bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomimetic Self-Assembled Chiral Inorganic Nanomaterials: A New Strategy for Solving Medical Problems
Authors: Wei Rong , Gao Xueying , Cao Ziwei , Wang Jing , Ma Yu
Published: October 2022

The rapid expansion of the study of chiral inorganic structures has led to the extension of the functional boundaries of inorganic materials. Nature-inspired self-assembled chiral inorganic structures exhibit diverse morphologies due to their high assembly efficiency and controlled assembly process, and they exhibit superior inherent properties such as mechanical properties, chiral optical activity, and chiral fluorescence. Although chiral self-assembled inorganic structures are becoming more mature in chiral catalysis and chiral optical regulation, biomedical research is still in its infancy. In this paper, various forms of chiral self-assembled inorganic structures are summarized, which provides a structural starting point for various applications of chiral self-assembly inorganic structures in biomedical fields. Based on the few existing research statuses and mechanism discussions on the chiral self-assembled materials-mediated regulation of cell behavior, molecular probes, and tumor therapy, this paper provides guidance for future chiral self-assembled structures to solve the same or similar medical problems. In the field of chiral photonics, chiral self-assembled structures exhibit a chirality-induced selection effect, while selectivity is exhibited by chiral isomers in the medical field. It is worth considering whether there is some correspondence or juxtaposition between these phenomena. Future chiral self-assembled structures in medicine will focus on the precise treatment of tumors, induction of soft and hard tissue regeneration, explanation of the biochemical mechanisms and processes of its medical effects, and improvement of related theories.
The Involvement of Cell-Type-Specific Glycans in Hydra Temporary Adhesion Revealed by a Lectin Screen
Authors: Seabra Sofia , Zenleser Theresa , Grosbusch Alexandra L. , Hobmayer Bert , Lengerer Birgit
Published: October 2022

Hydra is a freshwater solitary polyp, capable of temporary adhesion to underwater surfaces. The reversible attachment is based on an adhesive material that is secreted from its basal disc cells and left behind on the substrate as a footprint. Despite Hydra constituting a standard model system in stem cell biology and tissue regeneration, few studies have addressed its bioadhesion. This project aimed to characterize the glycan composition of the Hydra adhesive, using a set of 23 commercially available lectins to label Hydra cells and footprints. The results indicated the presence of N-acetylglucosamine, N-acetylgalactosamine, fucose, and mannose in the adhesive material. The labeling revealed a meshwork-like substructure in the footprints, implying that the adhesive is mainly formed by fibers. Furthermore, lectins might serve as a marker for Hydra cells and structures, e.g., many labeled as glycan-rich nematocytes. Additionally, some unexpected patterns were uncovered, such as structures associated with radial muscle fibers and endodermal gland cells in the hypostome of developing buds.
Electrospinning-Based Biosensors for Health Monitoring
Authors: Ji Guojing , Chen Zhou , Li Hui , Awuye Desire Emefa , Guan Mengdi , Zhu Yingbao
Published: October 2022

In recent years, many different biosensors are being used to monitor physical health. Electrospun nanofiber materials have the advantages of high specific surface area, large porosity and simple operation. These properties play a vital role in biosensors. However, the mechanical properties of electrospun nanofibers are poor relative to other techniques of nanofiber production. At the same time, the organic solvents used in electrospinning are generally toxic and expensive. Meanwhile, the excellent performance of electrospun nanofibers brings about higher levels of sensitivity and detection range of biosensors. This paper summarizes the principle and application of electrospinning technology in biosensors and its comparison with other technologies.
Fast and Accurate Determination of Minute Ochratoxin A Levels in Cereal Flours and Wine with the Label-Free White Light Reflectance Spectroscopy Biosensing Platform
Authors: Karachaliou Chrysoula-Evangelia , Koukouvinos Georgios , Zisis Grigoris , Kizis Dimosthenis , Krystalli Evangelia , Siragakis George , Goustouridis Dimitris , Kakabakos Sotirios , Petrou Panagiota , Livaniou Evangelia , Raptis Ioannis
Published: October 2022

Ochratoxin A (OTA) is one of the most toxic naturally encountered contaminants and is found in a variety of foods and beverages, including cereals and wine. Driven by the strict regulations regarding the maximum allowable OTA concentration in foodstuff and the necessity for on-site determination, the development of fast and sensitive methods for the OTA determination in cereal flours and wine samples, based on white light reflectance spectroscopy, is presented. The method relied on appropriately engineered silicon chips, on top of which an OTA-protein conjugate was immobilized. A polyclonal antibody against OTA was then employed to detect the analyte in the framework of a competitive immunoassay; followed by the subsequent addition of a biotinylated secondary antibody and streptavidin for signal enhancement. A small size instrument performed all assay steps automatically and the bioreactions were monitored in real time as the software converted the spectral shifts into effective biomolecular adlayer thickness increase. The assay developed had a detection limit of 0.03 ng/mL and a working range up to 200 ng/mL. The assay lasted 25 min (less than 1h, including calibrators/antibody pre-incubation) and was accomplished following a simple sample preparation protocol. The method was applied to corn and wheat flour samples and white and red wines with recovery values ranging from 87.2 to 111%. The simplicity of the overall assay protocol and convenient instrumentation demonstrates the potential of the immunosensor developed for OTA detection at the point of need.
Numerical Study on a Bio-Inspired Micropillar Array Electrode in a Microfluidic Device
Authors: Chen Chaozhan , Ran Bin , Liu Bo , Liu Xiaoxuan , Jin Jing , Zhu Yonggang
Published: October 2022

The micropillar array electrode (µAE) has been widely applied in microchip-based electrochemical detection systems due to a large current response. However, it was found that amplifying the current through further adjusting geometrical parameters is generally hindered by the shielding effect. To solve this problem, a bio-inspired micropillar array electrode (bµAE) based on the microfluidic device has been proposed in this study. The inspiration is drawn from the structure of leatherback sea turtles’ mouths. By deforming a μAE to rearrange the micropillars on bilateral sides of the microchannel, the contact area between micropillars and analytes increases, and thus the current is substantially improved. A numerical simulation was then used to characterize the electrochemical performance of bµAEs. The effects of geometrical and hydrodynamic parameters on the current of bµAEs were investigated. Moreover, a prototypical microchip integrated with bµAE was fabricated for detailed electrochemical measurement. The chronoamperometry measurements were conducted to verify the theoretical performance of bµAEs, and the results suggest that the experimental data are in good agreement with those of the simulation model. This work presents a novel bµAE with great potential for highly sensitive electrochemical detection and provides a new perspective on the efficient configuration of the µAE.
Fundamentals of SARS-CoV-2 Biosensors
Authors: Torres-Torres Carlos , García-Pérez Blanca Estela
Published: October 2022

A beautiful topic in its essence and content is represented by the powerful assistance of sensing methods and techniques for automatically revealing biological agents and biological functions in this era [...]
Decoding Visual fMRI Stimuli from Human Brain Based on Graph Convolutional Neural Network
Authors: Meng Lu , Ge Kang
Published: October 2022

Brain decoding is to predict the external stimulus information from the collected brain response activities, and visual information is one of the most important sources of external stimulus information. Decoding functional magnetic resonance imaging (fMRI) based on visual stimulation is helpful in understanding the working mechanism of the brain visual function regions. Traditional brain decoding algorithms cannot accurately extract stimuli features from fMRI. To address these shortcomings, this paper proposed a brain decoding algorithm based on a graph convolution network (GCN). Firstly, 11 regions of interest (ROI) were selected according to the human brain visual function regions, which can avoid the noise interference of the non-visual regions of the human brain; then, a deep three-dimensional convolution neural network was specially designed to extract the features of these 11 regions; next, the GCN was used to extract the functional correlation features between the different human brain visual regions. Furthermore, to avoid the problem of gradient disappearance when there were too many layers of graph convolutional neural network, the residual connections were adopted in our algorithm, which helped to integrate different levels of features in order to improve the accuracy of the proposed GCN. The proposed algorithm was tested on the public dataset, and the recognition accuracy reached 98.67%. Compared with the other state-of-the-art algorithms, the proposed algorithm performed the best.
The Co-Construction of an Elegant Ending—Polyphonic Musical Intervention in Palliative Care: A Case Study
Authors: Schiavo Raffaele
Published: October 2022

The complexity of creative processes, within which human nature pines and finds itself, reflects a state of relational emergency. The weak structure of our multicultural system gives us a series of behavioral flaws, denouncing our inability to welcome diversity and treasure it. In the search for the way out, using the metaphor of polyphony is increasingly frequent. However, since the term Polyphony is borrowed from musical language, it would be necessary to experience it concretely, and this usually does not happen. Those musicians who aspire to be artists in helping relationships should constantly train themselves in this sense and force themselves to make their ability understood externally, helping those who for reasons of life find themselves experiencing the limit. The field of palliative care is probably the most suitable socio-cultural setting for getting in touch with the personal (mis)interpretations, idiosyncrasies, and pain of those who feel close to the end. To their aid, the aesthetic criterion advances. Making sacred the unifying experience of loss and finiteness turns into an educational process moreover therapeutic, in the co-construction of an elegant “finale” able to reach the heart and intelligence of those who remain.
Assessing Teaching Effectiveness in Blended Learning Methodologies: Validity and Reliability of an Instrument with Behavioral Anchored Rating Scales
Authors: Matosas-López Luis , Cuevas-Molano Elena
Published: October 2022

The evaluation of teaching effectiveness in blended learning methodologies is usually carried out using Likert-type questionnaires; however, instruments with Behavioral Anchored Rating Scales (BARS) are sometimes employed for this purpose. This paper examines the validity and reliability of an instrument with BARS designed to assess teaching effectiveness in blended learning environments, within the university setting. The research involves a sample of 1436 students from a medium size university in Spain. Using this sample (n = 1436), the authors carry out a psychometric study that consists of four phases: (1) comprehension validity analysis, (2) construct validity analysis, (3) confirmation of construct validity, and (4) analysis of the instrument reliability. The findings provide satisfactory values for all the parameters analyzed (for instance: Variance explained = 77.61%; RMSEA = 0.042; or Cronbach’s alpha = 0.956), indicating that the BARS instrument examined is perfectly valid and reliable for the appraisal of teaching effectiveness in blended learning methodologies. The authors conclude that this paper fills an important gap in the literature by presenting an instrument that, thanks to the use of behavioral scales, facilitates this task in the university context.
Study on Mechanical and Rheological Properties of Solid Waste-Based ECC
Authors: Wang Xiao , Sun Ke , Shao Jinggan , Ma Juntao
Published: October 2022

As one of the main raw materials of engineered cementitious composite (ECC), fly ash exerts the “ball effect” and “pozzolanic effect” in concrete, which improves the working performance of concrete and enhances the strength of the concrete matrix. Polyvinyl alcohol (PVA) fiber has been widely used in the preparation of ECC, while ground fly ash can be used to enhance the performance of ECC as a kind of high-activity admixture. In this paper, the compressive strength, flexural strength and flexural toughness of ECC prepared from different types of fly ash (raw fly ash, sorted fly ash and ground fly ash) are compared, and the rheological properties of the ECC are analyzed by studying the two parameters of yield stress and plastic viscosity. The results show that the smaller the particle size of fly ash is, the more sufficient it reacts with Ca(OH)2 produced by cement hydration, and the more it can improve the compressive strength and flexural strength of the matrix. In addition, the smaller the particle size of fly ash, the higher the yield stress and plastic viscosity of ECC; therefore, the distribution of PVA fiber in ECC is more uniform, thereby improving the flexural toughness and ductility of ECC.
Effects of C$H2 and CH on Strength and Hydration of Calcium Sulphoaluminate Cement Prepared from Phosphogypsum
Authors: Zhang Jixin , Chang Jun , Zhang Ping , Wang Tong
Published: October 2022

Using phosphogypsum (PG) as a raw material to prepare calcium sulphoaluminate cement (CAS) is an effective way of treating phosphogypsum. In order to meet the different application requirements of CSA cement and promote the application of CAS cement, it is necessary to add mineral admixtures to adjust the performance of cement. This paper incorporated two minerals, gypsum dihydrate (C$H2) and calcium hydroxide (CH), into cement clinker prepared from phosphogypsum. The compressive strength and hydration process of the mixtures with different blending levels were investigated around the C4A3$-C$H2 system (SC) and the C4A3$-C$H2-CH system (SCC). The optimum dosing level was determined on the basis of the strength and hydration properties. In the SC system, adding C$H2 promoted the hydration of C4A3$. The compressive strength of the cement was highest at a C$H2/C4A3$ molar ratio of 1.5, with a 7-day compressive strength of 56.5 MPa. AFt was mostly needle-rod and columnar and was tightly cemented to the gel phase, improving the denseness of the matrix. When the molar ratio was 2, the strength of the cement was inverted, and the shape of the AFt changed from needle and rod to columnar, the size of the grains increased, and it could not be filled with the AH3 phase in an excellent staggered manner. At the same time, C$H2 was not fully reacted, increasing matrix porosity and inversion of strength. In the SCC system, adding CH reduced the cement’s compressive strength, and the compressive strength reduction increased with the increase in admixture. According to the experimental results, CH inhibited the formation of AFt, resulting in the appearance of new hydration products, AFm. As the amount of CH increased, the amount of hydration products, AFm, increased, while the amount of AFt and AH3 decreased. However, adding CH raised the paste’s pH and later facilitated the development of strength. The optimum admixture of CH/C4A3$ was 0.5 mol.
Study on Wind Load Characteristics and Wind-Induced Response of Supertall Buildings with Single-Sided Large-Span Straight Platforms
Authors: Zhang Lixin , Jia Jie , Dong Lin
Published: October 2022

The presence of large-span straight platforms can complicate the airflow around buildings and alter surface wind pressure, gas bypass and wind response in supertall buildings. The article uses the Reynolds-averaged Navier–Stokes (RANS) method in Computational Fluid Dynamics (CFD) to investigate the differences in surface mean wind pressure, gas bypass, wind coefficients, displacement and acceleration responses between the models with and without platforms, and the wind load on the platforms themselves at different wind directions. The results show that: the presence of platforms generally reduces the maximum negative pressure coefficient on the building surface, reaching a maximum reduction of 31.56% at 30°, and causes a small increase in the maximum positive pressure coefficient, reaching a maximum increase of 5.30% at 0°. The mean wind pressure on the lower surface of the platform is greater than the upper surface. The target building has a lower frequency of vortex shedding than the reference model, with a maximum reduction of 5.68%. The presence of platforms increases the vertex displacement of the building by up to 22.85% and decreases the vertex acceleration by up to 9.14%. These results can be used as references for the ventilation, comfort and safety assessment of similar supertall buildings.
Field Measurement on Translational and Torsional Wind-Induced Response of a High-Rise Building during Typhoon Khanun
Authors: Hu Jiaxing , Li Zhengnong , Zhao Zhefei
Published: October 2022

Full measurements for the wind field atop a 32-storey building (supported by four huge columns) and for the dynamic responses of different floors were conducted on 15 October 2017 to obtain the translational and torsional responses of the high-rise building during the Typhoon Khanun. The time histories of the torsional angular acceleration responses on the 24th and 32nd floors of the high-rise building were obtained using RA013 rotational accelerometer, and those of the translational acceleration responses on the 6th, 12th, 18th, 24th, 30th and 32nd floors along axial direction were recorded by the translational accelerometer. The variation rules of the translational and torsional acceleration responses with floor height and mean wind speed were disclosed, and the response ratios between the torsional and translational acceleration were analyzed when basic time intervals were 10 min. Based on the target probability method, the value range of the acceleration peak factor with different target reliability under Typhoon Khanun was proposed. The results show that the translational and torsional acceleration peak values and root mean squares are the power functions of mean wind speed. The values of acceleration peak factors are recommended to be 3.0 and 5.0 if target reliabilities are determined as 99.38% and 100%, respectively. Research on torsional response measurements can accumulate valuable scientific data and lay solid foundations for the subsequent studies on the torsional wind-resistant design of high-rise buildings.
The Study of Quality of Life as a Guide to Urban Regeneration Analysis of Estepona’s New City Hall as a Sustainable Model
Authors: Ros-García Juan
Published: October 2022

Given the immersion of cities in a global situation of social emergency since the latest environmental and health events, current research on increasing the quality of life of citizens has become a priority in the attempt to provide the set of sustainable strategic conditions that must be met in favour of the necessary urban regeneration associated with the improvement of the habitable environment. Thus, being directly concerned by this matter, the construction of new buildings will have to follow concordant dynamics aiming at the improvement of the quality of life of their users and of the city as a whole, thus contributing to their mandatory healthy, habitable and equitable nature. It is necessary to redefine in the design of buildings certain potential criteria with a positive effect on the quality of life. These can be grouped into the following five key factors that define architectural work in relation to its habitability conditions: identity, character, image, materiality and implementation. These quality-of-life descriptors are assessed in a particular building, which serves as a real case study as follows: the new town hall of Estepona (Malaga, Spain). The aim is to provide an answer to the potential use of indicators that determine the improvement of the quality of life provided by a building in the city as a whole. The fact that it is a public building also turns it into a model of management that is consistent with the requirements of sustainable environmental progress in the general interest of a socially just city.
3D Printing in Sustainable Buildings: Systematic Review and Applications in the United Arab Emirates
Authors: Ibrahim Iman , Eltarabishi Fatma , Abdalla Hadeer , Abdallah Mohamed
Published: October 2022

Three-dimensional printing (3DP) has been rapidly evolving to be one of the leading technology fields in the coming decades. However, as in the early years of new technologies, 3DP suffers from technical limitations and various implications. This study focuses on the applications of 3DP in the construction industry, emphasizing its environmental, financial, and social sustainability aspects. A systematic bibliographic analysis was carried out for the relevant publications which increased by 25-fold from 2014 to 2021. The 3D-printed construction projects in the United Arab Emirates (UAE) are presented to demonstrate the early 3DP technology penetration into its booming construction sector. The UAE case is of particular interest from a sustainability perspective due to the environmental footprint of the ample construction activities in the country, combined with the ambitious strategic plans to achieve sustainable development goals. This critical analysis shows that, despite the limited literature, 3DP could potentially be a sustainable alternative with up to 49% less environmental footprint and 78% more cost-effectiveness compared to conventional construction techniques. As the social sustainability aspect was the least addressed, this study discusses relevant social impact indicators and systematic assessment criteria. It is evident that 3DP is already reshaping the future of the built environment, especially in cases where 3DP is advantageous, such as customized designs, quick project delivery, and sustainability-oriented constructions.
CLDN1 Sensitizes Triple-Negative Breast Cancer Cells to Chemotherapy
Authors: Lemesle Marine , Geoffroy Marine , Alpy Fabien , Tomasetto Catherine-Laure , Kuntz Sandra , Grillier-Vuissoz Isabelle
Published: October 2022

Triple-negative breast cancer (TNBC) is an aggressive subtype that constitutes 15–20% of breast cancer cases worldwide. Current therapies often evolve into chemoresistance and lead to treatment failure. About 77% of the TNBC lacks claudin-1 (CLDN1) expression, a major tight junction component, and this absence is correlated with poorer prognostic. Little is known about CLDN1 role on the chemosensitivity of breast cancer. Our clinical data analysis reveals that CLDN1 low expression is correlated to a poor prognostic in TNBC patients. Next, the sensitivity of various TNBC “claudin-1-high” or “claudin-1-low” cells to three compounds belonging to the main class of chemotherapeutic agents commonly used for the treatment of TNBC patients: 5-fluorouracil (5-FU), paclitaxel (PTX) and doxorubicin (DOX). Using RNA interference and stable overexpressing models, we demonstrated that CLDN1 expression increased the sensitivity of TNBC cell lines to these chemotherapeutic agents. Taken together, our data established the important role of CLDN1 in TNBC cells chemosensitivity and supported the hypothesis that CLDN1 could be a chemotherapy response predictive marker for TNBC patients. This study could allow new treatment protocols creation aimed to induce CLDN1 expression in TNBCs to increase their sensitivity to chemotherapy.
Molecular Biomarker Expression in Window of Opportunity Studies for Oestrogen Receptor Positive Breast Cancer—A Systematic Review of the Literature
Authors: Francis James W. M. , Saundh Manmeet , Parks Ruth M. , Cheung Kwok-Leung
Published: October 2022

Window of opportunity (WoO) trials create the opportunity to demonstrate pharmacodynamic parameters of a drug in vivo and have increasing use in breast cancer research. Most breast cancer tumours are oestrogen receptor-positive (ER+), leading to the development of multiple treatment options tailored towards this particular tumour subtype. The aim of this literature review is to review WoO trials pertaining to the pharmacodynamic activity of drugs available for use in ER+ breast cancer in order to help guide treatment for patients receiving neoadjuvant and primary endocrine therapy. Five databases (EMBASE, Cochrane, MEDLINE, PubMed, Web of Science) were searched for eligible studies. Studies performed in treatment-naïve patients with histologically confirmed ER+ breast cancer were included if they acquired pre- and post-treatment biopsies, compared measurement of a proteomic biomarker between these two biopsies and delivered treatment for a maximum mean duration of 31 days. Fifteen studies were eligible for inclusion and covered six different drug classes: three endocrine therapies (ETs) including aromatase inhibitors (AIs), selective oestrogen receptor modulators (SERMs), selective oestrogen receptor degraders (SERDs) and three non-ETs including mTOR inhibitors, AKT inhibitors and synthetic oestrogens. Ki67 was the most frequently measured marker, appearing in all studies. Progesterone receptor (PR) and ER were the next most frequently measured markers, appearing five and four studies, respectively. All three of these markers were significantly downregulated in both AIs and SERDs; Ki67 alone was downregulated in SERMs. Less commonly assessed markers including pS6, pGSH3B, FSH and IGF1 were downregulated while CD34, pAKT and SHBG were significantly upregulated. There were no significant changes in the other biomarkers measured such as phosphate and tensin homolog (PTEN), Bax and Bcl-2.WoO studies have been widely utilised within the ER+ breast cancer subtype, demonstrating their worth in pharmacodynamic research. However, research remains focused upon routinely measured biomarkers such ER PR and Ki67, with an array of less common markers sporadically used.
Genomic Instability in Cerebrospinal Fluid Cell-Free DNA Predicts Poor Prognosis in Solid Tumor Patients with Meningeal Metastasis
Authors: Wang Peng , Zhang Qiaoling , Han Lei , Cheng Yanan , Sun Zengfeng , Yin Qiang , Zhang Zhen , Yu Jinpu
Published: October 2022

Genomic instability (GI), which leads to the accumulation of DNA loss, gain, and rearrangement, is a hallmark of many cancers such as lung cancer, breast cancer, and colon cancer. However, the clinical significance of GI has not been systematically studied in the meningeal metastasis (MM) of solid tumors. Here, we collected both cerebrospinal fluid (CSF) and plasma samples from 56 solid tumor MM patients and isolated cell-free ctDNA to investigate the GI status using a next-generation sequencing-based comprehensive genomic profiling of 543 cancer-related genes. According to the unfiltered heterozygous mutation data-derived GI score, we found that 37 (66.1%) cases of CSF and 3 cases (6%) of plasma had a high GI status, which was further validated by low-depth whole-genome sequencing analysis. It is demonstrated that a high GI status in CSF was associated with poor prognosis, high intracranial pressure, and low Karnofsky performance status scores. More notably, a high GI status was an independent poor prognostic factor of poor MM-free survival and overall survival in lung adenocarcinoma MM patients. Furthermore, high occurrences of the co-mutation of TP53/EGFR, TP53/RB1, TP53/ERBB2, and TP53/KMT2C were found in MM patients with a high GI status. In summary, the GI status in CSF ctDNA might be a valuable prognostic indicator in solid tumor patients with MM.
The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition
Authors: Hornick Emma L. , Stunz Laura L. , Sabree Shakoora , Wu Xiaosheng , Witzig Thomas E. , Bishop Gail A.
Published: October 2022

TNF receptor-associated factor 3 (TRAF3) is an adapter protein that inhibits many signals that promote B cell survival and activation. Mice with a B cell-specific TRAF3 deficiency and humans with a rare haploinsufficiency in TRAF3 have enhanced development of BCLs as they age. Loss-of-function mutations in TRAF3 are common in B cell malignancies. Recent studies show that pharmacological inhibition of the enzyme glycogen synthase kinase 3 (GSK3), which regulates cellular growth, survival, and metabolism, inhibits growth and survival of BCL-derived B cells. In this study, we found that TRAF3 and GSK3 associated in B cells. The relative levels of TRAF3 in BCL cell lines correlated positively with the ratio of inactive to total GSK3β, and negatively correlated with susceptibility to GSK3 inhibition by the GSK3 inhibitory drug 9-ING-41, currently in clinical trials. Uniquely in BCLs with low TRAF3, GSK3 inhibition caused increased loss of the TRAF3-regulated, anti-apoptotic protein Mcl-1. GSK3 inhibition also blocked hyperresponsiveness to IL-6 receptor signaling in TRAF3-deficient BCL cells. Together, these results support the utility of 9-ING-41 as a treatment for BCL, and suggest that a decrease or loss of TRAF3 in BCLs could act as a biomarker for increased susceptibility to GSK3 inhibitor treatment.
Immune Checkpoint Inhibitor-Related Cytopenias: About 68 Cases from the French Pharmacovigilance Database
Authors: Martin Mickaël , Nguyen Hoan-My , Beuvon Clément , Bene Johana , Palassin Pascale , Atzenhoffer Marina , Rouby Franck , Sassier Marion , Pérault-Pochat Marie-Christine , Roblot Pascal , Allouchery Marion , Puyade Mathieu
Published: October 2022

Immune checkpoint inhibitor (ICI)-related cytopenias have been poorly described. This study aimed to further characterize ICI-related cytopenias, using the French pharmacovigilance database. All grade ≥ 2 hematological adverse drug reactions involving at least one ICI coded as suspected or interacting drug according to the World Health Organization criteria and reported up to 31 March 2022, were extracted from the French pharmacovigilance database. Patients were included if they experienced ICI-related grade ≥ 2 cytopenia. We included 68 patients (75 ICI-related cytopenias). Sixty-three percent were male, and the median age was 63.0 years. Seven patients (10.3%) had a previous history of autoimmune disease. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) were the most frequently reported (50.7% and 25.3%, respectively). The median time to onset of ICI-related cytopenias was 2 months. Nearly half were grade ≥ 4, and three patients died from bleeding complications of refractory ITP and from thromboembolic disease with active AIHA. Out of 61 evaluable responses, complete or partial remission was observed after conventional treatment in 72.1% of ICI-related cytopenias. Among the 10 patients with ICI resumption after grade ≥ 2 ICI-related cytopenia, three relapsed. ICI-related cytopenias are rare but potentially life-threatening. Further studies are needed to identify risk factors of ICI-related cytopenias.
Decitabine-Mediated Upregulation of CSPG4 in Ovarian Carcinoma Cells Enables Targeting by CSPG4-Specific CAR-T Cells
Authors: Harrer Dennis Christoph , Schenkel Charlotte , Berking Carola , Herr Wolfgang , Abken Hinrich , Dörrie Jan , Schaft Niels
Published: October 2022

The addition of CAR-T cells to the armamentarium of immunotherapy revigorated the field of oncology by inducing long-lasting remissions in patients with relapsing/refractory hematological malignancies. Nevertheless, in the lion’s share of patients diagnosed with solid tumors, CAR-T-cell therapy so far failed to demonstrate satisfactory anti-tumor activity. A crucial cause of resistance against the antigen-specific attack of CAR-T cells is predicated on the primary or secondary absence of suitable target antigens. Thus, the necessity to create a broad repertoire of different target antigens is vital. We aimed to evaluate the potential of the well-established melanoma antigen chondroitin sulfate proteoglycan 4 (CSPG4) as an inducible antigen in ovarian cancer cells, using CSPG4-negative SKOV-3 ovarian cancer cells as a model. Based on the hypomethylating activity of the FDA-approved drug decitabine, we refined a protocol to upregulate CSPG4 in the majority of decitabine-treated SKOV-3 cells. CSPG4-specific CAR-T cells generated by mRNA-electroporation showed CSPG4-directed cytokine secretion and cytotoxicity towards decitabine-treated SKOV-3. Another ovarian cancer cell line (Caov-3) and the neoplastic cell line 293T behaved similar. In aggregate, we generated proof-of-concept data paving the way for the further exploration of CSPG4 as an inducible antigen for CAR-T cells in ovarian cancer.
The Application of Magnetic Nanoparticles for Sentinel Lymph Node Detection in Clinically Node-Negative Breast Cancer Patients: A Systemic Review and Meta-Analysis
Authors: Liu Pengcheng , Tan Jie , Song Yuting , Huang Kai , Zhang Qingyi , Xie Huiqi
Published: October 2022

Superparamagnetic iron oxide (SPIO), an alternative mapping agent, can be used to identify sentinel lymph nodes in patients with clinically node-negative breast cancer. However, its performance in comparison with the standard method, using a radioisotope (technetium-99 m, Tc) alone or in combination with blue dye, remains controversial. Hence, a systematic review and meta-analysis were conducted to evaluate the diagnostic accuracy of SPIO and its clinical impact in the management of breast cancer. The PubMed, Embase, and Cochrane databases were comprehensively searched from inception to 1 May 2022. Cohort studies regarding the comparison of SPIO with standard methods for sentinel lymph node identification were included. A total of 19 prospective cohort studies, which collectively included 2298 clinically node-negative breast cancer patients undergoing sentinel lymph node identification through both the standard method and SPIO, were identified. The detection rate for sentinel lymph nodes (RR, 1.06; 95% CI, 1.05–1.08; p < 0.001) was considerably higher in the SPIO cohorts than in the standard method cohorts, although this difference was not significant in detected patients, patients with positive sentinel lymph nodes, or positive sentinel lymph nodes. Compared with the standard method, the SPIO method could be considered as an alternative standard of care for sentinel lymph node detection in patients with clinically node-negative breast cancer.
Long-Term Follow-Up, Treatment Strategies, Functional Outcome, and Health-Related Quality of Life after Surgery for WHO Grade 2 and 3 Intracranial Meningiomas
Authors: Pettersson-Segerlind Jenny , Fletcher-Sandersjöö Alexander , von Vogelsang Ann-Christin , Persson Oscar , Kihlström Burenstam Linder Lars , Förander Petter , Mathiesen Tiit , Edström Erik , Elmi-Terander Adrian
Published: October 2022

Progression-free survival (PFS) and overall survival (OS) for WHO grade 2 and 3 intracranial meningiomas are poorly described, and long-term results and data evaluating the routine use of supplementary fractionated radiotherapy (RT) or stereotactic radiosurgery (SRS) has been inconclusive. The aim of this study was to determine the long-term PFS and OS at a center that does not employ routine adjuvant RT. For this purpose, a retrospective population-based cohort study was conducted of all WHO grade 2 and 3 meningiomas surgically treated between 2005 and 2013. The cohort was uniformly defined according to the WHO 2007 criteria to allow comparisons to previously published reports. Patient records were reviewed, and patients were then prospectively contacted for structured quality-of-life assessments. In total, 51 consecutive patients were included, of whom 43 were WHO grade 2 and 8 were grade 3. A Simpson grade 1–2 resection was achieved in 62%. The median PFS was 31 months for grade 2 tumors, and 3.4 months for grade 3. The median OS was 13 years for grade 2, and 1.4 years for grade 3. The MIB-1-index was significantly associated with an increased risk for recurrence (p = 0.018, OR 1.12). The median PFS was significantly shorter for high-risk tumors compared to the low-risk group (10 vs. 46 months; p = 0.018). The surviving meningioma patients showed HRQoL measures comparable to that of the general population, with the exception of significantly more anxiety and depression. All patients who worked before surgery returned to work after their treatment. In conclusion, we confirm dismal prognoses in patients with grade 2 and 3 meningiomas, with tumor-related deaths resulting in severely reduced OS. However, the cohort was heterogenous, and a large subgroup of both grade 2 and 3 meningiomas was alive at 10 years follow-up, suggesting that a cure is possible. In addition, fractionated radiotherapy and chemotherapy had little benefit when introduced for recurrent and progressive diseases.
Identification of Disparities in Personalized Cancer Care—A Joint Approach of the German WERA Consortium
Authors: Lüke Florian , Haller Florian , Utpatel Kirsten , Krebs Markus , Meidenbauer Norbert , Scheiter Alexander , Spoerl Silvia , Heudobler Daniel , Sparrer Daniela , Kaiser Ulrich , Keil Felix , Schubart Christoph , Tögel Lars , Einhell Sabine , Dietmaier Wolfgang , Huss Ralf , Dintner Sebastian , Sommer Sebastian , Jordan Frank , Goebeler Maria-Elisabeth , Metz Michaela , Haake Diana , Scheytt Mithun , Gerhard-Hartmann Elena , Maurus Katja , Brändlein Stephanie , Rosenwald Andreas , Hartmann Arndt , Märkl Bruno , Einsele Hermann , Mackensen Andreas , Herr Wolfgang , Kunzmann Volker , Bargou Ralf , Beckmann Matthias W. , Pukrop Tobias , Trepel Martin , Evert Matthias , Claus Rainer , Kerscher Alexander
Published: October 2022

(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy.
Renal Medullary Carcinomas Harbor a Distinct Methylation Phenotype and Display Aberrant Methylation of Genes Related to Early Nephrogenesis
Authors: Fincke Victoria E. , Krulik Mateja E. , Joshi Piyush , Frühwald Michael C. , Chen Ying-Bei , Johann Pascal D.
Published: October 2022

Renal medullary carcinomas (RMC) are rare aggressive tumors of the kidneys, characterized by a loss of SMARCB1. Characteristically, these tumors arise in patients with sickle cell trait or other hemoglobinopathies. Recent characterization efforts have unraveled oncogenic pathways that drive tumorigenesis. Among these, gene sets that characterize replicative stress and the innate immune response are upregulated in RMCs. Despite comprehensive genetic and transcriptomic characterizations, commonalities or differences to other SMARCB1 deficient entities so far have not been investigated. We analyzed the methylome of seven primary RMC and compared it to other SMARCB1 deficient entities such as rhabdoid tumors (RT) and epithelioid sarcomas using 850 K methylation arrays. Moreover, we evaluated the differential gene expression of RMC using RNA-sequencing in comparison to other rhabdoid tumors. In accordance with previous gene expression data, we found that RMCs separate from other SMARCB1 deficient entities, pointing to a potentially different cell of origin and a role of additional genetic aberrations that may drive tumorigenesis and thus alter the methylome when compared to rhabdoid tumors. In a focused analysis of genes that are important for nephrogenesis, we particularly detected genes that govern early nephrogenesis such as FOXI1 to be hypomethylated and expressed at high levels in RMC. Overall, our analyses underscore the fact that RMCs represent a separate entity with limited similarities to rhabdoid tumors, warranting specific treatment tailored to the aggressiveness of the disease.
Pediatric Neuroendocrine Neoplasms: Rare Malignancies with Incredible Variability
Authors: Castle Jennifer T. , Levy Brittany E. , Chauhan Aman
Published: October 2022

Neuroendocrine neoplasms (NENs) encompass a variety of neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) which can arise anywhere in the body. While relatively rare in the pediatric population, the incidence of NENs has increased in the past few decades. These neoplasms can be devastating if not diagnosed and treated early, however, symptoms are variable and can be indolent for many years. There is a reported median of 10 years from the appearance of the first symptoms to time of diagnosis. Considering some of these neoplasms have a mortality rate as high as 90%, it is crucial healthcare providers are aware of NENs and remain vigilant. With better provider education and easily accessible resources for information about these neoplasms, awareness can be improved leading to earlier disease recognition and diagnosis. This manuscript aims to provide an overview of both the most common NENs as well as the rarer NENs with high lethality in the pediatric population. This review provides up to date evidence and recommendations, encompassing recent changes in classification and advances in treatment modalities, including recently completed and ongoing clinical trials.
Event-Free Survival in Patients with Early HER2-Positive Breast Cancer with a Pathological Complete Response after HER2-Targeted Therapy: A Pooled Analysis
Authors: Swain Sandra M. , Macharia Harrison , Cortes Javier , Dang Chau , Gianni Luca , Hurvitz Sara A. , Jackisch Christian , Schneeweiss Andreas , Slamon Dennis , Valagussa Pinuccia , du Toit Yolande , Heinzmann Dominik , Knott Adam , Song Chunyan , Cortazar Patricia
Published: October 2022

The standard-of-care for patients with pathological complete response (pCR) after neoadjuvant human epidermal growth factor receptor 2 (HER2)-targeted therapy plus chemotherapy is continuation of HER2-targeted therapy in the adjuvant setting. Our objective was to evaluate risk of recurrence or death in these patients and determine if outcomes differed by the HER2-targeted regimen received in each setting. We analyzed patient-level data from five randomized trials evaluating trastuzumab, pertuzumab, or both as part of systemic neoadjuvant and adjuvant therapy for HER2-positive early breast cancer, and assessed event-free survival (EFS) in 1763 patients. Patients with pCR had decreased risk of an EFS event versus those with residual disease (unadjusted hazard ratio [HR] = 0.35; 95% confidence interval [CI]: 0.27–0.46). Regardless of pCR status, after adjusting for baseline factors, reduction in EFS event risk was greater in patients administered pertuzumab/trastuzumab in both settings versus those administered only trastuzumab in both settings (HR = 0.36; 95% CI: 0.26–0.49), or pertuzumab/trastuzumab in the neoadjuvant setting and only trastuzumab in the adjuvant setting (HR = 0.67; 95% CI: 0.47–0.96). Patients with pCR had longer EFS than those with residual disease. Patients treated with pertuzumab/trastuzumab in both the neoadjuvant and adjuvant settings had the lowest risk of breast cancer recurrence.
Dialysis as a Novel Adjuvant Treatment for Malignant Cancers
Authors: Hobro Sture , Nilsson Anders , Sternby Jan , Öberg Carl , Pietras Kristian , Axelson Håkan , Carneiro Ana , Kinhult Sara , Christensson Anders , Fors Jonas , Maciejewski Steven , Knox Jason , Forsal Innas , Källquist Linda , Roos Viktoria
Published: October 2022

Cancer metabolism is characterized by an increased utilization of fermentable fuels, such as glucose and glutamine, which support cancer cell survival by increasing resistance to both oxidative stress and the inherent immune system in humans. Dialysis has the power to shift the patient from a state dependent on glucose and glutamine to a ketogenic condition (KC) combined with low glutamine levels—thereby forcing ATP production through the Krebs cycle. By the force of dialysis, the cancer cells will be deprived of their preferred fermentable fuels, disrupting major metabolic pathways important for the ability of the cancer cells to survive. Dialysis has the potential to reduce glucose levels below physiological levels, concurrently increase blood ketone body levels and reduce glutamine levels, which may further reinforce the impact of the KC. Importantly, ketones also induce epigenetic changes imposed by histone deacetylates (HDAC) activity (Class I and Class IIa) known to play an important role in cancer metabolism. Thus, dialysis could be an impactful and safe adjuvant treatment, sensitizing cancer cells to traditional cancer treatments (TCTs), potentially making these significantly more efficient.
Atypical Macropinocytosis Contributes to Malignant Progression: A Review of Recent Evidence in Endometrioid Endometrial Cancer Cells
Authors: Kohno Takayuki , Kojima Takashi
Published: October 2022

Macropinocytosis is an essential mechanism for the non-specific uptake of extracellular fluids and solutes. In recent years, additional functions have been identified in macropinocytosis, such as the intracellular introduction pathway of drugs, bacterial and viral infection pathways, and nutritional supplement pathway of cancer cells. However, little is known about the changes in cell function after macropinocytosis. Recently, it has been reported that macropinocytosis is essential for endometrial cancer cells to initiate malignant progression in a dormant state. Macropinocytosis is formed by a temporary split of adjacent bicellular junctions of epithelial sheets, rather than from the apical surface or basal membrane, as a result of the transient reduction of tight junction homeostasis. This novel type of macropinocytosis has been suggested to be associated with the malignant pathology of endometriosis and endometrioid endometrial carcinoma. This review outlines the induction of malignant progression of endometrial cancer cells by macropinocytosis based on a new mechanism and the potential preventive mechanism of its malignant progression.