bluuebunny/crossref_metadata_2025 huggingface dataset:
X-Vectors: New Quantitative Biomarkers for Early Parkinson's Disease Detection From Speech
Authors: Jeancolas Laetitia , Petrovska-Delacrétaz Dijana , Mangone Graziella , Benkelfat Badr-Eddine , Corvol Jean-Christophe , Vidailhet Marie , Lehéricy Stéphane , Benali Habib
Published: February 2021

Many articles have used voice analysis to detect Parkinson's disease (PD), but few have focused on the early stages of the disease and the gender effect. In this article, we have adapted the latest speaker recognition system, called x-vectors, in order to detect PD at an early stage using voice analysis. X-vectors are embeddings extracted from Deep Neural Networks (DNNs), which provide robust speaker representations and improve speaker recognition when large amounts of training data are used. Our goal was to assess whether, in the context of early PD detection, this technique would outperform the more standard classifier MFCC-GMM (Mel-Frequency Cepstral Coefficients—Gaussian Mixture Model) and, if so, under which conditions. We recorded 221 French speakers (recently diagnosed PD subjects and healthy controls) with a high-quality microphone and via the telephone network. Men and women were analyzed separately in order to have more precise models and to assess a possible gender effect. Several experimental and methodological aspects were tested in order to analyze their impacts on classification performance. We assessed the impact of the audio segment durations, data augmentation, type of dataset used for the neural network training, kind of speech tasks, and back-end analyses. X-vectors technique provided better classification performances than MFCC-GMM for the text-independent tasks, and seemed to be particularly suited for the early detection of PD in women (7–15% improvement). This result was observed for both recording types (high-quality microphone and telephone).
Beating Rate Variability of Isolated Mammal Sinoatrial Node Tissue: Insight Into Its Contribution to Heart Rate Variability
Authors: Shemla Ori , Tsutsui Kenta , Behar Joachim A. , Yaniv Yael
Published: February 2021

Background

Because of the complexity of the interaction between the internal pacemaker mechanisms, cell interconnected signals, and interaction with other body systems, study of the role of individual systems must be performed under in vivo and in situ conditions. The in situ approach is valuable when exploring the mechanisms that govern the beating rate and rhythm of the sinoatrial node (SAN), the heart’s primary pacemaker. SAN beating rate changes on a beat-to-beat basis. However, to date, there are no standard methods and tools for beating rate variability (BRV) analysis from electrograms (EGMs) collected from different mammals, and there is no centralized public database with such recordings.

Methods

We used EGM recordings obtained from control SAN tissues of rabbits (n = 9) and mice (n = 30) and from mouse SAN tissues (n = 6) that were exposed to drug intervention. The data were harnessed to develop a beat detector to derive the beat-to-beat interval time series from EGM recordings. We adapted BRV measures from heart rate variability and reported their range for rabbit and mouse.

Results

The beat detector algorithm performed with 99% accuracy, sensitivity, and positive predictive value on the test (mouse) and validation (rabbit and mouse) sets. Differences in the frequency band cutoff were found between BRV of SAN tissue vs. heart rate variability (HRV) of in vivo recordings. A significant reduction in power spectrum density existed in the high frequency band, and a relative increase was seen in the low and very low frequency bands. In isolated SAN, the larger animal had a slower beating rate but with lower BRV, which contrasted the phenomena reported for in vivo analysis. Thus, the non-linear inverse relationship between the average HR and HRV is not maintained under in situ conditions. The beat detector, BRV measures, and databases were contributed to the open-source PhysioZoo software (available at: https://physiozoo.com/).

Conclusion

Our approach will enable standardization and reproducibility of BRV analysis in mammals. Different trends were found between beating rate and BRV or HRV in isolated SAN tissue vs. recordings collected under in vivo conditions, respectively, implying a complex interaction between the SAN and the autonomic nervous system in determining HRV in vivo.
nMNSD—A Spiking Neuron-Based Classifier That Combines Weight-Adjustment and Delay-Shift
Authors: Susi Gianluca , Antón-Toro Luis F. , Maestú Fernando , Pereda Ernesto , Mirasso Claudio
Published: February 2021

The recent “multi-neuronal spike sequence detector” (MNSD) architecture integrates the weight- and delay-adjustment methods by combining heterosynaptic plasticity with the neurocomputational feature spike latency, representing a new opportunity to understand the mechanisms underlying biological learning. Unfortunately, the range of problems to which this topology can be applied is limited because of the low cardinality of the parallel spike trains that it can process, and the lack of a visualization mechanism to understand its internal operation. We present here the nMNSD structure, which is a generalization of the MNSD to any number of inputs. The mathematical framework of the structure is introduced, together with the “trapezoid method,” that is a reduced method to analyze the recognition mechanism operated by the nMNSD in response to a specific input parallel spike train. We apply the nMNSD to a classification problem previously faced with the classical MNSD from the same authors, showing the new possibilities the nMNSD opens, with associated improvement in classification performances. Finally, we benchmark the nMNSD on the classification of static inputs (MNIST database) obtaining state-of-the-art accuracies together with advantageous aspects in terms of time- and energy-efficiency if compared to similar classification methods.
Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer’s Disease
Authors: Toledo Juan P. , Fernández-Pérez Eduardo J. , Ferreira Ildete L. , Marinho Daniela , Riffo-Lepe Nicolas O. , Pineda-Cuevas Benjamin N. , Pinochet-Pino Luis F. , Burgos Carlos F. , Rego A. Cristina , Aguayo Luis G.
Published: February 2021

Alzheimer’s disease (AD) is the most common cause of senile dementia worldwide, characterized by both cognitive and behavioral deficits. Amyloid beta peptide (Aβ) oligomers (AβO) have been found to be responsible for several pathological mechanisms during the development of AD, including altered cellular homeostasis and synaptic function, inevitably leading to cell death. Such AβO deleterious effects provide a way for identifying new molecules with potential anti-AD properties. Available treatments minimally improve AD symptoms and do not extensively target intracellular pathways affected by AβO. Naturally-derived compounds have been proposed as potential modifiers of Aβ-induced neurodysfunction and cytotoxicity based on their availability and chemical diversity. Thus, the aim of this study was to evaluate boldine, an alkaloid derived from the bark and leaves of the Chilean tree Peumus boldus, and its capacity to block some dysfunctional processes caused by AβO. We examined the protective effect of boldine (1–10 μM) in primary hippocampal neurons and HT22 hippocampal-derived cell line treated with AβO (24–48 h). We found that boldine interacts with Aβ in silico affecting its aggregation and protecting hippocampal neurons from synaptic failure induced by AβO. Boldine also normalized changes in intracellular Ca2+ levels associated to mitochondria or endoplasmic reticulum in HT22 cells treated with AβO. In addition, boldine completely rescued the decrease in mitochondrial membrane potential (ΔΨm) and the increase in mitochondrial reactive oxygen species, and attenuated AβO-induced decrease in mitochondrial respiration in HT22 hippocampal cells. We conclude that boldine provides neuroprotection in AD models by both direct interactions with Aβ and by preventing oxidative stress and mitochondrial dysfunction. Additional studies are required to evaluate the effect of boldine on cognitive and behavioral deficits induced by Aβ in vivo.
Cathodal Transcranial Direct Current Stimulation Over the Right Temporoparietal Junction Suppresses Its Functional Connectivity and Reduces Contralateral Spatial and Temporal Perception
Authors: Dalong Guo , Jiyuan Li , Yubin Zhou , Yufei Qin , Jinghua Yang , Cong Wang , Hongbo Jia
Published: February 2021

The temporoparietal junction plays key roles in vestibular function, motor-sensory ability, and attitude stability. Conventional approaches to studying the temporoparietal junction have drawbacks, and previous studies have focused on self-motion rather than on vestibular spatial perception. Using transcranial direct current stimulation, we explored the temporoparietal junction’s effects on vestibular-guided orientation for self-motion and vestibular spatial perception. Twenty participants underwent position, motion, and time tasks, as well as functional magnetic resonance imaging scans. In the position task, cathodal transcranial direct current stimulation yielded a significantly lower response in the −6, −7, −8, −9, −10, −11, and −12 stimulus conditions for leftward rotations (P < 0.05). In the time task, the temporal bias for real transcranial direct current stimulation significantly differed from that for sham stimulation (P < 0.01). Functional magnetic resonance imaging showed that cathodal transcranial direct current stimulation suppressed functional connectivity between the temporoparietal junction, right insular cortex, and right supplementary motor area. Moreover, the change in connectivity between the right temporoparietal junction seed and the right insular cortex was positively correlated with temporal bias under stimulation. The above mentioned results show that cathodal transcranial direct current stimulation induces immediate and extended vestibular effects, which could suppress the functional connectivity of the temporoparietal junction and in turn reduce contralateral spatial and temporal perception. The consistent variation in temporal and spatial bias suggested that the temporoparietal junction may be the cortical temporal integrator for the internal model. Moreover, transcranial direct current stimulation could modulate the integration process and may thus have potential clinical applications in vestibular disorders caused by temporoparietal junction dysfunction.
In vivo Genome Editing Therapeutic Approaches for Neurological Disorders: Where Are We in the Translational Pipeline?
Authors: Lubroth Pablo , Colasante Gaia , Lignani Gabriele
Published: February 2021

In vivo genome editing tools, such as those based on CRISPR, have been increasingly utilized in both basic and translational neuroscience research. There are currently nine in vivo non-CNS genome editing therapies in clinical trials, and the pre-clinical pipeline of major biotechnology companies demonstrate that this number will continue to grow. Several biotechnology companies commercializing in vivo genome editing and modification technologies are developing therapies for CNS disorders with accompanying large partnering deals. In this review, the authors discuss the current genome editing and modification therapy pipeline and those in development to treat CNS disorders. The authors also discuss the technical and commercial limitations to translation of these same therapies and potential avenues to overcome these hurdles.
Repetitive Peripheral Magnetic Stimulation of Wrist Extensors Enhances Cortical Excitability and Motor Performance in Healthy Individuals
Authors: Nito Mitsuhiro , Katagiri Natsuki , Yoshida Kaito , Koseki Tadaki , Kudo Daisuke , Nanba Shigehiro , Tanabe Shigeo , Yamaguchi Tomofumi
Published: February 2021

Repetitive peripheral magnetic stimulation (rPMS) may improve motor function following central nervous system lesions, but the optimal parameters of rPMS to induce neural plasticity and mechanisms underlying its action remain unclear. We examined the effects of rPMS over wrist extensor muscles on neural plasticity and motor performance in 26 healthy volunteers. In separate experiments, the effects of rPMS on motor evoked potentials (MEPs), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), direct motor response (M-wave), Hoffmann-reflex, and ballistic wrist extension movements were assessed before and after rPMS. First, to examine the effects of stimulus frequency, rPMS was applied at 50, 25, and 10 Hz by setting a fixed total number of stimuli. A significant increase in MEPs of wrist extensors was observed following 50 and 25 Hz rPMS, but not 10 Hz rPMS. Next, we examined the time required to induce plasticity by increasing the number of stimuli, and found that at least 15 min of 50 and 25 Hz rPMS was required. Based on these parameters, lasting effects were evaluated following 15 min of 50 or 25 Hz rPMS. A significant increase in MEP was observed up to 60 min following 50 and 25 Hz rPMS; similarly, an attenuation of SICI and enhancement of ICF were also observed. The maximal M-wave and Hoffmann-reflex did not change, suggesting that the increase in MEP was due to plastic changes at the motor cortex. This was accompanied by increasing force and electromyograms during wrist ballistic extension movements following 50 and 25 Hz rPMS. These findings suggest that 15 min of rPMS with 25 Hz or more induces an increase in cortical excitability of the relevant area rather than altering the excitability of spinal circuits, and has the potential to improve motor output.
Adipose Tissue Macrophage Polarization in Healthy and Unhealthy Obesity
Authors: Ruggiero Alistaire D. , Key Chia-Chi Chuang , Kavanagh Kylie
Published: February 2021

Over 650 million adults are obese (body mass index ≥ 30 kg/m2) worldwide. Obesity is commonly associated with several comorbidities, including cardiovascular disease and type II diabetes. However, compiled estimates suggest that from 5 to 40% of obese individuals do not experience metabolic or cardiovascular complications. The existence of the metabolically unhealthy obese (MUO) and the metabolically healthy obese (MHO) phenotypes suggests that underlying differences exist in both tissues and overall systemic function. Macrophage accumulation in white adipose tissue (AT) in obesity is typically associated with insulin resistance. However, as plastic cells, macrophages respond to stimuli in their microenvironments, altering their polarization between pro- and anti-inflammatory phenotypes, depending on the state of their surroundings. The dichotomous nature of MHO and MUO clinical phenotypes suggests that differences in white AT function dictate local inflammatory responses by driving changes in macrophage subtypes. As obesity requires extensive AT expansion, we posit that remodeling capacity with adipose expansion potentiates favorable macrophage profiles in MHO as compared with MUO individuals. In this review, we discuss how differences in adipogenesis, AT extracellular matrix deposition and breakdown, and AT angiogenesis perpetuate altered AT macrophage profiles in MUO compared with MHO. We discuss how non-autonomous effects of remote organ systems, including the liver, gastrointestinal tract, and cardiovascular system, interact with white adipose favorably in MHO. Preferential AT macrophage profiles in MHO stem from sustained AT function and improved overall fitness and systemic health.
Prognostic Value of MicroRNA-20b in Acute Myeloid Leukemia
Authors: Cheng Zhiheng , Dai Yifeng , Huang Wenhui , Zhong Qingfu , Zhu Pei , Zhang Wenjuan , Wu Zhihua , Lin Qing , Zhu Huoyan , Cui Longzhen , Qian Tingting , Deng Cong , Fu Lin , Liu Yan , Zeng Tiansheng
Published: February 2021

Acute myeloid leukemia (AML) is a highly heterogeneous disease that requires fine-grained risk stratification for the best prognosis of patients. As a class of small non-coding RNAs with important biological functions, microRNAs play a crucial role in the pathogenesis of AML. To assess the prognostic impact of miR-20b on AML in the presence of other clinical and molecular factors, we screened 90 AML patients receiving chemotherapy only and 74 also undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) from the Cancer Genome Atlas (TCGA) database. In the chemotherapy-only group, high miR-20b expression subgroup had shorter event-free survival (EFS) and overall survival (OS, both P < 0.001); whereas, there were no significant differences in EFS and OS between high and low expression subgroups in the allo-HSCT group. Then we divided all patients into high and low expression groups based on median miR-20b expression level. In the high expression group, patients treated with allo-HSCT had longer EFS and OS than those with chemotherapy alone (both P < 0.01); however, there were no significant differences in EFS and OS between different treatment subgroups in the low expression group. Further analysis showed that miR-20b was negatively correlated with genes in “ribosome,” “myeloid leukocyte mediated immunity,” and “DNA replication” signaling pathways. ORAI2, the gene with the strongest correlation with miR-20b, also had significant prognostic value in patients undergoing chemotherapy but not in the allo-HSCT group. In conclusion, our findings suggest that high miR-20b expression is a poor prognostic indicator for AML, but allo-HSCT may override its prognostic impact.
Detailed Molecular Mechanism and Potential Drugs for COL1A1 in Carboplatin-Resistant Ovarian Cancer
Authors: Yang Feng , Zhao Ziyu , Cai Shaoyi , Ling Li , Hong Leying , Tao Liang , Wang Qin
Published: February 2021

Carboplatin resistance in ovarian cancer (OV) is a major medical problem. Thus, there is an urgent need to find novel therapeutic targets to improve the prognosis of patients with carboplatin-resistant OV. Accumulating evidence indicates that the gene COL1A1 (collagen type I alpha 1 chain) has an important role in chemoresistance and could be a therapeutic target. However, there have been no reports about the role of COL1A1 in carboplatin-resistant OV. This study aimed to establish the detailed molecular mechanism of COL1A1 and predict potential drugs for its treatment. We found that COL1A1 had a pivotal role in carboplatin resistance in OV by weighted gene correlation network analysis and survival analysis. Moreover, we constructed a competing endogenous RNA network (LINC00052/SMCR5-miR-98-COL1A1) based on multi-omics data and experiments to explore the upstream regulatory mechanisms of COL1A1. Two key pathways involving COL1A1 in carboplatin resistance were identified by co-expression analysis and pathway enrichment: the “ECM-receptor interaction” and “focal adhesion” Kyoto Encyclopedia of Genes and Genomes pathways. Furthermore, combining these results with those of cell viability assays, we proposed that ZINC000085537017 and quercetin were potential drugs for COL1A1 based on virtual screening and the TCMSP database, respectively. These results might help to improve the outcome of OV in the future.
Detection of Circulating Tumor Cells in Resectable Pancreatic Ductal Adenocarcinoma: A Prospective Evaluation as a Prognostic Marker
Authors: Song Byeong Geun , Kwon Wooil , Kim Hyemin , Lee Eun Mi , Han Young Min , Kim Hongbeom , Byun Yoonhyeong , Lee Kyung Bun , Lee Kwang Hyuck , Lee Kyu Taek , Lee Jong Kyun , Jang Jin-Young , Park Joo Kyung
Published: February 2021

Circulating tumor cells (CTCs) are useful biomarkers of many solid tumors, but are infrequently detected in early stage pancreatic ductal adenocarcinomas (PDACs). The first drainage of pancreatic venous blood flow come to portal vein and pass through the liver, and they finally go out for peripheral blood. We thought that comparing CTCs from portal vein and peripheral blood could enable us to understand the clinical meaning of CTCs from each different site in PDACs. Therefore, we aimed to determine 1) whether CTCs could be reliably identified in early stages (operable) of PDACs, 2) if there are any differences in the detected number of CTC in portal vein blood and peripheral blood, and 3) whether CTCs can be sensitive biomarkers for the prognosis of resectable PDAC patients. Newly diagnosed PDAC patients who underwent operation with curative intention between 2013 and 2015 were prospectively enrolled. Blood draws from portal and peripheral vein ran through the microfabricated porous filter, and anti-epithelial cell adhesion molecule (EpCAM) and anti-Plectin-1 antibodies were used for CTC identification. Baseline clinical characteristics, tumor characteristics, treatment, and clinical outcomes were assessed. The clinical stages of the 32 enrolled patients were as follows: IA/IB 1 (3.1%); IIA 9 (28.1%); IIB 17 (53.1%); III 5 (15.6%). Twenty-seven patients (84.4%) received R0 resection, while five patients (15.6%) received R1 resection. EpCAM+ CTCs were detected in 20 portal blood (62.5%) and 22 peripheral blood (68.8%). Plectin-1+ CTCs were identified in 14 portal blood (43.8%) and 16 peripheral blood (50%). Plectin-1-expressing CTCs were picked from CTC platform (microfabricated porous filter) and we could find out all KRAS mutation. Patients with detectable EpCAM+ CTC less than one in peripheral blood showed longer overall survival (OS) compared to patients with detectable CTCs more than one (35.5 months vs. 16.0 months). EpCAM and Plectin-1 successfully identified CTCs at the early stage of PDACs. Also, the number of CTCs could be a prognostic marker for survival in resectable PDACs.
Long Noncoding RNA Nuclear Paraspeckle Assembly Transcript 1 Promotes Progression and Angiogenesis of Esophageal Squamous Cell Carcinoma Through miR-590-3p/MDM2 Axis
Authors: Luo Jing , Xie Kai , Gao Xiang , Yao Yu , Wang Gaoming , Shao Chenye , Li Xiaokun , Xu Yang , Ren Binhui , Hu Liwen , Shen Yi
Published: February 2021

Angiogenesis has been identified as one of the hallmarks of cancer and aggravates cancer development and progression. Accumulating evidence indicated that long noncoding RNAs (lncRNAs) are powerful factors in regulating various cancer behaviors. The aim of this study is to verify the function and potential mechanisms of lncRNA NEAT1 in progression and angiogenesis of esophageal squamous cell carcinoma (ESCC). We found that NEAT1 was overexpressed in ESCC tissues and correlated with clinical characteristics of patients. Silence of NEAT1 inhibited proliferation, migration, invasion and angiogenesis of ESCC cells. High throughput sequencing and western blotting revealed that NEAT1 regulated MDM2/p53 pathway. Rescue of MDM2 restored the effect of NEAT1 on progression and angiogenesis of ESCC cells. Nude mice xenograft models further validated the role of NEAT1 in vivo. Importantly, NEAT1 functioned as a competing endogenous RNA for miR-590-3p to regulate MDM2 expression and miR-590-3p acted as a tumor suppressor in ESCC progression and angiogenesis. These findings suggested that NEAT1/miR-590-3p/MDM2 axis might serve as potential therapeutic targets for ESCC patients.
Intracavitary/Interstitial Applicator Plus Distal Parametrial Free Needle Interstitial Brachytherapy in Locally Advanced Cervical Cancer: A Dosimetric Study
Authors: Qu Hong-Da , Han Dong-Mei , Zhang Ning , Mao Zhuang , Cheng Guang-Hui
Published: February 2021

Purpose

To explore the dosimetric advantage of combining intracavitary/interstitial applicator with distal parametrial free needle interstitial brachytherapy (IC/IS+ISBT DP) based on MRI for locally advanced cervical cancer.

Methods and Materials

77 IC/IS+ISBT DP treatment plans were developed for 34 patients with locally advanced cervical cancer from June 2016 to January 2020 in this study. We removed the free needles and devised a new IC/ISBT treatment plan based on the same principle. We then compared the dosimetric differences of D90, D98, V100, V150, V200 for HR-CTV (high-risk clinical target volume), D90 for IR-CTV (Intermediate risk-CTV) and D2cc for OARs (organs at risk) between the two groups of treatment plans for the same patient, and the paired T test was performed in parallel. Further, the dosage differences between the two group plans under different parametrial extension widths (the maximum distance of HR-CTV from the vertical direction of the uterine tandem at coronal position) were compared. The survival rate was calculated using the Kaplan-Meier method. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were determined by Cox regression method. RTOG/EORTC criteria were used to grade toxicities.

Results

A total of 297 free needles were used, with a weight ratio of 15.8% ± 0.11, and a mean insertion depth of 6.52cm ± 2.8cm. D90, D98, V100 for HR-CTV, and D90 for IR-CTV for IC/IS+ISBT DP were significantly higher than IC/ISBT for which free needles were removed (p<0.05). And the V200 for HR-CTV and D2cc for bladder, rectum and sigmoid were decreased (p<0.05). When the parametrial extension widths were greater than 3cm, the HR-CTV D90 and the D2CC for rectum, bladder and sigmoid colon for IC/IS-ISBT DP were advantageous compared to IC/ISBT (p<0.05). The 2-yr OS, PFS and local control rate (LC) were 82.3, 66.8, and 93.1%, respectively. Parametrial extension widths was the only statistically prognostic factors for PFS (p = 0.002) on univariate analysis. No grade 3 or 4 Treatment-related toxicities were observed.

Conclusion

Our institutional experiences showed that IC/IS+ISBT DP is an effective treatment for cervical cancer patients with distal parametrial extension. IC/IS-ISBT DP had dosage advantage and clinical feasibility in locally advanced cervical cancer with distal parametrial extension when the parametrial extension widths were greater than 3cm.
Prediction of Clinical Outcome in Locally Advanced Non-Small Cell Lung Cancer Patients Treated With Chemoradiotherapy by Plasma Markers
Authors: Sui Xin , Jiang Leilei , Teng Huajing , Mi Lan , Li Bo , Shi Anhui , Yu Rong , Li Dongming , Dong Xin , Yang Dan , Yu Huiming , Wang Weihu
Published: February 2021

Purpose

To identify cytokines in plasma that may predict objective response and progression-free survival (PFS) in patients with locally advanced non-small cell lung cancer (NSCLC) treated with chemoradiotherapy.

Materials and Methods

From April 2016 to May 2017, thirty-one patients with locally advanced inoperable/unresectable NSCLC were included, and treated with concurrent chemoradiotherapy (CCRT). No immune checkpoint inhibitors were administered after CCRT. Plasma from each patient was collected before radiotherapy, and 25 cytokines in the plasma were measured by Luminex or U-PLEX assays. Logistic regression and COX regression were performed to identify the predictive factors for objective response and PFS, respectively. Kaplan-Meier survival analysis was used to compare the PFS between the groups.

Results

High levels of IL-13 and TNF-α, and low levels of ICAM-1, IFN-γ, and soluble PD-L1 (sPD-L1) were significantly associated with objective response (P <0.05). High levels of IL-8, CCL5, and CXCL3 also showed a trend toward association with objective response (P <0.1). The combination of cytokines (IL-8 and ICAM-1, or TNF-α and sPD-L1) improved predictive accuracy. Univariate analysis identified IL-8 and ICAM-1 as potential markers to predict PFS. Multivariate analysis suggested that high level of IL-8 (P =0.010) and low level of ICAM-1 (P =0.011) correlated significantly with a longer PFS.

Conclusion

IL-8 and ICAM-1 in plasma have the potential to predict objective response and PFS in patients with locally advanced NSCLC underwent chemoradiotherapy.
Anti-Tumor Mechanisms Associated With Regulation of Non-Coding RNA by Active Ingredients of Chinese Medicine: A Review
Authors: Liu Tian-Jia , Hu Shuang , Qiu Zhi-Dong , Liu Da
Published: February 2021

Cancer has become the second leading cause of death worldwide; however, its complex pathogenesis remains largely unclear. Previous research has shown that cancer development and progression are closely associated with various non-coding RNAs, including long non-coding RNAs and microRNAs, which regulate gene expression. Target gene abnormalities are regulated and engaged in the complex mechanism underlying tumor formation, thereby controlling apoptosis, invasion, and migration of tumor cells and providing potentially effective targets for the treatment of malignant tumors. Chemotherapy is a commonly used therapeutic strategy for cancer; however, its effectiveness is limited by general toxicity and tumor cell drug resistance. Therefore, increasing attention has been paid to developing new cancer treatment modalities using traditional Chinese medicines, which exert regulatory effects on multiple components, targets, and pathways. Several active ingredients in Chinese medicine, including ginsenoside, baicalin, and matrine have been found to regulate ncRNA expression levels, thus, exerting anti-tumor effects. This review summarizes the scientific progress made regarding the anti-tumor mechanisms elicited by various active ingredients of Chinese medicine in regulating non-coding RNAs, to provide a theoretical foundation for treating tumors using traditional Chinese medicine.
Pre- and Postoperative Models for Prediction of Recurrence in Non-B, Non-C Hepatocellular Carcinoma
Authors: Lin Kongying , Huang Qizhen , Wang Lei , Zeng Jianxing , Ding Zongren , Liu Hongzhi , Fu Jun , Guo Pengfei , Chen Zhenwei , Zeng Yongyi , Zhou Weiping , Liu Jingfeng
Published: February 2021

Background and Aims

The incidence of non-B, non-C hepatocellular carcinoma (NBNC-HCC) is increasing. Like in hepatitis B virus (HBC)/HCV-associated HCC, treatment of NBNC-HCC after resection is challenging due to its high recurrence rate. However, few studies on the recurrence of NBNC-HCC have been published in the past decades. Hence, we aimed to investigate the risk factors for recurrence of NBNC-HCC and construct pre- and postoperative prognostic models for predicting recurrence in these patients who underwent curative resection.

Methods

We retrospectively analyzed 608 patients who underwent liver resection for NBNC-HCC. A multivariate Cox proportional hazard regression analysis was conducted to identify the independent risk factors of recurrence, based on which the prediction nomogram models were constructed and validated. The predictive performance of the models was assessed using the concordance index, time-dependent receiver operating characteristic curve, prediction error cure, and calibration curve. To facilitate clinical use, we stratified the patients into three distinct risk groups based on the score of the models. The cutoff scores of the models were determined by a survival tree analysis.

Results

Multivariable analysis identified neutrophil-to-lymphocyte ratio, alpha fetoprotein, tumor number, and tumor diameter as independent preoperative risk factors for recurrence. In addition to these variables, microvascular invasion was an independent postoperative risk factor for recurrence. The pre- and postoperative nomograms were constructed based on these variables. The C-index of the pre- and postoperative nomograms was 0.689 and 0.702 in the training cohort, 0.682 and 0.688 in the validation cohort, respectively, which were both higher than those of the conventional Barcelona Clinic Liver Cancer (BCLC) and 8th edition of the American Joint Committee on Cancer (AJCC8th) staging systems. In addition, the pre- and postoperative nomograms could also re-stratify patients with BCLC stage 0/A or AJCC8th stage IA/IB/II into distinct risk groups.

Conclusions

We constructed pre- and postoperative prognostic models for predicting recurrence in patients with NBNC-HCC who underwent curative resection. They can play a supplementary role to the traditional staging system.
Feasibility and Oncological Outcome of Preoperative Chemoradiation With IMRT Dose Intensification for Locally Advanced Esophageal and Gastroesophageal Cancer
Authors: Innocente Roberto , Navarria Federico , Petri Roberto , Palazzari Elisa , Vecchiato Massimo , Polesel Jerry , Ziccarelli Antonio , Martino Antonio , Ubiali Paolo , Tonin Dino , Lauretta Andrea , Belluco Claudio , Foltran Luisa , Buonadonna Angela , Lleshi Arben , Colombo Carlotta Benedetta , Barresi Loredana , Gigante Marco , Franchin Giovanni , De Paoli Antonino
Published: February 2021

Purpose

To explore the feasibility and efficacy of a dose intensification with Intensity Modulated Radiation Therapy and Simultaneous Integrated Boost (IMRT-SIB) in locally advanced esophageal and gastroesophageal cancer (GEJ).

Methods and Materials

We retrospectively analyzed a series of 69 patients with esophageal or GEJ cancer treated at our Institute, between 2016 and 2019, with preoperative IMRT and SIB up to 52.5–54 Gy in 25 fractions in 5 weeks and concurrent carboplatin (AUC2) and paclitaxel (50 mg/m2), as in the CROSS regimen.

Results

All patients completed the planned IMRT–SIB program with a median of four (range 1–5) cycles of concurrent paclitaxel/carboplatin. Compliance to IMRT–SIB was 93%, whereas 54% of patients received four to five cycles and 87% at least three cycles of concurrent carboplatin/paclitaxel. Grade 3 toxicity was reported in 19% of patients. Complete clinical response (cCR) was achieved in 48%, and 13% had disease progression after chemoradiation (CRT). Overall, 49% of patients underwent surgery; reasons for non-operation included cCR in cervical tumor location (10%) or cCR and patient decision (13%). A pathologic complete response (pCR) was achieved in 44% of resected patients. Postoperative complications and mortality rates were 21 and 6%, respectively. At a median follow-up of 12 months (6–25), 2-year overall and progression-free (PFS) survival rates were 81 and 54%, respectively. No difference in PFS by histologic type in operated patients was reported. Non-operated cCR patients had higher PFS, including cervical locations and selected cCR patients who decided for non-operation (75 vs 30%, p < 0.01).

Conclusion

The study reported favorable results in safety and feasibility of the IMRT–SIB dose intensification in our preoperative CRT program. The toxicity was acceptable, allowing a high compliance to intensified radiation doses with dose reduction of concurrent paclitaxel/carboplatin in some patients. The high rate of cCR and pCR suggested this intensified program is effective in the preoperative CRT and, for selected responsive patients, in the non-operative approach to esophageal and GEJ cancer. The 2-year survival rates were promising. A prospective study is being planned to confirm these observations.
Research Interest and Public Interest in Melanoma: A Bibliometric and Google Trends Analysis
Authors: Zhang Hanlin , Wang Yuanzhuo , Zheng Qingyue , Tang Keyun , Fang Rouyu , Wang Yuchen , Sun Qiuning
Published: February 2021

Introduction

Melanoma is a severe skin cancer that metastasizes quickly. Bibliometric analysis can quantify hotspots of research interest. Google Trends can provide information to address public concerns.

Methods

The top 15 most frequently cited articles on melanoma each year from 2015 to 2019, according to annual citations, were retrieved from the Web of Science database. Original articles, reviews, and research letters were included in this research. For the Google Trends analysis, the topic “Melanoma” was selected as the keyword. Online search data from 2004 to 2019 were collected. Four countries (New Zealand, Australia, the United States and the United Kingdom) were selected for seasonal analysis. Annual trends in relative search volume and seasonal variation were analyzed, and the top related topics and rising related topics were also selected and analyzed.

Results

The top 15 most frequently cited articles each year were all original articles that focused on immunotherapy (n=8), omics (n=5), and the microbiome (n=2). The average relative search volume remained relatively stable across the years. The seasonal variation analysis revealed that the peak appeared in summer, and the valley appeared in winter. The diseases associated with or manifestations of melanoma, treatment options, risk factors, diagnostic tools, and prognosis were the topics in which the public was most interested. Most of the topics revealed by bibliometric and Google Trends analyses were consistent, with the exception of issues related to the molecular biology of melanoma.

Conclusion

This study revealed the trends in research interest and public interest in melanoma, which may pave the way for further research.
m6A-Mediated Upregulation of LINC00857 Promotes Pancreatic Cancer Tumorigenesis by Regulating the miR-150-5p/E2F3 Axis
Authors: Meng Xiangrui , Deng Yanyao , He Shuhan , Niu Li , Zhu Hongwei
Published: February 2021

The mortality and morbidity rates of pancreatic cancer (PC) have been increasing over the past two decades. Recent evidence indicates that long non-coding RNAs (lncRNAs) are usually dysregulated in the tumorigenesis and progression of PC. In the present study, we showed that the expression of LINC00857 was upregulated in PC and associated with poor prognosis based on the Gene Expression Profiling Interactive Analysis (GEPIA) database and validated in our PC tissues and cell lines. N6-Methyladenosine (m6A) was highly enriched within LINC00857 and enhanced its RNA stability. Knockdown of LINC00857 remarkably inhibited the proliferation and promoted the apoptosis of PC cells. Then, by using bioinformation analysis and verified experiments, we identified that LINC00857 functioned as a competing endogenous RNA (ceRNA) for sponging miR-150-5p, leading to the upregulation of its target E2F3 in PC cells. Taken above, our study revealed a potential ceRNA regulatory pathway in which LINC00857 modulates E2F3 expression by binding to miR-150-5p, ultimately promoting tumorigenesis in PC. LINC00857/miR-150-5p/E2F3 regulatory axis may be taken as an alternative therapeutic target for treating PC.
Molecular Subtype May Be More Associated With Prognosis and Chemotherapy Benefit Than Tumor Size in T1N0 Breast Cancer Patients: An Analysis of 2,168 Patients for Possible De-Escalation Treatment
Authors: Zhu Siji , Li Yafen , Chen Weiguo , Fei Xiaochun , Shen Kunwei , Chen Xiaosong
Published: February 2021

Purpose

Breast cancer (BC) patients with T1N0 tumors have relatively favorable clinical outcomes. However, it remains unclear whether molecular subtypes can aide in prognostic prediction for such small, nodal-negative BC cases and guide decision-making about escalating or de-escalating treatments.

Patients and Methods

T1N0 BC patients diagnosed between 2009 and 2017 were included and classified into three subgroups according to receptor status: 1) hormonal receptor (HR)+/human epidermal growth factor receptor-2 (HER2)−; 2) HER2+; and 3) triple negative (TN) (HR−/HER2−). Patients’ characteristics and relapse events were reviewed. Kaplan–Meier analysis and Cox regression were used to assess the iDFS and BCSS. The effects of risk factors and adjuvant treatment benefits were evaluated by calculating hazard ratios (HRs) for invasive disease-free survival (iDFS) and breast cancer-specific survival (BCSS) with Cox proportional hazards models.

Results

In total, 2,168 patients (1,435 HR+/HER2−, 427 HER2+, 306 TN) were enrolled. The 5-year iDFS rates were 93.6, 92.7, and 90.6% for HR+/HER2−, HER2+, and TN patients, respectively (P = 0.039). Multivariate analysis demonstrated that molecular subtype (P = 0.043), but not tumor size (P = 0.805), was independently associated with iDFS in T1N0 BC. TN patients [HRs = 1.77, 95% confidence interval (CI) = 1.11–2.84, P = 0.018] had a higher recurrence risk than HR+/HER2− patients. Adjuvant chemotherapy benefit was not demonstrated in all T1N0 patients but interacted with molecular subtype status. TN (adjusted HRs = 2.31, 95% CI = 0.68–7.54) and HER2+ (adjusted HRs = 2.26, 95% CI = 0.95–5.63) patients receiving chemotherapy had superior iDFS rates. Regarding BCSS, molecular subtype tended to be related to outcome (P = 0.053) and associated with chemotherapy benefit (P = 0.005).

Conclusion

Molecular subtype was more associated with disease outcome and chemotherapy benefit than tumor size in T1N0 BC patients, indicating that it may guide possible clinical de-escalating therapy in T1N0 BC.
CircHIPK3 Promotes the Tumorigenesis and Development of Gastric Cancer Through miR-637/AKT1 Pathway
Authors: Yang Dejun , Hu Zunqi , Zhang Yu , Zhang Xin , Xu Jiapeng , Fu Hongbing , Zhu Zhenxin , Feng Dan , Cai Qingping
Published: February 2021

Circular RNA is a kind of RNA with a covalently closed loop, which has a complex ability to modulate genes in the process of tumorigenesis and metastasis. Nevertheless, how circular RNA functions in gastric cancer (GC) remains unclear. The effect of circHIPK3 in vitro was studied here. Quantitative real-time PCR (qRT-PCR) was employed to found that circHIPK3 markedly increased in GC tissues and cell lines. And low expression of circHIPK3 suppressed the GC cells growing and metabolizing. Then the bioinformatics tool predicted the downstream target of circHIPK3, and it was proved by the dual-luciferase report experiment. According to the results of bioinformatics analysis and experimental data, it was clarified that circHIPK3 acted as a sponge of miR-637, releasing its direct target AKT1. The dual-luciferase assay revealed that mir-637 could bind circHIPK3 and AKT1. qRT-PCR data indicated that overexpression circHIPK3 led to the low level of miR-637 and overexpressed miR-637 would reduce AKT1 level. Finally, we demonstrated that the low expression of miR-637 or overexpression of AKT1 could attenuate the anti-proliferative effects of si-circHIPK3. These results suggest that the circHIPK3/miR-637/AKT1 regulatory pathway may be associated with the oncogene and growth of gastric cancer. In short, a new circular RNA circHIPK3 and its function are identified, and the regulatory pathway of circHIPK3/miR-637/AKT1 in the tumorigenesis and development of gastric cancer is discovered.
Biomarkers of Oxidative Stress for Neonatal Lung Disease
Authors: Ferrante Giuliana , Carota Giuseppe , Li Volti Giovanni , Giuffrè Mario
Published: February 2021

The transition from prenatal to postnatal life causes a significant increase in arterial oxygen tension and the activation of metabolic pathways enabling the newborn's adaptation to the extra-uterine environment. The balance between pro-oxidant and anti-oxidant systems is critical to preserve cellular functions. Indeed, oxidative stress (OS) occurs when the production of free radicals is not balanced by the activity of intracellular antioxidant systems, contributing to cellular and tissue damage. Perinatal OS may have serious health consequences during the postnatal period and later in life. Namely, OS has been recognized as the major cause of lung injury in newborns, especially those preterm born, due to their immature lung and antioxidant systems. The development of OS biomarkers has gained increasing research interest since they may provide useful insights about pathophysiological pathways underlying OS-mediated pulmonary diseases in newborns. Moreover, their implementation in clinical settings may help to early identify high risk-newborns and to provide targeted treatment. Ideally, a biomarker should demonstrate ease of use, biological validity and reproducibility, high sensitivity and specificity. However, none of the clinically validated biomarkers so far have been qualified for neonatal lung disease. Additionally, the complex technical procedures and the high cost of such determinations have hampered the use of OS biomarkers in clinical practice. This review aims to evaluate the current evidence on the application of biomarkers of oxidative stress for neonatal lung disease and exploring the most relevant issues affecting their implementation in practice, as well as the associated evidence gaps and research limitations.
Racial Disparities in Necrotizing Enterocolitis
Authors: Cuna Alain , Sampath Venkatesh , Khashu Minesh
Published: February 2021

Necrotizing enterocolitis (NEC) is a serious disease of the intestinal tract affecting 5–10% of pre-term infants with up to 50% mortality in those that require surgery. There is wide variation in the rates and outcomes of NEC by race and ethnicity, and the reasons for this disparity are poorly understood. In this article, we review the epidemiology and discuss possible explanations for racial and ethnic differences in NEC. Most of the current evidence investigating the role of race in NEC comes from North America and suggests that Hispanic ethnicity and non-Hispanic Black race are associated with higher risk of NEC compared to non-Hispanic White populations. Differences in pre-term births, breastfeeding rates, and various sociodemographic factors does not fully account for the observed disparities in NEC incidence and outcomes. While genetic studies are beginning to identify candidate genes that may increase or decrease risk for NEC among racial populations, current data remain limited by small sample sizes and lack of validation. Complex interactions between social and biological determinants likely underly the differences in NEC outcomes among racial groups. Larger datasets with detailed social, phenotypic, and genotypic information, coupled with advanced bioinformatics techniques are needed to comprehensively understand racial disparities in NEC.
Pharmacological Therapies and Their Clinical Targets in Irritable Bowel Syndrome With Diarrhea
Authors: Colomier Esther , Algera Joost , Melchior Chloé
Published: February 2021

Irritable bowel syndrome (IBS) is one of the most common disorders of the gut-brain axis, which affects approximately 4% of the global population. The Rome IV criteria define IBS as chronic or recurrent abdominal pain associated with altered bowel habits. Patients can be categorized in four subtypes: IBS with predominant constipation (IBS-C), predominant diarrhea (IBS-D), mixed bowel habits (IBS-M), and unclassified (IBS-U). IBS is associated with a lower quality of life, reduced work productivity, and high healthcare costs. When comparing subtypes, patients with IBS-D report lower disease related quality of life. Due to the scope of this review, we have solely focused on patients with IBS-D. Choosing the right pharmacological treatment in these patients remains challenging due to the heterogeneous patient population, patients’ expectation of the treatment outcome, unavailability of efficacious drugs, and the multifactorial and incompletely understood underlying pathophysiology. Currently, pharmacological treatment options target individual symptoms, such as abdominal pain, altered bowel habits, and bloating. In this review, we aimed to summarize the current and recent pharmacological treatment options in IBS-D, targeting the predominant gastrointestinal symptoms. Additionally, we proposed a pharmacological treatment algorithm which healthcare professionals could use when treating individual patients with IBS-D.
Addressing Pain for a Proper Rehabilitation Process in Patients With Severe Disorders of Consciousness
Authors: Riganello F. , Soddu A. , Tonin P.
Published: February 2021

Consciousness constitutes a fundamental prerequisite in the individual appraisal and experience of pain. In the same way, a person needs to be able to report on pain perception. Patients who suffered a severe brain injury with disorders of consciousness (DOC) represent a spectrum of pathologies affecting patients' capacity to interact with the external world. In these patients, the most relevant aspects in response to pain are physiologic and behavioral. The treatments and management of pain are challenging issues in these patients, arising serious ethical concerns and bringing emotional load among medical staff, caregivers, and relatives. In this review, we report the importance of having a correct pain management in DOC patients, to individuate the best pharmacological treatment that can make the difference in detecting a behavioral response, indicative of a change in the level of consciousness, and in planning a more effective rehabilitative approach.