bluuebunny/crossref_metadata_2025 huggingface dataset:
The Volatilomic Footprints of Human HGC-27 and CLS-145 Gastric Cancer Cell Lines
Authors: Leiherer Andreas , Ślefarska Daria , Leja Marcis , Heinzle Christine , Mündlein Axel , Kikuste Ilze , Mezmale Linda , Drexel Heinz , Mayhew Chris A. , Mochalski Paweł
Published: January 2021

The presence of certain volatile biomarkers in the breath of patients with gastric cancer has been reported by several studies; however, the origin of these compounds remains controversial. In vitro studies, involving gastric cancer cells may address this problem and aid in revealing the biochemical pathways underlying the production and metabolism of gastric cancer volatile indicators. Gas chromatography with mass spectrometric detection, coupled with headspace needle trap extraction as the pre-concentration technique, has been applied to map the volatilomic footprints of human HGC-27 and CLS-145 gastric cancer cell lines and normal Human Stomach Epithelial Cells (HSEC). In total, 27 volatile compounds are found to be associated with metabolism occurring in HGC-27, CLS-145, and HSEC. Amongst these, the headspace concentrations of 12 volatiles were found to be reduced compared to those above just the cultivating medium, namely there was an observed uptake of eight aldehydes (2-methylpropanal, 2-methyl-2-propenal, 2-methylbutanal, 3-methylbutanal, hexanal, heptanal, nonanal, and benzaldehyde), three heterocyclic compounds (2-methyl-furan, 2-ethyl-furan, and 2-pentyl-furan), and one sulfur-containing compound (dimethyl disulphide). For the other 15 volatiles, the headspace concentrations above the healthy and cancerous cells were found to be higher than those found above the cultivating medium, namely the cells were found to release three esters (ethyl acetate, ethyl propanoate, and ethyl 2-methylbutyrate), seven ketones (2-pentanone, 2-heptanone, 2-nonanone, 2-undecanone, 2-tridecanone, 2-pentadecanone, and 2-heptadecanone), three alcohols (2-methyl-1-butanol, 3-methyl-1-butanol, and 2-ethyl-1-hexanol), one aromatic compound (toluene), and one sulfur containing compound [2-methyl-5-(methylthio) furan]. In comparison to HSEC, HGC-27 cancer cell lines were found to have significantly altered metabolism, manifested by an increased production of methyl ketones containing an odd number of carbons. Amongst these species, three volatiles were found exclusively to be produced by this cell line, namely 2-undecanone, 2-tridecanone, and 2-heptadecanone. Another interesting feature of the HGC-27 footprint is the lowered level of alcohols and esters. The CLS-145 cells exhibited less pronounced changes in their volatilomic pattern compared to HSEC. Their footprint was characterized by the upregulated production of esters and 2-ethyl-hexanol and downregulated production of other alcohols. We have therefore demonstrated that it is possible to differentiate between cancerous and healthy gastric cells using biochemical volatile signatures.
Identification of a Five-Autophagy-Related-lncRNA Signature as a Novel Prognostic Biomarker for Hepatocellular Carcinoma
Authors: Deng Xiaoyu , Bi Qinghua , Chen Shihan , Chen Xianhua , Li Shuhui , Zhong Zhaoyang , Guo Wei , Li Xiaohui , Deng Youcai , Yang Yao
Published: January 2021

Although great progresses have been made in the diagnosis and treatment of hepatocellular carcinoma (HCC), its prognostic marker remains controversial. In this current study, weighted correlation network analysis and Cox regression analysis showed significant prognostic value of five autophagy-related long non-coding RNAs (AR-lncRNAs) (including TMCC1-AS1, PLBD1-AS1, MKLN1-AS, LINC01063, and CYTOR) for HCC patients from data in The Cancer Genome Atlas. By using them, we constructed a five-AR-lncRNA prognostic signature, which accurately distinguished the high- and low-risk groups of HCC patients. All of the five AR lncRNAs were highly expressed in the high-risk group of HCC patients. This five-AR-lncRNA prognostic signature showed good area under the curve (AUC) value (AUC = 0.751) for the overall survival (OS) prediction in either all HCC patients or HCC patients stratified according to several clinical traits. A prognostic nomogram with this five-AR-lncRNA signature predicted the 3- and 5-year OS outcomes of HCC patients intuitively and accurately (concordance index = 0.745). By parallel comparison, this five-AR-lncRNA signature has better prognosis accuracy than the other three recently published signatures. Furthermore, we discovered the prediction ability of the signature on therapeutic outcomes of HCC patients, including chemotherapy and immunotherapeutic responses. Gene set enrichment analysis and gene mutation analysis revealed that dysregulated cell cycle pathway, purine metabolism, and TP53 mutation may play an important role in determining the OS outcomes of HCC patients in the high-risk group. Collectively, our study suggests a new five-AR-lncRNA prognostic signature for HCC patients.
Importance of Veins for Neurosurgery as Landmarks Against Brain Shifting Phenomenon: An Anatomical and 3D-MPRAGE MR Reconstruction of Superficial Cortical Veins
Authors: Tomasi Santino Ottavio , Umana Giuseppe Emmanuele , Scalia Gianluca , Rubio-Rodriguez Roberto Luis , Cappai Pier Francesco , Capone Crescenzo , Raudino Giuseppe , Chaurasia Bipin , Salvati Maurizio , Jorden Nicolas , Winkler Peter A.
Published: January 2021

Modern neurosurgery uses preoperative imaging daily. Three-dimensional reconstruction of the cortical anatomy and of the superficial veins helps the surgeons plan and perform neurosurgical procedures much more safely. The target is always to give the patient maximum benefit in terms of outcome and minimize intraoperative and postoperative complications. This study aims to develop a method for the combined representation of the cerebral cortex anatomy and the superficial cerebral veins, whose integration is beneficial in daily practice. Only those patients who underwent surgical procedures with craniotomy and a large opening of the dura mater were included in this study, for a total of 23 patients, 13 females (56.5%) and 10 males (43.5%). The average age was 50.1 years. We used a magnetic resonance tomograph Magnetom Vision® 1.5T (Siemens AG). Two sequences were applied: a strongly T1-weighted magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequence to visualize cerebral anatomical structures, and a FLASH-2D-TOF angiography sequence to visualize the venous vessels on the cortical surface after the administration of a paramagnetic contrast agent. The two data sets were superimposed manually, co-registered in an interactive process, and merged to create a combined data set, segmented and visualized as a three-dimensional reconstruction. Furthermore, we present our method for visualizing superficial veins, which helps manage brain shift (BS). We also performed anatomical observations on the reconstructions. The reconstructions of the cortical and venous anatomy proved to be a valuable tool in surgical planning and positively influenced the surgical procedure. Due to the good correlation with the existing surgical site, this method should be validated on a larger cohort or in a multicentric study.
The Neurotransmitters Involved in Drosophila Alcohol-Induced Behaviors
Authors: Chvilicek Maggie M. , Titos Iris , Rothenfluh Adrian
Published: January 2021

Alcohol is a widely used and abused substance with numerous negative consequences for human health and safety. Historically, alcohol's widespread, non-specific neurobiological effects have made it a challenge to study in humans. Therefore, model organisms are a critical tool for unraveling the mechanisms of alcohol action and subsequent effects on behavior. Drosophila melanogaster is genetically tractable and displays a vast behavioral repertoire, making it a particularly good candidate for examining the neurobiology of alcohol responses. In addition to being experimentally amenable, Drosophila have high face and mechanistic validity: their alcohol-related behaviors are remarkably consistent with humans and other mammalian species, and they share numerous conserved neurotransmitters and signaling pathways. Flies have a long history in alcohol research, which has been enhanced in recent years by the development of tools that allow for manipulating individual Drosophila neurotransmitters. Through advancements such as the GAL4/UAS system and CRISPR/Cas9 mutagenesis, investigation of specific neurotransmitters in small subsets of neurons has become ever more achievable. In this review, we describe recent progress in understanding the contribution of seven neurotransmitters to fly behavior, focusing on their roles in alcohol response: dopamine, octopamine, tyramine, serotonin, glutamate, GABA, and acetylcholine. We chose these small-molecule neurotransmitters due to their conservation in mammals and their importance for behavior. While neurotransmitters like dopamine and octopamine have received significant research emphasis regarding their contributions to behavior, others, like glutamate, GABA, and acetylcholine, remain relatively unexplored. Here, we summarize recent genetic and behavioral findings concerning these seven neurotransmitters and their roles in the behavioral response to alcohol, highlighting the fitness of the fly as a model for human alcohol use.
“Complex” Vasovagal Syncope: A Zebra Among Horses
Authors: Siddiqi Anwer Zohaib , Blackmore Derrick , Siddiqi Zaeem Azfer
Published: January 2021

Background: Vasovagal syncope (VVS) occurs due to cerebral hypoperfusion from a fall in blood pressure, with accompanying bradycardia in most cases. Seizure and/or asystole may accompany VVS, though their prediction within the VVS cohort remains elusive.

Objective: To further characterize VVS and to find predictive features of “complex” VVS (defined as VVS associated with seizures and/or asystole).

Methods: We reviewed medical records of all patients who were referred for orthostatic intolerance and had a definite VVS during the head-up tilt table testing (HUTT). The following variables were recorded: cardiovascular indices during HUTT, autonomic testing results, and semiology of asystole and/or seizure when present. Simple frequency and correlation analysis were performed using the ANOVA.

Results: A total of 78 independent VVS were recorded in 60 patients of which 24% were not preceded by presyncope. Vasodepressor (45%) and mixed (38%) VVS were the most prevalent types. Eighteen (23%) were complex VVS; five had an associated seizure (SySz), nine were accompanied by asystole (SyAs), and four had both (SySzAs). Males were significantly more likely to have complex VVS. Mean asystole duration was somewhat longer in the SyAsSz group. The severity of bradycardia significantly correlated with complex VVS and was a predictor of SySz. Autonomic abnormalities were frequent but did not distinguish the two VVS subgroups. Seizures had multiple distinguishing features from those typically associated with epileptic seizures.

Conclusions: The underlying pathophysiologic mechanisms of complex VVS remain unclear, but the severity of cerebral hypoperfusion due to bradycardia likely plays a key role in seizure generation.
Risk of Valproic Acid-Related Tremor: A Systematic Review and Meta-Analysis
Authors: Zhang Chen qi , He Bao ming , Hu Mei ling , Sun Hong bin
Published: January 2021

Purpose: To evaluate the incidence and risk of tremor in patients treated with valproic aid (VPA) monotherapy.

Methods: We searched the PubMed, Embase, and Cochrane Library databases to gather relevant data on tremor in patients taking VPA and other drugs and performed a meta-analysis using Stata15.1 software.

Results: Twenty-nine randomized controlled trials (RCTs) met the inclusion criteria and were included in the meta-analysis. The overall incidence of tremor in patients receiving VPA therapy was 14% [OR = 0.14, 95% CI (0.10–0.17)]. The pooled estimate risk of tremor showed a significant difference between patients treated with VPA and all other drugs [OR = 5.40, 95% CI (3.22–9.08)], other antiepileptic drugs (AEDs) [OR = 5.78, 95% CI (3.18–10.50)], and other non-AEDs [OR = 4.77, 95% CI (1.55–14.72)]. Both a dose of <1,500 mg/d of VPA [included 500 mg/d: OR = 3.57, 95% CI (1.24–10.26), 500–999 mg/d: OR = 3.99, 95% CI (1.95–8.20), 1,000–1,499 mg/d: OR = 8.82, 95% CI (3.25–23.94)] and a VPA treatment duration of <12 m [included ≤ 3 months: OR = 3.06, 95% CI (1.16–8.09), 3–6 months: OR = 16.98, 95% CI (9.14–31.57), and 6–12 months: OR = 4.15, 95% CI (2.74–6.29)] led to a higher risk of tremor than did other drugs, as did higher doses and longer treatment times.

Conclusion: Compared with other drugs, VPA led to a higher risk of tremor, and the level of risk was associated with the dose and duration of treatment.
Pathomechanisms of HIV-Associated Cerebral Small Vessel Disease: A Comprehensive Clinical and Neuroimaging Protocol and Analysis Pipeline
Authors: Murray Kyle D. , Singh Meera V. , Zhuang Yuchuan , Uddin Md Nasir , Qiu Xing , Weber Miriam T. , Tivarus Madalina E. , Wang Henry Z. , Sahin Bogachan , Zhong Jianhui , Maggirwar Sanjay B. , Schifitto Giovanni
Published: January 2021

Rationale: We provide an in-depth description of a comprehensive clinical, immunological, and neuroimaging study that includes a full image processing pipeline. This approach, although implemented in HIV infected individuals, can be used in the general population to assess cerebrovascular health.

Aims: In this longitudinal study, we seek to determine the effects of neuroinflammation due to HIV-1 infection on the pathomechanisms of cerebral small vessel disease (CSVD). The study focuses on the interaction of activated platelets, pro-inflammatory monocytes and endothelial cells and their impact on the neurovascular unit. The effects on the neurovascular unit are evaluated by a novel combination of imaging biomarkers.

Sample Size: We will enroll 110 HIV-infected individuals on stable combination anti-retroviral therapy for at least three months and an equal number of age-matched controls. We anticipate a drop-out rate of 20%.

Methods and Design: Subjects are followed for three years and evaluated by flow cytometric analysis of whole blood (to measure platelet activation, platelet monocyte complexes, and markers of monocyte activation), neuropsychological testing, and brain MRI at the baseline, 18- and 36-month time points. MRI imaging follows the recommended clinical small vessel imaging standards and adds several advanced sequences to obtain quantitative assessments of brain tissues including white matter microstructure, tissue susceptibility, and blood perfusion.

Discussion: The study provides further understanding of the underlying mechanisms of CSVD in chronic inflammatory disorders such as HIV infection. The longitudinal study design and comprehensive approach allows the investigation of quantitative changes in imaging metrics and their impact on cognitive performance.
Possibility of Worsening Flow Diversion Effect Due to Morphological Changes of a Stented Artery With Multiple Overlapping Stents for Partially Thrombosed Vertebral Artery Aneurysms
Authors: Suzuki Tomoaki , Hasegawa Hitoshi , Ando Kazuhiro , Shibuya Kouhei , Takahashi Haruhiko , Saito Shoji , Oishi Makoto , Fujii Yukihiko
Published: January 2021

Background: Morphological changes of a stented artery can cause a flow diversion effect to reduce intra-aneurysmal flow; however, there is a potential for the negative effect of increased intra-aneurysmal flow. We present cases with multiple overlapping stents for a partially thrombosed vertebral artery aneurysm and characterize the hemodynamic properties of a recurrent case by focusing on the morphological changes of the stented artery.

Methods: Between October 2017 and April 2019, four consecutive cases of symptomatic unruptured large and giant partially thrombosed vertebral artery aneurysms were treated with multiple overlapping low-profile visualized intraluminal support stents and no coils. Both angiographic and clinical outcomes were assessed. Computational fluid dynamics analysis was performed to clarify hemodynamic features. The degree of pressure elevation was calculated as the pressure difference (Pd). Wall shear stress (WSS) was also calculated.

Results: In three of the four cases, successful flow reduction was achieved with no morphological change of the stented arteries. The patients' symptoms were gradually improved. The remaining case required additional stents after the initial treatment. In the recurrent case, Pd was noticeably elevated at the aneurysm neck after treatment, and WSS was generally increased in the area due to altered blood flow into the aneurysm dome caused by morphological changes of the stented artery.

Conclusion: Overlapping stents can be used for the treatment of large and giant thrombosed vertebral artery aneurysms with flow diversion effect; however, morphological changes of the stented artery requires careful attention as it may lead to an increase in the intra-aneurysmal flow, causing negative outcomes.
Neural and Genetic Bases for Human Ability Traits
Authors: Pinto Camila Bonin , Bielefeld Jannis , Jabakhanji Rami , Reckziegel Diane , Griffith James W. , Apkarian A. Vania
Published: January 2021

The judgement of human ability is ubiquitous, from school admissions to job performance reviews. The exact make-up of ability traits, however, is often narrowly defined and lacks a comprehensive basis. We attempt to simplify the spectrum of human ability, similar to how five personality traits are widely believed to describe most personalities. Finding such a basis for human ability would be invaluable since neuropsychiatric disease diagnoses and symptom severity are commonly related to such differences in performance. Here, we identified four underlying ability traits within the National Institutes of Health Toolbox normative data (n= 1, 369): (1) Motor-endurance, (2) Emotional processing, (3) Executive and cognitive function, and (4) Social interaction. We used the Human Connectome Project young adult dataset (n= 778) to show that Motor-endurance and Executive and cognitive function were reliably associated with specific brain functional networks (r2= 0.305 ± 0.021), and the biological nature of these ability traits was also shown by calculating their heritability (31 and 49%, respectively) from twin data.
Anti-sortilin1 Antibody Up-Regulates Progranulin via Sortilin1 Down-Regulation
Authors: Miyakawa Shuuichi , Sakuma Hiroyuki , Warude Dnyaneshwar , Asanuma Satomi , Arimura Naoto , Yoshihara Tomoki , Tavares Daniel , Hata Akito , Ida Koh , Hori Yuri , Okuzono Yuumi , Yamamoto Syunsuke , Iida Koichi , Shimizu Hisao , Kondo Shinichi , Sato Shuji
Published: January 2021

Progranulin (PGRN) haploinsufficiency associated with loss-of-function mutations in the granulin gene causes frontotemporal dementia (FTD). This suggests that increasing PGRN levels could have promising therapeutic implications for patients carrying GRN mutations. In this study, we explored the therapeutic potential of sortilin1 (SORT1), a clearance receptor of PGRN, by generating and characterizing monoclonal antibodies against SORT1. Anti-SORT1 monoclonal antibodies were generated by immunizing Sort1 knockout mice with SORT1 protein. The antibodies were classified into 7 epitope bins based on their competitive binding to the SORT1 protein and further defined by epitope bin-dependent characteristics, including SORT1-PGRN blocking, SORT1 down-regulation, and binding to human and mouse SORT1. We identified a positive correlation between PGRN up-regulation and SORT1 down-regulation. Furthermore, we also characterized K1-67 antibody via SORT1 down-regulation and binding to mouse SORT1 in vivo and confirmed that K1-67 significantly up-regulated PGRN levels in plasma and brain interstitial fluid of mice. These data indicate that SORT1 down-regulation is a key mechanism in increasing PGRN levels via anti-SORT1 antibodies and suggest that SORT1 is a potential target to correct PGRN reduction, such as that in patients with FTD caused by GRN mutation.
Hyperscanning EEG and Classification Based on Riemannian Geometry for Festive and Violent Mental State Discrimination
Authors: Simar Cédric , Cebolla Ana-Maria , Chartier Gaëlle , Petieau Mathieu , Bontempi Gianluca , Berthoz Alain , Cheron Guy
Published: January 2021

Interactions between two brains constitute the essence of social communication. Daily movements are commonly executed during social interactions and are determined by different mental states that may express different positive or negative behavioral intent. In this context, the effective recognition of festive or violent intent before the action execution remains crucial for survival. Here, we hypothesize that the EEG signals contain the distinctive features characterizing movement intent already expressed before movement execution and that such distinctive information can be identified by state-of-the-art classification algorithms based on Riemannian geometry. We demonstrated for the first time that a classifier based on covariance matrices and Riemannian geometry can effectively discriminate between neutral, festive, and violent mental states only on the basis of non-invasive EEG signals in both the actor and observer participants. These results pave the way for new electrophysiological discrimination of mental states based on non-invasive EEG recordings and cutting-edge machine learning techniques.
Mechanisms Underlying Unconscious Processing and Their Alterations in Post-traumatic Stress Disorder: Neuroimaging of Zero Monetary Outcomes Contextually Framed as “No Losses” vs. “No Gains”
Authors: Elman Igor , Upadhyay Jaymin , Lowen Steven , Karunakaran Keerthana , Albanese Mark , Borsook David
Published: January 2021

Although unconscious processing is a key element of mental operation, its neural correlates have not been established. Also, clinical observations suggest that unconscious processing may be involved in the pathophysiology of post-traumatic stress disorder (PTSD), but the neurobiological mechanisms underlying such impairments remain unknown. The purpose of the present study was to examine putative mechanisms underlying unconscious processing by healthy participants and to determine whether these mechanisms may be altered in PTSD patients. Twenty patients with PTSD and 27 healthy individuals were administered a validated wheel of fortune-type gambling task during functional magnetic resonance imaging (fMRI). Unconscious processing was elicited using unconscious contextual framing of the zero monetary outcomes as “no loss,” “no gain” or as “neutral.” Brief passive visual processing of the “no loss” vs. “no gain” contrast by healthy participants yielded bilateral frontal-, temporal- and insular cortices and striatal activations. Between-group comparison revealed smaller activity in the left anterior prefrontal-, left dorsolateral prefrontal-, right temporal- and right insular cortices and in bilateral striatum in PTSD patients with the left dorsolateral prefrontal cortex activity been more pronounced in those with greater PTSD severity. These observations implicate frontal-, temporal-, and insular cortices along with the striatum in the putative mechanisms underlying unconscious processing of the monetary outcomes. Additionally, our results support the hypothesis that PTSD is associated with primary cortical and subcortical alterations involved in the above processes and that these alterations may be related to some aspects of PTSD symptomatology.
Predictors of CT Morphologic Features to Identify Spread Through Air Spaces Preoperatively in Small-Sized Lung Adenocarcinoma
Authors: Qi Lin , Xue Ke , Cai Yongjun , Lu Jinjuan , Li Xiaohu , Li Ming
Published: January 2021

Objectives

This study aimed to explore the predictive CT features of spread through air spaces (STAS) in patients with small-sized lung adenocarcinoma.

Methods

From January 2017 to May 2019, patients with confirmed pathology of small-sized lung adenocarcinoma (less than or equal to 2 cm) and who underwent surgery were retrospectively analyzed. The clinical, pathological, and surgical information and CT features were analyzed.

Results

A total of 47 patients with STAS (males, 61.7%; mean age, 56 ± 8years) and 143 patients without STAS (males, 58%; mean age, 53 ± 11 years) were included. Pathologically, papillary, micropapillary, solid predominant subtypes, and vascular and pleural invasion were most commonly observed features in the STAS group. Radiologically, higher consolidation tumor ratio (CTR), presence of spiculation, satellites, ground glass ribbon sign, pleural attachment, and unclear tumor–lung interface were more commonly observed features in the STAS group. CTR, presence of ground glass ribbons and pleural connection, and absence of cystic airspaces were considered as stable predictors of STAS in multivariate logistic models. The receiver operating characteristic curve (ROC) analysis for predicting STAS demonstrated higher area under the curve (AUC) in the model that used CTR (0.760, 95% confidence interval, 0.69–0.83) for predicting STAS than in the model that used long diameter of entire lesion (0.640).

Conclusions

CTR is the best CT sign for predicting STAS in small-sized lung adenocarcinoma. The ground glass ribbon is a newly found indicator and has the potential for predicting STAS.
The Performance of a Dual-Energy CT Derived Radiomics Model in Differentiating Serosal Invasion for Advanced Gastric Cancer Patients After Neoadjuvant Chemotherapy: Iodine Map Combined With 120-kV Equivalent Mixed Images
Authors: Wang Lingyun , Zhang Yang , Chen Yong , Tan Jingwen , Wang Lan , Zhang Jun , Yang Chunxue , Ma Qianchen , Ge Yingqian , Xu Zhihan , Pan Zilai , Du Lianjun , Yan Fuhua , Yao Weiwu , Zhang Huan
Published: January 2021

Objectives

The aim was to determine whether the dual-energy CT radiomics model derived from an iodine map (IM) has incremental diagnostic value for the model based on 120-kV equivalent mixed images (120 kVp) in preoperative restaging of serosal invasion with locally advanced gastric cancer (LAGC) after neoadjuvant chemotherapy (NAC).

Methods

A total of 155 patients (110 in the training cohort and 45 in the testing cohort) with LAGC who had standard NAC before surgery were retrospectively enrolled. All CT images were analyzed by two radiologists for manual classification. Volumes of interests (VOIs) were delineated semi-automatically, and 1,226 radiomics features were extracted from every segmented lesion in both IM and 120 kVp images, respectively. Spearman’s correlation analysis and the least absolute shrinkage and selection operator (LASSO) penalized logistic regression were implemented for filtering unstable and redundant features and screening out vital features. Two predictive models (120 kVp and IM-120 kVp) based on 120 kVp selected features only and 120 kVp combined with IM selected features were established by multivariate logistic regression analysis. We then build a combination model (ComModel) developed with IM-120 kVp signature and ycT. The performance of these three models and manual classification were evaluated and compared.

Result

Three radiomics models showed great predictive accuracy and performance in both the training and testing cohorts (ComModel: AUC: training, 0.953, testing, 0.914; IM-120 kVp: AUC: training, 0.953, testing, 0.879; 120 kVp: AUC: training, 0.940, testing, 0.831). All these models showed higher diagnostic accuracy (ComModel: 88.9%, IM-120 kVp: 84.4%, 120 kVp: 80.0%) than manual classification (68.9%) in the testing group. ComModel and IM-120 kVp model had better performances than manual classification both in the training (both p<0.001) and testing cohorts (p<0.001 and p=0.034, respectively).

Conclusions

Dual-energy CT-based radiomics models demonstrated convincible diagnostic performance in differentiating serosal invasion in preoperative restaging for LAGC. The radiomics features derived from IM showed great potential for improving the diagnostic capability.
Case Report: Significant Response to the Combination of Lenvatinib and Immune Checkpoint Inhibitor in a Patient With Heavily Pretreated Metastatic Triple Negative Breast Cancer
Authors: Lee Jin Sun , Yost Susan E. , Yuan Yuan
Published: January 2021

Background

Triple negative breast cancer (TNBC) has poor prognosis without targetable mutations. The combination of lenvatinib and pembrolizumab has shown clinical activity in different types of solid tumors.

Case Presentation

We report a case of one patient with metastatic TNBC who has been heavily pretreated. The patient had been treated with multiple lines (≥ 8 lines) of chemotherapy without durable clinical responses. Her tumor regressed significantly under the combination of lenvatinib and immune checkpoint inhibitor, and remains stable for 10 months.

Conclusions

The combination of lenvatinib and immune checkpoint inhibitor may have significant clinical activity in selective patients with heavily pretreated metastatic TNBC.
Dosimetry of Submandibular Glands on Xerostomia for Nasopharyngeal Carcinoma
Authors: Pan Xin-Bin , Liu Yang , Huang Shi-Ting , Pei Su , Chen Kai-Hua , Qu Song , Li Ling , Zhu Xiao-Dong
Published: January 2021

Purpose

To investigate dosimetry of submandibular glands on xerostomia after intensity-modulated radiotherapy for nasopharyngeal carcinoma (NPC).

Methods

From September 2015 to March 2016, 195 NPC patients were investigated. Xerostomia was evaluated at 12 months after treatment via the RTOG/EORTC system. The least absolute shrinkage and selection operator regression model was used to optimize feature selection for grades 2–3 xerostomia. Multivariable logistic regression analysis was applied to build a predicting model incorporating the feature selected in the least absolute shrinkage and selection operator regression model. Discrimination, calibration, and clinical usefulness of the predicting model were assessed using the C-index, calibration plot, and decision curve analysis.

Results

The V30 of the parotid glands was selected based on the least absolute shrinkage and selection operator regression. The nomogram displayed good discrimination with a C-index of 0.698 (95% confidence interval [CI]: 0.626–0.771) and good calibration (model 1). Addition of the dosimetric parameters including the mean dose to the submandibular glands, V50 of the submandibular glands, and volume of the submandibular glands to the model 1 failed to show incremental prognostic value (model 2). The model 2 showed a C-index of 0.704 (95% CI: 0.632–0.776). Decision curve analysis demonstrated that the model 1 was clinically useful when intervention was decided at the possibility threshold of > 20%. Within this range, net benefit was comparable between the model 1 and model 2.

Conclusion

PGv30 was a major predictive factor of grades 2–3 xerostomia for NPC. In contrast, the mean dose to the submandibular glands, V50 of the submandibular glands, and volume of the submandibular glands were not independent predictive factors.
Identification of STRBP as a Novel JAK2 Fusion Partner Gene in a Young Adult With Philadelphia Chromosome-Like B-Lymphoblastic Leukemia
Authors: Zhang Xin-Yue , Dai Hai-Ping , Li Zheng , Yin Jia , Lang Xing-Ping , Yang Chun-Xiao , Xiao Sheng , Zhu Ming-Qing , Liu Dan-Dan , Liu Hong , Shen Hong-Jie , Wu De-Pei , Tang Xiao-Wen
Published: January 2021

Philadelphia chromosome-like B-lymphoblastic leukemia (Ph-like ALL) describes a group of genetically heterogeneous, Ph-negative entities with high relapse rates and poor prognoses. A Janus-kinase-2 (JAK2) rearrangement has been reported in approximately 7% of Ph-like ALL patients whose therapeutic responses to JAK inhibitors have been studied in clinical trials. Here, we report a novel STRBP-JAK2 fusion gene in a 21-year-old woman with Ph-like ALL. Although a normal karyotype was observed, a hitherto unreported JAK2 rearrangement was detected cytogenetically. STRBP-JAK2 fusion was identified by RNA sequencing and validated by Sanger sequencing. The Ph-like ALL proved refractory to traditional induction chemotherapy combined with ruxolitinib. The patient consented to infusion of autologous chimeric antigen receptor (CAR) T cells against both CD19 and CD22, which induced morphologic remission. Haplo-identical stem cell transplantation was then performed; however, she suffered relapse at just one month after transplantation. The patient subsequently received donor lymphocyte infusion after which she achieved and maintained a minimal residual disease negative remission. However, she succumbed to grade IV graft-versus-host disease 7 months post-transplant. In conclusion, this report describes a novel STRBP-JAK2 gene fusion in a Ph-like ALL patient with a very aggressive disease course, which proved resistant to chemotherapy combined with ruxolitinib but sensitive to immunotherapy. Our study suggests that CAR T-cell therapy may be a viable option for this type of leukemia.
NRF2 -617 C/A Polymorphism Impacts Proinflammatory Cytokine Levels, Survival, and Transplant-Related Mortality After Hematopoietic Stem Cell Transplantation in Adult Patients Receiving Busulfan-Based Conditioning Regimens
Authors: Huang Jingjing , Hao Chenxia , Li Ziwei , Wang Ling , Jiang Jieling , Tang Wei , Wang Lining , Zhang Weixia , Hu Jiong , Yang Wanhua
Published: January 2021

Busulfan (BU) is widely used in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT). The exposure-escalated BU directed by therapeutic drug monitoring (TDM) is extremely necessary for the patients with high-risk hematologic malignancies in order to diminish relapse, but it increases the risk of drug-induced toxicity. BU exposure, involved in the glutathione- (GSH-) glutathione S-transferases (GSTs) pathway and proinflammatory response, is associated with clinical outcomes after HSCT. However, the expression of genes in the GSH-GSTs pathway is regulated by NF-E2-related factor 2 (Nrf2) that can also alleviate inflammation. In this study, we evaluated the influence of NRF2 polymorphisms on BU exposure, proinflammatory cytokine levels, and clinical outcomes in HSCT patients. A total of 87 Chinese adult patients receiving twice-daily intravenous BU were enrolled. Compared with the patients carrying wild genotypes, those with NRF2 -617 CA/AA genotypes showed higher plasma interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α levels, poorer overall survival (OS; RR = 3.91), and increased transplant-related mortality (TRM; HR = 4.17). High BU exposure [area under the concentration-time curve (AUC) > 9.27 mg/L × h)] was related to BU toxicities. Furthermore, NRF2 -617 CA/AA genotypes could significantly impact TRM (HR = 4.04; p = 0.0142) and OS (HR = 3.69; p = 0.0272) in the patients with high BU AUC. In vitro, we found that high exposure of endothelial cell (EC) to BU, in the absence of Nrf2, elicited the hyperstimulation of NF-κB-p65, accompanied with the elevated secretion of proinflammatory cytokines, and led to EC death. These results showed that NRF2 -617 CA/AA genotypes, correlated with high proinflammatory cytokine levels, could predict inferior outcomes in HSCT patients with high BU AUC. Thus, NRF2 -617 CA/AA genotyping combined with TDM would further optimize personalized BU dosing for sufficient efficacy and safety endpoint.
Salvianolic Acid B Protects Against Fatty Acid-Induced Renal Tubular Injury via Inhibition of Endoplasmic Reticulum Stress
Authors: Mai Xiaoyi , Yin Xin , Chen Peipei , Zhang Minzhou
Published: January 2021

Background/Aims: Obesity-related kidney disease is associated with elevated levels of saturated free fatty acids (SFA). SFA lipotoxicity in tubular cells contributes to significant cellular apoptosis and injury. Salvianolic acid B (SalB) is the most abundant bioactive molecule from Radix Salviae Miltiorrhizae. In this study, we investigated the effect of SalB on SFA-induced renal tubular injury and endoplasmic reticulum (ER) stress, in vivo and in vitro.

Methods: C57BL/6 mice were assigned to five groups: a control group with normal diet (Nor), high-fat diet group (HFD), and HFD with three different SalB treatment doses, low (SalBL; 3 mg/kg), medium (SalBM; 6.25 mg/kg), and high (SalBH; 12.5 mg/kg) doses. SalB was intraperitoneally injected daily for 4 weeks after 8 weeks of HFD. After 12 weeks, mice were sacrificed and kidneys and sera were collected. Apoptosis and ER stress were induced in human proximal tubule epitelial (HK2) cells by palmitic acid (PA, 0.6 mM), tunicamycin (TM, 1 μg/ml), or thapsigargin (TG, 200 nM) in vitro.

Results: C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks exhibited increased apoptosis (Bax and cleaved caspase-3) and ER stress (BIP, P-eIF2α, ATF4, CHOP, ATF6, IRE1α, and XBP1s) markers expression in the kidney, compared with control mice, which were remarkably suppressed by SalB treatment. In vitro studies showed that PA (0.6 mM) induced apoptosis and ER stress in cultured HK2 cells. SalB treatment attenuated all the adverse effects of PA. However, SalB failed to inhibit TM or TG-induced ER stress in HK2 cells.

Conclusion: The study indicated that SalB may play an important role in obesity-related kidney injury via mediating SFA-induced ER stress.
The Large Action of Chlorpromazine: Translational and Transdisciplinary Considerations in the Face of COVID-19
Authors: Stip Emmanuel , Rizvi Tahir A. , Mustafa Farah , Javaid Syed , Aburuz Salahdein , Ahmed Nahida Nayaz , Abdel Aziz Karim , Arnone Danilo , Subbarayan Aravinthan , Al Mugaddam Fadwa , Khan Gulfaraz
Published: January 2021

Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome (SARS) in humans that is caused by SARS-associated coronavirus type 2 (SARS-CoV-2). In the context of COVID-19, several aspects of the relations between psychiatry and the pandemic due to the coronavirus have been described. Some drugs used as antiviral medication have neuropsychiatric side effects, and conversely some psychotropic drugs have antiviral properties. Chlorpromazine (CPZ, Largactil®) is a well-established antipsychotic medication that has recently been proposed to have antiviral activity against SARS-CoV-2. This review aims to 1) inform health care professionals and scientists about the history of CPZ use in psychiatry and its potential anti- SARS-CoV-2 activities 2) inform psychiatrists about its potential anti-SARS-CoV-2 activities, and 3) propose a research protocol for investigating the use of CPZ in the treatment of COVID-19 during the potential second wave. The history of CPZ’s discovery and development is described in addition to the review of literature from published studies within the discipline of virology related to CPZ. The early stages of infection with coronavirus are critical events in the course of the viral cycle. In particular, viral entry is the first step in the interaction between the virus and the cell that can initiate, maintain, and spread the infection. The possible mechanism of action of CPZ is related to virus cell entry via clathrin-mediated endocytosis. Therefore, CPZ could be useful to treat COVID-19 patients provided that its efficacy is evaluated in adequate and well-conducted clinical trials. Interestingly, clinical trials of very good quality are in progress. However, more information is still needed about the appropriate dosage regimen. In short, CPZ repositioning is defined as a new use beyond the field of psychiatry.
A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept
Authors: Hartman Stan J. F. , Swaving Joost G. E. , van Beek Stijn W. , van Groen Bianca D. , de Hoop Marika , van der Zanden Tjitske M. , ter Heine Rob , de Wildt Saskia N.
Published: January 2021

Background: Modeling and simulation is increasingly used to study pediatric pharmacokinetics, but clinical implementation of age-appropriate doses lags behind. Therefore, we aimed to develop model-informed doses using published pharmacokinetic data and a decision framework to adjust dosing guidelines based on these doses, using piperacillin and amikacin in critically ill children as proof of concept.

Methods: Piperacillin and amikacin pharmacokinetic models in critically ill children were extracted from literature. Concentration-time profiles were simulated for various dosing regimens for a virtual PICU patient dataset, including the current DPF dose and doses proposed in the studied publications. Probability of target attainment (PTA) was compared between the different dosing regimens. Next, updated dosing recommendations for the DPF were proposed, and evaluated using a new framework based on PK study quality and benefit-risk analysis of clinical implementation.

Results: Three studies for piperacillin (critically ill children) and one for amikacin (critically ill pediatric burn patients) were included. Simulated concentration-time profiles were performed for a virtual dataset of 307 critically ill pediatric patients, age range 0.1–17.9 y. PTA for unbound piperacillin trough concentrations >16 mg/L was >90% only for continuous infusion regimens of 400 mg/kg/day vs. 9.7% for the current DPF dose (80 mg/kg/6 h, 30 min infusion). Amikacin PTA was >90% with 20 mg/kg/d, higher than the PTA of the DPF dose of 15 mg/kg/d (63.5%). Using our new decision framework, altered DPF doses were proposed for piperacillin (better PTA with loading dose plus continuous infusion), but not for amikacin (studied and target population were not comparable and risk for toxicity with higher dose).

Conclusions: We show the feasibility to develop model-informed dosing guidelines for clinical implementation using existing pharmacokinetic data. This approach could complement literature and consensus-based dosing guidelines for off-label drugs in the absence of stronger evidence to support pediatricians in daily practice.
Dickkopf-3: Current Knowledge in Kidney Diseases
Authors: Fang Xiangdong , Hu Jing , Chen Yanxia , Shen Wen , Ke Ben
Published: January 2021

Dickkopf-related protein 3 (DKK3) is a secreted glycoprotein that has been implicated in the pathogenesis of a variety of diseases. Recent evidence suggests that urinary DKK3 may serve as a potential biomarker for monitoring kidney disease progression and assessing the effects of interventions. We review the biological role of DKK3 as an agonist in chronic kidney disease (CKD) and autosomal dominant polycystic kidney disease (ADPKD) and as an antagonist in idiopathic membranous nephropathy (IMN). In addition, we present the clinical applications of DKK3 in acute kidney disease and tubulointerstitial fibrosis, suggesting that urine DKK3 may be a potential biomarker for acute kidney disease and CKD. Further research into the mechanism of DKK3 and its use as a diagnostic tool, alone or in combination with other biomarkers, could prove clinically useful for better understanding the pathology of kidney diseases and improving early detection and treatment.
Renal Sensory Activity Regulates the γ-Aminobutyric Acidergic Inputs to the Paraventricular Nucleus of the Hypothalamus in Goldblatt Hypertension
Authors: Milanez Maycon I. O. , Veiga Amanda C. , Martins Beatriz S. , Pontes Roberto B. , Bergamaschi Cassia T. , Campos Ruy R. , Nishi Erika E.
Published: January 2021

Renal sensory activity is centrally integrated within brain nuclei involved in the control of cardiovascular function, suggesting that renal afferents regulate basal and reflex sympathetic vasomotor activity. Evidence has shown that renal deafferentation (DAx) evokes a hypotensive and sympathoinhibitory effect in experimental models of cardiovascular diseases; however, the underlying mechanisms involved in this phenomenon need to be clarified, especially those related to central aspects. We aimed to investigate the role of renal afferents in the control of γ-aminobutyric acid (GABA)ergic inputs to the paraventricular nucleus (PVN) of the hypothalamus in renovascular hypertensive (2K1C) rats and their influence in the regulation of cardiovascular function. Hypertension was induced by clipping the left renal artery. After 4 weeks, renal DAx was performed by exposing the left renal nerve to a 33 mM capsaicin solution for 15 min. After 2 weeks of DAx, microinjection of muscimol into the PVN was performed in order to evaluate the influence of GABAergic activity in the PVN and its contribution to the control of renal sympathetic nerve activity (rSNA) and blood pressure (BP). Muscimol microinjected into the PVN triggered a higher drop in BP and rSNA in the 2K1C rats and renal DAx mitigated these responses. These results suggest that renal afferents are involved in the GABAergic changes found in the PVN of 2K1C rats. Although the functional significance of this phenomenon needs to be clarified, it is reasonable to speculate that GABAergic alterations occur to mitigate microglia activation-induced sympathoexcitation in the PVN of 2K1C rats.
Cerebral Ultrasound Time-Harmonic Elastography Reveals Softening of the Human Brain Due to Dehydration
Authors: Kreft Bernhard , Bergs Judith , Shahryari Mehrgan , Danyel Leon Alexander , Hetzer Stefan , Braun Jürgen , Sack Ingolf , Tzschätzsch Heiko
Published: January 2021

Hydration influences blood volume, blood viscosity, and water content in soft tissues – variables that determine the biophysical properties of biological tissues including their stiffness. In the brain, the relationship between hydration and stiffness is largely unknown despite the increasing importance of stiffness as a quantitative imaging marker. In this study, we investigated cerebral stiffness (CS) in 12 healthy volunteers using ultrasound time-harmonic elastography (THE) in different hydration states: (i) during normal hydration, (ii) after overnight fasting, and (iii) within 1 h of drinking 12 ml of water per kg body weight. In addition, we correlated shear wave speed (SWS) with urine osmolality and hematocrit. SWS at normal hydration was 1.64 ± 0.02 m/s and decreased to 1.57 ± 0.04 m/s (p < 0.001) after overnight fasting. SWS increased again to 1.63 ± 0.01 m/s within 30 min of water drinking, returning to values measured during normal hydration (p = 0.85). Urine osmolality at normal hydration (324 ± 148 mOsm/kg) increased to 784 ± 107 mOsm/kg (p < 0.001) after fasting and returned to normal (288 ± 128 mOsm/kg, p = 0.83) after water drinking. SWS and urine osmolality correlated linearly (r = −0.68, p < 0.001), while SWS and hematocrit did not correlate (p = 0.31). Our results suggest that mild dehydration in the range of diurnal fluctuations is associated with significant softening of brain tissue, possibly due to reduced cerebral perfusion. To ensure consistency of results, it is important that cerebral elastography with a standardized protocol is performed during normal hydration.