bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenotypic prevalence of obesity and metabolic syndrome among an underdiagnosed and underscreened population of over 50 million children and adults
Authors: Kim Eric GR , Kaelber David C
Published: September 2022

Background: Metabolic syndrome is a phenotypic condition associated with a variety of genotypes. Studies of rare genotypes can be made more difficult by clinical underscreening of the population for the phenotypic traits that define metabolic syndrome to clinicians. Studies have demonstrated underdiagnosis of pediatric obesity, as well as reduced rates of pediatric screening for obesity related conditions, including conditions leading to a diagnosis of metabolic syndrome. If true, there may be a significant underdiagnosis of metabolic syndrome among the pediatric population compared to the adult population.

Methods: Using Epic’s Cosmos Data Network aggregated, de-identified patient data collected from healthcare organizations using the Epic electronic health record (EHR), we examined obesity and metabolic syndrome rates among adult and pediatric patients. We also examined screening rates for obesity related conditions and metabolic syndrome among adult and pediatric patients across the United States. We also sought to compare rates between subgroups within the population including age, sex, and race.

Results: In our population, 45% of adults and 27% of pediatric population were obese by age and gender specific BMI criteria. 38% of the obese adult population had an ICD-10 code associated with the diagnosis vs. 52% of the pediatric population. Of adults meeting obesity criteria, 36% had results for appropriate, guideline-based blood laboratory testing for insulin resistance, 40–42% for dyslipidemia, and 55% for hepatic steatosis. 36% of obese adult patients had none of the recommended blood laboratory testing. 31% of the adult population met diagnostic criteria for metabolic syndrome. Of pediatric patients meeting obesity criteria, 27% had results for appropriate blood laboratory testing for insulin resistance, 28% for dyslipidemia, and 33% for hepatic steatosis. 59% of obese pediatric patients had none of the recommended blood laboratory testing. 3% of the pediatric population met criteria for diagnosis of metabolic syndrome.

Discussion: This study represents one of the largest multicenter national cohorts assembled for studying metabolic syndrome (over 50 million patients) and demonstrates the power of emerging aggregated EHR tools for research. Although obesity is better diagnosed in pediatric patients than in adult patients, significantly lower screening rates for obesity related conditions occurred in pediatric patients compared to adults. Statistically significant, but clinically negligible differences in screening rates were found by race and gender. These results support smaller prior studies that suggest that obesity is under-diagnosed and obesity related conditions underscreened in pediatric and adult populations, and additionally suggests underdiagnosis of metabolic syndrome among United States pediatric and adult patients.
Multi‑institutional development and validation of a nomogram to predict prognosis of early-onset gastric cancer patients
Authors: Liu Hongda , Li Zequn , Zhang Qun , Li Qingya , Zhong Hao , Wang Yawen , Yang Hui , Li Hui , Wang Xiao , Li Kangshuai , Wang Dehai , Kong Xiangrong , He Zhongyuan , Wang Weizhi , Wang Linjun , Zhang Diancai , Xu Hao , Yang Li , Chen Yuxin , Zhou Yanbing , Xu Zekuan
Published: September 2022

Background

Early-onset gastric cancer (EOGC, ≤45 years old) is characterized with increasing incidence and more malignant phenotypes compared with late-onset gastric cancer, which exhibits remarkable immune cell infiltration and is potential immunotherapeutic population. Till now, restricted survival information of EOGC is available due to limited case numbers. This study established a novel nomogram to help evaluate cancer-specific survival (CSS) of EOGC patients who underwent gastrectomy, and may provide evidence for predicting patients’ survival.

Methods

We retrospectively enrolled a cohort containing 555 EOGC cases from five independent medical centers in China, among which 388 cases were randomly selected into a training set while the other 167 cases were assigned into the internal validation set. Asian or Pacific Islander (API) patients diagnosed with EOGC during 1975-2016 were retrieved from the SEER database (n=299) and utilized as the external validation cohort. Univariate and multivariate analyses were conducted to test prognostic significances of clinicopathological factors in the training set. Accordingly, two survival nomogram models were established and compared by concordance index (C-index), calibration curve, receiver operating characteristics (ROC) curves and decision curve analyses (DCA).

Results

The 5-year CSS rate of training cohort was 61.3% with a median survival time as 97.2 months. High consistency was observed on calibration curves in all three cohorts. Preferred nomogram was selected due to its better performance on ROC and DCA results. Accordingly, a novel predicative risk model was introduced to better stratify high-risk EOGC patients with low-risk patients. In brief, the 5-year CSS rates for low-risk groups were 92.9% in training set, 83.1% in internal validation set, 89.9% in combined NQSQS cohort, and 85.3% in SEER-API cohort. In contrast, the 5-year CSS rates decreased to 38.5%, 44.3%, 40.5%, and 36.9% in the high-risk groups of the four cohorts above, respectively. The significant survival difference between high-risk group (HRG) and low-risk group (LRG) indicated the precise accuracy of our risk model. Furthermore, the risk model was validated in patients with different TNM stages, respectively. Finally, an EOGC web-based survival calculator was established with public access, which can help predict prognosis.

Conclusions

Our data provided a precise nomogram on predicting CSS of EOGC patients with potential clinical applicability.
Longitudinal profiles of plasma gelsolin, cytokines and antibody expression predict COVID-19 severity and hospitalization outcomes
Authors: Asare-Werehene Meshach , McGuinty Michaeline , Vranjkovic Agatha , Galipeau Yannick , Cowan Juthaporn , Cameron Bill , Cooper Curtis L. , Langlois Marc-André , Crawley Angela M. , Tsang Benjamin K.
Published: September 2022

Background

Prognostic markers for COVID-19 disease outcome are currently lacking. Plasma gelsolin (pGSN) is an actin-binding protein and an innate immune marker involved in disease pathogenesis and viral infections. Here, we demonstrate the utility of pGSN as a prognostic marker for COVID-19 disease outcome; a test performance that is significantly improved when combined with cytokines and antibodies compared to other conventional markers such as CRP and ferritin.

Methods

Blood samples were longitudinally collected from hospitalized COVID-19 patients as well as COVID-19 negative controls and the levels of pGSN in μg/mL, cytokines and anti- SARS-CoV-2 spike protein antibodies assayed. Mean ± SEM values were correlated with clinical parameters to develop a prognostic platform.

Results

pGSN levels were significantly reduced in COVID-19 patients compared to healthy individuals. Additionally, pGSN levels combined with plasma IL-6, IP-10 and M-CSF significantly distinguished COVID-19 patients from healthy individuals. While pGSN and anti-spike IgG titers together strongly predict COVID-19 severity and death, the combination of pGSN and IL-6 was a significant predictor of milder disease and favorable outcomes.

Conclusion

Taken together, these findings suggest that multi-parameter analysis of pGSN, cytokines and antibodies could predict COVID-19 hospitalization outcomes with greater certainty compared with conventional clinical laboratory markers such as CRP and ferritin. This research will inform and improve clinical management and health system interventions in response to SARS-CoV-2 infection.
Oral N-acetylcysteine decreases IFN-γ production and ameliorates ischemia-reperfusion injury in steatotic livers
Authors: Liggett Jedson R. , Kang Jiman , Ranjit Suman , Rodriguez Olga , Loh Katrina , Patil Digvijay , Cui Yuki , Duttargi Anju , Nguyen Sang , He Britney , Lee Yichien , Oza Kesha , Frank Brett S. , Kwon DongHyang , Li Heng-Hong , Kallakury Bhaskar , Libby Andrew , Levi Moshe , Robson Simon C. , Fishbein Thomas M. , Cui Wanxing , Albanese Chris , Khan Khalid , Kroemer Alexander
Published: September 2022

Type 1 Natural Killer T-cells (NKT1 cells) play a critical role in mediating hepatic ischemia-reperfusion injury (IRI). Although hepatic steatosis is a major risk factor for preservation type injury, how NKT cells impact this is understudied. Given NKT1 cell activation by phospholipid ligands recognized presented by CD1d, we hypothesized that NKT1 cells are key modulators of hepatic IRI because of the increased frequency of activating ligands in the setting of hepatic steatosis. We first demonstrate that IRI is exacerbated by a high-fat diet (HFD) in experimental murine models of warm partial ischemia. This is evident in the evaluation of ALT levels and Phasor-Fluorescence Lifetime (Phasor-FLIM) Imaging for glycolytic stress. Polychromatic flow cytometry identified pronounced increases in CD45+CD3+NK1.1+NKT1 cells in HFD fed mice when compared to mice fed a normal diet (ND). This observation is further extended to IRI, measuring ex vivo cytokine expression in the HFD and ND. Much higher interferon-gamma (IFN-γ) expression is noted in the HFD mice after IRI. We further tested our hypothesis by performing a lipidomic analysis of hepatic tissue and compared this to Phasor-FLIM imaging using “long lifetime species”, a byproduct of lipid oxidation. There are higher levels of triacylglycerols and phospholipids in HFD mice. Since N-acetylcysteine (NAC) is able to limit hepatic steatosis, we tested how oral NAC supplementation in HFD mice impacted IRI. Interestingly, oral NAC supplementation in HFD mice results in improved hepatic enhancement using contrast-enhanced magnetic resonance imaging (MRI) compared to HFD control mice and normalization of glycolysis demonstrated by Phasor-FLIM imaging. This correlated with improved biochemical serum levels and a decrease in IFN-γ expression at a tissue level and from CD45+CD3+CD1d+ cells. Lipidomic evaluation of tissue in the HFD+NAC mice demonstrated a drastic decrease in triacylglycerol, suggesting downregulation of the PPAR-γ pathway.
Developing dendritic cell for SARS-CoV-2 vaccine: Breakthrough in the pandemic
Authors: Jonny Jonny , Putranto Terawan Agus , Irfon Raoulian , Sitepu Enda Cindylosa
Published: September 2022

Finding a vaccine that can last a long time and effective against viruses with high mutation rates such as SARS-CoV-2 is still a challenge today. The various vaccines that have been available have decreased in effectiveness and require booster administration. As the professional antigen presenting cell, Dendritic Cells can also activate the immune system, especially T cells. This ability makes dendritic cells have been developed as vaccines for some types of diseases. In SARS-CoV-2 infection, T cells play a vital role in eliminating the virus, and their presence can be detected in the long term. Hence, this condition shows that the formation of T cell immunity is essential to prevent and control the course of the disease. The construction of vaccines oriented to induce strong T cells response can be formed by utilizing dendritic cells. In this article, we discuss and illustrate the role of dendritic cells and T cells in the pathogenesis of SARS-CoV-2 infection and summarizing the crucial role of dendritic cells in the formation of T cell immunity. We arrange the basis concept of developing dendritic cells for SARS-CoV-2 vaccines. A dendritic cell-based vaccine for SARS-CoV-2 has the potential to be an effective vaccine that solves existing problems.
In silico metatranscriptomic approach for tracking biofilm-related effectors in dairies and its importance for improving food safety
Authors: de Almeida Otávio Guilherme Gonçalves , Pereira Marita Gimenez , Oxaran Virginie , De Martinis Elaine Cristina Pereira , Alves Virgínia Farias
Published: September 2022

Sessile microorganisms are usually recalcitrant to antimicrobial treatments, and it is possible that finding biofilm-related effectors in metatranscriptomics datasets helps to understand mechanisms for bacterial persistence in diverse environments, by revealing protein-encoding genes that are expressed in situ. For this research, selected dairy-associated metatranscriptomics bioprojects were downloaded from the public databases JGI GOLD and NCBI (eight milk and 45 cheese samples), to screen for sequences encoding biofilm-related effectors. Based on the literature, the selected genetic determinants were related to adhesins, BAP, flagellum-related, intraspecific QS (AHL, HK, and RR), interspecific QS (LuxS), and QQ (AHL-acylases, AHL-lactonases). To search for the mRNA sequences encoding for those effector proteins, a custom database was built from UniprotKB, yielding 1,154,446 de-replicated sequences that were indexed in DIAMOND for alignment. The results revealed that in all the dairy-associated metatranscriptomic datasets obtained, there were reads assigned to genes involved with flagella, adhesion, and QS/QQ, but BAP-reads were found only for milk. Significant Pearson correlations (p < 0.05) were observed for transcripts encoding for flagella, RR, histidine kinases, adhesins, and LuxS, although no other significant correlations were found. In conclusion, the rationale used in this study was useful to demonstrate the presence of biofilm-associated effectors in metatranscriptomics datasets, pointing out to possible regulatory mechanisms in action in dairy-related biofilms, which could be targeted in the future to improve food safety.
Transcriptome sequencing analysis of echovirus 30 infection reveals its potential pathogenesis
Authors: Sun Qiang , Li Jichen , Zhang Bo , Wang Rui , Wang Congcong , Li Xiaoliang , Liu Ying , Zhang Yong
Published: September 2022

Echovirus 30 (E30) causes various diseases, such as viral encephalitis; aseptic meningitis; hand, foot, and mouth diseases; and acute flaccid paralysis. Related neurological infections are most concerning. However, the molecular mechanisms of E30 pathogenesis are not fully understood. There is a growing research interest in E30 as a cause of neurological disease. The aim of this study was to describe E30 infection, especially the changes in differential factor expressions after infection, in human glioma (U251) cells and mice brains using transcriptome sequencing analysis. Clear changes in the gene expression of factors associated with the defense response to viruses, inflammation-related signaling pathways, and neurological complication-related pathways were observed. Our results suggest that after E30 infection, the genes related to immune response were induced in the human glioma cells and mice brains, whereas genes functioning in the development and function of neural tissue were inhibited. Overall, this study successfully established E30 infection of U251 and mouse brain tissue, profiled the infection-induced changes in cellular and organizational transcriptomes, and revealed the molecular level changes during E30 infection.
The bacteriocin Angicin interferes with bacterial membrane integrity through interaction with the mannose phosphotransferase system
Authors: Vogel Verena , Olari Lia-Raluca , Jachmann Marie , Reich Sebastian J. , Häring Michelle , Kissmann Ann-Kathrin , Rosenau Frank , Riedel Christian U. , Münch Jan , Spellerberg Barbara
Published: September 2022

In a natural environment, bacteria are members of multispecies communities. To compete with rival species, bacteria produce antimicrobial peptides (AMPs), called bacteriocins. Bacteriocins are small, cationic, ribosomally synthesized peptides, which normally inhibit closely related species of the producing organism. Bacteriocin production is best studied in lactic bacteria (LAB). Streptococcus anginosus, belonging to LAB, produces the potent bacteriocin Angicin, which shows inhibitory activity against other streptococci, Listeria monocytogenes and vancomycin resistant Enterococcus faecium (VRE). Furthermore, Angicin shows a high resistance toward pH changes and heat, rendering it an interesting candidate for food preservation or clinical applications. The inhibitory activity of Angicin depends on the presence of a mannose phosphotransferase system (Man-PTS) in target cells, since L. monocytogenes harboring a deletion in an extracellular loop of this system is no longer sensitive to Angicin. Furthermore, we demonstrated by liposome leakage and pHluorin assays that Angicin destroys membrane integrity but shows only low cytotoxicity against human cell lines. In conclusion, we show that Angicin has a detrimental effect on the membrane of target organisms by using the Man-PTS as a receptor.
Coordinate regulation of methanol utilization pathway genes of Komagataella phaffii by transcription factors and chromatin modifiers
Authors: Gupta Aditi , Rangarajan Pundi N.
Published: September 2022

The methylotrophic yeast Komagataella phaffii (a.k.a. Pichia pastoris) harbors a methanol utilization (MUT) pathway, enabling it to utilize methanol as the sole source of carbon. The nexus between transcription factors such as Mxr1p and Trm1p and chromatin-modifying enzymes in the regulation of genes of MUT pathway has not been well studied in K. phaffii. Using transcriptomics, we demonstrate that Gcn5, a histone acetyltransferase, and Gal83, one of the beta subunits of nuclear-localized SNF1 (sucrose non-fermenting 1) kinase complex are essential for the transcriptional regulation by the zinc finger transcription factors Mxr1p and Trm1p. We conclude that interactions among Gcn5, Snf1, Mxr1p, and Trm1p play a critical role in the transcriptional regulation of genes of MUT pathway of K. phaffii.
Diagnostic and predictive values of serum metabolic profiles in sudden sensorineural hearing loss patients
Authors: Wang Xiangsheng , Gao Yan , Jiang Ruirui
Published: September 2022

Sudden sensorineural hearing loss (SSNHL) is an otologic emergency, and metabolic disturbance is involved in its pathogenesis. This study recruited 20 SSNHL patients and 20 healthy controls (HCs) and collected their serum samples. Serum metabolites were detected by liquid chromatography-mass spectrometry, and metabolic profiles were analyzed. All patients were followed up for 3 months and categorized into recovery and non-recovery groups. The distinctive metabolites were assessed between two groups, and their predictive values for hearing recovery were evaluated. Analysis results revealed that SSNHL patients exhibited significantly characteristic metabolite signatures compared to HCs. The top 10 differential metabolites were further analyzed, and most of them showed potential diagnostic values based on receiver operator characteristic (ROC) curves. Finally, 14 SSNHL patients were divided into the recovery group, and six patients were included in the non-recovery group. Twelve distinctive metabolites were observed between the two groups, and ROC curves demonstrated that N4-acetylcytidine, p-phenylenediamine, sphingosine, glycero-3-phosphocholine, and nonadecanoic acid presented good predictabilities in the hearing recovery. Multivariate analysis results demonstrated that serum N4-Acetylcytidine, sphingosine and nonadecanoic acid levels were associated with hearing recovery in SSNHL patients. Our results identified that SSNHL patients exhibited distinctive serum metabolomics signatures, and several serum biomarkers were proved to be potential in predicting hearing recovery. The discriminative metabolites might contribute to illustrating the mechanisms of SSNHL and provide possible clues for its treatments.
The Charlotte Project: Recommendations for patient-reported outcomes and clinical parameters in Dravet syndrome through a qualitative and Delphi consensus study
Authors: Aledo-Serrano Ángel , Mingorance Ana , Villanueva Vicente , García-Peñas Juan José , Gil-Nagel Antonio , Boronat Susana , Aibar JoséÁngel , Cámara Silvia , Yániz María José , Aras Luis Miguel , Blanco Bárbara , Sánchez-Carpintero Rocío
Published: September 2022

Objective

The appropriate management of patients with Dravet Syndrome (DS) is challenging, given the severity of symptoms and the burden of the disease for patients and caregivers. This study aimed to identify, through a qualitative methodology and a Delphi consensus-driven process, a set of recommendations for the management of DS to guide clinicians in the assessment of the clinical condition and quality of life (QoL) of DS patients, with a special focus on patient- and caregiver-reported outcomes (PROs).

Methods

This study was conducted in five phases, led by a multidisciplinary scientific committee (SC) including pediatric neurologists, epileptologists, a neuropsychologist, an epilepsy nurse, and members of DS patient advocates. In phases 1 and 2, a questionnaire related to patients' QoL was prepared and answered by caregivers and the SC. In phase 3, the SC generated, based on these answers and on a focus group discussion, a 70-item Delphi questionnaire, covering six topic categories on a nine-point Likert scale. In phase 4, 32 panelists, from different Spanish institutions and with a multidisciplinary background, answered the questionnaire. Consensus was obtained and defined as strong or moderate if ≥80% and 67–79% of panelists, respectively, rated the statement with ≥7. Phase 5 consisted of the preparation of the manuscript.

Results

The panelists agreed on a total of 69 items (98.6%), 54 (77.14%), and 15 (21.43%) with strong and moderate consensus, respectively. The experts' recommendations included the need for frequent assessment of patient and caregivers QoL parameters. The experts agreed that QoL should be assessed through specific questionnaires covering different domains. Likewise, the results showed consensus regarding the regular evaluation of several clinical parameters related to neurodevelopment, attention, behavior, other comorbidities, and sudden unexpected death in epilepsy (SUDEP). A consensus was also reached on the instruments, specific parameters, and caregivers' education in the routine clinical management of patients with DS.

Conclusions

This consensus resulted in a set of recommendations for the assessment of clinical and QoL parameters, including PROs, related to the general evaluation of QoL, neurodevelopment, attention, behavior, other comorbidities affecting QoL, SUDEP, and QoL of caregivers/relatives and patients with DS.
Pathological pericyte expansion and impaired endothelial cell-pericyte communication in endothelial Rbpj deficient brain arteriovenous malformation
Authors: Selhorst Samantha , Nakisli Sera , Kandalai Shruthi , Adhicary Subhodip , Nielsen Corinne M.
Published: September 2022

Pericytes, like vascular smooth muscle cells, are perivascular cells closely associated with blood vessels throughout the body. Pericytes are necessary for vascular development and homeostasis, with particularly critical roles in the brain, where they are involved in regulating cerebral blood flow and establishing the blood-brain barrier. A role for pericytes during neurovascular disease pathogenesis is less clear—while some studies associate decreased pericyte coverage with select neurovascular diseases, others suggest increased pericyte infiltration in response to hypoxia or traumatic brain injury. Here, we used an endothelial loss-of-function Recombination signal binding protein for immunoglobulin kappa J region (Rbpj)/Notch mediated mouse model of brain arteriovenous malformation (AVM) to investigate effects on pericytes during neurovascular disease pathogenesis. We tested the hypothesis that pericyte expansion, via morphological changes, and Platelet-derived growth factor B/Platelet-derived growth factor receptor β (Pdgf-B/Pdgfrβ)-dependent endothelial cell-pericyte communication are affected, during the pathogenesis of Rbpj mediated brain AVM in mice. Our data show that pericyte coverage of vascular endothelium expanded pathologically, to maintain coverage of vascular abnormalities in brain and retina, following endothelial deletion of Rbpj. In Rbpj-mutant brain, pericyte expansion was likely attributed to cytoplasmic process extension and not to increased pericyte proliferation. Despite expanding overall area of vessel coverage, pericytes from Rbpj-mutant brains showed decreased expression of Pdgfrβ, Neural (N)-cadherin, and cluster of differentiation (CD)146, as compared to controls, which likely affected Pdgf-B/Pdgfrβ-dependent communication and appositional associations between endothelial cells and pericytes in Rbpj-mutant brain microvessels. By contrast, and perhaps by compensatory mechanism, endothelial cells showed increased expression of N-cadherin. Our data identify cellular and molecular effects on brain pericytes, following endothelial deletion of Rbpj, and suggest pericytes as potential therapeutic targets for Rbpj/Notch related brain AVM.
Quantitative description of the relationship between the enhancement of distraction-suppression and brain local state alteration after transcranial direct current stimulation
Authors: Zhang Di , Liu Jiaojiao , Fan Li , Liu Qiang
Published: September 2022

Anodal transcranial direct current stimulation (tDCS) over the left dorsal lateral prefrontal cortex (lDLPFC) can improve distraction suppression ability, possibly by distantly regulating the connection properties of several large-scale brain networks and local brain state changes. However, little is known about the local state alteration that tDCS can induce in distant but task-related regions and the relationship between performance enhancement and local state alteration in potentially related regions, resulting in inefficient and uncertain tDCS regulation. We aimed to examine the alteration of brain local state before and after tDCS and its relationship with performance enhancement. With the within-subject design, the participants received anodal (1.5 mA) and sham tDCS at F3 (lDLPFC) for 20 min. The visual search task and resting-state functional magnetic resonance imaging (rsfMRI) were performed before and after stimulation. Anodal tDCS significantly enhanced distraction suppression. The amplitude of low-frequency fluctuation (ALFF) in the left parietal region significantly decreased, the decrement significantly positively correlated with performance enhancement after anodal tDCS. As well, the regional homogeneity (ReHo) in the left precuneus significantly increased, and the increasement significantly positively correlated with performance enhancement. Anodal tDCS over the lDLPFC can distantly modulate the local state of the brain and improve the distraction suppression ability. These two aspects are closely related and provide a direct and efficient approach to enhancing performance.
Wheat supplement with buckwheat affect gut microbiome composition and circulate short-chain fatty acids
Authors: Yao Di , Yu Qiaoru , Xu Lei , Su Tingting , Ma Lixue , Wang Xiaoyu , Wu Mengna , Li Zhijiang , Zhang Dongjie , Wang Changyuan
Published: September 2022

Buckwheat has beneficial effects on human intestinal health, which is often compounded with wheat to make food. Therefore, the effect of cereals mixture via in vitro fermentation on gut microbes and short-chain fatty acids (SCFAs) were investigated in this study. The mixture of wheat and tartary buckwheat (WT) produced more lactate and acetate, and the mixture of wheat and sweet buckwheat (WE) produced more propionate and butyrate. Compared with wheat (WA), the relative abundance of some beneficial bacteria significantly increased, such as Sutterella in WT and Faecalibacterium in WE. Cereals mixture also affected the expression of functional genes, involved in metabolic pathways and carbohydrate-active enzymes (CAZymes) that modulated SCFAs generation. This study provides new insights into the effects of sweet and tartary buckwheat on intestinal function, which is beneficial to applying both types of buckwheat in practical.
Prospective evaluation of the role of imaging techniques and TMPRSS2:ERG mutation for the diagnosis of clinically significant prostate cancer
Authors: Lazzeri Massimo , Fasulo Vittorio , Lughezzani Giovanni , Benetti Alessio , Soldà Giulia , Asselta Rosanna , De Simone Ilaria , Paciotti Marco , Avolio Pier Paolo , Contieri Roberto , Saitta Cesare , Saita Alberto , Hurle Rodolfo , Guazzoni Giorgio , Buffi Nicolò Maria , Casale Paolo
Published: September 2022

Objectives

To test the hypothesis of a relationship between a specific genetic lesion (T2:ERG) and imaging scores, such as PI-RADS and PRI-MUS, and to test the effectiveness of these parameters for the diagnosis of prostate cancer (PCa) and clinically significant PCa (csPCa).

Materials and methods

This is a prospective study of men with suspected PCa enrolled between 2016 and 2019 at a high-volume tertiary hospital. Patients underwent systematic US-guided biopsy, plus targeted biopsy if they were presenting with >=1 suspicious lesion (PI-RADS>2) at mpMRI or PR-IMUS >2 at micro-ultrasound assessment. For each patient, one core from the highest PI-RADS or PRI-MUS lesion was collected for T2:ERG analysis. Multivariable logistic regression models (LRMs) were fitted for csPCa with a clinical model (age, total PSA, previous biopsy, family history for PCa), a clinical plus PI-RADS, clinical plus T2:ERG, clinical plus PI-RADS plus T2:ERG, and T2:ERG plus PI-RADS alone.

Results

The cohort consists of 158 patients: 83.5% and 66.2% had respectively a diagnosis of PCa and csPCa after biopsy. A T2:ERG fusion was found in 37 men and 97.3% of these patients harbored PCa, while 81.1% were diagnosed with csPCa. SE of T2:ERG assay for csPCa was 28.8%, SP 87.0%, NPV 38.8%, and PPV 81.1%. Of 105 patients who performed mpMRI 93.% had PIRADS ≥3. SE of mpMRI for csPCa was 98.5%, SP was 12.8%, NPV was 83.3%, and PPV was 65.7%. Among 67 patients who were subjected to micro-US, 90% had a PRI-MUS ≥3. SE of micro-US for csPCa was 89.1%, SP was 9.52%, NPV was 28.6%, and PPV was 68.3%. At univariable LRM T2:ERG was confirmed as independent of mpMRI and micro-US result (OR 1.49, p=0.133 and OR 1.82, p=0.592, respectively). At multivariable LRM the clinical model alone had an AUC for csPCa of 0.74 while the clinical model including PI-RADS and T2:ERG achieved an AUC of 0.83.

Conclusions

T2:ERG translocation and imaging results are independent of each other, but both are related csPCa. To evaluate the best diagnostic work-up for PCa and csPCa detection, all available tools (T2:ERG detection and imaging techniques) should be employed together as they appear to have a complementary role.
microRNA-145-5p inhibits prostate cancer bone metastatic by modulating the epithelial-mesenchymal transition
Authors: Luo Bingfeng , Yuan Yuan , Zhu Yifei , Liang Songwu , Dong Runan , Hou Jian , Li Ping , Xing Yaping , Lu Zhenquan , Lo Richard , Kuang Guan-Ming
Published: September 2022

Objective

To investigate the effects of miRNA-145-5p on the tumor development and progression of prostate cancer (Pca) bone metastasis.

Methods

Levels of miRNA-145-5p were assessed by real-time quantitative PCR in PC3 (bone metastatic Pca cells), 22RV1 (non-metastatic Pca cells), RWPE-1 (non-cancerous prostate epithelial cells) and Pca tissues collected from patients with and without bone metastases. The impact of miRNA-145-5p on cell proliferation was tested by CCK8 assay, colony formation assay and flow cytometric cell cycle analysis. Effects on invasion and migration of PC3 cells were determined by Transwell and wound healing assays. Western blotting, enzyme-linked immunosorbent assay, and flow cytometry apoptosis analyses were also performed to assess roles in metastasis.

Results

Levels of miRNA-145-5p were decreased in Pca bone metastases and miRNA-145-5p inhibited cell proliferation, migration and invasion. miRNA-145-5p inhibited the expression of basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF) and transforming growth factor-β (TGF-β) in PC3 cells. miR-145-5p increased the expression of the epithelial marker E-cadherin and reduced the expression of matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9). It was found that miRNA-145-5p mediated the epithelial-mesenchymal transition (EMT) and induced apoptosis.

Conclusions

miRNA-145-5p negatively regulated the EMT, inhibited Pca bone metastasis and promoted apoptosis in Pca bone metastasis. Mimicry of miRNA-145-5p action raises the possibility of a novel target for treating Pca with bone metastases.
A systematic review and meta-analysis of surgeries performed for cerebral cavernous malformation-related epilepsy in pediatric patients
Authors: Gao Xiangyu , Yue Kangyi , Sun Jidong , Fang Zheng , Cao Yuan , Zhao Boyan , Zhang Haofuzi , Dai Shuhui , Zhang Lei , Luo Peng , Jiang Xiaofan
Published: September 2022

Background

The clinical benefit of surgery for the treatment of cerebral cavernous malformation (CCM)-related epilepsy in pediatric patients is still controversial. Although surgical treatment of CCM-related epilepsy in children is widely recognized, the clinical benefits of controlling the seizure rate must be balanced against the risk of leading to perioperative morbidity.

Methods

We conducted a comprehensive search to identify relevant studies via Ovid Medline, Web of Science and PubMed (January 1995–June 2020). The following search terms were used: “hemangioma, cavernous, central nervous system,” “brain cavernous hemangioma,” “cerebral cavernous hemangioma,” “CCM,” “epilepsy,” and “seizures.” The seizure control rate and the risk of postoperative adverse outcomes along with their 95% confidence intervals (CIs) were calculated.

Results

A total of 216 patients across 10 studies were included in meta-analysis. The results showed that the control rate of epilepsy was 88% (95% CI: 76–95%). Four percent (95% CI: 2–10%) of the patients experienced temporary symptomatic adverse effects following surgical resection, and 3% (95% CI: 0–26%) of the patients developed permanent symptomatic adverse effects in the long-term follow-up after surgical excision of the CCMs. None of the patients died as a result of the CCMs or surgical treatment.

Conclusion

Surgery is an effective and safe treatment for CCM –related epilepsy in pediatric patients with a low risk of postoperative complications and death.
Uncovering incontinentia pigmenti: From DNA sequence to pathophysiology
Authors: How Kang Nien , Leong Hazel Jing Yi , Pramono Zacharias Aloysius Dwi , Leong Kin Fon , Lai Zee Wei , Yap Wei Hsum
Published: September 2022

Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis. The disease is known to be caused by recurrent deletion of exons 4–10 of the Inhibitor Of Nuclear Factor Kappa B Kinase Regulatory Subunit Gamma (IKBKG) gene located at the Xq28 chromosomal region, which encodes for NEMO/IKKgamma, a regulatory protein involved in the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB plays a prominent role in the modulation of cellular proliferation, apoptosis, and inflammation. IKBKG mutation that results in a loss-of-function or dysregulated NF-κB pathway contributes to the pathophysiology of IP. Aside from typical skin characteristics such as blistering rash and wart-like skin growth presented in IP patients, other clinical manifestations like central nervous system (CNS) and ocular anomalies have also been detected. To date, the clinical genotype-phenotype correlation remains unclear due to its highly variable phenotypic expressivity. Thus, genetic findings remain an essential tool in diagnosing IP, and understanding its genetic profile allows a greater possibility for personalized treatment. IP is slowly and gradually gaining attention in research, but there is much that remains to be understood. This review highlights the progress that has been made in IP including the different types of mutations detected in various populations, current diagnostic strategies, IKBKG pathophysiology, genotype-phenotype correlation, and treatment strategies, which provide insights into understanding this rare mendelian disorder.
Correlation between arterial blood pressures and regional cerebral oxygen saturation in preterm neonates during postnatal transition-an observational study
Authors: Pfurtscheller Daniel , Wolfsberger Christina H. , Höller Nina , Schwaberger Bernhard , Mileder Lukas , Baik-Schneditz Nariae , Urlesberger Berndt , Pichler Gerhard
Published: September 2022

Objective

To assess whether blood pressure (systolic (SABP), diastolic (DABP), and mean arterial blood pressure (MABP) and cerebral-regional-oxygen-saturation (crSO2) and cerebral-fractional-tissue-oxygen-extraction (cFTOE) are associated after immediate fetal-to-neonatal transition in preterm neonates with and without respiratory support.

Study design

Post-hoc analyses of secondary outcome parameters of prospective observational studies were performed. We included moderate and late preterm neonates with and without respiratory support with cerebral NIRS monitoring (INVOS 5100c) and an oscillometric blood pressure measurement at minute 15 after birth. Heart rate (HR) and arterial oxygen saturation (SpO2) were monitored routinely. Blood pressure values were correlated with crSO2 and cFTOE.

Results

47 preterm neonates with NIRS measurements and blood pressure measurement during immediate transition after birth were included. Twenty-five preterm neonates (gestational age: 34.4±1.6 weeks) received respiratory support. In these neonates crSO2 correlated significantly positively with systolic blood pressure (SABP; r = 0.46, p = 0.021), diastolic blood pressure (DABP; r = 0.51, p = 0.009) and, mean arterial pressure (MABP; r = 0.48, p = 0.015). cFTOE correlated significantly negatively with SABP (r = −0.44, p = 0.027), DABP (r = −0.49, p = 0.013) and mean MABP (r = −0.44, p = 0.029). Twenty-two preterm neonates (gestational age: 34.5 ± 1.5 weeks) did not receive respiratory support. In those neonates, neither crSO2 nor cFTOE correlated with blood pressure.

Conclusion

In compromised moderate and late preterm neonates with respiratory support, both, crSO2 and cFTOE correlated with blood pressure. These findings suggest that passive pressure-dependent cerebral perfusion was present in preterm neonates with respiratory support, indicating an impaired cerebral autoregulation in those compromised preterm neonates.
m7G regulator-mediated molecular subtypes and tumor microenvironment in kidney renal clear cell carcinoma
Authors: Chen Mei , Nie Zhenyu , Gao Yuanhui , Cao Hui , Zheng Linlin , Guo Na , Peng Yanling , Zhang Shufang
Published: September 2022

Background: RNA methylation modification plays an important role in immune regulation. m7G RNA methylation is an emerging research hotspot in the RNA methylation field. However, its role in the tumor immune microenvironment of kidney renal clear cell carcinoma (KIRC) is still unclear.

Methods: We analyzed the expression profiles of 29 m7G regulators in KIRC, integrated multiple datasets to identify a novel m7G regulator-mediated molecular subtype, and developed the m7G score. We evaluated the immune tumor microenvironments in m7G clusters and analyzed the correlation of the m7G score with immune cells and drug sensitivity. We tested the predictive power of the m7G score for prognosis of patients with KIRC and verified the predictive accuracy of the m7G score by using the GSE40912 and E-MTAB-1980 datasets. The genes used to develop the m7G score were verified by qRT-PCR. Finally, we experimentally analyzed the effects of WDR4 knockdown on KIRC proliferation, migration, invasion, and drug sensitivity.

Results: We identified three m7G clusters. The expression of m7G regulators was higher in cluster C than in other clusters. m7G cluster C was related to immune activation, low tumor purity, good prognosis, and low m7G score. Cluster B was related to drug metabolism, high tumor purity, poor survival, and high m7G score. Cluster A was related to purine metabolism. The m7G score can well-predict the prognosis of patients with KIRC, and its prediction accuracy based on the m7G score nomogram was very high. Patients with high m7G scores were more sensitive to rapamycin, gefitinib, sunitinib, and vinblastine than other patients. Knocking down WDR4 can inhibit the proliferation, migration, and invasion of 786-0 and Caki-1 cells and increase sensitivity to sorafenib and sunitinib.

Conclusion: We proposed a novel molecular subtype related to m7G modification and revealed the immune cell infiltration characteristics of different subtypes. The developed m7G score can well-predict the prognosis of patients with KIRC, and our research provides a basis for personalized treatment of patients with KIRC.
Modulating effect of Xuanfei Baidu granule on host metabolism and gut microbiome in rats
Authors: He Qiaoyu , Shi Yumeng , Xing Hong , Tang Qian , Liu Jing , Li Chunxia , Zhang Han , Zhang Boli , Zhang Junhua , Chen Xiaopeng
Published: September 2022

Xuanfei Baidu granule (XFBD) is a recommended patented drug for the prevention and treatment of Corona Virus Disease 2019 (COVID-19), which is approved by the National Medical Products Administration. XFBD suppresses the over-activated immune response caused by inflammatory factor storms in COVID-19 infection. The intestine plays a crucial role in the immune system. The mass spectrometry based fecal metabolomics with 16S rDNA sequencing were combined to evaluate the effects of XFBD on host metabolism and gut microbiome. Short-chain fatty acids (SCFAs) contents in fecal matter were quantified by gas chromatography-mass spectrometry (GC-MS). Plasma samples were used to detect immune and inflammatory levels. The results were verified with a rat model of intestinal disorder. Results indicated that XFBD could increase the immune level of Immunoglobulin A (IgA), Immunoglobulin G (IgG) and Immunoglobulin M (IgM) (p < 0.05). The OPLS-DA analysis results showed that a total of 271 differential metabolites (178 up-regulated and 93 down-regulated) were identified based on the VIP ≥1, p < 0.05, FC ≥ 2 and FC ≤ 0.5. The metabolic pathways mainly involved D-Glutamine and D-glutamate metabolism, Arginine biosynthesis, Biotin metabolism, et al. XFBD modified the gut bacteria structure according to the principal component analysis (PCA), that is, 2 phyla, 3 classes, 5 orders, 11 families and 14 genera were significantly different based on taxonomic assignment. In addition, it could partially callback the relative abundance of intestinal microflora in bacterial disorder rats caused by antibiotics. It is suggested that the intervention mechanism of XFBD might be related to the regulation of intestinal flora composition. The evidence obtained in the study provides a useful reference for understanding the mechanism of XFBD.
Paeoniflorin directly binds to TNFR1 to regulate podocyte necroptosis in diabetic kidney disease
Authors: Wang Xian , Liu Xue-qi , Jiang Ling , Huang Yue-bo , Zeng Han-xu , Zhu Qi-jin , Qi Xiang-ming , Wu Yong-gui
Published: September 2022

Necroptosis was elevated in both tubulointerstitial and glomerular renal tissue in patients with diabetic kidney disease (DKD), and was most pronounced on glomerulus in the stage with macroalbuminuria. This study further explored whether paeoniflorin (PF) could affect podocyte necroptosis to protect kidney injure in vivo and in vitro. Our study firstly verified that there are obvious necroptosis-related changes in the glomeruli of DKD through bioinformatics analysis combined with clinicopathological data. STZ-induced mouse diabetes model and high-glucose induced podocyte injury model were used to evaluate the renoprotection, podocyte injury protection and necroptosis regulation of PF in DKD. Subsequently, the target protein-TNFR1 that PF acted on podocytes was found by computer target prediction, and then molecular docking and Surface plasmon resonance (SPR) experiments were performed to verify that PF had the ability to directly bind to TNFR1 protein. Finally, knockdown of TNFR1 on podocytes in vitro verified that PF mainly regulated the programmed necrosis of podocytes induced by high glucose through TNFR1. In conclusion, PF can directly bind and promote the degradation of TNFR1 in podocytes and then regulate the RIPK1/RIPK3 signaling pathway to affect necroptosis, thus preventing podocyte injury in DKD. Thus, TNFR1 may be used as a new potential target to treat DKD.
Protein-protein interaction-based high throughput screening for adenylyl cyclase 1 inhibitors: Design, implementation, and discovery of a novel chemotype
Authors: Dwyer Tiffany S. , O’Brien Joseph B. , Ptak Christopher P. , LaVigne Justin E. , Flaherty Daniel P. , Watts Val J. , Roman David L.
Published: September 2022

Genetic and preclinical studies have implicated adenylyl cyclase 1 (AC1) as a potential target for the treatment of chronic inflammatory pain. AC1 activity is increased following inflammatory pain stimuli and AC1 knockout mice show a marked reduction in responses to inflammatory pain. Previous drug discovery efforts have centered around the inhibition of AC1 activity in cell-based assays. In the present study, we used an in vitro approach focused on inhibition of the protein-protein interaction (PPI) between Ca2+/calmodulin (CaM) and AC1, an interaction that is required for activation of AC1. We developed a novel fluorescence polarization (FP) assay focused on the PPI between an AC1 peptide and CaM and used this assay to screen over 23,000 compounds for inhibitors of the AC1-CaM PPI. Next, we used a cellular NanoBiT assay to validate 21 FP hits for inhibition of the AC1-CaM PPI in a cellular context with full-length proteins. Based on efficacy, potency, and selectivity for AC1, hits 12, 13, 15, 18, 20, and 21 were prioritized. We then tested these compounds for inhibition of AC1 activity in cyclic AMP (cAMP) accumulation assays, using HEK293 cells stably expressing AC1. Hit 15 contained a dithiophene scaffold and was of particular interest because it shared structural similarities with our recently reported benzamide series of AC1 inhibitors. We next tested a small set of 13 compounds containing the dithiophene scaffold for structure-activity relationship studies. Although many compounds were non-selective, we observed trends for tuning AC1/AC8 selectivity based on heterocycle type and substituents. Having an ethyl on the central thiophene caused the scaffold to be more selective for AC8. Cyclization of the alkyl substituent fused to the thiophene significantly reduced activity and also shifted selectivity toward AC8. Notably, combining the fused cyclohexane-thiophene ring system with a morpholine heterocycle significantly increased potency at both AC1 and AC8. Through designing a novel FP screen and NanoBiT assay, and evaluating hits in cAMP accumulation assays, we have discovered a novel, potent, dithiophene scaffold for inhibition of the AC1- and AC8-CaM PPI. We also report the most potent fully efficacious inhibitor of AC8 activity known to-date.