bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicenter Performance Evaluation of MALDI-TOF MS for Rapid Detection of Carbapenemase Activity in Enterobacterales: The Future of Networking Data Analysis With Online Software
Authors: Gato Eva , Anantharajah Ahalieyah , Arroyo Manuel J. , Artacho María José , Caballero Juan de Dios , Candela Ana , Chudějová Kateřina , Constanso Ignacio Pedro , Elías Cristina , Fernández Javier , Jiménez Jesús , Lumbreras Pilar , Méndez Gema , Mulet Xavier , Pérez-Palacios Patricia , Rodríguez-Sánchez Belén , Cantón Rafael , Hrabák Jaroslav , Mancera Luis , Martínez-Martínez Luis , Oliver Antonio , Pascual Álvaro , Verroken Alexia , Bou Germán , Oviaño Marina
Published: January 2022

In this study, we evaluate the performance of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for rapid detection of carbapenemase activity in Enterobacterales in clinical microbiology laboratories during a multicenter networking validation study. The study was divided into three different stages: “software design,” “intercenter evaluation,” and “clinical validation.” First, a standardized procedure with an online software for data analysis was designed. Carbapenem resistance was detected by measuring imipenem hydrolysis and the results were automatically interpreted using the Clover MS data analysis software (Clover BioSoft, Spain). Second, a series of 74 genotypically characterized Enterobacterales (46 carbapenemase-producers and 28 non carbapenemase-producers) were analyzed in 8 international centers to ensure the reproducibility of the method. Finally, the methodology was evaluated independently in all centers during a 2-month period and results were compared with the reference standard for carbapenemase detection used in each center. The overall agreement rate relative to the reference method for carbapenemase resistance detection in clinical samples was 92.5%. The sensitivity was 93.9% and the specificity, 100%. Results were obtained within 60 min and accuracy ranged from 83.3 to 100% among the different centers. Further, our results demonstrate that MALDI-TOF MS is an outstanding tool for rapid detection of carbapenemase activity in Enterobacterales in clinical microbiology laboratories. The use of a simple in-house procedure with online software allows routine screening of carbapenemases in diagnostics, thereby facilitating early and appropriate antimicrobial therapy.
Prolonged Continuous Theta Burst Stimulation to Demonstrate a Larger Analgesia as Well as Cortical Excitability Changes Dependent on the Context of a Pain Episode
Authors: Liu Ying , Yu Lina , Che Xianwei , Yan Min
Published: January 2022

A series of neuropathic pain conditions have a prevalence in older adults potentially associated with declined functioning of the peripheral and/or central nervous system. Neuropathic pain conditions demonstrate defective cortical excitability and intermissions, which raises questions of the impact of pain on cortical excitability changes and when to deliver repetitive transcranial magnetic stimulation (rTMS) to maximize the analgesic effects. Using prolonged continuous theta-burst stimulation (pcTBS), a relatively new rTMS protocol to increase excitability, this study was designed to investigate pcTBS analgesia and cortical excitability in the context of pain. With capsaicin application, twenty-nine healthy participants received pcTBS or Sham stimulation either in the phase of pain initialization (capsaicin applied) or pain ascending (20 min after capsaicin application). Pain intensity was measured with a visual-analogic scale (VAS). Cortical excitability was assessed by motor-evoked potential (MEP) and cortical silent period (CSP) which evaluates corticospinal excitability and GABAergic intracortical inhibition, respectively. Our data on pain dynamics demonstrated that pcTBS produced a consistent analgesic effect regardless of the time frame of pcTBS. More importantly, pcTBS delivered at pain initialization induced a larger pain reduction and a higher response rate compared to the stimulation during pain ascending. We further provide novel findings indicating distinct mechanisms of pcTBS analgesia dependent on the context of pain, in which pcTBS delivered at pain initialization was able to reverse depressed MEP, whereby pcTBS during pain ascending was associated with increased CSP. Overall, our data indicate pcTBS to be a potential protocol in pain management that could be delivered before the initialization of a pain episode to improve rTMS analgesia, potentially through inducing early corticospinal excitability changes that would be suppressed by nociceptive transmission.
Contrasting Sodium and Potassium Perturbations in the Hippocampus Indicate Potential Na+/K+-ATPase Dysfunction in Vascular Dementia
Authors: Philbert Sasha A. , Xu Jingshu , Scholefield Melissa , Church Stephanie J. , Unwin Richard D. , Cooper Garth J. S.
Published: January 2022

Vascular dementia (VaD) is thought to be the second most common cause of age-related dementia amongst the elderly. However, at present, there are no available disease-modifying therapies for VaD, probably due to insufficient understanding about the molecular basis of the disease. While the notion of metal dyshomeostasis in various age-related dementias has gained considerable attention in recent years, there remains little comparable investigation in VaD. To address this evident gap, we employed inductively coupled-plasma mass spectrometry to measure the concentrations of nine essential metals in both dry- and wet-weight hippocampal post-mortem tissue from cases with VaD (n = 10) and age-/sex-matched controls (n = 10). We also applied principal component analysis to compare the metallomic pattern of VaD in the hippocampus with our previous hippocampal metal datasets for Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and type-2 diabetes, which had been measured using the same methodology. We found substantive novel evidence for elevated hippocampal Na levels and Na/K ratios in both wet- and dry-weight analyses, whereas decreased K levels were present only in wet tissue. Multivariate analysis revealed no distinguishable hippocampal differences in metal-evoked patterns between these dementia-causing diseases in this study. Contrasting levels of Na and K in hippocampal VaD tissue may suggest dysfunction of the Na+/K+-exchanging ATPase (EC 7.2.2.13), possibly stemming from deficient metabolic energy (ATP) generation. These findings therefore highlight the potential diagnostic importance of cerebral sodium measurement in VaD patients.
Are High Frequency Oscillations in Scalp EEG Related to Age?
Authors: Windhager Philipp Franz , Marcu Adrian V. , Trinka Eugen , Bathke Arne , Höller Yvonne
Published: January 2022

Background

High-frequency oscillations (HFOs) have received much attention in recent years, particularly in the clinical context. In addition to their application as a marker for pathological changes in patients with epilepsy, HFOs have also been brought into context with several physiological mechanisms. Furthermore, recent studies reported a relation between an increase of HFO rate and age in invasive EEG recordings. The present study aimed to investigate whether this relation can be replicated in scalp-EEG.

Methods

We recorded high-density EEG from 11 epilepsy patients at rest as well as during motor performance. Manual detection of HFOs was performed by two independent raters following a standardized protocol. Patients were grouped by age into younger (<25 years) and older (>50 years) participants.

Results

No significant difference of HFO-rates was found between groups [U = 10.5, p = 0.429, r = 0.3].

Conclusions

Lack of replicability of the age effect of HFOs may be due to the local propagation patterns of age-related HFOs occurring in deep structures. However, limitations such as small sample size, decreased signal-to-noise ratio as compared to invasive recordings, as well as HFO-mimicking artifacts must be considered.
Functional and Structural Architectures of Allocentric and Egocentric Spatial Coding in Aging: A Combined DTI and fMRI Study
Authors: Derbie Abiot Y. , Chau Bolton K. H. , Chan Chetwyn C. H.
Published: January 2022

Background

Aging disrupts the optimal balance between neural nodes underlying orienting and attention control functions. Previous studies have suggested that age-related changes in cognitive process are associated to the changes in the myelinated fiber bundles, which affected the speed and actions of the signal propagation across different neural networks. However, whether the age-related difference in allocentric and egocentric spatial coding is accounted by the difference in white-matter integrity is unclear. In this study, using diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI), we sought to elucidate whether age-related differences in white matter integrity accounts for the difference in nodes to the distributed spatial coding-relevant brain networks.

Material and Method

Older (n = 24) and younger (n = 27) participants completed the structural DTI and fMRI scans during which they engaged in a cue-to-target task to elicit allocentric or egocentric processes.

Results and Conclusion

Efficient modulation of both allocentric and egocentric spatial coding in fronto-parietal attention network (FPAN) requires structure–function interaction. Allocentric task-modulated connectivity of the fronto-parietal network (FPN) and dorsal attention network (DAN) with the temporal lobe was influenced by the aging differences of the white-matter tracts of the posterior and superior corona radiata (PCR and SCR), respectively. On the other hand, aging difference of the superior longitudinal fasciculus mainly influenced the egocentric-task-modulated connections of the DAN and FPN with frontal regions and posterior cingulate cortex. This study suggested that functional connections of the FPAN with near and far task-relevant nodes vary significantly with age and conditions.
Mechanisms of False Alarm in Response to Fear Stimulus: An Event-Related Potential Study
Authors: Wang Xiai , Sun Jicheng , Yang Jinghua , Cheng Shan , Liu Cui , Hu Wendong , Ma Jin
Published: January 2022

Background and Objective

There is a paucity of research that has explored “False Alarm” mechanisms. In order to remedy this deficiency in knowledge, the present study used event-related potential (ERP) technology to reveal the mechanisms underlying False Alarm in response to fear stimuli.

Methods

This study selected snakes as experimental materials and the “oddball paradigm” was used to simulate the conditions of False Alarm. The mechanism underlying False Alarm was revealed by comparing cognitive processing similarities and differences between real snakes and toy snakes.

Results

Event-related potential findings demonstrated that there was no significant difference between N1 and P2 components induced by real and toy snakes in the early processing stage. Compared with toy snakes, real snakes induced smaller N2 amplitude, larger P3 amplitude, and a shorter P3 latency at the late processing stage. The results of brain topographic mapping analysis showed that the brain regions activated by a real or toy snake were basically the same within the time windows of 110–150 and 220–270 ms, respectively. In the time window of 300–360 and 400–500 ms, the degree of brain regions activation with a real snake was significantly greater than that induced by a toy snake.

Conclusion

False Alarm is caused by the brain’s inability to distinguish, in the early stage of cognitive processing, stimulus objects with similar appearances. When the brain is able to distinguish the differences between different stimulus objects in the late stage of cognitive processing, False Alarm disappears.
Radiomics Analysis Based on Magnetic Resonance Imaging for Preoperative Overall Survival Prediction in Isocitrate Dehydrogenase Wild-Type Glioblastoma
Authors: Wang Shouchao , Xiao Feng , Sun Wenbo , Yang Chao , Ma Chao , Huang Yong , Xu Dan , Li Lanqing , Chen Jun , Li Huan , Xu Haibo
Published: January 2022

Purpose

This study aimed to develop a radiomics signature for the preoperative prognosis prediction of isocitrate dehydrogenase (IDH)-wild-type glioblastoma (GBM) patients and to provide personalized assistance in the clinical decision-making for different patients.

Materials and Methods

A total of 142 IDH-wild-type GBM patients classified using the new classification criteria of WHO 2021 from two centers were included in the study and randomly divided into a training set and a test set. Firstly, their clinical characteristics were screened using univariate Cox regression. Then, the radiomics features were extracted from the tumor and peritumoral edema areas on their contrast-enhanced T1-weighted image (CE-T1WI), T2-weighted image (T2WI), and T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) magnetic resonance imaging (MRI) images. Subsequently, inter- and intra-class correlation coefficient (ICC) analysis, Spearman’s correlation analysis, univariate Cox, and the least absolute shrinkage and selection operator (LASSO) Cox regression were used step by step for feature selection and the construction of a radiomics signature. The combined model was established by integrating the selected clinical factors. Kaplan–Meier analysis was performed for the validation of the discrimination ability of the model, and the C-index was used to evaluate consistency in the prediction. Finally, a Radiomics + Clinical nomogram was generated for personalized prognosis analysis and then validated using the calibration curve.

Results

Analysis of the clinical characteristics resulted in the screening of four risk factors. The combination of ICC, Spearman’s correlation, and univariate and LASSO Cox resulted in the selection of eight radiomics features, which made up the radiomics signature. Both the radiomics and combined models can significantly stratify high- and low-risk patients (p < 0.001 and p < 0.05 for the training and test sets, respectively) and obtained good prediction consistency (C-index = 0.74–0.86). The calibration plots exhibited good agreement in both 1- and 2-year survival between the prediction of the model and the actual observation.

Conclusion

Radiomics is an independent preoperative non-invasive prognostic tool for patients who were newly classified as having IDH-wild-type GBM. The constructed nomogram, which combined radiomics features with clinical factors, can predict the overall survival (OS) of IDH-wild-type GBM patients and could be a new supplement to treatment guidelines.
RIBEYE B-Domain Is Essential for RIBEYE A-Domain Stability and Assembly of Synaptic Ribbons
Authors: Shankhwar Soni , Schwarz Karin , Katiyar Rashmi , Jung Martin , Maxeiner Stephan , Südhof Thomas C. , Schmitz Frank
Published: January 2022

Synaptic ribbons are presynaptic specializations that define eponymous ribbon synapses. Synaptic ribbons are largely composed of RIBEYE, a protein containing an N-terminal A-domain and a carboxyterminal B-domain that is identical with CtBP2, a NAD(H)-binding transcriptional co-repressor. Previously we showed that synaptic ribbons are completely absent in RIBEYE knockout mice in which the RIBEYE A-domain-encoding exon had been deleted, but CtBP2 is still made, demonstrating that the A-domain is required for synaptic ribbon assembly. In the present study, we asked whether the RIBEYE B-domain also has an essential role in the assembly of synaptic ribbons. For this purpose, we made use of RIBEYE knockin mice in which the RIBEYE B-domain was replaced by a fluorescent protein domain, whereas the RIBEYE A-domain was retained unchanged. We found that replacing the RIBEYE B-domain with a fluorescent protein module destabilizes the resulting hybrid protein and causes a complete loss of synaptic ribbons. Our results thus demonstrate an essential role of the RIBEYE B-domain in enabling RIBEYE assembly into synaptic ribbons, reinforcing the notion that RIBEYE is the central organizer of synaptic ribbons.
Maternal Choline Supplementation and High-Fat Feeding Interact to Influence DNA Methylation in Offspring in a Time-Specific Manner
Authors: Korsmo Hunter W. , Dave Bhoomi , Trasino Steven , Saxena Anjana , Liu Jia , Caviglia Jorge Matias , Edwards Kaydine , Dembitzer Moshe , Sheeraz Shameera , Khaldi Sarah , Jiang Xinyin
Published: January 2022

Maternal methyl donor supplementation during pregnancy has demonstrated lasting influence on offspring DNA methylation. However, it is unknown whether an adverse postnatal environment, such as high-fat (HF) feeding, overrides the influence of prenatal methyl donor supplementation on offspring epigenome. In this study, we examined whether maternal supplementation of choline (CS), a methyl donor, interacts with prenatal and postnatal HF feeding to alter global and site-specific DNA methylation in offspring. We fed wild-type C57BL/6J mouse dams a HF diet with or without CS throughout gestation. After weaning, the offspring were exposed to HF feeding for 6 weeks resembling a continued obesogenic environment. Our results suggest that maternal CS under the HF condition (HFCS) increased global DNA methylation and DNA methyltransferase 1 (Dnmt1) expression in both fetal liver and brain. However, during the postnatal period, HFCS offspring demonstrated lower global DNA methylation and Dnmt1 expression was unaltered in both the liver and visceral adipose tissue. Site-specific DNA methylation analysis during both fetal and postnatal periods demonstrated that HFCS offspring had higher methylation of CpGs in the promoter of Srebf1, a key mediator of de novo lipogenesis. In conclusion, the influence of maternal CS on offspring DNA methylation is specific to HF feeding status during prenatal and postnatal periods. Without continued CS during the postnatal period, global DNA methylation enhanced by prenatal CS in the offspring was overridden by postnatal HF feeding.
Outcomes in Patients With Lung Adenocarcinoma With Transformation to Small Cell Lung Cancer After EGFR Tyrosine Kinase Inhibitors Resistance: A Systematic Review and Pooled Analysis
Authors: Xu Jinhe , Xu Lihuan , Wang Baoshan , Kong Wencui , Chen Ying , Yu Zongyang
Published: January 2022

Background

Lung adenocarcinoma can transform into small-cell lung cancer (SCLC) when resistance to tyrosine kinase inhibitors (TKIs) develops. Approximately 3% to 10% of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) could transform to SCLC. This phenomenon has been described in several case reports and small patient series. However, the characteristics and treatment outcomes of this population have not been comprehensively reported, and their clinical course is poorly characterized.

Methods

We performed a systematic review of the published literature to summarize the clinical and pathological features and prognosis of the reported cases and analyzed the demographics, disease features, and outcomes.

Results

A total of 72 patients (50 females and 22 males) initially diagnosed with lung adenocarcinoma were included. EGFR mutations included 19-deletion (75%), L858R (22%), and G719X (3%). All patients received EGFR-TKIs before SCLC transformation. The median time from diagnosis to transformation was 20.5 months (95% CI, 15.45 to 26.55 months). Of the 67 patients with post-translational gene test results, 58 maintained their EGFR mutation, and only 1 of 18 with prior T790M positivity retained T790M mutation. After the pathological transformation, both conventional chemotherapy regimen and chemotherapy combined targeted therapy yielded high response rates. The disease control rate of first-line therapy after transformation was 76%, while the objective response rate was 48%. The median overall survival (OS) since diagnosis was 27 months (95% CI, 22.90 to 31.10 months), whereas median OS since SCLC transformation was 8.5 months (95% CI, 5.50 to 11.60 months).

Conclusion

The prognosis of transformed SCLC is worse than primary SCLC. The response rate to conventional chemotherapy was high. However, the progression-free survival and OS after transformation were short and the prognosis was poor with first-line therapies. New therapies are needed in the management of transformed SCLC.
Ethyl Ferulate Suppresses Esophageal Squamous Cell Carcinoma Tumor Growth Through Inhibiting the mTOR Signaling Pathway
Authors: Pang Mengjun , Xie Xiaomeng , Zhang Yuanyuan , Laster Kyle Vaughn , Liu Kangdong , Kim Dong Joon
Published: January 2022

Ethyl ferulate is a phenylpropanoid compound isolated from the medicinal herb Ferula. Although ethyl ferulate has anti-inflammatory, antioxidant, and neuroprotective activities with potential use in the nutraceutical and pharmaceutical industry, its anticancer effects and underlying molecular mechanisms against esophageal squamous cell carcinoma (ESCC) have not been investigated. This study investigates the anticancer activity and molecular mechanism of ethyl ferulate in ESCC. MTT, focus formation, soft agar, and cell cycle analysis were used to determine the effect of ethyl ferulate on cell proliferation and cell cycle. Potential candidate proteins were screened and verified via Western blotting, in vitro kinase assay, and in vitro pull-down assay. Mammalian target of rapamycin (mTOR) knockdown cell lines were established by lentiviral infection with shmTOR. The effect of ethyl ferulate on tumor growth was assessed using ESCC patient-derived xenograft models. Ethyl ferulate significantly inhibited cell growth and induced G1 phase cell cycle arrest in ESCC cells. Ethyl ferulate reduced the activity of mTOR in vitro. The inhibition of ESCC cell growth by ethyl ferulate is dependent on mTOR expression. In addition, ethyl ferulate strongly reduced ESCC patient-derived xenograft tumor growth in an in vivo mouse model. Ethyl ferulate is an mTOR inhibitor that can suppress ESCC progression and may be a novel candidate compound for esophageal cancer chemoprevention.
AttR2U-Net: A Fully Automated Model for MRI Nasopharyngeal Carcinoma Segmentation Based on Spatial Attention and Residual Recurrent Convolution
Authors: Zhang Jiajing , Gu Lin , Han Guanghui , Liu Xiujian
Published: January 2022

Radiotherapy is an essential method for treating nasopharyngeal carcinoma (NPC), and the segmentation of NPC is a crucial process affecting the treatment. However, manual segmentation of NPC is inefficient. Besides, the segmentation results of different doctors might vary considerably. To improve the efficiency and the consistency of NPC segmentation, we propose a novel AttR2U-Net model which automatically and accurately segments nasopharyngeal carcinoma from MRI images. This model is based on the classic U-Net and incorporates advanced mechanisms such as spatial attention, residual connection, recurrent convolution, and normalization to improve the segmentation performance. Our model features recurrent convolution and residual connections in each layer to improve its ability to extract details. Moreover, spatial attention is fused into the network by skip connections to pinpoint cancer areas more accurately. Our model achieves a DSC value of 0.816 on the NPC segmentation task and obtains the best performance compared with six other state-of-the-art image segmentation models.
PET/MR Imaging of Somatostatin Receptor Expression and Tumor Vascularity in Meningioma: Implications for Pathophysiology and Tumor Outcomes
Authors: Roytman Michelle , Kim Sean , Glynn Shannon , Thomas Charlene , Lin Eaton , Feltus Whitney , Magge Rajiv S. , Liechty Benjamin , Schwartz Theodore H. , Ramakrishna Rohan , Karakatsanis Nicolas A. , Pannullo Susan C. , Osborne Joseph R. , Knisely Jonathan P. S. , Ivanidze Jana
Published: January 2022

Background and Purpose

Meningiomas, the most common primary intracranial tumor, are vascular neoplasms that express somatostatin receptor-2 (SSTR2). The purpose of this investigation was to evaluate if a relationship exists between tumor vascularity and SSTR2 expression, which may play a role in meningioma prognostication and clinical management.

Materials and Methods

Gallium-68-DOTATATE PET/MRI with dynamic contrast-enhanced (DCE) perfusion was prospectively performed. Clinical and demographic patient characteristics were recorded. Tumor volumes were segmented and superimposed onto parametric DCE maps including flux rate constant (Kep), transfer constant (Ktrans), extravascular volume fraction (Ve), and plasma volume fraction (Vp). Meningioma PET standardized uptake value (SUV) and SUV ratio to superior sagittal sinus (SUVRSSS) were recorded. Pearson correlation analyses were performed. In a random subset, analysis was repeated by a second investigator, and intraclass correlation coefficients (ICCs) were determined.

Results

Thirty-six patients with 60 meningiomas (20 WHO-1, 27 WHO-2, and 13 WHO-3) were included. Mean Kep demonstrated a strong significant positive correlation with SUV (r = 0.84, p < 0.0001) and SUVRSSS (r = 0.81, p < 0.0001). When stratifying by WHO grade, this correlation persisted in WHO-2 (r = 0.91, p < 0.0001) and WHO-3 (r = 0.92, p = 0.0029) but not WHO-1 (r = 0.26, p = 0.4, SUVRSSS). ICC was excellent (0.97–0.99).

Conclusion

DOTATATE PET/MRI demonstrated a strong significant correlation between tumor vascularity and SSTR2 expression in WHO-2 and WHO-3, but not WHO-1 meningiomas, suggesting biological differences in the relationship between tumor vascularity and SSTR2 expression in higher-grade meningiomas, the predictive value of which will be tested in future work.
Syntenin Regulated by miR-216b Promotes Cancer Progression in Pancreatic Cancer
Authors: Zu Fuqiang , Chen Hui , Liu Qingfeng , Zang Hui , Li Zeyu , Tan Xiaodong
Published: January 2022

Outcomes for patients with pancreatic cancer (PC) are poor; therefore, there is an urgent need to identify novel therapeutic targets involved in the progression of PC. We previously identified 161 differentially expressed proteins (DEPs) in PC. Syntenin (SDCBP) was identified as a survival-related protein through integrated, survival, and Cox analyses. High expression of SDCBP was associated with a poor prognosis in PC tissue and promoted the proliferation, migration, and invasion of PC cells, and induced epithelial–mesenchymal transition (EMT) via the PI3K/AKT pathway. Additionally, we elucidated the regulatory mechanism underlying these roles of SDCBP at the post-transcriptional level. microRNAs (miRNAs) of SDCBP were predicted using bioinformatics. Low levels of miR-216b expression were confirmed in PC tissues and were negatively correlated with SDCBP expression. miR-216b was found to directly regulate SDCBP expression through luciferase reporter assays. Furthermore, agomiR-216b restrained PC proliferation, migration, invasion, and EMT via the PI3K/AKT pathway, whereas antagomiR-216b facilitated this process. Notably, the knockout of SDCBP counteracted the effect of antagomiR-216b in PC, which suggested that miR-216b and SDCBP represent molecular targets underlying PC progression and EMT. Finally, the results were validated in in vivo studies. These findings indicated that low expression of miR-216b and the oncogene SDCBP contributes to PC migration, invasion, and EMT, and that they have potential as future therapeutic targets for patients with PC.
Serum Metabolomic Profiling Reveals Biomarkers for Early Detection and Prognosis of Esophageal Squamous Cell Carcinoma
Authors: Wang Pan Pan , Song Xin , Zhao Xue Ke , Wei Meng Xia , Gao She Gan , Zhou Fu You , Han Xue Na , Xu Rui Hua , Wang Ran , Fan Zong Min , Ren Jing Li , Li Xue Min , Wang Xian Zeng , Yang Miao Miao , Hu Jing Feng , Zhong Kan , Lei Ling Ling , Li Liu Yu , Chen Yao , Chen Ya Jie , Ji Jia Jia , Yang Yuan Ze , Li Jia , Wang Li Dong
Published: January 2022

Esophageal squamous cell carcinoma (ESCC) is one of the most common aggressive malignancies worldwide, particularly in northern China. The absence of specific early symptoms and biomarkers leads to late-stage diagnosis, while early diagnosis and risk stratification are crucial for improving overall prognosis. We performed UPLC-MS/MS on 450 ESCC patients and 588 controls consisting of a discovery group and two validation groups to identify biomarkers for early detection and prognosis. Bioinformatics and clinical statistical methods were used for profiling metabolites and evaluating potential biomarkers. A total of 105 differential metabolites were identified as reliable biomarker candidates for ESCC with the same tendency in three cohorts, mainly including amino acids and fatty acyls. A predictive model of 15 metabolites [all-trans-13,14-dihydroretinol, (±)-myristylcarnitine, (2S,3S)-3-methylphenylalanine, 3-(pyrazol-1-yl)-L-alanine, carnitine C10:1, carnitine C10:1 isomer1, carnitine C14-OH, carnitine C16:2-OH, carnitine C9:1, formononetin, hyodeoxycholic acid, indole-3-carboxylic acid, PysoPE 20:3, PysoPE 20:3(2n isomer1), and resolvin E1] was developed by logistic regression after LASSO and random forest analysis. This model held high predictive accuracies on distinguishing ESCC from controls in the discovery and validation groups (accuracies > 89%). In addition, the levels of four downregulated metabolites [hyodeoxycholic acid, (2S,3S)-3-methylphenylalanine, carnitine C9:1, and indole-3-carboxylic acid] were significantly higher in early cancer than advanced cancer. Furthermore, three independent prognostic markers were identified by multivariate Cox regression analyses with and without clinical indicators: a high level of MG(20:4)isomer and low levels of 9,12-octadecadienoic acid and L-isoleucine correlated with an unfavorable prognosis; the risk score based on these three metabolites was able to stratify patients into low or high risk. Moreover, pathway analysis indicated that retinol metabolism and linoleic acid metabolism were prominent perturbed pathways in ESCC. In conclusion, metabolic profiling revealed that perturbed amino acids and lipid metabolism were crucial metabolic signatures of ESCC. Both panels of diagnostic and prognostic markers showed excellent predictive performances. Targeting retinol and linoleic acid metabolism pathways may be new promising mechanism-based therapeutic approaches. Thus, this study would provide novel insights for the early detection and risk stratification for the clinical management of ESCC and potentially improve the outcomes of ESCC.
Progression-Free Survival and Time to Progression as Potential Surrogate Endpoints for Overall Survival in Chemoradiotherapy Trials in Limited-Stage Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis
Authors: Yang Yin , Wang Jianyang , Wang Wenqing , Zhang Tao , Zhao Jingjing , Wang Yu , Li Yexiong , Wang Luhua , Bi Nan
Published: January 2022

Purpose

To investigate whether progression-free survival (PFS) or time to progression (TTP) could be a valid surrogate endpoint for overall survival (OS) in patients with limited-stage small-cell lung cancer (LS-SCLC) receiving combined chemoradiotherapy.

Methods

Literature searching was performed in PubMed, Embase, and The Cochrane Library up to 2021. Prediction models were firstly established using data from phase III randomized controlled trials (RCTs) and then externally validated in phase II and retrospective studies. Correlation analysis was evaluated by a weighted linear regression model at both trial and arm levels. Cross-validation was performed to assess the consistency and robustness of the established models.

Results

37 studies, including 15 phase III RCTs, 12 phase II studies, and 10 retrospective studies, were selected in the final analysis. In trial-level surrogacy, a very good correlation was observed between hazard ratios (HRs) of PFS/TTP and OS (R2 = 0.783, 95% CI 0.771–0.794). In arm-level surrogacy, very good correlations were also observed between 2-year (R2 = 0.823, 95% CI 0.814–0.832), 3-year (R2 = 0.843, 95% CI 0.833–0.850), 5-year (R2 = 0.852, 95% CI 0.843–0.859) PFS/TTP, and 5-year OS. An excellent correlation was observed between 4-year PFS/TTP and 5-year OS (R2 = 0.906, 95% CI 0.901–0.910). Cross-validation demonstrated reasonable overall consistency. External validation in phase II and retrospective studies showed good agreement (R2, 0.728–0.824).

Conclusions

PFS/TTP was a valid surrogate endpoint for OS in patients with LS-SCLC receiving combined chemoradiotherapy. The finding provides high-level evidence to support PFS/TTP as the primary endpoint in clinical trials so as to speed up introducing novel agents to the treatment of LS-SCLC.
Long Non-Coding RNA in Gastric Cancer: Mechanisms and Clinical Implications for Drug Resistance
Authors: Liu Ying , Ao Xiang , Wang Yu , Li Xiaoge , Wang Jianxun
Published: January 2022

Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, with high recurrence and mortality rate. Chemotherapy, including 5-fluorouracil (5-FU), adriamycin (ADR), vincristine (VCR), paclitaxel (PTX), and platinum drugs, remains one of the fundamental methods of GC treatment and has efficiently improved patients’ prognosis. However, most patients eventually develop resistance to chemotherapeutic agents, leading to the failure of clinical treatment and patients’ death. Recent studies suggest that long non-coding RNAs (lncRNAs) are involved in the drug resistance of GC by modulating the expression of drug resistance-related genes via sponging microRNAs (miRNAs). Moreover, lncRNAs also play crucial roles in GC drug resistance via a variety of mechanisms, such as the regulation of the oncogenic signaling pathways, inhibition of apoptosis, induction of autophagy, modulation of cancer stem cells (CSCs), and promotion of the epithelial-to-mesenchymal transition (EMT) process. Some of lncRNAs exhibit great potential as diagnostic and prognostic biomarkers, as well as therapeutic targets for GC patients. Therefore, understanding the role of lncRNAs and their mechanisms in GC drug resistance may provide us with novel insights for developing strategies for individual diagnosis and therapy. In this review, we summarize the recent findings on the mechanisms underlying GC drug resistance regulated by lncRNAs. We also discuss the potential clinical applications of lncRNAs as biomarkers and therapeutic targets in GC.
Wave Reflection and Ventriculo-Arterial Coupling in Bicuspid Aortic Valve Patients With Repaired Aortic Coarctation
Authors: Milano Elena Giulia , Neumann Sandra , Sophocleous Froso , Pontecorboli Giulia , Curtis Stephanie L. , Bedair Radwa , Caputo Massimo , Luciani Giovanni Battista , Bucciarelli-Ducci Chiara , Biglino Giovanni
Published: January 2022

Background

Ventriculo-arterial (VA) coupling in bicuspid aortic valve (BAV) patients can be affected by the global aortopathy characterizing BAV disease and the presence of concomitant congenital lesions such as aortic coarctation (COA). This study aimed to isolate the COA variable and use cardiovascular magnetic resonance (CMR) imaging to perform wave intensity analysis non-invasively to shed light on VA coupling changes in BAV. The primary hypothesis was that BAV patients with COA exhibit unfavorable VA coupling, and the secondary hypothesis was that BAV patients with COA exhibit increased wave speed as a marker of reduced aortic distensibility despite successful surgical correction.

Methods

Patients were retrospectively identified from a CMR database and divided into two groups: isolated BAV and BAV associated with repaired COA. Aortic and ventricular dimensions, global longitudinal strain (GLS), and ascending aortic flow data and area were collected and used to derive wave intensity from CMR data. The main variables for the analysis included all wave magnitudes (forward compression/expansion waves, FCW and FEW, respectively, and reflected backward compression wave, BCW) and wave speed.

Results

In the comparison of patients with isolated BAV and those with BAV associated with repaired COA (n = 25 in each group), no differences were observed in left ventricular ejection fraction, GLS, or ventricular volumes, whilst significant increases in FCW and FEW magnitude were noted in the BAV and repaired COA group. The FCW inversely correlated with age and aortic size. Whilst the BCW was not significantly different compared with that in patients with/without COA, its magnitude tends to increase with a lower COA index. Patients with repaired COA exhibited higher wave speed velocity. Aortic wave speed (inversely related to distensibility) was not significantly different between the two groups.

Conclusion

In the absence of a significant restenosis, VA coupling in patients with BAV and COA is not negatively affected compared to patients with isolated BAV. A reduction in the magnitude of the early systolic FCW was observed in patients who were older and with larger aortic diameters.
The SARS-CoV-2 Pandemic Impacts the Management of Swiss Pediatric Intensive Care Units
Authors: Soomann Maarja , Wendel-Garcia Pedro D. , Kaufmann Mark , Grazioli Serge , Perez Marie-Helene , Hilty Matthias P. , André Maya C. , Brotschi Barbara
Published: January 2022

The impact of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic on pediatric intensive care units (PICUs) is difficult to quantify. We conducted an observational study in all eight Swiss PICUs between 02/24/2020 and 06/15/2020 to characterize the logistical and medical aspects of the pandemic and their impact on the management of the Swiss PICUs. The nine patients admitted to Swiss PICUs during the study period suffering from pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and constituting 14% (9/63) of all SARS-CoV-2 positive hospitalized patients in Swiss children's hospitals caused a higher workload [total Nine Equivalents of nursing Manpower use Score (NEMS) points, p = 0.0008] and were classified to higher workload categories (p < 0.0001) than regular PICU patients (n = 4,881) admitted in 2019. The comparison of the characteristics of the eight Swiss PICUs shows that they were confronted by different organizational issues arising from temporary regulations put in place by the federal council. These general regulations had different consequences for the eight individual PICUs due to the differences between the PICUs. In addition, the temporal relationship of these different regulations influenced the available PICU resources, dependent on the characteristics of the individual PICUs. As pandemic continues, reflecting and learning from experience is essential to reduce workload, optimize bed occupancy and manage resources in each individual PICU. In a small country as Switzerland, with a relatively decentralized health care local differences between PICUs are considerable and should be taken into account when making policy decisions.
Non-invasively Measured Venous Oxygen Saturation as Early Marker of Impaired Oxygen Delivery in Preterm Neonates
Authors: Mileder Lukas P. , Buchmayer Julia , Baik-Schneditz Nariae , Schwaberger Bernhard , Höller Nina , Andersen Chad C. , Stark Michael J. , Pichler Gerhard , Urlesberger Berndt
Published: January 2022

Introduction

Adequate oxygen supply for preterm neonates may be defined through non-invasive measurement of venous oxygen saturation (SvO2) and fractional oxygen extraction using near-infrared spectroscopy (NIRS). We investigated whether there was a difference in peripheral muscle SvO2 (pSvO2) and peripheral fractional oxygen extraction (pFOE) in preterm neonates with early inflammation/infection compared to healthy subjects during the first 72 h after birth.

Materials and Methods

We retrospectively analyzed secondary outcome parameters of prospective observational studies, including preterm neonates at risk of infection in whom peripheral NIRS measurements were performed in combination with venous occlusions. Early neonatal inflammation/infection was diagnosed by clinical signs and laboratory parameters. Peripheral muscle tissue oxygenation index (pTOI) was measured using either NIRO 300 or NIRO 200-NX (both Hamamatsu Photonics, Japan) on the patients' lower legs. Using 20-s venous occlusions, pSvO2 and pFOE were calculated incorporating simultaneous measurements of arterial oxygen saturation (SpO2).

Results

We analyzed measurements from 226 preterm neonates (median gestational age 33.9 weeks), 64 (28.3%) of whom were diagnosed with early neonatal inflammation/infection. During the first 24 h after birth, pSvO2 (66.9% [62.6–69.2] vs. 69.4% [64.6–72.0]; p = 0.04) and pTOI (68.6% [65.3–71.9] vs. 71.7% [67.3–75.1]; p = 0.02) were lower in those neonates with inflammation/infection, while there was no such difference for measurements between 24–48 and 48–72 h.

Discussion

NIRS measurement of pSvO2 and pFOE is feasible and may be utilized for early detection of impaired peripheral oxygen delivery. As pTOI was also significantly lower, this parameter may serve as substitute for diminished regional oxygen supply.
UPLC/Q-TOF MS Screening and Identification of Antibacterial Compounds in Forsythia suspensa (Thunb.) Vahl Leaves
Authors: Zhou Mingyue , Huo Jinhai , Wang Cairen , Wang Weiming
Published: January 2022

Forsythia suspensa (Thunb.) Vahl (F. suspensa) is a traditional Chinese medical herb and only its fruit is currently used in clinical therapies. However, the discarded parts like leaves also contain a large number of active components. In this study, we used macroporous adsorption resin to enrich the effective components from F. suspensa leaves. The separated active compounds were then identified and quantified by ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC/Q-TOF MS) and high-performance liquid chromatography Active components with antibacterial properties extracted from F. suspensa leaves were confirmed in vitro and the corresponding mechanisms were explored. In sum, a stable and effective method for extracting antibacterial active components from F. suspensa leaves was established in this study, which proved the practicability of F. suspensa leaves as traditional Chinese medicine and is conducive to the more comprehensive utilization of the plant.
Ketamine Induced Bladder Fibrosis Through MTDH/P38 MAPK/EMT Pathway
Authors: Zhu Quan , Li Kaixuan , Li Haozhen , Han Feng , Tang Zhengyan , Wang Zhao
Published: January 2022

Purpose: Ketamine is an anesthetic in clinical, but it has also been used as an abusing drug due to its low price and hallucinogenic effects. It is proved that ketamine abusing would cause multiple system damage including the urinary system, which is called ketamine-induced cystitis (KIC). Bladder fibrosis is late stage in KIC and threaten abusers’ life. This study aimed to investigate the molecular mechanism of ketamine-induced bladder fibrosis.

Methods: Female Sprague Dawley (SD) rats were randomly divided into 3 groups. 2 groups were treated with tail vein injection of ketamine (25 mg/kg/day, 50 mg/kg/day ketamine hydrochloride solution, respectively) for 12 weeks, whereas the control group was treated with normal saline solution. In each group, rat bladders were extracted and samples were examined for pathological and morphological alterations via hematoxylin and eosin (HE) staining, Masson’s trichrome staining and immunohistochemistry (IHC). SV-HUC-1 cells were treated with different concentrations of ketamine solution (0, 0.1, 0.5, 1 mmol/L). Rat bladder and SV-HUC-1 cells were extracted protein and RNA for Western blot and RT-PCR detection. Metadherin (MTDH) siRNAs and overexpression plasmids were used to knock down and overexpress the relative genes. P38 mitogen-activated protein kinase (MAPK) inhibitor was utilized to inhibit the MAPK pathway.

Results: Rats in the ketamine group exhibited fibrosis compared to rats of the control group and fibrosis were also markedly upregulated in SV-HUC-1 cells after treated with ketamine, which were ketamine concentration-dependent. After treating with ketamine in SV-HUC-1 cells, there was an increase expression of MTDH, epithelial-mesenchymal transition (EMT) markers, P38 MAPK. MTDH knockdown would suppresses P38 MAPK/EMT pathway to inhibit fibrosis, however, MTDH overexpression could promote the pathway in SV-HUC-1 cells.

Conclusion: In rats and SV-HUC-1 cells ketamine-treated models, MTDH can regulate EMT through the P38 MAPK pathway to regulate the process of bladder fibrosis.
Recombinant Human Nerve Growth Factor (Cenegermin)–Driven Corneal Wound Healing Process: An Evidence-Based Analysis
Authors: Bonzano Chiara , Olivari Sara , Cutolo Carlo Alberto , Macrì Angelo , Sindaco Daniele , Borroni Davide , Bonzano Elisabetta , Traverso Carlo Enrico
Published: January 2022

Purpose: To evaluate anterior segment optical coherence tomography (AS-OCT) to detect the wound healing process as per monitoring the effectiveness of cenegermin to treat moderate to severe neurotrophic keratoplasty.

Methods: A retrospective chart review was realized to identify patients treated with cenegermin at the Clinica Oculistica, University of Genoa, Italy. All patients underwent careful examinations at baseline and follow-up visits. AS-OCT scans centered on the minimum corneal thickness (CT) area were always performed. We compared findings of AS-OCT with the findings from the slit-lamp examination. A linear regression analysis was used to evaluate factors associated with corneal healing. A further analysis, including a control group treated with 50% autologous serum (AS), was done to investigate and compare the efficacy of cenegermin.

Results: Data from 16 eyes were studied. The average patients' age was 60.9 ± 21.1 years; five (31.2%) eyes experienced persistent epithelial defect and 11 (68.8%) eyes had neurotrophic corneal ulcer. The average reepithelialization time was 3.9 ± 0.5 weeks in the cenegermin group versus 5.9 ± 1.9 weeks in the AS group (p < 0.01). The AS‐OCT scans revealed an average CT at the thinnest point of 276.3 ± 74.1 μm before treatment with an average increase of 176.5 ± 60.3 μm at the end of the cenegermin treatment (B = −0.15; p = 0.035). The AS-OCT percentage increase in corneal thickness between the two groups was statistically significant (p < 0.02).

Conclusion: Understanding the cascade of events involved in the nerve growth factor–driven corneal wound healing process is clinically meaningful for the clinician. AS-OCT is an effective tool for systematic anterior segment imaging, allowing the detailed detection of the front-to-back layered corneal structure for quantitative analysis and monitoring of the healing process.
Dermal Fibroblast Migration and Proliferation Upon Wounding or Lipopolysaccharide Exposure is Mediated by Stathmin
Authors: Cen Ruiyan , Wang Liqun , He Yongqing , Yue Chenda , Tan Yang , Li Lingfei , Lei Xia
Published: January 2022

The dermal fibroblast is a crucial executor involved in wound healing, and lipopolysaccharide is a key factor in initiating the migration and proliferation of the dermal fibroblasts, followed by wound healing. However, the underlying molecular mechanism is still unknown. In this study, we demonstrated that stathmin increased concomitantly with p38/MAPK pathway activation by lipopolysaccharide stimulation of the human dermal fibroblast (HDF), which induced microtubule (MT) depolymerization followed by increased HDF migration and proliferation. In contrast, the application of taxol, the small interfering RNA transfection of stathmin, or the application of the p38/MAPK inhibitor SB203580 suppressed MT depolymerization and HDF migration and proliferation. Additionally, the overexpression of a MKK6(Glu) mutant, which constitutively activated p38/MAPK, resulted in MT depolymerization and, subsequently, promoted HDF migration and proliferation. Our data reveal a crucial role of stathmin in HDF migration and proliferation. These findings will provide new targets and strategies for clinical interventions in wound healing.