bluuebunny/crossref_metadata_2025 huggingface dataset:
Determination of Genetic and Epigenetic Modifications-Related Prognostic Biomarkers of Breast Cancer: Genome High-Throughput Data Analysis
Authors: Gao Chundi , Li Huayao , Liu Cun , Wu Jibiao , Zhou Chao , Liu Lijuan , Zhuang Jing , Sun Changgang
Published: September 2021

The high heterogeneity of breast cancer (BRCA) makes it more challenging to interpret the genetic variation mechanisms involved in BRCA pathogenesis and prognosis. Areas with high DNA methylation (such as CpG islands) were accompanied by copy number variation (CNV), and these genomic variations affected the level of DNA methylation. In this study, we characterized intertumor heterogeneity and analyzed the effects of CNV on DNA methylation and gene expression. In addition, we performed a Genetic Set Enrichment Analysis (GSEA) to identify key pathways for changes between patients with low and high expression of genes. Our analysis found two key genes, namely, HPDL and SOX17. The protein expressed by HPDL is 4-hydroxyphenylpyruvate dioxygenase-like protein, which has dioxygenase activity. SOX17 is a transcription factor that can inhibit Wnt signaling, promote the degradation of activated CTNNB1, and participate in cell proliferation. Our analysis found that the CNV of HPDL and SOX17 is not only related to the patient’s prognosis, but also related to gene methylation and expression levels affecting the patient’s survival time. Among them, the high-methylation, low-expression HPDL and SOX17 showed poor prognosis. And the addition of two copies of SOX17 is associated with a lower survival rate, while a decrease in the copy number of HPDL also suggests a poor prognosis. This study provided an effective bioinformatics basis for further exploration of molecular mechanisms related to BRCA and assessment of patient prognosis, but the development of biomarkers for diagnosis and treatment still requires further clinical data validation.
Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer
Authors: Cuda Tahleesa J. , He Yaowu , Kryza Thomas , Khan Tashbib , Tse Brian W. , Sokolowski Kamil A. , Liu Cheng , Lyons Nicholas , Gough Madeline , Snell Cameron E. , Wyld David K. , Rose Stephen , Riddell Andrew D. , Stevenson Andrew R. L. , Thomas Paul A. , Clark David A. , Puttick Simon , Hooper John D.
Published: September 2021

Colorectal cancer (CRC) is the third most common malignancy in the world, with 22% of patients presenting with metastatic disease and a further 50% destined to develop metastasis. Molecular imaging uses antigen-specific ligands conjugated to radionuclides to detect and characterise primary cancer and metastases. Expression of the cell surface protein CDCP1 is increased in CRC, and here we sought to assess whether it is a suitable molecular imaging target for the detection of this cancer. CDCP1 expression was assessed in CRC cell lines and a patient-derived xenograft to identify models suitable for evaluation of radio-labelled 10D7, a CDCP1-targeted, high-affinity monoclonal antibody, for preclinical molecular imaging. Positron emission tomography-computed tomography was used to compare zirconium-89 (89Zr)-10D7 avidity to a nonspecific, isotype control 89Zr-labelled IgGκ1 antibody. The specificity of CDCP1-avidity was further confirmed using CDCP1 silencing and blocking models. Our data indicate high avidity and specificity for of 89Zr-10D7 in CDCP1 expressing tumors at. Significantly higher levels than normal organs and blood, with greatest tumor avidity observed at late imaging time points. Furthermore, relatively high avidity is detected in high CDCP1 expressing tumors, with reduced avidity where CDCP1 expression was knocked down or blocked. The study supports CDCP1 as a molecular imaging target for CRC in preclinical PET-CT models using the radioligand 89Zr-10D7.
Adaptive Backstepping Sliding Mode Control for Quadrotor UAV
Authors: Huang Sibo , Huang Jianfeng , Cai Zhaoquan , Cui Han
Published: September 2021

Quadrotor UAV has a strong mobility and flexibility in flight and has been widely used in military and civil fields in recent years. An adaptive backstepping sliding mode control (ABSMC) method is proposed to address the trajectory tracking control problem of quadrotor UAV based on actuator fault and external disturbance. In the proposed method, the switching gain of adaptive sliding mode control is constructed in the backstepping design process in order to suppress the chattering effect of sliding mode control effectively by differential iteration. Firstly, the dynamic model of quadrotor UAV with actuator fault and external disturbance is proposed, and then the controllers are designed based on the ABSMC method. Finally, the comparison experiments between sliding mode control (SMC) method and ABSMC method show that the ABSMC method can not only effectively suppress the chattering problem for the SMC method but also perform a perfect control effect.
Evaluation of Poly(Glycidyl Methacrylate) Nanocoating for Chiral Separation with Glu-β-CD as Chiral Selector in Capillary Electrophoresis
Authors: Xu Jin , Sun Xuecheng , Sun Xiaodong , Lu Ye
Published: September 2021

In this paper, a capillary coated with poly(glycidyl methacrylate) nanoparticles (PGMA NPs) was prepared and applied to construct a capillary electrophoresis (CE) enantioseparation system with glucosyl-β-cyclodextrin (Glu-β-CD) as a chiral selector. The PGMA NP coating can be easily introduced through a simple ring-opening reaction. Two basic drugs were used as models to evaluate the separation performance of the PGMA coating. Under the optimal conditions selected, the separation of the two enantiomers was obtained.
Pachychoroid Spectrum Disorder Findings in Patients with Coronavirus Disease 2019
Authors: Abrishami Mojtaba , Daneshvar Ramin , Shoeibi Nasser , Saeedian Neda , Heidarzadeh Hamid Reza , Hosseini Seyedeh Maryam
Published: September 2021

Purpose. To report the occurrence of acute, bilateral, central serous chorioretinopathy (CSC), and pachychoroid spectrum disorder findings in patients with coronavirus disease 2019 (COVID-19). Methods. In recovered cases of COVID-19 with visual disturbances, complete ocular examinations with multimodal retinal and choroidal evaluation, including enhanced depth imaging optical coherence tomography, fluorescein or indocyanine green angiography, and blue autofluorescence, were obtained. Results. Four COVID-19 recovered patients presented with bilateral blurred vision. Ocular examination and imaging revealed pachychoroid and pachyvessels associated with choroidal hyperpermeability without any obvious intraocular inflammation. Bilateral localized serous retinal detachment was obvious in three cases compatible with pachychoroid associated with CSC manifestation and pachychoroid pigment epitheliopathy in one patient. CSC was resolved with treatment by steroidal antimineralocorticoid (Eplerenone) in two patients and by photodynamic therapy in one patient. None of the patients reported emotional stress and history of corticosteroid consumption. Conclusion. Hyperpermeability of the choroid, pachychoroidopathy, or choroidal vessel congestion can be observed or exacerbated in association with COVID-19.
Effect of Uncaria rhynchophylla against Thioacetamide-Induced Acute Liver Injury in Rat
Authors: Shin Mi-Rae , Kim Min Ju , Lee Jin A , Roh Seong-Soo
Published: September 2021

Both oxidative stress (OS) and inflammation are two fundamental pathological processes of acute liver injury (ALI). The current work is to investigate the effect and possible mechanism of Uncaria rhynchophylla (UR) on thioacetamide- (TAA-) induced ALI in rats. UR (100 and 200 mg/kg) was orally administrated with TAA (200 mg/kg of bodyweight, intraperitoneal injection) for 3 consecutive days. ALI was confirmed using histological examination and the factors associated with OS and liver function activity measured in serum. Moreover, expressions of inflammation and collagen-related proteins were measured by the Western blot analysis. Myeloperoxidase (MPO), which mediates OS in the ALI control group, was manifested by a significant rise compared with the normal group. UR significantly reduced AST, ALT, and ammonia levels in serum. The nuclear factor-κB (NF-κB) activation induced by TAA led to increase both inflammatory mediators and cytokines. Whereas, UR administration remarkably suppressed such an overexpression. UR supplementation improved matrix metalloproteinases (MMPs) such as MMP-1, -2, and -8. In contrast, tissue inhibitors of metalloproteinases- (TIMP-) 1 level increased significantly by UR treatment. In addition, the histopathological analysis showed that the liver tissue lesions were improved obviously by UR treatment. UR may ameliorate the effects of TAA-induced ALI in rats by suppressing both OS through MPO activation and proinflammatory factors through NF-κB activation. In conclusion, UR exhibited a potent hepatoprotective effect on ALI through the suppression of OS.
Stock Trend Prediction Algorithm Based on Deep Recurrent Neural Network
Authors: Lu Ruochen , Lu Muchao
Published: September 2021

With the return of deep learning methods to the public eye, more and more scholars and industry researchers have tried to start exploring the possibility of neural networks to solve the problem, and some progress has been made. However, although neural networks have powerful function fitting ability, they are often criticized for their lack of explanatory power. Due to the large number of parameters and complex structure of neural network models, academics are unable to explain the predictive logic of most neural networks, test the significance of model parameters, and summarize the laws that humans can understand and use. Inspired by the technical analysis theory in the field of stock investment, this paper selects neural network models with different characteristics and extracts effective feature combinations from short‐term stock price fluctuation data. In addition, on the basis of ensuring that the prediction effect of the model is not lower than that of the mainstream models, this paper uses the attention mechanism to further explore the predictive K‐line patterns, which summarizes usable judgment experience for human researchers on the one hand and explains the prediction logic of the hybrid neural network on the other. Experiments show that the classification effect is better using this model, and the investor sentiment is obtained more accurately, and the accuracy rate can reach 85%, which lays the foundation for the establishment of the whole stock trend prediction model. In terms of explaining the prediction logic of the model, it is experimentally demonstrated that the K‐line patterns mined using the attention mechanism have more significant predictive power than the general K‐line patterns, and this result explains the prediction basis of the hybrid neural network.
Early Sexual Debut among Ghanaian Women: Correlates and Psychological Effect
Authors: Alhassan Abdul Rauf , Abdulai Kasim , Alhassan Mohammed Awal
Published: September 2021

Early sexual initiation is linked to an increased risk of HIV/AIDS and other STIs among teenagers, as well as having multiple partners, not using contraception, unintended pregnancy, and illegal abortions. Aim. To identify the correlates and psychological effects of early sexual debut among not‐in‐union women in Ghana. A descriptive cross‐sectional survey was used for this study using data from Ghana Multiple Indicator Cluster Survey (MICS) for the year 2017/2018. SPSS software was used for data analysis, bivariate analysis for association was done using chi‐square, and the prediction was done using a binary logistic regression model. The national prevalence of nonmarital early sexual initiation this current study recorded was 56.9%. Predictors variables were age, 15‐24/≥35 years (AOR = 1.51, 1.28‐1.78), ever educated (AOR = 0.50, 0.43‐0.60), urban address (AOR = 0.85, 0.74‐0.98), married/single (AOR = 1.23, 1.07‐1.42), cohabitation/single (AOR = 1.43, 1.19‐1.72), Greater Accra Region/Upper West Region (AOR = 0.67, 0.49‐0.92), and health insurance (AOR = 0.89, 0.79‐0.998). As the wealth indices of the woman decrease from the richest to poorest, the likelihood of early sexual debut inversely increases: fourth/richest (AOR = 1.23, 1.04‐1.45), middle/richest (AOR = 1.31, 1.09‐1.58), second/richest (AOR = 1.38, 1.11‐1.72), and poorest/richest (AOR = 1.44, 1.12‐1.86); use of the internet (AOR = 0.58, 0.50‐068); substance use and alcohol ever use (AOR = 1.32, 1.17‐1.49); cigarette ever use (AOR = 2.58, 1.44‐4.64); contraceptive use (AOR = 1.31, 1.16‐1.49); and ever heard of HIV (AOR = 59, 0.42‐0.82). In conclusion, the prevalence of early sexual debut is still high in Ghana, especially among the northern regions. Several factors predicted early sex debut, and low life satisfaction and happiness were related to early sexual debut.
Eliciting Fairness in N‐Player Network Games through Degree‐Based Role Assignment
Authors: Teixeira Andreia Sofia , Santos Francisco C. , Francisco Alexandre P. , Santos Fernando P.
Published: September 2021

From social contracts to climate agreements, individuals engage in groups that must collectively reach decisions with varying levels of equality and fairness. These dilemmas also pervade distributed artificial intelligence, in domains such as automated negotiation, conflict resolution, or resource allocation, which aim to engineer self‐organized group behaviors. As evidenced by the well‐known Ultimatum Game, where a Proposer has to divide a resource with a Responder, payoff‐maximizing outcomes are frequently at odds with fairness. Eliciting equality in populations of self‐regarding agents requires judicious interventions. Here, we use knowledge about agents’ social networks to implement fairness mechanisms, in the context of Multiplayer Ultimatum Games. We focus on network‐based role assignment and show that attributing the role of Proposer to low‐connected nodes increases the fairness levels in a population. We evaluate the effectiveness of low‐degree Proposer assignment considering networks with different average connectivities, group sizes, and group voting rules when accepting proposals (e.g., majority or unanimity). We further show that low‐degree Proposer assignment is efficient, in optimizing not only individuals’ offers but also the average payoff level in the population. Finally, we show that stricter voting rules (i.e., imposing an accepting consensus as a requirement for collectives to accept a proposal) attenuate the unfairness that results from situations where high‐degree nodes (hubs) play as Proposers. Our results suggest new routes to use role assignment and voting mechanisms to prevent unfair behaviors from spreading on complex networks.
Targeting Inflammatory Cytokines to Improve Type 2 Diabetes Control
Authors: Velikova Tsvetelina V. , Kabakchieva Plamena P. , Assyov Yavor S. , Georgiev Tsvetoslav А.
Published: September 2021

Type 2 diabetes (T2D) is one of the most common chronic metabolic disorders in adulthood worldwide, whose pathophysiology includes an abnormal immune response accompanied by cytokine dysregulation and inflammation. As the T2D‐related inflammation and its progression were associated with the balance between pro and anti‐inflammatory cytokines, anticytokine treatments might represent an additional therapeutic option for T2D patients. This review focuses on existing evidence for antihyperglycemic properties of disease‐modifying antirheumatic drugs (DMARDs) and anticytokine agents (anti‐TNF‐α, anti‐interleukin‐(IL‐) 6, ‐IL‐1, ‐IL‐17, ‐IL‐23, etc.). Emphasis is placed on their molecular mechanisms and on the biological rationale for clinical use. Finally, we briefly summarize the results from experimental model studies and promising clinical trials about the potential of anticytokine therapies in T2D, discussing the effects of these drugs on systemic and islet inflammation, beta‐cell function, insulin secretion, and insulin sensitivity.
A Note on the Stability Analysis of Fuzzy Nonlinear Fractional Differential Equations Involving the Caputo Fractional Derivative
Authors: El Mfadel Ali , Melliani Said , Elomari M’hamed
Published: September 2021

In this paper, we present and establish a new result on the stability analysis of solutions for fuzzy nonlinear fractional differential equations by extending Lyapunov’s direct method from the fuzzy ordinary case to the fuzzy fractional case. As an application, several examples are presented to illustrate the proposed stability result.
Based on Artificial Intelligence in the Judicial Field Operation Status and Countermeasure Analysis
Authors: Zhu Kongze , Zheng Lei
Published: September 2021

Artificial intelligence is a recently emerging system that uses computers and big data as the basis to simulate human-like behavior with machines. Artificial intelligence is a way to imitate human thinking by learning massive data knowledge and using algorithms to reason and analyze the data. In the current age of advanced technology, many jobs in the justice system can be replaced by artificial technology technologies. Many courts have now scrutinized the use of artificial intelligence in the judiciary. With artificial intelligence, timely warnings on all aspects of admissions can effectively protect random or outdated trials and allocate social resources appropriately. In addition, it may better redress cases of misconduct and irregular conduct in the judiciary, which is conducive to justice. Based on BP neural network, research on related content and other methods has drawn relevant arguments, which will provide a certain theoretical basis for artificial intelligence to assist the judicial field in the future. The research in this article shows that artificial intelligence is conducive to suppressing duty crimes in the judicial field, promoting the transformation of extensive processing to intensive processing, and is conducive to judicial efficiency. In 2017, there were more than 8 million first-instance civil cases, but only 100,000 cases were closed. But by 2020, with the construction of smart courts, millions of cases out of more than 10 million first-instance civil cases are expected to be closed. The situation has been greatly improved. But at the same time, we also need to prevent the leakage of artificial intelligence to personal privacy, establish and improve corresponding laws and regulations, and coordinate the judgment relationship between the human brain and the machine brain. Artificial intelligence may be more suitable for assisting judicial judgments.
PBDT: Python Backdoor Detection Model Based on Combined Features
Authors: Fang Yong , Xie Mingyu , Huang Cheng
Published: September 2021

Application security is essential in today’s highly development period. Backdoor is a means by which attackers can invade the system to achieve illegal purposes and damage users’ rights. It has posed a serious threat to network security. Thus, it is urgent to take adequate measures to defend such attacks. Previous research work was mainly focused on numerous PHP webshells, with less research on Python backdoor files. Language differences make the method not entirely applicable. This paper proposes a Python backdoor detection model named PBDT based on combined features. The model summarizes the common functional modules and functions in the backdoor files and extracts the number of calls in the text to form sample features. What is more, we consider the text’s statistical characteristics, including the information entropy, the longest string, etc., to identify the obfuscated Python code. Besides, the opcode sequence is used to represent code characteristics, such as TF-IDF vector and FastText classifier, to eliminate the influence of interference items. Finally, we introduce the Random Forest algorithm to build a classifier. Covering most types of backdoors, some samples are obfuscated, the model achieves an accuracy of 97.70%, and the TNR index is as high as 98.66%, showing a good classification performance in Python backdoor detection.
Rothia mucilaginosa Meningitis in a Child with Myelodysplastic Syndromes
Authors: Ochi Fumihiro , Nakamura Ryota , Miyawaki Reiji , Moritani Kyoko , Murakami Shinobu , Tauchi Hisamichi
Published: September 2021

Rothia mucilaginosa is a Gram-positive coccus and an opportunistic pathogen in immunocompromised hosts. The microorganism has been implicated in serious infections, including bacteremia meningitis or endocarditis. However, there is a dearth of investigations on meningitis, especially in children. As this infection is rare and only a few cases have been recorded, evidence-based guidelines for adequate infection treatment are lacking. We herein report the case of a 12-year-old boy with myelodysplastic syndromes (MDS) presenting with a change in mental status who was diagnosed as having febrile neutropenia and bacterial meningitis caused by R. mucilaginosa at 23 days after unrelated cord blood transplant. In our case, the minimum inhibitory concentrations (MICs) of meropenem and vancomycin (VCM) were both ≤1 μg/mL, whereas the MIC of daptomycin (DAP) was 4 μg/mL. The patient was treated with intravenous antimicrobial therapy due to meropenem for 43 days because he had febrile neutropenia. During follow-up, the patient had no neurological complications. We retrospectively reviewed the antimicrobial susceptibility of all R. mucilaginosa isolates (n = 5) from blood or cerebrospinal fluid cultures at our hospital. The MIC of VCM was <0.5 μg/mL for all strains, whereas the MIC of DAP was ≥2 μg/mL for all strains. The MIC of MEPM was >1 μg/mL for one strain. We recommend choosing VCM as the primary treatment for invasive R. mucilaginosa infections until antimicrobial susceptibility results are known, especially in immunocompromised children.
LncRNA SNHG17 Contributes to Proliferation, Migration, and Poor Prognosis of Hepatocellular Carcinoma
Authors: Luo Yue , Lin Junhao , Zhang Jiakang , Song Zhenghui , Zheng Dayong , Chen Fengsheng , Zhuang Xuefen , Li Aimin , Liu Xinhui
Published: September 2021

Long noncoding RNAs (lncRNAs) have been substantially reported to have critical roles in regulating tumorigenesis in recent years. However, the expression pattern and biological function of SNHG17 in hepatocellular carcinoma (HCC) remain unclear. Bioinformatics analysis and qRT-PCR were performed to detect the expression pattern of SNHG17 in HCC tissues, adjacent nontumorous tissues, and cell lines. The effect of SNHG17 on proliferation, migration, and apoptosis of HCC was investigated by knockdown and overexpressing SNHG17 in HCC cell lines. RNA sequencing was utilized to explore the underlying mechanism. Utilizing publicly available TCGA-LIHC, GSE102079 HCC datasets, and qRT-PCR, we found SNHG17 was significantly upregulated in HCC tissues and cell lines and was notably associated with larger tumor size, poorly differentiation, presence of vascular invasion, and advanced TNM stage. Furthermore, gain- and loss-of-function studies demonstrated that SNHG17 promoted cell proliferation and migration and inhibited apoptosis of HCC. By employing RNA sequencing, we found knockdown of SNHG17 caused 1037 differentially expressed genes, highly enriched in several pathways, including metabolic, PI3K-Akt, cell adhesion, regulation of cell proliferation, and apoptotic pathway; among them, 92 were overlapped with SNHG17-related genes in the TCGA-LIHC dataset. Furthermore, ERH, TBCA, TDO2, and PDK4 were successfully validated and found significantly dysregulated in HCC tissues. Moreover, HCC patients with higher SNHG17 expression had a relatively poor overall survival and disease-free survival, and ERH and PDK4 also played a marked role in the prognosis of HCC. Broadly, our findings illustrate that SNHG17 acts as a noncoding oncogene in HCC progression, suggesting its potential value as a novel target for HCC therapy.
Evaluating Serum Thymidine Kinase 1 in Patients with Hormone Receptor–Positive Metastatic Breast Cancer Receiving First-line Endocrine Therapy in the SWOG S0226 Trial
Authors: Paoletti Costanza , Barlow William E. , Cobain Erin F. , Bergqvist Mattias , Mehta Rita S. , Gralow Julie R. , Hortobagyi Gabriel N. , Albain Kathy S. , Pusztai Lajos , Sharma Priyanka , Godwin Andrew K. , Thompson Alastair M. , Hayes Daniel F. , Rae James M.
Published: September 2021

Purpose:

Serum thymidine kinase 1 (sTK1) activity is associated with poor prognosis in metastatic breast cancer (MBC). We assessed the prognostic effect of sTK1 in patients with hormone receptor–positive MBC treated on a prospective randomized trial of anastrozole (A) versus A plus fulvestrant (A + F).

Patients and Methods:

sTK1 was assessed in 1,726 serums [baseline (BL), cycles 2, 3, 4, and 7] using the DiviTum assay. A prespecified cutoff of ≥200 Du/L was considered high. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan–Meier, log-rank tests, and Cox regression.

Results:

BL sTK1 was elevated in 171 (40%) of 432 patients. Patients with high versus low BL sTK1 had significantly worse PFS [median 11.2 vs. 17.3 months, HR = 1.76; 95% confidence interval (CI; 1.43–2.16); P < 0.0001] and OS [median 30 vs. 58 months, HR = 2.38; 95% CI (1.91–2.98); P < 0.0001]. OS was significantly better for patients with high sTK1 who did not have prior adjuvant tamoxifen and who received A + F versus A alone [median 46 vs. 21 months, HR = 0.58; 95% CI (0.38–0.87); P = 0.0087]. Patients with low sTK1 had no difference in outcomes by therapy (P = 0.44). At serial timepoints, high versus low sTK1 had significantly worse subsequent PFS and OS [at cycle 2: PFS HR = 1.70, 95% CI (1.34–2.17); P < 0.0001, OS HR = 2.51, 95% CI (1.93–3.26); P < 0.0001].

Conclusions:

High sTK1 at BL and subsequent timepoints is associated with worse prognosis in patients with MBC starting first-line endocrine therapy (ET). Patients with low sTK1 at BL have comparable outcomes on single-agent or combination ET.
Gilteritinib Inhibits Glutamine Uptake and Utilization in FLT3-ITD–Positive AML
Authors: Zavorka Thomas Megan E. , Lu Xiyuan , Talebi Zahra , Jeon Jae Yoon , Buelow Daelynn R. , Gibson Alice A. , Uddin Muhammad Erfan , Brinton Lindsey T. , Nguyen Julie , Collins Meghan , Lodi Alessia , Sweeney Shannon R. , Campbell Moray J. , Sweet Douglas H. , Sparreboom Alex , Lapalombella Rosa , Tiziani Stefano , Baker Sharyn D.
Published: September 2021

Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy associated with frequent relapse and poor overall survival. The tyrosine kinase inhibitor gilteritinib is approved for the treatment of relapse/refractory AML with FLT3 mutations, yet its mechanism of action is not completely understood. Here, we sought to identify additional therapeutic targets that can be exploited to enhance gilteritinib's antileukemic effect. Based on unbiased transcriptomic analyses, we identified the glutamine transporter SNAT1 (SLC38A1) as a novel target of gilteritinib that leads to impaired glutamine uptake and utilization within leukemic cells. Using metabolomics and metabolic flux analyses, we found that gilteritinib decreased glutamine metabolism through the TCA cycle and cellular levels of the oncometabolite 2-hydroxyglutarate. In addition, gilteritinib treatment was associated with decreased ATP production and glutathione synthesis and increased reactive oxygen species, resulting in cellular senescence. Finally, we found that the glutaminase inhibitor CB-839 enhanced antileukemic effect of gilteritinib in ex vivo studies using human primary FLT3-ITD–positive AML cells harboring mutations in the enzyme isocitrate dehydrogenase, which catalyzes the oxidative decarboxylation of isocitrate, producing α-ketoglutarate. Collectively, this work has identified a previously unrecognized, gilteritinib-sensitive metabolic pathway downstream of SLC38A1 that causes decreased glutaminolysis and disruption of redox homeostasis. These findings provide a rationale for the development and therapeutic exploration of targeted combinatorial treatment strategies for this subset of relapse/refractory AML.
Simultaneously Combined Cancer Cell- and CTLA4-Targeted NIR-PIT Causes a Synergistic Treatment Effect in Syngeneic Mouse Models
Authors: Kato Takuya , Okada Ryuhei , Furusawa Aki , Inagaki Fuyuki , Wakiyama Hiroaki , Furumoto Hideyuki , Okuyama Shuhei , Fukushima Hiroshi , Choyke Peter L. , Kobayashi Hisataka
Published: September 2021

Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that utilizes antibody–IRDye700DX (IR700) conjugates. The clinical use of NIR-PIT has recently been approved in Japan for patients with inoperable head and neck cancer targeting human epidermal growth factor receptor (hEGFR). Previously, cytotoxic T-lymphocyte antigen 4 (CTLA4)–targeted NIR-PIT has been shown to strongly inhibit tumor progression and prolonged survival was seen in different tumor models due to enhanced T-cell–mediated antitumor immunity. In this study, combined NIR-PIT targeting CTLA4 expressing cells and cancer cells was investigated in four tumor models including a newly established hEGFR-expressing murine oropharyngeal cancer cell (mEERL-hEGFR). While single molecule–targeted therapy (NIR-PIT targeting hEGFR or CTLA4) did not inhibit tumor progression in poorly immunogenic mEERL-hEGFR tumor, dual (CTLA4/hEGFR)-targeted NIR-PIT significantly suppressed tumor growth and prolonged survival resulting in a 38% complete response rate. After the dual-targeted NIR-PIT, depletion of CTLA4 expressing cells, which were mainly regulatory T cells (Tregs), and an increase in the CD8+/Treg ratio in the tumor bed were observed, suggesting enhanced host antitumor immunity. Furthermore, dual-targeted NIR-PIT showed antitumor immunity in distant untreated tumors of the same type. Thus, simultaneous cancer cell–targeted NIR-PIT and CTLA4-targeted NIR-PIT is a promising new cancer therapy strategy, especially in poorly immunogenic tumors where NIR-PIT monotherapy is suboptimal.
Mouse Models for Human Skin Transplantation: A Systematic Review
Authors: Cristóbal Lara , Asúnsolo Ángel , Sánchez Jorge , Ortega Miguel A. , Álvarez-Mon Melchor , García-Honduvilla Natalio , Buján Julia , Maldonado Andrés A.
Published: September 2021

Immunodeficient mouse models with human skin xenografts have been developed in the past decades to study different conditions of the skin. Features such as follow-up period and size of the graft are of different relevance depending on the purpose of an investigation. The aim of this study is to analyze the different mouse models grafted with human skin. A systematic review of the literature was performed in line with the PRISMA statement using MEDLINE/PubMed databases from January 1970 to June 2020. Articles describing human skin grafted onto mice were included. Animal models other than mice, skin substitutes, bioengineered skin, postmortem or fetal skin, and duplicated studies were excluded. The mouse strain, origin of human skin, graft dimensions, follow-up of the skin graft, and goals of the study were analyzed. Ninety-one models were included in the final review. Five different applications were found: physiology of the skin (25 models, mean human skin graft size 1.43 cm2 and follow-up 72.92 days), immunology and graft rejection (17 models, mean human skin graft size 1.34 cm2 and follow-up 86 days), carcinogenesis (9 models, mean human skin graft size 1.98 cm2 and follow-up 253 days), skin diseases (25 models, mean human skin graft size 1.55 cm2 and follow-up 86.48 days), and would healing/scars (15 models, mean human skin graft size 2.54 cm2 and follow-up 129 days). The follow-up period was longer in carcinogenesis models (253 ± 233.73 days), and the skin graft size was bigger in wound healing applications (2.54 ± 3.08 cm2). Depending on the research application, different models are suggested. Careful consideration regarding graft size, follow-up, immunosuppression, and costs should be analyzed and compared before choosing any of these mouse models. To our knowledge, this is the first systematic review of mouse models with human skin transplantation.
A Case of a 49-Year-Old Man with Nonclassical Fabry Disease Diagnosed by Renal Biopsy
Authors: Fu Lanjun , Zhang Peipei , Ye Qingqing , Wu Manman , He Lingzhi
Published: September 2021

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase A (GLA) gene that result in deficiency of α-GLA activity, leading to major organ failure and premature mortality. According to different disease courses, FD can be divided into classical and nonclassical phenotypes. The nonclassical FD phenotype is always absent of characteristic symptoms, which makes identifying it challenging. This article presents a 49-year-old man with a 10-year history of proteinuria and decreased glomerular filtration rate. An electrocardiogram showed a complete right bundle branch block and abnormal Q waves in high lateral, accompanied by dramatically elevated ST segment. Consequently, a renal biopsy was performed. Vacuolation was found in many podocytes in light microscopic examinations. Similarly, a myelin-like structure was detected by electron microscopy. Pathological findings were most consistent with FD. Consequently, genetic analysis, p.R301Q (c.902G>A [p.Arg301Gln]), confirmed the FD diagnosis. Angiotensin receptor blocker and traditional Chinese medicine, but not enzyme replacement therapy, were prescribed due to financial constraints. The patient had stabilization of kidney disease 6 months later. The case showed that renal biopsy should be performed in patients with cardiac and renal symptoms, which could contribute toward the correct diagnosis for nonclassical FD type.
Advances in the Etiology, Detection, and Clinical Management of Seborrheic Keratoses
Authors: Sun Mary D. , Halpern Allan C.
Published: September 2021

Seborrheic keratoses (SKs) are ubiquitous, generally benign skin tumors that exhibit high clinical variability. While age is a known risk factor, the precise roles of UV exposure and immune abnormalities are currently unclear. The underlying mechanisms of this benign disorder are paradoxically driven by oncogenic mutations and may have profound implications for our understanding of the malignant state. Advances in molecular pathogenesis suggest that inhibition of Akt and APP, as well as existing treatments for skin cancer, may have therapeutic potential in SK. Dermoscopic criteria have also become increasingly important to the accurate detection of SK, and other noninvasive diagnostic methods, such as reflectance confocal microscopy and optical coherence tomography, are rapidly developing. Given their ability to mimic malignant tumors, SK cases are often used to train artificial intelligence-based algorithms in the computerized detection of skin disease. These technologies are becoming increasingly accurate and have the potential to significantly augment clinical practice. Current treatment options for SK cause discomfort and can lead to adverse post-treatment effects, especially in skin of color. In light of the discontinuation of ESKATA in late 2019, promising alternatives, such as nitric-zinc and trichloroacetic acid topicals, should be further developed. There is also a need for larger, head-to-head trials of emerging laser therapies to ensure that future treatment standards address diverse patient needs.
Platelet Decreases following Continuous Renal Replacement Therapy Initiation as a Novel Risk Factor for Renal Nonrecovery
Authors: Griffin Benjamin R. , Ten Eyck Patrick , Faubel Sarah , Jalal Diana , Gallagher Martin , Bellomo Rinaldo
Published: September 2021

Background: Continuous renal replacement therapy (CRRT) is a form of dialysis used in critically ill patients, and has recently been associated with renal nonrecovery. Decreases in platelets following CRRT initiation are common and are associated with mortality, but associations with renal recovery are unclear. Our objective was to determine if platelet nadir or the degree of platelet decrease following CRRT initiation was associated with renal nonrecovery. Methods: This is a secondary analysis of the Randomized Evaluation of Normal versus Augmented Level (RENAL) trial. Primary predictors were platelet nadir discretized by median value and percent platelet decrease following CRRT initiation, with cut points evaluated by decile from 30 to 60%. The 2 primary outcomes were time to RRT-independence and RRT-free days. Secondary outcomes were 28-day mortality, 90-day mortality, intensive care unit (ICU)-free, and hospital-free days. Results: Time to RRT independence censored for death was achieved less frequently in patients with low platelet nadir (hazard ratio [HR] 0.77, confidence interval [CI] 0.66–0.91) and in those with >50% platelet decrease (HR 0.84, CI 0.72–0.97). RRT-free days were lower in both low platelet nadir (odds ratio [OR] 0.94, CI 0.90–0.97) and >50% platelet decrease (OR 0.91, CI 0.88–0.95). These groups also had higher rates of 28- and 90-day mortality and fewer ICU-free and hospital-free days. Thrombocytopenia at CRRT initiation was also associated with renal nonrecovery, although the clinical effect was small. Conclusions: Platelet nadir <100 × 103/µL and platelet decrease by >50% following CRRT initiation were both associated with lower rates of renal recovery. Further research is needed to evaluate mechanisms-linking platelet changes and renal nonrecovery in CRRT.
The Association of Frontal Alopecia with a History of Facial and Scalp Surgical Procedures
Authors: Pham Christine T. , Juhasz Margit , Ekelem Chloe , Conic Rosalynn R.Z. , Hashemi Kiana , Csuka David , Csuka Ella , Chao Tiffany , Mesinkovska Natasha Atanaskova
Published: September 2021

Introduction: The prevalence of frontal fibrosing alopecia (FFA) is increasing worldwide, though the pathogenesis remains unknown. Anecdotal reports describe alopecia occurring in an FFA pattern following facial surgical procedures, but this potential link remains unexplored. Objective: The objective of this study is to determine if a significant association exists between the diagnosis of FFA and a history of facial and scalp surgical procedures. Methods: This retrospective study comparing data from frontal alopecia patients to controls was conducted at a tertiary medical center. Additionally, a literature review was conducted on scarring alopecias occurring from scalp procedures. Results: Fifty percent of frontal alopecia patients (n = 54) reported a history of facial surgical procedures compared to 9.8% of controls (n = 51) (OR: 7.8 [95% CI: 2.77–25.98, p < 0.001]). Although no significant differences were observed in current daily facial sunscreen use, sunscreen use prior to alopecia onset was significantly higher in frontal alopecia (p = 0.295; p = 0.021). Sunscreen use was not a significant modifier in the association between frontal alopecia and facial surgical procedures (p = 0.89). Conclusions: A significant association exists between frontal alopecia clinically consistent with FFA and a history of facial surgery, the nature of which is unclear. The role of sunscreen use and frontal alopecia development in this setting needs to be better elucidated.
A Forgotten Ureteral Stent: Potential Risks for the Urinary Function
Authors: Distler Florian A. , Veelken Roland , Wagner Annette , Klein Tilman , Huettenbrink Clemens , Pahernik Sascha
Published: September 2021

A 32-year-old man presented with painless macrohaematuria. An endoscopic stone removal of the upper moiety of a left double kidney with ureter duplex was performed 4 years ago. The inserted ureteral catheter (DJ) was not removed although it was communicated to the patient and written in the discharge report. The DJ led to a large bladder stone, a total incrustation of the DJ, and a staghorn calculus of the upper moiety. Furthermore, renal function scintigraphy showed no clinically significant function of the upper moiety. Therefore, a heminephrectomy was performed with corresponding ureterectomy and sectio alta for bladder stone removal.
Nivolumab-Induced Autoimmune Haemolytic Anaemia and Safety of Subsequent Use of Ipilimumab: A Case Report
Authors: Carbó-Bagué Anna , Fort-Culillas Roser , Pla-Juher Helena , Rubió-Casadevall Jordi
Published: September 2021

Autoimmune haemolytic anaemia (AIHA) is a rare immune-related adverse event and appears to be more common with anti-PD1/PDL1 than anti-CTLA4. Little is known about the safety of re-treating with anti-PD1/PDL1 or changing to anti-CTLA4. We present a case of grade 4 AIHA due to nivolumab (PD1-inhibitor) treatment in a patient with melanoma for adjuvant setting after surgery and the safeness of subsequent treatment with ipilimumab (anti-CTLA4). After the remission of AIHA with steroids, ipilimumab was started with the rationale of its different mechanism of action. Fortunately, AIHA did not recur. The mechanism by which checkpoint inhibitors cause AIHA is likely by augmenting or redirecting immune surveillance, especially by activating pre-existing red blood cell autoantibodies, but further studies must be done. To our knowledge, this is the first case published in the literature with the change of immunotherapy treatment to anti-CTLA4.
Penile Lichen Sclerosus and “Nevus Elasticus”
Authors: de Souza Maiara Ferreira , Kruschewsky Wendel Souza , Pinheiro Junior Nathanael de Freitas , Athanazio Daniel Abensur
Published: September 2021

The association between penile lichen sclerosus and striking accumulation of elastic fibers in deep dermis has been described in rare reports, mostly in vulvar lesions. We describe one case of severe balanopreputial adhesions related to lichen sclerosus and this form of elastosis, with no concomitant neoplasia. Aggregates of elastic fibers were seen in deep dermis and in blood vessels. The lesion mirrors nevus elasticus and nevus elasticus vascularis – a well described cutaneous lesion with no known association with lichen sclerosus.
Movimento a Dança se Move diante de retrocessos das políticas culturais estruturantes
Authors: Bastos Helena , Macedo Vanessa
Published: September 2021

“O que veio primeiro: arte ou mercado financeiro?” (Gielen, 2015). Nesta provocação, está implícito que investir é uma atividade criativa. Dimensões úmidas e planas vão se constituindo e povoando cada vez mais nosso modo de lidar com criação. Os atuais modos de aglutinação praticam outros tipos de cooperação que se transformam em coletivos temporários. Desejamos investigar tais fenômenos através das formas de comunicação que inventam e da ambivalência e da dissimetria que os constituem. Dessas perspectivas, propomos uma discussão no cruzamento entre três eixos: Movimento a Dança se Move, AtoFórum contra a Criminalização da ArteCultura e Capitalismo Criativo. Autores como Giorgio Agamben e Pascal Gielen são norteadores nessa discussão.
Estado e financiamento teatral: apontamentos para uma perspectiva classista
Authors: Bustamante Fernando
Published: September 2021

Resgatando brevemente algumas experiências de movimentos teatrais vinculados à classe trabalhadora ou a uma perspectiva popular e de oposição aos valores da classe dominante e do capitalismo, tanto internacionalmente como no Brasil – remontando a genealogia desses movimentos desde o Théâtre Libre de Antoine ao movimento Arte contra a Barbárie do teatro de grupo em São Paulo – o artigo procura discutir como o financiamento estatal a tais iniciativas constitui necessariamente momentos de exceção que, pela própria natureza do Estado capitalista, não podem se sustentar, e aponta a perspectiva da vinculação ao movimento operário organizado como a forma capaz de fomentar tal tipo de produção teatral.
Particularidades da Lei de Fomento ao Teatro para a cidade de São Paulo
Authors: Romeo Simone do Prado
Published: September 2021

Este artigo debate a Lei de Fomento ao Teatro para a cidade de São Paulo sob a ótica de que ela representa uma inovação no campo das políticas culturais brasileiras. Assim, discutiremos os principais aspectos dessa lei, incluindo os critérios de percepção e apreciação que ela fixa – interpretados por nós enquanto um conjunto de afirmações que revelam uma nova legitimidade em matéria de teatro. A partir do exame dessa lei e de suas particularidades pretendemos demonstrar, ainda, que as políticas culturais são  detentoras de poder simbólico atuante no campo cultural.
Territórios do historiador: recordações e práticas da vida acadêmica
Authors: Avelino Yvone Dias
Published: September 2021

O artigo aqui apresentado busca recuperar os caminhos percorridos por famosos pesquisadores, desde a verdadeira “revolução” causada pelos historiadores participantes da Escola dos Annales francesa, nas suas diferentes gerações, e como a historiografia incorporou tais ideias, objetos e sujeitos, não apenas os grandes fatos e personagens políticos, mas ideias, costumes, imagens e mentalidades em cada um dos seus períodos.   Desde 1929, com Lucien Febvre e Marc Bloch, até a atualidade com Roger Chartier e outros, indo, em cada etapa, em direção a novas abordagens, para a compreensão e interpretação da História em suas temáticas variadas.    Com exemplos pontuais de pesquisas, a presente narrativa pretende colaborar com a devida discussão dessas suaves e, às vezes, bruscas mudanças, gerando novos diálogos interdisciplinares e a valorização da subjetividade do pesquisador.
Marca Chile: “Todo Chile es un Torres del Paine”
Authors: Muñoz Bernardo
Published: September 2021

Este artigo pretende ser uma proposta metodológica sobre o caso do turismo no Chile, colocando-se como paradigma o caso das Torres del Paine e a possibilidade de que todo o Chile bem administrado e gerido turisticamente possa converter-se em um Torres del Paine. O Chile apresenta um elevado nível de qualidade de vida no contexto da América Latina e do Caribe (ALC), alcançando pleno consenso em aproveitar de maneira sustentável e soberana a riqueza turística do país para benefício de todos os seus habitantes. O conceito “Turismo, um segundo soldo para o Chile” propõe-se com base no que se considera que o cobre ainda com seus atuais altos preços se constitui como o primeiro soldo do Chile. Em segundo lugar, atualmente as exportações de frutas, madeiras e vinos poderiam haver se considerado durante os últimos vinte anos como uma das rentabilidades económicas mais importantes do país. Logo, o atual e acelerado crescimento da industria turística, as entradas de visitantes, a inteligencia de mercado necessária de desenvolver e as rendas que deixam para o país e os empreendimentos turísticos, transformarão o turismo na segunda fonte de renda de maior relevancia como industria, sendo além disso uma industria daquelas denominadas limpas ainda quando presente também impactos negativos pela quantidade de visitantes que se produz e as atividades inherentes à indústria turística.
Os silêncios de Stefan Zweig: considerações de Hannah Arendt e Friederike Zweig
Authors: Bôas Glaucia Villas
Published: September 2021

O artigo retoma as críticas que Hannah Arendt e Friderike Zweig fizeram ao livro Autobiografia: o mundo de ontem: memórias de um europeu de Stefan Zweig, publicado em Estocolmo em 1942. Exiladas em Nova York, as duas mulheres escreveram, respectivamente, Stefan Zweig: jews in the world of yesterday (1943) e Married to Stefan Zweig (1947, pouco depois do lançamento do livro.  Apesar de adotarem pontos de vista   muito diferentes, elas argumentam que, na Autobiografia, os silêncios do autor relativamente a fatos importantes de sua vida, estavam associados à sua profunda insegurança.  A leitura dos referidos trabalhos não somente possibilita um melhor entendimento do legado de Stefan Zweig, como permite ponderar sobre assunto hoje em voga, que diz respeito ao que se deve falar ou calar no âmbito da esfera pública – da perspectiva da relação entre segurança e silêncio.