bluuebunny/crossref_metadata_2025 huggingface dataset:
Merkel Cell Carcinoma
Authors: Dellambra Elena , Carbone Maria Luigia , Ricci Francesca , Ricci Francesco , Di Pietro Francesca Romana , Moretta Gaia , Verkoskaia Sofia , Feudi Elisa , Failla Cristina M. , Abeni Damiano , Fania Luca
Published: June 2021

Merkel cell carcinoma (MCC) is a rare and extremely aggressive neuroendocrine carcinoma of the skin, with increasing incidence worldwide. This review intends to propose a comprehensive evaluation of MCC epidemiology, clinical features, pathogenetic mechanisms, diagnosis, and therapies. A section is dedicated to immunological aspects and another to the involvement of angiogenesis and angiogenic growth factors in MCC progression, proposing novel diagnostic and therapeutic approaches. Advanced MCC tumors have been treated with immune checkpoint inhibitors with effective results. Therefore, the state of art of this immunotherapy is also examined, reporting on the most recent clinical trials in the field. We conclude by underlining the achievements in the understanding of MCC pathology and indicating the present needs for effective diagnosis and therapeutic management of the disease.
miR-208b Reduces the Expression of Kcnj5 in a Cardiomyocyte Cell Line
Authors: Hupfeld Julia , Ernst Maximilian , Knyrim Maria , Binas Stephanie , Kloeckner Udo , Rabe Sindy , Quarch Katja , Misiak Danny , Fuszard Matthew , Grossmann Claudia , Gekle Michael , Schreier Barbara
Published: June 2021

MicroRNAs (miRs) contribute to different aspects of cardiovascular pathology, among them cardiac hypertrophy and atrial fibrillation. Cardiac miR expression was analyzed in a mouse model with structural and electrical remodeling. Next-generation sequencing revealed that miR-208b-3p was ~25-fold upregulated. Therefore, the aim of our study was to evaluate the impact of miR-208b on cardiac protein expression. First, an undirected approach comparing whole RNA sequencing data to miR-walk 2.0 miR-208b 3′-UTR targets revealed 58 potential targets of miR-208b being regulated. We were able to show that miR-208b mimics bind to the 3′ untranslated region (UTR) of voltage-gated calcium channel subunit alpha1 C and Kcnj5, two predicted targets of miR-208b. Additionally, we demonstrated that miR-208b mimics reduce GIRK1/4 channel-dependent thallium ion flux in HL-1 cells. In a second undirected approach we performed mass spectrometry to identify the potential targets of miR-208b. We identified 40 potential targets by comparison to miR-walk 2.0 3′-UTR, 5′-UTR and CDS targets. Among those targets, Rock2 and Ran were upregulated in Western blots of HL-1 cells by miR-208b mimics. In summary, miR-208b targets the mRNAs of proteins involved in the generation of cardiac excitation and propagation, as well as of proteins involved in RNA translocation (Ran) and cardiac hypertrophic response (Rock2).
New-Onset Diabetes, Endothelial Dysfunction, and Cardiovascular Outcomes in Hypertensive Patients: An Illness-Event Model Analysis
Authors: Maio Raffaele , Suraci Edoardo , Caroleo Benedetto , Politi Cristina , Gigliotti Simona , Sciacqua Angela , Andreozzi Francesco , Perticone Francesco , Perticone Maria
Published: June 2021

Background. Insulin resistance and endothelial dysfunction are common findings in hypertensives, both predisposing to a higher risk of diabetes and cardiovascular events. We designed this study to evaluate the role of endothelial dysfunction in three pathogenetic pathways: (1) from baseline to cardiovascular events, (2) from baseline to diabetes, and (3) from new-onset diabetes to cardiovascular events. Methods. We enrolled 653 Caucasian never-treated hypertensives. Endothelial dysfunction was investigated by strain-gauge plethysmography; incident diabetes and cardiovascular events were evaluated by an illness-event model analysis. Results. During the follow-up (median 113 months), we documented 191 new cardiovascular events and 92 new cases of diabetes. In a multiple Cox regression analysis, acetylcholine-stimulated forearm blood flow [100% decrease, hazard ratio: 2.42 (95% confidence interval = 1.72–3.40)] and serum high-sensitivity C-reactive protein [hazard ratio: 1.30 (95% confidence interval = 1.21–1.40)] had an independent association with cardiovascular outcomes. The incidence rate of cardiovascular outcomes in diabetes-developer patients was higher than in the diabetes-free ones (34.9 vs. 2.5 events per 100 persons-year). In an illness-event model, a 100% decrease in forearm blood flow was associated with a 55.5% hazard ratio increase (hazard ratio: 1.56, 95% confidence interval: 1.33–1.82) of transition 1 (from baseline status to cardiovascular events) and to an almost doubled increase (hazard ratio: 2.54, 95% CI: 2.00–3.25) of the risk of transition 2 (from baseline status to diabetes). No such effects were found in transition 3 (from diabetes to cardiovascular events). Conclusions. Endothelial dysfunction plays a primary role in the pathways leading to diabetes and cardiovascular events in hypertensives. When diabetes is overt, endothelial dysfunction has no predictive value for subsequent cardiovascular events.
Magnetic Separation and Centri-Chronoamperometric Detection of Foodborne Bacteria Using Antibiotic-Coated Metallic Nanoparticles
Authors: Diouani Mohamed Fethi , Sayhi Maher , Djafar Zehaira Romeissa , Ben Jomaa Samir , Belgacem Kamel , Gharbi Hayet , Ghita Mihai , Popescu Laura-Madalina , Piticescu Roxana , Laouini Dhafer
Published: June 2021

Quality and food safety represent a major stake and growing societal challenge in the world. Bacterial contamination of food and water resources is an element that pushes scientists to develop new means for the rapid and efficient detection and identification of these pathogens. Conventional detection tools are often bulky, laborious, expensive to buy, and, above all, require an analysis time of a few hours to several days. The interest in developing new, simple, rapid, and nonlaborious bacteriological diagnostic methods is therefore increasingly important for scientists, industry, and regulatory bodies. In this study, antibiotic-functionalized metallic nanoparticles were used to isolate and identify the foodborne bacterial strains Bacillus cereus and Shigella flexneri. With this aim, a new diagnostic tool for the rapid detection of foodborne pathogenic bacteria, gold nanoparticle-based centri-chronoamperometry, has been developed. Vancomycin was first stabilized at the surface of gold nanoparticles and then incubated with the bacteria B. cereus or S. flexneri to form the AuNP@vancomycin/bacteria complex. This complex was separated by centrifugation, then treated with hydrochloric acid and placed at the surface of a carbon microelectrode. The gold nanoparticles of the formed complex catalyzed the hydrogen reduction reaction, and the generated current was used as an analytical signal. Our results show the possibility of the simple and rapid detection of the S. flexneri and B. cereus strains at very low numbers of 3 cells/mL and 12 cells/mL, respectively. On the other hand, vancomycin-capped magnetic beads were easily synthesized and then used to separate the bacteria from the culture medium. The results show that vancomycin at the surface of these metallic nanoparticles is able to interact with the bacteria membrane and then used to separate the bacteria and to purify an inoculated medium.
Bidirectional Association between Physical Activity and Dopamine Across Adulthood—A Systematic Review
Authors: Marques Adilson , Marconcin Priscila , Werneck André O. , Ferrari Gerson , Gouveia Élvio R. , Kliegel Matthias , Peralta Miguel , Ihle Andreas
Published: June 2021

Physical activity (PA) may influence the secretion of neurotransmitters and thereby have positive consequences for an individual’s vulnerability (i.e., reducing anxiety and depressive symptoms). This systematic review aims to analyse the potential bidirectional effects of exercise on dopamine from young adulthood to old age. The article search was conducted in PubMed, Scopus, and Web of Science in December 2020. The inclusion criteria were longitudinal and experimental study design; outcomes included dopamine and exercise; effect of exercise on dopamine and vice versa; adults; and articles published in English, Portuguese, or Spanish. Fifteen articles were included in the review. We observed robust findings concerning the potential effects of PA on dopamine, which notably seem to be observable across a wide range of participants characteristics (including age and sex), a variety of PA characteristics, and a broad set of methods to analyse dopamine. By contrast, regarding the potential effects of dopamine on PA, findings were mixed across studies. Thus, there are robust effects of physical exercise on dopamine. These findings further strengthen the idea that innovative approaches could include PA interventions for treating and preventing mental disorders. Therefore, it seems that PA is a potential alternative to deal with mental health issues.
How Visual Word Decoding and Context-Driven Auditory Semantic Integration Contribute to Reading Comprehension: A Test of Additive vs. Multiplicative Models
Authors: Li Yu , Xing Hongbing , Zhang Linjun , Shu Hua , Zhang Yang
Published: June 2021

Theories of reading comprehension emphasize decoding and listening comprehension as two essential components. The current study aimed to investigate how Chinese character decoding and context-driven auditory semantic integration contribute to reading comprehension in Chinese middle school students. Seventy-five middle school students were tested. Context-driven auditory semantic integration was assessed with speech-in-noise tests in which the fundamental frequency (F0) contours of spoken sentences were either kept natural or acoustically flattened, with the latter requiring a higher degree of contextual information. Statistical modeling with hierarchical regression was conducted to examine the contributions of Chinese character decoding and context-driven auditory semantic integration to reading comprehension. Performance in Chinese character decoding and auditory semantic integration scores with the flattened (but not natural) F0 sentences significantly predicted reading comprehension. Furthermore, the contributions of these two factors to reading comprehension were better fitted with an additive model instead of a multiplicative model. These findings indicate that reading comprehension in middle schoolers is associated with not only character decoding but also the listening ability to make better use of the sentential context for semantic integration in a severely degraded speech-in-noise condition. The results add to our better understanding of the multi-faceted reading comprehension in children. Future research could further address the age-dependent development and maturation of reading skills by examining and controlling other important cognitive variables, and apply neuroimaging techniques such as functional magmatic resonance imaging and electrophysiology to reveal the neural substrates and neural oscillatory patterns for the contribution of auditory semantic integration and the observed additive model to reading comprehension.
Experimental Study on the Compressive Behaviors of Brick Masonry Strengthened with Modified Oyster Shell Ash Mortar
Authors: Chen Zhouyi , Chen Wenyuan , Mai Chenglin , Shi Jianguang , Xie Yiren , Hu Hongmei
Published: June 2021

Masonry bricks were widely used in construction of the walls in most of Chinese historical buildings. The low strength of lime–clay mortar used in existing historical brick masonry walls has usually led to poor performance such as cracking and collapse during earthquakes. As the composition of modified oyster shell ash mortar (MOSA mortar) with higher strength is similar to that of lime–clay mortar, it can be used to partially replace original lime–clay mortar for historical brick masonry buildings in order to improve their seismic performance. Previous research has proven that this strengthening method for brick masonry is effective in improving shear strength. In this paper, we present further experimental research regarding the compressive behaviors of brick masonry strengthened by replacing mortar with a MOSA mortar. The test results showed that the compressive strength of brick masonry specimens strengthened by the proposed method meets the design requirements. The formula for calculating compressive strength for brick masonry strengthened by replacing mortar was obtained by fitting the test results. The calculated values were consistent with the tested ones. In addition, the stress–strain relationship of tested specimens under axial compression was simulated using the parabolic model.
Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Molecularly Classified Endometrial Carcinoma
Authors: Loukovaara Mikko , Pasanen Annukka , Bützow Ralf
Published: June 2021

The aggressiveness of mismatch repair (MMR) deficient endometrial carcinomas was examined in a single institution retrospective study. Outcomes were similar for MMR proficient (n = 508) and deficient (n = 287) carcinomas, identified by immunohistochemistry. In accordance with molecular classification based on The Cancer Genome Atlas (TCGA), tumors with abnormal p53 staining or polymerase-ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, termed as “no specific molecular profile” (NSMP). Compared with NSMP (n = 218), MMR deficiency (n = 191) was associated with poor disease-specific survival (p = 0.001). MMR deficiency was associated with an increased risk of cancer-related death when controlling for confounders (hazard ratio 2.0). In the absence of established clinicopathologic risk factors, MMR deficiency was invariably associated with an increased risk of cancer-related death in univariable analyses (hazard ratios ≥ 2.0). In contrast, outcomes for MMR deficient and NSMP subgroups did not differ when risk factors were present. Lymphatic dissemination was more common (p = 0.008) and the proportion of pelvic relapses was higher (p = 0.029) in the MMR deficient subgroup. Our findings emphasize the need for improved triage to adjuvant therapy and new therapeutic approaches in MMR deficient endometrial carcinomas.
Therapeutic Potential of Antibody-Drug Conjugate-Based Therapy in Head and Neck Cancer: A Systematic Review
Authors: Perrotti Vittoria , Caponio Vito Carlo Alberto , Mascitti Marco , Lo Muzio Lorenzo , Piattelli Adriano , Rubini Corrado , Capone Emily , Sala Gianluca
Published: June 2021

Background: Antibody-drug conjugates (ADCs) are designed to deliver potent cytotoxic agents into tumor tissues. During the last two decades, a plethora of ADCs have been successfully developed and used for several indications, including hematologic and solid tumors. In this work, we systematically reviewed the progress in ADC development for the treatment of HNC. Methods: This review was registered in PROSPERO database. A comprehensive search was conducted following PRISMA guidelines and using PubMed, Scopus and Web of Science database. Results: In total, 19 studies were included. Due to the significant heterogeneity of the outcome measures, meta-analysis was not performed, and data were summarized in tables. HNC results are poorly represented in the cohorts of completed clinical trials; published data are mostly focused on safety evaluation rather than efficacy of ADCs. Conclusions: Although several novel agents against a wide range of different antigens were investigated, showing promising results at a preclinical level, most of the targets reported in this review are not specific for HNC; hence, the development of ADCs tailored for the HNC phenotype could open up new therapeutic perspectives. Moreover, the results from the present systematic review call attention to how limited is the application of current clinical trials in HNC.
Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma
Authors: Paczkowska Julia , Janiszewska Joanna , Ustaszewski Adam , Bein Julia , Skalski Marcin , Dzikiewicz-Krawczyk Agnieszka , Rozwadowska Natalia , Hansmann Martin-Leo , Hartmann Sylvia , Giefing Maciej
Published: June 2021

A hallmark of classical Hodgkin lymphoma (cHL) is the attenuation of B-cell transcription factors leading to global transcriptional reprogramming. The role of miRNAs (microRNAs) involved in this process is poorly studied. Therefore, we performed global miRNA expression profiling using RNA-seq on commonly used cHL cell lines, non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells as controls and characterized the cHL miRNome (microRNome). Among the 298 miRNAs expressed in cHL, 56 were significantly overexpressed and 23 downregulated (p < 0.05) compared to the controls. Moreover, we identified five miRNAs (hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-196a-5p, hsa-miR-21-5p, hsa-miR-155-5p) as especially important in the pathogenesis of this lymphoma. Target genes of the overexpressed miRNAs in cHL were significantly enriched (p < 0.05) in gene ontologies related to transcription factor activity. Therefore, we further focused on selected interactions with the SPI1 and ELF1 transcription factors attenuated in cHL and the NF-ĸB inhibitor TNFAIP3. We confirmed the interactions between hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1, hsa-miR-450b-5p:ELF-1 and hsa-miR-23a-3p:TNFAIP3, which suggest that overexpression of these miRNAs contributes to silencing of the respective genes. Moreover, by analyzing microdissected HRS cells, we demonstrated that these miRNAs are also overexpressed in primary tumor cells. Therefore, these miRNAs play a role in silencing the B-cell phenotype in cHL.
The Effects of Chemotherapeutics on the Ovarian Cancer Microenvironment
Authors: Eckert Mark A. , Orozco Carlos , Xiao Jason , Javellana Melissa , Lengyel Ernst
Published: June 2021

High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor–stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics.
Technical Advances in Segmentectomy for Lung Cancer: A Minimally Invasive Strategy for Deep, Small, and Impalpable Tumors
Authors: Eguchi Takashi , Sato Toshihiko , Shimizu Kimihiro
Published: June 2021

With the increased detection of early-stage lung cancer and the technical advancement of minimally invasive surgery (MIS) in the field of thoracic surgery, lung segmentectomy using MIS, including video- and robot-assisted thoracic surgery, has been widely adopted. However, lung segmentectomy can be technically challenging for thoracic surgeons due to (1) complex segmental and subsegmental anatomy with frequent anomalies, and (2) difficulty in localizing deep, small, and impalpable tumors, leading to difficulty in obtaining adequate margins. In this review, we summarize the published evidence and discuss key issues related to MIS segmentectomy, focusing on preoperative planning/simulation and intraoperative tumor localization. We also demonstrate two of our techniques: (1) three-dimensional computed tomography (3DCT)-based resection planning using a novel 3DCT processing software, and (2) tumor localization using a novel radiofrequency identification technology.
DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome—Relevance as Complementary Prognostic Biomarkers
Authors: Gonçalves Ana Cristina , Alves Raquel , Baldeiras Inês , Marques Bárbara , Oliveiros Bárbara , Pereira Amélia , Nascimento Costa José Manuel , Cortesão Emília , Mota Vieira Luisa , Sarmento Ribeiro Ana Bela
Published: June 2021

Oxidative stress and abnormal DNA methylation have been implicated in cancer, including myelodysplastic syndromes (MDSs). This fact leads us to investigate whether oxidative stress is correlated with localized and global DNA methylations in the peripheral blood of MDS patients. Sixty-six MDS patients and 26 healthy individuals were analyzed. Several oxidative stress and macromolecule damage parameters were analyzed. Localized (gene promotor) and global DNA methylations (5-mC and 5-hmC levels; LINE-1 methylation) were assessed. MDS patients had lower levels of reduced glutathione and total antioxidant status (TAS) and higher levels of peroxides, nitric oxide, peroxides/TAS, and 8-hydroxy-2-deoxyguanosine compared with controls. These patients had higher 5-mC levels and lower 5-hmC/5-mC ratio and LINE-1 methylation and increased methylation frequency of at least one methylated gene. Peroxide levels and peroxide/TAS ratio were higher in patients with methylated genes than those without methylation and negatively correlated with LINE-1 methylation and positively with 5-mC levels. The 5-hmC/5-mC ratio was significantly associated with progression to acute leukemia and peroxide/TAS ratio with overall survival. This study points to a relationship between oxidative stress and DNA methylation, two common pathogenic mechanisms involved in MDS, and suggests the relevance of 5-hmC/5-mC and peroxide/TAS ratios as complementary prognostic biomarkers.
Plasma Metabolomics for Discovery of Early Metabolic Markers of Prostate Cancer Based on Ultra-High-Performance Liquid Chromatography-High Resolution Mass Spectrometry
Authors: Lin Xiangping , Lécuyer Lucie , Liu Xinyu , Triba Mohamed N. , Deschasaux-Tanguy Mélanie , Demidem Aïcha , Liu Zhicheng , Palama Tony , Rossary Adrien , Vasson Marie-Paule , Hercberg Serge , Galan Pilar , Savarin Philippe , Xu Guowang , Touvier Mathilde
Published: June 2021

Background: The prevention and early screening of PCa is highly dependent on the identification of new biomarkers. In this study, we investigated whether plasma metabolic profiles from healthy males provide novel early biomarkers associated with future risk of PCa. Methods: Using the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, we identified plasma samples collected from 146 PCa cases up to 13 years prior to diagnosis and 272 matched controls. Plasma metabolic profiles were characterized using ultra-high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Results: Orthogonal partial least squares discriminant analysis (OPLS-DA) discriminated PCa cases from controls, with a median area under the receiver operating characteristic curve (AU-ROC) of 0.92 using a 1000-time repeated random sub-sampling validation. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) identified the top 10 most important metabolites (p < 0.001) discriminating PCa cases from controls. Among them, phosphate, ethyl oleate, eicosadienoic acid were higher in individuals that developed PCa than in the controls during the follow-up. In contrast, 2-hydroxyadenine, sphinganine, L-glutamic acid, serotonin, 7-keto cholesterol, tiglyl carnitine, and sphingosine were lower. Conclusion: Our results support the dysregulation of amino acids and sphingolipid metabolism during the development of PCa. After validation in an independent cohort, these signatures may promote the development of new prevention and screening strategies to identify males at future risk of PCa.
A New Paradigm in the Relationship between Melatonin and Breast Cancer: Gut Microbiota Identified as a Potential Regulatory Agent
Authors: Laborda-Illanes Aurora , Sánchez-Alcoholado Lidia , Boutriq Soukaina , Plaza-Andrades Isaac , Peralta-Linero Jesús , Alba Emilio , González-González Alicia , Queipo-Ortuño María Isabel
Published: June 2021

In this review we summarize a possible connection between gut microbiota, melatonin production, and breast cancer. An imbalance in gut bacterial population composition (dysbiosis), or changes in the production of melatonin (circadian disruption) alters estrogen levels. On the one hand, this may be due to the bacterial composition of estrobolome, since bacteria with β-glucuronidase activity favour estrogens in a deconjugated state, which may ultimately lead to pathologies, including breast cancer. On the other hand, it has been shown that these changes in intestinal microbiota stimulate the kynurenine pathway, moving tryptophan away from the melatonergic pathway, thereby reducing circulating melatonin levels. Due to the fact that melatonin has antiestrogenic properties, it affects active and inactive estrogen levels. These changes increase the risk of developing breast cancer. Additionally, melatonin stimulates the differentiation of preadipocytes into adipocytes, which have low estrogen levels due to the fact that adipocytes do not express aromatase. Consequently, melatonin also reduces the risk of breast cancer. However, more studies are needed to determine the relationship between microbiota, melatonin, and breast cancer, in addition to clinical trials to confirm the sensitizing effects of melatonin to chemotherapy and radiotherapy, and its ability to ameliorate or prevent the side effects of these therapies.
Prognostic Factors for Wilms Tumor Recurrence: A Review of the Literature
Authors: Groenendijk Alissa , Spreafico Filippo , de Krijger Ronald R. , Drost Jarno , Brok Jesper , Perotti Daniela , van Tinteren Harm , Venkatramani Rajkumar , Godziński Jan , Rübe Christian , Geller James I. , Graf Norbert , van den Heuvel-Eibrink Marry M. , Mavinkurve-Groothuis Annelies M. C.
Published: June 2021

In high-income countries, the overall survival of children with Wilms tumors (WT) is ~90%. However, overall, 15% of patients experience tumor recurrence. The adverse prognostic factors currently used for risk stratification (advanced stage, high risk histology, and combined loss of heterozygosity at 1p and 16q in chemotherapy-naïve WTs) are present in only one third of these cases, and the significance of these factors is prone to change with advancing knowledge and improved treatment regimens. Therefore, we present a comprehensive, updated overview of the published prognostic variables for WT recurrence, ranging from patient-, tumor- and treatment-related characteristics to geographic and socioeconomic factors. Improved first-line treatment regimens based on clinicopathological characteristics and advancing knowledge on copy number variations unveil the importance of further investigating the significance of biological markers for WT recurrence in international collaborations.
Reporting of Incidence and Outcome of Bone Metastases in Clinical Trials Enrolling Patients with Epidermal Growth Factor Receptor Mutated Lung Adenocarcinoma—A Systematic Review
Authors: Brouns Anita , Dursun Safiye , Bootsma Gerben , Dingemans Anne-Marie C. , Hendriks Lizza
Published: June 2021

Bone metastases, occurring in 30–60% of patients with non-small cell lung cancer (NSCLC), are associated with decreased survival, cancer-induced bone pain, and skeletal-related events (SREs). Those with an activating epidermal growth factor mutation (EGFR+) seem to be more prone to develop bone metastases. To gain more insight into bone metastases-related outcomes in EGFR+ NSCLC, we performed a systematic review on Pubmed (2006–2021). Main inclusion criteria: prospective, phase II/III trials evaluating EGFR-tyrosine kinase inhibitors, ≥10 EGFR+ patients included, data on bone metastases and/or bone-related outcomes available. Out of 663 articles, 21 (3176 EGFR+ patients) met the eligibility criteria; 4 phase III (one double blind), 17 phase II trials (three randomized) were included. In seven trials dedicated bone imaging was performed at baseline. Mean incidence of bone metastases at diagnosis was 42%; 3–33% had progression in the bone upon progression. Except for one trial, it was not specified whether the use of bone target agents was permitted, and in none of the trials, occurrence of SREs was reported. Despite the high incidence of bone metastases in EGFR+ adenocarcinoma, there is a lack of screening for, and reporting on bone metastases in clinical trials, as well as permitted bone-targeted agents and SREs.
Cancer-Associated Fibroblasts in Breast Cancer Treatment Response and Metastasis
Authors: Fernández-Nogueira Patricia , Fuster Gemma , Gutierrez-Uzquiza Álvaro , Gascón Pere , Carbó Neus , Bragado Paloma
Published: June 2021

Breast cancer (BrCa) is the leading cause of death among women worldwide, with about one million new cases diagnosed each year. In spite of the improvements in diagnosis, early detection and treatment, there is still a high incidence of mortality and failure to respond to current therapies. With the use of several well-established biomarkers, such as hormone receptors and human epidermal growth factor receptor-2 (HER2), as well as genetic analysis, BrCa patients can be categorized into multiple subgroups: Luminal A, Luminal B, HER2-enriched, and Basal-like, with specific treatment strategies. Although chemotherapy and targeted therapies have greatly improved the survival of patients with BrCa, there is still a large number of patients who relapse or who fail to respond. The role of the tumor microenvironment in BrCa progression is becoming increasingly understood. Cancer-associated fibroblasts (CAFs) are the principal population of stromal cells in breast tumors. In this review, we discuss the current understanding of CAFs’ role in altering the tumor response to therapeutic agents as well as in fostering metastasis in BrCa. In addition, we also review the available CAFs-directed molecular therapies and their potential implications for BrCa management.
Epithelial-Mesenchymal Transition (EMT): The Type-2 EMT in Wound Healing, Tissue Regeneration and Organ Fibrosis
Authors: Marconi Guya D. , Fonticoli Luigia , Rajan Thangavelu Soundara , Pierdomenico Sante D. , Trubiani Oriana , Pizzicannella Jacopo , Diomede Francesca
Published: June 2021

The epithelial–mesenchymal transition (EMT) is an essential event during cell development, in which epithelial cells acquire mesenchymal fibroblast-like features including reduced intercellular adhesion and increased motility. EMT also plays a key role in wound healing processes, which are mediated by inflammatory cells and fibroblasts. These cells secrete specific factors that interact with molecules of the extracellular matrix (ECM) such as collagens, laminins, elastin and tenascins. Wound healing follows four distinct and successive phases characterized by haemostasis, inflammation, cell proliferation and finally tissue remodeling. EMT is classified into three diverse subtypes: type-1 EMT, type-2 EMT and type-3 EMT. Type-1 EMT is involved in embryogenesis and organ development. Type-2 EMT is associated with wound healing, tissue regeneration and organ fibrosis. During organ fibrosis, type-2 EMT occurs as a reparative-associated process in response to ongoing inflammation and eventually leads to organ destruction. Type-3 EMT is implicated in cancer progression, which is linked to the occurrence of genetic and epigenetic alterations, in detail the ones promoting clonal outgrowth and the formation of localized tumors. The current review aimed at exploring the role of EMT process with particular focus on type-2 EMT in wound healing, fibrosis and tissue regeneration, as well as some recent progresses in the EMT and tissue regeneration field, including the modulation of EMT by biomaterials.
Preparation of CuCrO2 Anisotropic Dela-fossite-Type Thin Film by Electrospinning on Glass Substrates
Authors: Yu Chung-Lun , Weng Chia-Hsuan , Huang Rong-Jun , Sakthinathan Subramanian , Chiu Te-Wei , Dong Chaofang
Published: June 2021

Anisotropic CuCrO2 thin films were successfully prepared on glass substrate by the electrospinning method followed by annealing at 600 °C. The directionality of the nanowires increased with increases in rotation speed. In addition, the structural formation and optoelectronic behavior of the CuCrO2 thin films have been studied by X-ray powder diffraction studies, transmission electron microscopy, field emission scanning electron microscopy, and UV-vis spectroscopy. The X-ray diffraction studies revealed a delafossite properties of the CuCrO2. The electrical conductivity in the parallel and vertical directions of the films produced at 2000–3000 rpm differed by two to three orders of magnitude. The optical transmittance properties of the CuCrO2 thin films were improved by increasing the rotation speed.
Aging Behavior of Al- and Ga- Stabilized Li7La3Zr2O12 Garnet-Type, Solid-State Electrolyte Based on Powder and Single Crystal X-ray Diffraction
Authors: Redhammer Günther J. , Tippelt Gerold , Portenkirchner Andreas , Rettenwander Daniel
Published: June 2021

Li7La3Zr2O12 garnet (LLZO) belongs to the most promising solid electrolytes for the development of solid-state Li batteries. The stability of LLZO upon exposure to air is still a matter of discussion. Therefore, we performed a comprehensive study on the aging behavior of Al-stabilized LLZO (space group (SG) Ia3¯d) and Ga-stabilized LLZO (SG I4¯3d) involving 98 powder and 51 single-crystal X-ray diffraction measurements. A Li+/H+ exchange starts immediately on exposure to air, whereby the exchange is more pronounced in samples with smaller particle/single-crystal diameter. A slight displacement of Li from interstitial Li2 (96h) toward the regular tetrahedral Li1 (24d) sites occurs in Al-stabilized LLZO. In addition, site occupancy at the 96h site decreases as Li+ is exchanged by H+. More extensive hydration during a mild hydrothermal treatment of samples at 90 °C induces a structural phase transition in Al-LLZO to SG I4¯3d with a splitting of the 24d site into two independent tetrahedral sites (i.e., 12a and 12b), whereby Al3+ solely occupies the 12a site. Li+ is preferably removed from the interstitial 48e site (equivalent to 96h). Analogous effects are observed in Ga-stabilized LLZO, which has SG I4¯3d in the pristine state.
Chondroitin Sulfate Disaccharides, a Serum Marker for Primary Serous Epithelial Ovarian Cancer
Authors: Biskup Karina , Stellmach Caroline , Braicu Elena Ioana , Sehouli Jalid , Blanchard Véronique
Published: June 2021

Glycosaminoglycans are long polysaccharidic chains, which are mostly present in connective tissues. Modified GAG expression in tissues surrounding malignant cells has been shown to contribute to tumor progression, aggressive status and metastasis in many types of cancer. Ovarian cancer is one of the most lethal gynecological malignancies due to its late diagnosis because of the absence of clear symptoms and unavailability of early disease markers. We investigated for the first time GAG changes at the molecular level as a novel biomarker for primary epithelial ovarian cancer. To this end, serum of a cohort of 68 samples was digested with chondroitinase ABC, which releases chondroitin sulfate into disaccharides. After labeling and purification, they were measured by HPLC, yielding a profile of eight disaccharides. We proposed a novel GAG-based score named “CS- bio” from the measured abundance of disaccharides present that were of statistical relevance. CS-bio’s performance was compared with CA125, the clinically used serum tumor marker in routine diagnostics. CS-bio had a better sensitivity and specificity than CA125. It was more apt in differentiating early-stage patients from healthy controls, which is of high interest for oncologists.
Evaluation of Complete Pathological Regression after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients with BRCA1 Founder Mutation Aided Bayesian A/B Testing Approach
Authors: Kedzierawski Piotr , Macek Pawel , Ciepiela Izabela , Kowalik Artur , Gozdz Stanislaw
Published: June 2021

The aim of this study was to evaluate the probability of pathologic complete regression (pCR) by the BRCA1 gene mutation status in patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy. The study involved 143 women (mean age 55.4 ± 13.1 years) with TNBC. The BRCA1 mutation was observed in 17% of the subjects. The most commonly used (85.3%) chemotherapy regimen was four cycles of adriamycine and cyclophosphamide followed by 12 cycles of paclitaxel (4AC + 12T). The differences between clinico-pathological factors by BRCA1 status were estimated. Odds ratios and 95% confidence intervals for pCR vs. non-pCR were calculated using logistic regression. The probability distribution of pCR based on BRCA1 status was estimated using beta distributions. The presence of T3–T4 tumours, cancer in stages II and III, lymphovascular invasion, and the use of chemotherapy schedules other than 4AC + 12T significantly decreased the odds of pCR. It was established that there was a 20% chance that pCR in patients with the BRCA1 mutation was 50% or more times as frequent than in patients without the mutation. Thus, the BRCA1 mutation can be a predictive factor for pCR in patients with TNBC.
The Link between Obesity, Microbiota Dysbiosis, and Neurodegenerative Pathogenesis
Authors: Vamanu Emanuel , Rai Sachchida Nand
Published: June 2021

Current research in medicine in several parts of the world has attempted to establish a link between the occurrence of neurodegenerative pathologies, microbiota dysbiosis, and the incidence of obesity. The body’s response to different physicochemical factors has also been influenced by the proper assimilation of bioactive compounds contained in the food that is ingested. Oxidative stress is one of the major factors that directly affects the functioning of the human microbiota. The body’s reaction to this imbalance is crucial to the progression of inflammatory processes, which are based on molecular mechanisms. Microbial dysbiosis can result in a possibly permanent alteration in the physiological response. This review aims to highlight recent contributions made to alleviating human dysbiosis in degenerative diseases, especially for neurodegenerative pathologies based on the rising prevalence of obesity. We discuss the significance of both microbiota modulation and possible alleviations of pathologies by a modulatory function. We argue that pre- and probiotics (including phenolic compounds stimulating the favorable strain from the microbiota) are an effective alternative that can support the microbiota pattern’s modulation over time and the attenuation of indirect causes that determine dysbiosis. Molecular aspects are presented in support of the modulating role of the microbiota following the use of probiotics.
Two-Step Measurement of Water–Energy–Food Symbiotic Coordination and Identification of Key Influencing Factors in the Yangtze River Basin
Authors: Chen Weizhong , Chen Yan
Published: June 2021

With the intensification of people’s production and life behaviors, the systemic risks of water, energy and food in the Yangtze River Basin have become increasingly prominent, which has become a bottleneck for sustainable development of social, economic and ecological in the basin. Therefore, studying the symbiotic coordination between water, energy and food is of great significance to promoting regional sustainable development. First, from the perspective of water–energy–food symbiosis, with the water–energy–food ecosystem conceptual model as the nexus, the two-step measurement model of the symbiotic index and the symbiotic level index is used to study the water–energy–food symbiosis of the Yangtze River. Then, we use the BP-DEMATEL-GTCW model to identify the key influencing factors that affect the symbiotic security of the water–energy–food ecosystem. In this research, it is found that the average value of the symbiotic degree of the water–energy–food ecosystem of the 11 provinces or municipalities in the Yangtze River Basin only reached the risk grade. It can also be seen from the identification results of key influencing factors that energy microsystem-related indicators have a greater impact on the symbiotic development of the entire WEF ecosystem. Therefore, special attention needs to be paid to increasing energy sources and reducing expenditure. Relevant departments need to effectively develop primary energy production and expand energy-saving investment through multiple channels to expand energy self-sufficiency and ultimately promote the coordinated and effective development of water, energy and food in the Yangtze River Basin.
Numerical Investigation into the Gas Production from Hydrate Deposit under Various Thermal Stimulation Modes in a Multi-Well System in Qilian Mountain
Authors: Li Bo , Ye Yuan , Zhang Tingting , Wan Qingcui
Published: June 2021

The primary objective of this study was to investigate the energy recovery performance of the permafrost hydrate deposit in the Qilian Mountain at site DK-2 using depressurization combined with thermal injection by the approach of numerical simulation. A novel multi-well system with five horizontal wells was applied for large-scale hydrate mining. The external heat is provided by means of water injection, wellbore heating, or the combinations of them through the central horizontal well, while the fluids are extracted outside from the other four production wells under constant depressurization conditions. The injected water can carry the heat into the hydrate deposit with a faster rate by thermal convection regime, while it also raises the local pressure obviously, which results in a strong prohibition effect on hydrate decomposition in the region close to the central well. The water production rate is always controllable when using the multi-well system. No gas seepage is observed in the reservoir due to the resistance of the undissociated hydrate. Compared with hot water injection, the electric heating combined with normal temperature water flooding basically shows the same promotion effect on gas recovery. Although the hydrate regeneration is more severe in the case of pure electric heating, the external heat can be more efficiently assimilated by gas hydrate, and the efficiency of gas production is best compared with the cases involving water injection. Thus, pure wellbore heating without water injection would be more suitable for hydrate development in deposits characterized by low-permeability conditions.
Understanding Conceptions of ‘Nature’ for Environmental Sustainability: A Case Study in Tāmaki Makaurau Auckland, Aotearoa New Zealand
Authors: Fehnker Lissy , Pearson Diane , Howland Peter J.
Published: June 2021

Empirical research that inductively investigates lay conceptions of ‘nature’ is scarce, despite global environmental narratives around sustainability calling for humans to have harmonious relationships with ‘nature’. This paper presents inductive research that attends to the empirical knowledge gap by exploring how respondents self-reportedly conceive ‘nature’ using Auckland, New Zealand as a case study. Results suggested that conceptions of ‘nature’ within the respondent group are diverse and range across 17 themes. Most commonly, respondents conceived ‘nature’ as being something that neither humans nor human influence or activities are a part of. This finding is consistent with what has been found by previous deductive research approaches to understanding conceptions of ‘nature’. However, this research provides a deeper understanding by identifying that respondents form associations with over 60 ‘aspects’ of ‘nature’. By highlighting the complexity of ‘nature’ from a human perspective and being able to identify significant components of ‘nature’ that people associate with, this study not only provides valuable insight for environmental management in the New Zealand study site, but also has potential to support improved management of human–nature interactions that can have a more targeted impact towards achieving sustainability goals at the global scale.
Teaching in Hospitals and Healthcare Resorts: A Qualitative Study of Teachers’ Needs
Authors: Małkowska-Szkutnik Agnieszka , Berkowska Aleksandra , Gajda Maja , Kleszczewska Dorota
Published: June 2021

The daily functioning of children who suffer from chronic conditions may be limited by the disease and by hospitalization. Hospital schools have an important role in counterbalancing those negative effects. The aim of the study was to define hospital schools’ teachers’ needs. The data from qualitative research conducted on 21 Polish hospital school teachers was included in the analysis. A semi-structured interview method was chosen. Researchers played an active role as moderators. Thirty-four descriptive codes were assigned to the main five areas of needs related to: work conditions, the character of work, psychological support, self-fulfillment, and social relations. The results showed that the teachers were concerned about hospital school marginalization, they received no mental health support, and felt that the extent of their role was underestimated by medical staff. The lack of recognition is likely to make teachers feel frustrated, and demotivated. By learning more about what hospital teachers think of their work, it is possible to create recommendations for changes. There seems to be a need to raise awareness of the importance of schools in health care institutions.
Pneumonia Detection from Chest X-ray Images Based on Convolutional Neural Network
Authors: Zhang Dejun , Ren Fuquan , Li Yushuang , Na Lei , Ma Yue
Published: June 2021

Pneumonia has caused significant deaths worldwide, and it is a challenging task to detect many lung diseases such as like atelectasis, cardiomegaly, lung cancer, etc., often due to limited professional radiologists in hospital settings. In this paper, we develop a straightforward VGG-based model architecture with fewer layers. In addition, to tackle the inadequate contrast of chest X-ray images, which brings about ambiguous diagnosis, the Dynamic Histogram Enhancement technique is used to pre-process the images. The parameters of our model are reduced by 97.51% compared to VGG-16, 85.86% compared to Res-50, 83.94% compared to Xception, 51.92% compared to DenseNet121, but increased MobileNet by 4%. However, the proposed model’s performance (accuracy: 96.068%, AUC: 0.99107 with a 95% confidence interval of [0.984, 0.996], precision: 94.408%, recall: 90.823%, F1 score: 92.851%) is superior to the models mentioned above (VGG-16: accuracy, 94.359%, AUC: 0.98928; Res-50: accuracy, 92.821%, AUC, 0.98780; Xception: accuracy, 96.068%, AUC, 0.99623; DenseNet121: accuracy, 87.350%, AUC, 0.99347; MobileNet: accuracy, 95.473%, AUC, 0.99531). The original Pneumonia Classification Dataset in Kaggle is split into three sub-sets, training, validation and test sets randomly at ratios of 70%, 10% and 20%. The model’s performance in pneumonia detection shows that the proposed VGG-based model could effectively classify normal and abnormal X-rays in practice, hence reducing the burden of radiologists.