bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicentered analysis of percutaneous sclerotherapies in venous malformations of the face
Authors: Schmidt Vanessa F. , Masthoff Max , Goldann Constantin , Brill Richard , Sporns Peter B. , Segger Laura , Schulze-Zachau Victor , Takes Martin , Köhler Michael , Deniz Sinan , Öcal Osman , Mansour Nabeel , Ümütlü Muzaffer Reha , Shemwetta Mwivano Dunstan , Baraka Balowa Musa , Mbuguje Eric M. , Naif Azza A. , Ukweh Ofonime , Seidensticker Max , Ricke Jens , Gebauer Bernhard , Wohlgemuth Walter A. , Wildgruber Moritz
Published: December 2022

Objectives

To evaluate the safety and outcome of image-guided sclerotherapy for treating venous malformations (VMs) of the face.

Materials and methods

A multicenter cohort of 68 patients with VMs primarily affecting the face was retrospectively investigated. In total, 142 image-guided sclerotherapies were performed using gelified ethanol and/or polidocanol. Clinical and imaging findings were assessed to evaluate clinical response, lesion size reduction, and complication rates. Sub-analyses of complication rates depending on type and injected volume of the sclerosant as well as of pediatric versus adult patient groups were conducted.

Results

Mean number of procedures per patient was 2.1 (±1.7) and mean follow-up consisted of 8.7 months (±6.8 months). Clinical response (n = 58) revealed a partial relief of symptoms in 70.7% (41/58), 13/58 patients (22.4%) presented symptom-free while only 4/58 patients (6.9%) reported no improvement. Post-treatment imaging (n = 52) revealed an overall objective response rate of 86.5% (45/52). The total complication rate was 10.6% (15/142) including 4.2% (7/142) major complications, mostly (14/15, 93.3%) resolved by conservative means. In one case, a mild facial palsy persisted over time. The complication rate in the gelified ethanol subgroup was significantly higher compared to polidocanol and to the combination of both sclerosants (23.5 vs. 6.0 vs. 8.3%, p = 0.01). No significant differences in complications between the pediatric and the adult subgroup were observed (12.1 vs. 9.2%, p = 0.57). Clinical response did not correlate with lesion size reduction on magnetic resonance imaging (MRI).

Conclusion

Image-guided sclerotherapy is effective for treating VMs of the face. Clinical response is not necessarily associated with size reduction on imaging. Despite the complex anatomy of this location, the procedures are safe for both adults and children.
Spatiotemporal and ontogenetic variation, microbial selection, and predicted Bd-inhibitory function in the skin-associated microbiome of a Rocky Mountain amphibian
Authors: Goodwin Kenen B. , Hutchinson Jaren D. , Gompert Zachariah
Published: December 2022

Host-associated microbiomes play important roles in host health and pathogen defense. In amphibians, the skin-associated microbiota can contribute to innate immunity with potential implications for disease management. Few studies have examined season-long temporal variation in the amphibian skin-associated microbiome, and the interactions between bacteria and fungi on amphibian skin remain poorly understood. We characterize season-long temporal variation in the skin-associated microbiome of the western tiger salamander (Ambystoma mavortium) for both bacteria and fungi between sites and across salamander life stages. Two hundred seven skin-associated microbiome samples were collected from salamanders at two Rocky Mountain lakes throughout the summer and fall of 2018, and 127 additional microbiome samples were collected from lake water and lake substrate. We used 16S rRNA and ITS amplicon sequencing with Bayesian Dirichlet-multinomial regression to estimate the relative abundances of bacterial and fungal taxa, test for differential abundance, examine microbial selection, and derive alpha diversity. We predicted the ability of bacterial communities to inhibit the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd), a cutaneous fungal pathogen, using stochastic character mapping and a database of Bd-inhibitory bacterial isolates. For both bacteria and fungi, we observed variation in community composition through time, between sites, and with salamander age and life stage. We further found that temporal trends in community composition were specific to each combination of salamander age, life stage, and lake. We found salamander skin to be selective for microbes, with many taxa disproportionately represented relative to the environment. Salamander skin appeared to select for predicted Bd-inhibitory bacteria, and we found a negative relationship between the relative abundances of predicted Bd-inhibitory bacteria and Bd. We hope these findings will assist in the conservation of amphibian species threatened by chytridiomycosis and other emerging diseases.
Toxic effect and inability of L-homoserine to be a nitrogen source for growth of Escherichia coli resolved by a combination of in vivo evolution engineering and omics analyses
Authors: Alkim Ceren , Farias Daniele , Fredonnet Julie , Serrano-Bataille Helene , Herviou Pauline , Picot Marc , Slama Nawel , Dejean Sebastien , Morin Nicolas , Enjalbert Brice , François Jean M.
Published: December 2022

L-homoserine is a pivotal intermediate in the carbon and nitrogen metabolism of E. coli. However, this non-canonical amino acid cannot be used as a nitrogen source for growth. Furthermore, growth of this bacterium in a synthetic media is potently inhibited by L-homoserine. To understand this dual effect, an adapted laboratory evolution (ALE) was applied, which allowed the isolation of a strain able to grow with L-homoserine as the nitrogen source and was, at the same time, desensitized to growth inhibition by this amino acid. Sequencing of this evolved strain identified only four genomic modifications, including a 49 bp truncation starting from the stop codon of thrL. This mutation resulted in a modified thrL locus carrying a thrL* allele encoding a polypeptide 9 amino acids longer than the thrL encoded leader peptide. Remarkably, the replacement of thrL with thrL* in the original strain MG1655 alleviated L-homoserine inhibition to the same extent as strain 4E, but did not allow growth with this amino acid as a nitrogen source. The loss of L-homoserine toxic effect could be explained by the rapid conversion of L-homoserine into threonine via the thrL*-dependent transcriptional activation of the threonine operon thrABC. On the other hand, the growth of E. coli on a mineral medium with L-homoserine required an activation of the threonine degradation pathway II and glycine cleavage system, resulting in the release of ammonium ions that were likely recaptured by NAD(P)-dependent glutamate dehydrogenase. To infer about the direct molecular targets of L-homoserine toxicity, a transcriptomic analysis of wild-type MG1655 in the presence of 10 mM L-homoserine was performed, which notably identified a potent repression of locomotion-motility-chemotaxis process and of branched-chain amino acids synthesis. Since the magnitude of these effects was lower in a ΔthrL mutant, concomitant with a twofold lower sensitivity of this mutant to L-homoserine, it could be argued that growth inhibition by L-homoserine is due to the repression of these biological processes. In addition, L-homoserine induced a strong upregulation of genes in the sulfate reductive assimilation pathway, including those encoding its transport. How this non-canonical amino acid triggers these transcriptomic changes is discussed.
Soil CO2 and N2O emissions and microbial abundances altered by temperature rise and nitrogen addition in active-layer soils of permafrost peatland
Authors: Song Yanyu , Cheng Xiaofeng , Song Changchun , Li Mengting , Gao Siqi , Liu Zhendi , Gao Jinli , Wang Xianwei
Published: December 2022

Changes in soil CO2 and N2O emissions due to climate change and nitrogen input will result in increased levels of atmospheric CO2 and N2O, thereby feeding back into Earth’s climate. Understanding the responses of soil carbon and nitrogen emissions mediated by microbe from permafrost peatland to temperature rising is important for modeling the regional carbon and nitrogen balance. This study conducted a laboratory incubation experiment at 15 and 20°C to observe the impact of increasing temperature on soil CO2 and N2O emissions and soil microbial abundances in permafrost peatland. An NH4NO3 solution was added to soil at a concentration of 50 mg N kg−1 to investigate the effect of nitrogen addition. The results indicated that elevated temperature, available nitrogen, and their combined effects significantly increased CO2 and N2O emissions in permafrost peatland. However, the temperature sensitivities of soil CO2 and N2O emissions were not affected by nitrogen addition. Warming significantly increased the abundances of methanogens, methanotrophs, and nirK-type denitrifiers, and the contents of soil dissolved organic carbon (DOC) and ammonia nitrogen, whereas nirS-type denitrifiers, β-1,4-glucosidase (βG), cellobiohydrolase (CBH), and acid phosphatase (AP) activities significantly decreased. Nitrogen addition significantly increased soil nirS-type denitrifiers abundances, β-1,4-N- acetylglucosaminidase (NAG) activities, and ammonia nitrogen and nitrate nitrogen contents, but significantly reduced bacterial, methanogen abundances, CBH, and AP activities. A rising temperature and nitrogen addition had synergistic effects on soil fungal and methanotroph abundances, NAG activities, and DOC and DON contents. Soil CO2 emissions showed a significantly positive correlation with soil fungal abundances, NAG activities, and ammonia nitrogen and nitrate nitrogen contents. Soil N2O emissions showed positive correlations with soil fungal, methanotroph, and nirK-type denitrifiers abundances, and DOC, ammonia nitrogen, and nitrate contents. These results demonstrate the importance of soil microbes, labile carbon, and nitrogen for regulating soil carbon and nitrogen emissions. The results of this study can assist simulating the effects of global climate change on carbon and nitrogen cycling in permafrost peatlands.
Evaluating the effects of antimicrobial drug use on the ecology of antimicrobial resistance and microbial community structure in beef feedlot cattle
Authors: Doster Enrique , Pinnell Lee J. , Noyes Noelle R. , Parker Jennifer K. , Anderson Cameron A. , Booker Calvin W. , Hannon Sherry J. , McAllister Tim A. , Gow Sheryl P. , Belk Keith E. , Morley Paul S.
Published: December 2022

Introduction

Use of antimicrobial drugs (AMDs) in food producing animals has received increasing scrutiny because of concerns about antimicrobial resistance (AMR) that might affect consumers. Previously, investigations regarding AMR have focused largely on phenotypes of selected pathogens and indicator bacteria, such as Salmonella enterica or Escherichia coli. However, genes conferring AMR are known to be distributed and shared throughout microbial communities. The objectives of this study were to employ target-enriched metagenomic sequencing and 16S rRNA gene amplicon sequencing to investigate the effects of AMD use, in the context of other management and environmental factors, on the resistome and microbiome in beef feedlot cattle.

Methods

This study leveraged samples collected during a previous longitudinal study of cattle at beef feedlots in Canada. This included fecal samples collected from randomly selected individual cattle, as well as composite-fecal samples from randomly selected pens of cattle. All AMD use was recorded and characterized across different drug classes using animal defined daily dose (ADD) metrics.

Results

Overall, fecal resistome composition was dominated by genes conferring resistance to tetracycline and macrolide-lincosamide-streptogramin (MLS) drug classes. The diversity of bacterial phyla was greater early in the feeding period and decreased over time in the feedlot. This decrease in diversity occurred concurrently as the microbiome represented in different individuals and different pens shifted toward a similar composition dominated by Proteobacteria and Firmicutes. Some antimicrobial drug exposures in individuals and groups were associated with explaining a statistically significant proportion of the variance in the resistome, but the amount of variance explained by these important factors was very small (<0.6% variance each), and smaller than associations with other factors measured in this study such as time and feedlot ID. Time in the feedlot was associated with greater changes in the resistome for both individual animals and composite pen-floor samples, although the proportion of the variance associated with this factor was small (2.4% and 1.2%, respectively).

Discussion

Results of this study are consistent with other investigations showing that, compared to other factors, AMD exposures did not have strong effects on antimicrobial resistance or the fecal microbial ecology of beef cattle.
Novel characterization discoveries of ferroptosis-associated molecules in COAD microenvironment based TCGA data
Authors: Baldi Salem , He Yun , Ivanov Igor , Sun Yaping , Feng Wei , Refat Moath , Mohammed Shadi A. D. , Adlat Salah , Tian Zixuan , Wang Yi , Gao Yaping , Tian Hui
Published: December 2022

Background and Objective: One of the most recent forms of programmed cell death, ferroptosis, is crucial in tumorigenesis. Ferroptosis is characterized by iron-dependent oxidative destruction of cellular membranes following the antioxidant system’s failure. However, it is unknown whether ferroptosis-related genes (FRGs) are associated with colon adenocarcinoma (COAD) metastasis, immune cell infiltration, and oxidative stress in COAD. The current study concentrated on FRGs expression in colon cancer metastasis, their relationship to immune cell infiltration (ICI), and potential pathological pathways in COAD.

Methods and Results: Clinical information and mRNA expression patterns for patients with COAD metastasis were obtained from the public TCGA database. Patients with low mRNA levels showed good overall survival than patients with high mRNA levels. The genomic-clinicopathologic nomogram was subsequently created by combining risk score and clinicopathological features. Absolute Shrinkage and Selection Operator have shown a 4 gene signature that can stratify cancer patients into high-risk versus low-risk. These four FRGs were found to be significantly linked to the overall survival of COAD patients and predicted high risk score. Next, age, stage, and PTNM were combined in univariate and multivariate cox regression models to perform a filtering procedure. The receiver operating characteristic (ROC) and calibration curves indicated that constructed signature model exhibited high prediction accuracy and clinical relevance in COAD. ARID3A showed a strong negative correlation with a wide range of immune tumour-infiltrating cells in COAD microenvironment. According to the single sample gene set enrichment analysis (ssGSEA) results, FRGs are involved in variety of pathological pathways including PI3K-AKT-mTOR pathway, reactive oxygen species (ROS) pathway, response to hypoxia pathway, and other inflammation related pathways. Moreover, dysregulation of FRGs in COAD patients showed a significance correlation with wide range of miRNAs and transcription factors (TFs).

Conclusion: We identified new diagnostic biomarkers and established prognostic models for ferroptosis related programmed cell death in COAD metastasis. FRGs may improve tumor cell survival by activating the TGFB pathway, which can stimulate ROS production, accelerates ECM breakdown, and promote tumor progression and invasion. Genes implicated in ferroptosis, as revealed by the Kaplan Meier and a genomic-clinicopathologic nomogram, are potential therapeutic targets and prognosis indications for metastasis COAD patients.
Kinematic strategies for obstacle-crossing in older adults with mild cognitive impairment
Authors: Lu Shiuan-Huei , Kuan Yi-Chun , Wu Kuan-Wen , Lu Hsuan-Yu , Tsai Yu-Lin , Chen Hsiang-Ho , Lu Tung-Wu
Published: December 2022

Introduction

Mild cognitive impairment (MCI) is considered a transitional stage between soundness of mind and dementia, often involving problems with memory, which may lead to abnormal postural control and altered end-point control when dealing with neuromechanical challenges during obstacle-crossing. The study aimed to identify the end-point control and angular kinematics of the pelvis-leg apparatus while crossing obstacles for both leading and trailing limbs.

Methods

12 patients with MCI (age: 66.7 ± 4.2 y/o; height: 161.3 ± 7.3 cm; mass: 62.0 ± 13.6 kg) and 12 healthy adults (age: 67.7 ± 2.9 y/o; height: 159.3 ± 6.1 cm; mass: 61.2 ± 12.0 kg) each walked and crossed obstacles of three different heights (10, 20, and 30% of leg length). Angular motions of the pelvis and lower limbs and toe-obstacle clearances during leading- and trailing-limb crossings were calculated. Two-way analyses of variance were used to study between-subject (group) and within-subject (obstacle height) effects on the variables. Whenever a height effect was found, a polynomial test was used to determine the trend. A significance level of α = 0.05 was set for all tests.

Results

Patients with MCI significantly increased pelvic anterior tilt, hip abduction, and knee adduction in the swing limb during leading-limb crossing when compared to controls (p < 0.05). During trailing-limb crossing, the MCI group showed significantly decreased pelvic posterior tilt, as well as ankle dorsiflexion in the trailing swing limb (p < 0.05).

Conclusion

Patients with MCI adopt altered kinematic strategies for successful obstacle-crossing. The patients were able to maintain normal leading and trailing toe-obstacle clearances for all tested obstacle heights with a specific kinematic strategy, namely increased pelvic anterior tilt, swing hip abduction, and knee adduction during leading-limb crossing, and decreased pelvic posterior tilt and swing ankle dorsiflexion during trailing-limb crossing. The current results suggest that regular monitoring of obstacle-crossing kinematics for reduced toe-obstacle clearance or any signs of changes in crossing strategy may be helpful for early detection of compromised obstacle-crossing ability in patients with single-domain amnestic MCI. Further studies using a motor/cognitive dual-task approach on the kinematic strategies adopted by multiple-domain MCI will be needed for a complete picture of the functional adaptations in such a patient group.
Molecular mechanisms of neuronal death in brain injury after subarachnoid hemorrhage
Authors: Chen Junhui , Li Mingchang , Liu Zhuanghua , Wang Yuhai , Xiong Kun
Published: December 2022

Subarachnoid haemorrhage (SAH) is a common cerebrovascular disease with high disability and mortality rates worldwide. The pathophysiological mechanisms involved in an aneurysm rupture in SAH are complex and can be divided into early brain injury and delayed brain injury. The initial mechanical insult results in brain tissue and vascular disruption with hemorrhages and neuronal necrosis. Following this, the secondary injury results in diffused cerebral damage in the peri-core area. However, the molecular mechanisms of neuronal death following an aneurysmal SAH are complex and currently unclear. Furthermore, multiple cell death pathways are stimulated during the pathogenesis of brain damage. Notably, particular attention should be devoted to necrosis, apoptosis, autophagy, necroptosis, pyroptosis and ferroptosis. Thus, this review discussed the mechanism of neuronal death and its influence on brain injury after SAH.
Chronic jet lag-like conditions dysregulate molecular profiles of neurological disorders in nucleus accumbens and prefrontal cortex
Authors: Siddique Rabeea , Awan Faryal Mehwish , Nabi Ghulam , Khan Suliman , Xue Mengzhou
Published: December 2022

Background

Patients with neurological disorders often display altered circadian rhythms. The disrupted circadian rhythms through chronic jetlag or shiftwork are thought to increase the risk and severity of human disease including, cancer, psychiatric, and related brain diseases.

Results

In this study, we investigated the impact of shiftwork or chronic jetlag (CJL) like conditions on mice’s brain. Transcriptome profiling based on RNA sequencing revealed that genes associated with serious neurological disorders were differentially expressed in the nucleus accumbens (NAc) and prefrontal cortex (PFC). According to the quantitative PCR (qPCR) analysis, several key regulatory genes associated with neurological disorders were significantly altered in the NAc, PFC, hypothalamus, hippocampus, and striatum. Serotonin levels and the expression levels of serotonin transporters and receptors were significantly altered in mice treated with CJL.

Conclusion

Overall, these results indicate that CJL may increase the risk of neurological disorders by disrupting the key regulatory genes, biological functions, serotonin, and corticosterone. These molecular linkages can further be studied to investigate the mechanism underlying CJL or shiftwork-mediated neurological disorders in order to develop treatment strategies.
Association between abnormal plasma metabolism and brain atrophy in alcohol-dependent patients
Authors: Zhang Zheyu , Zhang Sifang , Huang Jianhua , Cao Xiaoyun , Hou Chao , Luo Zhihong , Wang Xiaoyan , Liu Xuejun , Li Qiang , Zhang Xi , Guo Yujun , Xiao Huiqiong , Xie Ting , Zhou Xuhui
Published: December 2022

Objective

In this study, we aimed to characterize the plasma metabolic profiles of brain atrophy and alcohol dependence (s) and to identify the underlying pathogenesis of brain atrophy related to alcohol dependence.

Methods

We acquired the plasma samples of alcohol-dependent patients and performed non-targeted metabolomic profiling analysis to identify alterations of key metabolites in the plasma of BA-ADPs. Machine learning algorithms and bioinformatic analysis were also used to identify predictive biomarkers and investigate their possible roles in brain atrophy related to alcohol dependence.

Results

A total of 26 plasma metabolites were significantly altered in the BA-ADPs group when compared with a group featuring alcohol-dependent patients without brain atrophy (NBA-ADPs). Nine of these differential metabolites were further identified as potential biomarkers for BA-ADPs. Receiver operating characteristic curves demonstrated that these potential biomarkers exhibited good sensitivity and specificity for distinguishing BA-ADPs from NBA-ADPs. Moreover, metabolic pathway analysis suggested that glycerophospholipid metabolism may be highly involved in the pathogenesis of alcohol-induced brain atrophy.

Conclusion

This plasma metabolomic study provides a valuable resource for enhancing our understanding of alcohol-induced brain atrophy and offers potential targets for therapeutic intervention.
High adherence to the Mediterranean diet and Alternative Healthy Eating Index are associated with reduced odds of metabolic syndrome and its components in participants of the ORISCAV-LUX2 study
Authors: Al Kudsee Kinda , Vahid Farhad , Bohn Torsten
Published: December 2022

Background

Metabolic syndrome (MetS) is a major risk factor for cardiometabolic complications. Certain dietary patterns play a pivotal role in improving MetS components. The aim of this investigation was to study associations between the Mediterranean Diet Score (MDS) and the Alternative Healthy Eating Index (AHEI) and the odds of MetS and its components in adults living in Luxembourg.

Methods

Data from 1,404 adults participating in the cross-sectional ORISCAV-LUX2 study were analyzed by a self-reported questionnaire, anthropometric measures, a food frequency questionnaire (174 items), and blood/urine samples.

Results

A significant association of dietary indices and MetS was not found except when expressing MetS as a score (continuous variable, log-transformed), based on the weighting of compounds using exploratory factor analysis with the MDS (β = −0.118, 95% CI: −0.346, −0.120) and AHEI (β = −0.133, 95% CI: −0.059, −0.019). Fully adjusted linear regression models further showed significant inverse associations between components of MetS and MDS (all as log-transformed variables), including body mass index (BMI) (β = −0.0067, 95% CI: −0.0099, −0.0036), waist-circumference (WC) (β = −0.0048, 95% CI: −0.0072, −0.0024), systolic blood pressure (SBP) (β = −0.0038, 95% CI: −0.0061, −0.0016), and diastolic blood pressure (DBP) (β = −0.0035, 95% CI: −0.0060, −0.0009). Similarly, significant inverse associations between AHEI and components of MetS (log-transformed) included BMI (β = −0.0001, 95% CI: −0.0016, −0.0002), WC (β = −0.0007, 95% CI: −0.0011, −0.0002), SBP (β = −0.0006, 95% CI: −0.0010, −0.0002), and DBP (β = −0.0006, 95% CI: −0.0011, −0.0001).

Conclusion

Higher adherence to a Mediterranean diet and following healthy eating guidelines were associated with reduced odds of MetS and several of its components in Luxembourgish residents, highlighting that balanced and healthy eating patterns are a crucial cornerstone in the fight against MetS.
Resistance mechanisms in BRAFV600E paediatric high-grade glioma and current therapeutic approaches
Authors: Lehmann R. , Rayner B. S. , Ziegler D. S.
Published: December 2022

Paediatric high-grade gliomas (pHGG) are aggressive central nervous system tumours with a poor prognosis. BRAFV600E mutant pHGGs can be treated with targeted BRAF inhibitors, which have shown both preclinical activity and potent clinical efficacy. Unfortunately, the development of drug resistance results in disease relapse or progression and is the primary cause of treatment failure. While there is a lot of data to explain mechanisms of resistance in other BRAFV600E tumours, comparatively little is known about the mechanisms of BRAF inhibitor resistance in BRAFV600E pHGG. Recent literature has identified aberrations in members of the RAS/RAF/ERK pathway, the PI3K/AKT/MTOR pathway and the cell cycle as major contributors to the resistance profile. A range of novel therapies have been suggested to overcome BRAF inhibitor drug resistance in BRAFV600E pHGG. This review will discuss the current literature available for BRAF inhibitor resistant BRAFV600E pHGGs and provide an overview of the currently available and proposed therapies.
Survival trends and prognostic factors for patients with extramedullary plasmacytoma: A population-based study
Authors: Shen Xuxing , Zhang Lina , Wang Jing , Chen Lijuan , Liu Shu , Zhang Run
Published: December 2022

Background

Extramedullary plasmacytoma (EMP) is a localized plasma cell neoplasm that originates from tissues other than bone. The survival trends and prognostic factors of patients with EMP in recent years remain unreported.

Methods

We used the SEER databases to extract the data. Survival curves were calculated using the Kaplan-Meier method and a nomogram was created based on the Cox’s proportional hazards model.

Results

A total of 1676 cases of EMP were identified. Patients in period-2 (2008-2016) show similar survival (p=0.8624) to those in period-1(1975-2007). Age, gender, race, and sites were prognostic of patient outcomes. And the use of surgery was associated with improved survival. The patients were randomly assigned to the training cohort and the validation cohort in a ratio of 2:1. Four factors including age, gender, race, and sites were identified to be independently predictive of the overall survival of patients with EMP. A prognostic model (EMP prognostic index, EMP-PI) comprising these four factors was constructed. Within the training cohort, three risk groups displayed significantly different 10-year survival rates: low-risk (73.0%, [95%CI 66.9-78.2]), intermediate-risk (39.3%, [95%CI 34.3-44.3]), and high-risk (22.6%, [95%CI 15.3-30.9]) (p<0.0001). Three risk groups were confirmed in the internal validation cohort. We also constructed a 5-factor nomogram based on multivariate logistic analyses.

Conclusion

The survival of patients with EMP did not improve in recent years. The EMP-PI will facilitate the risk stratification and guide the risk-adapted therapy in patients with EMP.
Prognostic value of KRAS subtype in patients with PDAC undergoing radical resection
Authors: Dai Manxiong , Jahanzaib Raja , Liao Yan , Yao Fengxuan , Li Jia , Teng Xiong , Chen Kang , Cheng Wei
Published: December 2022

Objective

To explore the frequency distribution of KRAS mutant subtypes in patients with resectable PDAC in China and then evaluate the prognostic value of different KRAS subtypes in patients with PDAC undergoing radical resection.

Methods

The clinicopathological data and gene test reports of 227 patients undergoing PDAC radical surgery at Hunan Provincial People’s Hospital from 1 January 2016 to 1 January 1 2020 were retrospectively evaluated. There were 118 men (52%) and 109 women (48%). The mean age was 58.8 ± 10.3 years. After univariate analysis of the clinicopathological factors (sex, age, presence or absence of underlying disease, location of the primary tumour, tumour TNM stage, T stage, N stage, presence or absence of vascular invasion, presence or absence of nerve invasion, surgical margin, KRAS mutation subtype), variables with P < 0.1 were included in the multivariate Cox regression model analysis, and the log-rank sum test and Kaplan−Meier curves were used to assess the correlation of the KRAS mutation subtype with the overall survival time.

Results

KRAS mutations were detected in 184 of 227 patients (81.1%) (G12D: 66; G12V: 65; G12R: 27; Q61:26) and were not detected in 43 patients (18.9%). KRAS mutations were associated with tumour differentiation (P = 0.001), TNM stage (P = 0.013), and T stage (P < 0.001). Multivariate Cox regression model analysis showed that N stage, surgical margin, tumour differentiation, and KRAS-G12D mutation were independent prognostic factors for DFS and OS. Patients with the KRAS-G12D subtype had shorter OS with a median OS of 12 months (HR: 0.55, CI: 0.39–0.77, P < 0.001), and patients with KRAS wild-type had longer OS with a median OS of 19 months (HR: 0.57, CI: 0.42–0.76, P < 0.001).

Conclusion

KRAS wild-type individuals are more prevalent in the Chinese population than in European or American populations. Patients undergoing surgery had a reduced percentage of tumors with KRAS-G12D. When determining the prognosis of individuals with radically resected PDAC, reference markers for KRAS mutation subtypes can be employed.
Diagnosis of architectural distortion on digital breast tomosynthesis using radiomics and deep learning
Authors: Chen Xiao , Zhang Yang , Zhou Jiahuan , Wang Xiao , Liu Xinmiao , Nie Ke , Lin Xiaomin , He Wenwen , Su Min-Ying , Cao Guoquan , Wang Meihao
Published: December 2022

Purpose

To implement two Artificial Intelligence (AI) methods, radiomics and deep learning, to build diagnostic models for patients presenting with architectural distortion on Digital Breast Tomosynthesis (DBT) images.

Materials and Methods

A total of 298 patients were identified from a retrospective review, and all of them had confirmed pathological diagnoses, 175 malignant and 123 benign. The BI-RADS scores of DBT were obtained from the radiology reports, classified into 2, 3, 4A, 4B, 4C, and 5. The architectural distortion areas on craniocaudal (CC) and mediolateral oblique (MLO) views were manually outlined as the region of interest (ROI) for the radiomics analysis. Features were extracted using PyRadiomics, and then the support vector machine (SVM) was applied to select important features and build the classification model. Deep learning was performed using the ResNet50 algorithm, with the binary output of malignancy and benignity. The Gradient-weighted Class Activation Mapping (Grad-CAM) method was utilized to localize the suspicious areas. The predicted malignancy probability was used to construct the ROC curves, compared by the DeLong test. The binary diagnosis was made using the threshold of ≥ 0.5 as malignant.

Results

The majority of malignant lesions had BI-RADS scores of 4B, 4C, and 5 (148/175 = 84.6%). In the benign group, a substantial number of patients also had high BI-RADS ≥ 4B (56/123 = 45.5%), and the majority had BI-RADS ≥ 4A (102/123 = 82.9%). The radiomics model built using the combined CC+MLO features yielded an area under curve (AUC) of 0.82, the sensitivity of 0.78, specificity of 0.68, and accuracy of 0.74. If only features from CC were used, the AUC was 0.77, and if only features from MLO were used, the AUC was 0.72. The deep-learning model yielded an AUC of 0.61, significantly lower than all radiomics models (p<0.01), which was presumably due to the use of the entire image as input. The Grad-CAM could localize the architectural distortion areas.

Conclusion

The radiomics model can achieve a satisfactory diagnostic accuracy, and the high specificity in the benign group can be used to avoid unnecessary biopsies. Deep learning can be used to localize the architectural distortion areas, which may provide an automatic method for ROI delineation to facilitate the development of a fully-automatic computer-aided diagnosis system using combined AI strategies.
Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccination
Authors: Phares Timothy W. , Huang Jing , Kotraiah Vinayaka , Hauser Mary J. , Domi Arban , Oruganti Sreenivasa , Browne Cecille D. , Buontempo Peter , Mansour Marc , Pannucci James , Tsuji Moriya , Gutierrez Gabriel M.
Published: December 2022

Modern, subunit-based vaccines have so far failed to induce significant T cell responses, contributing to ineffective vaccination against many pathogens. Importantly, while today’s adjuvants are designed to trigger innate and non-specific immune responses, they fail to directly stimulate the adaptive immune compartment. Programmed cell death 1 (PD-1) partly regulates naïve-to-antigen-specific effector T cell transition and differentiation by suppressing the magnitude of activation. Indeed, we previously reported on a microbial-derived, peptide-based PD-1 checkpoint inhibitor, LD01, which showed potent T cell-stimulating activity when combined with a vaccine. Here we sought to improve the potency of LD01 by designing and testing new LD01 derivatives. Accordingly, we found that a modified version of an 18-amino acid metabolite of LD01, LD10da, improved T cell activation capability in a malaria vaccine model. Specifically, LD10da demonstrates improved antigen-specific CD8+T cell expansion when combined prophylactically with an adenovirus-based malaria vaccine. A single dose of LD10da at the time of vaccination is sufficient to increase antigen-specific CD8+T cell expansion in wild-type mice. Further, we show that LD10 can be encoded and delivered by a Modified Vaccinia Ankara viral vector and can enhance antigen-specific CD8+T cell expansion comparable to that of synthetic peptide administration. Therefore, LD10da represents a promising biologic-based immunomodulator that can be genetically encoded and delivered, along with the antigen, by viral or other nucleic acid vectors to improve the efficacy and delivery of vaccines for ineradicable and emerging infectious diseases.
Pharmacist-led olaparib follow-up service for ambulatory ovarian cancer patients: A prospective study in a tertiary specialized cancer hospital in China
Authors: Wang Yanting , Du Di , Yang Jun , Lau Alan H. , Dai Yuanyuan , Qin Wangjun , Li Ning , Li Guohui
Published: December 2022

Purpose: To establish a pharmacist-led olaparib follow-up program for ovarian cancer patients, provide patient education, get information on adverse drug reactions (ADRs), and identify and manage drug-related problems.

Methods: Ambulatory adult patients with ovarian cancer receiving olaparib were enrolled. At least one follow-up session was conducted by clinical pharmacists. Pharmacists collected data on the type and grade of ADRs, drug adherence, olaparib dosing, concomitant medications, and pharmacists’ suggestions.

Results: 83 patients were enrolled with the median age of 58. The average number of the follow-up sessions provided to each patient was 1.31, and the average duration of each follow-up was 17.78 min. The olaparib starting dose for most patients (97.59%) was 600 mg/d. 36.14% of the patients had missed olaparib doses and 27.71% of the patients had dose adjustments due to ADRs. The most common ADRs (incidence≥10%) were: fatigue (40.96%), anemia (36.14%), leukopenia (36.14%), nausea (28.92%), thrombocytopenia (16.87%), anorexia (16.87%), dyspepsia (15.66%). The tolerability profiles were generally similar between patients treated for “first-line maintenance” and those treated for “recurrence maintenance” (p > .05). There were 42% of the patients who were concomitantly taking medications without exact chemical contents (such as formulated Chinese medicines and Chinese decoctions), and common types of concomitant medications with exact drug names were antihypertensive, anti-hyperglycemic, and anti-hyperlipidemic medications. The pharmacists identified 4 clinically significant drug-drug interactions (DDIs) in two patients. Pharmacists made 196 suggestions mainly related to rational use of the medications and management of ADRs.

Conclusion: The study provides the first report about pharmacist-led follow-up service for olaparib. The types of ADRs were similar to those previously observed in clinical trials, and the profiles of ADRs in different types of patients (first-line maintenance vs. recurrence maintenance) were also similar. Pharmacists identified drug-related problems (such as adherence, DDIs and management of ADRs) and offer suggestions for the patients.
Role of histone methyltransferase SETDB1 in regulation of tumourigenesis and immune response
Authors: Zhao Zhipeng , Feng Lu , Peng Xuerun , Ma Tingnan , Tong Rongsheng , Zhong Lei
Published: December 2022

Epigenetic alterations are implicated in tumour immune evasion and immune checkpoint blockade (ICB) resistance. SET domain bifurcated histone methyltransferase 1 (SETDB1) is a histone lysine methyltransferase that catalyses histone H3K9 di- and tri-methylation on euchromatin, and growing evidence indicates that SETDB1 amplification and abnormal activation are significantly correlated with the unfavourable prognosis of multiple malignant tumours and contribute to tumourigenesis and progression, immune evasion and ICB resistance. The main underlying mechanism is H3K9me3 deposition by SETDB1 on tumour-suppressive genes, retrotransposons, and immune genes. SETDB1 targeting is a promising approach to cancer therapy, particularly immunotherapy, because of its regulatory effects on endogenous retroviruses. However, SETDB1-targeted therapy remains challenging due to potential side effects and the lack of antagonists with high selectivity and potency. Here, we review the role of SETDB1 in tumourigenesis and immune regulation and present the current challenges and future perspectives of SETDB1 targeted therapy.
Cell volume restriction by mercury chloride reduces M1-like inflammatory response of bone marrow-derived macrophages
Authors: Chuang Yen-Chieh , Wu Shu-Yu , Huang Yu-Chuan , Peng Chung-Kan , Tang Shih-En , Huang Kun-Lun
Published: December 2022

Dysregulation of macrophages in the pro-inflammatory (M1) and anti-inflammatory (M2) sub-phenotypes is a crucial element in several inflammation-related diseases and injuries. We investigated the role of aquaporin (AQP) in macrophage polarization using AQP pan-inhibitor mercury chloride (HgCl2). Lipopolysaccharides (LPSs) induced the expression of AQP-1 and AQP-9 which increased the cell size of bone marrow-derived macrophages. The inhibition of AQPs by HgCl2 abolished cell size changes and significantly suppressed M1 polarization. HgCl2 significantly reduced the activation of the nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) pathways and inhibited the production of IL-1β. HgCl2 attenuated LPS-induced activation of mitochondria and reactive oxygen species production and autophagy was promoted by HgCl2. The increase in the light chain three II/light chain three I ratio and the reduction in PTEN-induced kinase one expression suggests the recycling of damaged mitochondria and the restoration of mitochondrial activity by HgCl2. In summary, the present study demonstrates a possible mechanism of the AQP inhibitor HgCl2 in macrophage M1 polarization through the restriction of cell volume change, suppression of the p38 MAPK/NFκB pathway, and promotion of autophagy.
Cost-effectiveness of janus kinase inhibitors for rheumatoid arthritis: A systematic review and meta-analysis of cost-utility studies
Authors: Kumar S. Sajith , Haridoss Madhumitha , Venkataraman Krishnamurthy , Bagepally Bhavani Shankara
Published: December 2022

Introduction: Janus kinase inhibitors (JAK-i), a class of targeted synthetic disease-modifying antirheumatic drugs (tDMARDs), are suggested as second or third-line therapies in rheumatoid arthritis (RA). Synthesized cost-effective evidence would aid in informed decision-making given the similar clinical effectiveness of JAKi, but incongruent cost-effectiveness reports.

Methods: Literature search was conducted in PubMed, Embase, Scopus, and Tufts Medical Centers’ cost-effective analysis registry. We pooled the incremental net benefit (INB) with 95% confidence interval (CI) using random-effects model and the heterogeneity was assessed using Cochrane-Q test and I2 statistic. Modified economic evaluation bias checklist was used to assess the quality of selected studies. Publication bias was assessed using a funnel plot and Egger’s test. The Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) assessment was performed to assess the certainty of outcomes presented.

Results: We included seventeen relevant studies for systematic review, of which fifteen were eligible for meta-analysis. The meta-analysis results showed that JAK-i is cost-effective compared to csDMARDS/bDMARDs with a pooled INB (INBp) of $19,886 (95% CI, 1,635 to 38,137) but with considerable heterogeneity (I2 = 99.14). As a second-line treatment for csDMARD failed RA, JAK-i is cost-effective than csDMARD/bDMARD with a pooled INB of $23,144 (74.1–46,214) and high heterogeneity (I2 = 99.67). But on a separate analysis JAK-i as second-line treatment is not cost-effective than TNF-a-i (INBp = $25,813, -5,714 to 57,340). However, leave-one-out analysis found that omitting a single outlier makes JAK-i cost-effective. Further, JAK-i is not cost-effective as a third-line treatment for csDMARD-TNF-a-I failed RA, compared to csDMARDs/bDMARDs with INBp $26,157 (-7,284 to 59,598).

Conclusion: Meta-analysis suggests that JAK-i is cost-effective when used after csDMARD failure but not cost-effective when used after csDMARD-TNF-a-i failure with low certainty of evidence.

Clinical Trial Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021222541, identifier CRD42021222541
Toward a high-precision mass–energy test of the equivalence principle with atom interferometers
Authors: Zhou Lin , Yan Si-Tong , Ji Yu-Hang , He Chuan , Jiang Jun-Jie , Hou Zhuo , Xu Run-Dong , Wang Qi , Li Zhi-Xin , Gao Dong-Feng , Liu Min , Ni Wei-Tou , Wang Jin , Zhan Ming-Sheng
Published: December 2022

The equivalence principle (EP) is a basic assumption of the general relativity. The quantum test of the equivalence principle with atoms is an important way to examine the applicable scope of the current physical framework so as to discover new physics. Recently, we extended the traditional pure mass or energy tests of the equivalence principle to the joint test of mass–energy by atom interferometry (Zhou et al.,Phys.Rev.A 104,022822). The violation parameter of mass is constrained to η0 = (−0.8 ± 1.4) × 10–10 and that of internal energy to ηE = (0.0 ± 0.4) × 10–10 per reduced energy ratio. Here, we first briefly outline the joint test idea and experimental results, and then, we analyze and discuss how to improve the test accuracy. Finally, we report the latest experimental progress toward a high-precision mass–energy test of the equivalence principle. We realize atom interference fringes of 2T = 2.6 s in the 10-m long-baseline atom interferometer. This free evolution time T, to the best of our knowledge, is the longest duration realized in the laboratory, and the corresponding resolution of gravity measurement is 4.5 × 10−11 g per shot.
An evaluation of the rat intestinal monoamine biogeography days following exposure to acute stress
Authors: Bauer Ella E. , Reed Carter H. , Lyte Mark , Clark Peter J.
Published: December 2022

Stress-induced abnormalities in gut monoamine levels (e.g., serotonin, dopamine, norepinephrine) have been linked to gastrointestinal (GI) dysfunction, as well as the worsening of symptoms in GI disorders. However, the influence of stress on changes across the entire intestinal monoamine biogeography has not been well-characterized, especially in the days following stress exposure. Therefore, the aim of this study was to comprehensively assess changes to monoamine neurochemical signatures across the entire rat intestinal tract days after exposure to an acute stressor. To the end, adult male F344 rats were subjected to an episode of unpredictable tail shocks (acute stress) or left undisturbed. Forty-eight hours later rats were euthanized either following a 12 h period of fasting or 30 min of food access to evaluate neurochemical profiles during the peri- and early postprandial periods. Monoamine-related neurochemicals were measured via UHPLC in regions of the small intestine (duodenum, jejunum, ileum), large intestine (cecum, proximal colon, distal colon), cecal contents, fecal contents, and liver. The results suggest a relatively wide-spread increase in measures of serotonin activity across intestinal regions can be observed 48 h after exposure to acute stress, however some evidence was found supporting localized differences in serotonin metabolization. Moreover, acute stress exposure reduced catecholamine-related neurochemical concentrations most notably in the ileum, and to a lesser extent in the cecal contents. Next, stress-related fecal serotonin concentrations were consistent with intestinal profiles. However, fecal dopamine was elevated in association with stress, which did not parallel findings in any other intestinal area. Finally, stress exposure and the food access period together only had minor effects on intestinal monoamine profiles. Taken together, these data suggest nuanced differences in monoaminergic profiles exist across intestinal regions the days following exposure to an acute stressor, highlighting the importance of assessments that consider the entire intestinal tract biogeography when investigating stress-related biological outcomes that may be relevant to GI pathophysiology.