bluuebunny/crossref_metadata_2025 huggingface dataset:
New Therapeutic Perspectives in the Treatment of Uveal Melanoma: A Systematic Review
Authors: Toro Mario Damiano , Gozzo Lucia , Tracia Luciano , Cicciù Marco , Drago Filippo , Bucolo Claudio , Avitabile Teresio , Rejdak Robert , Nowomiejska Katarzyna , Zweifel Sandrine , Yousef Yacoub A. , Nazzal Rashed , Romano Giovanni Luca
Published: September 2021

Uveal melanoma (UM) is a rare disease, but the most common primary intraocular cancer, mostly localized in the choroid. Currently, the first-line treatment options for UM are radiation therapy, resection, and enucleation. However, although these treatments could potentially be curative, half of all patients will develop metastatic disease, whose prognosis is still poor. Indeed, effective therapeutic options for patients with advanced or metastatic disease are still lacking. Recently, the development of new treatment modalities with a lower incidence of adverse events, a better disease control rate, and new therapeutic approaches, have merged as new potential and promising therapeutic strategies. Additionally, several clinical trials are ongoing to find new therapeutic options, mainly for those with metastatic disease. Many interventions are still in the preliminary phases of clinical development, being investigated in phase I trial or phase I/II. The success of these trials could be crucial for changing the prognosis of patients with advanced/metastatic UM. In this systematic review, we analyzed all emerging and available literature on the new perspectives in the treatment of UM and patient outcomes; furthermore, their current limitations and more common adverse events are summarized.
Multi-Omics Reveals the Immunological Role and Prognostic Potential of Mitochondrial Ubiquitin Ligase MARCH5 in Human Breast Cancer
Authors: Chu Pei-Yi , Tzeng Yen-Dun Tony , Chiu Yi-Han , Lin Hung-Yu , Kuo Chen-Hsin , Hou Ming-Feng , Li Chia-Jung
Published: September 2021

E3 ubiquitin-linked enzyme MARCH5, also known as membrane-associated circular finger 5, is an enzyme encoded by the human MARCH5 gene. The main objective of this study was to visualize the prognosis of MARCH5 in breast cancer and to determine the relationship between MARCH5 expression and tumor immunity. MARCH5 expression was significantly higher in several cancers, including breast cancer (BRCA), compared with corresponding normal tissues. Not only was high MARCH5 expression associated with poorer overall survival, but also MARCH5 expression was positively correlated with the number of tumor-infiltrating immune cells in BRCA malignant tissues. Furthermore, MARCH5 expression showed a strong correlation with various immune markers of BRCA, suggesting its role in regulating tumor immunity. MARCH5 is a useful prognostic biomarker in several cancers, and its expression is highly correlated with tumor immune cell infiltration, and increased MARCH5 expression may serve as a new biomarker for BRCA diagnosis and prognosis.
Expression Profile and Prognostic Value of Wnt Signaling Pathway Molecules in Colorectal Cancer
Authors: Wu Yung-Fu , Wang Chih-Yang , Tang Wan-Chun , Lee Yu-Cheng , Ta Hoang Dang Khoa , Lin Li-Chia , Pan Syu-Ruei , Ni Yi-Chun , Anuraga Gangga , Lee Kuen-Haur
Published: September 2021

Colorectal cancer (CRC) is a heterogeneous disease with changes in the genetic and epigenetic levels of various genes. The molecular assessment of CRC is gaining increasing attention, and furthermore, there is an increase in biomarker use for disease prognostication. Therefore, the identification of different gene biomarkers through messenger RNA (mRNA) abundance levels may be useful for capturing the complex effects of CRC. In this study, we demonstrate that the high mRNA levels of 10 upregulated genes (DPEP1, KRT80, FABP6, NKD2, FOXQ1, CEMIP, ETV4, TESC, FUT1, and GAS2) are observed in CRC cell lines and public CRC datasets. Moreover, we find that a high mRNA expression of DPEP1, NKD2, CEMIP, ETV4, TESC, or FUT1 is significantly correlated with a worse prognosis in CRC patients. Further investigation reveals that CTNNB1 is the key factor in the interaction of the canonical Wnt signaling pathway with 10 upregulated CRC-associated genes. In particular, we identify NKD2, FOXQ1, and CEMIP as three CTNNB1-regulated genes. Moreover, individual inhibition of the expression of three CTNNB1-regulated genes can cause the growth inhibition of CRC cells. This study reveals efficient biomarkers for the prognosis of CRC and provides a new molecular interaction network for CRC.
Role of the Uteroplacental Renin–Angiotensin System in Placental Development and Function, and Its Implication in the Preeclampsia Pathogenesis
Authors: Yart Lucile , Roset Bahmanyar Edith , Cohen Marie , Martinez de Tejada Begoña
Published: September 2021

Placental development and function implicate important morphological and physiological adaptations to thereby ensure efficient maternal–fetal exchanges, as well as pregnancy-specific hormone secretion and immune modulation. Incorrect placental development can lead to severe pregnancy disorders, such as preeclampsia (PE), which endangers both the mother and the infant. The implication of the systemic renin–angiotensin system (RAS) in the pregnancy-related physiological changes is now well established. However, despite the fact that the local uteroplacental RAS has been described for several decades, its role in placental development and function seems to have been underestimated. In this review, we provide an overview of the multiple roles of the uteroplacental RAS in several cellular processes of placental development, its implication in the regulation of placental function during pregnancy, and the consequences of its dysregulation in PE pathogenesis.
Determining Particle Size and Position in a Coplanar Electrode Setup Using Measured Opacity for Microfluidic Cytometry
Authors: de Bruijn Douwe S. , Jorissen Koen F. A. , Olthuis Wouter , van den Berg Albert
Published: September 2021

Microfluidic impedance flow cytometers enable high-throughput, non-invasive, and label-free detection of single-cells. Cytometers with coplanar electrodes are easy and cheap to fabricate, but are sensitive to positional differences of passing particles, owing to the inhomogeneous electric field. We present a novel particle height compensation method, which employs the dependence of measured electrical opacity on particle height. The measured electrical opacity correlates with the particle height as a result of the constant electrical double layer series capacitance of the electrodes. As an alternative to existing compensation methods, we use only two coplanar electrodes and multi-frequency analysis to determine the particle size of a mixture of 5, 6, and 7 µm polystyrene beads with an accuracy (CV) of 5.8%, 4.0%, and 2.9%, respectively. Additionally, we can predict the bead height with an accuracy of 1.5 µm (8% of channel height) using the measured opacity and we demonstrate its application in flow cytometry with yeast. The use of only two electrodes is of special interest for simplified, easy-to-use chips with a minimum amount of instrumentation and of limited size.
High-Performance Passive Plasma Separation on OSTE Pillar Forest
Authors: Xiao Zhiqing , Sun Lexin , Yang Yuqian , Feng Zitao , Dai Sihan , Yang Hao , Zhang Xingwei , Sheu Chia-Lin , Guo Weijin
Published: September 2021

Plasma separation is of high interest for lateral flow tests using whole blood as sample liquids. Here, we built a passive microfluidic device for plasma separation with high performance. This device was made by blood filtration membrane and off-stoichiometry thiol–ene (OSTE) pillar forest. OSTE pillar forest was fabricated by double replica moldings of a laser-cut polymethylmethacrylate (PMMA) mold, which has a uniform microstructure. This device utilized a filtration membrane to separate plasma from whole blood samples and used hydrophilic OSTE pillar forest as the capillary pump to propel the plasma. The device can be used to separate blood plasma with high purity for later use in lateral flow tests. The device can process 45 μL of whole blood in 72 s and achieves a plasma separation yield as high as 60.0%. The protein recovery rate of separated plasma is 85.5%, which is on par with state-of-the-art technologies. This device can be further developed into lateral flow tests for biomarker detection in whole blood.
Oncolytic Virotherapy for Melanoma Brain Metastases, a Potential New Treatment Paradigm?
Authors: Soldozy Sauson , Mulligan Kathleen M. , Zheng David X. , Levoska Melissa A. , Cullison Christopher R. , Elarjani Turki , Eichberg Daniel G. , Ampie Leonel E. , Shah Ashish H. , Yağmurlu Kaan , Shaffrey Mark E. , Scott Jeffrey F. , Komotar Ricardo J.
Published: September 2021

Introduction: Melanoma brain metastases remain a devastating disease process with poor prognosis. Recently, there has been a surge in studies demonstrating the efficacy of oncolytic virotherapy for brain tumor treatment. Given their specificity and amenability to genetic modification, the authors explore the possible role of oncolytic virotherapy as a potential treatment option for patients with melanoma brain metastases. Methods: A comprehensive literature review including both preclinical and clinical evidence of oncolytic virotherapy for the treatment of melanoma brain metastasis was performed. Results: Oncolytic virotherapy, specifically T-VEC (Imlygic™), was approved for the treatment of melanoma in 2015. Recent clinical trials demonstrate promising anti-tumor changes in patients who have received T-VEC; however, there is little evidence for its use in metastatic brain disease based on the existing literature. To date, only two single cases utilizing virotherapy in patients with metastatic brain melanoma have been reported, specifically in patients with treatment refractory disease. Currently, there is not sufficient data to support the use of T-VEC or other viruses for intracranial metastatic melanoma. In developing a virotherapy treatment paradigm for melanoma brain metastases, several factors must be considered, including route of administration, need to bypass the blood–brain barrier, viral tumor infectivity, and risk of adverse events. Conclusions: Evidence for oncolytic virotherapy treatment of melanoma is limited primarily to T-VEC, with a noticeable paucity of data in the literature with respect to brain tumor metastasis. Given the promising findings of virotherapy for other brain tumor types, oncolytic virotherapy has great potential to offer benefits to patients afflicted with melanoma brain metastases and warrants further investigation.
Cognitive Intervention Strategies Directed to Speech and Language Deficits in Primary Progressive Aphasia: Practice-Based Evidence from 18 Cases
Authors: Machado Thais Helena , Carthery-Goulart Maria Teresa , Campanha Aline Carvalho , Caramelli Paulo
Published: September 2021

Background: Practice-based evidence can inform and support clinical decision making. Case-report series about the implementation of programs in real-world clinical settings may contribute to verifying the effectiveness of interventions for treating PPA in specific contexts, as well as illustrating challenges that need to be overcome. Objective: To describe and provide practice-based evidence on the effectiveness of four cognitive rehabilitation programs designed for individuals with PPA and directed to speech and language impairments, which were implemented in a specialized outpatient clinic. Methods: Multiple single-case study. Eighteen individuals with different subtypes of PPA were each assigned to one out of four training programs based on comprehensive speech and language assessments. The treatments targeted naming deficits, sentence production, speech apraxia, and phonological deficits. Pre- and post-treatment assessments were undertaken to compare trained and untrained items. Gains were generalized to a different task in the first two types of intervention (naming and sentence production). A follow-up assessment was conducted 1–8 months after treatment among 7 participants. Results: All individuals presented better performance in the trained items at the post-test for each rehabilitation program accomplished, demonstrating that learning of the trained strategies was achieved during the active phase of treatment. For 13 individuals, statistical significance was reached; while for five, the results were maintained. Results about untrained items, generalization to other tasks, and follow-up assessments are presented. Conclusions: The positive results found in our sample bring some practice-based evidence for the benefits of speech and language treatment strategies for clinical management of individuals with PPA.
The Big Five Personality Traits and Brain Arousal in the Resting State
Authors: Jawinski Philippe , Markett Sebastian , Sander Christian , Huang Jue , Ulke Christine , Hegerl Ulrich , Hensch Tilman
Published: September 2021

Based on Eysenck’s biopsychological trait theory, brain arousal has long been considered to explain individual differences in human personality. Yet, results from empirical studies remained inconclusive. However, most published results have been derived from small samples and, despite inherent limitations, EEG alpha power has usually served as an exclusive indicator for brain arousal. To overcome these problems, we here selected N = 468 individuals of the LIFE-Adult cohort and investigated the associations between the Big Five personality traits and brain arousal by using the validated EEG- and EOG-based analysis tool VIGALL. Our analyses revealed that participants who reported higher levels of extraversion and openness to experience, respectively, exhibited lower levels of brain arousal in the resting state. Bayesian and frequentist analysis results were especially convincing for openness to experience. Among the lower-order personality traits, we obtained the strongest evidence for neuroticism facet ‘impulsivity’ and reduced brain arousal. In line with this, both impulsivity and openness have previously been conceptualized as aspects of extraversion. We regard our findings as well in line with the postulations of Eysenck and consistent with the recently proposed ‘arousal regulation model’. Our results also agree with meta-analytically derived effect sizes in the field of individual differences research, highlighting the need for large (collaborative) studies.
The Neurobiological Basis of Cognitive Side Effects of Electroconvulsive Therapy: A Systematic Review
Authors: Bassa Adriana , Sagués Teresa , Porta-Casteràs Daniel , Serra Pilar , Martínez-Amorós Erika , Palao Diego , Cano Marta , Cardoner Narcís
Published: September 2021

Decades of research have consistently demonstrated the efficacy of electroconvulsive therapy (ECT) for the treatment of major depressive disorder (MDD), but its clinical use remains somewhat restricted because of its cognitive side effects. The aim of this systematic review is to comprehensively summarize current evidence assessing potential biomarkers of ECT-related cognitive side effects. Based on our systematic search of human studies indexed in PubMed, Scopus, and Web of Knowledge, a total of 29 studies evaluating patients with MDD undergoing ECT were reviewed. Molecular biomarkers studies did not consistently identify concentration changes in plasma S-100 protein, neuron-specific enolase (NSE), or Aβ peptides significantly associated with cognitive performance after ECT. Importantly, these findings suggest that ECT-related cognitive side effects cannot be explained by mechanisms of neural cell damage. Notwithstanding, S-100b protein and Aβ40 peptide concentrations, as well as brain-derived neurotrophic factor (BDNF) polymorphisms, have been suggested as potential predictive biomarkers of cognitive dysfunction after ECT. In addition, recent advances in brain imaging have allowed us to identify ECT-induced volumetric and functional changes in several brain structures closely related to memory performance such as the hippocampus. We provide a preliminary framework to further evaluate neurobiological cognitive vulnerability profiles of patients with MDD treated with ECT.
Effects of Cognitive Training Programs on Executive Function in Children and Adolescents with Autism Spectrum Disorder: A Systematic Review
Authors: Pasqualotto Angela , Mazzoni Noemi , Bentenuto Arianna , Mulè Anna , Benso Francesco , Venuti Paola
Published: September 2021

Background. Autism Spectrum Disorder is often associated with deficits in executive functions (EFs), which is contributing significantly to individuals with ASD’s difficulties in conducting an independent life, particularly considering social skills. Technologies offer promising opportunities to structure EF intervention programs for children on the autistic spectrum. Methods. This study aimed to review the effectiveness of randomized controlled trials or quasi-experimental studies of EF interventions delivered to children and young people (up to 23 years old) with a diagnosis of ASD. A special focus was dedicated to document the effectiveness of computerized and non-computerized cognitive training on (1) EFs and on (2) ASD symptomatology and social skills. Of 2601 studies retrieved, 19 fulfilled the inclusion criteria. Results. Most of the interventions identified were effective in enhancing EFs and reducing symptoms in children and young people with ASD. Limited evidence is available on their generalization to untrained skills (i.e., social abilities) as well as long-term effects. Conclusions. There is growing evidence for overall effectiveness of EF training, particularly when computerized. However, caution should be taken when interpreting these findings owing to methodological limitations, the minimal number of papers retrieved, and a small samples of included studies.
The Alignment of Australia’s National Construction Code and the Sendai Framework for Disaster Risk Reduction in Achieving Resilient Buildings and Communities
Authors: Wei Wesley , Mojtahedi Mohammad , Yazdani Maziar , Kabirifar Kamyar
Published: September 2021

The risks associated with extreme weather events induced by climate change are increasingly being recognized, and must be addressed through each country’s construction regulations, building codes, and standards. Ensuring that buildings and cities are resilient against disasters is becoming more important. Few studies have analyzed the impact of global polices and frameworks in reducing disaster risks and increasing resilience in built environments. This research reviews disasters associated with climate change in the Sendai Framework for Disaster Risk Reduction 2015–2030, analyzing how Australia’s National Construction Code is aligned with the framework and the potential implications for reducing disaster risk. Decision-makers in construction companies in Sydney, Australia, were surveyed. The results show there is a statistically significant link among the National Construction Code, the Sendai Framework, and building resilience. The Sendai Framework is an effective mediator in this three-pronged relationship that can further enhance building resilience in Australia. Stakeholders in the construction industry will need to incorporate disaster risk reduction practices, especially authorities, such as local governments, building commissioners, and building certifiers that are responsible for the approval, quality, and defects mitigation of development applications and best practices. Overall, implementation of the Sendai Framework will help develop more regulations and standards for resilient buildings, set targets, and make improvements over time in the Australian construction industry.
Dispatch Strategies for the Utilisation of Battery Storage Systems in Smart Grid Optimised Buildings
Authors: Georgakarakos Andreas , Vand Behrang , Hathway Elizabeth , Mayfield Martin
Published: September 2021

This study investigates Smart Grid Optimised Buildings (SGOBs) which can respond to real-time electricity prices by utilising battery storage systems (BSS). Different building design characteristics are assessed to evaluate the impact on energy use, the interaction with the battery, and potential for peak load shifting. Two extreme cases based on minimum and maximum annual energy consumption were selected for further investigation to assess their capability of utilising BSS to perform arbitrage, under real-time pricing. Three operational dispatch strategies were modelled to allow buildings to provide such services. The most energy-efficient building was capable of shifting a higher percentage of its peak loads and export more electricity, when this is allowed. When using the biggest battery (220 kWh) to only meet the building loads, the energy-efficient building was able to shift 39.68% of its original peak loads in comparison to the 33.95% of the least efficient building. With exports allowed, the shifting percentages went down to 31.76% and 29.46%, respectively, while exports of 18.08 and 16.34 kWh/m2 took place. The formation of a regulatory framework is vital in order to establish proper motives for buildings to undertake an active role in the smart grid.
Market Commonality and Competition in Communities—An Empirical Study Based on Bidding Data of the Construction Market
Authors: Chen Keda , Ye Kunhui
Published: September 2021

In contrast to traditional enterprise rivalry, the construction market competition is irregular on the surface due to the randomization of client targets and the one-time competition organization, which conflicts with construction businesses’ perceptions of the nature and future trend of rivalry. Therefore, contractors urgently need to accurately understand the competitive environment in which they will operate. In construction, few empirical studies exist on competitive environments from the standpoint of enterprise-to-enterprise competitive interactions. Based on market commonality, several hypotheses concerning the competitive pattern of the construction market have been proposed. To test these, a model of competing relationship networks is created using 7402 bid-winner notices for construction projects in Chongqing, China, from 2015 to 2018, followed by quantitative analysis and discussion of the model’s characteristic features. The findings suggest that there is a “community-type” rivalry in the building market, which represents the essential characteristics of market commonality. The research shows that the competitive action of construction enterprises is affected by construction technology, industrial division of labor and regional markets, and the competitive relationship between them tends to be “strong-strong”. This study reveals that the “community” competitive relationship in the construction industry may be a unique phenomenon, expands the application and development of market commonality and enterprise clusters in the construction economy, and provides theoretical guidance for construction enterprises to accurately recognize competitive behavior and decision making.
Fibroblasts Influence Metastatic Melanoma Cell Sensitivity to Combined BRAF and MEK Inhibition
Authors: Morales Delphine , Vigneron Pascale , Ferreira Ines , Hamitou Warda , Magnano Mikael , Mahenthiran Laxsika , Lok Catherine , Vayssade Muriel
Published: September 2021

The sensitivity of melanoma cells to targeted therapy compounds depends on the tumor microenvironment. Three-dimensional (3D) in vitro coculture systems better reflect the native structural architecture of tissues and are ideal for investigating cellular interactions modulating cell sensitivity to drugs. Metastatic melanoma (MM) cells (SK-MEL-28 BRAF V600E mutant and SK-MEL-2 BRAF wt) were cultured as a monolayer (2D) or cocultured on 3D dermal equivalents (with fibroblasts) and treated with a BRAFi (vemurafenib) combined with a MEK inhibitor (MEKi, cobimetinib). The drug combination efficiently inhibited 2D and 3D MM cell proliferation and survival regardless of their BRAF status. Two-dimensional and three-dimensional cancer-associated fibroblasts (CAFs), isolated from a cutaneous MM biopsy, were also sensitive to the targeted therapy. Conditioned media obtained from healthy dermal fibroblasts or CAFs modulated the MM cell’s response differently to the treatment: while supernatants from healthy fibroblasts potentialized the efficiency of drugs on MM, those from CAFs tended to increase cell survival. Our data indicate that the secretory profiles of fibroblasts influence MM sensitivity to the combined vemurafenib and cobimetinib treatment and highlight the need for 3D in vitro cocultures representing the complex crosstalk between melanoma and CAFs during preclinical studies of drugs.
RBMX Protein Expression in T-Cell Lymphomas Predicts Chemotherapy Response and Prognosis
Authors: Schümann Franziska Lea , Bauer Marcus , Groß Elisabeth , Terziev Denis , Wienke Andreas , Wickenhauser Claudia , Binder Mascha , Weber Thomas
Published: September 2021

T-cell non-Hodgkin’s lymphomas (T-NHL) are a heterogeneous group of lymphomas with a mature T-cell phenotype. While in some hematological diseases the prognosis improved over the last decades, T-NHL cases often relapse early or present with an initially refractory course. Recently, it has been shown that RNA binding proteins have a crucial role for malignant tumor initiation, progression and treatment response while contributing to chemotherapy resistance. Therefore, we investigated the protein expression of the RNA binding protein X (RBMX), which has been shown to be of great relevance in disease initiation and progression in hematological diseases in 53 T-NHL cases using conventional immunohistochemistry. Low RBMX expression was associated with better response to anthracycline-containing first-line treatment. Furthermore, low RBMX expression predicted an improved overall survival and progression-free survival in univariate analysis. Multivariable Cox regression revealed RBMX as an independent prognostic marker for overall survival (p = 0.007; hazard ratio (HR) = 0.204; 95% confidence interval (CI): 0.064–0.646) and progression-free survival (p = 0.006; HR = 0.235; 95% CI: 0.083–0.666). The study identifies low RBMX expression to predict better chemotherapy response, overall survival and progression-free survival in patients with T-cell non-Hodgkin’s lymphomas. These results suggest that RBMX protein expression levels might be a contributing factor towards chemotherapy resistance and thus affect prognosis. Hence, RBMX may be a potential therapeutic target and prognostic marker in T-cell lymphomas.
HER3 PET Imaging: 68Ga-Labeled Affibody Molecules Provide Superior HER3 Contrast to 89Zr-Labeled Antibody and Antibody-Fragment-Based Tracers
Authors: Rinne Sara S. , Leitao Charles Dahlsson , Abouzayed Ayman , Vorobyeva Anzhelika , Tolmachev Vladimir , Ståhl Stefan , Löfblom John , Orlova Anna
Published: September 2021

HER3 (human epidermal growth factor receptor type 3) is a challenging target for diagnostic radionuclide molecular imaging due to the relatively modest overexpression in tumors and substantial expression in healthy organs. In this study, we compared four HER3-targeting PET tracers based on different types of targeting molecules in a preclinical model: the 89Zr-labeled therapeutic antibody seribantumab, a seribantumab-derived F(ab)2-fragment labeled with 89Zr and 68Ga, and the 68Ga-labeled affibody molecule [68Ga]Ga-ZHER3. The novel conjugates were radiolabeled and characterized in vitro using HER3-expressing BxPC-3 and DU145 human cancer cells. Biodistribution was studied using Balb/c nu/nu mice bearing BxPC-3 xenografts. HER3-negative RAMOS xenografts were used to demonstrate binding specificity in vivo. Autoradiography was conducted on the excised tumors. nanoPET/CT imaging was performed. New conjugates specifically bound to HER3 in vitro and in vivo. [68Ga]Ga-DFO-seribantumab-F(ab’)2 was considered unsuitable for imaging due to the low stability and high uptake in normal organs. The highest tumor-to-non-tumor contrast with [89Zr]Zr-DFO-seribantumab and [89Zr]Zr-DFO-seribantumab-F(ab’)2 was achieved at 96 h and 48 h pi, respectively. Despite lower tumor uptake, [68Ga]Ga-ZHER3 provided the best imaging contrast due to the fastest clearance from blood and normal organs. The results of our study suggest that affibody-based tracers are more suitable for PET imaging of HER3 expression than antibody- and antibody-fragment-based tracers.
Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer
Authors: Hussein Shaimaa , Khanna Pooja , Yunus Neha , Gatza Michael L.
Published: September 2021

Metabolic reprogramming enables cancer cells to adapt to the changing microenvironment in order to maintain metabolic energy and to provide the necessary biological macromolecules required for cell growth and tumor progression. While changes in tumor metabolism have been long recognized as a hallmark of cancer, recent advances have begun to delineate the mechanisms that modulate metabolic pathways and the consequence of altered signaling on tumorigenesis. This is particularly evident in hormone receptor positive (HR+) breast cancers which account for approximately 70% of breast cancer cases. Emerging evidence indicates that HR+ breast tumors are dependent on multiple metabolic processes for tumor progression, metastasis, and therapeutic resistance and that changes in metabolic programs are driven, in part, by a number of key nuclear receptors including hormone-dependent signaling. In this review, we discuss the mechanisms and impact of hormone receptor mediated metabolic reprogramming on HR+ breast cancer genesis and progression as well as the therapeutic implications of these metabolic processes in this disease.
Multi-Stage Harmonization for Robust AI across Breast MR Databases
Authors: Whitney Heather M. , Li Hui , Ji Yu , Liu Peifang , Giger Maryellen L.
Published: September 2021

Radiomic features extracted from medical images may demonstrate a batch effect when cases come from different sources. We investigated classification performance using training and independent test sets drawn from two sources using both pre-harmonization and post-harmonization features. In this retrospective study, a database of thirty-two radiomic features, extracted from DCE-MR images of breast lesions after fuzzy c-means segmentation, was collected. There were 944 unique lesions in Database A (208 benign lesions, 736 cancers) and 1986 unique lesions in Database B (481 benign lesions, 1505 cancers). The lesions from each database were divided by year of image acquisition into training and independent test sets, separately by database and in combination. ComBat batch harmonization was conducted on the combined training set to minimize the batch effect on eligible features by database. The empirical Bayes estimates from the feature harmonization were applied to the eligible features of the combined independent test set. The training sets (A, B, and combined) were then used in training linear discriminant analysis classifiers after stepwise feature selection. The classifiers were then run on the A, B, and combined independent test sets. Classification performance was compared using pre-harmonization features to post-harmonization features, including their corresponding feature selection, evaluated using the area under the receiver operating characteristic curve (AUC) as the figure of merit. Four out of five training and independent test scenarios demonstrated statistically equivalent classification performance when compared pre- and post-harmonization. These results demonstrate that translation of machine learning techniques with batch data harmonization can potentially yield generalizable models that maintain classification performance.
Targeted Sequencing Revealed Distinct Mutational Profiles of Ocular and Extraocular Sebaceous Carcinomas
Authors: Na Hee Young , Park Jeong Hwan , Shin Sun Ah , Lee Sejoon , Lee Heonyi , Chae Heejoon , Choung HoKyung , Kim Namju , Chung Jin-Haeng , Kim Ji Eun
Published: September 2021

The biological behavior of sebaceous carcinoma (SeC) is relatively indolent; however, local invasion or distant metastasis is sometimes reported. Nevertheless, a lack of understanding of the genetic background of SeC makes it difficult to apply effective systemic therapy. This study was designed to investigate major genetic alterations in SeCs in Korean patients. A total of 29 samples, including 20 ocular SeCs (SeC-Os) and 9 extraocular SeCs (SeC-EOs), were examined. Targeted next-generation sequencing tests including 171 cancer-related genes were performed. TP53 and PIK3CA genes were frequently mutated in both SeC-Os and SeC-EOs with slight predominance in SeC-Os, whereas the NOTCH1 gene was more commonly mutated in SeC-EOs. In clinical correlation, mutations in RUNX1 and ATM were associated with development of distant metastases, and alterations in MSH6 and BRCA1 were associated with inferior progression-free survival (all p < 0.05). In conclusion, our study revealed distinct genetic alterations between SeC-Os and SeC-EOs and some important prognostic molecular markers. Mutations in potentially actionable genes, including EGFR, ERBB2, and mismatch repair genes, were noted, suggesting consideration of a clinical trial in intractable cases.
Neuroendocrine Carcinoma of the Larynx and Pharynx: A Clinical and Histopathological Study
Authors: Strojan Primož , Šifrer Robert , Ferlito Alfio , Grašič-Kuhar Cvetka , Lanišnik Boštjan , Plavc Gaber , Zidar Nina
Published: September 2021

Neuroendocrine carcinomas (NECs) of the head and neck are rare and the experience scanty. The Cancer Registry of Slovenia database was used to identify cases of laryngeal and pharyngeal NECs diagnosed between 1995–2020. Biopsies were analyzed for the expression of standard neuroendocrine markers (synaptophysin, chromogranin, CD56), INSM1, Ki-67, p16, and PD-L1 (using the combined positive score, CPS). In situ hybridization for human papillomavirus (HPV) and Epstein–Barr virus (EBV) was performed. Twenty patients (larynx, 12; pharynx, 8) were identified. One tumor was well differentiated (WD), five were moderately differentiated (MD), and 14 were poorly differentiated (PD). Disease control was achieved solely by surgery in 4/4 MD/PD T1-2N0-1 tumors. Eight patients died of the disease, seven of which were due to distant metastases. All three traditional markers were positive in 11/17 NECs and the INSM1 marker in all 20 tumors. Two of fourteen p16-positive tumors were HPV-positive, but all three nasopharyngeal NECs were EBV-negative. Three tumors had CPSs ≥ 1. In conclusion, INSM1 was confirmed to be a reliable marker of neuroendocrine differentiation. Except in WD and early-stage MD/PD tumors, aggressive multimodal therapy is needed; the optimal systemic therapy remains to be determined. p16, HPV, and EBV seem to bear no prognostic information.
Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance
Authors: Alves Raquel , Gonçalves Ana Cristina , Rutella Sergio , Almeida António M. , De Las Rivas Javier , Trougakos Ioannis P. , Sarmento Ribeiro Ana Bela
Published: September 2021

Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.
Evaluation of the Thermal Behavior, Synergistic Catalysis, and Pollutant Emissions during the Co-Combustion of Sewage Sludge and Coal Gasification Fine Slag Residual Carbon
Authors: Guo Yang , Wu Jianjun , Jia Wenke , Guo Fanhui , Qiu Guofeng , Wang Rumeng , Zhang Yixin , Dai Baiqian
Published: September 2021

The conversion of solid waste into energy through combustion is sustainable and economical. This study aims to comprehensively evaluate and quantify the co-combustion characteristics, synergistic catalysis, and gaseous pollutant emission patterns of sewage sludge (SS) and coal gasification fine slag residual carbon (RC) as well as their blends through thermogravimetry coupled with mass spectrometry (TG-MS). The results showed that the co-combustion of SS and RC can not only improve the ignition and burnout property but also maintain the combustion stability and comprehensive combustion performance at a better level. The kinetic analysis results showed that a first-order chemical reaction and three-dimensional diffusion are the reaction mechanisms during the co-combustion of SS and RC. The synergistic catalysis between SS and RC can well explain the changes in activation energy and reaction mechanism. Furthermore, the blending ratio of SS is recommended to be maintained at 40% because of the lowest activation energy (Ea = 81.6 kJ/mol) and the strongest synergistic effect (Xi = 0.36). The emission of gaseous pollutants is corresponding to the primary combustion stages of SS, RC, and their blends. In co-combustion, the NH3, HCN, NOx, and SO2 emissions gradually rise with the increase of SS proportion in the blends due to the high content of organic compounds in SS.
Sulfonic Acid-Functionalized Inorganic Materials as Efficient Catalysts in Various Applications: A Minireview
Authors: Testa Maria Luisa , La Parola Valeria
Published: September 2021

Acid catalysis is widely used in the chemical industry, and nowadays many efforts are being focused on replacing the more common homogeneous catalysts with heterogeneous ones in order to make greener the industrial processes. In this perspective, sulfonic solid acid materials represent a valid alternative to the homogenous mineral acid in several acid catalyzed reactions. In this minireview, an overview of the recent advances on the preparation, stability and application of these materials is reported. Special attention is addressed to the sustainability of the considered processes, starting from the catalyst’s preparation, the use of green solvents and reducing the possible reaction steps. Ways to tackle the main drawback represented by easy leaching of acid groups are described. For an easy catalyst recovery, the use of a magnetic core in a catalyst particle, with the related synthetic approaches, is also illustrated. Finally, a section is dedicated to the principal characterization techniques to identify the structural properties of the catalysts.
Highly Porous SnO2/TiO2 Heterojunction Thin-Film Photocatalyst Using Gas-Flow Thermal Evaporation and Atomic Layer Deposition
Authors: Kim Sungjin , Chang Hyeon-Kyung , Kim Kwang Bok , Kim Hyun-Jong , Lee Ho-Nyun , Park Tae Joo , Park Young Min
Published: September 2021

Highly porous heterojunction films of SnO2/TiO2 were prepared using gas-flow thermal evaporation followed by atomic layer deposition (ALD). Highly porous SnO2 was fabricated by introducing an inert gas, Ar, during thermal evaporation. To build heterogeneous structures, the TiO2 layers were conformally deposited on porous SnO2 with a range of 10 to 100 cycles by means of ALD. The photocatalytic properties for different TiO2 thicknesses on the porous SnO2 were compared using the degradation of methylene blue (MB) under UV irradiation. The comparisons showed that the SnO2/TiO2-50 heterostructures had the highest photocatalytic efficiency. It removed 99% of the MB concentration, and the decomposition rate constant (K) was 0.013 min−1, which was approximately ten times that of the porous SnO2. On the other hand, SnO2/TiO2-100 exhibited a lower photocatalytic efficiency despite having a TiO2 layer thicker than SnO2/TiO2-50. After 100 cycles of TiO2 ALD deposition, the structure was transferred from the heterojunction to the core–sell structure covered with TiO2 on the porous SnO2, which was confirmed by TEM analysis. Since the electrons photogenerated by light irradiation were separated into SnO2 and produced reactive oxygen, O2−, the heterojunction structure, in which SnO2 was exposed to the surface, contributed to the high performance of the photocatalyst.
Pre-Coking Strategy Strengthening Stability Performance of Supported Nickel Catalysts in Chloronitrobenzene Hydrogenation
Authors: Wang Ping , Wang Shiyi , Lin Ronghe , Mou Xiaoling , Ding Yunjie
Published: September 2021

Supported nickel catalysts represent a class of important catalytic materials in selective hydrogenations, but applications are frequently limited by metal agglomeration or active-site blocking induced by the presence of hydrogen halides. Herein, we report a novel pre-coking strategy, exposing the nickel nanoparticles under methane dry reforming conditions to manipulate performance in the continuous-flow hydrogenation of 1,2-dichloro-4-nitrobenzene. Compared with the pristine nickel catalyst, the nanotube-like coke-modified nickel catalyst showed weakened hydrogenating ability, but much improved stability and slightly better selectivity to the target product, 3,4-dichloroaniline. Characterization results revealed that the strengthened stability performance can be mainly linked to the reduced propensity to retain chlorine species, which seems to block the access of the substrate molecules to the active sites, and thus is a major cause of catalyst deactivation on the pristine nickel catalyst. Coke deposition can occur on the pre-coked nickel catalyst but not on the pristine analog; however, the impact on the stability performance is much milder compared with that on chlorine uptake. In addition, the presence of coke is also beneficial in restraining the growth of the nickel nanoparticles. Generally, the developed method might provide an alternative perspective on the design of novel transition-metal-based catalytic materials for other hydrogenation applications under harsh conditions.
Multifunctional Electrocatalysis on Single-Site Metal Catalysts: A Computational Perspective
Authors: Cepitis Ritums , Kongi Nadezda , Grozovski Vitali , Ivaništšev Vladislav , Lust Enn
Published: September 2021

Multifunctional electrocatalysts are vastly sought for their applications in water splitting electrolyzers, metal-air batteries, and regenerative fuel cells because of their ability to catalyze multiple reactions such as hydrogen evolution, oxygen evolution, and oxygen reduction reactions. More specifically, the application of single-atom electrocatalyst in multifunctional catalysis is a promising approach to ensure good atomic efficiency, tunability and additionally benefits simple theoretical treatment. In this review, we provide insights into the variety of single-site metal catalysts and their identification. We also summarize the recent advancements in computational modeling of multifunctional electrocatalysis on single-site catalysts. Furthermore, we explain each modeling step with open-source-based working examples of a standard computational approach.
Progressive Domain Segregation in Early Embryonic Development and Underlying Correlation to Genetic and Epigenetic Changes
Authors: Quan Hui , Tian Hao , Liu Sirui , Xue Yue , Zhang Yu , Xie Wei , Gao Yi Qin
Published: September 2021

Chromatin undergoes drastic structural organization and epigenetic reprogramming during embryonic development. We present here a consistent view of the chromatin structural change, epigenetic reprogramming, and the corresponding sequence-dependence in both mouse and human embryo development. The two types of domains, identified earlier as forests (CGI-rich domains) and prairies (CGI-poor domains) based on the uneven distribution of CGI in the genome, become spatially segregated during embryonic development, with the exception of zygotic genome activation (ZGA) and implantation, at which point significant domain mixing occurs. Structural segregation largely coincides with DNA methylation and gene expression changes. Genes located in mixed prairie domains show proliferation and ectoderm differentiation-related function in ZGA and implantation, respectively. The chromatin of the ectoderm shows the weakest and the endoderm the strongest domain segregation in germ layers. This chromatin structure difference between different germ layers generally enlarges upon further differentiation. The systematic chromatin structure establishment and its sequence-based segregation strongly suggest the DNA sequence as a possible driving force for the establishment of chromatin 3D structures that profoundly affect the expression profile. Other possible factors correlated with or influencing chromatin structures, including transcription, the germ layers, and the cell cycle, are discussed for an understanding of concerted chromatin structure and epigenetic changes in development.
Carbonic Anhydrase IV Selective Inhibitors Counteract the Development of Colitis-Associated Visceral Pain in Rats
Authors: Lucarini Elena , Nocentini Alessio , Bonardi Alessandro , Chiaramonte Niccolò , Parisio Carmen , Micheli Laura , Toti Alessandra , Ferrara Valentina , Carrino Donatello , Pacini Alessandra , Romanelli Maria Novella , Supuran Claudiu T. , Ghelardini Carla , Di Cesare Mannelli Lorenzo
Published: September 2021

Persistent pain affecting patients with inflammatory bowel diseases (IBDs) is still very difficult to treat. Carbonic anhydrase (CA) represents an intriguing pharmacological target considering the anti-hyperalgesic efficacy displayed by CA inhibitors in both inflammatory and neuropathic pain models. The aim of this work was to evaluate the effect of inhibiting CA IV, particularly when expressed in the gut, on visceral pain associated with colitis induced by 2,4-di-nitrobenzene sulfonic acid (DNBS) in rats. Visceral sensitivity was assessed by measuring animals’ abdominal responses to colorectal distension. Repeated treatment with the selective CA IV inhibitors AB-118 and NIK-67 effectively counteracted the development of visceral pain induced by DNBS. In addition to pain relief, AB-118 showed a protective effect against colon damage. By contrast, the anti-hyperalgesic activity of NIK-67 was independent of colon healing, suggesting a direct protective effect of NIK-67 on visceral sensitivity. The enzymatic activity and the expression of CA IV resulted significantly increased after DNBS injection. NIK-67 normalised CA IV activity in DNBS animals, while AB-118 was partially effective. None of these compounds influenced CA IV expression through the colon. Although further investigations are needed to study the underlying mechanisms, CA IV inhibitors are promising candidates in the search for therapies to relieve visceral pain in IBDs.