

Objectives: This study aimed to explore changes in carbapenem-resistant Klebsiella pneumoniae (CR-KP) isolates collected in Guangdong over the period of 2016–2020.

Methods: Antibacterial susceptibility was quantified through VITEK 2 compact and K-B method. Carbapenemase phenotypes and genotypes were characterized by modified carbapenem inactivation method (mCIM), EDTA-carbapenem inactivation method (eCIM), and polymerase chain reaction (PCR). Molecular characteristics and evolutionary trends were analyzed by multilocus sequence typing and evolutionary tree.

Results: Isolates (2,847) of K. pneumoniae were separated in 2016–2020, and the separate rate of CR-KP increased from 5.65 to 9.90% (p = 0.009). The top 3 wards were intensive care unit (ICU) (21.92%), neonatal wards (13.70%), and respiratory wards (12.33%). In 146 CR-KP strains, serine carbapenemase was the main phenotype, and KPC was the main genotype, and 57 contained two resistant genes, and 1 contained three resistant genes. Two polygenic strains were first found: IMP + GES and KPC + NDM + VIM, but all the phenotypes were metalloenzyme, which indicated that metalloenzyme was usually the first choice for CR-KP resistance. In addition, all the ST54 of metalloenzyme type contained IMP, and all the ST45, ST37, and ST76 contained OXA. ST11 was the most prevalent (42.47%); ST11 and its mutants proved the predominant sequence type making up 51.1% of the carbapenemase-producing isolates. A novel type of ST11 mutation, the rpoB was mutated from sequence 1 to sequence 146, was in an independent separate branch on the evolutionary tree and was resistant to all antibacterial agents. The other three mutants, rpoB 1–15, infB 3–148, and infB 3–80, are also resistant to all antibacteria. Of note, all the four mutants produced serine carbapenemase and contained KPC, and indicated that the prevalent strain in China, ST11, has serious consequences and potential outbreaks.

Conclusion: The infection rate of CR-KP has increased, and ICU and neonatal wards have become the key infection areas. Producing serine enzyme, the KPC genotype, and ST11 are the predominant CR-KP. Polygenic strains and ST11 mutation made clinical treatment difficult and may become a potential threat.
A Novel DCL2-Dependent Micro-Like RNA Vm-PC-3p-92107_6 Affects Pathogenicity by Regulating the Expression of Vm-VPS10 in Valsa mali
Authors: Guo Feiran , Liang Jiahao , Xu Ming , Zhang Gao , Huang Lili , Feng Hao
Published: October 2021

Dicer proteins are mainly responsible for generating small RNAs (sRNAs), which are involved in gene silencing in most eukaryotes. In previous research, two DCL proteins in Valsa mali, the pathogenic fungus causing apple tree Valsa canker, were found associated with both the pathogenicity and generation of sRNAs. In this study, the differential expression of small interfering RNAs (siRNAs) and miRNA-like RNAs (milRNAs) was analyzed based on the deep sequencing of the wild type and Vm-DCL2 mutant, respectively. Overall, the generation of 40 siRNAs and 18 milRNAs was evidently associated with Vm-DCL2. The target genes of milRNAs were then identified using degradome sequencing; according to the prediction results, most candidate targets are related to pathogenicity. Further, expression of Vm-PC-3p-92107_6 was confirmed in the wild type but not in the Vm-DCL2 mutant. Moreover, the pathogenicity of Vm-PC-3p-92107_6 deletion mutants (ΔVm-PC-3p-92107_6) and the over-expression transformants (Vm-PC-3p-92107_6-OE) was significantly increased and decreased, respectively. Based on those degradome results, vacuolar protein sorting 10 (Vm-VPS10) was identified as the target of Vm-PC-3p-92107_6. Co-expression analysis in tobacco leaves further confirmed that Vm-PC-3p-92107_6 could suppress the expression of Vm-VPS10. Meanwhile, the expression levels of Vm-PC-3p-92107_6 and Vm-VPS10 displayed divergent trends in ΔVm-PC-3p-92107_6 and Vm-PC-3p-92107_6-OE, respectively. Perhaps most importantly, ΔVm-VPS10 featured a significant reduction in pathogenicity. Taken together, our results indicate that a DCL2-dependent milRNA Vm-PC-3p-92107_6 plays roles in pathogenicity by regulating the expression of Vm-VPS10. This study lays a foundation for the comprehensive analysis of pathogenic mechanisms of V. mali and deepens our understanding of the generation and function of fungal sRNA.
Phosphorylation of Extracellular Proteins in Acinetobacter baumannii in Sessile Mode of Growth
Authors: Massier Sébastien , Robin Brandon , Mégroz Marianne , Wright Amy , Harper Marina , Hayes Brooke , Cosette Pascal , Broutin Isabelle , Boyce John D. , Dé Emmanuelle , Hardouin Julie
Published: October 2021

Acinetobacter baumannii is a problematic nosocomial pathogen owing to its increasing resistance to antibiotics and its great ability to survive in the hospital environment, which is linked to its capacity to form biofilms. Structural and functional investigations of post-translational modifications, such as phosphorylations, may lead to identification of candidates for therapeutic targets against this pathogen. Here, we present the first S/T/Y phosphosecretome of two A. baumannii strains, the reference strain ATCC 17978 and the virulent multi-drug resistant strain AB0057, cultured in two modes of growth (planktonic and biofilm) using TiO2 chromatography followed by high resolution mass spectrometry. In ATCC 17978, we detected a total of 137 (97 phosphoproteins) and 52 (33 phosphoproteins) phosphosites in biofilm and planktonic modes of growth, respectively. Similarly, in AB0057, 155 (119 phosphoproteins) and 102 (74 phosphoproteins) phosphosites in biofilm and planktonic modes of growth were identified, respectively. Both strains in the biofilm mode of growth showed a higher number of phosphosites and phosphoproteins compared to planktonic growth. Several phosphorylated sites are localized in key regions of proteins involved in either drug resistance (β-lactamases), adhesion to host tissues (pilins), or protein secretion (Hcp). Site-directed mutagenesis of the Hcp protein, essential for type VI secretion system-mediated interbacterial competition, showed that four of the modified residues are essential for type VI secretion system activity.
cAMP Receptor Protein Positively Regulates the Expression of Genes Involved in the Biosynthesis of Klebsiella oxytoca Tilivalline Cytotoxin
Authors: Rodríguez-Valverde Diana , León-Montes Nancy , Soria-Bustos Jorge , Martínez-Cruz Jessica , González-Ugalde Ricardo , Rivera-Gutiérrez Sandra , González-y-Merchand Jorge A. , Rosales-Reyes Roberto , García-Morales Lázaro , Hirakawa Hidetada , Fox James G. , Girón Jorge A. , De la Cruz Miguel A. , Ares Miguel A.
Published: October 2021

Klebsiella oxytoca is a resident of the human gut. However, certain K. oxytoca toxigenic strains exist that secrete the nonribosomal peptide tilivalline (TV) cytotoxin. TV is a pyrrolobenzodiazepine that causes antibiotic-associated hemorrhagic colitis (AAHC). The biosynthesis of TV is driven by enzymes encoded by the aroX and NRPS operons. In this study, we determined the effect of environmental signals such as carbon sources, osmolarity, and divalent cations on the transcription of both TV biosynthetic operons. Gene expression was enhanced when bacteria were cultivated in tryptone lactose broth. Glucose, high osmolarity, and depletion of calcium and magnesium diminished gene expression, whereas glycerol increased transcription of both TV biosynthetic operons. The cAMP receptor protein (CRP) is a major transcriptional regulator in bacteria that plays a key role in metabolic regulation. To investigate the role of CRP on the cytotoxicity of K. oxytoca, we compared levels of expression of TV biosynthetic operons and synthesis of TV in wild-type strain MIT 09-7231 and a Δcrp isogenic mutant. In summary, we found that CRP directly activates the transcription of the aroX and NRPS operons and that the absence of CRP reduced cytotoxicity of K. oxytoca on HeLa cells, due to a significant reduction in TV production. This study highlights the importance of the CRP protein in the regulation of virulence genes in enteric bacteria and broadens our knowledge on the regulatory mechanisms of the TV cytotoxin.
Effect of Enterococcus faecium as a Water and/or Feed Additive on the Gut Microbiota, Hematologic and Immunological Parameters, and Resistance Against Francisellosis and Streptococcosis in Nile Tilapia (Oreochromis niloticus)
Authors: Suphoronski Suelen Aparecida , de Souza Felipe Pinheiro , Chideroli Roberta Torres , Mantovani Favero Leonardo , Ferrari Natália Amoroso , Ziemniczak Henrique Momo , Gonçalves Daniela Dib , Lopera Barrero Nelson Mauricio , Pereira Ulisses de Padua
Published: October 2021

In the present study, we evaluated the effects of administering Enterococcus faecium in food and/or water on the hematological and immunological parameters, intestinal microbiota, resistance to bacterial diseases (streptococcosis and francisellosis) and growth of Nile tilapia. Before the in vivo experiment, probiotic bacteria isolated from Nile tilapia were selected via inhibition tests. Sequencing, annotation, and assembly of the complete genome of the selected bacteria as well as other tests were performed using bioinformatics tools. Three treatments were implemented: G1 (probiotic feeding), G2 (probiotic in water), and G3 (probiotic in food and water); and a negative control (NC) was also employed. Treatment lasted 38 days, and each group consisted of fish and two repetitions. The fish were divided and infected with Streptococcus agalactiae S13 (serotype Ib) and Francisella orientalis. The G1 group had a higher average final weight gain than the G2, G3, and NC groups. Further, a significant increase in the number of thrombocytes was observed in the groups administered probiotics in the diet (G1 and G3). A statistical difference was observed in the mortality of fish infected with S. agalactiae in the NC compared to the treated groups. Cetobacterium was the 43 most abundant genus in the intestinal microbiota of all groups, including the NC group. E. faecium increased the immunity of fish administered the treatment and decreased the mortality caused by S. agalactiae. As an autochtone probiotic, E. faecium does not interfere with the local ecosystem and thus has a great probiotic potential for Nile tilapia in Brazil.
σS-Mediated Stress Response Induced by Outer Membrane Perturbation Dampens Virulence in Salmonella enterica serovar Typhimurium
Authors: Kim Seul I , Kim Eunsuk , Yoon Hyunjin
Published: October 2021

Salmonella alters cellular processes as a strategy to improve its intracellular fitness during host infection. Alternative σ factors are known to rewire cellular transcriptional regulation in response to environmental stressors. σs factor encoded by the rpoS gene is a key regulator required for eliciting the general stress response in many proteobacteria. In this study, Salmonella Typhimurium deprived of an outer membrane protein YcfR was attenuated in intracellular survival and exhibited downregulation in Salmonella pathogenicity island-2 (SPI-2) genes. This decreased SPI-2 expression caused by the outer membrane perturbation was abolished in the absence of rpoS. Interestingly, regardless of the defects in the outer membrane integrity, RpoS overproduction decreased transcription from the common promoter of ssrA and ssrB, which encode a two-component regulatory system for SPI-2. RpoS was found to compete with RpoD for binding to the PssrA region, and its binding activity with RNA polymerase (RNAP) to form Eσs holoenzyme was stimulated by the small regulatory protein Crl. This study demonstrates that Salmonella undergoing RpoS-associated stress responses due to impaired envelope integrity may reciprocally downregulate the expression of SPI-2 genes to reduce its virulence.
Peripheral Clock System Abnormalities in Patients With Parkinson’s Disease
Authors: Li Tianbai , Cheng Cheng , Jia Congcong , Leng Yue , Qian Jin , Yu Hang , Liu Yufei , Wang Nanxing , Yang Yuting , Al-Nusaif Murad , Le Weidong
Published: October 2021

Objective: To evaluate the altered expression of peripheral clock genes, circulating melatonin levels, and their correlations with sleep-wake phenotypes including probable rapid eye movement sleep behavior disorder (pRBD) symptoms in a relatively large population of Parkinson’s disease (PD) patients.

Methods: We determined the expression profiles of five principal clock genes, BMAL1, CLOCK, CRY1, PER1, and PER2, in the peripheral blood mononuclear cells (PBMCs) of PD patients (n = 326), and healthy controls (HC, n = 314) using quantitative real-time PCR. Melatonin concentration in the plasma of two groups was evaluated by enzyme-linked immunosorbent assay. Then we performed comprehensive association analyses on the PBMCs clock gene expression, plasma melatonin levels and sleep characteristics.

Results: Our data showed that the expression levels of BMAL1, CLOCK, CRY1, PER1, and PER2 were significantly decreased in the PBMCs of PD as compared with that of HC (P < 0.05). PD patients had reduced plasma melatonin levels compared with HC (P < 0.0001). pRBD and excessive daytime sleepiness are common in these PD patients and are associated with the expression levels of all five clock genes (r = −0.344∼−0.789, P < 0.01) and melatonin concentration (r = −0.509∼−0.753, P < 0.01). Statistical analyses also revealed that a combination of five clock genes and melatonin could reach a high diagnostic performance (areas under the curves, 97%) for PD comorbid pRBD.

Conclusion: This case-control study demonstrates that peripheral BMAL1, CLOCK, CRY1, PER1, PER2, and melatonin levels are altered in PD patients and may serve as endogenous markers for sleep and wakefulness disturbances of PD.
Continuous Multi-DoF Wrist Kinematics Estimation Based on a Human–Machine Interface With Electrical-Impedance-Tomography
Authors: Zheng Enhao , Zhang Jingzhi , Wang Qining , Qiao Hong
Published: October 2021

This study proposed a multiple degree-of-freedom (DoF) continuous wrist angle estimation approach based on an electrical impedance tomography (EIT) interface. The interface can inspect the spatial information of deep muscles with a soft elastic fabric sensing band, extending the measurement scope of the existing muscle-signal-based sensors. The designed estimation algorithm first extracted the mutual correlation of the EIT regions with a kernel function, and second used a regularization procedure to select the optimal coefficients. We evaluated the method with different features and regression models on 12 healthy subjects when they performed six basic wrist joint motions. The average root-mean-square error of the 3-DoF estimation task was 7.62°, and the average R2 was 0.92. The results are comparable to state-of-the-art with sEMG signals in multi-DoF tasks. Future endeavors will be paid in this new direction to get more promising results.
Molecular Expression Profile of Changes in Rat Acute Spinal Cord Injury
Authors: Wang Jun-Juan , Ye Guo , Ren Hao , An Cheng-Rui , Huang Lvxing , Chen Hengyi , Zhang Hui , Lin Jun-Xin , Shen Xilin , Heng Boon Chin , Zhou Jing
Published: October 2021

Background: Spinal cord injury (SCI) is a highly lethal and debilitating disease with a variety of etiologies. To date, there is no effective therapeutic modality for a complete cure. The pathological mechanisms of spinal cord injury at the molecular gene and protein expression levels remain unclear.

Methods: This study used single-cell transcriptomic analysis and protein microarray analysis to analyzes changes in the gene expression profiles of cells and secretion of inflammatory factors respectively, around the lesion site in a rat SCI model.

Results: Single-cell transcriptomic analysis found that three types of glial cells (microglia, astrocyte, and oligodendrocyte) becomes activated after acute injury, with GO exhibiting a variety of inflammatory-related terms after injury, such as metabolic processes, immune regulation, and antigen presentation. Protein microarray results showed that the levels of four inflammatory cytokines favoring SCI repair decreased while the levels of nine inflammatory cytokines hindering SCI repair increased after injury.

Conclusion: These findings thus reveal the changes in cellular state from homeostatic to reactive cell type after SCI, which contribute to understand the pathology process of SCI, and the potential relationship between glial cells and inflammatory factors after SCI, and provides new theoretical foundation for further elucidating the molecular mechanisms of secondary SCI.
Tight Regulation of Major Histocompatibility Complex I for the Spatial and Temporal Expression in the Hippocampal Neurons
Authors: Shen Yuqing , Zhang Jianqiong
Published: October 2021

The expression and function of immune molecules, such as major histocompatibility complex (MHC), within the developing and adult brain have been discovered over the past few years. Studies utilizing classical class I MHC knockout animals suggest that these molecules, in fact, play essential roles in the establishment, function, and modification of synapses in the CNS. Altered neuronal expression of class I MHC, as has been reported in pathological conditions, leads to aberrations in neuronal development and repair. In the hippocampus, cellular and molecular mechanisms that regulate synaptic plasticity have heretofore been extensively studied. It is for this reason that multiple studies directed at better understanding the expression, regulation, and function of class I MHC within the hippocampus have been undertaken. Since several previous reviews have addressed the roles of class I MHC in the formation and function of hippocampal connections, the present review will focus on describing the spatial and temporal expression of class I MHC in developing, healthy adult, and aging hippocampus. Herein, we also review current literatures exploring mechanisms that regulate class I MHC expression in murine hippocampus. With this review, we aim to facilitate a deeper mechanistic understanding into the complex tight regulation of MHC I expression in hippocampus, which are needed as we explore the potential for targeting MHC I for therapeutic intervention in normal aging and in neurodegenerative diseases in the future.
Neuronal Circuits for Social Decision-Making and Their Clinical Implications
Authors: Báez-Mendoza Raymundo , Vázquez Yuriria , Mastrobattista Emma P. , Williams Ziv M.
Published: October 2021

Social living facilitates individual access to rewards, cognitive resources, and objects that would not be otherwise accessible. There are, however, some drawbacks to social living, particularly when competing for scarce resources. Furthermore, variability in our ability to make social decisions can be associated with neuropsychiatric disorders. The neuronal mechanisms underlying social decision-making are beginning to be understood. The momentum to study this phenomenon has been partially carried over by the study of economic decision-making. Yet, because of the similarities between these different types of decision-making, it is unclear what is a social decision. Here, we propose a definition of social decision-making as choices taken in a context where one or more conspecifics are involved in the decision or the consequences of it. Social decisions can be conceptualized as complex economic decisions since they are based on the subjective preferences between different goods. During social decisions, individuals choose based on their internal value estimate of the different alternatives. These are complex decisions given that conspecifics beliefs or actions could modify the subject’s internal valuations at every choice. Here, we first review recent developments in our collective understanding of the neuronal mechanisms and circuits of social decision-making in primates. We then review literature characterizing populations with neuropsychiatric disorders showing deficits in social decision-making and the underlying neuronal circuitries associated with these deficits.
Dietary Intake of Total Carbohydrates, Sugar and Sugar-Sweetened Beverages, and Risk of Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Prospective Cohort Studies
Authors: Khademi Zeinab , Milajerdi Alireza , Larijani Bagher , Esmaillzadeh Ahmad
Published: October 2021

Objectives: No earlier study has summarized findings from prospective cohort studies on the association of dietary carbohydrates, sugar, and sugar-sweetened beverages (SSBs) consumption and risk of inflammatory bowel disease (IBD). The current study was done to quantitatively summarize earlier information from prospective cohort studies on the link between dietary carbohydrates, sugar, and SSBs intake with risk of IBD.

Methods: Relevant studies published up to June 2021 were searched through PubMed, Medline, SCOPUS, EMBASE, and Google Scholar with the use of relevant keywords. All prospective cohort studies investigating the association of dietary carbohydrates, sugar, and SSBs consumption with risk of IBD were included.

Results: Combining 5 effect sizes from 4 cohort studies, no significant association was found between dietary intake of carbohydrates and risk of ulcerative colitis (UC) (RR: 1.22; 95% CI: 0.70–2.14). The same findings were obtained for risk of Crohn's disease (CD) (RR: 1.06; 95% CI: 0.64–1.75) based on 4 studies with 5 effect sizes. A significant positive association was observed between sugar intake and risk of UC (RR: 1.59; 95% CI: 1.15–2.20), as well as CD (RR: 1.90; 95% CI: 1.06–3.41) when 5 effect sizes from 4 cohort studies were combined. The overall effect size, based on 4 estimates, revealed no significant association between SSBs consumption and risk of UC (RR: 1.02; 95% CI: 0.92–1.12) and CD (RR: 1.22; 95% CI: 0.91–1.64).

Conclusions: Summarizing earlier studies, sugar intake was found to be associated with increased risk of IBD and its subtypes. Any significant association between dietary intake of carbohydrates and SSBs and risk of IBD and its subtypes was not found.
A3 Adenosine and P2X7 Purinergic Receptors as New Targets for an Innovative Pharmacological Therapy of Malignant Pleural Mesothelioma
Authors: Vincenzi Fabrizio , Rotondo John Charles , Pasquini Silvia , Di Virgilio Francesco , Varani Katia , Tognon Mauro
Published: October 2021

Human malignant pleural mesothelioma (MPM) is a rare, but aggressive tumor of the serosal cavities whose 5-year survival rate is 15%. At present, there are no effective therapies for MPM. Although recent findings suggest that A3 adenosine (A3AR) and P2X7 (P2X7R) receptors can be employed as antitumoral pharmacological targets in MPM, their potential role in a combined therapy is currently unknown. The A3AR agonist Cl-IB-MECA and the P2X7 receptor antagonist AZ10606120, as a single compound or in combination, were investigated in vitro for their anti-tumor activities. Assays were carried out in MPM cell lines IST-Mes2 and MPP89 and in primary human normal mesothelial cells (HMCs), as control. Single treatment with Cl-IB-MECA reduced cell proliferation and favored a pro-apoptotic effect in both MPP89 and IST-Mes2 cell lines, whereas AZ10606120 inhibited cell proliferation and induced apoptosis in IST-Mes2, only. The combined treatment with Cl-IB-MECA and AZ10606120 reduced cell proliferation and favored apoptosis in MPP89 and IST-Mes2 cell lines, whereas no synergistic effect was detected. These data cumulatively suggest the absence of a synergistic effect in combined targeting of A3 adenosine and P2X7 receptors of MPM cell lines. This study may stimulate further investigations aimed at determining new combinations of antitumor compounds and more effective therapeutic strategies against MPM.
Development of a Nomogram Combining Clinical Risk Factors and Dual-Energy Spectral CT Parameters for the Preoperative Prediction of Lymph Node Metastasis in Patients With Colorectal Cancer
Authors: Cao Yuntai , Zhang Jing , Bao Haihua , Zhang Guojin , Yan Xiaohong , Wang Zhan , Ren Jialiang , Chai Yanjun , Zhao Zhiyong , Zhou Junlin
Published: October 2021

Objective

This study aimed to develop a dual-energy spectral computed tomography (DESCT) nomogram that incorporated both clinical factors and DESCT parameters for individual preoperative prediction of lymph node metastasis (LNM) in patients with colorectal cancer (CRC).

Material and Methods

We retrospectively reviewed 167 pathologically confirmed patients with CRC who underwent enhanced DESCT preoperatively, and these patients were categorized into training (n = 117) and validation cohorts (n = 50). The monochromatic CT value, iodine concentration value (IC), and effective atomic number (Eff-Z) of the primary tumors were measured independently in the arterial phase (AP) and venous phase (VP) by two radiologists. DESCT parameters together with clinical factors were input into the prediction model for predicting LNM in patients with CRC. Logistic regression analyses were performed to screen for significant predictors of LNM, and these predictors were presented as an easy-to-use nomogram. The receiver operating characteristic curve and decision curve analysis (DCA) were used to evaluate the clinical usefulness of the nomogram.

Results

The logistic regression analysis showed that carcinoembryonic antigen, carbohydrate antigen 199, pericolorectal fat invasion, ICAP, ICVP, and Eff-ZVP were independent predictors in the predictive model. Based on these predictors, a quantitative nomogram was developed to predict individual LNM probability. The area under the curve (AUC) values of the nomogram were 0.876 in the training cohort and 0.852 in the validation cohort, respectively. DCA showed that our nomogram has outstanding clinical utility.

Conclusions

This study presents a clinical nomogram that incorporates clinical factors and DESCT parameters and can potentially be used as a clinical tool for individual preoperative prediction of LNM in patients with CRC.
MR-Linac Radiotherapy – The Beam Angle Selection Problem
Authors: Bijman Rik , Rossi Linda , Janssen Tomas , de Ruiter Peter , van Triest Baukelien , Breedveld Sebastiaan , Sonke Jan-Jakob , Heijmen Ben
Published: October 2021

Background

With the large-scale introduction of volumetric modulated arc therapy (VMAT), selection of optimal beam angles for coplanar static-beam IMRT has increasingly become obsolete. Due to unavailability of VMAT in current MR-linacs, the problem has re-gained importance. An application for automated IMRT treatment planning with integrated, patient-specific computer-optimization of beam angles (BAO) was used to systematically investigate computer-aided generation of beam angle class solutions (CS) for replacement of computationally expensive patient-specific BAO. Rectal cancer was used as a model case.

Materials and Methods

23 patients treated at a Unity MR-linac were included. BAOx plans (x=7-12 beams) were generated for all patients. Analyses of BAO12 plans resulted in CSx class solutions. BAOx plans, CSx plans, and plans with equi-angular setups (EQUIx, x=9-56) were mutually compared.

Results

For x>7, plan quality for CSx and BAOx was highly similar, while both were superior to EQUIx. E.g. with CS9, bowel/bladder Dmean reduced by 22% [11%, 38%] compared to EQUI9 (p<0.001). For equal plan quality, the number of EQUI beams had to be doubled compared to BAO and CS.

Conclusions

Computer-generated beam angle CS could replace individualized BAO without loss in plan quality, while reducing planning complexity and calculation times, and resulting in a simpler clinical workflow. CS and BAO largely outperformed equi-angular treatment. With the developed CS, time consuming beam angle re-optimization in daily adaptive MR-linac treatment could be avoided. Further systematic research on computerized development of beam angle class solutions for MR-linac treatment planning is warranted.
Valproic Acid Enhanced Temozolomide-Induced Anticancer Activity in Human Glioma Through the p53–PUMA Apoptosis Pathway
Authors: Tsai Hong-Chieh , Wei Kuo-Chen , Chen Pin-Yuan , Huang Chiung-Yin , Chen Ko-Ting , Lin Ya-Jui , Cheng Hsiao-Wei , Chen Yi-Rou , Wang Hsiang-Tsui
Published: October 2021

Glioblastoma (GBM), the most lethal type of brain tumor in adults, has considerable cellular heterogeneity. The standard adjuvant chemotherapeutic agent for GBM, temozolomide (TMZ), has a modest response rate due to the development of drug resistance. Multiple studies have shown that valproic acid (VPA) can enhance GBM tumor control and prolong survival when given in conjunction with TMZ. However, the beneficial effect is variable. In this study, we analyzed the impact of VPA on GBM patient survival and its possible correlation with TMZ treatment and p53 gene mutation. In addition, the molecular mechanisms of TMZ in combination with VPA were examined using both p53 wild-type and p53 mutant human GBM cell lines. Our analysis of clinical data indicates that the survival benefit of a combined TMZ and VPA treatment in GBM patients is dependent on their p53 gene status. In cellular experiments, our results show that VPA enhanced the antineoplastic effect of TMZ by enhancing p53 activation and promoting the expression of its downstream pro-apoptotic protein, PUMA. Our study indicates that GBM patients with wild-type p53 may benefit from a combined TMZ+VPA treatment.
Subphrenic Lymph Node Metastasis Predicts Poorer Prognosis for Nasopharyngeal Carcinoma Patients With Metachronous Metastasis
Authors: Zhang Xue-Fang , Zhang Yan , Liang Xu-Wei , Chen Jia-Luo , Zhi Sheng-Fang , Yin Wen-Jing , Wang Meng-Yao , Dong En-Lai , Chen Dong-Ping
Published: October 2021

Aim

We retrospectively analyzed the distribution of distant lymph node metastasis and its impact on prognosis in patients with metastatic NPC after treatment.

Methods

From 2010 to 2016, 219 NPC patients out of 1,601 (182 from the Affiliated Cancer Hospital and Institute of Guangzhou Medical University, and 37 from the Affiliated Dongguan Hospital, Southern Medical University) developed distant metastasis after primary radiation therapy. Metastatic lesions were divided into groups according to location: bones above the diaphragm (supraphrenic bone, SUP-B); bones below the diaphragm (subphrenic bone, SUB-B); distant lymph nodes above the diaphragm (supraphrenic distant lymph nodes, SUP-DLN); distant lymph nodes below the diaphragm (subphrenic distant lymph nodes, SUB-DLN), liver, lung, and other lesions beyond bone/lung/distant lymph node above the diaphragm (supraphrenic other lesions, SUP-OL); other lesions beyond bone/liver/distant lymph node below the diaphragm (subphrenic other lesions, SUB-OL); the subtotal above the diaphragm (supraphrenic total lesions, SUP-TL); and the subtotal below the diaphragm (subphrenic total lesions, SUB-TL). Kaplan–Meier methods were used to estimate the probability of patients’ overall survival (OS). Univariate and multivariate analyses were applied using the Cox proportional hazard model to explore prediction factors of OS.

Results

The most frequent metastatic locations were bone (45.2%), lung (40.6%), liver (32.0%), and distant lymph nodes (20.1%). The total number of distant lymph node metastasis was 44, of which 22 (10.0%) were above the diaphragm, 18 (8.2%) were below the diaphragm, and 4 (1.8%) were both above and below the diaphragm. Age (HR: 1.02, 95% CI: 1.00, 1.03, p = 0.012), N stage (HR: 1.26, 95% CI: 1.04, 1.54, p = 0.019), number of metastatic locations (HR: 1.39, 95% CI: 1.12, 1.73, p = 0.003), bone (HR: 1.65, 95% CI: 1.20, 2.25, p = 0.002), SUB-B (HR: 1.51, 95% CI: 1.07, 2.12, p = 0.019), SUB-DLN (HR: 1.72, 95% CI: 1.03, 2.86, p = 0.038), and SUB-O L(HR: 4.46, 95% CI: 1.39, 14.3, p = 0.012) were associated with OS. Multivariate analyses revealed that a higher N stage (HR: 1.23, 95% CI: 1.00, 1.50, p = 0.048), SUB-DLN (HR: 1.72, 95% CI: 1.02, 2.90, p = 0.043), and SUB-OL (HR: 3.72, 95% CI: 1.14, 12.16, p = 0.029) were associated with worse OS.

Conclusion

Subphrenic lymph node metastasis predicts poorer prognosis for NPC patients with metachronous metastasis; however, this needs validation by large prospective studies.
Diagnostic Performance of FDG-PET/CT Scan as Compared to US-Guided FNA in Prediction of Axillary Lymph Node Involvement in Breast Cancer Patients
Authors: Assi Hazem I. , Alameh Ibrahim A. , Khoury Jessica , Bou Zerdan Maroun , Akiki Vanessa , Charafeddine Maya , El Saheb Ghida I. , Sukhon Fares , Sbaity Eman , Baydoun Serine , Shabb Nina , Berjawi Ghina , Haidar Mohamad B.
Published: October 2021

Purpose

The aim of this study was to evaluate the diagnostic ability of 2-deoxy-2-[fluorine-18]fluoro-d-glucose (18F-FDG) PET/non-contrast CT compared with those of ultrasound (US)-guided fine needle aspiration (FNA) for axillary lymph node (ALN) staging in breast cancer patients.

Patients and Methods

Preoperative 18F-FDG PET/non-contrast CT was performed in 268 women with breast cancer, as well as ALN dissection or sentinel lymph node (SLN) biopsy. One hundred sixty-four patients underwent US-guided FNA in combination with 18F-FDG PET/CT. The diagnostic performance of each modality was evaluated using histopathologic assessments as the reference standard. The receiver operating characteristic (ROC) curves were compared to evaluate the diagnostic ability of several imaging modalities.

Results

Axillary 18F-FDG uptake was positive in 180 patients, and 125 patients had axillary metastases according to the final pathology obtained by ALN dissection and/or SLN dissection. Of the patients with positive 18F-FDG uptake in the axilla, 21% had false-positive results, whereas 79% were truly positive. Eighty-eight patients had negative 18F-FDG uptake in the axilla, among which 25% were false-negative. 18F-FDG-PET/CT had a sensitivity of 86.59% and a specificity of 63.46% in the assessment of ALN metastasis; on the other hand, US-guided FNA had a sensitivity of 91.67% and a specificity of 87.50%. The mean primary cancer size (p = 0.04) and tumor grade (p = 0.04) in combination were the only factors associated with the accuracy of 18F-FDG PET/CT for detecting metastatic ALNs.

Conclusion

The diagnostic performance of 18F-FDG PET/CT for the detection of axillary node metastasis in breast cancer patients was not significantly different from that of US-guided FNA. Combining 18F-FDG PET/CT with US-guided FNA or SLN biopsy could improve the diagnostic performance compared to 18F-FDG PET/CT alone.
High-Throughput Strategies for the Discovery of Anticancer Drugs by Targeting Transcriptional Reprogramming
Authors: Huang Lijun , Yi Xiaohong , Yu Xiankuo , Wang Yumei , Zhang Chen , Qin Lixia , Guo Dale , Zhou Shiyi , Zhang Guanbin , Deng Yun , Bao Xilinqiqige , Wang Dong
Published: October 2021

Transcriptional reprogramming contributes to the progression and recurrence of cancer. However, the poorly elucidated mechanisms of transcriptional reprogramming in tumors make the development of effective drugs difficult, and gene expression signature is helpful for connecting genetic information and pharmacologic treatment. So far, there are two gene-expression signature-based high-throughput drug discovery approaches: L1000, which measures the mRNA transcript abundance of 978 “landmark” genes, and high-throughput sequencing-based high-throughput screening (HTS2); they are suitable for anticancer drug discovery by targeting transcriptional reprogramming. L1000 uses ligation-mediated amplification and hybridization to Luminex beads and highlights gene expression changes by detecting bead colors and fluorescence intensity of phycoerythrin signal. HTS2 takes advantage of RNA-mediated oligonucleotide annealing, selection, and ligation, high throughput sequencing, to quantify gene expression changes by directly measuring gene sequences. This article summarizes technological principles and applications of L1000 and HTS2, and discusses their advantages and limitations in anticancer drug discovery.
Risk Factors for the Development of Hemophagocytic Lymphohistiocytosis in Children With Severe Adenovirus Pneumonia: A Single-Center Retrospective Study
Authors: Zhang Hua-yong , Xiao Min , Yan Fan , Zhang Mao-rong , Zhang Yong
Published: October 2021

Objective: To investigate and analyze the relevant risk factors for hemophagocytic lymphohistiocytosis (HLH) in children with severe adenovirus pneumonia (SAP).

Methods: A retrospective study of children with SAP was performed in 30 cases developing HLH and 94 cases not developing HLH from December 2018 to August 2019. The binary logistic regression analysis was used to identify risk factors that were significantly associated with the development of HLH after the univariate analysis, and the receiver operating characteristic (ROC) curve was performed to find out the cut-off value for the significant relevant factors.

Results: Two factors were associated with the development of HLH, which were the length of fever (OR = 1.331, 95%CI: 1.002–1.769) and triglycerides (TG) (OR = 17.345, 95%CI: 1.358–221.538). The cut-off value of the length of fever was 12.5 days, and the cut-off value of TG was 3.02 mmol/L.

Conclusion: Children with SAP who had a duration of fever over 12.5 days and the TG level over 3.02 mmol/L are more likely to develop HLH.
Case Report: High-Gamma Oscillations on an Ictal Electroencephalogram in a Newborn Patient With Hypoxic–Ischemic Encephalopathy
Authors: Takeuchi Akihito , Inoue Takushi , Nakamura Makoto , Kageyama Misao , Akiyama Tomoyuki , Kobayashi Katsuhiro
Published: October 2021

Fast oscillations (FOs) >40 Hz in electroencephalograms (EEGs) are associated with ictogenesis and epileptogenesis in adults and children with epilepsy. However, only a few previous studies showed FOs in neonates. Reported frequencies of such neonatal FOs were in the low-gamma (<60 Hz) band and, therefore, they were not high compared to those in pediatric patients. We herein report a newborn patient with severe hypoxic–ischemic encephalopathy (HIE), who showed pathological FOs with a frequency in the high-gamma band. She was born at a gestational age of 39 weeks 4 days by emergency cesarean section because of non-reassuring fetal status. She had focal motor seizures involving unilateral upper and lower limbs lasting for tens of seconds on days 0, 1, 4, 5, 8, and 9 and subclinical seizures on days 4–11. Phenobarbital (PB) was intravenously administered on days 0, 2, 4, 5, and 6. We found FOs that were superimposed on the ictal delta activities using visual inspection and time–frequency analysis on 8–11 days of age. Among them, we detected high-gamma (71.4–100 Hz) oscillations that appeared to be temporally independent of low-gamma activities in the ictal EEG on 11 days of age. To the best of our knowledge, this is one of the earliest reports showing pathological FOs with a frequency of >60 Hz in the high-gamma band in human neonatal seizures, which were previously observed in animal studies. Further studies are needed to elucidate the pathophysiology of ictal FOs in neonatal seizures.
Sleep Monitoring of Children With Nocturnal Enuresis: A Narrative Review
Authors: Zhu Binbin , Zou Kun , He Jianhua , Huang Xueqin , Zhu Weichao , Ahmad Harb Ahmad Khaled , Wang Jianhua , Luo Aiping
Published: October 2021

The purpose of this article is to provide a succinct summary of the sleep monitoring efforts that have been used in nocturnal enuresis (NE) and an overview of the knowledge that has accrued. This is not intended to be a comprehensive review, but rather is intended to highlight how polysomnography (PSG), a common sleep detection tool, has contributed to our understanding of NE, as arousal disorder is considered to be one of the important mechanisms. The authors have organized this report by analysis and display of different ingredients of PSG, starting with comparing the electroencephalogram (EEG) of controls and the enuretic children and then moving to evaluation of respiratory patterns of NE and comorbid disease obstructive sleep apnea (OSA). In addition, the authors' goal is to better understand the mechanism of NE by integrating various levels of sleep monitoring; those sleep-related clinical scale scores for NE are presented to date. Finally, we propose further research of NE to explore the microstructure alterations via PSG combined with EEG–fMRI or to use novel technology like portable device internet and deep learning strategy.