bluuebunny/crossref_metadata_2025 huggingface dataset:
High Prevalence of Early Parkinson's Disease in Patients With Subtle Parkinsonian Signs
Authors: Sasaki Shoichi
Published: July 2021

Background: Little is known about how frequently patients with a Unified Parkinson Disease Rating Scale part III (UPDRS-III) score of 3 or 4, including postural and action tremor, could be classified into early Parkinson's disease (PD).

Objective: To examine the prevalence of early PD in patients with subtle parkinsonian signs (rest tremor, postural tremor, and rigidity) without bradykinesia, having a UPDRS-III score of 3 or 4.

Methods: Parkinsonism was assessed using UPDRS-III based on both the United Kingdom PD Society Brain Bank criteria and the Movement Disorder Society PD criteria. Ninety patients with a UPDRS-III score of 3 or 4, including postural tremor, were evaluated by 123I-FP-CIT SPECT (DaTscan), brain MRI, the Mini-Mental State Examination, and smell test. Some patients were additionally examined by 123I-metaiodobenzylguanidine myocardial scintigraphy or 123I-N-isopropyl-p-iodoamphetamine SPECT.

Results: Seventy-five [mean age (standard deviation): 76.9 (8.1)] out of 90 patients (83.3%) showed abnormal findings on DaTscan imaging: 57 out of 75 (76.0%) showed a reduced specific binding ratio (SBR) accompanied by an egg shape pattern (n = 37, 49.3%) or a mixed type pattern (n = 14, 18.7%), both reduced SBR and increased asymmetry index (AI) with a normal shape (n = 4, 5.3%), and reduced SBR only (n = 2, 2.7%); 18 (24.0%) showed an egg shape pattern or a mixed type pattern without reduced SBR. In other words, 69 out of 75 patients (92.0%) showed either an egg shape or a mixed type pattern with or without reduced SBR. All patients were free of dementia, and their olfactory function was significantly impaired compared with controls (n = 141) on the odor-stick identification test for Japanese (p < 0.0001).

Conclusions: The prevalence of patients with subtle parkinsonian signs having a UPDRS-III score of 3 or 4, including postural tremor, is unexpectedly high in daily clinical practice, and most of these patients could be categorized into mild early-stage PD.
Sex Differences in the Association Between Obesity and Cognitive Impairment in a Low-Income Elderly Population in Rural China: A Population-Based Cross-Sectional Study
Authors: Guo Dandan , Zhang Xin , Zhan Changqing , Lin Qiuxing , Liu Jie , Yang Qiaoxia , Tu Jun , Ning Xianjia , Wang Jinghua , Song Yijun
Published: July 2021

Background: Obesity is a potentially modifiable risk factor for cognitive impairment. However, sex-specific relationships between obesity and cognitive impairment in late life remain unclear.

Objective: We aimed to assess sex differences in the association between various obesity parameters and cognitive impairment in a low-income elderly population in rural China.

Methods: A population-based cross-sectional study was conducted to collect basic information from elderly residents aged 60 years and older from April 2014 to August 2014 in rural areas of Tianjin, China. Obesity parameters, including body mass index (BMI) and waist circumference (WC), and Mini Mental State Examination scores were measured, and the relationships between these variables were assessed.

Results: A total of 1,081 residents with a mean age of 67.70 years were enrolled in this study. After adjusting for age, educational attainment, smoking status, drinking status, physical exercise participation, and the presence of diabetes and hyperlipidemia, blood pressure group; a high BMI was found to be associated with an increased prevalence of cognitive impairment in elderly women. Each 1-unit increase in BMI was associated with a 5.9% increase in the prevalence of cognitive impairment. WC was related to the prevalence of cognitive impairment in elderly men, and each 1-cm increase in WC was associated with a 4.0% decrease in the prevalence of cognitive impairment. However, there were no significant associations between WC and cognitive function in women or between BMI and cognitive impairment in men.

Conclusion: A greater WC was positively associated with better cognitive function in low-income elderly men in rural China, whereas a higher BMI was associated with an increased risk of cognitive impairment in elderly women, independent of sociodemographic, lifestyle, and health-related comorbid factors. Our results suggest weight management of elderly women in rural China may have cognitive benefits. However, randomized controlled trials would be needed to confirm causality.
Structural and Functional Connectivity Substrates of Cognitive Impairment in Multiple Sclerosis
Authors: Zhang Jian , Cortese Rosa , De Stefano Nicola , Giorgio Antonio
Published: July 2021

Cognitive impairment (CI) occurs in 43 to 70% of multiple sclerosis (MS) patients at both early and later disease stages. Cognitive domains typically involved in MS include attention, information processing speed, memory, and executive control. The growing use of advanced magnetic resonance imaging (MRI) techniques is furthering our understanding on the altered structural connectivity (SC) and functional connectivity (FC) substrates of CI in MS. Regarding SC, different diffusion tensor imaging (DTI) measures (e.g., fractional anisotropy, diffusivities) along tractography-derived white matter (WM) tracts showed relevance toward CI. Novel diffusion MRI techniques, including diffusion kurtosis imaging, diffusion spectrum imaging, high angular resolution diffusion imaging, and neurite orientation dispersion and density imaging, showed more pathological specificity compared to the traditional DTI but require longer scan time and mathematical complexities for their interpretation. As for FC, task-based functional MRI (fMRI) has been traditionally used in MS to brain mapping the neural activity during various cognitive tasks. Analysis methods of resting fMRI (seed-based, independent component analysis, graph analysis) have been applied to uncover the functional substrates of CI in MS by revealing adaptive or maladaptive mechanisms of functional reorganization. The relevance for CI in MS of SC–FC relationships, reflecting common pathogenic mechanisms in WM and gray matter, has been recently explored by novel MRI analysis methods. This review summarizes recent advances on MRI techniques of SC and FC and their potential to provide a deeper understanding of the pathological substrates of CI in MS.
Peripheral Nerve Focused Ultrasound Lesioning—Visualization and Assessment Using Diffusion Weighted Imaging
Authors: Walker Matthew R. , Zhong Jidan , Waspe Adam C. , Piorkowska Karolina , Nguyen Lananh N. , Anastakis Dimitri J. , Drake James M. , Hodaie Mojgan
Published: July 2021

Objectives: Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive targeted tissue ablation technique that can be applied to the nervous system. Diffusion weighted imaging (DWI) can visualize and evaluate nervous system microstructure. Tractography algorithms can reconstruct fiber bundles which can be used for treatment navigation and diffusion tensor imaging (DTI) metrics permit the quantitative assessment of nerve microstructure in vivo. There is a need for imaging tools to aid in the visualization and quantitative assessment of treatment-related nerve changes in MRgFUS. We present a method of peripheral nerve tract reconstruction and use DTI metrics to evaluate the MRgFUS treatment effect.

Materials and Methods: MRgFUS was applied bilaterally to the sciatic nerves in 6 piglets (12 nerves total). T1-weighted and diffusion images were acquired before and after treatment. Tensor-based and constrained spherical deconvolution (CSD) tractography algorithms were used to reconstruct the nerves. DTI metrics of fractional anisotropy (FA), and mean (MD), axial (AD), and radial diffusivities (RD) were measured to assess acute (<1–2 h) treatment effects. Temperature was measured in vivo via MR thermometry. Histological data was collected for lesion assessment.

Results: The sciatic nerves were successfully reconstructed in all subjects. Tract disruption was observed after treatment using both CSD and tensor models. DTI metrics in the targeted nerve segments showed significantly decreased FA and increased MD, AD, and RD. Transducer output power was positively correlated with lesion volume and temperature and negatively correlated with MD, AD, and RD. No correlations were observed between FA and other measured parameters.

Conclusions: DWI and tractography are effective tools for visualizing peripheral nerve segments for targeting in non-invasive surgical methods and for assessing the microstructural changes that occur following MRgFUS treatment.
Reliability and Validity of Alzheimer's Disease Screening With a Semi-automated Smartphone Application Using Verbal Fluency
Authors: Kwon Soon Jai , Kim Hye Sung , Han Ji Hyun , Bae Jong Bin , Han Ji Won , Kim Ki Woong
Published: July 2021

Introduction: This study aimed to examine the reliability and validity of Alzheimer's disease (AD) screening with a self-administered categorical verbal fluency test using a semi-automated Android application (app; tCVFT). Furthermore, its diagnostic accuracy concerning AD was compared with both that of a conventional categorical verbal fluency test (cCVFT) administered by a health professional and the Mini-Mental State Examination (MMSE).

Materials and Methods: Participants included 100 community-dwelling patients with early AD, whose Clinical Dementia Rating was either 0.5 or 1, and a further 100 sex-matched cognitively normal controls. The internal consistency and test-retest reliability of the tCVFT weighted sum score (tCVFT-WS) was examined using Cronbach's alpha and Pearson's correlation analyses (adjusted for age and education), respectively. The concurrent validity of the tCVFT-WS was examined by testing its correlations with the cCVFT weighted sum score (cCVFT-WS) and MMSE using Pearson's correlation tests. The diagnostic accuracies for early AD of the tCVFT-WS, cCVFT-WS, and MMSE were estimated and compared using receiver operating characteristic (ROC) analyses.

Results: The tCVFT-WS exhibited strong internal consistency (Cronbach's alpha = 0.79). However, its test-retest reliability was moderate (r = 0.54) owing to the low test-retest reliability of the second-half responses. The patient group exhibited a higher tCVFT-WS than the control group (p < 0.001). Correlations between the tCVFT-WS, cCVFT-WS, and MMSE were significant. The tCVFT-WS's area under the ROC curve for AD was 0.861. At its optimal cutoff, the sensitivity and specificity for AD were 0.78 and 0.77, respectively.

Conclusions: The self-administered tCVFT-WS, using an Android app, proved valid and reliable at distinguishing people with early AD from cognitively normal controls.
Treatment of Intracranial Aneurysms Using the New Silk Vista Flow Diverter: Safety Outcomes at Short-Term Follow-Up
Authors: Pumar José M. , Mosqueira Antonio , Olier Jorge , Rodriguez-Fernandez Claudio , Vega Pedro , Gonzalez-Diaz Eva
Published: July 2021

Background: Flow diverters are widely used as the first endovascular treatment option for complex brain aneurysms due to their high percentage of occlusion and low morbi-mortality. The Silk Vista device is a new generation of flow diverters designed to facilitate full visibility, improve apposition to the vessel wall, and enhance navigability. Indeed, its greatest advantage is that it enables the easier navigation of stents between 3.5 and 4.75 mm through a 0.021 microcatheter. The objective of this study was to evaluate the safety and effectiveness of Silk Vista systems for treating cerebral aneurysms.

Methods: This prospective observational study included 25 consecutive patients with 27 wide-necked unruptured aneurysms treated with SILK Vista who were retrospectively analyzed for safety and efficacy.

Results: Endovascular treatment was successfully performed in all patients. The final morbidity and mortality rates were both 0.0%. Short-term (3–5 months) angiographic follow-up revealed 21 complete occlusions and 6 near-complete occlusions. No significant parent artery stenosis was observed.

Conclusions: This report demonstrates the efficacy of Silk Vista in treating brain aneurysms, although longer experiences should be carried out to confirm our results.
Behavioral Approaches to Study Top-Down Influences on Active Listening
Authors: Clayton Kameron K. , Asokan Meenakshi M. , Watanabe Yurika , Hancock Kenneth E. , Polley Daniel B.
Published: July 2021

The massive network of descending corticofugal projections has been long-recognized by anatomists, but their functional contributions to sound processing and auditory-guided behaviors remain a mystery. Most efforts to characterize the auditory corticofugal system have been inductive; wherein function is inferred from a few studies employing a wide range of methods to manipulate varying limbs of the descending system in a variety of species and preparations. An alternative approach, which we focus on here, is to first establish auditory-guided behaviors that reflect the contribution of top-down influences on auditory perception. To this end, we postulate that auditory corticofugal systems may contribute to active listening behaviors in which the timing of bottom-up sound cues can be predicted from top-down signals arising from cross-modal cues, temporal integration, or self-initiated movements. Here, we describe a behavioral framework for investigating how auditory perceptual performance is enhanced when subjects can anticipate the timing of upcoming target sounds. Our first paradigm, studied both in human subjects and mice, reports species-specific differences in visually cued expectation of sound onset in a signal-in-noise detection task. A second paradigm performed in mice reveals the benefits of temporal regularity as a perceptual grouping cue when detecting repeating target tones in complex background noise. A final behavioral approach demonstrates significant improvements in frequency discrimination threshold and perceptual sensitivity when auditory targets are presented at a predictable temporal interval following motor self-initiation of the trial. Collectively, these three behavioral approaches identify paradigms to study top-down influences on sound perception that are amenable to head-fixed preparations in genetically tractable animals, where it is possible to monitor and manipulate particular nodes of the descending auditory pathway with unparalleled precision.
Semi-Supervised Support Vector Machine for Digital Twins Based Brain Image Fusion
Authors: Wan Zhibo , Dong Youqiang , Yu Zengchen , Lv Haibin , Lv Zhihan
Published: July 2021

The purpose is to explore the feature recognition, diagnosis, and forecasting performances of Semi-Supervised Support Vector Machines (S3VMs) for brain image fusion Digital Twins (DTs). Both unlabeled and labeled data are used regarding many unlabeled data in brain images, and semi supervised support vector machine (SVM) is proposed. Meantime, the AlexNet model is improved, and the brain images in real space are mapped to virtual space by using digital twins. Moreover, a diagnosis and prediction model of brain image fusion digital twins based on semi supervised SVM and improved AlexNet is constructed. Magnetic Resonance Imaging (MRI) data from the Brain Tumor Department of a Hospital are collected to test the performance of the constructed model through simulation experiments. Some state-of-art models are included for performance comparison: Long Short-Term Memory (LSTM), Convolutional Neural Network (CNN), Recurrent Neural Network (RNN), AlexNet, and Multi-Layer Perceptron (MLP). Results demonstrate that the proposed model can provide a feature recognition and extraction accuracy of 92.52%, at least an improvement of 2.76% compared to other models. Its training lasts for about 100 s, and the test takes about 0.68 s. The Root Mean Square Error (RMSE) and Mean Absolute Error (MAE) of the proposed model are 4.91 and 5.59%, respectively. Regarding the assessment indicators of brain image segmentation and fusion, the proposed model can provide a 79.55% Jaccard coefficient, a 90.43% Positive Predictive Value (PPV), a 73.09% Sensitivity, and a 75.58% Dice Similarity Coefficient (DSC), remarkably better than other models. Acceleration efficiency analysis suggests that the improved AlexNet model is suitable for processing massive brain image data with a higher speedup indicator. To sum up, the constructed model can provide high accuracy, good acceleration efficiency, and excellent segmentation and recognition performances while ensuring low errors, which can provide an experimental basis for brain image feature recognition and digital diagnosis.
Age-Related Transcriptional Deregulation of Genes Coding Synaptic Proteins in Alzheimer's Disease Murine Model: Potential Neuroprotective Effect of Fingolimod
Authors: Jęśko Henryk , Wieczorek Iga , Wencel Przemysław Leonard , Gąssowska-Dobrowolska Magdalena , Lukiw Walter J. , Strosznajder Robert Piotr
Published: July 2021

Alzheimer's disease (AD) induces time-dependent changes in sphingolipid metabolism, which may affect transcription regulation and neuronal phenotype. We, therefore, analyzed the influence of age, amyloid β precursor protein (AβPP), and the clinically approved, bioavailable sphingosine-1-phosphate receptor modulator fingolimod (FTY720) on the expression of synaptic proteins. RNA was isolated, reverse-transcribed, and subjected to real-time PCR. Expression of mutant (V717I) AβPP led to few changes at 3 months of age but reduced multiple mRNA coding for synaptic proteins in a 12-month-old mouse brain. Complexin 1 (Cplx1), SNAP25 (Snap25), syntaxin 1A (Stx1a), neurexin 1 (Nrxn1), neurofilament light (Nefl), and synaptotagmin 1 (Syt1) in the hippocampus, and VAMP1 (Vamp1) and neurexin 1 (Nrxn1) in the cortex were all significantly reduced in 12-month-old mice. Post mortem AD samples from the human hippocampus and cortex displayed lower expression of VAMP, synapsin, neurofilament light (NF-L) and synaptophysin. The potentially neuroprotective FTY720 reversed most AβPP-induced changes in gene expression (Cplx1, Stx1a, Snap25, and Nrxn1) in the 12-month-old hippocampus, which is thought to be most sensitive to early neurotoxic insults, but it only restored Vamp1 in the cortex and had no influence in 3-month-old brains. Further study may reveal the potential usefulness of FTY720 in the modulation of deregulated neuronal phenotype in AD brains.
Spatiotemporal Regulation of Transcript Isoform Expression in the Hippocampus
Authors: Park Joun , Farris Shannon
Published: July 2021

Proper development and plasticity of hippocampal neurons require specific RNA isoforms to be expressed in the right place at the right time. Precise spatiotemporal transcript regulation requires the incorporation of essential regulatory RNA sequences into expressed isoforms. In this review, we describe several RNA processing strategies utilized by hippocampal neurons to regulate the spatiotemporal expression of genes critical to development and plasticity. The works described here demonstrate how the hippocampus is an ideal investigative model for uncovering alternate isoform-specific mechanisms that restrict the expression of transcripts in space and time.
Challenges of Diagnosing Primary Ewing’s Sarcoma in the Small Intestine of the Elderly: A Case Report
Authors: Yang Jianchuan , Wei Hong , Lin Yucheng , Lin Ning , Wu Songsong , Yu Xunbin
Published: July 2021

Extraosseous Ewing’s sarcoma (EES) is a malignant tumor that is classified as a rare disease. EES is common in children and adolescents, with a rarer incidence being present in the elderly. ES of the primary intestine is rare, with only a few reports described in the literature. Here we report a case of a 69-year-old male patient who was experiencing abdominal pain for over 3 months. Ultrasonography (US) revealed a solid hypoechoic lesion with multiple irregular necrotic areas in the left lower abdomen close to the dome of the bladder. Contrast-enhanced ultrasonography (CEUS) showed that the lesion exhibited heterogeneous enhancement and quick peripheral enhanced tissue wash-out classifying this mass as malignant. PET–CT showed a high metabolic mass in the lower abdomen, multiple metabolic nodules in the mesentery, considered as a small intestinal stromal tumor with lymph nodes metastasis, and that a diagnosis of lymphoma should be excluded. Esophagogastroduodenoscopy performed at another hospital 1 month prior to CT showed an abnormal density in the pelvic cavity that was considered as a colonic diverticulum with an abscess. The endoscopy showed no obvious occupying lesions. The mass was removed and postoperative pathology confirmed ES of the small intestine. The patient avoided receiving chemotherapy. After 2 months, skull metastasis was diagnosed and surgical intervention was done. His survival was only six months after the second surgery. To our knowledge, our case is the first report of ultrasound and CEUS manifestation of EES in the small intestine in elderly.
Association of Sarcopenia With Toxicity and Survival in Postoperative Recurrent Esophageal Squamous Cell Carcinoma Patients Receiving Chemoradiotherapy
Authors: Xu Ying-Ying , Zhou Xi-Lei , Yu Chang-Hua , Wang Wan-Wei , Ji Fu-Zhi , He Dong-Cheng , Zhu Wei-Guo , Tong Yu-Suo
Published: July 2021

Background

Sarcopenia has been associated with treatment-related toxicities and poor survival in cancer patients. Our aim was to investigate the prevalence of sarcopenia in postoperative recurrent esophageal squamous cell carcinoma (ESCC) patients receiving chemoradiotherapy (CRT) and evaluate associations with treatment-related toxicity and prognosis.

Methods

One hundred and eighty-four patients with postoperative locoregional recurrent ESCC receiving CRT between January 2014 and December 2016 were included. The skeletal muscle area (SMA) was measured at the third lumbar vertebra level. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height2) less than 47.24/cm2/m2 for men and 36.92/cm2/m2 for women. Association of sarcopenia with overall survival (OS) was analyzed using univariate and multivariate cox regression models.

Results

Sarcopenia was observed in 94 of 184 (51.1%) patients. Sarcopenic patients had significantly higher rates of grade 3-4 toxicities compared to those without sarcopenia (36.2% vs 21.1%, p = 0.034). The survival rate at 12 and 24 months was 36.2% and 3.2% in the sarcopenic patients and 57.8% and 17.8% in the non-sarcopenic patients (p < 0.001). Multivariate cox regression analysis showed that sarcopenia was significantly associated with decreased OS (HR = 1.729, 95% CI 1.231-2.428, p = 0.002).

Conclusions

Sarcopenia is an independent indicator of poor survival in postoperative locoregional recurrent ESCC patients treated with CRT. Early nutritional interventions before treatment may improve the prognosis.
A Network Meta-Analysis of Cancer Immunotherapies Versus Chemotherapy for First-Line Treatment of Patients With Non-Small Cell Lung Cancer and High Programmed Death-Ligand 1 Expression
Authors: Herbst Roy , Jassem Jacek , Abogunrin Seye , James Daniel , McCool Rachael , Belleli Rossella , Giaccone Giuseppe , De Marinis Filippo
Published: July 2021

In the absence of head-to-head trials of first-line treatments for metastatic non-small cell lung cancer (NSCLC), synthesis of available evidence is needed. We conducted a systematic literature review and network meta-analysis of randomized controlled trials in patients with stage IV NSCLC and high programmed death-ligand 1 (PD-L1) expression. Patients with other-stage NSCLC or without PD-L1 expression and populations with < 80% stage IV NSCLC were excluded. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events. English records from MEDLINE and Embase published through October 2020 were eligible, supplemented by hand searches of other sources. Three evidence networks were constructed based on histology (mixed, squamous, non-squamous). OS and PFS results were analyzed applying Bayesian fractional polynomial random-effects models. Hazard ratios over time with 95% credible intervals (CrIs) and expected differences in OS and PFS between each cancer immunotherapy regimen and the chemotherapy common comparator were generated. Seventeen clinical trials were included after screening 32,527 records. Heterogeneity and risk of bias were generally low across trials. In the mixed-histology network of PD-L1–high patients, expected OS was significantly longer with atezolizumab (estimated difference: 10.4 months [95% CrI: 1.9, 18.2]), pembrolizumab (7.2 [2.2, 12.3]), and cemiplimab (13.0 [4.2, 21.0]) versus chemotherapy but not with nivolumab (3.5 [−2.5, 10.6]) or nivolumab plus ipilimumab (6.7 [−0.5, 14.2]) versus chemotherapy. OS improvements were not significant compared with chemotherapy for any regimen in the squamous and non-squamous networks, except pembrolizumab plus chemotherapy in the non-squamous network. All regimens showed significantly longer expected PFS versus chemotherapy in the non-squamous network, whereas the increases were not significant in the mixed or squamous networks. ORR was significantly higher with pembrolizumab and cemiplimab versus chemotherapy in the mixed-histology network, with sintilimab in the non-squamous network, and with combination regimens, including pembrolizumab or atezolizumab, in the squamous and non-squamous networks, except with atezolizumab plus carboplatin, paclitaxel, and bevacizumab. Survival and safety versus chemotherapy were generally similar across cancer immunotherapies and histology networks. These findings may support treatment decisions for patients with high PD-L1 status receiving first-line treatment for NSCLC.
The Emerging Role of Poly (ADP-Ribose) Polymerase Inhibitors as Effective Therapeutic Agents in Renal Cell Carcinoma
Authors: Pletcher Jerred P. , Bhattacharjee Sayani , Doan Jonathan P. , Wynn Rebecca , Sindhwani Puneet , Nadiminty Nagalakshmi , Petros Firas G.
Published: July 2021

Renal cell carcinoma (RCC) is the sixth most common cancer in the US. However, no significant changes in management have occurred since the tyrosine kinase era until the recent breakthrough with checkpoint inhibitors. Therefore, the need for more therapeutic options is paramount. Our objective was to determine whether PARP inhibition represents a novel therapeutic option for RCC. We used publicly available COSMIC, GDC Data Portal, and cBioPortal databases to explore mutations in DNA repair genes in RCC tissues from the TCGA cohort. We treated a human normal renal epithelial cell line RPTEC/TERT1 and two human renal cancer cell lines ACHN and CAKI-2 with PARPi niraparib, olaparib, rucaparib, veliparib, and talazoparib. Cell survival, cell proliferation, clonogenic ability, and apoptosis were assessed. RCC xenografts in SCID mice were treated with PARPi to evaluate their efficacy in vivo. Data mining revealed that ~27-32% of RCC tissues contain mutations in homologous recombination genes. Niraparib and talazoparib were the most effective at reducing cell survival, proliferation, and clonogenic ability in vitro. Niraparib, talazoparib, and rucaparib were the most effective in reducing RCC xenograft growth in vivo. Agents such as PARPi that exploit mutations in DNA damage repair genes may be effective therapeutic options for RCC.
Molecular Interplays Between Cell Invasion and Radioresistance That Lead to Poor Prognosis in Head-Neck Cancer
Authors: You Guo-Rung , Chang Joseph T. , Li Yan-Liang , Chen Yin-Ju , Huang Yu-Chen , Fan Kang-Hsing , Chen Yen-Chao , Kang Chung-Jan , Cheng Ann-Joy
Published: July 2021

Background

Cancer metastasis and recurrence after radiotherapy are the significant causes of poor prognosis in head-neck cancer (HNC). Clinically, it is commonly found that patients with either condition may accompany the outcome of the other. We hypothesized that HNC cells might exhibit a cross-phenotypic attribute between cell invasion and radioresistance. To discover effective biomarkers for the intervention of aggressive cancer at one time, the potential molecules that interplay between these two phenotypes were investigated.

Materials and Methods

Three isogenic HNC cell sublines with high invasion or radioresistance properties were established. Transcriptomic and bioinformatic methods were used to globally assess the phenotypic-specific genes, functional pathways, and co-regulatory hub molecules. The associations of gene expressions with patient survival were analyzed by Kaplan-Meier plotter, a web-based tool, using the HNSCC dataset (n=500). The molecular and cellular techniques, including RT-qPCR, flow cytometry, cell invasion assay, and clonogenic survival assay, were applied.

Results

The phenotypic crosstalk between cell invasion and radioresistance was validated, as shown by the existence of mutual properties in each HNC subline. A total of 695 genes was identified in associations with these two phenotypes, including 349 upregulated and 346 downregulated in HNC cells. The focal adhesion mechanism showed the most significant pathway to co-regulate these functions. In the analysis of 20 up-regulatory genes, a general portrait of correlative expression was found between these phenotypic cells (r=0.513, p=0.021), and nine molecules exhibited significant associations with poor prognosis in HNC patients (HR>1, p<0.050). Three hub genes were identified (ITGA6, TGFB1, and NDRG1) that represented a signature of interplayed molecules contributing to cell invasion, radioresistance and leading to poor prognosis. The ITGA6 was demonstrated as a prominent biomarker. The expression of ITGA6 correlated with the levels of several extracellular and apoptotic/anti-apoptotic molecules. Functionally, silencing ITGA6 suppressed cell migration, invasion, and attenuated radioresistance in HNC cells.

Conclusions

A panel of interplay molecules was identified that contribute to cell invasion and radioresistance, leading to poor prognosis. These panel molecules, such as ITGA6, may serve as predictive markers of radioresistance, prognostic markers of metastasis, and molecular therapeutic targets for refractory HNC.
Modulation of Astrocytic Glutamine Synthetase by Endocannabinoid 2-Arachidonoylglycerol in JNK-Independent Pathway
Authors: Wang Jing , Wang Shenghong , Zhang Hua
Published: July 2021

Background and Objective: The glutamine synthetase (GS), an astrocyte-specific enzyme, plays an important role in neuroprotection through the glutamate/glutamine shuttle and can be modulated by endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) through extracellular signal-regulated protein kinase ½ (ERK1/2) and p38 signaling pathways. However, the role of c-Jun N-terminal kinase (JNK) signaling pathway in the modulation of GS in astrocytes by 2-AG is not clear.

Materials and Methods: The expression of GS and JNK in astrocytes following the exposure to lipopolysaccharide (LPS) was examined with Western blotting and immunochemistry.

Results: The results revealed that short-term exposure to LPS activated GS and increased phosphorylation of JNK in astrocytes in a time-dependent manner. Treatment with 2-AG reversed the changes in GS but had no effect on the activation of JNK.

Conclusions: These findings suggest that the activation of JNK induced by LPS is not involved in the modulation of astrocytic GS by 2-AG.
CS-semi5 Inhibits NF-κB Activation to Block Synovial Inflammation, Cartilage Loss and Bone Erosion Associated With Collagen-Induced Arthritis
Authors: Li Xiang , Tang Xiaonan , Wang Yufei , Chai Changwei , Zhao Zhehui , Zhang Haijing , Peng Ying , Wu Lianqiu
Published: July 2021

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that affects 1% of the population. CS-semi5 is a semisynthetic chondroitin sulfate. In this study, CS-semi5 was shown to have positive effects on a model of collagen-induced arthritis (CIA). CS-semi5 treatment had obvious effects on weight loss and paw swelling in CIA mice. Post-treatment analysis revealed that CS-semi5 alleviated three main pathologies (i.e., synovial inflammation, cartilage erosion and bone loss) in a dose-dependent manner. Further study showed that CS-semi5 could effectively reduce TNF‐α and IL‐1β production in activated macrophages via the NF‐κB pathway. CS-semi5 also blocked RANKL-trigged osteoclast differentiation from macrophages. Therefore, CS-semi5 may effectively ameliorate synovial inflammation, cartilage erosion and bone loss in RA through NF-κB deactivation.
Therapeutic Effects of Traditional Chinese Medicine on Cardiovascular Diseases: the Central Role of Calcium Signaling
Authors: Li Yuxin , Zhang Zhang , Li Sen , Yu Tingting , Jia Zhaoqi
Published: July 2021

Calcium, as a second messenger, plays an important role in the pathogenesis of cardiovascular diseases (CVDs). The malfunction of calcium signaling in endothelial cells and vascular smooth muscle cells promotes hypertension. In cardiomyocytes, calcium overload induces apoptosis, leading to myocardial infarction and arrhythmias. Moreover, the calcium–calcineurin–nuclear factor of activated T cells (NFAT) pathway is essential for expressing the cardiac pro-hypertrophic gene. Heart failure is also characterized by reduced calcium transient amplitude and enhanced sarcoplasmic reticulum (SR) calcium leakage. Traditional Chinese medicine (TCM) has been used to treat CVDs for thousands of years in China. Because of its multicomponent and multitarget characteristics, TCM's unique advantages in CVD treatment are closely related to the modulation of multiple calcium handling proteins and calcium signaling pathways in different types of cells involved in distinct CVDs. Thus, we systematically review the diverse mechanisms of TCM in regulating calcium pathways to treat various types of CVDs, ranging from hypertrophic cardiomyopathy to diabetic heart disease.
PPM-18, an Analog of Vitamin K, Induces Autophagy and Apoptosis in Bladder Cancer Cells Through ROS and AMPK Signaling Pathways
Authors: Lu Huiai , Mei Chunlei , Yang Luhao , Zheng Junyan , Tong Junwei , Duan Fengsen , Liang Huageng , Hong Ling
Published: July 2021

PPM-18, identified as a novel analog of vitamin K, has been reported to play a critical role in the suppression of seizures. However, the concerns that whether PPM-18, like vitamin K, exerts anticancer activity remain to be further investigated. Here, we found that PPM-18 remarkably suppressed the proliferation and induced apoptosis in bladder cancer cells. Furthermore, a significant autophagic effect of PPM-18 on bladder cancer cells was also demonstrated, which profoundly promoted apoptotic cell death. Mechanistically, PPM-18 activated AMP-activated protein kinase (AMPK), whereas it repressed PI3K/AKT and mTORC1 pathways in bladder cancer cells. Inhibition of AMPK markedly relieved PPM-18–induced autophagy and apoptosis, indicating that PPM-18 is able to induce autophagy and apoptosis in bladder cancer cells via AMPK activation. Moreover, reactive oxygen species (ROS) were notably accumulated in PPM-18–treated bladder cancer cells, and treatment with ROS scavengers not only eliminated ROS production but also abrogated AMPK activation, which eventually rescued bladder cancer cells from PPM-18–triggered autophagy and apoptotic cell death. In bladder cancer xenografts, the anticancer activities of PPM-18, including suppressing the growth of tumors and inducing autophagy and apoptosis in tumor cells, were also established. Collectively, this study was the first to demonstrate the anticancer effect of PPM-18 on bladder cancer cells in vitro and in vivo through eliciting autophagy and apoptosis via ROS and AMPK pathways, which might provide new insights into the potential utilization of PPM-18 for future bladder cancer treatment.
The Association Between STX1B Polymorphisms and Treatment Response in Patients With Epilepsy
Authors: Wang Shitao , Zhou Liang , He Chenglu , Wang Dan , Cai Xuemei , Yu Yanying , Chen Liling , Lu Di , Bian Ligong , Du Sunbing , Wu Qian , Han Yanbing
Published: July 2021

Background: Epilepsy is a debilitating brain disease with complex inheritance and frequent treatment resistance. However, the role of STX1B single nucleotide polymorphisms (SNPs) in epilepsy treatment remains unknown.

Objective: This study aimed to explore the genetic association of STX1B SNPs with treatment response in patients with epilepsy in a Han Chinese population.

Methods: We first examined the associations between STX1B SNPs and epilepsy in 1000 Han Chinese and the associations between STX1B SNPs and drug-resistant epilepsy in 450 subjects. Expression quantitative trait loci analysis was then conducted using 16 drug-resistant epileptic brain tissue samples and results from the BrainCloud database (http://eqtl.brainseq.org).

Results: The allelic frequencies of rs140820592 were different between the epilepsy and control groups (p = 0.002) after Bonferroni correction. The rs140820592 was associated with significantly lower epilepsy risk among 1,000 subjects in the dominant model after adjusting for gender and age and Bonferroni correction (OR = 0.542, 95%CI = 0.358–0.819, p = 0.004). The rs140820592 also conferred significantly lower risk of drug-resistant epilepsy among 450 subjects using the same dominant model after adjusting for gender and age and Bonferroni correction (OR = 0.260, 95%CI = 0.103–0.653, p = 0.004). Expression quantitative trait loci analysis revealed that rs140820592 was associated with STX1B expression level in drug-resistant epileptic brain tissues (p = 0.012), and this result was further verified in the BrainCloud database (http://eqtl.brainseq.org) (p = 2.3214 × 10–5).

Conclusion: The STX1B rs140820592 may influence the risks of epilepsy and drug-resistant epilepsy by regulating STX1B expression in brain tissues.
AT1R Regulates Macrophage Polarization Through YAP and Regulates Aortic Dissection Incidence
Authors: Wang Xinhao , Zhang Hongpeng , Ge Yangyang , Cao Long , He Yuan , Sun Guoyi , Jia Senhao , Ma Airong , Liu Jie , Rong Dan , Guo Wei
Published: July 2021

Aortic dissection (AD) is one of the most fatal cardiovascular emergency. At the anatomical level, AD occurs due to the formation of intimal tears. However, the molecular mechanism underlying this phenomenon remains unknown. Angiotensin II (Ang II) is a important effector in the development of cardiovascular disease that acts through binding to angiotensin type 1 receptor (AT1R). Yes-associated protein (YAP) was recently recognized as a key protein in macrophage activation. To determine whether AT1R and YAP are involved in macrophage-induced endothelial cell (EC) inflammation and AD incidence, we co-cultured THP-1 cells and HAECs in transwell chambers under different culture conditions and apply different conditions to the AD mice model. The results showed that Ang II promoted macrophage M1 polarization and adhesion, upregulated YAP phosphorylation, and induced EC injury that was related to increased levels of multiple pro-inflammatory chemokines. Blocking AT1R function pharmacologically or by transfection with AT1R siRNA can reduce the pro-inflammatory effect induced by Ang II. In addition, siRNA knock down of YAP expression further aggravated the pro-inflammatory effects of Ang II. Treatment with ARB effectively alleviated these pro-inflammatory effects. In the mice AD model, ARB effectively reduced the incidence of AD in mice, decreased M1 macrophages infiltration and AT1R content in the aortic wall and increased the tissue content of YAP. We found that AT1R induces YAP phosphorylation through binding to Ang II, and further promotes macrophage M1 polarization and adhesion to ECs. ARB reduces the incidence of AD in mice and affect macrophage polarization in mice aorta.
Endothelial Nitric Oxide Production and Antioxidant Response in Breath-Hold Diving: Genetic Predisposition or Environment Related?
Authors: Cialoni Danilo , Brizzolari Andrea , Samaja Michele , Bosco Gerardo , Paganini Matteo , Sponsiello Nicola , Lancellotti Valentina , Marroni Alessandro
Published: July 2021

Introduction

Nitric oxide (NO) is an essential signaling molecule modulating the endothelial adaptation during breath-hold diving (BH-diving). This study aimed to investigate changes in NO derivatives (NOx) and total antioxidant capacity (TAC), searching for correlations with different environmental and hyperbaric exposure.

Materials and methods

Blood samples were obtained from 50 breath-hold divers (BH-divers) before, and 30 and 60 min after the end of training sessions performed both in a swimming pool or the sea. Samples were tested for NOx and TAC differences in different groups related to their hyperbaric exposure, experience, and additional genetic polymorphism.

Results

We found statistically significant differences in NOx plasma concentration during the follow-up (decrease at T30 and increase at T60) compared with the pre-dive values. At T30, we found a significantly lower decrease of NOx in subjects with a higher diving experience, but no difference was detected between the swimming pool and Sea. No significant difference was found in TAC levels, as well as between NOx and TAC levels and the genetic variants.

Conclusion

These data showed how NO consumption in BH-diving is significantly lower in the expert group, indicating a possible training-related adaptation process. Data confirm a significant NO use during BH-diving, compatible with the well-known BH-diving related circulatory adaptation suggesting that the reduction in NOx 30 min after diving can be ascribed to the lower NO availability in the first few minutes after the dives. Expert BH-divers suffered higher oxidative stress. A preliminary genetic investigation seems to indicate a less significant influence of genetic predisposition.
Multi-Locus Genome-Wide Association Study and Genomic Selection of Kernel Moisture Content at the Harvest Stage in Maize
Authors: Zhou Guangfei , Zhu Qiuli , Mao Yuxiang , Chen Guoqing , Xue Lin , Lu Huhua , Shi Mingliang , Zhang Zhenliang , Song Xudong , Zhang Huimin , Hao Derong
Published: July 2021

Kernel moisture content at the harvest stage (KMC) is an important trait that affects the mechanical harvesting of maize grain, and the identification of genetic loci for KMC is beneficial for maize molecular breeding. In this study, we performed a multi-locus genome-wide association study (ML-GWAS) to identify quantitative trait nucleotides (QTNs) for KMC using an association mapping panel of 251 maize inbred lines that were genotyped with an Affymetrix CGMB56K SNP Array and phenotypically evaluated in three environments. Ninety-eight QTNs for KMC were detected using six ML-GWAS models (mrMLM, FASTmrMLM, FASTmrEMMA, PLARmEB, PKWmEB, and ISIS EM-BLASSO). Eleven of these QTNs were considered to be stable, as they were detected by at least four ML-GWAS models under a uniformed environment or in at least two environments and BLUP using the same ML-GWAS model. With qKMC5.6 removed, the remaining 10 stable QTNs explained <10% of the phenotypic variation, suggesting that KMC is mainly controlled by multiple minor-effect genetic loci. A total of 63 candidate genes were predicted from the 11 stable QTNs, and 10 candidate genes were highly expressed in the kernel at different time points after pollination. High prediction accuracy was achieved when the KMC-associated QTNs were included as fixed effects in genomic selection, and the best strategy was to integrate all KMC QTNs identified by all six ML-GWAS models. These results further our understanding of the genetic architecture of KMC and highlight the potential of genomic selection for KMC in maize breeding.
Anthropometric Indicators as a Tool for Diagnosis of Obesity and Other Health Risk Factors: A Literature Review
Authors: Piqueras Paola , Ballester Alfredo , Durá-Gil Juan V. , Martinez-Hervas Sergio , Redón Josep , Real José T.
Published: July 2021

Obesity is characterized by the accumulation of an excessive amount of fat mass (FM) in the adipose tissue, subcutaneous, or inside certain organs. The risk does not lie so much in the amount of fat accumulated as in its distribution. Abdominal obesity (central or visceral) is an important risk factor for cardiovascular diseases, diabetes, and cancer, having an important role in the so-called metabolic syndrome. Therefore, it is necessary to prevent, detect, and appropriately treat obesity. The diagnosis is based on anthropometric indices that have been associated with adiposity and its distribution. Indices themselves, or a combination of some of them, conform to a big picture with different values to establish risk. Anthropometric indices can be used for risk identification, intervention, or impact evaluation on nutritional status or health; therefore, they will be called anthropometric health indicators (AHIs). We have found 17 AHIs that can be obtained or estimated from 3D human shapes, being a noninvasive alternative compared to X-ray-based systems, and more accessible than high-cost equipment. A literature review has been conducted to analyze the following information for each indicator: definition; main calculation or obtaining methods used; health aspects associated with the indicator (among others, obesity, metabolic syndrome, or diabetes); criteria to classify the population by means of percentiles or cutoff points, and based on variables such as sex, age, ethnicity, or geographic area, and limitations.
How Do Specific Social Supports (Family, Friend, and Specialist) Reduce Stress in Patients With Substance Use Disorders: A Multiple Mediation Analysis
Authors: Yang Chunyu , Xia Mengfan , Li Tianshu , Zhou You
Published: July 2021

Perceived social support has been found to reduce the stress of individuals who suffer from substance use disorders. However, the mediating effects of resilience and affect balance in the relationships between specific social supports (family, friend, and significant others) and perceived stress are still unclear. This study focused on substance use disorders (SUD) patients, exploring the mediating roles of resilience and affect balance on the relationships between three dimensions of social supports (family, friend, and specialist) and stress. Three hundred thirty-nine participants completed questionnaires of perceived social support, resilience, affect balance, and stress. After controlling resilience and affect balance, the results suggested the effects of perceived family and specialist supports on perceived stress were fully mediated, and the association between perceived friend support and perceived stress is partially mediated. The multiple mediation analysis showed resilience is significant in mediating the relationship between specific perceived supports in all models, while affect balance is only significant in mediating the relationship between specialist support and perceived stress. Implications for enriching current theoretical research and strategies for government and practitioners were also discussed.