bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered Brain Activity in Depression of Parkinson’s Disease: A Meta-Analysis and Validation Study
Authors: Su Dongning , Cui Yusha , Liu Zhu , Chen Huimin , Fang Jinping , Ma Huizi , Zhou Junhong , Feng Tao
Published: March 2022

Background

The pathophysiology of depression in Parkinson’s disease (PD) is not fully understood. Studies based upon functional MRI (fMRI) showed the alterations in the blood-oxygen-level-dependent (BOLD) fluctuations in multiple brain regions pertaining to depression in PD. However, large variance was observed across previous studies. Therefore, we conducted a meta-analysis to quantitatively evaluate the results in previous publications and completed an independent regions-of-interests (ROIs)-based analysis using our own data to validate the results of the meta-analysis.

Methods

We searched PubMed, Embase, and Web of Science to identify fMRI studies in PD patients with depression. Using signed differential mapping (SDM) method, we performed a voxel-based meta-analysis. Then, a validation study by using multiscale entropy (MSE) in 28 PD patients with depression and 25 PD patients without depression was conducted. The fMRI scan was completed in anti-depression-medication-off state. The ROIs of the MSE analysis were the regions identified by the meta-analysis.

Results

A total of 126 PD patients with depression and 153 PD patients without depression were included in meta-analysis. It was observed that the resting-state activities within the posterior cingulate gyrus, supplementary motor area (SMA), and cerebellum were altered in depressed patients. Then, in the validation study, these regions were used as ROIs. PD patients with depression had significantly lower MSE of the BOLD fluctuations in these regions (posterior cingulate gyrus: F = 0.856, p = 0.049; SMA: F = 0.914, p = 0.039; cerebellum: F = 0.227, p = 0.043).

Conclusion

Our study revealed that the altered BOLD activity in cingulate, SMA, and cerebellum of the brain were pertaining to depression in PD.
The Impact of Exercise and Virtual Reality Executive Function Training on Cognition Among Heavy Drinking Veterans With Traumatic Brain Injury: A Pilot Feasibility Study
Authors: Pennington David L. , Reavis Jill V. , Cano Monique T. , Walker Erica , Batki Steven L.
Published: March 2022

Executive function (EF) underlies self-control deficits in alcohol use disorder (AUD) and traumatic brain injury (TBI). Cognitive training is a promising adjunctive treatment targeting TBI- and AUD- related cognitive dysfunction. However, major limitations related to compliance and generalizability in the field of cognitive training exist. Physical activity is associated with enhanced cognitive performance across several executive functions and may enhance the benefits of cognitive training. Virtual reality provides multisensory embodied experiences which are likely to engage brain networks more efficiently than standard cognitive training systems, ultimately resulting in greater near- and far-transfer effects. This pilot study aimed to obtain feasibility data and a preliminary assessment of an enriched virtual reality (VR) EF training (EFT) intervention combined with exercise (NCT03786276). Using an 8-week randomized adaptive design study, 30 AUD treatment seeking U.S. Veterans completed nine sessions of exercise-only (n = 15) or gameplay control (n = 15) over 3 weeks, followed by a week-4 repeat assessment in Phase 1. Twenty-three participants completed and moved onto Phase II, where they completed up to nine sessions of VR-EFT plus exercise and completed a week-8 end-of-study assessment. Primary outcomes included feasibility to retain participants, usability, and satisfaction of using VR-EFT. Secondary and exploratory outcomes included within group assessment of change in cognitive function, alcohol use, alcohol craving, and post-concussive symptoms among the three treatment conditions.VR-EFT was feasible with moderate usability and high acceptability ratings.The most common VR-related adverse effect was motion sickness (n = 2/16, 12.5%). The VR-EFT condition was associated with significant improvement in inhibition-switching and visual scanning (both p < 0.05) during Phase II. Exercise-only was associated with significant improvements in cognitive inhibition, cognitive flexibility, reductions in alcohol craving, and number of standard alcohol drinks per week (all p ≤ 0.05). The gaming-control condition was associated with improvement in cognitive flexibility and visuospatial immediate recall (both p < 0.05) during Phase 1. Recruitment and retention of U.S. veterans with AUD and TBI into an exercise plus VR-EFT intervention is feasible, but technological barriers may impact usability. VR-EFT was associated with improvement in executive function domains that were targeted in as little as 3-week and nine sessions of VR-EFT exposure. Results are promising and indicate the need for a larger controlled investigation to assess the efficacy of VR-EFT to enhance treatment outcomes among AUD treatment-seeking U.S. veterans with co-occurring AUD and TBI.

Clinical Trial Registration

www.ClinicalTrials.gov, Identifier: NCT03786276.
Local Neuronal Responses to Intracortical Microstimulation in Rats' Barrel Cortex Are Dependent on Behavioral Context
Authors: Butovas Sergejus , Schwarz Cornelius
Published: March 2022

The goal of cortical neuroprosthetics is to imprint sensory information as precisely as possible directly into cortical networks. Sensory processing, however, is dependent on the behavioral context. Therefore, a specific behavioral context may alter stimulation effects and, thus, perception. In this study, we reported how passive vs. active touch, i.e., the presence or absence of whisker movements, affects local field potential (LFP) responses to microstimulation in the barrel cortex in head-fixed behaving rats trained to move their whiskers voluntarily. The LFP responses to single-current pulses consisted of a short negative deflection corresponding to a volley of spike activity followed by a positive deflection lasting ~100 ms, corresponding to long-lasting suppression of spikes. Active touch had a characteristic effect on this response pattern. While the first phase including the negative peak remained stable, the later parts consisting of the positive peak were considerably suppressed. The stable phase varied systematically with the distance of the electrode from the stimulation site, pointing to saturation of neuronal responses to electrical stimulation in an intensity-dependent way. Our results suggest that modulatory effects known from normal sensory processing affect the response to cortical microstimulation as well. The network response to microstimulation is highly amenable to the behavioral state and must be considered for future approaches to imprint sensory signals into cortical circuits with neuroprostheses.
A Noninvasive BCI System for 2D Cursor Control Using a Spectral-Temporal Long Short-Term Memory Network
Authors: Pan Kang , Li Li , Zhang Lei , Li Simeng , Yang Zhuokun , Guo Yuzhu
Published: March 2022

Two-dimensional cursor control is an important and challenging problem in the field of electroencephalography (EEG)-based brain computer interfaces (BCIs) applications. However, most BCIs based on categorical outputs are incapable of generating accurate and smooth control trajectories. In this article, a novel EEG decoding framework based on a spectral-temporal long short-term memory (stLSTM) network is proposed to generate control signals in the horizontal and vertical directions for accurate cursor control. Precisely, the spectral information is used to decode the subject's motor imagery intention, and the error-related P300 information is used to detect a deviation in the movement trajectory. The concatenated spectral and temporal features are fed into the stLSTM network and mapped to the velocities in vertical and horizontal directions of the 2D cursor under the velocity-constrained (VC) strategy, which enables the decoding network to fit the velocity in the imaginary direction and simultaneously suppress the velocity in the non-imaginary direction. This proposed framework was validated on a public real BCI control dataset. Results show that compared with the state-of-the-art method, the RMSE of the proposed method in the non-imaginary directions on the testing sets of 2D control tasks is reduced by an average of 63.45%. Besides, the visualization of the actual trajectories distribution of the cursor also demonstrates that the decoupling of velocity is capable of yielding accurate cursor control in complex path tracking tasks and significantly improves the control accuracy.
Are Smartwatches a Suitable Tool to Monitor Noise Exposure for Public Health Awareness and Otoprotection?
Authors: Fischer Tim , Schraivogel Stephan , Caversaccio Marco , Wimmer Wilhelm
Published: March 2022

Introduction and Objectives

Noise-induced hearing loss (NIHL) and tinnitus are common problems that can be prevented with hearing protection measures. Sound level meters and noise dosimeters enable to monitor and identify health-threatening occupational or recreational noise, but are limited in their daily application because they are usually difficult to operate, bulky, and expensive. Smartwatches, which are becoming increasingly available and popular, could be a valuable alternative to professional systems. Therefore, the aim of this study was to evaluate the applicability of smartwatches for accurate environmental noise monitoring.

Methods

The A-weighted equivalent continuous sound pressure level (LAeq) was recorded and compared between a professional sound level meter and a popular smartwatch. Noise exposure was assessed in 13 occupational and recreational settings, covering a large range of sound pressure levels between 35 and 110 dBA. To assess measurement agreement, a Bland-Altman plot, linear regression, the intra-class correlation coefficient, and descriptive statistics were used.

Results

Overall, the smartwatch underestimated the sound level meter measurements by 0.5 dBA (95% confidence interval [0.2, 0.8]). The intra-class correlation coefficient showed excellent agreement between the two devices (ICC = 0.99), ranging from 0.65 (music club) to 0.99 (concert) across settings. The smartwatch's sampling rate decreased significantly with lower sound pressure levels, which could have introduced measurement inaccuracies in dynamic acoustic environments.

Conclusions

The assessment of ambient noise with the tested smartwatch is sufficiently accurate and reliable to improve awareness of hazardous noise levels in the personal environment and to conduct exploratory clinical research. For professional and legally binding measurements, we recommend specialized sound level meters or noise dosimeters. In the future, smartwatches will play an important role in monitoring personal noise exposure and will provide a widely available and cost-effective measure for otoprotection.
Distinguishing the Roles of the Dorsomedial Prefrontal Cortex and Right Temporoparietal Junction in Altruism in Situations of Inequality: A Transcranial Direct Current Stimulation Study
Authors: Zhang Hanqi , Dong Zhiqiang , Cai Shenggang , Zhao Jun
Published: March 2022

The right temporoparietal junction (rTPJ) and dorsomedial prefrontal cortex (dmPFC), which are involved in social cognition, have been proposed to play key roles in guiding human altruistic behavior. However, no study has provided empirical evidence that the rTPJ and dmPFC play distinct roles in altruism under situations of inequality. A total of 107 healthy young adults were randomly assigned to receive anodal or sham transcranial direct current stimulation (tDCS) to either the dmPFC or rTPJ, and they participated in a modified dictator game. The stimulation of the dmPFC increased the level of altruistic behavior, while the stimulation of the rTPJ did not. Furthermore, we determined that the increase in altruism induced by tDCS of the dmPFC could be modulated by perspective taking. These results demonstrate that the dmPFC and rTPJ play distinct roles in the enhancement of altruism in situations of inequality; this finding is consistent with theories proposing that the dmPFC has evolved mechanisms dedicated to perspective taking.
BOLD Monitoring in the Neural Simulator ANNarchy
Authors: Maith Oliver , Dinkelbach Helge Ülo , Baladron Javier , Vitay Julien , Hamker Fred H.
Published: March 2022

Multi-scale network models that simultaneously simulate different measurable signals at different spatial and temporal scales, such as membrane potentials of single neurons, population firing rates, local field potentials, and blood-oxygen-level-dependent (BOLD) signals, are becoming increasingly popular in computational neuroscience. The transformation of the underlying simulated neuronal activity of these models to simulated non-invasive measurements, such as BOLD signals, is particularly relevant. The present work describes the implementation of a BOLD monitor within the neural simulator ANNarchy to allow an on-line computation of simulated BOLD signals from neural network models. An active research topic regarding the simulation of BOLD signals is the coupling of neural processes to cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2). The flexibility of ANNarchy allows users to define this coupling with a high degree of freedom and thus, not only allows to relate mesoscopic network models of populations of spiking neurons to experimental BOLD data, but also to investigate different hypotheses regarding the coupling between neural processes, CBF and CMRO2 with these models. In this study, we demonstrate how simulated BOLD signals can be obtained from a network model consisting of multiple spiking neuron populations. We first demonstrate the use of the Balloon model, the predominant model for simulating BOLD signals, as well as the possibility of using novel user-defined models, such as a variant of the Balloon model with separately driven CBF and CMRO2 signals. We emphasize how different hypotheses about the coupling between neural processes, CBF and CMRO2 can be implemented and how these different couplings affect the simulated BOLD signals. With the BOLD monitor presented here, ANNarchy provides a tool for modelers who want to relate their network models to experimental MRI data and for scientists who want to extend their studies of the coupling between neural processes and the BOLD signal by using modeling approaches. This facilitates the investigation and model-based analysis of experimental BOLD data and thus improves multi-scale understanding of neural processes in humans.
Cell Type-Specific Transcriptional Control of Gsk3β in the Developing Mammalian Neocortex
Authors: Nomura Tadashi , Gotoh Hitoshi , Kiyonari Hiroshi , Ono Katsuhiko
Published: March 2022

Temporal control of neurogenesis is central for the development and evolution of species-specific brain architectures. The balance between progenitor expansion and neuronal differentiation is tightly coordinated by cell-intrinsic and cell-extrinsic cues. Wnt signaling plays pivotal roles in the proliferation and differentiation of neural progenitors in a temporal manner. However, regulatory mechanisms that adjust intracellular signaling amplitudes according to cell fate progression remain to be elucidated. Here, we report the transcriptional controls of Gsk3β, a critical regulator of Wnt signaling, in the developing mouse neocortex. Gsk3β expression was higher in ventricular neural progenitors, while it gradually declined in differentiated neurons. We identified active cis-regulatory module (CRM) of Gsk3β that responded to cell type-specific transcription factors, such as Sox2, Sox9, and Neurogenin2. Furthermore, we found extensive conservation of the CRM among mammals but not in non-mammalian amniotes. Our data suggest that a mammalian-specific CRM drives the cell type-specific activity of Gsk3β to fine tune Wnt signaling, which contributes to the tight control of neurogenesis during neocortical development.
Human Galectin-7 Gene LGALS7 Promoter Sequence Polymorphisms and Risk of Spontaneous Intracerebral Hemorrhage: A Prospective Study
Authors: Wang Ming-Dong , Tian Jing , Zhang John H. , Zhao Shun-Ying , Song Ming-Jing , Wang Zhan-Xiang
Published: March 2022

Background and purpose

Despite evidence for the role of genetic factors in stroke, only a small proportion of strokes have been clearly attributed to monogenic factors, due to phenotypic heterogeneity. The goal of this study was to determine whether a significant relationship exists between human galectin-7 gene LGALS7 promoter region polymorphisms and the risk of stroke due to non-traumatic intracerebral hemorrhage (ICH).

Methods

This two-stage genetic association study included an initial exploratory stage followed by a discovery stage. During the exploratory stage, transgenic galectin-7 mice or transgenic mice with the scrambled sequence of the hairpin structure –silenced down gene LGALS7—were generated and then expressed differentially expressed proteins and galectin-7-interacting proteins were identified through proteomic analysis. During the discovery stage, a single-nucleotide polymorphism (SNP) genotyping approach was used to determine associations between 2 LGALS7 SNPs and ICH stroke risk for a cohort of 24 patients with stroke of the Chinese Han population and 70 controls.

Results

During the exploratory phase, LGALS7 expression was found to be decreased in TGLGALS–DOWN mice as compared to its expression in TGLGALS mice. During the discovery phase, analysis of LGALS7 sequences of 24 non-traumatic ICH cases and 70 controls led to the identification of 2 ICH susceptibility loci: a genomic region on 19q13.2 containing two LGALS7 SNPs, rs567785577 and rs138945880, whereby the A allele of rs567785577 and the T allele of rs138945880 were associated with greater risk of contracting ICH [for T and A vs. C and G, unadjusted odds ratio (OR) = 13.5; 95% CI = 2.249–146.5; p = 0.002]. This is the first study to genotype the galectin-7 promoter in patients with hemorrhagic stroke. Genotype and allele association tests and preliminary analysis of patients with stroke revealed that a single locus may be a genetic risk factor for hemorrhagic stroke.

Conclusion

A and T alleles of two novel SNP loci of 19q13.2, rs567785577 and rs138945880, respectively, were evaluated for associations with susceptibility to ICH. Further studies with expanded case numbers that include subjects of other ethnic populations are needed to elucidate mechanisms underlying associations between these SNPs and ICH risk.
The Acute Effects of Furosemide on Na-K-Cl Cotransporter-1, Fetuin-A and Pigment Epithelium-Derived Factor in the Guinea Pig Cochlea
Authors: Edvardsson Rasmussen Jesper , Lundström Patrik , Eriksson Per Olof , Rask-Andersen Helge , Liu Wei , Laurell Göran
Published: March 2022

Background

Furosemide is a loop diuretic used to treat edema; however, it also targets the Na-K-Cl cotransporter-1 (NKCC1) in the inner ear. In very high doses, furosemide abolishes the endocochlear potential (EP). The aim of the study was to gain a deeper understanding of the temporal course of the acute effects of furosemide in the inner ear, including the protein localization of Fetuin-A and PEDF in guinea pig cochleae.

Material and Method

Adult guinea pigs were given an intravenous injection of furosemide in a dose of 100 mg per kg of body weight. The cochleae were studied using immunohistochemistry in controls and at four intervals: 3 min, 30 min, 60 min and 120 min. Also, cochleae of untreated guinea pigs were tested for Fetuin-A and PEDF mRNA using RNAscope® technology.

Results

At 3 min, NKCC1 staining was abolished in the type II fibrocytes in the spiral ligament, followed by a recovery period of up to 120 min. In the stria vascularis, the lowest staining intensity of NKCC1 presented after 30 min. The spiral ganglion showed a stable staining intensity for the full 120 min. Fetuin-A protein and mRNA were detected in the spiral ganglion type I neurons, inner and outer hair cells, pillar cells, Deiters cells and the stria vascularis. Furosemide induced an increased staining intensity of Fetuin-A at 120 min. PEDF protein and mRNA were found in the spiral ganglia type I neurons, the stria vascularis, and in type I and type II fibrocytes of the spiral ligament. PEDF protein staining intensity was high in the pillar cells in the organ of Corti. Furosemide induced an increased staining intensity of PEDF in type I neurons and pillar cells after 120 min.

Conclusion

The results indicate rapid furosemide-induced changes of NKCC1 in the type II fibrocytes. This could be part of the mechanism that causes reduction of the EP within minutes after high dose furosemide injection. Fetuin-A and PEDF are present in many cells of the cochlea and probably increase after furosemide exposure, possibly as an otoprotective response.
Effect of Dietary Modification on Gastric Mucosa, Gastrointestinal Symptoms and Nutritional Status of Patients With Early Gastric Cancer After Endoscopic Submucosal Dissection Surgery: A Retrospective Cohort Study
Authors: Zhang Yebing , Liu Chengxia , Ma Xingbin , Xu Lei , Wang Xiuhua , Wang Xin , Cao Jingrun , Ma Aiguo , Gao Tao
Published: March 2022

Food is an important factor affecting the treatment of patients with early gastric cancer (EGC). We have established a hospital cohort to guide dietary patterns and observe the health status of patients with EGC after endoscopic submucosal dissection (ESD) after dietary modification. A total of 273 patients with EGC who underwent ESD were recruited to the cohort. They were given dietary instruction and education through a dietary manual and were followed up for 12 months. If the dietary pattern changed to the “traditional food” pattern (high consumption of vegetables, wheat products, and red meat) after the nutritional guidance, subjects were defined as the improvement diet group. Dietary patterns focused on “alcohol and fish” (drink a lot of wine and beer and eating freshwater and marine fish) or “coarse cereals” (mainly whole grains, beans and poultry) were the main ones in the unimproved diet group. The nutritional status, gastric mucosa, and gastrointestinal symptoms of the two groups of patients before and after the dietary instruction were compared. Compared with the unimproved diet group, the endoscopic performance score and the symptom score in the improved diet group were decreased by an average of 1.31 and 1.90, respectively. Except for lymphocyte count (P = 0.227), total protein (P < 0.000), albumin (P = 0.003), globulin (P = 0.014), red blood cell count (P < 0.000), and hemoglobin (P < 0.000) values were improved to varying degrees. After changing the diet, the intake of wheat products and vegetables in the improved diet group increased by 15.58 and 17.52%, respectively, while the intake of alcohol, fish, and pickled products was reduced by 43.36, 36.43, and 31.41%, respectively. After 1 year of dietary adjustment, the nutritional status, gastric mucosa, and gastrointestinal symptoms of patients with EGC after ESD eating the "traditional food" diet were all improved.
A Dietitian-Led Vegan Program May Improve GlycA, and Other Novel and Traditional Cardiometabolic Risk Factors in Patients With Dyslipidemia: A Pilot Study
Authors: Chiu Tina H. T. , Kao Yun-Chun , Wang Ling-Yi , Chang Huai-Ren , Lin Chin-Lon
Published: March 2022

Background

Systematic inflammation and lipid profiles are two major therapeutic targets for cardiovascular diseases. The effect of a nutritionally balanced vegan diet on systematic inflammation and lipoprotein subclass awaits further examination.

Objective

To investigate the change in novel and traditional cardiometabolic risk factors before and after a dietitian-led vegan program, and to test the bioavailability of vitamin B12 in Taiwanese purple laver as part of a vegan diet.

Design

A one-arm pilot intervention study.

Participants/Setting

Nine patients with dyslipidemia participated in this 12-week vegan program.

Main Outcome Measures

Nuclear Magnetic Resonance (NMR) detected GlycA signals (systematic inflammation) and lipoprotein subclass (atherogenicity); trimethylamine N-oxide (TMAO); and other cardiometabolic risk factors.

Statistical Analyses Performed

Wilcoxon signed-rank test.

Results

In this 12-week vegan intervention emphasizing whole foods, systematic inflammation improved as indicated by a reduction in GlycA (median: −23 μmol/L, p = 0.01). LDL-c (low-density lipoprotein cholesterol) (median −24 mg/dl, p = 0.04) and LDL-p (low-density lipoprotein particles) (median −75 nmol/L, p = 0.02) both decreased significantly. VLDL (very-low-density lipoprotein) and chylomicron particles showed a decreasing trend (−23.6 nmol/L, p = 0.05). Without caloric restriction, body mass index (BMI) (−0.7 kg/m2, p = 0.03), waist circumferences (−2.0 cm, p < 0.001), HbA1c (−0.2%, p = 0.02), and (HOMA-IR) homeostatic model assessment for insulin resistance (−0.7, p = 0.04) have all improved. The change in the TMAO and vitamin B12 status as measured by holo-transcobalamin appeared to depend on baseline diets, TMAO, and vitamin B12 status.

Conclusions

A dietitian-led vegan program may improve systematic inflammation and other novel and traditional cardiometabolic risk factors in high-risk individuals.
Impact of Dietary Palmitic Acid on Lipid Metabolism
Authors: Murru Elisabetta , Manca Claudia , Carta Gianfranca , Banni Sebastiano
Published: March 2022

Palmitic acid (PA) is ubiquitously present in dietary fat guaranteeing an average intake of about 20 g/d. The relative high requirement and relative content in the human body, which accounts for 20–30% of total fatty acids (FAs), is justified by its relevant nutritional role. In particular physiological conditions, such as in the fetal stage or in the developing brain, the respectively inefficient placental and brain blood–barrier transfer of PA strongly induces its endogenous biosynthesis from glucose via de novo lipogenesis (DNL) to secure a tight homeostatic control of PA tissue concentration required to exert its multiple physiological activities. However, pathophysiological conditions (insulin resistance) are characterized by a sustained DNL in the liver and aimed at preventing the excess accumulation of glucose, which result in increased tissue content of PA and disrupted homeostatic control of its tissue concentration. This leads to an overaccumulation of tissue PA, which results in dyslipidemia, increased ectopic fat accumulation, and inflammatory tone via toll-like receptor 4. Any change in dietary saturated FAs (SFAs) usually reflects a complementary change in polyunsaturated FA (PUFA) intake. Since PUFA particularly n-3 highly PUFA, suppress lipogenic gene expression, their reduction in intake rather than excess of dietary SFA may promote endogenous PA production via DNL. Thereby, the increase in tissue PA and its deleterious consequences from dysregulated DNL can be mistakenly attributed to dietary intake of PA.
Effect of Purple Corn Anthocyanin on Antioxidant Activity, Volatile Compound and Sensory Property in Milk During Storage and Light Prevention
Authors: Tian Xing-Zhou , Wang Xu , Ban Chao , Luo Qing-Yuan , Li Jia-Xuan , Lu Qi
Published: March 2022

The aim of this study was to observe the effect of purple corn anthocyanin on the light-induced antioxidant activity, free radicals, volatile compounds, color parameters, and sensory properties of milk during storage. There were four groups: (1) negative control, no addition of anthocyanins + exposure to fluorescent light (NC); (2) positive control 1, no addition of anthocyanins + protected from fluorescent light (PC1); (3) positive control 2, the addition of 0.3% (w/v) anthocyanins + exposure to fluorescent light (PC2); and (4) the addition of 0.3% anthocyanins + protected from fluorescent light (AC). The results indicated that the concentration of antioxidant activity parameters in the NC group decreased during the entire storage period, whereas antioxidant activity parameters were unchanged except for the glutathione peroxidase (GSH-Px) in the AC group. Moreover, the NC group showed lower levels of 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity and higher levels of superoxide anion and hydrogen peroxide than the other groups after 1 d of storage period. The extent of malondialdehyde accumulation and lipid peroxidation in the control groups were greater than that of the AC group. Twenty-two volatile compounds were determined in milk, which consisted of eight alcohols, three ketones, five aldehydes, two esters, and four hydrocarbons by headspace gas chromatography mass spectrometer analysis. Specifically, individual aldehydes, esters and hydrocarbons in the AC group remained at relatively stable values during storage relative to the other three groups. Stronger positive correlations were detected between several antioxidant activities (superoxide dismutase, GSH-Px) and DPPH scavenging activity as well as total ketones in milk. Adding of anthocyanin did not impact on the color values of L*, a* and b* in light-protected milk during the entire storage period. Some sensory evaluation parameters (flat, garlic/onion/weedy, oxidized-light, oxidized-metal, rancid) in AC group were significantly higher than that of the control group at the end of the period. In conclusion, the current study revealed that the addition of purple corn anthocyanin pigment to light-protected milk had the potential to prevent lipid oxidation, enhance antioxidant activity, maintain volatile compounds and increase the sensory scores.
Case Report: Neuromyelitis Optica After Treatment of Uveal Melanoma With Nivolumab and Ipilimumab
Authors: Khimani Karima , Patel Sapna P. , Whyte Andrew , Al-Zubidi Nagham
Published: March 2022

The development of immune checkpoint inhibitors (ICIs) has greatly improved survival of patients with advanced malignancies. ICIs can cause immune-related adverse effects (irAEs) involving any organ. Neurological irAEs are infrequent and have mostly been reported in patients with melanoma. We describe the case of a 57-year-old male with right eye uveal melanoma, gene expression profile (class 2), and PRAME (preferentially expressed antigen in melanoma) positivity, who received plaque brachytherapy with Iodine-125 for 4 days with subsequent adjuvant ICIs (immune checkpoint inhibitors), nivolumab and ipilimumab. 18 weeks after discontinuation of immunotherapy, the patient presented with acute onset of left-sided headaches, pain with eye movements, and vision loss. The patient was tested positive for serum anti-aquaporin-4 antibody (AQP4-Ab) and was diagnosed with neuromyelitis optica spectrum disorder (NMOSD). Subsequently, he was treated with 5 days of intravenous methylprednisolone followed by an oral prednisone taper over 10 weeks, with improvement in symptoms. We report a unique case of neuromyelitis optica spectrum disorder (NMOSD) following treatment with ICIs. To our best knowledge, this is the third reported case in English literature of NMOSD following ICI therapy and the first reported case of NMOSD caused by ICI treatment in uveal melanoma.
Exome and Tissue-Associated Microbiota as Predictive Markers of Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer
Authors: Takenaka Isabella Kuniko T. M. , Bartelli Thais F. , Defelicibus Alexandre , Sendoya Juan M. , Golubicki Mariano , Robbio Juan , Serpa Marianna S. , Branco Gabriela P. , Santos Luana B. C. , Claro Laura C. L. , dos Santos Gabriel Oliveira , Kupper Bruna E. C. , da Silva Israel T. , Llera Andrea S. , de Mello Celso A. L. , Riechelmann Rachel P. , Dias-Neto Emmanuel , Iseas Soledad , Aguiar Samuel , Nunes Diana Noronha
Published: March 2022

The clinical and pathological responses to multimodal neoadjuvant therapy in locally advanced rectal cancers (LARCs) remain unpredictable, and robust biomarkers are still lacking. Recent studies have shown that tumors present somatic molecular alterations related to better treatment response, and it is also clear that tumor-associated bacteria are modulators of chemotherapy and immunotherapy efficacy, therefore having implications for long-term survivorship and a good potential as the biomarkers of outcome. Here, we performed whole exome sequencing and 16S ribosomal RNA (rRNA) amplicon sequencing from 44 pre-treatment LARC biopsies from Argentinian and Brazilian patients, treated with neoadjuvant chemoradiotherapy or total neoadjuvant treatment, searching for predictive biomarkers of response (responders, n = 17; non-responders, n = 27). In general, the somatic landscape of LARC was not capable to predict a response; however, a significant enrichment in mutational signature SBS5 was observed in non-responders (p = 0.0021), as well as the co-occurrence of APC and FAT4 mutations (p < 0.05). Microbiota studies revealed a similar alpha and beta diversity of bacteria between response groups. Yet, the linear discriminant analysis (LDA) of effect size indicated an enrichment of Hungatella, Flavonifractor, and Methanosphaera (LDA score ≥3) in the pre-treatment biopsies of responders, while non-responders had a higher abundance of Enhydrobacter, Paraprevotella (LDA score ≥3) and Finegoldia (LDA score ≥4). Altogether, the evaluation of these biomarkers in pre-treatment biopsies could eventually predict a neoadjuvant treatment response, while in post-treatment samples, it could help in guiding non-operative treatment strategies.
Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors Using Dried Blood Microsamples
Authors: Verougstraete Nick , Stove Veronique , Verstraete Alain G. , Stove Christophe P.
Published: March 2022

Therapeutic drug monitoring (TDM) of tyrosine kinase inhibitors (TKIs) is not yet performed routinely in the standard care of oncology patients, although it offers a high potential to improve treatment outcome and minimize toxicity. TKIs are perfect candidates for TDM as they show a relatively small therapeutic window, a wide inter-patient variability in pharmacokinetics and a correlation between drug concentration and effect. Moreover, most of the available TKIs are susceptible to various drug-drug interactions and medication adherence can be checked by performing TDM. Plasma, obtainedviatraditional venous blood sampling, is the standard matrix for TDM of TKIs. However, the use of plasma poses some challenges related to sampling and stability. The use of dried blood microsamples can overcome these limitations. Collection of samplesviafinger-prick is minimally invasive and considered convenient and simple, enabling sampling by the patients themselves in their home-setting. The collection of small sample volumes is especially relevant for use in pediatric populations or in pharmacokinetic studies. Additionally, working with dried matrices improves compound stability, resulting in convenient and cost-effective transport and storage of the samples. In this review we focus on the different dried blood microsample-based methods that were used for the quantification of TKIs. Despite the many advantages associated with dried blood microsampling, quantitative analyses are also associated with some specific difficulties. Different methodological aspects of microsampling-based methods are discussed and applied to TDM of TKIs. We focus on sample preparation, analytics, internal standards, dilution of samples, external quality controls, dried blood spot specific validation parameters, stability and blood-to-plasma conversion methods. The various impacts of deviating hematocrit values on quantitative results are discussed in a separate section as this is a key issue and undoubtedly the most widely discussed issue in the analysis of dried blood microsamples. Lastly, the applicability and feasibility of performing TDM using microsamples in a real-life home-sampling context is discussed.
Regulation of Intrinsic Functions of PD-L1 by Post-Translational Modification in Tumors
Authors: Nihira Naoe Taira , Miki Yoshio
Published: March 2022

Tumor cells are eliminated by the immune system, including T lymphocytes and natural killer cells; however, many types of tumor cells acquire the immune tolerance by inhibiting T-cell activation and functions via immune checkpoint molecules. Immunotherapy targeting immune checkpoint molecules such as Programmed death receptor 1 (PD-1)/Programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) have shown successful outcomes for multiple cancer treatments, however some patients show the lack of durable responses. Thus, discovering the chemical compounds or drugs manipulating the expression or function of immune checkpoint molecules are anticipated to overcome the drug resistance of immune checkpoint inhibitors. Function of inhibitory immune checkpoint molecules is often dysregulated by the transcriptional and post-translational levels in tumors. Here, this review focuses on the post-translational modification of intrinsic PD-L1 functions and regulators for PD-L1 transcription.
Transmembrane Protein-Based Risk Model and H3K4me3 Modification Characteristics in Lung Adenocarcinoma
Authors: Fan Tao , Liu Yu , Liu Hengchang , Wang Liyu , Tian He , Zheng Yujia , Zheng Bo , Xue Liyan , Li Chunxiang , He Jie
Published: March 2022

The role and mechanism of transmembrane proteins (TMEMs) in tumorigenesis remain unclear. Based on 4 independent cohorts containing 1,208 cases, we identified 3 TMEMs (TMEM273, TMEM164, and TMEM125), which were used to construct a risk model to predict the prognosis of LUAD. The two patterns based on the risk score exhibited a high degree of consistency with the characteristics of immune cell infiltration and epigenetic distribution. Patients with a low-risk score, characterized by an increased activation of immunity, H3K4me3 modification, tumor cell apoptosis, chemokine secretion, and TMB, had better disease-free survival (DFS) and overall survival (OS). Obvious immunosuppression, increased epithelial–mesenchymal transition, a low H3K4me3 level, shortened cell cycle, and accelerated cell division manifested in high-risk patients, with poorer DFS and OS. The model showed a better prognostic value than the tumor immune dysfunction and exclusion score. Correlation analysis told us that patients with high scores were suitable for treatment with CD276 inhibitors for their higher levels of CD276 expression. The risk score had a strong negative correlation with HAVCR2 and ICOS among patients with EGFR-WT, KRAS-WT, STK11-WT, or TP53-MUT, and patients with these mutation types with low scores were suitable for treatment with HAVCR2 or ICOS inhibitors. This work comprehensively analyzed the role and mechanism of TMEMs in LUAD and revealed the characteristics of histone methylation modification. The TMEM-based signature gave us deep insight into immune cell infiltration profiles and provided an individualized immunotherapy strategy.
Preoperative Prediction of Microvascular Invasion Risk Grades in Hepatocellular Carcinoma Based on Tumor and Peritumor Dual-Region Radiomics Signatures
Authors: Hu Fang , Zhang Yuhan , Li Man , Liu Chen , Zhang Handan , Li Xiaoming , Liu Sanyuan , Hu Xiaofei , Wang Jian
Published: March 2022

Objective

To predict preoperative microvascular invasion (MVI) risk grade by analyzing the radiomics signatures of tumors and peritumors on enhanced magnetic resonance imaging (MRI) images of hepatocellular carcinoma (HCC).

Methods

A total of 501 HCC patients (training cohort n = 402, testing cohort n = 99) who underwent preoperative Gd-EOB-DTPA-enhanced MRI and curative liver resection within a month were studied retrospectively. Radiomics signatures were selected using the least absolute shrinkage and selection operator (Lasso) algorithm. Unimodal radiomics models based on tumors and peritumors (10mm or 20mm) were established using the Logistic algorithm, using plain T1WI, arterial phase (AP), portal venous phase (PVP), and hepatobiliary phase (HBP) images. Multimodal radiomics models based on different regions of interest (ROIs) were established using a combinatorial modeling approach. Moreover, we merged radiomics signatures and clinico-radiological features to build unimodal and multimodal clinical radiomics models.

Results

In the testing cohort, the AUC of the dual-region (tumor & peritumor 20 mm)radiomics model and single-region (tumor) radiomics model were 0.741 vs 0.694, 0.733 vs 0.725, 0.667 vs 0.710, and 0.559 vs 0.677, respectively, according to AP, PVP, T1WI, and HBP images. The AUC of the final clinical radiomics model based on tumor and peritumoral 20mm incorporating radiomics features in AP&PVP&T1WI images for predicting MVI classification in the training and testing cohorts were 0.962 and 0.852, respectively.

Conclusion

The radiomics signatures of the dual regions for tumor and peritumor on AP and PVP images are of significance to predict MVI.
Current Status and Future Directions of Neuromonitoring With Emerging Technologies in Neonatal Care
Authors: Variane Gabriel Fernando Todeschi , Camargo João Paulo Vasques , Rodrigues Daniela Pereira , Magalhães Maurício , Mimica Marcelo Jenné
Published: March 2022

Neonatology has experienced a significant reduction in mortality rates of the preterm population and critically ill infants over the last few decades. Now, the emphasis is directed toward improving long-term neurodevelopmental outcomes and quality of life. Brain-focused care has emerged as a necessity. The creation of neonatal neurocritical care units, or Neuro-NICUs, provides strategies to reduce brain injury using standardized clinical protocols, methodologies, and provider education and training. Bedside neuromonitoring has dramatically improved our ability to provide assessment of newborns at high risk. Non-invasive tools, such as continuous electroencephalography (cEEG), amplitude-integrated electroencephalography (aEEG), and near-infrared spectroscopy (NIRS), allow screening for seizures and continuous evaluation of brain function and cerebral oxygenation at the bedside. Extended and combined uses of these techniques, also described as multimodal monitoring, may allow practitioners to better understand the physiology of critically ill neonates. Furthermore, the rapid growth of technology in the Neuro-NICU, along with the increasing use of telemedicine and artificial intelligence with improved data mining techniques and machine learning (ML), has the potential to vastly improve decision-making processes and positively impact outcomes. This article will cover the current applications of neuromonitoring in the Neuro-NICU, recent advances, potential pitfalls, and future perspectives in this field.
Alpha-Asaronol Alleviates Dysmyelination by Enhancing Glutamate Transport Through the Activation of PPARγ-GLT-1 Signaling in Hypoxia-Ischemia Neonatal Rats
Authors: Ge Yuhang , Zhen Fei , Liu Ziqi , Feng Zhaowei , Wang Gui , Zhang Chu , Wang Xingqi , Sun Ying , Zheng Xiaohui , Bai Yajun , Yao Ruiqin
Published: March 2022

Preterm white matter injury (PWMI) is the most common form of brain damage in premature infants caused by hypoxia-ischemia (HI), inflammation, or excitotoxicity. It is characterized by oligodendrocyte precursor cell (OPC) differentiation disorder and dysmyelination. Our previous study confirmed that alpha-asarone (α-asaronol), a major compound isolated from the Chinese medicinal herb Acorus gramineus by our lab, could alleviate neuronal overexcitation and improve the cognitive function of aged rats. In the present study, we investigated the effect and mechanism of α-asaronol on myelination in a rat model of PWMI induced by HI. Notably, α-asaronol promoted OPC differentiation and myelination in the corpus callosum of PWMI rats. Meanwhile, the concentration of glutamate was significantly decreased, and the levels of PPARγ and glutamate transporter 1 (GLT-1) were increased by α-asaronol treatment. In vitro, it was also confirmed that α-asaronol increased GLT-1 expression and recruitment of the PPARγ coactivator PCG-1a in astrocytes under oxygen and glucose deprivation (OGD) conditions. The PPARγ inhibitor GW9662 significantly reversed the effect of α-asaronol on GLT-1 expression and PCG-1a recruitment. Interestingly, the conditioned medium from α-asaronol-treated astrocytes decreased the number of OPCs and increased the number of mature oligodendrocytes. These results suggest that α-asaronol can promote OPC differentiation and relieve dysmyelination by regulating glutamate levels via astrocyte PPARγ-GLT-1 signaling. Although whether α-asaronol binds to PPARγ directly or indirectly is not investigated here, this study still indicates that α-asaronol may be a promising small molecular drug for the treatment of myelin-related diseases.
Qinglong Zhidong Decoction Alleviated Tourette Syndrome in Mice via Modulating the Level of Neurotransmitters and the Composition of Gut Microbiota
Authors: Wang Na , Wu Xinchen , Yang Qi , Wang Dingyue , Wu Zhao , Wei Yuanyuan , Cui Jieqiong , Hong Li , Xiong Lei , Qin Dongdong
Published: March 2022

Qinglong Zhidong Decoction (QLZDD), a traditional Chinese medicine (TCM) prescription, has been effectively used to alleviate Tourette syndrome (TS) in children. However, the therapeutic mechanism of QLZDD on TS has not been evaluated. The present study aims to elucidate the therapeutic effect and the possible therapeutic mechanism of QLZDD on TS in mouse model. A 3,3-iminodipropionitrile (IDPN, 350 mg/kg)-induced-TS mouse model was established. The mice were randomly divided into the control group, the model group, the haloperidol group (14 mg/kg), the low-, middle-, or high-QLZDD-dose groups (6.83 g/kg, 13.65 g/kg, 27.3 g/kg). QLZDD was administrated orally once a day for 4 weeks. The tic-like behavior was recorded weekly. Then, neurotransmitters and neurotransmitter receptors were analyzed by ELISA, immunohistochemistry (IHC), and quantitative reverse transcription PCR in striatum. Further, the alteration to intestinal flora was monitored by 16s rRNA sequencing, and the role of gut microbiota in the alleviation of TS by QLZDD was investigated. QLZDD ameliorated the tic-like behavior, and decreased the level of excitatory neurotransmitters such as Glu and DA and increased the level of the inhibitory neurotransmitter GABA significantly. Moreover, QLZDD significantly blocked the mRNA expression and the protein expression of D1R and D2R in the striatum, while activated the levels of DAT and GABAR. Interestingly, QLZDD mediated the composition of gut microbiota by increasing the abundance of Lactobacillus and Bacteroides but decreasing the abundance of Alloprevotella and Akkermansia. Taken together, QLZDD ameliorated the tic-like behavior in TS mouse, its mechanism of action may be associated with restoring the balance of gut microbiota and neurotransmitters. The study indicated a promising role of QLZDD in alleviating TS and a therapeutic strategy for fighting TS in clinical settings.