bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementasi Pasal 17 Undang-Undang Nomor 5 tahun 1999 terhadap Rule Of Reason (Studi di Komisi Pengawasan Persaingan Usaha Wilayah II Kota Batam)
Authors: Ukas Ukas , Zulkifli Zulkifli
Published: November 2021

Undang-Undang Nomor 5 Tahun 1999 Tentang Larangan Praktek Monopoli dan Persaingan Usaha Tidak Sehat sebenarnya tidak lepas dari krisis moneter yang kemudian berlanjut kepada krisis ekonomi yang melanda Indonesia dipertengahan tahun 1997, dimana pemerintah didasarkan bahwa sebenarnya Fundamental ekomoni Indonesia terjadi karena beberapa kebijakan pemerintah di beberapa sektor ekonomi yang kurang tepat yang menyebabkan pasar menjadi terdistorsi (penjelasan Undang-Undang Nomor 5 Tahun 1999 Tentang Larangan Praktek Monopoli dan Persaingan Usaha Tidak Sehat). Dunia persaingan usaha adalah dunia yang kompleks dan mencangkup beberapa sektor kehidupan termasuk sektor-sektor vital yang bersentuhan langsung dengan kehidupan masyarakat. Harmonisasi Pasal 17 Undang-Undang Nomor 5 Tahun 1999 Tentang Larangan Praktek Monopoli dan Persaingan Usaha Tidak Sehat yang tertuang didalam BAB IV Tentang Kegiatan yang dilarang pada bahagian Monopoli pelaku usaha dilarang melakukan penguasaan atas produksi dan/atau pemasaran barang dan/atau jasa yang dapat menyebabkan terjadinya praktek Monopoli atau persaingan usaha yang tidak sehat. Pelaku usaha patut di duga atau di anggap bersalah.

Tujuan dari pengajuan penelitian ini nantinya di harapkan untuk: Pertama, Memberikan Pemahaman Kepada Pelaku Usaha Hal-Hal atau Pendekatan Terhadap Pelanggaran Baik Bersifat Perjanjian yang di Larang Maupun Pelanggaran Bentuk Lainnya. Kedua, Memberikan Pemahaman Kepada Pihak (Pelaku Usaha) Tentang Mencegah Praktek Monopoli dan/atau Perjanjian Usaha yang Tidak Sehat Baik yang di Atur dalam Pasal 5 dan Pasal 17 Undang-Undang Nomor 5 Tahun 1999 Tentang Larangan Praktek Monopoli dan Persaingan Usaha Tidak Sehat, Termasuk Sanksi atas Pelanggaran dari Kedua Pasal Tersebut. Penelitian ini di lakukan dengan jenis Penelitian yuridis empiris yaitu penelitian yang langsung terjun ke lapangan.
SISTEM PAKAR DIAGNOSA KERUSAKAN MOTOR KAWASAKI KLX150 MENGGUNAKAN METODE CASE-BASED REASONING DENGAN ALGORITMA 3W-JACCARD
Authors: Purnajaya Akhmad Rezki , Indriani Fatma , Faisal Mohammad Reza
Published: November 2021

Banjar language used in conversation and daily life around the area. So foreigners who come to the regions of South Kalimantan will have difficulty in communicating. Besides, most local residents in the backwoods of South Kalimantan can not use Indonesian language properly, they would be more convenient to use regional language to interact. For that reason we need an Android application can help users to find the translation of a word or phrase whenever and wherever. With the help of Google Voice Search, this application can also listen to the voice of the user to be converted into text and insert into the input translation. Speech recognition of Banjar language required a literacy training data by using the method of statistical inference to make results appropriated. Testing using method of Black Box Testing to measure the percentage of suitability of the results of translation, speech recognition for Indonesian language and speech recognition Banjar language using method of Statistical inference. So the results of translation accuracy 100% and accuracy of speech recognition Indonesian language and Banjar language by 97.85% and 82.74%.
IMPLEMENTASI DETERMINISTIC FINITE AUTOMATA (DFA) PADA PERANCANGAN APLIKASI PERHITUNGAN UANG HARIAN PERJALANAN DINAS KEMENTERIAN
Authors: Robyanto Deny , Priyatna Ade Priyatna , Hermaliani Eni Heni , Frieyadie Frieyadie , Gata Windu
Published: November 2021

Each ministry always has a budget for official travel, especially for the daily money given to personnel who travel in exchange for daily expenses. With the current pendemi need to be held an application system that can reduce contact when handling official travel files. The design of this application will use the implementation of Deterministic Finite Automata (DFA) as an abstract machine to determine the state or stages to determine the transition between these stages to determine the daily money calculation of official travel. From the calculation of daily money will be made recapitulation to be verified and if it is considered appropriate and correct will be transferred to the account that travels to the office. This is the role in making abstract machines for the calculation of daily money using Deterministic Finite Automata (DFA) because each stage is right to one stage next until the last stage that prints proof of transfer.
Nanosized Contrast Agents in Ultrasound Molecular Imaging
Authors: Zeng Fengyi , Du Meng , Chen Zhiyi
Published: December 2021

Applying nanosized ultrasound contrast agents (nUCAs) in molecular imaging has received considerable attention. nUCAs have been instrumental in ultrasound molecular imaging to enhance sensitivity, identification, and quantification. nUCAs can achieve high performance in molecular imaging, which was influenced by synthetic formulations and size. This review presents an overview of nUCAs from different synthetic formulations with a discussion on imaging and detection technology. Then we also review the progress of nUCAs in preclinical application and highlight the recent challenges of nUCAs.
Comfort Evaluation of Slow-Recovery Ejection Seat Cushions Based on Sitting Pressure Distribution
Authors: Bao Jiayi , Zhou Qianxiang , Wang Xingwei , Yin Chao
Published: December 2021

Sitting discomfort not only affects the health of pilots carrying out long-endurance missions but also affects operational performance. The experimental objects included four ejection seat cushions: N1 was a fast-recovery foam as the comparison group, and the experimental groups were slow-recovery foams with different indentation force deflection (IFD), named N2 (hard), N3 (mid), and N4 (soft). The sitting comfort of 20 participants was tested on the four cushions by using subjective rating and sitting pressure distribution analysis. The results showed that compared with fast-recovery cushion N3 and N4 slow-recovery cushions have lower contact pressure and more uniform pressure distribution. Slow-recovery cushions that were too soft or too hard would reduce the comfort. No matter from the subjective rating or the analysis of the contact pressure data, the N3 cushion with a thickness of 3 cm and 65% IFD of 280 N had the highest comfort. In addition, the seat pressure distribution (SPD%) has a significant correlation with the subjective rating (p = 0.019, R = −0.98), which is more suitable for evaluating the comfort of the cushions. However, the slow-recovery cushions would show a decrease in support after a period of sitting, while the fast-recovery cushion could always maintain constant support.
Efficient Photoacoustic Imaging With Biomimetic Mesoporous Silica-Based Nanoparticles
Authors: Huang Chuangjia , Guan Xiaoling , Lin Hui , Liang Lu , Miao Yingling , Wu Yueheng , Bao Huiqiong , Wu Xiaodan , Shen Ao , Wei Minyan , Huang Jionghua
Published: December 2021

Indocyanine green (ICG), a near-infrared (NIR) fluorescent dye approved by the Food and Drug Administration (FDA), has been extensively used as a photoacoustic (PA) probe for PA imaging. However, its practical application is limited by poor photostability in water, rapid body clearance, and non-specificity. Herein, we fabricated a novel biomimetic nanoprobe by coating ICG-loaded mesoporous silica nanoparticles with the cancer cell membrane (namely, CMI) for PA imaging. This probe exhibited good dispersion, large loading efficiency, good biocompatibility, and homologous targeting ability to Hela cells in vitro. Furthermore, the in vivo and ex vivo PA imaging on Hela tumor-bearing nude mice demonstrated that CMI could accumulate in tumor tissue and display a superior PA imaging efficacy compared with free ICG. All these results demonstrated that CMI might be a promising contrast agent for PA imaging of cervical carcinoma.
Kinetic and Kinematic Features of Pedestrian Avoidance Behavior in Motor Vehicle Conflicts
Authors: Li Quan , Shang Shi , Pei Xizhe , Wang Qingfan , Zhou Qing , Nie Bingbing
Published: December 2021

The active behaviors of pedestrians, such as avoidance motions, affect the resultant injury risk in vehicle–pedestrian collisions. However, the biomechanical features of these behaviors remain unquantified, leading to a gap in the development of biofidelic research tools and tailored protection for pedestrians in real-world traffic scenarios. In this study, we prompted subjects (“pedestrians”) to exhibit natural avoidance behaviors in well-controlled near-real traffic conflict scenarios using a previously developed virtual reality (VR)-based experimental platform. We quantified the pedestrian–vehicle interaction processes in the pre-crash phase and extracted the pedestrian postures immediately before collision with the vehicle; these were termed the “pre-crash postures.” We recorded the kinetic and kinematic features of the pedestrian avoidance responses—including the relative locations of the vehicle and pedestrian, pedestrian movement velocity and acceleration, pedestrian posture parameters (joint positions and angles), and pedestrian muscle activation levels—using a motion capture system and physiological signal system. The velocities in the avoidance behaviors were significantly different from those in a normal gait (p < 0.01). Based on the extracted natural reaction features of the pedestrians, this study provides data to support the analysis of pedestrian injury risk, development of biofidelic human body models (HBM), and design of advanced on-vehicle active safety systems.
Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance
Authors: Chen Enping , Wang Ting , Zhang Junmei , Zhou Xiang , Niu Yafan , Liu Fu , Zhong Yinan , Huang Dechun , Chen Wei
Published: December 2021

Multidrug resistance (MDR) is one of the leading causes of the failure of cancer chemotherapy and mainly attributed to the overexpression of drug efflux transporters in cancer cells, which is dependent on adenosine triphosphate (ATP). To overcome this phenomenon, herein, a mitochondrial-directed pH-sensitive polyvinyl alcohol (PVA) nanogel incorporating the hexokinase inhibitor lonidamine (LND) and the chemotherapeutic drug paclitaxel (PTX) was developed to restore the activity of PTX and synergistically treat drug-resistant tumors. The introduction of 2-dimethylaminoethanethiol (DMA) moiety into the nanogels not only promoted the drug loading capacity but also enabled the lysosomal escape of the nanogels. The subsequent mitochondrial targeting facilitated the accumulation and acid-triggered payload release in the mitochondria. The released LND can destroy the mitochondria by exhausting the mitochondrial membrane potential (MMP), generating reactive oxygen species (ROS) and restraining the energy supply, resulting in apoptosis and susceptibility of the MCF-7/MDR cells to PTX. Hence, the nanogel-enabled combination regimen of LND and PTX showed a boosted anti-tumor efficacy in MCF-7/MDR cells. These mitochondrial-directed pH-sensitive PVA nanogels incorporating both PTX and LND represent a new nanoplatform for MDR reversal and enhanced therapeutic efficacy.
Emerging Roles of Long Noncoding RNAs in Immuno-Oncology
Authors: Wang Xin , Wang Xu , Xu Midie , Sheng Weiqi
Published: December 2021

Long noncoding RNAs (lncRNAs), defined as ncRNAs no longer than 200 nucleotides, play an important role in cancer development. Accumulating research on lncRNAs offers a compelling new aspect of genome modulation, in which they are involved in chromatin remodeling, transcriptional and post-transcriptional regulation, and cross-talk with other nucleic acids. Increasing evidence suggests that lncRNAs reshape the tumor microenvironment (TME), which accounts for tumor development and progression. At the same time, the insightful findings on lncRNAs in immune recognition and evasion in tumor-infiltrating immune cells raise concerns with regard to immuno-oncology. In this review, we describe the essential characteristics of lncRNAs, elucidate functions of immune components engaged in tumor surveillance, and present some instructive examples in this new area.
Long Non-coding RNAs LINC01679 as a Competitive Endogenous RNAs Inhibits the Development and Progression of Prostate Cancer via Regulating the miR-3150a-3p/SLC17A9 Axis
Authors: Mi Yuan-yuan , Sun Chuan-yu , Zhang Li-feng , Wang Jun , Shao Hong-bao , Qin Feng , Xia Guo-wei , Zhu Li-jie
Published: December 2021

Long non-coding RNAs (lncRNAs) have been indicated as the candidate factors to predict cancer prognosis. However, it is still unknown whether lncRNA combinations may be utilized for predicting overall survival (OS) of prostate cancer (PCa). The present work focused on selecting the potent OS-related lncRNA signature for PCa and studying its molecular mechanism to enhance the prognosis prediction accuracy. Differentially expressed lncRNAs (DElncRNAs) or differentially expressed genes (DEGs) were obtained based on TCGA database by R software “edgeR” package. lncRNAs or mRNAs significantly related to PCa were screened through univariate as well as multivariate Cox regression, for the construction of the risk model for prognosis prediction. Moreover, this constructed risk model was validated through ROC analysis, univariate regression, and Kaplan–Meier (KM) analysis. Additionally, we built a lncRNA–miRNA–mRNA ceRNA network through bioinformatics analysis. Colony formation, CCK-8, flow cytometry, scratch, and Transwell assays were performed based on PCa cells subjected to small interfering RNA (siRNA) targeting LINC01679/SLC17A9 and vector expressing LINC01679/SLC17A9 transfection. Thereafter, the ceRNA mechanism was clarified via qRT-PCR, Western blotting (WB), RNA pull-down, and luciferase reporter assays. Nude mouse tumor xenograft was established to examine LINC01679’s oncogenicity within PCa cells. According to our results, LINC01679 depletion promoted cell proliferation, metastasis, tumor growth, and inhibited cell apoptosis in vivo and in vitro, which was also associated with poor survival. LINC01679 regulated miR-3150a-3p level by sponging it. Importantly, miR-3150a-3p overexpression was related to the increased proliferation and decreased apoptosis of PCa cells. Rescue assays suggested that miR-3150a-3p mimics rescued the repression on PCa progression mediated by LINC01679 upregulation, but SLC17A9 downregulation reversed the miR-3150a-3p inhibitor-mediated repression on PC progression. Importantly, SLC17A9 downregulation rescued the repression on PCa progression mediated by LINC01679 upregulation. LINC01679 and SLC17A9 are tightly associated with certain clinicopathological characteristics of PCa and its prognostic outcome. In addition, LINC01679 is the ceRNA that suppresses PCa development through modulating the miR-3150a-3p/SLC17A9 axis.
Dimensions of a Living Cochlear Hair Bundle
Authors: Miller Katharine K. , Atkinson Patrick , Mendoza Kyssia Ruth , Ó Maoiléidigh Dáibhid , Grillet Nicolas
Published: December 2021

The hair bundle is the mechanosensory organelle of hair cells that detects mechanical stimuli caused by sounds, head motions, and fluid flows. Each hair bundle is an assembly of cellular-protrusions called stereocilia, which differ in height to form a staircase. Stereocilia have different heights, widths, and separations in different species, sensory organs, positions within an organ, hair-cell types, and even within a single hair bundle. The dimensions of the stereociliary assembly dictate how the hair bundle responds to stimuli. These hair-bundle properties have been measured previously only to a limited degree. In particular, mammalian data are either incomplete, lack control for age or position within an organ, or have artifacts owing to fixation or dehydration. Here, we provide a complete set of measurements for postnatal day (P) 11 C57BL/6J mouse apical inner hair cells (IHCs) obtained from living tissue, tissue mildly-fixed for fluorescent imaging, or tissue strongly fixed and dehydrated for scanning electronic microscopy (SEM). We found that hair bundles mildly-fixed for fluorescence had the same dimensions as living hair bundles, whereas SEM-prepared hair bundles shrank uniformly in stereociliary heights, widths, and separations. By determining the shrinkage factors, we imputed live dimensions from SEM that were too small to observe optically. Accordingly, we created the first complete blueprint of a living IHC hair bundle. We show that SEM-prepared measurements strongly affect calculations of a bundle’s mechanical properties – overestimating stereociliary deflection stiffness and underestimating the fluid coupling between stereocilia. The methods of measurement, the data, and the consequences we describe illustrate the high levels of accuracy and precision required to understand hair-bundle mechanotransduction.
Increased ATG5 Expression Predicts Poor Prognosis and Promotes EMT in Cervical Carcinoma
Authors: Zhou Suna , Wang Xuequan , Ding Jiapei , Yang Haihua , Xie Youyou
Published: December 2021

Cervical cancer has the second-highest incidence and mortality of female malignancy. The major causes of mortality in patients with cervical cancer are invasion and metastasis. The epithelial–mesenchymal transition (EMT) process plays a major role in the acquisition of metastatic potential and motility. Autophagy-related genes (ARGs) are implicated in the EMT process, and autophagy exerts a dual function in EMT management at different phases of tumor progression. However, the role of specific ARGs during the EMT process has not yet been reported in cervical cancer. Based on the data from the Cancer Genome Atlas (TCGA) cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) sequencing database, we performed the prognosis analysis for those ARGs obtained from the Human Autophagy database. ATG5 was identified as the only important harmful marker influencing survival of cervical cancer patients by univariate Cox regression (HR 1.7; 95% CI: 1.0–2.8, p = 0.047), and the 5-years survival rate for the high- and low-ATG5 expression groups was 0.486 (0.375–0.631) and 0.782 (0.708–0.863), respectively. TCGA CESC methylation data showed that eight methylation sites of ATG5 could also be significantly associated with the overall survival (OS) of cervical cancer patients. Single-sample gene-set enrichment and gene functional enrichment results showed that ATG5 was correlated with some cancer-related pathways, such as phagocytosis-related genes, endocytosis-related genes, immune-related genes, EMT score, and some EMT signature-related genes. Next, cell migration and invasion assay and Western blot were applied to detect the function of ATG5 in EMT of cervical cancer. In cervical cancer cells, ATG5 knockdown resulted in attenuation of migration and invasion. The functional study showed that knockdown of ATG5 could reverse EMT process by P-ERK, P-NFκBp65, P-mTOR pathways, and so on. In conclusion, the present study implies that ATG5 was a major contributor to EMT regulation and poor prognosis in cervical cancer.
Hypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma
Authors: Hong Shuo , Zhang Yueming , Cao Manming , Lin Anqi , Yang Qi , Zhang Jian , Luo Peng , Guo Linlang
Published: December 2021

Objective: Resistance to immune checkpoint inhibitors (ICIs) has been a massive obstacle to ICI treatment in metastatic urothelial carcinoma (MUC). Recently, increasing evidence indicates the clinical importance of the association between hypoxia and immune status in tumor patients. Therefore, it is necessary to investigate the relationship between hypoxia and prognosis in metastatic urothelial carcinoma.

Methods: Transcriptomic and clinical data from 348 MUC patients who underwent ICI treatment from a large phase 2 trial (IMvigor210) were investigated in this study. The cohort was randomly divided into two datasets, a training set (n = 213) and a testing set (n = 135). Data of hypoxia-related genes were downloaded from the molecular signatures database (MSigDB), and screened by univariate and multivariate Cox regression analysis to construct a prognosis-predictive model. The robustness of the model was evaluated in two melanoma cohorts. Furthermore, an external validation cohort, the bladder cancer cohort, from the Cancer Genome Atlas (TCGA) database, was t used to explore the mechanism of gene mutation, immune cell infiltration, signaling pathway enrichment, and drug sensitivity.

Results: We categorized patients as the high- or low- risk group using a four-gene hypoxia risk model which we constructed. It was found that patients with high-risk scores had significantly worse overall survival (OS) compared with those with low-risk scores. The prognostic model covers 0.71 of the area under the ROC curve in the training set and 0.59 in the testing set, which is better than the survival prediction of MUC patients using the clinical characteristics. Mutation analysis results showed that deletion mutations in RB1, TP53, TSC1 and KDM6A were correlated with hypoxic status. Immune cell infiltration analysis illustrated that the infiltration T cells, B cells, Treg cells, and macrophages was correlated with hypoxia. Functional enrichment analysis revealed that a hypoxic microenvironment activated inflammatory pathways, glucose metabolism pathways, and immune-related pathways.

Conclusion: In this investigation, a four-gene hypoxia risk model was developed to evaluate the degree of hypoxia and prognosis of ICI treatment, which showed a promising clinical prediction value in MUC. Furthermore, the hypoxia risk model revealed a close relationship between hypoxia and the tumor immune microenvironment.
Induction and Maturation of Hepatocyte-Like Cells In Vitro: Focus on Technological Advances and Challenges
Authors: Xie Ye , Yao Jia , Jin Weilin , Ren Longfei , Li Xun
Published: December 2021

Limited by the poor proliferation and restricted sources of adult hepatocytes, there is an urgent need to find substitutes for proliferation and cultivation of mature hepatocytes in vitro for use in disease treatment, drug approval, and toxicity testing. Hepatocyte-like cells (HLCs), which originate from undifferentiated stem cells or modified adult cells, are considered good candidates because of their advantages in terms of cell source and in vitro expansion ability. However, the majority of induced HLCs are in an immature state, and their degree of differentiation is heterogeneous, diminishing their usability in basic research and limiting their clinical application. Therefore, various methods have been developed to promote the maturation of HLCs, including chemical approaches, alteration of cell culture systems, and genetic manipulation, to meet the needs of in vivo transplantation and in vitro model establishment. This review proposes different cell types for the induction of HLCs, and provide a comprehensive overview of various techniques to promote the generation and maturation of HLCs in vitro.
The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function
Authors: Li Mu-Hang , Marty-Santos Leilani M. , van Ginkel Paul R. , McDermott Aubrey E. , Rasky Andrew J. , Lukacs Nicholas W. , Wellik Deneen M.
Published: December 2021

Hox genes encode transcription factors that are critical for embryonic skeletal patterning and organogenesis. The Hoxa5, Hoxb5, and Hoxc5 paralogs are expressed in the lung mesenchyme and function redundantly during embryonic lung development. Conditional loss-of-function of these genes during postnatal stages leads to severe defects in alveologenesis, specifically in the generation of the elastin network, and animals display bronchopulmonary dysplasia (BPD) or BPD-like phenotype. Here we show the surprising results that mesenchyme-specific loss of Hox5 function at adult stages leads to rapid disruption of the mature elastin matrix, alveolar enlargement, and an emphysema-like phenotype. As the elastin matrix of the lung is considered highly stable, adult disruption of the matrix was not predicted. Just 2 weeks after deletion, adult Hox5 mutant animals show significant increases in alveolar space and changes in pulmonary function, including reduced elastance and increased compliance. Examination of the extracellular matrix (ECM) of adult Tbx4rtTA; TetOCre; Hox5afafbbcc lungs demonstrates a disruption of the elastin network although the underlying fibronectin, interstitial collagen and basement membrane appear unaffected. An influx of macrophages and increased matrix metalloproteinase 12 (MMP12) are observed in the distal lung 3 days after Hox5 deletion. In culture, fibroblasts from Hox5 mutant lungs exhibit reduced adhesion. These findings establish a novel role for Hox5 transcription factors as critical regulators of lung fibroblasts at adult homeostasis.
Establishment and Validation of Prognostic Nomograms Based on Serum Copper Level for Patients With Early-Stage Triple-Negative Breast Cancer
Authors: Duan Fangfang , Li Jianpei , Huang Jiajia , Hua Xin , Song Chenge , Wang Li , Bi Xiwen , Xia Wen , Yuan Zhongyu
Published: December 2021

Background: Altered copper levels have been observed in several cancers, but studies on the relationship between serum copper and early-stage triple-negative breast cancer (TNBC) remain scare. We sought to establish a predictive model incorporating serum copper levels for individualized survival predictions.

Methods: We retrospectively analyzed clinicopathological information and baseline peripheric blood samples of patients diagnosed with early-stage TNBC between September 2005 and October 2016 at Sun Yat-sen University Cancer Center. The optimal cut-off point of serum copper level was determined using maximally selected log-rank statistics. Kaplan-Meier curves were used to estimate survival probabilities. Independent prognostic indicators associated with survival were identified using multivariate Cox regression analysis, and subsequently, prognostic nomograms were established to predict individualized disease-free survival (DFS) and overall survival (OS). The nomograms were validated in a separate cohort of 86 patients from the original randomized clinical trial SYSUCC-001 (SYSUCC-001 cohort).

Results: 350 patients were eligible in this study, including 264 in the training cohort and 86 in the SYSUCC-001 cohort. An optimal cut-off value of 21.3 μmol/L of serum copper was determined to maximally divide patients into low- and high-copper groups. After a median follow-up of 87.1 months, patients with high copper levels had significantly worse DFS (p = 0.002) and OS (p < 0.001) than those with low copper levels in the training cohort. Multivariate Cox regression analysis revealed that serum copper level was an independent factor for DFS and OS. Further, prognostic models based on serum copper were established for individualized predictions. These models showed excellent discrimination [C-index for DFS: 0.689, 95% confidence interval (CI): 0.621–0.757; C-index for OS: 0.728, 95% CI: 0.654–0.802] and predictive calibration, and were validated in the SYSUCC-001 cohort.

Conclusion: Serum copper level is a potential predictive biomarker for patients with early-stage TNBC. Predictive nomograms based on serum copper might be served as a practical tool for individualized prognostication.
The Expression of Programmed Death Ligand 1 and Vimentin in Resected Non-Metastatic Non-Small-Cell Lung Cancer: Interplay and Prognostic Effects
Authors: Bravaccini Sara , Bronte Giuseppe , Petracci Elisabetta , Puccetti Maurizio , D’Arcangelo Manolo , Ravaioli Sara , Tumedei Maria Maddalena , Maltoni Roberta , Delmonte Angelo , Cappuzzo Federico , Crinò Lucio
Published: December 2021

Programmed death ligand 1 (PD-L1) is an immune checkpoint with a role in cancer-related immune evasion. It is a target for cancer immunotherapy and its expression is detected for the use of some immune checkpoint inhibitors in advanced non-small cell lung cancer patients (NSCLC). Vimentin is a key component of the epithelial-to-mesenchymal transition phenotype. Its expression has negative prognostic effects in NSCLC. In this study, we retrospectively evaluated PD-L1 and vimentin expression in tumor cells, immune infiltrate and PD-L1 positive immune infiltrate via immunohistochemistry in tissue samples from resected non-metastatic NSCLC patients. We explored the interplay between PD-L1 and vimentin expression through Spearman’s correlation test. We performed univariate analysis through the Cox models for demographic and clinico-pathological variables, and also for dichotomized biomarkers, i.e., PD-L1 and vimentin in tumor cells, both with 1 and 50% cutoffs. We used Kaplan-Meier method to estimate the overall survival, comparing both vimentin and PD-L1 positive patients with all the others. We found a weak positive correlation between PD-L1 and vimentin expressions in tumor cells (r = 0.25; p = 0.001). We also observed a statistically not significant trend towards a shorter overall survival in patients with both PD-L1 and vimentin expression >1% (HR = 1.36; 95% CI: 0.96–1.93, p = 0.087). In conclusion, these findings suggest that interplay between PD-L1 and vimentin may exist in non-metastatic NSCLC patients and the positivity of both markers in tumor tissue is associated with a trend towards a worse prognosis.
Synuclein Regulates Synaptic Vesicle Clustering and Docking at a Vertebrate Synapse
Authors: Fouke Kaitlyn E. , Wegman M. Elizabeth , Weber Sarah A. , Brady Emily B. , Román-Vendrell Cristina , Morgan Jennifer R.
Published: December 2021

Neurotransmission relies critically on the exocytotic release of neurotransmitters from small synaptic vesicles (SVs) at the active zone. Therefore, it is essential for neurons to maintain an adequate pool of SVs clustered at synapses in order to sustain efficient neurotransmission. It is well established that the phosphoprotein synapsin 1 regulates SV clustering at synapses. Here, we demonstrate that synuclein, another SV-associated protein and synapsin binding partner, also modulates SV clustering at a vertebrate synapse. When acutely introduced to unstimulated lamprey reticulospinal synapses, a pan-synuclein antibody raised against the N-terminal domain of α-synuclein induced a significant loss of SVs at the synapse. Both docked SVs and the distal reserve pool of SVs were depleted, resulting in a loss of total membrane at synapses. In contrast, antibodies against two other abundant SV-associated proteins, synaptic vesicle glycoprotein 2 (SV2) and vesicle-associated membrane protein (VAMP/synaptobrevin), had no effect on the size or distribution of SV clusters. Synuclein perturbation caused a dose-dependent reduction in the number of SVs at synapses. Interestingly, the large SV clusters appeared to disperse into smaller SV clusters, as well as individual SVs. Thus, synuclein regulates clustering of SVs at resting synapses, as well as docking of SVs at the active zone. These findings reveal new roles for synuclein at the synapse and provide critical insights into diseases associated with α-synuclein dysfunction, such as Parkinson’s disease.
Steroid-Induced Osteonecrosis of the Femoral Head: Novel Insight Into the Roles of Bone Endothelial Cells in Pathogenesis and Treatment
Authors: Huang Cheng , Wen Zeqin , Niu Junjie , Lin Subin , Wang Weiguo
Published: December 2021

Steroid-induced osteonecrosis of the femoral head (SONFH) is a disease characterized by the collapse of the femoral head. SONFH occurs due to the overuse of glucocorticoids (GCs) in patients with immune-related diseases. Among various pathogenesis proposed, the mechanism related to impaired blood vessels is gradually becoming the most convincing hypothesis. Bone endothelial cells including bone microvascular endothelial cells (BMECs) and endothelial progenitor cells (EPCs) play a crucial role in the maintenance of vascular homeostasis. Therefore, bone endothelial cells are key regulators in the occurrence and progression of SONFH. Impaired angiogenesis, abnormal apoptosis, thrombosis and fat embolism caused by the dysfunctions of bone endothelial cells are considered to be the pathogenesis of SONFH. In addition, even with high disability rates, SONFH lacks effective therapeutic approach. Icariin (ICA, a flavonoid extracted from Epimedii Herba), pravastatin, and VO-OHpic (a potent inhibitor of PTEN) are candidate reagents to prevent and treat SONFH through improving above pathological processes. However, these reagents are still in the preclinical stage and will not be widely used temporarily. In this case, bone tissue engineering represented by co-transplantation of bone endothelial cells and bone marrow mesenchymal stem cells (BMSCs) may be another feasible therapeutic strategy.
Insights Into the Regulation of Gynecological Inflammation-Mediated Malignancy by Metalloproteinases
Authors: Begum Yasmin , Pandit Anuradha , Swarnakar Snehasikta
Published: December 2021

Gynecological illness accounts for around 4.5% of the global disease burden, which is higher than other key global health concerns such as malaria (1.04%), TB (1.9%), ischemic heart disease (2.2%), and maternal disorders (3.5%). Gynecological conditions in women of reproductive age are linked to both in terms of diagnosis and treatment, especially in low-income economies, which poses a serious social problem. A greater understanding of health promotion and illness management can help to prevent diseases in gynecology. Due to the lack of established biomarkers, the identification of gynecological diseases, including malignancies, has proven to be challenging in most situations, and histological exams remain the gold standard. Metalloproteinases (MMPs, ADAMs, ADAMTSs) and their endogenous inhibitors (TIMPs) modulate the protease-dependent bioavailability of local niche components (e.g., growth factors), matrix turnover, and cellular interactions to govern specific physical and biochemical characteristics of the environment. Matrix metalloproteinases (MMPs), A Disintegrin and Metalloproteinase (ADAM), and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) are zinc-dependent endopeptidases that contribute significantly to the disintegration of extracellular matrix proteins and shedding of membrane-bound receptor molecules in several diseases, including arthritis. MMPs are noteworthy genes associated with cancer development, functional angiogenesis, invasion, metastasis, and immune surveillance evasion. These genes are often elevated in cancer and multiple benign gynecological disorders like endometriosis, according to research. Migration through the extracellular matrix, which involves proteolytic activity, is an essential step in tumor cell extravasation and metastasis. However, none of the MMPs’ expression patterns, as well as their diagnostic and prognostic potential, have been studied in a pan-cancer context. The latter plays a very important role in cell signaling and might be used as a cancer treatment target. ADAMs are implicated in tumor cell proliferation, angiogenesis, and metastasis. This review will focus on the contribution of the aforementioned metalloproteinases in regulating gynecological disorders and their subsequent manipulation for therapeutic intervention.
Review: The Role of Wnt/β-Catenin Signalling in Neural Crest Development in Zebrafish
Authors: Sutton Gemma , Kelsh Robert N. , Scholpp Steffen
Published: December 2021

The neural crest (NC) is a multipotent cell population in vertebrate embryos with extraordinary migratory capacity. The NC is crucial for vertebrate development and forms a myriad of cell derivatives throughout the body, including pigment cells, neuronal cells of the peripheral nervous system, cardiomyocytes and skeletogenic cells in craniofacial tissue. NC induction occurs at the end of gastrulation when the multipotent population of NC progenitors emerges in the ectodermal germ layer in the neural plate border region. In the process of NC fate specification, fate-specific markers are expressed in multipotent progenitors, which subsequently adopt a specific fate. Thus, NC cells delaminate from the neural plate border and migrate extensively throughout the embryo until they differentiate into various cell derivatives. Multiple signalling pathways regulate the processes of NC induction and specification. This review explores the ongoing role of the Wnt/β-catenin signalling pathway during NC development, focusing on research undertaken in the Teleost model organism, zebrafish (Danio rerio). We discuss the function of the Wnt/β-catenin signalling pathway in inducing the NC within the neural plate border and the specification of melanocytes from the NC. The current understanding of NC development suggests a continual role of Wnt/β-catenin signalling in activating and maintaining the gene regulatory network during NC induction and pigment cell specification. We relate this to emerging models and hypotheses on NC fate restriction. Finally, we highlight the ongoing challenges facing NC research, current gaps in knowledge, and this field’s potential future directions.
Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits
Authors: Maneshi Parniyan , Mason James , Dongre Mitesh , Öhlund Daniel
Published: December 2021

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes among cancers with a 5-years survival rate of below 10%. This is a result of late diagnosis and the lack of effective treatments. The tumor is characterized by a highly fibrotic stroma containing distinct cellular components, embedded within an extracellular matrix (ECM). This ECM-abundant tumor microenvironment (TME) in PDAC plays a pivotal role in tumor progression and resistance to treatment. Cancer-associated fibroblasts (CAFs), being a dominant cell type of the stroma, are in fact functionally heterogeneous populations of cells within the TME. Certain subtypes of CAFs are the main producer of the ECM components of the stroma, with the most abundant one being the collagen family of proteins. Collagens are large macromolecules that upon deposition into the ECM form supramolecular fibrillar structures which provide a mechanical framework to the TME. They not only bring structure to the tissue by being the main structural proteins but also contain binding domains that interact with surface receptors on the cancer cells. These interactions can induce various responses in the cancer cells and activate signaling pathways leading to epithelial-to-mesenchymal transition (EMT) and ultimately metastasis. In addition, collagens are one of the main contributors to building up mechanical forces in the tumor. These forces influence the signaling pathways that are involved in cell motility and tumor progression and affect tumor microstructure and tissue stiffness by exerting solid stress and interstitial fluid pressure on the cells. Taken together, the TME is subjected to various types of mechanical forces and interactions that affect tumor progression, metastasis, and drug response. In this review article, we aim to summarize and contextualize the recent knowledge of components of the PDAC stroma, especially the role of different collagens and mechanical traits on tumor progression. We furthermore discuss different experimental models available for studying tumor-stromal interactions and finally discuss potential therapeutic targets within the stroma.
Human Glomerular Endothelial Cells Treated With Shiga Toxin Type 2 Activate γδ T Lymphocytes
Authors: Rosso David Antonio , Rosato Micaela , Gómez Fernando Daniel , Álvarez Romina Soledad , Shiromizu Carolina Maiumi , Keitelman Irene Angélica , Ibarra Cristina , Amaral María Marta , Jancic Carolina Cristina
Published: December 2021

The hemolytic uremic syndrome associated with diarrhea, a consequence of Shiga toxin (Stx)-producing Escherichia coli infection, is a common cause of pediatric acute renal failure in Argentina. Stx type 2a (Stx2a) causes direct damage to renal cells and induces local inflammatory responses that involve secretion of inflammatory mediators and the recruitment of innate immune cells. γδ T cells constitute a subset of T lymphocytes, which act as early sensors of cellular stress and infection. They can exert cytotoxicity against infected and transformed cells, and produce cytokines and chemokines. In this study, we investigated the activation of human peripheral γδ T cells in response to the incubation with Stx2a-stimulated human glomerular endothelial cells (HGEC) or their conditioned medium, by analyzing in γδ T lymphocytes, the expression of CD69, CD107a, and perforin, and the production of TNF-α and IFN-γ. In addition, we evaluated by confocal microscopy the contact between γδ T cells and HGEC. This analysis showed an augmentation in cellular interactions in the presence of Stx2a-stimulated HGEC compared to untreated HGEC. Furthermore, we observed an increase in cytokine production and CD107a expression, together with a decrease in intracellular perforin when γδ T cells were incubated with Stx2a-treated HGEC or their conditioned medium. Interestingly, the blocking of TNF-α by Etanercept reversed the changes in the parameters measured in γδ T cells incubated with Stx2a-treated HGEC supernatants. Altogether, our results suggest that soluble factors released by Stx2a-stimulated HGEC modulate the activation of γδ T cells, being TNF-α a key player during this process.
Body Mass Index: An Effective Predictor of Ejection Fraction Improvement in Heart Failure
Authors: Ye Li-fang , Li Xue-ling , Wang Shao-mei , Wang Yun-fan , Zheng Ya-ru , Wang Li-hong
Published: December 2021

Background: Heart failure patients with higher body mass index (BMI) exhibit better clinical outcomes. Therefore, we assessed whether the BMI can predict left ventricular ejection fraction (EF) improvement following heart failure.

Methods and Results: We included 184 patients newly diagnosed with dilated cardiomyopathy and reduced EF in our center and who underwent follow-up examination of EF via echocardiography after 6 months. The EF improved at 6 months in 88 participants, who were included in the heart failure with recovered EF (HFrecEF) subgroup. Patients in whom the EF remained reduced were included in the heart failure with persistently reduced EF (persistent HFrEF) subgroup. Our analyses revealed that EF increase correlated with age (r = −0.254, P = 0.001), left ventricular diastolic dimension (LVDD; r = −0.210, P = 0.004), diabetes (P = 0.034), brain natriuretic peptide (r = −0.199, P = 0.007), and BMI grade (P = 0.000). BMI grade was significantly associated with elevated EF after adjustment for other variables (P = 0.001). On multivariable analysis, compared to patients with persistent HFrEF, those with HFrecEF had higher BMI [odds ratio (OR) = 2.342 per one standard deviation increase; P = 0.001] and lower LVDD (OR = 0.466 per one standard deviation increase; P = 0.001). ROC-curve analysis data showed that BMI > 22.66 kg/m2 (sensitivity 84.1%, specificity 59.4%, AUC 0.745, P = 0.000) indicate high probability of EF recovery in 6 months.

Conclusions: Our data suggest that higher BMI is strongly correlated with the recovered EF and that BMI is an effective predictor of EF improvement in patients with heart failure and reduced EF.
Comodulation of NO-Dependent Vasodilation by Erythroid Band 3 and Hemoglobin: A GP.Mur Athlete Study
Authors: Hsu Kate , Liu Yen-Yu , Tseng Wei-Chin , Huang Kuang-Tse , Liu Chia-Yuan , Chen Li-Yang , Lee Hui-Lin , Lin Hui-Ju , Tseng Kuo-Wei , Yeh Hung-I
Published: December 2021

GP.Mur, a red blood cell (RBC) hybrid protein encoded by glycophorin B-A-B, increases expression of erythroid band 3 (Anion Exchanger-1, SLC4A1). GP.Mur is extremely rare but has a prevalence of 1–10% in regions of Southeast Asia. We unexpectedly found slightly higher blood pressure (BP) among healthy Taiwanese adults with GP.Mur. Since band 3 has been suggested to interact with hemoglobin (Hb) to modulate nitric oxide (NO)-dependent hypoxic vasodilation during the respiratory cycle, we hypothesized that GP.Mur red cells could exert differentiable effects on vascular tone. Here we recruited GP.Mur-positive and GP.Mur-negative elite male college athletes, as well as age-matched, GP.Mur-negative non-athletes, for NO-dependent flow-mediated dilation (FMD) and NO-independent dilation (NID). The subjects were also tested for plasma nitrite and nitrate before and after arterial occlusion in FMD. GP.Mur+ and non-GP.Mur athletes exhibited similar heart rates and blood pressure, but GP.Mur+ athletes showed significantly lower FMD (4.8 ± 2.4%) than non-GP.Mur athletes (6.5 ± 2.1%). NO-independent vasodilation was not affected by GP.Mur. As Hb controls intravascular NO bioavailability, we examined the effect of Hb on limiting FMD and found it to be significantly stronger in GP.Mur+ subjects. Biochemically, plasma nitrite levels were directly proportional to individual band 3 expression on the red cell membrane. The increase of plasma nitrite triggered by arterial occlusion also showed small dependency on band 3 levels in non-GP.Mur subjects. By the GP.Mur comparative study, we unveiled comodulation of NO-dependent vasodilation by band 3 and Hb, and verified the long-pending role of erythroid band 3 in this process.
New Oral Anticoagulants vs. Vitamin K Antagonists Among Patients With Cardiac Amyloidosis: Prognostic Impact
Authors: Cariou Eve , Sanchis Kevin , Rguez Khailène , Blanchard Virginie , Cazalbou Stephanie , Fournier Pauline , Huart Antoine , Roussel Murielle , Cintas Pascal , Galinier Michel , Carrié Didier , Maury Philippe , Lavie-Badie Yoan , Lairez Olivier
Published: December 2021

Background: Atrial arrhythmia (AA) is common among patients with cardiac amyloidosis (CA), who have an increased risk of intracardiac thrombus. The aim of this study was to explore the prognostic impact of vitamin K-antagonists (VKA) and direct oral anticoagulants (DOAC) in patients with CA.

Methods and Results: 273 patients with CA and history of AA with long term anticoagulation−69 (25%) light chain amyloidosis (AL), 179 (66%) wild-type transthyretin amyloidosis (ATTRwt) and 25 (9%) variant transthyretin amyloidosis (ATTRv)–were retrospectively included between January 2012 and July 2020. 147 (54%) and 126 (46%) patients received VKA and DOAC, respectively. Patient receiving VKA were more likely to have AL with renal dysfunction, higher NT-proBNP and troponin levels. Patients with ATTRwt were more likely to receive DOAC therapy. There were more bleeding complications among patients with VKA (20 versus 10%; P = 0.013) but no difference for stroke events (4 vs. 2%; P = 0.223), as compared to patients with DOAC. A total of 124 (45%) patients met the primary endpoint of all-cause mortality: 96 (65%) and 28 (22%) among patients with VKAs and DOACs, respectively (P < 0.001). After multivariate analysis including age and renal function, VKA was no longer associated with all-cause mortality.

Conclusion: Among patients with CA and history of AA receiving oral anticoagulant, DOACs appear to be at least as effective and safe as VKAs.