bluuebunny/crossref_metadata_2025 huggingface dataset:
3D Virtual Reality Smartphone Training for Chemotherapy Drug Administration by Non-oncology Nurses: A Randomized Controlled Trial
Authors: Wang Chin-Yun , Lu Chi-Yu , Yang Su-Yueh , Tsai Shu-Chun , Huang Tsai-Wei
Published: June 2022

Chemotherapy agents are cytotoxic materials. Thus, there is a need for the operators to be familiar with the knowledge and procedures before operation. We conducted a randomized controlled trial investigating the effectiveness of an immersive 3D VR teaching of chemotherapy administration operated in a smartphone coupled with a visual and audio device. We adopted a two-arm single-blind design and recruited 83 nurses, and they were randomized using a cluster approach. The VR group learned chemotherapy administration through VR, while the controlled group learned through document reading. The Knowledge and Attitude of Chemotherapy Administration (KACA) was administrated before the intervention, while the Objective Structured Clinical Examination (OSCE) and the Checklist of Action Accomplishment (CAA) were administrated one month after the intervention. The VR group scored higher than the controlled group in the CAA (95.69 ± 5.37 vs. 91.98 ± 9.31, p = 0.02) and the OSCE (73.07 ± 10.99 vs. 67.44 ±10.65, p = 0.02). Stepwise regression demonstrated that service years, an education level of undergraduate or above, and VR exposure contributed positively to the OSCE score (adjusted R2 = 0.194, p = 0.028). The use of VR improves the learning efficacy of chemotherapy administration in non-oncology nurses. We recommend using VR as a teaching tool for chemotherapy administration and other chemotherapy-related skills in a VR learning group with senior nurses with higher education levels as advisors. The study provides an approach to online training, especially during the COVID-19 pandemic. (CONSORT 2010 guidelines, registry number: NCT 04840732).
A Novel Non-Invasive Approach Based on Serum Ceruloplasmin for Identifying Non-Alcoholic Steatohepatitis Patients in the Non-Diabetic Population
Authors: Wang Qingling , Zhou Da , Wang Mingjie , Zhu Mingyu , Chen Peizhan , Li Hu , Lu Meng , Zhang Xinxin , Shen Xizhong , Liu Taotao , Chen Li
Published: June 2022

Background and Aim

Few non-invasive models were established to identify patients with non-alcoholic steatohepatitis (NASH). Liver biopsy remains the gold standard in the clinic. Decreased serum ceruloplasmin (CP) is reported in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to develop a non-invasive model incorporating CP for identifying NASH from NAFLD without type 2 diabetes mellitus (T2DM).

Methods

A total of 138 biopsy-proven patients with NAFLD without T2DM were enrolled. The CP ratio was calculated for standardization as the CP value divided by the lower limit of normal. The clinical, anthropometric, biochemical, and histological parameters were compared between the low and high CP ratio groups divided by the median value. Multivariate logistic regression analysis was performed to develop a model for identifying NASH in patients with NAFLD.

Results

The medians of the high (n = 69) and low (n = 69) CP ratio groups were 1.43 (1.28–1.61) and 1.03 (0.94–1.12), respectively. A comparison of the two groups showed that the severity of steatosis, hepatocellular ballooning, inflammation activity, fibrosis, and liver iron deposition decreased along with the CP ratio (p < 0.05). The median CP ratio of patients with NASH was significantly lower than those with NAFL [1.15 (1.01–1.41) vs. 1.33 (1.24–1.54), p = 0.001]. A novel model which consists of the CP ratio, BMI, and aspartate aminotransferase (AST) was developed. The AUCs of the model in discriminating NASH from NAFLD was 0.796 (0.694–0.899) and 0.849 (0.713–0.984) in the training and validation groups, and 0.836 (0.659–1.000), 0.833 (0.705–0.962), and 0.821 (0.612–1.000) in patients with normal serum alanine aminotransferase, AST, and both levels, respectively.

Conclusions

Decreased CP ratio is associated with more severe histological activity, a diagnosis of NASH, and hepatic iron deposition among patients with NAFLD without T2DM. The CP ratio model could be served as a non-invasive approach to identifying patients with NASH, which might reduce the need for liver biopsy.
N6-Methyladenosine Methylomic Landscape of Ureteral Deficiency in Reflux Uropathy and Obstructive Uropathy
Authors: Shi Hua , Xiang Tianchao , Feng Jiayan , Yang Xue , Li Yaqi , Fang Ye , Xu Linan , Qi Qi , Shen Jian , Tang Liangfeng , Shen Qian , Wang Xiang , Xu Hong , Rao Jia
Published: June 2022

Background

Congenital anomalies of the kidneys and urinary tracts (CAKUT) represent the most prevalent cause for renal failure in children. The RNA epigenetic modification N6-methyladenosine (m6A) methylation modulates gene expression and function post-transcriptionally, which has recently been revealed to be critical in organ development. However, it is uncertain whether m6A methylation plays a role in the pathogenesis of CAKUT. Thus, we aimed to explore the pattern of m6A methylation in CAKUT.

Methods

Using m6A-mRNA epitranscriptomic microarray, we investigated the m6A methylomic landscape in the ureter tissue of children with obstructive megaureter (M group) and primary vesicoureteral reflux (V group).

Results

A total of 228 mRNAs engaged in multiple function-relevant signaling pathways were substantially differential methylated between the “V” and “M” groups. Additionally, 215 RNA-binding proteins that recognize differentially methylated regions were predicted based on public databases. The M group showed significantly higher mRNA levels of m6A readers/writers (YTHDF1, YTHDF2, YTHDC1, YTHDC2 and WTAP) and significantly lower mRNA levels of m6A eraser (FTO) according to real-time PCR. To further investigate the differentially methylated genes, m6A methylome and transcriptome data were integrated to identified 298 hypermethylated mRNAs with differential expressions (265 upregulation and 33 downregulation) and 489 hypomethylated mRNAs with differential expressions (431 upregulation and 58 downregulation) in the M/V comparison.

Conclusion

The current results highlight the pathogenesis of m6A methylation in obstructive and reflux uropathy.
Effects of LPS Composition in Escherichia coli on Antibacterial Activity and Bacterial Uptake of Antisense Peptide-PNA Conjugates
Authors: Goltermann Lise , Zhang Meiqin , Ebbensgaard Anna Elisabeth , Fiodorovaite Marija , Yavari Niloofar , Løbner-Olesen Anders , Nielsen Peter E.
Published: June 2022

The physical and chemical properties of the outer membrane of Gram-negative bacteria including Escherichia coli have a significant impact on the antibacterial activity and uptake of antibiotics, including antimicrobial peptides and antisense peptide-peptide nucleic acid (PNA) conjugates. Using a defined subset of E. coli lipopolysaccharide (LPS) and envelope mutants, components of the LPS-core, which provide differential susceptibility toward a panel of bacterial penetrating peptide (BPP)-PNA conjugates, were identified. Deleting the outer core of the LPS and perturbing the inner core only sensitized the bacteria toward (KFF)3K-PNA conjugates, but not toward conjugates carrying arginine-based BPPs. Interestingly, the chemical composition of the outer LPS core as such, rather than overall hydrophobicity or surface charge, appears to determine the susceptibility to different BPP-PNA conjugates thereby clearly demonstrating the complexity and specificity of the interaction with the LPS/outer membrane. Notably, mutants with outer membrane changes conferring polymyxin resistance did not show resistance toward the BPP-PNA conjugates, thereby eliminating one possible route of resistance for these molecules. Finally, envelope weakening, through deletion of membrane proteins such as OmpA as well as some proteins previously identified as involved in cationic antimicrobial peptide uptake, did not significantly influence BPP-PNA conjugate activity.
Identification and Engineering of Transporters for Efficient Melatonin Production in Escherichia coli
Authors: Yang Lei , Malla Sailesh , Özdemir Emre , Kim Se Hyeuk , Lennen Rebecca , Christensen Hanne B. , Christensen Ulla , Munro Lachlan J. , Herrgård Markus J. , Kell Douglas B. , Palsson Bernhard Ø.
Published: June 2022

Transporter discovery and engineering play an important role in cell factory development. Decreasing the intracellular concentration of the product reduces product inhibition and/or toxicity. Lowering intracellular concentrations is especially beneficial for achieving a robust strain at high titers. However, the identification of transporters for xenobiotic chemicals in the host strain is challenging. Here we present a high-throughput workflow to discover Escherichia coli transporters responsible for the efflux of the inhibitory xenobiotic compound melatonin. We took advantage of the Keio collection and screened about 400 transporter knockouts in the presence of a high concentration of melatonin. We found five transporters that when knocked out showed decreased tolerance to melatonin, indicating they are exporters of melatonin. We overexpressed these five genes individually in the production strain and found that one of them, yhjV, encoding a transporter with unknown substrates, resulted in a 27% titer increase in cultivation mimicking fed-batch fermentation. This study demonstrates how microbial cell factories can be improved through transporter identification and engineering. Further, these results lay the foundation for the scale-up of melatonin production in E. coli.
Global Taxonomy and Phylogeny of Irpicaceae (Polyporales, Basidiomycota) With Descriptions of Seven New Species and Proposals of Two New Combinations
Authors: Li Yue , He Shuang-Hui , Chen Che-Chih , Nakasone Karen K. , Ma Hai-Xia
Published: June 2022

The phylogenetic analyses of the family Irpicaceae were carried out based on a complete global sampling. The dataset that included concatenated ITS1-5.8S-ITS2 and nrLSU sequences of 67 taxa of Irpicaceae from around the world was subjected to the maximum likelihood analyses and Bayesian inference. In the phylogenetic tree, species from 14 genera were distributed in nine clades, among which five genera—Irpex, Phanerochaetella, Byssomerulius, Cytidiella, and Meruliopsis, received high support values. The genus Efibula was shown to be paraphyletic and four subclades could be recognized, while Phanerochaete allantospora, Leptoporus mollis, and several species from Ceriporia and Candelabrochaete formed a large clade with relatively strong support. Based on the molecular and morphological evidence, seven new corticioid species—Candelabrochaete guangdongensis, Efibula grandinosa, E. hainanensis, E. shenghuae, E. taiwanensis, Irpex alboflavescens, and Phanerochaetella sinensis, were revealed from the materials mostly from East Asia. The monotypic genus Flavodontia, newly described from southwestern China, is regarded as a later synonym of Irpex, and the new combination I. rosea is proposed. In addition, Phanerochaetella queletii is proposed for a taxon first described from Italy and newly recorded from China; Phanerochaete jose-ferreirae from Portugal is determined to be a later synonym. Descriptions and illustrations of the new species and the newly combined taxa are presented, and morphological comparisons for the known species of Efibula and Phanerochaetella are provided.
Simulating Developmental and Individual Differences of Drawing Behavior in Children Using a Predictive Coding Model
Authors: Philippsen Anja , Tsuji Sho , Nagai Yukie
Published: June 2022

Predictive coding has recently been proposed as a mechanistic approach to explain human perception and behavior based on the integration of perceptual stimuli (bottom-up information) and the predictions about the world based on previous experience (top-down information). However, the gap between the computational accounts of cognition and evidence of behavioral studies remains large. In this study, we used a computational model of drawing based on the mechanisms of predictive coding to systematically investigate the effects of the precision of top-down and bottom-up information when performing a drawing completion task. The results indicated that sufficient precision of both signals was required for the successful completion of the stimuli and that a reduced precision in either sensory or prediction (i.e., prior) information led to different types of atypical drawing behavior. We compared the drawings produced by our model to a dataset of drawings created by children aged between 2 and 8 years old who drew on incomplete drawings. This comparison revealed that a gradual increase in children's precision of top-down and bottom-up information as they develop effectively explains the observed change of drawing style from scribbling toward representational drawing. Furthermore, individual differences that are prevalent in children's drawings, might arise from different developmental pathways regarding the precision of these two signals. Based on these findings we propose a theory of how both general and individual development of drawing could be explained in a unified manner within the framework of predictive coding.
Telemedicine for Stroke: Quantifying the Long-Term National Costs and Health Benefits
Authors: Gao Lan , Tan Elise , Kim Joosup , Bladin Christopher F. , Dewey Helen M. , Bagot Kathleen L. , Cadilhac Dominique A. , Moodie Marj
Published: June 2022

Objective

Few countries have established national programs to maximize access and reduce operational overheads. We aimed to use patient-level data up to 12 months to model the potential long-term costs and health benefits attributable to implementing such a program for Australia.

Methods

A Markov model was created for Australia with an inception population of 10,000 people with stroke presenting to non–urban or suburban hospitals without stroke medical specialists that could receive stroke telemedicine under a national program. Seven Markov states represented the seven modified Rankin Scale (mRS) scores (0 no disability to 6 dead) plus an absorbing state for all other causes of death. The literature informed inputs for the model; for the telemedicine program (including program costs and effectiveness) and patients, these were extrapolated from the Victorian Stroke Telemedicine (VST) program with the initial status of patients being their health state at day 365 as determined by their mRS score. Costs (2018 Australian dollars, healthcare, non–medical, and nursing home) and benefits were reported for both the societal and healthcare perspectives for up to a 25 years (lifetime) time horizon.

Results

We assumed 4,997 to 12,578 ischemic strokes would arrive within 4.5 h of symptom onset at regional hospitals in 2018. The average per person lifetime costs were $126,461 and $127,987 from a societal perspective or $76,680 and $75,901 from a healthcare system perspective and benefits were 4.43 quality-adjusted life years (QALYs) and 3.98 QALYs gained, respectively, for the stroke telemedicine program and practice without such program. The stroke telemedicine program was associated with a cost saving of $1,526 (from the societal perspective) or an additional $779 (from the healthcare system perspective) and an additional 0.45 QALY gained per patient over the lifetime. The incremental costs of the stroke telemedicine program ($2,959) and management poststroke ($813) were offset by cost savings from rehospitalization (–$552), nursing home care (–$2178), and non–medical resource use (–$128).

Conclusion

The findings from this long-term model provide evidence to support ongoing funding for stroke telemedicine services in Australia. Our estimates are conservative since other benefits of the service outside the use of intravenous thrombolysis were not included.
Case Report: Drug-Induced (Neuro) Sarcoidosis-Like Lesion Under IL4 Receptor Blockade With Dupilumab
Authors: Tsitos Stergios , Niederauer Lisa Catherina , Albert i Gracenea Paula , Mueller Johanna , Straube Andreas , Von Baumgarten Louisa
Published: June 2022

Dupilumab is a new monoclonal antibody inhibiting IL-4 and IL-13 signaling transduction through the blockage of the α-subunit of the IL-4 receptor. It is used to treat type 2 inflammatory disorders including atopic dermatitis, asthma, and chronic rhinosinusitis. Here we describe the case of a 79-year-old male presenting with visual hallucinations, disorientation, cognitive decline, and behavioral changes, evolving over 3 weeks. He had been under treatment with dupilumab for atopic dermatitis for the previous 4 months. Radiology and CSF analysis showed a granulomatous meningoencephalitis suspicious of sarcoidosis. Underlying infectious and antibody-mediated causes for meningoencephalitis were ruled out. Pausing Dupilumab and steroids (i.v. and oral) led to rapid clinical improvement. Inhibition of IL-4 and IL-13, key players in the differentiation and activation of Th2 cells, may shift the Th1/Th2- ratio toward an excessive Th1-mediated response, granuloma formation, and drug-induced (neuro)sarcoidosis reaction. Attention should be raised to this side effect.
Positive Predictive Value of MOG-IgG for Clinically Defined MOG-AD Within a Real-World Cohort
Authors: Manzano Giovanna S. , Salky Rebecca , Mateen Farrah J. , Klawiter Eric C. , Chitnis Tanuja , Levy Michael , Matiello Marcelo
Published: June 2022

Myelin oligodendrocyte glycoprotein antibody associated disease (MOG-AD) is a CNS demyelinating disease, typically presenting with optic neuritis, transverse myelitis, and/or ADEM-like syndromes. The positive predictive value (PPV) of MOG-IgG testing by live cell-based assay was reported to be 72% in a study performed at the Mayo Clinic using a cut-off of 1:20. PPV may vary depending upon the tested population, thus supporting further investigation of MOG-IgG testing at other centers. In this real-world institutional cohort study, we determined the PPV of serum MOG-IgG for clinically defined MOG-AD in our patient population. The Massachusetts General Brigham Research Patient Data Registry database was queried for patients with positive serum MOG-IgG detection, at least once, between January 1, 2017 and March 25, 2021. All were tested via the MOG-IgG1 fluorescence-activated cell sorting assay (Mayo Laboratories, Rochester, MN). MOG-IgG positive cases were reviewed for fulfillment of typical MOG-AD clinical features, determined by treating neurologists and study authors. Of 1,877 patients tested, 78 (4.2%) patients tested positive for MOG-IgG with titer ≥1:20, and of these, 67 had validated MOG-AD yielding a PPV of 85.9%. Using a ≥1:40 titer cutoff, 65 (3.5%) tested positive and PPV was 93.8%. Three MOG positive cases had a prototypical multiple sclerosis diagnosis (RRMS n = 2, titers 1:20 and 1:40; PPMS n = 1; 1:100). The treating diagnosis for one RRMS patient with a 1:40 titer was subsequently modified to MOG-AD by treating neurologists. Validated diagnoses of the remaining positive patients without MOG-AD included: migraine (n = 2, titers 1:20, 1:100), inclusion body myositis (n = 1, titer 1:100), autoimmune encephalitis (n = 2, titers 1:20, 1:20), hypoxic ischemic brain injury (n = 1, titer 1:20), IgG4-related disease (n = 1, titer 1:20), and idiopathic hypertrophic pachymeningitis (n = 1, titer 1:20). In our cohort, the PPV for MOG-IgG improved utilizing a titer cut-off of ≥1:40. The presence of positive cases with and without demyelinating features, emphasizes a need for testing in the appropriate clinical context, analysis of titer value and clinical interpretation.
Effects of Online Single Pulse Transcranial Magnetic Stimulation on Prefrontal and Parietal Cortices in Deceptive Processing: A Preliminary Study
Authors: Luber Bruce , Beynel Lysianne , Spellman Timothy , Gura Hannah , Ploesser Markus , Termini Kate , Lisanby Sarah H.
Published: June 2022

Transcranial magnetic stimulation (TMS) was used to test the functional role of parietal and prefrontal cortical regions activated during a playing card Guilty Knowledge Task (GKT). Single-pulse TMS was applied to 15 healthy volunteers at each of three target sites: left and right dorsolateral prefrontal cortex and midline parietal cortex. TMS pulses were applied at each of five latencies (from 0 to 480 ms) after the onset of a card stimulus. TMS applied to the parietal cortex exerted a latency-specific increase in inverse efficiency score and in reaction time when subjects were instructed to lie relative to when asked to respond with the truth, and this effect was specific to when TMS was applied at 240 ms after stimulus onset. No effects of TMS were detected at left or right DLPFC sites. This manipulation with TMS of performance in a deception task appears to support a critical role for the parietal cortex in intentional false responding, particularly in stimulus selection processes needed to execute a deceptive response in the context of a GKT. However, this interpretation is only preliminary, as further experiments are needed to compare performance within and outside of a deceptive context to clarify the effects of deceptive intent.
A Programmable Ontology Encompassing the Functional Logic of the Drosophila Brain
Authors: Lazar Aurel A. , Turkcan Mehmet Kerem , Zhou Yiyin
Published: June 2022

The Drosophila brain has only a fraction of the number of neurons of higher organisms such as mice and humans. Yet the sheer complexity of its neural circuits recently revealed by large connectomics datasets suggests that computationally modeling the function of fruit fly brain circuits at this scale poses significant challenges. To address these challenges, we present here a programmable ontology that expands the scope of the current Drosophila brain anatomy ontologies to encompass the functional logic of the fly brain. The programmable ontology provides a language not only for modeling circuit motifs but also for programmatically exploring their functional logic. To achieve this goal, we tightly integrated the programmable ontology with the workflow of the interactive FlyBrainLab computing platform. As part of the programmable ontology, we developed NeuroNLP++, a web application that supports free-form English queries for constructing functional brain circuits fully anchored on the available connectome/synaptome datasets, and the published worldwide literature. In addition, we present a methodology for including a model of the space of odorants into the programmable ontology, and for modeling olfactory sensory circuits of the antenna of the fruit fly brain that detect odorant sources. Furthermore, we describe a methodology for modeling the functional logic of the antennal lobe circuit consisting of a massive number of local feedback loops, a characteristic feature observed across Drosophila brain regions. Finally, using a circuit library, we demonstrate the power of our methodology for interactively exploring the functional logic of the massive number of feedback loops in the antennal lobe.
Changes in Volume of Subregions Within Basal Ganglia in Obsessive–Compulsive Disorder: A Study With Atlas-Based and VBM Methods
Authors: Chen Jiaxiang , Tian Chong , Zhang Qun , Xiang Hui , Wang Rongpin , Hu Xiaofei , Zeng Xianchun
Published: June 2022

Background

The role of basal ganglia in the pathogenesis of obsessive–compulsive disorder (OCD) remains unclear. The studies on volume changes of basal ganglia in OCD commonly use the VBM method; however, the Atlas-based method used in such research has not been reported. Atlas-based method has a lower false positive rate compared with VBM method, thus having advantages partly.

Objectives

The current study aimed to detect the volume changes of subregions within basal ganglia in OCD using Atlas-based method to further delineate the precise neural circuitry of OCD. What is more, we explored the influence of software used in Atlas-based method on the volumetric analysis of basal ganglia and compared the results of Atlas-based method and regularly used VBM method.

Methods

We analyzed the brain structure images of 37 patients with OCD and 41 healthy controls (HCs) using the VBM method, Atlas-based method based on SPM software, or Freesurfer software to find the areas with significant volumetric variation between the two groups, and calculated the effects size of these areas.

Results

VBM analysis revealed a significantly increased volume of bilateral lenticular nucleus in patients compared to HCs. In contrast, Atlas-based method based on Freesurfer revealed significantly increased volume of left globus pallidus in patients, and the largest effect size of volumetric variation was revealed by Freesurfer analysis.

Conclusions

This study showed that the volume of bilateral lenticular nucleus significantly increased in patients compared to HCs, especially left globus pallidus, which was in accordance with the previous findings. In addition, Freesurfer is better than SPM and a good choice for Atlas-based volumetric analysis of basal ganglia.
Acute Water Supplementation Improved the Body Composition of Young Female Adults After Water Restriction of 12 h in Baoding, China: A Randomized Controlled Trial (RCT)
Authors: Zhang Jianfen , Zhang Na , Du Songming , Liu Shufang , Ma Guansheng
Published: June 2022

Insufficient intake of water may influence the balance of water in the human body. In this study, we explore the impacts of water supplementation on body composition indices among young adults after 12 h of water restriction, with the aim to determine the optimum volume of water for improving body water composition. A randomized controlled trial study was conducted among 64 young men and women in Baoding, China. After fasting overnight for 12 h, anthropometric measurements and urine and blood samples were collected as a baseline test at 8:00 a.m. of Day 2. Body composition was determined by measuring the ECW (extracellular water), ICW (intracellular water), and TBW (total body water) through bioelectrical impedance analysis (BIA). The participants were randomly divided into four groups, including water supplementation (WS) groups 1, 2, and 3, with 500, 200, and 100 mL of water, respectively, and a no water supplementation (NW) group. After 90 min, they were reassessed in a rehydration test (at 10:00 a.m. of Day 2). Repeated measurement ANOVA was used to assess the impact of water supplementation on body composition. Comparing the baseline and rehydration tests, interactions between time and volume were not significant among the men (all p > 0.05). Among women, a significant interaction was only found in ECW (p = 0.043), with TBW tending toward being significant (p = 0.055). Comparing the baseline and rehydration tests, the ECW in WS group 1, WS group 3, and the NW group all decreased (p = 0.028, p = 0.001, and p = 0.029), with reductions of 0.1, 0.3, and 0.2 kg, respectively; however, no significant decrease was observed in WS group 2 (p = 0.329). Furthermore, comparing the WS groups with the NW group in the rehydration test, the differences were not significant (p = 1.000, p = 1.000, and p = 0.288, respectively). Between men and women within groups, all of the body composition indices differed significantly, both at baseline and rehydration tests (all p < 0.05). Water supplementation led to changes in the distribution of the water content in young female adults in this study—but not men—after 12 h of water restriction, with no decrease in ECW. Finally, we found that 200 mL was the minimum volume capable of improving the water content distribution in participants in this study.

Trial Registration

[www.chictr.org.cn], identifier [ChiCTR-IOR-17011568].
Efficacy of Postoperative Adjuvant Transcatheter Arterial Chemoembolization in Hepatocellular Carcinoma Patients With Microscopic Portal Vein Invasion
Authors: Qiu Yiwen , Yang Yi , Wang Tao , Shen Shu , Wang Wentao
Published: June 2022

Background

Microscopic portal vein invasion (MPVI) strongly predicts poor prognosis in patients with hepatocellular carcinoma (HCC). This study aims to investigate the impact of MPVI on the efficacy of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE).

Methods

From April 2014 to July 2019, a total of 512 HCC patients who underwent curative liver resection (LR) with microscopic vascular invasion (MVI) confirmed by histopathological examination were enrolled and divided into LR alone and PA-TACE groups. They were subsequently stratified into subgroups according to the presence of MPVI. Recurrence-free survival (RFS) and overall survival (OS) were compared using Kaplan–Meier curves and the log-rank test. The efficacy of PA-TACE was tested using univariate and multivariate Cox regression analyses. Sensitivity analysis was conducted after propensity score matching (PSM).

Results

Among all patients, 165 (32.3%) patients underwent PA-TACE, and 196 (38.2%) patients presented MPVI. In the entire cohort, PA-TACE and the presence of MPVI were identified as independent predictors for RFS and OS (all p<0.05). In the subgroup analysis, patients without MPVI who received PA-TACE had significantly better outcomes than those who underwent LR alone before and after PSM (all p<0.05). For patients with MPVI, PA-TACE displayed no significant benefit in terms of improving either RFS or OS, which was consistent with the results from the PSM cohort.

Conclusion

Among the HCC patients without MPVI who underwent curative liver resection, those who received PA-TACE had better RFS and OS outcomes than those who underwent LR alone. For patients with MPVI, PA-TACE had no significant effect on either RFS or OS outcomes.
Anti-Angiogenetic and Anti-Lymphangiogenic Effects of a Novel 2-Aminobenzimidazole Derivative, MFB
Authors: Hsu Ming-Jen , Chen Han-Kun , Chen Cheng-Yu , Lien Jin-Cherng , Gao Jing-Yan , Huang Yu-Han , Hsu Justin Bo-Kai , Lee Gilbert Aaron , Huang Shiu-Wen
Published: June 2022

Background and Purpose

Benzimidazoles have attracted much attention over the last few decades due to their broad-spectrum pharmacological properties. Increasing evidence is showing the potential use of benzimidazoles as anti-angiogenic agents, although the mechanisms that impact angiogenesis remain to be fully defined. In this study, we aim to investigate the anti-angiogenic mechanisms of MFB, a novel 2-aminobenzimidazole derivative, to develop a novel angiogenesis inhibitor.

Experimental Approach

MTT, BrdU, migration and invasion assays, and immunoblotting were employed to examine MFB’s effects on vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration, invasion, as well as signaling molecules activation. The anti-angiogenic effects of MFB were analyzed by tube formation, aorta ring sprouting, and matrigel plug assays. We also used a mouse model of lung metastasis to determine the MFB’s anti-metastatic effects.

Key Results

MFB suppressed cell proliferation, migration, invasion, and endothelial tube formation of VEGF-A-stimulated human umbilical vascular endothelial cells (HUVECs) or VEGF-C-stimulated lymphatic endothelial cells (LECs). MFB suppressed VEGF-A and VEGF-C signaling in HUVECs or LECs. In addition, MFB reduced VEGF-A- or tumor cells-induced neovascularization in vivo. MFB also diminished B16F10 melanoma lung metastasis. The molecular docking results further showed that MFB may bind to VEGFR-2 rather than VEGF-A with high affinity.

Conclusions and Implications

These observations indicated that MFB may target VEGF/VEGFR signaling to suppress angiogenesis and lymphangiogenesis. It also supports the role of MFB as a potential lead in developing novel agents for the treatment of angiogenesis- or lymphangiogenesis-associated diseases and cancer.
The Risk of Heart Disease-Related Death Among Anaplastic Astrocytoma Patients After Chemotherapy: A SEER Population-Based Analysis
Authors: Lin Qi , Bao Jia-Hao , Xue Fei , Qin Jia-Jun , Chen Zhen , Chen Zhong-Rong , Li Chao , Yan Yi-Xuan , Fu Jin , Shen Zhao-Li , Chen Xian-Zhen
Published: June 2022

Background

Despite improved overall survival outcomes, chemotherapy has brought concerns for heart disease–related death (HDRD) among cancer patients. The effect of chemotherapy on the risk of HDRD in anaplastic astrocytoma (AA) patients remains unclear.

Methods

We obtained 7,129 AA patients from the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2016. Kaplan–Meier and Cox regression analysis were conducted to evaluate the effect of chemotherapy on the HDRD risk. Based on the competing risk model, we calculated the cumulative incidences of HDRD and non-HDRD and performed univariate and multivariate regression analyses. Then, a 1:1 propensity score matching (PSM) was used to improve the comparability between AA patients with and without chemotherapy. Landmark analysis at 216 and 314 months was employed to minimize immortal time bias.

Results

AA patients with chemotherapy were at a lower HDRD risk compared to those patients without chemotherapy (adjusted HR=0.782, 95%CI=0.736–0.83, P<0.001). For competing risk regression analysis, the cumulative incidence of HDRD in non-chemotherapy exceeded HDRD in the chemotherapy group (P<0.001) and multivariable analysis showed a lower HDRD risk in AA patients with chemotherapy (adjusted SHR=0.574, 95%CI=0.331–0.991, P=0.046). In the PSM-after cohort, there were no significant association between chemotherapy and the increased HDRD risk (adjusted SHR=0.595, 95%CI=0.316−1.122, P=0.11). Landmark analysis showed that AA patients who received chemotherapy had better heart disease–specific survival than those in the non-chemotherapy group (P=0.007) at the follow-up time points of 216 months. No difference was found when the follow-up time was more than 216 months.

Conclusion

AA patients with chemotherapy are associated with a lower risk of HDRD compared with those without chemotherapy. Our findings may help clinicians make a decision about the management of AA patients and provide new and important evidence for applying chemotherapy in AA patients as the first-line treatment. However, more research is needed to confirm these findings and investigate the correlation of the risk of HDRD with different chemotherapy drugs and doses.
Anti-Angiogenic Drugs Inhibit Interstitial Lung Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer
Authors: Wang Yanning , Gong Xiaoling , Hu Yuxuan , Yi Qing , Zhang Qianning , Miao Liyun , Zhou Yujie
Published: June 2022

Background

Interstitial lung disease (ILD) is the most serious complication of chemotherapy in lung cancer patients with pre-existing ILD. The effect of anti-angiogenic drugs in lung cancer patients with ILD remains unclear. We examined the effect of anti-angiogenic drugs on reducing the risk of ILD progression in non-small cell lung cancer (NSCLC) patients receiving chemotherapy.

Methods

We analyzed the risk of ILD progression in 52 patients with advanced NSCLC with ILD who received first-line chemotherapy with (anti-angiogenic group, n = 22) and without (non-anti-angiogenic group, n = 30) anti-angiogenic drugs between August 2014 and January 2021.

Results

The incidences of chemotherapy-related ILD progression were significantly lower in the anti-angiogenic than in the non-anti-angiogenic groups (0% vs. 20.0%, p = 0.033). However, there were no differences in other events as the competing risk factors of ILD progression between the two groups. The overall-cumulative incidence of ILD progression during the first-line and subsequent chemotherapy was 30.8% (16 of the 52). The median progression-free survival had no significant difference between the anti-angiogenic and the non-anti-angiogenic groups (10.3 vs. 8.1 months, p = 0.386).

Conclusions

The addition of anti-angiogenic drugs to chemotherapy regimens may reduce the risk of chemotherapy-related ILD progression in patients with NSCLC-ILD.
Discovering Innate Driver Variants for Risk Assessment of Early Colorectal Cancer Metastasis
Authors: Ding Ruo-Fan , Zhang Yun , Wu Lv-Ying , You Pan , Fang Zan-Xi , Li Zhi-Yuan , Zhang Zhong-Ying , Ji Zhi-Liang
Published: June 2022

Metastasis is the main fatal cause of colorectal cancer (CRC). Although enormous efforts have been made to date to identify biomarkers associated with metastasis, there is still a huge gap to translate these efforts into effective clinical applications due to the poor consistency of biomarkers in dealing with the genetic heterogeneity of CRCs. In this study, a small cohort of eight CRC patients was recruited, from whom we collected cancer, paracancer, and normal tissues simultaneously and performed whole-exome sequencing. Given the exomes, a novel statistical parameter LIP was introduced to quantitatively measure the local invasion power for every somatic and germline mutation, whereby we affirmed that the innate germline mutations instead of somatic mutations might serve as the major driving force in promoting local invasion. Furthermore, via bioinformatic analyses of big data derived from the public zone, we identified ten potential driver variants that likely urged the local invasion of tumor cells into nearby tissue. Of them, six corresponding genes were new to CRC metastasis. In addition, a metastasis resister variant was also identified. Based on these eleven variants, we constructed a logistic regression model for rapid risk assessment of early metastasis, which was also deployed as an online server, AmetaRisk (http://www.bio-add.org/AmetaRisk). In summary, we made a valuable attempt in this study to exome-wide explore the genetic driving force to local invasion, which provides new insights into the mechanistic understanding of metastasis. Furthermore, the risk assessment model can assist in prioritizing therapeutic regimens in clinics and discovering new drug targets, and thus substantially increase the survival rate of CRC patients.
Urine Exosomal AMACR Is a Novel Biomarker for Prostate Cancer Detection at Initial Biopsy
Authors: Jin Xin , Ji Jin , Niu Decao , Yang Yuchen , Tao Shuchun , Wan Lilin , Xu Bin , Chen Shuqiu , Wang Fubo , Chen Ming
Published: June 2022

Objectives

The aim of this study is to identify and validate urine exosomal AMACR (UE-A) as a novel biomarker to improve the detection of prostate cancer (PCa) and clinically significant PCa (Gleason score ≥ 7) at initial prostate biopsy.

Methods

A total of 289 first-catch urine samples after the digital rectal exam (DRE) were collected from patients who underwent prostatic biopsy, and 17 patients were excluded due to incomplete clinical information. Urine exosomes were purified, and urinary exosomal AMACR (UE-A) was measured by enzyme-linked immunosorbent assay (ELISA). The diagnostic performance of UE-A was evaluated by receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and waterfall plots.

Results

The expression of AMACR in PCa and csPCa was significantly higher than that in BPH and non-aggressive (p < 0.001). The UE-A presented good performance in distinguishing PCa from BPH or BPH plus non-significant PCa (nsPCa) from csPCa with an area under the ROC curve (AUC) of 0.832 and 0.78, respectively. The performance of UE-A was further validated in a multi-center cohort of patients with an AUC of 0.800 for detecting PCa and 0.749 for detecting csPCa. The clinical utility assessed by DCA showed that the benefit of patients using UE-A was superior to PSA, f/t PSA, and PSAD in both the training cohort and the validation cohort in terms of all threshold probabilities. Setting 95% sensitivity as the cutoff value, UE-A could avoid 27.57% of unnecessary biopsies, with only 4 (1.47%) csPCa patients missed.

Conclusions

We demonstrated the great performance of UE-A for the early diagnosis of PCa and csPCa. UE-A could be a novel non-invasive diagnostic biomarker to improve the detection of PCa and csPCa.
Efficacy and Safety of Conversion Therapy by Intraperitoneal and Intravenous Paclitaxel Plus Oral S-1 in Gastric Cancer Patients With Peritoneal Metastasis: A Prospective Phase II Study
Authors: Yang Zhong-Yin , Yuan Fei , Lu Sheng , Xu Wei , Wu Jun-Wei , Xi Wen-Qi , Shi Min , Wang Zhen-Qiang , Ni Zhen-Tian , He Chang-Yu , Yao Xue-Xin , Zheng Ya-Nan , Zhu Zheng-Lun , Liu Wen-Tao , Zhang Jun , Zhang Huan , Li Chen , Yan Chao , Yan Min , Zhu Zheng-Gang
Published: June 2022

Background

Neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) has shown promising results in gastric cancer (GC) with peritoneal metastasis. However, clinical practice experience of NIPS is still lacking in China. In this study, we investigate the efficacy and safety of NIPS in Chinese patients.

Methods

Eligible patients received NIPS every 3 weeks. Gastrectomy was performed for patients who met the criteria of conversion surgery. The primary end point was 1-year overall survival (OS) rate. Secondary end points were the response rate, toxic effects, conversion surgery outcomes and median survival time (MST).

Results

Sixty-seven patients were enrolled. The primary endpoint was achieved with 1-year OS rate reached 67.2% (95% CI, 56.8%-79.4%). Conversion surgery was performed in 42 patients (62.9%), and R0 resection was achieved in 23 patients (54.8%) with the MST of 31.3 months (95% CI, 24.3-38.3). And the MST was 19.3 months (95% CI, 16.4-22.2) for all patients. Toxicity and surgical complications were well-tolerated. Moreover, sex, R0 resection, pathological nodal stage and tumor regression grade (TRG) were independent prognostic factors for patients who underwent conversion surgery.

Conclusion

The NIPS is effective and safe in treating GC patients with peritoneal metastasis. Male patients, patients who underwent R0 resection, patients with ypN0-1 or TRG 1 after conversion surgery are more likely to benefit from the NIPS.

Clinical Trial Registration

http://www.chictr.org.cn/, identifier https://clinicaltrials.gov/ ().
Dosing Regimens of Immune Checkpoint Inhibitors: Attempts at Lower Dose, Less Frequency, Shorter Course
Authors: Jiang Mengjie , Hu Yujie , Lin Gang , Chen Chao
Published: June 2022

Immune checkpoint inhibitors (ICIs) are a revolutionary breakthrough in the field of cancer by modulating patient’s own immune system to exert anti-tumor effects. The clinical application of ICIs is still in its infancy, and their dosing regimens need to be continuously adjusted. Pharmacokinetic/pharmacodynamic studies showed a significant plateau in the exposure-response curve, with high receptor occupancy and plasma concentrations achieved at low dose levels. Coupled with concerns about drug toxicity and heavy economic costs, there has been an ongoing quest to reevaluate the current ICI dosing regimens while preserving maximum clinical efficacy. Many clinical data showed remarkable anticancer effects with ICIs at the doses far below the approved regimens, indicating the possibility of dose reduction. Our review attempts to summarize the clinical evidence for ICIs regimens with lower-dose, less-frequency, shorter-course, and provide clues for further ICIs regimen optimization.
Myopia Control With Multifocal Lens in School-Aged Children: A Meta-Analysis
Authors: Chen Meilan , Xu Lu , Li Hongyang , Cai Fengping , Wang Hao , Hu Chun , Wu Yi
Published: June 2022

Background

Myopia is one of the most common eye diseases in school-aged children. Multifocal lens (MFL) is one of the interventions that has being widely applied to control the progress of myopia. However, the treatment effects of MFLs in school-aged children require to be systematically evaluated.

Methods

A systematic analysis on qualified randomized controlled trials (RCTs) in which MFLs were prescribed as the intervention and single-vision lenses (SVLs) as the control was conducted. The treatment effects referring to the mean differences in spherical equivalent refraction (SER) and axial length (AL) between MFLs and SVLs groups were analyzed.

Results

With annual visit (3-years follow-up), the weighted mean differences (WMDs) in SER between MFLs and SVLs were 0.29 D (95% CI, 0.21 ∼ 0.37, p < 0.00001), 0.46 D (95% CI, 0.32 ∼ 0.60, p < 0.00001), and 0.64 D (95% CI, 0.40 ∼ 0.88, p < 0.00001) at the first, second, and third year; in AL were −0.12 mm (95% CI, −0.14 ∼−0.11, p < 0.00001), −0.19 mm (95% CI, −0.22 ∼−0.16, p < 0.00001), and −0.26 mm (95% CI, −0.31 ∼−0.21, p < 0.00001) at the first, second, and third year. With 6-months interval trials (2-years follow-up), the WMDs in SER from MFLs were 0.14 D (95% CI, 0.08 ∼ 0.20, p < 0.0001), 0.19 D (95% CI, 0.11 ∼ 0.28, p < 0.0001), 0.24 D (95% CI, 0.16 ∼ 0.33, p < 0.0001), 0.31 D (95% CI, 0.18 ∼ 0.44, p < 0.0001) and in AL from MFLs were −0.08 mm (95% CI, −0.09 ∼−0.07, p < 0.00001), −0.10 mm (95% CI, −0.12 ∼−0.09, p < 0.00001), −0.14 mm (95% CI, −0.17 ∼−0.11, p < 0.00001), and −0.18 mm (95% CI, −0.22 ∼−0.14, p < 0.00001) slower comparing with SVLs at follow up of 6, 12, 18, and 24 months, respectively.

Conclusion

The treatment effects of MFLs to slow down the myopic progress are positive in both 6-months and annual-visit trials and which could be sustained till 36 months. While a slight weaker treatment effect was observed after the first visit in 6-months visit, a slight rebound was observed at the following visit points. Furthermore, the treatment effects in annual visit are more profound than 6-months visit at almost all stages especially in SER. Our analysis encourages the MFLs users to maintain a long-term treatment with annual visit.
Recent Advances in Cancer Drug Discovery Through the Use of Phenotypic Reporter Systems, Connectivity Mapping, and Pooled CRISPR Screening
Authors: Salame Natasha , Fooks Katharine , El-Hachem Nehme , Bikorimana Jean-Pierre , Mercier François E. , Rafei Moutih
Published: June 2022

Multi-omic approaches offer an unprecedented overview of the development, plasticity, and resistance of cancer. However, the translation from anti-cancer compounds identified in vitro to clinically active drugs have a notoriously low success rate. Here, we review how technical advances in cell culture, robotics, computational biology, and development of reporter systems have transformed drug discovery, enabling screening approaches tailored to clinically relevant functional readouts (e.g., bypassing drug resistance). Illustrating with selected examples of “success stories,” we describe the process of phenotype-based high-throughput drug screening to target malignant cells or the immune system. Second, we describe computational approaches that link transcriptomic profiling of cancers with existing pharmaceutical compounds to accelerate drug repurposing. Finally, we review how CRISPR-based screening can be applied for the discovery of mechanisms of drug resistance and sensitization. Overall, we explore how the complementary strengths of each of these approaches allow them to transform the paradigm of pre-clinical drug development.