bluuebunny/crossref_metadata_2025 huggingface dataset:
Mucosal Healing Effectiveness and Safety of Anaprazole, a Novel PPI, vs. Rabeprazole in Patients With Duodenal Ulcers: A Randomized Double-Blinded Multicenter Phase II Clinical Trial
Authors: Shu Xu , Zhu Zhenhua , Fu Yu , Zhang Zhenyu , Wang Jiangbin , Li Xing , He Shuixiang , Fan Huizhen , Liu Side , Zhang Guoxin , Tang Jianhua , Huang Caibin , Du Qin , Wang Xiaoyan , Xu Baohong , Du Yiqi , Chen Qikui , Wang Bangmao , Chen Ying , Duan Xianghui , Xie Yong , Huo Lijuan , Hou Xiaohua , Lu Nonghua
Published: July 2021

Background:Proton pump inhibitors (PPIs) are validated gastric acid suppressors and have been widely used to treat patients with active duodenal ulcers. Although existing PPIs have shown great efficacy, many scientists are still devoted to developing more effective PPIs with better safety profile. Herein, we aimed to compare the safety and efficacy of anaprazole in duodenal mucosal healing, a novel PPI, to that of rabeprazole.

Methods:In this multicenter, randomized, positive-controlled, double-blinded, parallel-group phase II clinical trial, a total of 150 qualified patients with endoscopically confirmed active duodenal ulcers were randomized (1:1:1) to receive rabeprazole 10 mg, anaprazole 20 mg or anaprazole 40 mg for 4 weeks. The ulcer healing rates after 4 weeks of treatment were compared between groups by independent central review and investigator review. In addition, symptoms and safety were evaluated.

Results:Based on the independent central review, the ulcer healing rates of the 10 mg rabeprazole, 20 mg anaprazole and 40 mg anaprazole groups were 88.0, 85.1, and 87.5%, respectively, in the FAS population and 88.9, 86.0, and 90.9%, respectively, in the PPS population. The ulcer healing rate difference between anaprazole 20 mg and Rabeprazole 10 mg is −2.9% (95% CI, −16.5–10.7%), and −0.5% (95% CI, −13.5–12.5%) between anaprazole 40 mg and Rabeprazole 10 mg, in the FAS population. Based on the investigator review, the ulcer healing rates of the 10 mg rabeprazole, 20 mg anaprazole, and 40 mg anaprazole groups were 72.0, 70.2, and 77.1%, respectively, in the FAS population and 75.6, 72.1, and 79.5%, respectively, in the PPS population. The ulcer healing rate difference between anaprazole 20 mg and Rabeprazole 10 mg is −1.8% (95% CI, −19.8–16.3%), and 5.1% (95% CI, −12.2–22.3%) between anaprazole 40 mg and Rabeprazole 10 mg, in the FAS population. Most patients (>90%) eventually achieved complete symptom relief. The incidence rates of adverse events were of no significant differences among the treatment groups. Potential possible better liver tolerance was observed in two anaprazole dose groups than rabeprazole 10 mg group.

Conclusion:Both at a dosage of 20 and 40 mg daily, anaprazole, is effective with good safety profile in the treatment of active duodenal ulcers in this Phase 2 study, which allows anaprazole to be advanced to a phase III clinical trial.

Clinical Trial Registration:https://www.clinicaltrials.gov/ct2/results?cond=&term=NCT04503629&cntry=&state=&city=&dist=, Identifier: CTR20181464, NCT04503629.
A Novel Polyvalent Bacteriophage vB_EcoM_swi3 Infects Pathogenic Escherichia coli and Salmonella enteritidis
Authors: Sui Bingrui , Han Lili , Ren Huiying , Liu Wenhua , Zhang Can
Published: July 2021

A novel virulent bacteriophage vB_EcoM_swi3 (swi3), isolated from swine feces, lyzed 9% (6/65) of Escherichia coli and isolates 54% (39/72) of Salmonella enteritidis isolates, which were all clinically pathogenic multidrug-resistant strains. Morphological observation showed that phage swi3 belonged to the Myoviridae family with an icosahedral head (80 nm in diameter) and a contractile sheathed tail (120 nm in length). At the optimal multiplicity of infection of 1, the one-step growth analysis of swi3 showed a 25-min latent period with a burst size of 25-plaque-forming units (PFU)/infected cell. Phage swi3 remained stable both at pH 6.0–8.0 and at less than 50°C for at least 1 h. Genomic sequencing and bioinformatics analysis based on genomic sequences and the terminase large subunit showed that phage swi3 was a novel member that was most closely related to Salmonella phages and belonged to the Rosemountvirus genus. Phage swi3 harbored a 52-kb double-stranded DNA genome with 46.02% GC content. Seventy-two potential open reading frames were identified and annotated, only 15 of which had been assigned to functional genes. No gene associated with pathogenicity and virulence was identified. The effects of phage swi3 in treating pathologic E. coli infections in vivo were evaluated using a mouse model. The administration of a single intraperitoneal injection of swi3 (106 PFU) at 2 h after challenge with the E. coli strain (serotype K88) (108 colony-forming units) sufficiently protected all mice without toxic side effects. This finding highlighted that phage swi3 might be used as an effective antibacterial agent to prevent E. coli and S. enteritidis infection.
Genome-Scale Screening and Combinatorial Optimization of Gene Overexpression Targets to Improve Cadmium Tolerance in Saccharomyces cerevisiae
Authors: Chen Yongcan , Liang Jun , Chen Zhicong , Wang Bo , Si Tong
Published: July 2021

Heavy metal contamination is an environmental issue on a global scale. Particularly, cadmium poses substantial threats to crop and human health. Saccharomyces cerevisiae is one of the model organisms to study cadmium toxicity and was recently engineered as a cadmium hyperaccumulator. Therefore, it is desirable to overcome the cadmium sensitivity of S. cerevisiae via genetic engineering for bioremediation applications. Here we performed genome-scale overexpression screening for gene targets conferring cadmium resistance in CEN.PK2-1c, an industrial S. cerevisiae strain. Seven targets were identified, including CAD1 and CUP1 that are known to improve cadmium tolerance, as well as CRS5, NRG1, PPH21, BMH1, and QCR6 that are less studied. In the wild-type strain, cadmium exposure activated gene transcription of CAD1, CRS5, CUP1, and NRG1 and repressed PPH21, as revealed by real-time quantitative PCR analyses. Furthermore, yeast strains that contained two overexpression mutations out of the seven gene targets were constructed. Synergistic improvement in cadmium tolerance was observed with episomal co-expression of CRS5 and CUP1. In the presence of 200 μM cadmium, the most resistant strain overexpressing both CAD1 and NRG1 exhibited a 3.6-fold improvement in biomass accumulation relative to wild type. This work provided a new approach to discover and optimize genetic engineering targets for increasing cadmium resistance in yeast.
Evidence for Persistent Heteroplasmy and Ancient Recombination in the Mitochondrial Genomes of the Edible Yellow Chanterelles From Southwestern China and Europe
Authors: Zhang Ying , Wang Shaojuan , Li Haixia , Liu Chunli , Mi Fei , Wang Ruirui , Mo Meizi , Xu Jianping
Published: July 2021

Mitochondrial genes and genomes have patterns of inheritance that are distinctly different from those of nuclear genes and genomes. In nature, the mitochondrial genomes in eukaryotes are generally considered non-recombining and homoplasmic. If heteroplasmy and recombination exist, they are typically very limited in both space and time. Here we show that mitochondrial heteroplasmy and recombination may not be limited to a specific population nor exit only transiently in the basidiomycete Cantharellus cibarius and related species. These edible yellow chanterelles are an ecologically very important group of fungi and among the most prominent wild edible mushrooms in the Northern Hemisphere. At present, very little is known about the genetics and population biology of these fungia cross large geographical distances. Our study here analyzed a total of 363 specimens of edible yellow chanterelles from 24 geographic locations in Yunnan in southwestern China and six geographic locations in five countries in Europe. For each mushroom sample, we obtained the DNA sequences at two genes, one in the nuclear genome and one in the mitochondrial genome. Our analyses of the nuclear gene, translation elongation factor 1-alpha (tef-1) and the DNA barcode of C. cibarius and related species, suggested these samples belong to four known species and five potential new species. Interestingly, analyses of the mitochondrial ATP synthase subunit 6 (atp6) gene fragment revealed evidence of heteroplasmy in two geographic samples in Yunnan and recombination within the two new putative species in Yunnan. Specifically, all four possible haplotypes at two polymorphic nucleotide sites within the mitochondrial atp6 gene were found distributed across several geographic locations in Yunnan. Furthermore, these four haplotypes were broadly distributed across multiple phylogenetic clades constructed based on nuclear tef-1 sequences. Our results suggest that heteroplasmy and mitochondrial recombination might have happened repeatedly during the evolution of the yellow chanterelles. Together, our results suggest that the edible yellow chanterelles represent an excellent system from which to study the evolution of mitochondrial-nuclear genome relationships.
Light-Stress Response Mediated by the Transcription Factor KlMga2 in the Yeast Kluyveromyces lactis
Authors: Camponeschi Ilaria , Montanari Arianna , Beccaccioli Marzia , Reverberi Massimo , Mazzoni Cristina , Bianchi Michele M.
Published: July 2021

In unicellular organisms like yeasts, which do not have specialized tissues for protection against environmental challenges, the presence of cellular mechanisms to respond and adapt to stress conditions is fundamental. In this work, we aimed to investigate the response to environmental light in Kluyveromyces lactis. Yeast lacks specialized light-sensing proteins; however, Saccharomyces cerevisiae has been reported to respond to light by increasing hydrogen peroxide level and triggering nuclear translocation of Msn2. This is a stress-sensitive transcription factor also present in K. lactis. To investigate light response in this yeast, we analyzed the different phenotypes generated by the deletion of the hypoxia responsive and lipid biosynthesis transcription factor KlMga2. Alterations in growth rate, mitochondrial functioning, ROS metabolism, and fatty acid biosynthesis provide evidence that light was a source of stress in K. lactis and that KlMga2 had a role in the light-stress response. The involvement of KlMsn2 and KlCrz1 in light stress was also explored, but the latter showed no function in this response.
Cortical Engagement Metrics During Reactive Balance Are Associated With Distinct Aspects of Balance Behavior in Older Adults
Authors: Palmer Jacqueline A. , Payne Aiden M. , Ting Lena H. , Borich Michael R.
Published: July 2021

Heightened reliance on the cerebral cortex for postural stability with aging is well-known, yet the cortical mechanisms for balance control, particularly in relation to balance function, remain unclear. Here we aimed to investigate motor cortical activity in relation to the level of balance challenge presented during reactive balance recovery and identify circuit-specific interactions between motor cortex and prefrontal or somatosensory regions in relation to metrics of balance function that predict fall risk. Using electroencephalography, we assessed motor cortical beta power, and beta coherence during balance reactions to perturbations in older adults. We found that individuals with greater motor cortical beta power evoked following standing balance perturbations demonstrated lower general clinical balance function. Individual older adults demonstrated a wide range of cortical responses during balance reactions at the same perturbation magnitude, showing no group-level change in prefrontal- or somatosensory-motor coherence in response to perturbations. However, older adults with the highest prefrontal-motor coherence during the post-perturbation, but not pre-perturbation, period showed greater cognitive dual-task interference (DTI) and elicited stepping reactions at lower perturbation magnitudes. Our results support motor cortical beta activity as a potential biomarker for individual level of balance challenge and implicate prefrontal-motor cortical networks in distinct aspects of balance control involving response inhibition of reactive stepping in older adults. Cortical network activity during balance may provide a neural target for precision-medicine efforts aimed at fall prevention with aging.
Focused Ultrasound Thalamotomy for the Treatment of Essential Tremor: A 2-Year Outcome Study of Chinese People
Authors: Wu Peihan , Lin Wei , Li Kun Hong , Lai Hui-Chin , Lee Ming-Tsung , Tsai Kevin Wen-Kai , Chiu Pai-Yi , Chang Wei-Chieh , Wei Cheng-Yu , Taira Takaomi
Published: July 2021

Background: Essential tremor (ET) is a common movement disorder among elderly individuals worldwide and is occasionally associated with a high risk for mild cognitive impairment and dementia. This retrospective study aimed to determine the clinical outcome of unilateral magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in Chinese patients with ET.

Methods: In total, 31 male and 17 female patients with drug-refractory ET were enrolled in this research study from January 2017 to September 2019. The severity of tremor and disability were assessed using the Clinical Rating Scale for Tremor (CRST) within a 2-year follow-up period.

Results: The mean age of the participants was 59.14 ± 13.5 years. The mean skull density ratio (SDR) was 0.5 ± 0.1. The mean highest temperature was 57.0 ± 2.4°C. The mean number of sonications was 10.0 ± 2.6. The average maximum energy was 19,710.5 ± 8,624.9 J. The total CRST scores and sub-scores after MRgFUS thalamotomy significantly reduced during each follow-up (p < 0.001). All but four (8.3%) of the patients had reversible adverse events (AEs) after the procedure.

Conclusions: MRgFUS had sustained clinical efficacy 2 years after treatment for intractable ET. Only few patients presented with thalamotomy-related AEs including numbness, weakness, and ataxia for an extended period. Most Chinese patients were treated safely and effectively despite their low SDR.
Local Cisplatin Delivery in Mouse Reliably Models Sensorineural Ototoxicity Without Systemic Adverse Effects
Authors: Nacher-Soler German , Lenglet Sébastien , Coelho Marta , Thomas Aurélien , Voruz François , Krause Karl-Heinz , Senn Pascal , Rousset Francis
Published: July 2021

Cisplatin is a lifesaving chemotherapeutic drug with marked ototoxic adverse effects. Cisplatin-induced hearing loss affects a significant part of cancer-surviving patients and is an unmet clinical need with important socioeconomic consequences. Unfortunately, in current preclinical animal models of cisplatin ototoxicity, which are mainly based on systemic delivery, important morbidity is observed, leading to premature death. This methodology not only raises obvious animal welfare concerns but also increases the number of animals used in ototoxicity studies to compensate for dropouts related to early death. To overcome these important limitations, we developed a local delivery model based on the application of a cisplatin solution directly into the otic bulla through a retroauricular approach. The local delivery model reliably induced significant hearing loss with a mean threshold shift ranging from 10 to 30 dB, strongly affecting the high frequencies (22 and 32 kHz). Importantly, mice did not show visible stress or distress indicators and no significant morbidity in comparison with a traditional systemic delivery control group of mice injected intraperitoneally with 10 mg/kg cisplatin, where significant weight loss >10% in all treated animals (without any recovery) led to premature abortion of experiments on day 3. Mass spectrometry confirmed the absence of relevant systemic uptake after local delivery, with platinum accumulation restricted to the cochlea, whereas important platinum concentrations were detected in the liver and kidney of the systemic cisplatin group. A clear correlation between the cochlear platinum concentration and the auditory threshold shift was observed. Immunohistochemistry revealed statistically significant loss of outer hair cells in the basal and apical turns of the cochlea and an important and statistically significant loss of auditory neurons and synapses in all cochlear regions. In conclusion, local cisplatin delivery induces robust hearing loss with minimal morbidity, thereby offering a reliable rodent model for human cisplatin ototoxicity, reducing the number of animals required and showing improved animal welfare compared with traditional systemic models.
Multi-Modal Segmentation of 3D Brain Scans Using Neural Networks
Authors: Zopes Jonathan , Platscher Moritz , Paganucci Silvio , Federau Christian
Published: July 2021

Anatomical segmentation of brain scans is highly relevant for diagnostics and neuroradiology research. Conventionally, segmentation is performed on T1-weighted MRI scans, due to the strong soft-tissue contrast. In this work, we report on a comparative study of automated, learning-based brain segmentation on various other contrasts of MRI and also computed tomography (CT) scans and investigate the anatomical soft-tissue information contained in these imaging modalities. A large database of in total 853 MRI/CT brain scans enables us to train convolutional neural networks (CNNs) for segmentation. We benchmark the CNN performance on four different imaging modalities and 27 anatomical substructures. For each modality we train a separate CNN based on a common architecture. We find average Dice scores of 86.7 ± 4.1% (T1-weighted MRI), 81.9 ± 6.7% (fluid-attenuated inversion recovery MRI), 80.8 ± 6.6% (diffusion-weighted MRI) and 80.7 ± 8.2% (CT), respectively. The performance is assessed relative to labels obtained using the widely-adopted FreeSurfer software package. The segmentation pipeline uses dropout sampling to identify corrupted input scans or low-quality segmentations. Full segmentation of 3D volumes with more than 2 million voxels requires <1s of processing time on a graphical processing unit.
Functional Disruptions of the Brain in Low Back Pain: A Potential Imaging Biomarker of Functional Disability
Authors: Lamichhane Bidhan , Jayasekera Dinal , Jakes Rachel , Ray Wilson Z. , Leuthardt Eric C. , Hawasli Ammar H.
Published: July 2021

Chronic low back pain (LBP) is one of the leading causes of disability worldwide. While LBP research has largely focused on the spine, many studies have demonstrated a restructuring of human brain architecture accompanying LBP and other chronic pain states. Brain imaging presents a promising source for discovering noninvasive biomarkers that can improve diagnostic and prognostication outcomes for chronic LBP. This study evaluated graph theory measures derived from brain resting-state functional connectivity (rsFC) as prospective noninvasive biomarkers of LBP. We also proposed and tested a hybrid feature selection method (Enet-subset) that combines Elastic Net and an optimal subset selection method. We collected resting-state functional MRI scans from 24 LBP patients and 27 age-matched healthy controls (HC). We then derived graph-theoretical features and trained a support vector machine (SVM) to classify patient group. The degree centrality (DC), clustering coefficient (CC), and betweenness centrality (BC) were found to be significant predictors of patient group. We achieved an average classification accuracy of 83.1% (p< 0.004) and AUC of 0.937 (p< 0.002), respectively. Similarly, we achieved a sensitivity and specificity of 87.0 and 79.7%. The classification results from this study suggest that graph matrices derived from rsFC can be used as biomarkers of LBP. In addition, our findings suggest that the proposed feature selection method, Enet-subset, might act as a better technique to remove redundant variables and improve the performance of the machine learning classifier.
Sodium Intensity Changes Differ Between Relaxation- and Density-Weighted MRI in Multiple Sclerosis
Authors: Stobbe Robert , Boyd Annie , Smyth Penelope , Emery Derek , Valdés Cabrera Diana , Beaulieu Christian
Published: July 2021

Introduction: The source of Tissue Sodium Concentration (TSC) increase in Multiple Sclerosis (MS) remains unclear, and could be attributed to altered intracellular sodium concentration or tissue microstructure. This paper investigates sodium in MS using three new MRI sequences.

Methods: Three sodium scans were acquired at 4.7 T from 30 patients (11 relapsing-remitting, 10 secondary-progressive, 9 primary-progressive) and 9 healthy controls including: Density-Weighted (NaDW), with very short 30° excitation for more accurate TSC measurement; Projection Acquisition with Coherent MAgNetization (NaPACMAN), designed for enhanced relaxation-based contrast; and Soft Inversion Recovery FLuid Attenuation (NaSIRFLA), developed to reduce fluid space contribution. Signal was measured in both lesions (n = 397) and normal appearing white matter (NAWM) relative to controls in the splenium of corpus callosum and the anterior and posterior limbs of internal capsule. Correlations with clinical and cognitive evaluations were tested over all MS patients.

Results: Sodium intensity in MS lesions was elevated over control WM by a greater amount for NaPACMAN (75%) than NaDW (35%), the latter representing TSC. In contrast, NaSIRFLA exhibited lower intensity, but only for region specific analysis in the SCC (−7%). Sodium intensity in average MS NAWM was not significantly different than control WM for either of the three scans. NaSIRFLA in the average NAWM and specifically the posterior limb of internal capsules positively correlated with the Paced Auditory Serial Addition Test (PASAT).

Discussion: Lower NaSIRFLA signal in lesions and ~2× greater NaPACMAN signal elevation over control WM than NaDW can be explained with a demyelination model that also includes edema. A NAWM demyelination model that includes tissue atrophy suggests no signal change for NaSIRFLA, and only slightly greater NAWM signal than control WM for both NaDW and NaPACMAN, reflecting experimental results. Models were derived from previous total and myelin water fraction study in MS with T2-relaxometry, and for the first time include sodium within the myelin water space. Reduced auditory processing association with lower signal on NaSIRFLA cannot be explained by greater demyelination and its modeled impact on the three sodium MRI sequences. Alternative explanations include intra- or extracellular sodium concentration change. Relaxation-weighted sodium MRI in combination with sodium-density MRI may help elucidate microstructural and metabolic changes in MS.
Efficacy of Repetitive Transcranial Magnetic Stimulation Combined With Visual Scanning Treatment on Cognitive-Behavioral Symptoms of Unilateral Spatial Neglect in Patients With Traumatic Brain Injury: Study Protocol for a Randomized Controlled Trial
Authors: Di Gregorio Francesco , La Porta Fabio , Lullini Giada , Casanova Emanuela , Petrone Valeria , Simoncini Loredana , Ferrucci Enrico , Piperno Roberto
Published: July 2021

Left hemispatial neglect (LHSN) is a frequent and disabling condition affecting patients who suffered from traumatic brain injury (TBI). LHSN is a neuropsychological syndrome characterized clinically by difficulties in attending, responding, and consciously representing the right side of space. Despite its frequency, scientific evidence on effective treatments for this condition in TBI patients is still low. According to existing literature, we hypothesize that in TBI, LHSN is caused by an imbalance in inter-hemispheric activity due to hyperactivity of the left hemisphere, as observed in LHSN after right strokes. Thus, by inhibiting this left hyperactivity, repetitive Transcranial Magnetic Stimulation (rTMS) would have a rebalancing effect, reducing LHSN symptoms in TBI patients. We plan to test this hypothesis within a single-blind, randomized SHAM controlled trial in which TBI patients will receive inhibitory i-rTMS followed by cognitive treatment for 15 days. Neurophysiological and clinical measures will be collected before, afterward, and in the follow-up. This study will give the first empirical evidence about the efficacy of a novel approach to treating LHSN in TBI patients.

Clinical Trial Registration:https://www.clinicaltrials.gov/ct2/show/NCT04573413?cond=Neglect%2C+Hemispatial&cntry=IT&city=Bologna&draw=2&rank=2, identifier: NCT04573413.
Musical Interaction Reveals Music as Embodied Language
Authors: Dell’Anna Alessandro , Leman Marc , Berti Annamaria
Published: July 2021

Life and social sciences often focus on the social nature of music (and language alike). In biology, for example, the three main evolutionary hypotheses about music (i.e., sexual selection, parent-infant bond, and group cohesion) stress its intrinsically social character (Honing et al., 2015). Neurobiology thereby has investigated the neuronal and hormonal underpinnings of musicality for more than two decades (Chanda and Levitin, 2013;Salimpoor et al., 2015;Mehr et al., 2019). In line with these approaches, the present paper aims to suggest that the proper way to capture the social interactive nature of music (and, before it, musicality), is to conceive of it as an embodied language, rooted in culturally adapted brain structures (Clarke et al., 2015;D’Ausilio et al., 2015). This proposal heeds Ian Cross’ call for an investigation of music as an “interactive communicative process” rather than “a manifestation of patterns in sound” (Cross, 2014), with an emphasis on its embodied and predictive (coding) aspects (Clark, 2016;Leman, 2016;Koelsch et al., 2019). In the present paper our goal is: (i) to propose a framework of music as embodied language based on a review of the major concepts that define joint musical action, with a particular emphasis on embodied music cognition and predictive processing, along with some relevant neural underpinnings; (ii) to summarize three experiments conducted in our laboratories (and recently published), which provide evidence for, and can be interpreted according to, the new conceptual framework. In doing so, we draw on both cognitive musicology and neuroscience to outline a comprehensive framework of musical interaction, exploring several aspects of making music in dyads, from a very basic proto-musical action, like tapping, to more sophisticated contexts, like playing a jazz standard and singing a hocket melody. Our framework combines embodied and predictive features, revolving around the concept of joint agency (Pacherie, 2012;Keller et al., 2016;Bolt and Loehr, 2017). If social interaction is the “default mode” by which human brains communicate with their environment (Hari et al., 2015), music and musicality conceived of as an embodied language may arguably provide a route toward its navigation.
Changes in Resting-State Spontaneous Brain Activity in Patients With Allergic Rhinitis: A Pilot Neuroimaging Study
Authors: Gao Ziang , Chen Xixiang , Xiang Rong , Zhang Wei , Tan Lu , Fan Wenjun , Liu Peiqiang , Lv Hao , Xu Yu
Published: July 2021

Background

Allergic rhinitis (AR) is an inflammatory disorder of the nose caused by immunoglobulin E (IgE)-mediated immune response to allergens. Apart from the typical symptoms of sneezing, itching, rhinorrhea, and nasal congestion, behavioral complications were also reported to be associated with the progression of AR, such as cognitive deficits, mood changes, memory decline, attention deficiency, poor school performance, anxiety, and depression. Recent human studies have suggested that alterations in brain function caused by allergen exposure may precipitate high levels of anxiety and emotional reactivity in asthma patients. But until now, there is no direct evidence of the relationship between brain activity and allergic rhinitis.

Methods

Resting-state functional magnetic resonance imaging (rs-fMRI) was used to excavate whether there remain functional changes of brain activity in AR patients. We measured the amplitude of low-frequency fluctuation (ALFF) and the z conversion of ALFF (zALFF) in 20 patients with AR and 20 age- and sex-matched healthy controls (HCs) using the rs-fMRI data.

Results

Compared with healthy controls, AR patients exhibited lower ALFF values in the precuneus (PCUN) and higher ALFF values in the anterior cingulate cortex (ACC). The ALFF values of these features were significantly correlated with the visual analog scale (VAS) scores, the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, the subscales of RQLQ, and specific IgE, partly.

Conclusion

We found changes in resting-state spontaneous brain activity in AR patients with hypoactivity in the PCUN and hyperactivity of the ACC. The brain-related symptoms of AR might be another potential clinical intervention target for improving the life quality of AR patients. Further attention to brain activity is essential for a deeper understanding of AR.
The Effects of Repetitive Transcranial Magnetic Stimulation on Cognitive Impairment and the Brain Lipidome in a Cuprizone-Induced Mouse Model of Demyelination
Authors: Zhou Cuihong , Cai Min , Wang Ying , Wu Wenjun , Yin Yuezhen , Wang Xianli , Hu Guangtao , Wang Huaning , Tan Qingrong , Peng Zhengwu
Published: July 2021

The protective effects of repetitive transcranial magnetic stimulation (rTMS) on myelin integrity have been extensively studied, and growing evidence suggests that rTMS is beneficial in improving cognitive functions and promoting myelin repair. However, the association between cognitive improvement due to rTMS and changes in brain lipids remains elusive. In this study, we used the Y-maze and 3-chamber tests, as well as a mass spectrometry-based lipidomic approach in a CPZ-induced demyelination model in mice to assess the protective effects of rTMS on cuprizone (CPZ)-induced cognitive impairment and evaluate changes in lipid composition in the hippocampus, prefrontal cortex, and striatum. We found that CPZ induced cognitive impairment and remarkable changes in brain lipids, specifically in glycerophospholipids. Moreover, the changes in lipids within the prefrontal cortex were more extensive, compared to those observed in the hippocampus and striatum. Notably, rTMS ameliorated CPZ-induced cognitive impairment and partially normalized CPZ-induced lipid changes. Taken together, our data suggest that rTMS may reverse cognitive behavioral changes caused by CPZ-induced demyelination by modulating the brain lipidome, providing new insights into the therapeutic mechanism of rTMS.
Primary Diffuse Large B-Cell Lymphoma of the Urinary Tract: A Population-Based Analysis
Authors: Liu Zheng-Huan , Yang Lu-Chen , Song Pan , Fang Kun , Zhou Jing , Peng Zhu-Feng , Dong Qiang
Published: July 2021

Objective

Diffuse large B-cell lymphoma (DLBCL) is the most common histopathological type of non-Hodgkin’s lymphoma, which may arise from various extranodal sites. Little is known about the clinical characteristics and survival outcomes of primary DLBCL of the urinary tract (UT). Thus, we conducted this study to explore the independent prognostic factors of patients with UT-DLBCL using the Surveillance, Epidemiology, and End Results (SEER) database.

Materials and Methods

We searched the Surveillance, Epidemiology, and End Results (SEER) database for the data of patients diagnosed with UT-DLBCL between 1975 and 2016. Data, including demographic tumour stage and therapeutic strategies, such as surgical resection, radiation therapy, and chemotherapy, were collected. The impact of these factors on survival outcomes, including overall survival (OS) and disease-specific survival (DSS), was analysed using Kaplan–Meier curves.

Results

Four-hundred and eighty-nine patients who met the inclusion criteria were enrolled in the data analysis. The median age was 69 years old. Most cases of UT-DLBCL (72.39%) originated from the kidney, followed by the urinary bladder (24.95%). Both surgical resection and chemotherapy can significantly improve OS and DSS. Patients older than 75 years had the worst survival outcomes. Stage IV DLBCL may be a poor prognostic factor.

Conclusion

To the best of our knowledge, this is the largest population-based study of UT-DLBCL. Advanced age, male gender, lack of surgical resection or chemotherapy, and stage IV DLBCL were poor prognostic factors.
Prognostic Model for Predicting Overall and Cancer-Specific Survival Among Patients With Cervical Squamous Cell Carcinoma: A SEER Based Study
Authors: Li Zhuolin , Lin Yao , Cheng Bizhen , Zhang Qiaoxin , Cai Yingmu
Published: July 2021

Background

Cervical squamous cell carcinoma (CSCC) is the most common histological subtype of cervical cancer. The purpose of this study was to assess prognostic factors and establish personalized risk assessment nomograms to predict overall survival (OS) and cancer-specific survival (CSS) in CSCC patients.

Methods

CSCC patients diagnosed between 1988 and 2015 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox proportional hazard regression models were applied to select meaningful independent predictors and construct predictive nomogram models for OS and CSS. The concordance index (C-index), calibration curve, and receiver operating characteristic (ROC) curve were used to determine the predictive accuracy and discriminability of the nomogram.

Results

A total cohort (n=17962) was randomly divided into a training cohort (n=11974) and a validation cohort (n=5988). Age, race, histologic grade, clinical stage, tumor size, chemotherapy and historic stage were assessed as common independent predictors of OS and CSS. The C-index value of the nomograms for predicting OS and CSS was 0.771 (95% confidence interval 0.762-0.780) and 0.786 (95% confidence interval 0.777-0.795), respectively. Calibration curves of the nomograms indicated satisfactory consistency between nomogram prediction and actual survival for both 3-year and 5-year OS and CSS.

Conclusion

We constructed nomograms that could predict 3- and 5-year OS and CSS of CSCC patients. These nomograms showed good performance in prognostic prediction and can be used as an effective tool to evaluate the prognosis of CSCC patients, thus contributing to clinical decision making and individualized treatment planning.
Survival Prediction Analysis in Glioblastoma With Diffusion Kurtosis Imaging
Authors: Li Yuan , Kim Michelle M. , Wahl Daniel R. , Lawrence Theodore S. , Parmar Hemant , Cao Yue
Published: July 2021

Simple Summary

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Diffusion kurtosis imaging (DKI) has characterized non-Gaussian diffusion behaviors in brain normal tissue and gliomas, but there are very limited efforts in investigating treatment responses of kurtosis in GBM. This study aimed to investigate whether any parameter derived from the DKI is a significant predictor of overall survival (OS). We found that the large mean, 80 and 90 percentile kurtosis values in the contrast enhanced gross tumor volume (Gd-GTV) on post-Gd T1-weighted images pre-RT were significantly associated with reduced OS. In the multivariate Cox model, the mean kurtosis Gd-GTV pre-RT after considering effects of age, extent of surgery, and methylation were significant predictors of OS. In addition, the 80 and 90 percentile kurtosis values in Gd-GTV post RT were significantly associated with progression free survival (PFS). The DKI model demonstrates the potential to predict outcomes in the patients with GBM.

Purpose

Non-Gaussian diffusion behaviors in gliomas have been characterized by diffusion kurtosis imaging (DKI). But there are very limited efforts in investigating the kurtosis in glioblastoma (GBM) and its prognostic and predictive values. This study aimed to investigate whether any of the diffusion kurtosis parameters derived from DKI is a significant predictor of overall survival.

Methods and Materials

Thirty-three patients with GBM had pre-radiation therapy (RT) and mid-RT diffusion weighted (DW) images. Kurtosis and diffusion coefficient (DC) values in the contrast enhanced gross tumor volume (Gd-GTV) on post-Gd T1 weighted images pre-RT and mid-RT were calculated. Univariate and multivariate Cox models were used to evaluate the DKI parameters and clinical factors for prediction of OS and PFS.

Results

The large mean kurtosis values in the Gd-GTV pre-RT were significantly associated with reduced OS (p = 0.02), but the values at mid-RT were not (p > 0.8). In the multivariate Cox model, the mean kurtosis in the Gd-GTV pre-RT (p = 0.009) was still a significant predictor of OS after adjusting effects of age, O6-Methylguanine-DNA Methyl transferase (MGMT) methylation and extent of resection. In Gd-GTV post-RT, 80 and 90 percentile kurtosis values were significant predictors (p ≤ 0.05) for progression free survival (PFS).

Conclusion

The DKI model demonstrates the potential to predict OS and PFS in the patients with GBM. Further development and histopathological validation of the DKI model will warrant its role in clinical management of GBM.
Targeting the Stroma in the Management of Pancreatic Cancer
Authors: Edwards Penelope , Kang Byung Woog , Chau Ian
Published: July 2021

Pancreatic cancer (PC) presents extremely aggressive tumours and is associated with poor survival. This is attributed to the unique features of the tumour microenvironment (TME), which is known to create a dense stromal formation and poorly immunogenic condition. In particular, the TME of PC, including the stromal cells and extracellular matrix, plays an essential role in the progression and chemoresistance of PC. Consequently, several promising agents that target key components of the stroma have already been developed and are currently in multiple stages of clinical trials. Therefore, the authors review the latest available evidence on novel stroma-targeting approaches, highlighting the potential impact of the stroma as a key component of the TME in PC.
Cerebral Infarction in Childhood-Onset Craniopharyngioma Patients: Results of KRANIOPHARYNGEOM 2007
Authors: Boekhoff Svenja , Bison Brigitte , Genzel Daniela , Eveslage Maria , Otte Anna , Friedrich Carsten , Flitsch Jörg , Müller Hermann L.
Published: July 2021

Background

Cerebral infarction (CI) is a known vascular complication following treatment of suprasellar tumors. Risk factors for CI, incidence rate, and long-term prognosis are unknown for patients with childhood-onset craniopharyngioma (CP).

Methods

MRI of 244 CP patients, recruited between 2007 and 2019 in KRANIOPHARYNGEOM 2007, were reviewed for CI. Risk factors for CI and outcome after CI were analyzed.

Results

Twenty-eight of 244 patients (11%) presented with CI based on reference assessment of MRI. One CI occurred before initial surgery and one case of CI occurred after release of intracystic pressure by a cyst catheter. 26 of 28 CI were detected after surgical tumor resection at a median postoperative interval of one day (range: 0.5-53 days). Vascular lesions during surgical procedures were documented in 7 cases with CI. No relevant differences with regard to surgical approaches were found. In all 12 irradiated patients, CI occurred before irradiation. Multivariable analyses showed that hydrocephalus and gross-total resection at the time of primary diagnosis/surgery both were risk factors for CI. After CI, quality of life (PEDQOL) and functional capacity (FMH) were impaired.

Conclusions

CI occurs in 11% of surgically-treated CP cases. Degree of resection and increased intracranial pressure are risk factors, which should be considered in the planning of surgical procedures for prevention of CI.
Successful Chimeric Antigen Receptor (CAR) T-Cell Treatment in Aggressive Lymphoma Despite Coronavirus Disease 2019 (CoVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication - Case Report
Authors: Nilius-Eliliwi Verena , Mika Thomas , Baraniskin Alexander , Wünnenberg Max , Maslova Marina , Boy Christian , Klein-Scory Susanne , Schroers Roland , Vangala Deepak
Published: July 2021

In patients with compromised immune function, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (CoVID-19) impose particular challenges. Especially in hematological malignancies, including lymphoma, the demands by this novel virus disease are further enhanced during sophisticated treatments, such as chimeric antigen receptor (CAR) T-cell therapy. Here, we present the first case of a patient with refractory diffuse-large B-cell lymphoma, who underwent CAR T-cell treatment in the context of SARS-CoV-2. Irrespective of prolonged and active SARS-CoV-2 infection, T cells were successfully isolated by apheresis and processed to anti-CD19 CAR T cells (axicabtagene-ciloleucel). In light of the aggressive lymphoma course, lymphodepleting chemotherapy and CAR-T cells were administered in early recovery after oxygen-dependent CoVID-19 pneumonia. Except for moderate cytokine release, this cellular immunotherapy was well tolerated. Notably, there is no deterioration of the SARS-CoV-2 infection; however, complete lymphoma response and full clinical recovery were observed. In conclusion, CAR T-cell treatment in aggressive lymphoma in the setting of SARS-CoV-2 infection is feasible and may offer significant therapeutic activity in refractory disease.
Modulation of Glia-Mediated Processes by Spinal Cord Stimulation in Animal Models of Neuropathic Pain
Authors: Cedeño David L. , Kelley Courtney A. , Chakravarthy Krishnan , Vallejo Ricardo
Published: July 2021

Glial cells play an essential role in maintaining the proper functioning of the nervous system. They are more abundant than neurons in most neural tissues and provide metabolic and catabolic regulation, maintaining the homeostatic balance at the synapse. Chronic pain is generated and sustained by the disruption of glia-mediated processes in the central nervous system resulting in unbalanced neuron–glial interactions. Animal models of neuropathic pain have been used to demonstrate that changes in immune and neuroinflammatory processes occur in the course of pain chronification. Spinal cord stimulation (SCS) is an electrical neuromodulation therapy proven safe and effective for treating intractable chronic pain. Traditional SCS therapies were developed based on the gate control theory of pain and rely on stimulating large Aβ neurons to induce paresthesia in the painful dermatome intended to mask nociceptive input carried out by small sensory neurons. A paradigm shift was introduced with SCS treatments that do not require paresthesia to provide effective pain relief. Efforts to understand the mechanism of action of SCS have considered the role of glial cells and the effect of electrical parameters on neuron–glial interactions. Recent work has provided evidence that SCS affects expression levels of glia-related genes and proteins. This inspired the development of a differential target multiplexed programming (DTMP) approach using electrical signals that can rebalance neuroglial interactions by targeting neurons and glial cells differentially. Our group pioneered the utilization of transcriptomic and proteomic analyses to identify the mechanism of action by which SCS works, emphasizing the DTMP approach. This is an account of evidence demonstrating the effect of SCS on glia-mediated processes using neuropathic pain models, emphasizing studies that rely on the evaluation of large sets of genes and proteins. We show that SCS using a DTMP approach strongly affects the expression of neuron and glia-specific transcriptomes while modulating them toward expression levels of healthy animals. The ability of DTMP to modulate key genes and proteins involved in glia-mediated processes affected by pain toward levels found in uninjured animals demonstrates a shift in the neuron–glial environment promoting analgesia.
Risk Factors for Acute Kidney Injury in Critically Ill Neonates: A Systematic Review and Meta-Analysis
Authors: Hu Qian , Li Shao-Jun , Chen Qian-Ling , Chen Han , Li Qiu , Wang Mo
Published: July 2021

Background and Objective: Acute kidney injury (AKI) is recognized as an independent risk factor for mortality and long-term poor prognosis in neonates. The objective of the study was to identify the risk factors for AKI in critically ill neonates to provide an important basis for follow-up research studies and early prevention.

Methods: The PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, WanFang Med, SinoMed, and VIP Data were searched for studies of risk factors in critically ill neonates. Studies published from the initiation of the database to November 19, 2020, were included. The quality of studies was assessed by the Newcastle-Ottawa Scale and the Agency for Healthcare Research and Quality (AHRQ) checklist. The meta-analysis was conducted with Stata 15 and drafted according to the guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.

Results: Seventeen studies (five cohort studies, ten case-control studies, and two cross-sectional studies) were included in meta-analysis, with 1,627 cases in the case group and 5,220 cases in the control group. The incidence of AKI fluctuated from 8.4 to 63.3%. Fifteen risk factors were included, nine of which were significantly associated with an increased risk of AKI in critically ill neonates: gestational age [standardized mean difference (SMD) = −0.31, 95%CI = (−0.51, −0.12), P = 0.002], birthweight [SMD = −0.37, 95%CI = (−0.67, −0.07), P = 0.015], 1-min Apgar score [SMD = −0.61, 95%CI = (−0.78, −0.43), P = 0.000], 5-min Apgar score [SMD = −0.71, 95%CI = (−1.00, −0.41), P = 0.000], congenital heart disease (CHD) [odds ratio (OR) = 2.94, 95%CI = (2.08, 4.15), P = 0.000], hyperbilirubinemia [OR = 2.26, 95%CI = (1.40, 3.65), P = 0.001], necrotizing enterocolitis (NEC) [OR = 6.32, 95%CI = (2.98, 13.42), P = 0.000], sepsis [OR = 2.21, 95%CI = (1.25, 3.89), P = 0.006], and mechanical ventilation [OR = 2.37, 95%CI = (1.50, 3.75), P = 0.000]. Six of them were not significantly associated with AKI in critically ill neonates: age [SMD = −0.25, 95%CI = (−0.54, 0.04), P = 0.095], male sex [OR = 1.10, 95%CI =(0.97, 1.24), P = 0.147], prematurity [OR = 0.90, 95%CI(0.52, 1.56), P = 0.716], cesarean section [OR = 1.52, 95%CI(0.77, 3.01), P = 0.234], prenatal hemorrhage [OR = 1.41, 95%CI = (0.86, 2.33), P = 0.171], and vancomycin [OR = 1.16, 95%CI = (0.71, 1.89), P = 0.555].

Conclusions: This meta-analysis provides a preliminary exploration of risk factors in critically ill neonatal AKI, which may be useful for the prediction of AKI.

Systematic Review Registration: PROSPERO (CRD42020188032).
Norswertianolin Promotes Cystathionine γ-Lyase Activity and Attenuates Renal Ischemia/Reperfusion Injury and Hypertension
Authors: Niu Yaping , Du Congkuo , Cui Changting , Zhang Haizeng , Deng Yue , Cai Jun , Chen Zhenzhen , Geng Bin
Published: July 2021

Cystathionine gamma-lyase (CSE)/hydrogen sulfide (H2S) plays a protective role in cardiovascular diseases including hypertension and ischemia/reperfusion (I/R) injury. This study was aimed to screen natural small molecule compounds that activate CSE activity and then evaluate its effect(s) on kidney I/R injury and hypertension. Applying computer molecular docking technology, we screened the natural small molecule compound norswertianolin (NW)-specific binding to CSE. Using the microscale thermophoresis technology, we confirmed that the Leu68 site was the essential hydrogen bond site of NW binding to CSE. NW supplementation significantly increased CSE expression and its activity for H2S generation both in vivo and in vitro. In the model of acute and long-term kidney I/R injury, NW pretreatment dramatically attenuated kidney damage, associated with decreasing blood urea nitrogen (BUN), serum creatinine (Cr) level, reactive oxygen species (ROS) production, and cleaved caspase 3 expression. In spontaneously hypertensive rats (SHRs), NW treatment also lowered blood pressure, the media/lumen ratio of the femoral artery, and the mRNA level of inflammatory cytokines. In conclusion, NW acts as a novel small molecular chemical compound CSE agonist, directly binding to CSE, heightening CSE generation–H2S activity, and then alleviating kidney I/R injury and hypertension. NW has a potential therapeutic merit for cardiovascular diseases.