bluuebunny/crossref_metadata_2025 huggingface dataset:
Deoxygenation in Marginal Seas of the Indian Ocean
Authors: Naqvi S. Wajih A.
Published: February 2021

This article describes oxygen distributions and recent deoxygenation trends in three marginal seas – Persian Gulf and Red Sea in the Northwestern Indian Ocean (NWIO) and Andaman Sea in the Northeastern Indian Ocean (NEIO). Vertically mixed water column in the shallow Persian Gulf is generally well-oxygenated, especially in winter. Biogeochemistry and ecosystems of Persian Gulf are being subjected to enormous anthropogenic stresses including large loading of nutrients and organic matter, enhancing oxygen demand and causing hypoxia (oxygen < 1.4 ml l–1) in central and southern Gulf in summer. The larger and deeper Red Sea is relatively less affected by human activities. Despite its deep water having remarkably uniform thermohaline characteristics, the central and southern Red Sea has a well-developed perennial oxygen minimum at mid-depths. The available data point to ongoing deoxygenation in the northern Red Sea. Model simulations show that an amplified warming in the marginal seas of the NWIO may cause an intensification of the Arabian Sea oxygen minimum zone (OMZ). Increases in particulate organic carbon and decreases in oxygen contents of the outflows may also have a similar effect. In the Andaman Sea, waters above the sill depth (∼1.4 km) have characteristics similar to those in the Bay of Bengal, including an intense OMZ. As in the case of the Bay of Bengal, oxygen concentrations within the Andaman Sea OMZ appear to have declined slightly but significantly between early 1960s and 1995. The exceedingly isothermal and isohaline water that fills the deep Andaman Basin is also remarkably homogenous in terms of its oxygen content. A very slight but statistically significant decrease in oxygen content of this water also seems to have occurred over three decades preceding 1995. New information is badly needed to assess the extent of further change that may have occurred over the past 25 years. There have been some reports of coastal “dead zones” having developed in the Indian Ocean marginal seas, but they are probably under-reported and the effects of hypoxia on the rich and diverse tropical ecosystems – coral reefs, seagrasses, and mangroves – in these seas remain to be investigated.
Comparisons of Serum Progesterone and Progestagen Concentrations in Normal and Abnormal Bottlenose Dolphin (Tursiops truncatus) Pregnancies
Authors: Robeck Todd R. , Steinman Karen J. , Parry Celeste B. , Gomez Forrest M. , Jensen Eric D.
Published: February 2021

Although previous studies have described progesterone profiles during pregnancy in the bottlenose dolphin (Tursiops truncatus), most of these focused on normal pregnancy (NORM) or compared NORM to only one or two abnormal pregnancy types, such as abortion (AB) or perinatal loss (PNL). Hormonal pregnancy biomarker analysis from reproductive events with different outcomes may reveal differences in concentrations so that we are able to identify high risk pregnancies. The aim of this study was to describe longitudinal profiles of circulating progesterone and progestagens during reproductive events in the female bottlenose dolphin, including NORM, failure to thrive, PNL, AB, early loss (EL), and false pregnancy (FP). Progesterone differed from NORM during EL at EARLY (month post conception [MPC] 1–4), AB at MID (MPC 5–8), and FP at LATE (MPC 9–12) stages. Progestagens differed from NORM during AB and FP at MID and LATE stages and during MPC 12 in PNL and MPC 4 in EL. Progestagens may be better at predicting poor reproductive outcome in the bottlenose dolphin and a suite of hormone tests, including progesterone and progestagens, should be incorporated into existing clinical diagnostic and management practices in this species. Furthermore, analysis of multiple hormonal pregnancy biomarkers from a single sample may enable pregnancy diagnosis for wild animals.
TGF-β1 Signaling: Immune Dynamics of Chronic Kidney Diseases
Authors: Tang Philip Chiu-Tsun , Chan Alex Siu-Wing , Zhang Cai-Bin , García Córdoba Cristina Alexandra , Zhang Ying-Ying , To Ka-Fai , Leung Kam-Tong , Lan Hui-Yao , Tang Patrick Ming-Kuen
Published: February 2021

Chronic kidney disease (CKD) is a major cause of morbidity and mortality worldwide, imposing a great burden on the healthcare system. Regrettably, effective CKD therapeutic strategies are yet available due to their elusive pathogenic mechanisms. CKD is featured by progressive inflammation and fibrosis associated with immune cell dysfunction, leading to the formation of an inflammatory microenvironment, which ultimately exacerbating renal fibrosis. Transforming growth factor β1 (TGF-β1) is an indispensable immunoregulator promoting CKD progression by controlling the activation, proliferation, and apoptosis of immunocytes via both canonical and non-canonical pathways. More importantly, recent studies have uncovered a new mechanism of TGF-β1 for de novo generation of myofibroblast via macrophage-myofibroblast transition (MMT). This review will update the versatile roles of TGF-β signaling in the dynamics of renal immunity, a better understanding may facilitate the discovery of novel therapeutic strategies against CKD.
Genomic Characterization of Two Shiga Toxin–Converting Bacteriophages Induced From Environmental Shiga Toxin–Producing Escherichia coli
Authors: Zhang Yujie , Liao Yen-Te , Salvador Alexandra , Wu Vivian C. H.
Published: February 2021

Shiga toxin (Stx), encoded by stx genes located in prophage sequences, is the major agent responsible for the pathogenicity of Shiga toxin-producing Escherichia coli (STEC) and is closely associated with the development of hemolytic uremic syndrome (HUS). Although numerous Stx prophage sequences have been reported as part of STEC bacterial genomes, the information about the genomic characterization of Stx-converting bacteriophages induced from STEC strains is relatively scarce. The objectives of this study were to genomically characterize two Stx-converting phages induced from environmental STEC strains and to evaluate their correlations with published Stx-converting phages and STEC strains of different origins. The Stx1-converting phage Lys8385Vzw and the Stx2-converting phage Lys19259Vzw were induced from E. coli O103:H11 (RM8385) and E. coli O157:H7 (RM19259), respectively. Whole-genome sequencing of these phages was conducted on a MiSeq sequencer for genomic characterization. Phylogenetic analysis and comparative genomics were performed to determine the correlations between these two Stx-converting phages, 13 reference Stx-converting phages, and 10 reference STEC genomes carrying closely related Stx prophages. Both Stx-converting phages Lys8385Vzw and Lys19259Vzw had double-stranded DNA, with genome sizes of 50,953 and 61,072 bp, respectively. Approximately 40% of the annotated coding DNA sequences with the predicted functions were likely associated with the fitness for both phages and their bacterial hosts. The whole-genome–based phylogenetic analysis of these two Stx-converting phages and 13 reference Stx-converting phages revealed that the 15 Stx-converting phages were divided into three distinct clusters, and those from E. coli O157:H7, in particular, were distributed in each cluster, demonstrating the high genomic diversity of these Stx-converting phages. The genomes of Stx-converting phage Lys8385Vzw and Lys19259Vzw shared a high-nucleotide similarity with the prophage sequences of the selected STEC isolates from the clinical and environmental origin. The findings demonstrate the genomic diversity of Stx-converting phages induced from different STEC strains and provide valuable insights into the dissemination of stx genes among E. coli population via the lysogenization of Stx-converting phages.
Effects of Xylo-Oligosaccharides on Growth and Gut Microbiota as Potential Replacements for Antibiotic in Weaning Piglets
Authors: Chen Yuxia , Xie Yining , Zhong Ruqing , Liu Lei , Lin Changguang , Xiao Lin , Chen Liang , Zhang Hongfu , Beckers Yves , Everaert Nadia
Published: February 2021

Xylo-oligosaccharides (XOS) is a well-known kind of oligosaccharide and extensively applied as a prebiotic. The objective of this study was to investigate the effect of XOS supplementation substituting chlortetracycline (CTC) on growth, gut morphology, gut microbiota, and hindgut short chain fatty acid (SCFA) contents of weaning piglets. A total of 180 weaned piglets were randomly allocated to three treatments for 28 days, as follows: control group (basal diet, CON), basal diet with 500 mg/kg (XOS500) XOS, and positive control (basal diet with 100 mg/kg CTC). Compared with the CON group, the piglets in the XOS500 group improved body weight (BW) on days 28, average daily gain (ADG) and reduced feed: gain ratio during days 1–28 (P < 0.05). The XOS500 supplementation increased Villus height and Villus height: Crypt depth ratio in the ileum (P < 0.05). Villus Height: Crypt Depth of the ileum was also increased in the CTC treatment group (P < 0.05). Meanwhile, the XOS500 supplementation increased significantly the numbers of goblet cells in the crypt of the cecum. High-throughput 16S rRNA gene sequencing revealed distinct differences in microbial compositions between the ileum and cecum. XOS500 supplementation significantly increased the bacterial diversity. However, CTC treatment markedly reduced the microbial diversity (P < 0.05). Meanwhile, XOS500 supplementation in the diet significantly increased the abundance of Lactobacillus genus compared to the CON and CTC group in the ileum and cecum (P < 0.01), whereas the level of Clostridium_sensu_stricto_1, Escherichia-Shigella, and Terrisporobacter genus in the XOS500 group were markedly lower than the CON and CTC group (P < 0.05). In addition, dietary supplementation with XOS500 significantly increased the total short-chain fatty acids, propionate and butyrate concentrations and decreased the acetate concentration compared to the CON group in the cecum (P < 0.05). In summary, dietary supplemented with XOS500 could enhance specific beneficial microbiota abundance and decrease harmful microbiota abundance to maintain the structure of the intestinal morphology and improve growth performance of weaned piglets. Thus, XOS may potentially function as an alternative to in-feed antibiotics in weaned piglets in modern husbandry.
One-Step Biosynthesis of Vitamin C in Saccharomyces cerevisiae
Authors: Zhou Mengyu , Bi Yanhui , Ding Mingzhu , Yuan Yingjin
Published: February 2021

Vitamin C (VC) is comprehensively applied in foods, cosmetics, pharmaceuticals, and especially clinical medicine. Nowadays, the industrial production of VC mainly relies on the classic two-step fermentation route, and researchers have explored the way for one-step fermentation of VC in recent years. In this study, a VC biosynthesis pathway that directly produced VC from glucose was reconstructed in Saccharomyces cerevisiae, and the protein engineering and metabolic engineering strategies were adopted to improve it. First, five exogenous modules from Arabidopsis were introduced into the chassis cells by synthetic biology approaches to obtain the strain YLAA harboring VC biosynthesis. In addition, L-galactose dehydrogenase (L-GalDH) and L-galactono-1,4-lactone dehydrogenase (L-GLDH) were fused and expressed in S. cerevisiae cells for the first time, which increased the intracellular VC accumulation by 2.78-fold, reaching 9.97 ± 0.09 mg/L. Through copy number engineering, it was further confirmed that the last step catalyzed by L-GLDH is the rate-limiting step. GDP-L-galactose phosphorylase (GPP) encoded by vtc2 is another rate-limiting enzyme confirmed by GAL1p overexpression results. Finally, by balancing gene expression and cell growth, the highest production strain with overexpressing vtc2 by multicopy plasmids was constructed. The VC accumulation reached 24.94 ± 1.16 mg/L, which was currently the highest production from glucose in S. cerevisiae. The production of the recombinant strain reached nearly 44 mg/L with the exogenous addition of L-galactose or glutathione. The results further emphasized the importance of the step catalyzed by GPP. The investigation provided experience for the efficient biosynthesis of VC and the determination of rate-limiting steps.
Serum Uric Acid and the Risk of Dementia: A Systematic Review and Meta-Analysis
Authors: Zhou Zhike , Zhong Shanshan , Liang Yifan , Zhang Xiaoqian , Zhang Rongwei , Kang Kexin , Qu Huiling , Xu Ying , Zhao Chuansheng , Zhao Mei
Published: February 2021

Background: This meta-analysis aimed to evaluate the relationship between serum uric acid (UA) and the risk of dementia and its subtypes.

Methods: Embase, PubMed, and Web of Science were searched from inception to July 2020. Random-effect models were employed to analyze the standard mean difference (SMD) with the corresponding 95% confidence intervals (CI).

Results: Twenty-three eligible studies involving 5,575 participants were identified. The overall results showed lower levels of UA in dementia relative to non-dementia controls [SMD = −0.32 (−0.64; −0.01) p = 0.04]. The subgroup analysis of the type of dementia demonstrated a significant association of UA with Alzheimer's disease (AD) [SMD = −0.58 (−1.02; −0.15) p = 0.009] and Parkinson's disease with dementia (PDD) [SMD = −0.33 (−0.52; −0.14) p = 0.001] but not with vascular dementia (VaD). The stratification analysis of the concentrations of UA revealed that the UA quartile 1–2 was negatively correlated with dementia and neurodegenerative subtypes (p < 0.05), whereas a positive correlation of UA quartile 4 with dementia was noted (p = 0.028). Additionally, the meta-regression analysis on confounders showed that not age, body mass index, diabetes mellitus, hypertension, or smoking but education (p = 0.003) exerted an influence of the UA in the risk estimate of dementia.

Conclusions: Low concentrations of UA (< 292 μmol/L or 4.91 mg/dL) is a potential risk factor for AD and PDD but not for VaD. The mechanism of different concentrations of the UA in dementia needs to be confirmed through further investigation.
The Effects of Intravermis Cerebellar Microinjections of Dopaminergic Agents in Motor Learning and Aversive Memory Acquisition in Mice
Authors: Guilherme Evelyn M. , Gianlorenço Anna Carolyna L.
Published: February 2021

The cerebellum receives dopaminergic innervation and expresses the five types of described dopaminergic receptors. The cerebellar function involves both motor movement and cognition, but the role of cerebellar dopaminergic system on these processes remain unclear. The present study explores the behavioral responses to intracerebellar microinjection of dopaminergic agents in motor and emotional memory. For this, naïve Swiss mice had their cerebellar vermis implanted with a guide canula, received a intravermis microinjection of Dopamine, D1-like antagonist SCH-23390 or D2-like antagonist Eticlopride, and underwent a behavioral analysis of motor learning (by a Rotarod and balance beam learning protocol) or aversive memory acquisition (by the inhibitory avoidance task). The mixed-effects analysis was used to evaluate groups performance, followed by Tukey’s post hoc when appropriated. In this study, Dopamine, SCH-23390 and Eticlopride at the doses used did not affected motor control and motor learning. In addition, the administration of Dopamine and SCH-233390 had no effects on emotional memory acquisition, but the animals that received the highest dose of Eticlopride had an improvement in aversive memory acquisition, shown by a suppression of its innate preference for the dark compartment of the inhibitory avoidance apparatus following an exposure to a foot shock. We propose that cerebellar dopaminergic D2 receptors seem to participate on the modulation of aversive memory processes, without influencing motor performance at the doses used in this study.
Inflammation Spreading: Negative Spiral Linking Systemic Inflammatory Disorders and Alzheimer’s Disease
Authors: Ni Junjun , Wu Zhou
Published: February 2021

As a physiological response to injury in the internal body organs, inflammation is responsible for removing dangerous stimuli and initiating healing. However, persistent and exaggerative chronic inflammation causes undesirable negative effects in the organs. Inflammation occurring in the brain and spinal cord is known as neuroinflammation, with microglia acting as the central cellular player. There is increasing evidence suggesting that chronic neuroinflammation is the most relevant pathological feature of Alzheimer’s disease (AD), regulating other pathological features, such as the accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau. Systemic inflammatory signals caused by systemic disorders are known to strongly influence neuroinflammation as a consequence of microglial activation, inflammatory mediator production, and the recruitment of peripheral immune cells to the brain, resulting in neuronal dysfunction. However, the neuroinflammation-accelerated neuronal dysfunction in AD also influences the functions of peripheral organs. In the present review, we highlight the link between systemic inflammatory disorders and AD, with inflammation serving as the common explosion. We discuss the molecular mechanisms that govern the crosstalk between systemic inflammation and neuroinflammation. In our view, inflammation spreading indicates a negative spiral between systemic diseases and AD. Therefore, “dampening inflammation” through the inhibition of cathepsin (Cat)B or CatS may be a novel therapeutic approach for delaying the onset of and enacting early intervention for AD.
Diffusion Spectrum Imaging of Corticospinal Tracts in Idiopathic Normal Pressure Hydrocephalus
Authors: Zhang Hong , He Wen-Jie , Liang Li-Hong , Zhang Han-Wen , Zhang Xie-Jun , Zeng Liang , Luo Si-Ping , Lin Fan , Lei Yi
Published: February 2021

Purpose: The purpose of this study was to measure the diffusion spectrum imaging (DSI) parameters of corticospinal tracts (CSTs) and evaluate diffusional changes in CSTs in patients with idiopathic normal pressure hydrocephalus (iNPH) by DSI.

Methods: Twenty-three iNPH patients and twenty-one healthy controls (HCs) were involved in this study. Brain DSI data for all participants were collected through the same MR scanning procedure. The diffusion parameters measured and analyzed included quantitative anisotropy (QA), the isotropic diffusion component (ISO), general fractional anisotropy (GFA), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of corticospinal tracts.

Results: The QA and ISO values of corticospinal tracts in iNPH patients were significantly lower than those in HCs (PLQA = 0.008, PRQA = 0.016, PLISO = 0.024, PRISO = 0.016). The mean MD, AD, and RD values in iNPH patients were significantly higher than those in HCs (PMD = 0.032, PAD = 0.032, PRD = 0.048,). No significant differences in GFA and FA values were noted between iNPH patients and HCs.

Conclusion: Decreased QA and ISO values of corticospinal tracts were found in iNPH patients. Quantitative CST evaluation using DSI may lead to information that can improve the present understanding of the disease mechanism.
Early Laboratory Predictors for Necessity of Renal Replacement Therapy in Patients With Spontaneous Deep-Seated Intracerebral Hemorrhage
Authors: Schenk Lorena M. , Schneider Matthias , Bode Christian , Güresir Erdem , Junghanns Christoph , Müller Marcus , Putensen Christian , Vatter Hartmut , Zimmermann Julian , Schuss Patrick , Lehmann Felix
Published: February 2021

Objective: The need for continuous renal replacement therapy (CRRT) in patients with deep-seated intracerebral hemorrhage (ICH) requires sustained intensive care and often postpones further rehabilitation therapy. Therefore, an early identification of patients at risk is essential.

Methods: From 2014 to 2019, all patients with deep-seated ICH who were admitted to intensive care for >3 days were included in the further analysis and retrospectively reviewed for the need for CRRT. All patients underwent CRRT with regional citrate anticoagulation for continuous veno-venous hemodialysis (CVVHD). Outcome was evaluated after 3 months using the modified Rankin scale. A multivariate analysis was performed to identify potential predictors for CRRT in patients with deep-seated ICH.

Results: After applying the inclusion criteria, a total of 87 patients with deep-seated spontaneous ICH were identified and further analyzed. During the first 48 h after admission, 21 of these patients developed early acute kidney injury (AKI; 24%). During treatment course, CRRT became necessary in nine patients suffering from deep-seated ICH (10%). The multivariate analysis revealed “development of AKI during the first 48 h” [p = 0.025, odds ratio (OR) 6.1, 95% confidence interval (CI) 1.3–29.8] and “admission procalcitonin (PCT) value >0.5 μg/l” (p = 0.02, OR 7.7, 95% CI 1.4–43.3) as independent and significant predictors for CRRT in patients with deep-seated ICH.

Conclusions: Elevated serum levels of procalcitonin on admission as well as early development of acute renal injury are independent predictors of the need for renal replacement therapy in patients with deep-seated intracerebral bleeding. Therefore, further research is warranted to identify these vulnerable patients as early as possible to enable adequate treatment.
Structural and Functional Changes Are Related to Cognitive Status in Wilson’s Disease
Authors: Hu Sheng , Xu Chunsheng , Dong Ting , Wu Hongli , Wang Yi , Wang Anqin , Kan Hongxing , Li Chuanfu
Published: February 2021

Patients with Wilson’s disease (WD) suffer from prospective memory (PM) impairment, and some of patients develop cognitive impairment. However, very little is known about how brain structure and function changes effect PM in WD. Here, we employed multimodal neuroimaging data acquired from 22 WD patients and 26 healthy controls (HC) who underwent three-dimensional T1-weighted, diffusion tensor imaging (DTI), and resting state functional magnetic resonance imaging (RS-fMRI). We investigated gray matter (GM) volumes with voxel-based morphometry, DTI metrics using the fiber tractography method, and RS-fMRI using the seed-based functional connectivity method. Compared with HC, WD patients showed GM volume reductions in the basal ganglia (BG) and occipital fusiform gyrus, as well as volume increase in the visual association cortex. Moreover, whiter matter (WM) tracks of WD were widely impaired in association and limbic fibers. WM tracks in association fibers are significant related to PM in WD patients. Relative to HC, WD patients showed that the visual association cortex functionally connects to the thalamus and hippocampus, which is associated with global cognitive function in patients with WD. Together, these findings suggested that PM impairment in WD may be modulated by aberrant WM in association fibers, and that GM volume changes in the association cortex has no direct effect on cognitive status, but indirectly affect global cognitive function by its aberrant functional connectivity (FC) in patients with WD. Our findings may provide a new window to further study how WD develops into cognitive impairment, and deepen our understanding of the cognitive status and neuropathology of WD.
Characterizing Different Strategies for Resolving Approach-Avoidance Conflict
Authors: Bravo-Rivera Hector , Rubio Arzola Patricia , Caban-Murillo Albit , Vélez-Avilés Adriana N. , Ayala-Rosario Shantée N. , Quirk Gregory J.
Published: February 2021

The ability of animals to maximize benefits and minimize costs during approach-avoidance conflicts is an important evolutionary tool, but little is known about the emergence of specific strategies for conflict resolution. Accordingly, we developed a simple approach-avoidance conflict task in rats that pits the motivation to press a lever for sucrose against the motivation to step onto a distant platform to avoid a footshock delivered at the end of a 30 s tone (sucrose is available only during the tone). Rats received conflict training for 16 days to give them a chance to optimize their strategy by learning to properly time the expression of both behaviors across the tone. Rats unexpectedly separated into three distinct subgroups: those pressing early in the tone and avoiding later (Timers, 49%); those avoiding throughout the tone (Avoidance-preferring, 32%); and those pressing throughout the tone (Approach-preferring, 19%). The immediate early gene cFos revealed that Timers showed increased activity in the ventral striatum and midline thalamus relative to the other two subgroups, Avoidance-preferring rats showed increased activity in the amygdala, and Approach-preferring rats showed decreased activity in the prefrontal cortex. This pattern is consistent with low fear and high behavioral flexibility in Timers, suggesting the potential of this task to reveal the neural mechanisms of conflict resolution.
Brain Structural Network Compensation Is Associated With Cognitive Impairment and Alzheimer’s Disease Pathology
Authors: Sheng Xiaoning , Chen Haifeng , Shao Pengfei , Qin Ruomeng , Zhao Hui , Xu Yun , Bai Feng ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2021

Background

Structural network alterations in Alzheimer’s disease (AD) are related to worse cognitive impairment. The aim of this study was to quantify the alterations in gray matter associated with impaired cognition and their pathological biomarkers in AD-spectrum patients.

Methods

We extracted gray matter networks from 3D-T1 magnetic resonance imaging scans, and a graph theory analysis was used to explore alterations in the network metrics in 34 healthy controls, 70 mild cognitive impairment (MCI) patients, and 40 AD patients. Spearman correlation analysis was computed to investigate the relationships among network properties, neuropsychological performance, and cerebrospinal fluid pathological biomarkers (i.e., Aβ, t-tau, and p-tau) in these subjects.

Results

AD-spectrum individuals demonstrated higher nodal properties and edge properties associated with impaired memory function, and lower amyloid-β or higher tau levels than the controls. Furthermore, these compensations at the brain regional level in AD-spectrum patients were mainly in the medial temporal lobe; however, the compensation at the whole-brain network level gradually extended from the frontal lobe to become widely distributed throughout the cortex with the progression of AD.

Conclusion

The findings provide insight into the alterations in the gray matter network related to impaired cognition and pathological biomarkers in the progression of AD. The possibility of compensation was detected in the structural networks in AD-spectrum patients; the compensatory patterns at regional and whole-brain levels were different and the clinical significance was highlighted.
Progress in Brain Computer Interface: Challenges and Opportunities
Authors: Saha Simanto , Mamun Khondaker A. , Ahmed Khawza , Mostafa Raqibul , Naik Ganesh R. , Darvishi Sam , Khandoker Ahsan H. , Baumert Mathias
Published: February 2021

Brain computer interfaces (BCI) provide a direct communication link between the brain and a computer or other external devices. They offer an extended degree of freedom either by strengthening or by substituting human peripheral working capacity and have potential applications in various fields such as rehabilitation, affective computing, robotics, gaming, and neuroscience. Significant research efforts on a global scale have delivered common platforms for technology standardization and help tackle highly complex and non-linear brain dynamics and related feature extraction and classification challenges. Time-variant psycho-neurophysiological fluctuations and their impact on brain signals impose another challenge for BCI researchers to transform the technology from laboratory experiments to plug-and-play daily life. This review summarizes state-of-the-art progress in the BCI field over the last decades and highlights critical challenges.
Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma
Authors: Zhuang Zehang , Huang Jing , Wang Weiwang , Wang Cheng , Yu Pei , Hu Jing , Liu Haichao , Yin Hanqi , Hou Jinsong , Liu Xiqiang
Published: February 2021

Objectives

Recently long non-coding RNAs (lncRNAs) have emerged as novel gene regulators involved in tumorigenic processes, including oral squamous cell carcinoma (OSCC). Here, we identified a differentiation-related lncRNA, terminal differentiation-induced non-coding RNA (TINCR). However, its biological function and clinicopathological significance in OSCC still remain unclear.

Methods

The lncRNA expression profiles in OSCC tissues and paired adjacent non-tumor tissues (NATs) from 10 patients were detected by lncRNA microarrays. Weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) enrichment were performed to identify the most significant module and module functional annotation, respectively. Potential differentiation-related lncRNAs were screened by differential expression analysis. TINCR was further confirmed in OSCC cell lines and tissues of another patient cohort by using qRT-PCR. The correlation between the TINCR expression level and clinicopathological characteristics was analyzed. The effects of TINCR on cell differentiation, migration and invasion were assessed by knockdown or knock-in in vitro and in vivo.

Results

WGCNA and GO enrichment analysis showed that one co-expression network was significantly enriched for epithelial cell differentiation, among which, TINCR was significantly downregulated. qRT-PCR analyses validated down-regulation of TINCR in tumor tissues compared with paired NATs, and its expression was closely correlated with pathological differentiation and lymph node metastasis in patients with OSCC. Patients with lower TINCR expression levels had worse survival. Cell function experiments showed that TINCR played a crucial role in epithelial differentiation. Both TINCR and epithelial differentiation-associated genes, including IVL and KRT4, were significantly upregulated during OSCC cell calcium-induced differentiation but were reduced when cell dedifferentiation occurred in tumor spheres. Overexpression of TINCR dramatically suppressed cell dedifferentiation, migration and invasion in vitro, while knockdown of TINCR had the opposite effects. Upregulation of TINCR significantly elevated the expression of terminal differentiation genes and repressed tumor growth in vivo. Moreover, TINCR significantly suppressed the activation of JAK2/STAT3 signaling in OSCC cells.

Conclusion

Our study suggests that TINCR functions as a tumor suppressor by inducing cell differentiation through modulating JAK2/STAT3 signaling in OSCC. TINCR may serve as a prognostic biomarker and therapeutic target for OSCC.
The Prognostic Value of Circulating Soluble Programmed Death Ligand-1 in Cancers: A Meta-Analysis
Authors: Huang Pei , Hu Wei , Zhu Ying , Wu Yushen , Lin Huapeng
Published: February 2021

Background

Studies on the prognostic value of the soluble programmed death ligand 1 (sPD-L1) in cancer patients have not yielded consistent results.

Objective

This meta-analysis was performed to assess the association between sPD-L1 and the prognosis of cancer patients.

Methods

Published articles in Pubmed, EMBASE, and Cochrane clinical trial databases were searched from the inception to September 2020. Overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), and disease-free survival (DFS) data were evaluated using a hazard ratio (HR) at 95% confidence interval (95% CI).

Results

A total 31 studies involving 17 tumors and 3,780 patients were included. The overexpression of sPD-L1 was associated with shorter OS (HR 1.85, 95% CI 1.59–2.15, I2 = 33%). High sPD-L1 had worse PFS (HR 2.40, 95% CI 1.55–3.72, I2 = 83%), and worse DFS (HR 2.92, 95% CI 2.02–4.29, I2 = 40%), without significant statistical difference in RFS (HR 2.08, 95% CI 0.99–4.40, I2 = 0%).

Conclusions

High sPD-L1 levels were associated with worse survival prognosis in cancer patients. The sPD-L1 may be a potential prognostic, non-invasive, and dynamic monitoring biomarker for cancers in the future.
A Pre-Operative Prognostic Score for Patients With Advanced Hepatocellular Carcinoma Who Underwent Resection
Authors: Xiao Han , Li Jia-Li , Chen Shu-Ling , Tang Mi-Mi , Zhou Qian , Wu Ting-Fan , Li Xin , Peng Zhen-Wei , Feng Shi-Ting , Peng Sui , Kuang Ming
Published: February 2021

Background

Previous studies demonstrated a promising prognosis in advanced hepatocellular carcinoma (HCC) patients who underwent surgery, yet a consensus of which population would benefit most from surgery is still unreached.

Method

A total of 496 advanced HCC patients who initially underwent liver resection were consecutively collected. Least absolute shrinkage and selection operator (LASSO) regression was performed to select significant pre-operative factors for recurrence-free survival (RFS). A prognostic score constructed from these factors was used to divide patients into different risk groups. Survivals were compared between groups with log-rank test. The area under curves (AUC) of the time-dependent receiver operating characteristics was used to evaluate the predictive accuracy of prognostic score.

Result

For the entire cohort, the median overall survival (OS) was 23.0 months and the median RFS was 12.1 months. Patients were divided into two risk groups according to the prognostic score constructed with ALBI score, tumor size, tumor-invaded liver segments, gamma-glutamyl transpeptidase, alpha fetoprotein, and portal vein tumor thrombus stage. The median RFS of the low-risk group was significantly longer than that of the high-risk group in both the training (10.1 vs 2.9 months, P<0.001) and the validation groups (13.7 vs 4.6 months, P=0.002). The AUCs of the prognostic score in predicting survival were 0.70 to 0.71 in the training group and 0.71 to 0.72 in the validation group.

Conclusion

Surgery could provide promising survival for HCC patients at an advanced stage. Our developed pre-operative prognostic score is effective in identifying advanced-stage HCC patients with better survival benefit for surgery.
Association of Survival and Immune-Related Adverse Events With Anti-PD-1/PD-L1 and Anti-CTLA-4 Inhibitors, Alone or Their Combination for the Treatment of Cancer: A Systematic Review and Meta-Analysis of 13 Clinical Trials
Authors: Zhang Leyin , Sun Leitao , Zhou Yiwen , Yu Jieru , Lin Yingying , Wasan Harpreet S. , Shen Minhe , Ruan Shanming
Published: February 2021

Background

Cancer, with sustained high mortality, is a worldwide threat to public health. Despite the survival benefit over conventional therapies shown in immune checkpoint inhibitor (ICI), only a minority of patients benefit from single ICI. But combination therapy holds the promise of achieving better efficacy over monotherapy. We performed a systematic review and meta-analysis to assess the efficacy and safety of ICI-based combination therapy for cancer.

Methods

A search was conducted to retrieve relevant studies in electronic databases and major conferences. Two investigators independently performed data extraction, making a systematic data extraction, assembly, analysis and interpretation to compare the overall survival (OS), progression-free survival (PFS), overall response rate (ORR), all and high grade immune related adverse events (IRAEs) between combination therapy and monotherapy. Therefore, only the studies satisfying the criteria were included. Finally, we performed subgroup, sensitivity, and publication bias analysis to examine the heterogeneity and bias of resources.

Results

A total of 2,532 patients from thirteen studies were enrolled. Compared to ICI alone, combination therapy, with a high risk and high grade IRAEs for the majority of all, offers a better survival benefit (OS: HR: 0.86, 95% CI: 0.76 to 0.98; PFS: HR: 0.79, 95% CI: 0.69 to 0.90) and objective response (ORR: RR: 1.91, 95% CI: 1.40 to 2.60).

Conclusions

ICI-based combination therapy was confirmed as the optimum treatment for cancer, especially when using specific dosage and regimen to treat certain tumor types with no absolute demand for the detection of PD-L1 expression. Meanwhile, attention should also be paid on potential toxicity, especially the IRAEs.
Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer
Authors: Wei Kuo-Liang , Chou Jian-Liang , Chen Yin-Chen , Low Jie-Ting , Lin Guan-Ling , Liu Jing-Lan , Chang Te-Sheng , Chen Wei-Ming , Hsieh Yung-Yu , Yan Pearlly S. , Chuang Yu-Ming , Lin Jora M. J. , Wu Shu-Fen , Chiang Ming-Ko , Li Chin , Wu Cheng-Shyong , Chan Michael W. Y.
Published: February 2021

Purpose

The purpose of this study was to identify genes that were epigenetically silenced by STAT3 in gastric cancer.

Methods

MBDcap-Seq and expression microarray were performed to identify genes that were epigenetically silenced in AGS gastric cancer cell lines depleted of STAT3. Cell lines and animal experiments were performed to investigate proliferation and metastasis of miR-193a and YWHAZ in gastric cancer cell lines. Bisulfite pyrosequencing and tissue microarray were performed to investigate the promoter methylation of miR-193a and expression of STAT3, YWHAZ in patients with gastritis (n = 8) and gastric cancer (n = 71). Quantitative methylation-specific PCR was performed to examine miR-193a promoter methylation in cell-free DNA of serum samples in gastric cancer patients (n = 19).

Results

As compared with parental cells, depletion of STAT3 resulted in demethylation of a putative STAT3 target, miR-193a, in AGS gastric cancer cells. Although bisulfite pyrosequencing and epigenetic treatment confirmed that miR-193a was epigenetically silenced in gastric cancer cell lines, ChIP-PCR found that it may be indirectly affected by STAT3. Ectopic expression of miR-193a in AGS cells inhibited proliferation and migration of gastric cancer cells. Further expression microarray and bioinformatics analysis identified YWHAZ as one of the target of miR-193a in AGS gastric cancer cells, such that depletion of YWHAZ reduced migration in AGS cells, while its overexpression increased invasion in MKN45 cells in vitro and in vivo. Clinically, bisulfite pyrosequencing revealed that promoter methylation of miR-193a was significantly higher in human gastric cancer tissues (n = 11) as compared to gastritis (n = 8, p < 0.05). Patients infected with H. pylori showed a significantly higher miR-193a methylation than those without H. pylori infection (p < 0.05). Tissue microarray also showed a positive trend between STAT3 and YWHAZ expression in gastric cancer patients (n = 60). Patients with serum miR-193a methylation was associated with shorter overall survival than those without methylation (p < 0.05).

Conclusions

Constitutive activation of JAK/STAT signaling may confer epigenetic silencing of the STAT3 indirect target and tumor suppressor microRNA, miR-193a in gastric cancer. Transcriptional suppression of miR-193a may led to overexpression of YWHAZ resulting in tumor progression. Targeted inhibition of STAT3 may be a novel therapeutic strategy against gastric cancer.
Dynamic Changes in the Systemic Inflammation Response Index Predict the Outcome of Resectable Gastric Cancer Patients
Authors: Liu Zhenhua , Ge Haijue , Miao Zhilong , Shao Shoupeng , Shi Hongtai , Dong Congsong
Published: February 2021

The systemic inflammation response index (SIRI) has been revealed to be closely related to the prognosis of a variety of tumors. Whether the dynamic change in SIRI before and after surgery can be used to judge the prognosis of patients after radical gastrectomy has not yet been studied. In this study, the predictive ability of preoperative SIRI and changes in SIRI before and after surgery for the survival rate of gastric cancer patients was evaluated in two independent cohorts. It was found that SIRI was closely related to TNM staging. The higher the TNM stage, the higher the proportion of patients with a high SIRI. However, SIRI was not related to any other clinicopathological parameters. Kaplan-Meier survival analysis showed that a high SIRI was associated with poor prognosis in gastric cancer patients in the original cohort and in the validation cohort. SIRI, NLR, PLR, and MLR could be used to judge the prognosis of patients with operable gastric cancer. However, multivariate analysis suggested that only SIRI was an independent prognostic factor for patients with operable gastric cancer. In addition, the change in SIRI at 4 to 6 weeks after surgery compared with SIRI before surgery was closely related to the survival of gastric cancer patients. Compared with the unchanged group (absolute variation <50%), gastric cancer patients with a SIRI increase >50% had a worse OS, while patients with a SIRI decrease >50% had a better prognosis. In conclusion, SIRI can be used as a reliable index to evaluate the prognosis of patients with operable gastric cancer, and the dynamic change in SIRI before and after surgery is significantly related to the prognosis of patients with gastric cancer.
Positron Emission Tomography-Based Short-Term Efficacy Evaluation and Prediction in Patients With Non-Small Cell Lung Cancer Treated With Hypo-Fractionated Radiotherapy
Authors: Jiang Yi-Qing , Gao Qin , Chen Han , Shi Xiang-Xiang , Wu Jing-Bo , Chen Yue , Zhang Yan , Pang Hao-Wen , Lin Sheng
Published: February 2021

Background

Positron emission tomography is known to provide more accurate estimates than computed tomography when staging non–small cell lung cancer. The aims of this prospective study were to contrast the short-term efficacy of the two imaging methods while evaluating the effects of hypo-fractionated radiotherapy in non-small cell lung cancer, and to establish a short-term efficacy prediction model based on the radiomics features of positron emission tomography.

Methods

This nonrandomized-controlled trial was conducted from March 2015 to June 2019. Thirty-one lesions of 30 patients underwent the delineation of the regions of interest on positron emission tomography and computed tomography 1 month before, and 3 months after hypo-fractionated radiotherapy. Each patient was evaluated for the differences in local objective response rate between the two images. The Kaplan Meier method was used to analyze the local objective response and subsequent survival duration of the two imaging methods. The 3D Slicer was used to extract the radiomics features based on positron emission tomography. Least absolute shrinkage and selection operator regression was used to eliminate redundant features, and logistic regression analysis was used to develop the curative-effect-predicting model, which was displayed through a radiomics nomogram. Receiver operating characteristic curve and decision curve were used to evaluate the accuracy and clinical usefulness of the prediction model.

Results

Positron emission tomography-based local objective response rate was significantly higher than that based on computed tomography [70.97% (22/31) and 12.90% (4/31), respectively (p<0.001)]. The mean survival time of responders and non-responders assessed by positron emission tomography was 28.6 months vs. 11.4 months (p=0.29), whereas that assessed by computed tomography was 24.5 months vs. 26 months (p=0.66), respectively. Three radiomics features were screened to establish a personalized prediction nomogram with high area under curve (0.94, 95% CI 0.85–0.99, p<0.001). The decision curve showed a high clinical value of the radiomics nomogram.

Conclusions

We recommend positron emission tomography for evaluating the short-term efficacy of hypo-fractionated radiotherapy in non-small cell lung cancer, and that the radiomics nomogram could be an important technique for the prediction of short-term efficacy, which might enable an improved and precise treatment.

Registration number/URL

ChiCTR1900027768/http://www.chictr.org.cn/showprojen.aspx?proj=46057
Compound C, a Broad Kinase Inhibitor Alters Metabolic Fingerprinting of Extra Cellular Matrix Detached Cancer Cells
Authors: Shait Mohammed Mohammed Razeeth , Alghamdi Raed Ahmed , Alzahrani Abdulaziz Musa , Zamzami Mazin A. , Choudhry Hani , Khan Mohammad Imran
Published: February 2021

Most of the cancer related deaths are caused mainly by metastasis. Therefore, it is highly important to unfold the major mechanisms governing metastasis process in cancer. Throughout the metastatic cascade, cells need the ability to survive without attachment to neighboring cells and the original Extra Cellular Matrix (ECM). Recent reports showed that loss of ECM attachment shifts cancer cell metabolism towards glycolysis mostly through hypoxia. However, AMPK, a master metabolic regulator was also found to be upregulated under ECM detached conditions. Therefore, in this work we aimed to understand the consequences of targeting AMPK and other metabolic kinases by a broad kinase inhibitor namely Compound C in ECM detached cancer cells. Results showed that Compound C impacts glycolysis as evident by increased levels of pyruvate, but reduces its conversion to lactate thereby negatively regulating the Warburg effect. Simultaneously, Compound C induces block at multiple levels in TCA cycle as evident from accumulation of various TCA metabolites. Interestingly Compound C significantly reduces glutamine and reduced glutathione levels, suggesting loss of antioxidant potential of ECM detached cancer cells. Further, we found increased in metabolites associated with nucleotide synthesis, one carbon metabolism and PPP pathway during Compound C treatment of ECM detached cells. Finally, we also found induction in metabolites associated with DNA damage in ECM detached cancer cells during Compound C treatment, suggesting DNA damage regulatory role of metabolic kinases. Overall, our results showed that Compound C represses pyruvate to lactate conversion, reduces antioxidant potential and invokes DNA damage in ECM detached cancer cells. Our data provides a comprehensive metabolic map of ECM detached cancer cells that can be targeted with a broad kinase inhibitor, is Compound C. The data can be used for designing new combinational therapies to eradicate ECM detached cancer cells.
The Prognostic Impact of Tumor Architecture for Upper Urinary Tract Urothelial Carcinoma: A Propensity Score-Weighted Analysis
Authors: Liu Hui-Ying , Chen Yen Ta , Huang Shun-Chen , Wang Hung-Jen , Cheng Yuan-Tso , Kang Chih Hsiung , Lee Wei Ching , Su Yu-Li , Huang Chun-Chieh , Chang Yin-Lun , Chuang Yao-Chi , Luo Hao Lun , Chiang Po Hui
Published: February 2021

Purpose

To assess the association of tumor architecture with cancer recurrence, metastasis, and cancer-specific survival (CSS) in patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC) in Taiwan.

Materials and Methods

Data were collected from 857 patients treated with RNU between January 2005 and August 2016 in our hospital. Pathologic slides were reviewed by genitourinary pathologists. Propensity score weighting was performed for data analysis.

Results

Sessile growth pattern was observed in 212 patients (24.7%). Tumor architecture exhibited a significant association with bladder cancer history, chronic kidney disease (CKD), tumor stage, lymph node status, histological grade, lymphovascular invasion, concomitant carcinoma in situ, and the variant type [standardized mean difference (SMD) > 0.1 for all variables before weighting]. In the propensity score analysis, 424 papillary and sessile tumor architecture were analyzed to balance the baseline characteristics between the groups. Tumor architecture was an independent predictor of metastatic disease and CSS (p = 0.033 and p = 0.002, respectively). However, the associations of tumor architecture with bladder and contralateral recurrence were nonsignificant (p = 0.956 and p = 0.844, respectively).

Conclusions

Tumor architecture of UTUC after RNU is associated with established features of aggressive disease and predictors of metastasis and CSS. Assessment of tumor architecture may help identify patients who could benefit from close follow-up or early administration of systemic therapy after RNU. Tumor architecture should be included in UTUC staging after further confirmation.