bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Therapeutic Targets and Prognostic Biomarkers Among Chemokine (C-C Motif) Ligands in the Liver Hepatocellular Carcinoma Microenvironment
Authors: Jiang Zhongyi , Xing Changchang , Wang Pusen , Liu Xueni , Zhong Lin 
Published: December 2021

Background: Liver hepatocellular carcinoma (LIHC) is the third leading cause of cancer-related death and the sixth most common solid tumor worldwide. In the tumor microenvironment, the cross-talk between cancer cells, immune cells, and stromal cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. Chemokine (C-C motif) ligands (CCL) can directly target tumor cells and stromal cells, and they have been shown to regulate tumor cell proliferation, cancer stem-like cell properties, cancer invasiveness and metastasis, which directly and indirectly affect tumor immunity and influence cancer progression, therapy and patient outcomes. However, the prognostic values of chemokines CCL in LIHC have not been clarified.Methods: In this study, we comprehensively analyzed the relationship between transcriptional chemokines CCL and disease progression of LIHC using the ONCOMINE dataset, GEPIA, UALCAN, STRING, WebGestalt, GeneMANIA, TRRUST, DAVID 6.8, LinkedOmics, TIMER, GSCALite, and Open Targets. We validated the protein levels of chemokines CCL through western blot and immunohistochemistry.Results: The transcriptional levels of CCL5/8/11/13/15/18/20/21/25/26/27/28 in LIHC tissues were significantly elevated while CCL2/3/4/14/23/24 were significantly reduced. A significant correlation was found between the expression of CCL14/25 and the pathological stage of LIHC patients. LIHC patients with low transcriptional levels of CCL14/21 were associated with a significantly poor prognosis. The functions of differentially expressed chemokines CCL were primarily related to the chemokine signaling pathway, cytokine–cytokine receptor interactions, and TNF-α signaling pathway. Our data suggested that RELA/REL, NFKB1, STAT1/3/6, IRF3, SPI1, and JUN were key transcription factors for chemokines CCL. We found significant correlations among the expression of chemokines CCL and the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) and immune checkpoints (PD-1. PD-L1, and CTLA-4). The western blot and immunohistochemistry results showed that protein expression levels of CCL5 and CCL20 were upregulated in LIHC. CCL5 and CCL20 were significantly correlated with the clinical outcome of patients with LIHC, and could be negatively regulated by some drugs or small molecules.Conclusions: Our results may provide novel insights for the potential suitable targets of immunological therapy and prognostic biomarkers for LIHC.
Heterogeneity in the Epigenetic Landscape of Murine Testis-Specific Histone Variants TH2A and TH2B Sharing the Same Bi-Directional Promoter
Authors: Singh Isha , Parte Priyanka 
Published: December 2021

Testis-specific histone variants are crucial to promote open chromatin structure to enable nucleosome disassembly in the final stages of spermiogenesis. However, even after histone replacement, mature sperm retain a proportion of these variants, the function of which is unknown. The present study aimed to understand the functional relevance of the retained H2B and H2A variants, TH2B and TH2A. While no literature is available on the phenotype of TH2A knockouts, TH2B/TH2A double knockout male mice are reported to be infertile. In this study, ChIP-seq analysis was done for TH2B and TH2A to understand the epigenomics of the retained TH2B and TH2A, using murine caudal sperm. Distribution across genomic partitions revealed ∼35% of the TH2B peaks within ±5 kb of TSS whereas TH2A peaks distribution was sparse at TSS. Gene Ontology revealed embryo development as the most significant term associated with TH2B. Also, based on genomic regions, TH2B was observed to be associated with spindle assembly and various meiosis-specific genes, which is an important finding as TH2A/TH2B DKO mice have been reported to have defective cohesin release. A comparison of mouse and human TH2B-linked chromatin revealed 26% overlap between murine and human TH2B-associated genes. This overlap included genes crucial for embryogenesis. Most importantly, heterogeneity in the epigenetic landscape of TH2A and TH2B was seen, which is intriguing as TH2B and TH2A are well reported to be present in the same nucleosomes to promote open chromatin. Additionally, unlike TH2B, TH2A was enriched on the mitochondrial chromosome. TH2A was found to be associated with Nuclear insertion of Mitochondrial DNA sequences (NUMTs) in sperm. A comprehensive analysis of these observations indicates novel functions for the sperm-retained TH2B and TH2A.
An Evaluation of Speech-Based Recognition of Emotional and Physiological Markers of Stress
Authors: Baird Alice , Triantafyllopoulos Andreas , Zänkert Sandra , Ottl Sandra , Christ Lukas , Stappen Lukas , Konzok Julian , Sturmbauer Sarah , Meßner Eva-Maria , Kudielka Brigitte M. , Rohleder Nicolas , Baumeister Harald , Schuller Björn W. 
Published: December 2021

Life in modern societies is fast-paced and full of stress-inducing demands. The development of stress monitoring methods is a growing area of research due to the personal and economic advantages that timely detection provides. Studies have shown that speech-based features can be utilised to robustly predict several physiological markers of stress, including emotional state, continuous heart rate, and the stress hormone, cortisol. In this contribution, we extend previous works by the authors, utilising three German language corpora including more than 100 subjects undergoing a Trier Social Stress Test protocol. We present cross-corpus and transfer learning results which explore the efficacy of the speech signal to predict three physiological markers of stress—sequentially measured saliva-based cortisol, continuous heart rate as beats per minute (BPM), and continuous respiration. For this, we extract several features from audio as well as video and apply various machine learning architectures, including a temporal context-based Long Short-Term Memory Recurrent Neural Network (LSTM-RNN). For the task of predicting cortisol levels from speech, deep learning improves on results obtained by conventional support vector regression—yielding a Spearman correlation coefficient (ρ) of 0.770 and 0.698 for cortisol measurements taken 10 and 20 min after the stress period for the two corpora applicable—showing that audio features alone are sufficient for predicting cortisol, with audiovisual fusion to an extent improving such results. We also obtain a Root Mean Square Error (RMSE) of 38 and 22 BPM for continuous heart rate prediction on the two corpora where this information is available, and a normalised RMSE (NRMSE) of 0.120 for respiration prediction (−10: 10). Both of these continuous physiological signals show to be highly effective markers of stress (based on cortisol grouping analysis), both when available as ground truth and when predicted using speech. This contribution opens up new avenues for future exploration of these signals as proxies for stress in naturalistic settings.
Investigation of a Novel NTRK1 Variation Causing Congenital Insensitivity to Pain With Anhidrosis
Authors: Yang Kai , Xu Yi-Cheng , Hu Hua-Ying , Li Ya-Zhou , Li Qian , Luan Ying-Yi , Liu Yan , Sun Yong-Qing , Feng Zhan-Ke , Yan You-Sheng , Yin Cheng-Hong 
Published: December 2021

Background: Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive sensory neuropathy, was caused mainly by biallelic mutations in the NTRK1 gene. The pathogenesis of CIPA still needs further elucidation.Methods: Here, we recruited a CIPA case and introduced whole-exome sequencing (WES) to identify the causative variation. Subsequently, an in silico molecular dynamic (MD) analysis was performed to explore the intramolecular impact of the novel missense variant. Meanwhile, in vitro functional study on the novel variant from a metabolomic perspective was conducted via the liquid chromatography–mass spectrometry (LC-MS) approach, of which the result was verified by quantitative real-time PCR (qRT-PCR).Results: A novel compound heterozygous variation in NTRK1 gene was detected, consisting of the c.851–33T &gt; A and c.2242C &gt; T (p.Arg748Trp) variants. MD result suggested that p.Arg748Trp could affect the intramolecular structure stability. The results of the LC-MS and metabolic pathway clustering indicated that the NTRK1Arg748Trp variant would significantly affect the purine metabolism in vitro. Further analysis showed that it induced the elevation of NT5C2 mRNA level.Conclusion: The findings in this study extended the variation spectrum of NTRK1, provided evidence for counseling to the affected family, and offered potential clues and biomarkers to the pathogenesis of CIPA.
Characteristics of SP600125 Induced Tetraploid Cells in Comparison With Diploid and Tetraploid Cells of Fish
Authors: Fan Yunpeng , Zhang Guangjing , Zhao Kaiyue , Fu Wen , Chen Shujuan , Liu Jinhui , Liu Wenbin , Peng Liangyue , Ren Li , Liu Shaojun , Xiao Yamei 
Published: December 2021

In our previous research, SP600125 (Anthrapyrazolone) was used to induce autotetraploid of crucian carp cells (SP4N cells), and tetraploid fry was generated from the SP4N cells by somatic cell nuclear transfer technique. However, it is still unclear about biological characteristics of the SP4N cells. In this article, the cytological characteristic and gene expression profiles of the SP4N cells are investigated in comparison with the crucian carp cells (2N cells) and the tetraploid crucian carp cells (CC4N cells). The SP4N cells have tetraploid characteristics in terms of morphology and DNA ploidy levels, and their chromosome behavior is stable during the cell proliferation. The migration ability and the mtDNA copy number of SP4N cells are both lower than those in the CC4N cells and the 2N cells, but there exist giant mitochondria in the SP4N cells. The similar expression trends in the cell cycle regulation genes of the SP4N cells and 2N cells, while the corresponding expression profiles are clearly different between the SP4N cells and the CC4N cells. Moreover, the significant difference genes are associated with energy metabolism pathways among the SP4N cells, 2N cells and CC4N cells. These results can provide deeper understanding of SP600125 induction, as well as finding applications in polyploidization breeding of fish species.
The Sequence of Chemotherapy and Toripalimab Might Influence the Efficacy of Neoadjuvant Chemoimmunotherapy in Locally Advanced Esophageal Squamous Cell Cancer—A Phase II Study
Authors: Xing Wenqun , Zhao Lingdi , Zheng Yan , Liu Baoxing , Liu Xianben , Li Tiepeng , Zhang Yong , Ma Baozhen , Yang Yonghao , Shang Yiman , Fu Xiaomin , Liang Guanghui , Yuan Dongfeng , Qu Jinrong , Chai Xiaofei , Zhang He , Wang Zibing , Lin Hongwei , Liu Liang , Ren Xiubao , Zhang Jiangong , Gao Quanli 
Published: December 2021

BackgroundThere is no standard neoadjuvant therapy for locally advanced esophageal cancer in China. The role of neoadjuvant chemotherapy plus immunotherapy for locally advanced esophageal cancer is still being explored.MethodsThis open-label, randomized phase II study was conducted at a single center between July 2019 and September 2020; 30 patients with locally advanced esophageal squamous cell carcinoma (ESCC) (T3, T4, or lymph-node positive) were enrolled. Patients were randomized according to the enrollment order at a 1:1 ratio to receive chemotherapy on day 1 and toripalimab on day 3 (experimental group) or chemotherapy and toripalimab on day 1 (control group). The chemotherapeutic regimen was paclitaxel and cisplatin. Surgery was performed 4 to 6 weeks after the second cycle of chemoimmunotherapy. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoint was safety and disease-free survival.ResultsThirty patients completed at least one cycle of chemoimmunotherapy; 11 in the experimental group and 13 in the control group received surgery. R0 resection was performed in all these 24 patients. Four patients (36%) in the experimental group and one (7%) in the control group achieved pCR. The experimental group showed a statistically non-significant higher pCR rate (p = 0.079). PD-L1 combined positive score (CPS) examination was performed in 14 patients; one in the control group had a PD-L1 CPS of 10, and pCR was achieved; the remaining 13 all had ≤1, and 11 of the 13 patients received surgery in which two (in the experimental group) achieved pCR. Two patients endured ≥grade 3 adverse events, and one suffered from grade 3 immune-related enteritis after one cycle of chemoimmunotherapy and dropped off the study. Another patient died from severe pulmonary infection and troponin elevation after surgery.ConclusionsAlthough the primary endpoint was not met, the initial results of this study showed that delaying toripalimab to day 3 in chemoimmunotherapy might achieve a higher pCR rate than that on the same day, and further large-sample clinical trials are needed to verify this.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT 03985670.
Exosomes From Human Urine-Derived Stem Cells Encapsulated Into PLGA Nanoparticles for Therapy in Mice With Particulate Polyethylene-Induced Osteolysis
Authors: Li Hui , Hu Yihe , Zeng Min , Yang Junxiao , Fan Xiaolei , Wang Yinan , Xie Jie 
Published: December 2021

Background: Periprosthetic osteolysis is the primary reason for arthroplasty failure after total joint replacement because of the generation of wear particles and subsequent bone erosion around the prosthesis, which leads to aseptic loosening. Periprosthetic osteolysis is often treated with revision surgery because of the lack of effective therapeutic agents. As key messengers of intercellular interactions, exosomes can be independently used as therapeutic agents to promote tissue repair and regeneration. In this study, we fabricated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) that carry exosomes derived from human urine stem cells (USC-Exos) and explored their effects on polyethylene-induced osteolysis.Methods: USCs were identified by multipotent differentiation and flow cytometry analyses. USC-Exos were isolated and identified by transmission electron microscopy (TEM), dynamic light scattering (DLS), and western blotting. PLGA microspheres containing USC-Exos were fabricated to synthesize NPs using the mechanical double-emulsion method. The obtained NPs were characterized in terms of stability, toxicity, exosome release, and cell uptake. Then, these NPs were implanted into the murine air pouch model, and their effects on polyethylene-induced osteolysis were evaluated by microcomputed tomography (micro-CT) and histological analyses.Results: The average NP diameter was ~282 ± 0.4 nm, and the zeta potential was −2.02 ± 0.03 mV. After long-term storage at room temperature and 4°C, the NP solution was stable without significant coaggregation. In vitro release profiles indicated sustained release of exosomes for 12 days. In vivo, injection of NPs into the murine air pouch caused less osteolysis than that of USC-Exos, and NPs significantly reduced bone absorption, as indicated by histology and micro-CT scanning.Conclusion: Our findings suggest that USC-Exo-based PLGA NPs can prevent particulate polyethylene-induced osteolysis and bone loss.
NTF3 Correlates With Prognosis and Immune Infiltration in Hepatocellular Carcinoma
Authors: Liu Rongqiang , Li Rongqi , Yu Haoyuan , Liu Jianrong , Zheng Shiyang , Li Yang , Ye Linsen 
Published: December 2021

Background: The potential role of Neurotrophic factor-3(NTF3) in liver cancer is unknown. Therefore, we aimed to explore the clinical value of NTF3 in hepatocellular carcinoma (HCC).Methods: We used a variety of databases to analyze the expression, relationship with prognosis and immune significance of NTF3 in liver cancer through bioinformatics.Results: NTF3 was low expressed in HCC and was an independent prognostic factor in patients with HCC. CIBERSORT analysis indicated that NTF3 expression was positively correlated with CD4+ cells, mast cells, NK cells, macrophages and B cells in the tumor microenvironment. Furthermore, we found that NTF3 expression was negatively correlated with the immune checkpoints PD-L1, TIGIT and TIM-3. Functional network analysis revealed that NTF3 regulates HCC progression through a variety of cancer-related kinases, transcription factors and signaling pathways.Conclusions: We demonstrate that NTF3 correlates with prognosis and immune infiltration in HCC.
Whole Genome Sequencing of Drug Resistant and Drug Susceptible Mycobacterium tuberculosis Isolates From Tigray Region, Ethiopia
Authors: Welekidan Letemichael Negash , Yimer Solomon Abebe , Skjerve Eystein , Dejene Tsehaye Asmelash , Homberset Håvard , Tønjum Tone , Brynildsrud Ola 
Published: December 2021

Background: Tuberculosis, mainly caused by Mycobacterium tuberculosis (Mtb), is an ancient human disease that gravely affects millions of people annually. We wanted to explore the genetic diversity and lineage-specific association of Mtb with drug resistance among pulmonary tuberculosis patients.Methods: Sputum samples were collected from pulmonary tuberculosis patients at six different healthcare institutions in Tigray, Ethiopia, between July 2018 and August 2019. DNA was extracted from 74 Mtb complex isolates for whole-genome sequencing (WGS). All genomes were typed and screened for mutations with known associations with antimicrobial resistance using in silico methods, and results were cross-verified with wet lab methods.Results: Lineage (L) 4 (55.8%) was predominant, followed by L3 (41.2%); L1 (1.5%) and L2 (1.5%) occurred rarely. The most frequently detected sublineage was CAS (38.2%), followed by Ural (29.4%), and Haarlem (11.8%). The recent transmission index (RTI) was relatively low. L4 and Ural strains were more resistant than the other strains to any anti-TB drug (P &lt; 0.05). The most frequent mutations to RIF, INH, EMB, SM, PZA, ETH, FLQs, and 2nd-line injectable drugs occurred at rpoB S450L, katG S315T, embB M306I/V, rpsL K43R, pncA V139A, ethA M1R, gyrA D94G, and rrs A1401G, respectively. Disputed rpoB mutations were also shown in four (16%) of RIF-resistant isolates.Conclusion: Our WGS analysis revealed the presence of diverse Mtb genotypes. The presence of a significant proportion of disputed rpoB mutations highlighted the need to establish a WGS facility at the regional level to monitor drug-resistant mutations. This will help control the transmission of DR-TB and ultimately contribute to the attainment of 100% DST coverage for TB patients as per the End TB strategy.
Predictors of Polypharmacy Among Elderly Patients in China: The Role of Decision Involvement, Depression, and Taking Chinese Medicine Behavior
Authors: Chen Chaoyi , Feng Zhanchun , Fu Qian , Wang Jia , Zheng Zehao , Chen Hao , Feng Da 
Published: December 2021

Introduction: The prevalence of polypharmacy is gradually increasing in geriatrics, which may contribute to adverse effects, such as potential drug–drug and drug–disease interactions. These side effects remain an important challenge in patient safety, which has a significant impact on mortality and incidence rate.Aims: Therefore, this study aims to understand the epidemiology of polypharmacy and identify factors that have an impact on the management of potentially inappropriate prescribing.Methods: This study is a cross-sectional study, analyzing the prescription data from 720 hospitalized patients aged 50+ with a random cluster sampling method. We used inverse probability treatment weighting (IPTW) method to group and match polypharmacy and non-polypharmacy patients, and logistic regression was conducted to explore the factors associated with polypharmacy.Results: The prevalence of polypharmacy accounted for 50.14% among the old patients in this study. Female patients (67.34%) have more polypharmacy than male patients, and key predictors associated with polypharmacy in the logistic regression model included the following: domicile (AOR = 0.63, 95% CI 0.42–0.95), annual income (AOR = 0.38, 95% CI 0.20–0.70), the number of chronic diseases (AOR = 3.68, 95% CI 2.69–5.06), taking Chinese medicine (AOR = 1.70, 95% CI 1.22–2.36), decision involvement (AOR = 1.49 95% CI 1.10–2.03), and depression (AOR = 1.42, 95% CI 1.03–1.96).Conclusion: Polypharmacy is common among the participants with chronic diseases in Hubei province, China. The study emphasizes that gerontology practitioners should be prudent in applying clinical guidelines to provide personalized, comprehensive assessment of decision making of prescriptions, especially in socioeconomically deprived areas.
Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients
Authors: Dionisi Marco , Cairoli Sara , Simeoli Raffaele , De Gennaro Francesca , Paganelli Valeria , Carta Roberto , Rossi Francesca , Dionisi-Vici Carlo , Palumbo Giuseppe , Goffredo Bianca Maria 
Published: December 2021

Background: Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, approved for refractory primary immune thrombocytopenia (ITP) in pediatric patients. In two pediatric RCTs, EPAG led to an improvement of platelet counts and a reduction in bleeding severity. However, a significant number of pediatric patients did not achieve the primary endpoints. We performed a pharmacokinetic evaluation of EPAG in pediatric patients with refractory ITP.Methods: Outpatients aged from 1 to 17 y, affected by refractory ITP to first-line treatment, were enrolled for a pharmacokinetic assessment. The analysis of drug plasma concentration was performed by the LC-MS/MS platform. Non-compartmental and statistical subgroup analyses were carried out using the R package ncappc.Results: Among 36 patients eligible for PK analysis, the median dose of EPAG given once daily was 50 mg. The EPAG peak occurs between 2 and 4 h with a population Cmax and AUC 0–24 geo-mean of 23, 38 μg/ml, and 275, 4 µg*h/mL, respectively. The pharmacokinetic profile of EPAG did not show a dose proportionality. Female patients showed a statistically significant increase of dose-normalized exposure parameters, increasing by 110 and 123% for Cmax and AUC 0–24, respectively, when compared to male patients. Patients aged 1–5 y showed values increased by more than 100% considering both exposure parameters, compared to older children. Furthermore, patients presenting complete response (83%), showed augmented EPAG exposure parameters compared to subjects with partial or no response.Conclusion: These data highlight the need to further explore the variability of EPAG exposure and its pharmacokinetic/pharmacodynamic profile in pediatric patients also in a real-life setting.