bluuebunny/crossref_metadata_2025 huggingface dataset:
A Method for Computing Slip-Line Fields with Stress Discontinuity in Cohesionless Backfills
Authors: Yang Yang , Li Huanhuan , Meng Zhigang , Wang Hengyu
Published: February 2023

A method for computing slip-line fields in the case of cohesionless backfills with stress discontinuity was proposed. The potential failure zone is divided into the Rankine zone and the transition zone, and the Rankine zone is rigorously determined using the theory of plastic mechanics. The potential failure zone and the Rankine zone are then further divided into a series of triangular slices. On the basis of the force and moment equilibrium conditions of a typical triangular slice, the recurrence equation of the lateral force is established. Furthermore, the relationship between the failure surface inclination angle and the interslice force inclination angle is established by satisfying the Mohr–Coulomb criterion. An iterative procedure for calculating the lateral force of the triangular slices by changing the failure surface inclination in the transition zone is performed until the interslice force satisfies the stress condition of the transition zone boundary, resulting in a stress discontinuity line if the Rankine zone and the transition zone intersect and the intersection line satisfies the stress characteristics of stress discontinuity. Example studies are performed to verify the present method, which shows that the soil–wall interface friction has the most significant effect on stress discontinuity, and the location of the stress discontinuity line gradually approaches the backfill surface with an increase in retaining wall inclination.
Mortar with Internal Curing Bottom Ash for Sand Shortage and Proper Curing
Authors: Markpiban Pochpagee , Krudam Wittawat , Sahamitmongkol Raktipong
Published: February 2023

Using industrial waste such as bottom ash (BA) is a potential alternative to using sand for tackling the current shortage of natural resources in the construction industry. This, along with the internal curing concept, enables proper curing inside and out, especially for low water-to-cement (w/c) ratio concrete, which has low permeability. The current work investigated the flow, compressive strength, heat flow, and microstructure characteristics (using an electron microprobe analysis, EPMA) to evaluate the use of internal curing BA as a sand-replacing material. Partial replacements of fine aggregate with BA were prepared in five different mortars (0, 20%, and 45%), with a fixed water-to-cement (w/c) ratio of 0.35. Consequently, the heat peak increased when using BA compared to the control mortar, indicating a higher hydration rate. The compressive strength of mortar with BA exceeded 50–60 MPa by 28 days. On the microstructural level, BA showed an increase in the volume fraction of small pores from 3 to 50 mm. Moreover, the content of Ca(OH)2 in the mortar with BA increased from 3 to 28 d by enhancing the hydration. This study shows the possibility of valorizing BA as a sand replacement in the internal curing of concrete with a low w/c ratio.
Investigation on the Seismic Performance of RC Frame Buildings with Rubber Isolation Bearing Installed in Staircases
Authors: Bai Liang , Liang Xingwen , Xin Li , Liu Mingxiao , Yu Ziming , Chu Yage
Published: February 2023

A rubber isolation bearing installed in a staircase (RBS) was proposed to mitigate seismic damages to the component of staircases and improve their seismic performance. A series of quasi-static tests performed with respect to the horizontal and vertical mechanical properties of RBS as well as the numerical modelling were verified with experimental results. Next, the finite element models of typical types of reinforced concrete frames (without stairs, with cast-in-place reinforced concrete stairs, and with RBS stairs) were established. The modal dynamic and non-linear elasto-plastic analyses of system-level building models were herein conducted, respectively. The effect of the RBS on the dynamic response of the whole structure and the mechanical performance of stair components was revealed. The analysis results indicated that the RBS provided the desired floor-to-floor relative drift and effectively isolate the seismic action from the stair flight. Therefore, the presence of RBS can effectively mitigate the influence of a staircase on the entire building’s structure, weaken the diagonal strut effect of flights, and reduce the inner forces of staircase components.
Design of Rural Human Settlement Unit with the Integration of Production-Living-Ecology of China Based on Dynamic Emergy Analysis
Authors: Chang Yuan , Geng Geng , Wang Chongjie , Xue Yibing , Mu Tian
Published: February 2023

It is of great theoretical and practical significance to optimize and improve the design of rural human settlement units through system ecology analysis based on emergy evaluation indices. From the perspective of system ecology, the rural living environment system is multivariate and complicated, with strong correlations and obscure boundaries between levels. Therefore, the definition of a rural human settlement unit in China is proposed in this research and can be divided into three scales: the microcosmic scale, mesoscale, and macroscopic scale. This research adopted a new method for the design of rural human settlement units by adopting emergy as a common dimension in order to solve the problem of dimensionality disunity between resource environment elements and society economy elements. Through the establishment of the static emergy analysis model and dynamic emergy prediction model, qualitative and quantitative analysis approaches of the rural human settlement unit were combined. According to the design orientations of industry-invigorative, environment-friendly, and ecology-balanced, corresponding with production-living-ecology integration, emergy evaluation indices including the emergy self-sufficiency ratio, emergy investment ratio, net emergy yield ratio, environmental load ratio, and emergy sustainable indices were calculated and predicted by means of system dynamics simulation. The dynamic emergy prediction results showed that the emergy self-sufficiency ratio and emergy sustainable indices basically presented a decreasing tendency, from 0.34 to 0.15 and from 0.76 to 0.57, respectively, with the passage of time; the values of the emergy investment ratio, net emergy yield ratio, and environmental load ratio basically presented an increasing tendency, from 2.13 to 2.78, from 1.66 to 2.12, and from 2.23 to 3.61, respectively, with the passage of time. In practice, the evaluation method based on the emergy analysis of the technical strategies and spatial arrangements of the rural human settlement unit can provide data support for designing standards, planning guidelines, and creating constructional instructions for the rural living environment of China.
Microbial Air Quality in the Built Environment—Case Study of Darvas-La Roche Heritage Museum House, Oradea, Romania
Authors: Ilies Dorina Camelia , Caciora Tudor , Ilies Alexandru , Berdenov Zharas , Hossain Mallik Akram , Grama Vasile , Dahal Ranjan Kumar , Zdrinca Mihaela , Hassan Thowayeb H. , Herman Grigore Vasile , Wendt Jan Andrzej , Dejeu Paula
Published: February 2023

Problems in the degradation and biodegradation of cultural heritage objects exposed or stored in public buildings and museums and of construction materials are caused (between others) by the activity of microorganisms. Biodeterioration can be observed not only at the level of the building materials of museum buildings, but also at the level of materials from which art objects are made (natural or artificial) and is determined by factors such as the chemical composition and nature of the composition material, the microclimate characteristics and exposure objects, but also through the manner and frequency of surface cleaning and housekeeping in museums. Based on this, the present study offers, through classical methods, a qualitative and quantitative identification of microorganisms inside a heritage museum building located in a temperate climate country. The purpose of the work was to determine to what extent the bacteriological microflora inside can directly and indirectly contribute to the health quality of the building’s occupants as well as the degradation of its materials and structures. The results emphasize the presence of some fungi and bacteria, among them Alternaria spp., Aspergillus spp., Penicillium spp., Cladosporium spp., and Botrytis spp. All of the analyzed rooms have a high and very high degree of fungal contamination (between 524 and 3674 UFC/m3), which can represent a danger to both human health and the integrity of the exhibitions. This is more pronounced considering that some of species of fungi identified are associated with sick building syndrome, problems in humans due to harmful exposure to viruses, bacteria, and pathogens, which generate possible symptoms such as rhinorrhea, nasal congestion, hoarseness, coughing, sneezing, and irritability for the personnel and visitors.
Numerical Investigation of the Axial Stress Distribution of Self-Tapping Screws in Mass Timber Products during Wetting or Drying
Authors: Khan Mehsam , Ni Chun , Wang Jieying , Chui Ying
Published: February 2023

Self-tapping screws (STS) are used in wood-to-wood and wood-to-steel connections in timber structures. Premature failure of STS during the construction phase has been reported by structural engineers and contractors in relation to a few North American mass-timber projects. This STS failure type is suspected of having been precipitated by additional axial stress exerted on STS from swelling of the wood resulting from prolonged wetting. This study investigates the axial stress distribution of STS installed in two mass timber products, cross-laminated timber (CLT) and glulam, under axial loading and changing moisture conditions in the linear elastic regime. The focus is on modelling the stress distribution of STS during wood-wetting. Properties of self-tapping screws under axial loads, such as tensile and withdrawal properties, along with swelling properties of CLT and glulam, have been investigated. A numerical method to predict the axial stress distribution of the screw from these material property tests has been developed. The numerical model has been calibrated with test results. The method developed in this research helps in understanding the premature failure of self-tapping screw connections under the moisture content variation of wood. The next step will be developing an analytical model to predict the axial stress distribution of STS.
Enhancing Safety Training Performance Using Extended Reality: A Hybrid Delphi–AHP Multi-Attribute Analysis in a Type-2 Fuzzy Environment
Authors: Shringi Ankit , Arashpour Mehrdad , Golafshani Emadaldin Mohammadi , Dwyer Tim , Kalutara Pushpitha
Published: February 2023

Safety training effectively addresses the inexperience of and lack of knowledge among construction workers, which are some of the most significant contributors to workplace accidents on construction sites. This paper aims to understand the effectiveness of different extended reality (XR) technologies in imparting important construction safety training to construction workers in a virtual environment compared to conventional classroom training sessions. A group of experts were engaged to understand the most effective learning criteria and the impact of XR visualizations, and their responses were analysed using the interval type-2 fuzzy Delphi (IT2FD) method. Following this, a cohort of engineering students were subjected to construction safety training in traditional, augmented reality (AR) and virtual reality (VR) environments. Their feedback was collected using an online questionnaire and the responses were analysed using the interval type-2 fuzzy analytic hierarchy process (IT2F–AHP). The results revealed that addressing the virtual interface design of the training to maintain the attention of trainees and ensuring the virtual environment’s resemblance to the actual site and task were the most important factors in ensuring effective knowledge retention by the trainees. AR visualizations were most effective at imparting knowledge, and their interactive nature allowed trainees to retain the learned knowledge.
Pediatric Myeloid Sarcoma, More than Just a Chloroma: A Review of Clinical Presentations, Significance, and Biology
Authors: Zorn Kristin E. , Cunningham Ashley M. , Meyer Alison E. , Carlson Karen Sue , Rao Sridhar
Published: February 2023

Myeloid sarcomas (MS), commonly referred to as chloromas, are extramedullary tumors of acute myeloid leukemia (AML) with varying incidence and influence on outcomes. Pediatric MS has both a higher incidence and unique clinical presentation, cytogenetic profile, and set of risk factors compared to adult patients. Optimal treatment remains undefined, yet allogeneic hematopoietic stem cell transplantation (allo-HSCT) and epigenetic reprogramming in children are potential therapies. Importantly, the biology of MS development is poorly understood; however, cell-cell interactions, epigenetic dysregulation, cytokine signaling, and angiogenesis all appear to play key roles. This review describes pediatric-specific MS literature and the current state of knowledge about the biological determinants that drive MS development. While the significance of MS remains controversial, the pediatric experience provides an opportunity to investigate mechanisms of disease development to improve patient outcomes. This brings the hope of better understanding MS as a distinct disease entity deserving directed therapeutic approaches.
Antenna Arrangement in UWB Helmet Brain Applicators for Deep Microwave Hyperthermia
Authors: Zanoli Massimiliano , Ek Erika , Dobšíček Trefná Hana
Published: February 2023

Deep microwave hyperthermia applicators are typically designed as narrow-band conformal antenna arrays with equally spaced elements, arranged in one or more rings. This solution, while adequate for most body regions, might be sub-optimal for brain treatments. The introduction of ultra-wide-band semi-spherical applicators, with elements arranged around the head and not necessarily aligned, has the potential to enhance the selective thermal dose delivery in this challenging anatomical region. However, the additional degrees of freedom in this design make the problem non-trivial. We address this by treating the antenna arrangement as a global SAR-based optimization process aiming at maximizing target coverage and hot-spot suppression in a given patient. To enable the quick evaluation of a certain arrangement, we propose a novel E-field interpolation technique which calculates the field generated by an antenna at any location around the scalp from a limited number of initial simulations. We evaluate the approximation error against full array simulations. We demonstrate the design technique in the optimization of a helmet applicator for the treatment of a medulloblastoma in a paediatric patient. The optimized applicator achieves 0.3 °C higher T90 than a conventional ring applicator with the same number of elements.
The Heterogeneous Complexity of Myeloid Neoplasm: Multi-Level Approaches to Study the Disease
Authors: Awada Hussein , Visconte Valeria
Published: February 2023

Myeloid neoplasms (MNs) include a spectrum of bone marrow malignancies that result from the clonal expansion and arrest of differentiation of myeloid progenitor cells [...]
Impact of Preventive Strategies on HPV-Related Diseases: Ten-Year Data from the Italian Hospital Admission Registry
Authors: Restivo Vincenzo , Minutolo Giuseppa , Maranto Marianna , Maiorana Antonio , Vitale Francesco , Casuccio Alessandra , Amodio Emanuele
Published: February 2023

Human papillomavirus (HPV)-related diseases are still a challenge for public health. Some studies have shown the effects of preventive strategies on them, but studies at the national level are few in number. Therefore, a descriptive study through hospital discharge records (HDRs) was conducted in Italy between 2008 and 2018. Overall, 670,367 hospitalizations due to HPV-related diseases occurred among Italian subjects. In addition, a significant decrease in hospitalization rates for cervical cancer (average annual percentage change (AAPC) = −3.8%, 95% CI = −4.2, −3.5); vulval and vaginal cancer (AAPC = −1.4%, 95% CI = −2.2, −0.6); oropharyngeal cancer; and genital warts (AAPC = −4.0%, 95% CI = −4.5, −3.5) was observed during the study period. Furthermore, strong inverse correlations were found between screening adherence and invasive cervical cancer (r = −0.9, p < 0.001), as well as between HPV vaccination coverage and in situ cervical cancer (r = −0.8, p = 0.005). These results indicate the positive impact of HPV vaccination coverage and cervical cancer screening on hospitalizations due to cervical cancer. Indeed, HPV vaccination also resulted in a positive impact on the decrease in hospitalization rates due to other HPV-related diseases.
Extracellular Vesicle-DNA: The Next Liquid Biopsy Biomarker for Early Cancer Diagnosis?
Authors: Tatischeff Irène
Published: February 2023

After a short introduction about the history of liquid biopsy, aimed to noninvasively replace the common tissue biopsy as a help for cancer diagnosis, this review is focused on extracellular vesicles (EVs), as the main third component, which is now coming into the light of liquid biopsy. Cell-derived EV release is a recently discovered general cellular property, and EVs harbor many cellular components reflecting their cell of origin. This is also the case for tumoral cells, and their cargoes might therefore be a “treasure chest” for cancer biomarkers. This has been extensively explored for a decade, but the EV-DNA content escaped this worldwide query until recently. The aim of this review is to gather the pilot studies focused on the DNA content of circulating cell-derived EVs, and the following five years of studies about the circulating tumor EV-DNA. The recent preclinical studies about the circulating tEV-derived gDNA as a potential cancer biomarker developed into a puzzling controversy about the presence of DNA into exosomes, coupled with an increased unexpected non vesicular complexity of the extracellular environment. This is discussed in the present review, together with the challenges that need to be solved before any efficient clinical transfer of EV-DNA as a quite promising cancer diagnosis biomarker.
Immune Microenvironment in Sporadic Early-Onset versus Average-Onset Colorectal Cancer
Authors: Andric Fanny , Al-Fairouzi Ala , Wettergren Yvonne , Szeponik Louis , Bexe-Lindskog Elinor , Cusack James C. , Tumusiime Gerald , Quiding-Järbrink Marianne , Ljungman David
Published: February 2023

The incidence of left-sided colon and rectal cancer in young people are increasing worldwide, but its causes are poorly understood. It is not clear if the tumor microenvironment is dependent on age of onset, and little is known about the composition of tumor-infiltrating T cells in early-onset colorectal cancer (EOCRC). To address this, we investigated T-cell subsets and performed gene expression immune profiling in sporadic EOCRC tumors and matched average-onset colorectal cancer (AOCRC) tumors. Left-sided colon and rectal tumors from 40 cases were analyzed; 20 EOCRC (<45 years) patients were matched 1:1 to AOCRC (70–75 years) patients by gender, tumor location, and stage. Cases with germline pathogenic variants, inflammatory bowel disease or neoadjuvant-treated tumors were excluded. For T cells in tumors and stroma, a multiplex immunofluorescence assay combined with digital image analysis and machine learning algorithms was used. Immunological mediators in the tumor microenvironment were assessed by NanoString gene expression profiling of mRNA. Immunofluorescence revealed no significant difference between EOCRC and AOCRC with regard to infiltration of total T cells, conventional CD4+ and CD8+ T cells, regulatory T cells, or γδ T cells. Most T cells were located in the stroma in both EOCRC and AOCRC. Immune profiling by gene expression revealed higher expression in AOCRC of the immunoregulatory cytokine IL-10, the inhibitory NK cell receptors KIR3DL3 and KLRB1 (CD161), and IFN-a7 (IFNA7). In contrast, the interferon-induced gene IFIT2 was more highly expressed in EOCRC. However, in a global analysis of 770 tumor immunity genes, no significant differences could be detected. T-cell infiltration and expression of inflammatory mediators are similar in EOCRC and AOCRC. This may indicate that the immune response to cancer in left colon and rectum is not related to age of onset and that EOCRC is likely not driven by immune response deficiency.
Phase I Study of a Multivalent WT1 Peptide Vaccine (Galinpepimut-S) in Combination with Nivolumab in Patients with WT1-Expressing Ovarian Cancer in Second or Third Remission
Authors: Manning-Geist Beryl L. , Gnjatic Sacha , Aghajanian Carol , Konner Jason , Kim Sarah H. , Sarasohn Debra , Soldan Krysten , Tew William P. , Sarlis Nicholas J. , Zamarin Dmitriy , Kravetz Sara , Laface Ilaria , Rasalan-Ho Teresa , Qi Jingjing , Wong Phillip , Sabbatini Paul J. , O’Cearbhaill Roisin E.
Published: February 2023

We examined the safety and immunogenicity of sequential administration of a tetravalent, non-HLA (human leukocyte antigen) restricted, heteroclitic Wilms’ Tumor 1 (WT1) peptide vaccine (galinpepimut-S) with anti–PD-1 (programmed cell death protein 1) nivolumab. This open-label, non-randomized phase I study enrolled patients with WT1-expressing ovarian cancer in second or third remission from June 2016 to July 2017. Therapy included six (every two weeks) subcutaneous inoculations of galinpepimut-S vaccine adjuvanted with Montanide, low-dose subcutaneous sargramostim at the injection site, with intravenous nivolumab over 12 weeks, and up to six additional doses until disease progression or toxicity. One-year progression-free survival (PFS) was correlated to T-cell responses and WT1-specific immunoglobulin (Ig)G levels. Eleven patients were enrolled; seven experienced a grade 1 adverse event, and one experienced a grade ≥3 adverse event considered a dose-limiting toxicity. Ten (91%) of eleven patients had T-cell responses to WT1 peptides. Seven (88%) of eight evaluable patients had IgG against WT1 antigen and full-length protein. In evaluable patients who received >2 treatments of galinpepimut-S and nivolumab, the 1-year PFS rate was 70%. Coadministration of galinpepimut-S and nivolumab demonstrated a tolerable toxicity profile and induced immune responses, as indicated by immunophenotyping and WT1-specific IgG production. Exploratory analysis for efficacy yielded a promising 1-year PFS rate.
Dynamic NIR Fluorescence Imaging and Machine Learning Framework for Stratifying High vs. Low Notch-Dll4 Expressing Host Microenvironment in Triple-Negative Breast Cancer
Authors: Shafiee Shayan , Jagtap Jaidip , Zayats Mykhaylo , Epperlein Jonathan , Banerjee Anjishnu , Geurts Aron , Flister Michael , Zhuk Sergiy , Joshi Amit
Published: February 2023

Delta like canonical notch ligand 4 (Dll4) expression levels in tumors are known to affect the efficacy of cancer therapies. This study aimed to develop a model to predict Dll4 expression levels in tumors using dynamic enhanced near-infrared (NIR) imaging with indocyanine green (ICG). Two rat-based consomic xenograft (CXM) strains of breast cancer with different Dll4 expression levels and eight congenic xenograft strains were studied. Principal component analysis (PCA) was used to visualize and segment tumors, and modified PCA techniques identified and analyzed tumor and normal regions of interest (ROIs). The average NIR intensity for each ROI was calculated from pixel brightness at each time interval, yielding easily interpretable features including the slope of initial ICG uptake, time to peak perfusion, and rate of ICG intensity change after reaching half-maximum intensity. Machine learning algorithms were applied to select discriminative features for classification, and model performance was evaluated with a confusion matrix, receiver operating characteristic curve, and area under the curve. The selected machine learning methods accurately identified host Dll4 expression alterations with sensitivity and specificity above 90%. This may enable stratification of patients for Dll4 targeted therapies. NIR imaging with ICG can noninvasively assess Dll4 expression levels in tumors and aid in effective decision making for cancer therapy.
Impact of the COVID-19 Outbreak—Delayed Referral of Colorectal and Lung Cancer in Primary Care: A National Retrospective Cohort Study
Authors: Helsper Charles W. , Van Gils Carla H. , Van Erp Nicole F. , Siepman van den Berg Marinde F. R. , Rogouti Omar , Van Asselt Kristel M. , Maarsingh Otto R. , Muris Jean , Brandenbarg Daan , Siesling Sabine , De Wit Niek J. , Grant Matthew P. ,   on behalf of the COVID and Cancer Consortium
Published: February 2023

The Coronavirus disease 2019 (COVID-19) outbreak impacted health care. We investigated its impact on the time to referral and diagnosis for symptomatic cancer patients in The Netherlands. We performed a national retrospective cohort study utilizing primary care records linked to The Netherlands Cancer Registry. For patients with symptomatic colorectal, lung, breast, or melanoma cancer, we manually explored free and coded texts to determine the durations of the primary care (IPC) and secondary care (ISC) diagnostic intervals during the first COVID-19 wave and pre-COVID-19. We found that the median IPC duration increased for colorectal cancer from 5 days (Interquartile Range (IQR) 1–29 days) pre-COVID-19 to 44 days (IQR 6–230, p < 0.01) during the first COVID-19 wave, and for lung cancer, the duration increased from 15 days (IQR) 3–47) to 41 days (IQR 7–102, p < 0.01). For breast cancer and melanoma, the change in IPC duration was negligible. The median ISC duration only increased for breast cancer, from 3 (IQR 2–7) to 6 days (IQR 3–9, p < 0.01). For colorectal cancer, lung cancer, and melanoma, the median ISC durations were 17.5 (IQR (9–52), 18 (IQR 7–40), and 9 (IQR 3–44) days, respectively, similar to pre-COVID-19 results. In conclusion, for colorectal and lung cancer, the time to primary care referral was substantially prolonged during the first COVID-19 wave. In such crises, targeted primary care support is needed to maintain effective cancer diagnosis.
A Comparative Study of Automated Deep Learning Segmentation Models for Prostate MRI
Authors: Rodrigues Nuno M. , Silva Sara , Vanneschi Leonardo , Papanikolaou Nickolas
Published: February 2023

Prostate cancer is one of the most common forms of cancer globally, affecting roughly one in every eight men according to the American Cancer Society. Although the survival rate for prostate cancer is significantly high given the very high incidence rate, there is an urgent need to improve and develop new clinical aid systems to help detect and treat prostate cancer in a timely manner. In this retrospective study, our contributions are twofold: First, we perform a comparative unified study of different commonly used segmentation models for prostate gland and zone (peripheral and transition) segmentation. Second, we present and evaluate an additional research question regarding the effectiveness of using an object detector as a pre-processing step to aid in the segmentation process. We perform a thorough evaluation of the deep learning models on two public datasets, where one is used for cross-validation and the other as an external test set. Overall, the results reveal that the choice of model is relatively inconsequential, as the majority produce non-significantly different scores, apart from nnU-Net which consistently outperforms others, and that the models trained on data cropped by the object detector often generalize better, despite performing worse during cross-validation.
Patient Preferences for Unresectable Hepatocellular Carcinoma Treatments: A Discrete-Choice Experiment
Authors: Li Daneng , Tan Ruoding , Hernandez Sairy , Reilly Norelle , Bussberg Cooper , Mansfield Carol
Published: February 2023

Treatments for unresectable hepatocellular carcinoma (HCC) have varying benefit-risk profiles. We elicited 200 US patients’ preferences for attributes associated with various first-line systemic treatments for unresectable HCC in a discrete-choice experiment (DCE) survey. Respondents answered nine DCE questions, each offering a choice between two hypothetical treatment profiles defined by six attributes with varying levels: overall survival (OS), months of maintained daily function, severity of palmar-plantar syndrome, severity of hypertension, risk of digestive-tract bleeding, and mode and frequency of administration. A random-parameters logit model was used to analyze the preference data. Patients regarded an additional 10 months of maintaining daily function without decline to be as important or more important than 10 additional months of OS, on average. Respondents valued avoiding moderate-to-severe palmar-plantar syndrome and hypertension more than extended OS. A respondent would require >10 additional months of OS (the greatest increase presented in the study) on average to offset the increased burden of adverse events. Patients with unresectable HCC prioritize avoiding adverse events that would severely impact their quality of life over mode and frequency of administration or digestive-tract bleeding risk. For some patients with unresectable HCC, maintaining daily functioning is as important or more important than the survival benefit of a treatment.
Hedgehog-GLI and Notch Pathways Sustain Chemoresistance and Invasiveness in Colorectal Cancer and Their Inhibition Restores Chemotherapy Efficacy
Authors: Citarella Anna , Catanzaro Giuseppina , Besharat Zein Mersini , Trocchianesi Sofia , Barbagallo Federica , Gosti Giorgio , Leonetti Marco , Di Fiore Annamaria , Coppola Lucia , Autilio Tanja Milena , Spinello Zaira , Vacca Alessandra , De Smaele Enrico , Venneri Mary Anna , Ferretti Elisabetta , Masuelli Laura , Po Agnese
Published: February 2023

Colorectal cancer (CRC) is a leading cause of cancer-related mortality and chemoresistance is a major medical issue. The epithelial-to-mesenchymal transition (EMT) is the primary step in the emergence of the invasive phenotype and the Hedgehog-GLI (HH-GLI) and NOTCH signaling pathways are associated with poor prognosis and EMT in CRC. CRC cell lines harboring KRAS or BRAF mutations, grown as monolayers and organoids, were treated with the chemotherapeutic agent 5-Fluorouracil (5-FU) alone or combined with HH-GLI and NOTCH pathway inhibitors GANT61 and DAPT, or arsenic trioxide (ATO) to inhibit both pathways. Treatment with 5-FU led to the activation of HH-GLI and NOTCH pathways in both models. In KRAS mutant CRC, HH-GLI and NOTCH signaling activation co-operate to enhance chemoresistance and cell motility, while in BRAF mutant CRC, the HH-GLI pathway drives the chemoresistant and motile phenotype. We then showed that 5-FU promotes the mesenchymal and thus invasive phenotype in KRAS and BRAF mutant organoids and that chemosensitivity could be restored by targeting the HH-GLI pathway in BRAF mutant CRC or both HH-GLI and NOTCH pathways in KRAS mutant CRC. We suggest that in KRAS-driven CRC, the FDA-approved ATO acts as a chemotherapeutic sensitizer, whereas GANT61 is a promising chemotherapeutic sensitizer in BRAF-driven CRC.
Survival after Lung Metastasectomy from Esophageal Cancer: Results from a Multi-Institutional Database
Authors: Yamauchi Yoshikane , Nakajima Jun , Mun Mingyon , Shintani Yasushi , Kuroda Hiroaki , Iwata Takekazu , Endo Makoto , Azuma Yoko , Chida Masayuki , Sakao Yukinori , Yoshino Ichiro , Ikeda Norihiko , Matsuguma Haruhisa , Funai Kazuhito , Hashimoto Hiroshi , Kawamura Masafumi ,   on behalf of the Metastatic Lung Tumor Study Group of Japan
Published: February 2023

To clarify the clinical impact and to identify prognostic predictors of surgical intervention for pulmonary metastasis from esophageal cancer, a registry database analysis was performed. From January 2000 to March 2020, patients who underwent resection of pulmonary metastases from primary esophageal cancer at 18 institutions were registered in a database developed by the Metastatic Lung Tumor Study Group of Japan. An amount of 109 cases were reviewed and examined for the prognostic factors for pulmonary metastasectomy of metastases from esophageal cancer. As a result, five-year overall survival after pulmonary metastasectomy was 34.4% and five-year disease-free survival was 22.1%. The multivariate analysis for overall survival revealed that initial recurrence site, maximum tumor size, and duration from primary tumor treatment to lung surgery were selected as the significant prognostic factors (p = 0.043, p = 0.048, and p = 0.037, respectively). In addition, from the results of the multivariate analysis for disease free survival, number of lung metastases, initial recurrence site, duration from primary tumor treatment to lung surgery, and preoperative chemotherapy for lung metastasis were selected as the significant prognostic factors (p = 0.037, p = 0.008, p = 0.010, and p = 0.020, respectively). In conclusion, eligible patients with pulmonary metastasis from esophageal cancer selected based on the identified prognostic predictors would be good candidates for pulmonary metastasectomy.
Immune Phenotypic Characterization of a TRAIL-Knockout Mouse
Authors: Stoyanova Ani K. , Sattler Arne , Hahn Elisabeth M. , Hering Nina A. , Arndt Marco , Lauscher Johannes Christian , Speichinger-Hillenberg Fiona , Kotsch Katja , Berg Ann-Kathrin , Beyer Katharina
Published: February 2023

The TNF-superfamily member TRAIL is known to mediate selective apoptosis in tumor cells suggesting this protein as a potential antitumor drug target. However, initial successful pr-clinical results could not be translated into the clinic. Reasons for the ineffectiveness of TRAIL-targeting in tumor therapies could include acquired TRAIL resistance. A tumor cell acquires TRAIL resistance, for example, by upregulation of antiapoptotic proteins. In addition, TRAIL can also influence the immune system and thus, tumor growth. We were able to show in our previous work that TRAIL−/− mice show improved survival in a mouse model of pancreatic carcinoma. Therefore, in this study we aimed to immunologically characterize the TRAIL−/− mice. We observed no significant differences in the distribution of CD3+, CD4+, CD8+ T-cells, Tregs, and central memory CD4+ and CD8+ cells. However, we provide evidence for relevant differences in the distribution of effector memory T-cells and CD8+CD122+ cells but also in dendritic cells. Our findings suggest that T-lymphocytes of TRAIL−/− mice proliferate at a lower rate, and that the administration of recombinant TRAIL significantly increases their proliferation, while regulatory T-cells (Tregs) from TRAIL−/− mice are less suppressive. Regarding the dendritic cells, we found more type-2 conventional dendritic cells (DC2s) in the TRAIL−/− mice. For the first time (to the best of our knowledge), we provide a comprehensive characterization of the immunological landscape of TRAIL-deficient mice. This will establish an experimental basis for future investigations of TRAIL-mediated immunology.
CRP/Albumin Ratio and Glasgow Prognostic Score Provide Prognostic Information in Myelofibrosis Independently of MIPSS70—A Retrospective Study
Authors: Messerich Nora-Medea , Uda Narasimha Rao , Volken Thomas , Cogliatti Sergio , Lehmann Thomas , Holbro Andreas , Benz Rudolf , Graf Lukas , Gupta Vikas , Jochum Wolfram , Demmer Izadora , Rao Tata Nageswara , Silzle Tobias
Published: February 2023

In myelofibrosis, the C-reactive protein (CRP)/albumin ratio (CAR) and the Glasgow Prognostic Score (GPS) add prognostic information independently of the Dynamic International Prognostic Scoring System (DIPSS). Their prognostic impact, if molecular aberrations are considered, is currently unknown. We performed a retrospective chart review of 108 MF patients (prefibrotic MF n = 30; primary MF n = 56; secondary MF n = 22; median follow-up 42 months). In MF, both a CAR > 0.347 and a GPS > 0 were associated with a shorter median overall survival (21 [95% CI 0–62] vs. 80 months [95% CI 57–103], p < 0.001 and 32 [95% CI 1–63] vs. 89 months [95% CI 65–113], p < 0.001). Both parameters retained their prognostic value after inclusion into a bivariate Cox regression model together with the dichotomized Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70: CAR > 0.374 HR 3.53 [95% CI 1.36–9.17], p = 0.0095 and GPS > 0 HR 4.63 [95% CI 1.76–12.1], p = 0.0019. An analysis of serum samples from an independent cohort revealed a correlation of CRP with levels of interleukin-1β and albumin with TNF-α, and demonstrated that CRP was correlated to the variant allele frequency of the driver mutation, but not albumin. Albumin and CRP as parameters readily available in clinical routine at low costs deserve further evaluation as prognostic markers in MF, ideally by analyzing data from prospective and multi-institutional registries. Since both albumin and CRP levels reflect different aspects of MF-associated inflammation and metabolic changes, our study further highlights that combining both parameters seems potentially useful to improve prognostication in MF.
Correction: Wind et al. Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial. Cancers 2022, 14, 1510
Authors: Wind Selinde S. , Jansen Manon A. A. , Rijsbergen Melanie , van Esdonk Michiel J. , Ziagkos Dimitrios , Cheng Wing C. , Niemeyer-van der Kolk Tessa , Korsten John , Gruszka Agnieszka , Schmitz-Rohmer Debora , Bonnel David , Legouffe Raphael , Barré Florian , Bekkenk Marcel W. , de Haas Ellen R. M. , Quint Koen D. , Schnidar Harald , Rolli Melanie , Streefkerk Henk Johan , Burggraaf Jacobus , Vermeer Maarten H. , Rissmann Robert
Published: February 2023

The authors wish to make the following corrections to this paper [...]
Correction: Siódmiak et al. The High ‘Lipolytic Jump’ of Immobilized Amano A Lipase from Aspergillus niger in Developed ‘ESS Catalytic Triangles’ Containing Natural Origin Substrates. Catalysts 2022, 12, 853
Authors: Siódmiak Tomasz , Dulęba Jacek , Kocot Natalia , Wątróbska-Świetlikowska Dorota , Marszałł Michał Piotr
Published: February 2023

The authors wish to make the following corrections to this paper [...]
Thermal and Plasma-Assisted CO2 Methanation over Ru/Zeolite: A Mechanistic Study Using In-Situ Operando FTIR
Authors: Aceto Domenico , Bacariza Maria Carmen , Travert Arnaud , Henriques Carlos , Azzolina-Jury Federico
Published: February 2023

CO2 methanation is an attractive reaction to convert CO2 into a widespread fuel such as methane, being the combination of catalysts and a dielectric barrier discharge (DBD) plasma responsible for synergistic effects on the catalyst’s performances. In this work, a Ru-based zeolite catalyst, 3Ru/CsUSY, was synthesized by incipient wetness impregnation and characterized by TGA, XRD, H2-TPR, N2 sorption and CO2-TPD. Catalysts were tested under thermal and plasma-assisted CO2 methanation conditions using in-situ operando FTIR, with the aim of comparing the mechanism under both types of catalysis. The incorporation of Ru over the CsUSY zeolite used as support induced a decrease of the textural properties and an increase of the basicity and hydrophobicity, while no zeolite structural damage was observed. Under thermal conditions, a maximum CO2 conversion of 72% and CH4 selectivity above 95% were registered. These promising results were ascribed to the presence of small Ru0 nanoparticles over the support (16 nm), catalyst surface hydrophobicity and the presence of medium-strength basic sites in the catalyst. Under plasma-catalytic conditions, barely studied in similar setups in literature, CO2 was found to be excited by the plasma, facilitating its adsorption on the surface of 3Ru/CsUSY in the form of oxidized carbon species such as formates, aldehydes, carbonates, or carbonyls, which are afterwards progressively hydrogenated to methane. Adsorption and surface reaction of key intermediates, namely formate and aldehydic groups, was observed even on the support alone, an occurrence not reported before for thermal catalysis. Overall, similar reaction mechanisms were proposed for both thermal and plasma-catalysis conditions.
Blocking Store-Operated Ca2+ Entry to Protect HL-1 Cardiomyocytes from Epirubicin-Induced Cardiotoxicity
Authors: Liu Xian , Chang Yan , Choi Sangyong , Cai Chuanxi , Zhang Xiaoli , Pan Zui
Published: February 2023

Epirubicin (EPI) is one of the most widely used anthracycline chemotherapy drugs, yet its cardiotoxicity severely limits its clinical application. Altered intracellular Ca2+ homeostasis has been shown to contribute to EPI-induced cell death and hypertrophy in the heart. While store-operated Ca2+ entry (SOCE) has recently been linked with cardiac hypertrophy and heart failure, its role in EPI-induced cardiotoxicity remains unknown. Using a publicly available RNA-seq dataset of human iPSC-derived cardiomyocytes, gene analysis showed that cells treated with 2 µM EPI for 48 h had significantly reduced expression of SOCE machinery genes, e.g., Orai1, Orai3, TRPC3, TRPC4, Stim1, and Stim2. Using HL-1, a cardiomyocyte cell line derived from adult mouse atria, and Fura-2, a ratiometric Ca2+ fluorescent dye, this study confirmed that SOCE was indeed significantly reduced in HL-1 cells treated with EPI for 6 h or longer. However, HL-1 cells presented increased SOCE as well as increased reactive oxygen species (ROS) production at 30 min after EPI treatment. EPI-induced apoptosis was evidenced by disruption of F-actin and increased cleavage of caspase-3 protein. The HL-1 cells that survived to 24 h after EPI treatment demonstrated enlarged cell sizes, up-regulated expression of brain natriuretic peptide (a hypertrophy marker), and increased NFAT4 nuclear translocation. Treatment by BTP2, a known SOCE blocker, decreased the initial EPI-enhanced SOCE, rescued HL-1 cells from EPI-induced apoptosis, and reduced NFAT4 nuclear translocation and hypertrophy. This study suggests that EPI may affect SOCE in two phases: the initial enhancement phase and the following cell compensatory reduction phase. Administration of a SOCE blocker at the initial enhancement phase may protect cardiomyocytes from EPI-induced toxicity and hypertrophy.
Long Non-Coding RNAs of Plants in Response to Abiotic Stresses and Their Regulating Roles in Promoting Environmental Adaption
Authors: Yang Hong , Cui Yuting , Feng Yanrong , Hu Yong , Liu Li , Duan Liu
Published: February 2023

Abiotic stresses triggered by climate change and human activity cause substantial agricultural and environmental problems which hamper plant growth. Plants have evolved sophisticated mechanisms in response to abiotic stresses, such as stress perception, epigenetic modification, and regulation of transcription and translation. Over the past decade, a large body of literature has revealed the various regulatory roles of long non-coding RNAs (lncRNAs) in the plant response to abiotic stresses and their irreplaceable functions in environmental adaptation. LncRNAs are recognized as a class of ncRNAs that are longer than 200 nucleotides, influencing a variety of biological processes. In this review, we mainly focused on the recent progress of plant lncRNAs, outlining their features, evolution, and functions of plant lncRNAs in response to drought, low or high temperature, salt, and heavy metal stress. The approaches to characterize the function of lncRNAs and the mechanisms of how they regulate plant responses to abiotic stresses were further reviewed. Moreover, we discuss the accumulating discoveries regarding the biological functions of lncRNAs on plant stress memory as well. The present review provides updated information and directions for us to characterize the potential functions of lncRNAs in abiotic stresses in the future.
Current State and Future Directions in the Diagnosis of Amyotrophic Lateral Sclerosis
Authors: Vidovic Maximilian , Müschen Lars Hendrik , Brakemeier Svenja , Machetanz Gerrit , Naumann Marcel , Castro-Gomez Sergio
Published: February 2023

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease.
A Novel Technique of Amniotic Membrane Preparation Mimicking Limbal Epithelial Crypts Enhances the Number of Progenitor Cells upon Expansion
Authors: Bisevac Jovana , Moe Morten Carstens , Drolsum Liv , Kristianslund Olav , Petrovski Goran , Noer Agate
Published: February 2023

We aimed to investigate whether a novel technique of human amniotic membrane (HAM) preparation that mimics the crypts in the limbus enhances the number of progenitor cells cultured ex vivo. The HAMs were sutured on polyester membrane (1) standardly, to obtain a flat HAM surface, or (2) loosely, achieving the radial folding to mimic crypts in the limbus. Immunohistochemistry was used to demonstrate a higher number of cells positive for progenitor markers p63α (37.56 ± 3.34% vs. 62.53 ± 3.32%, p = 0.01) and SOX9 (35.53 ± 0.96% vs. 43.23 ± 2.32%, p = 0.04), proliferation marker Ki-67 (8.43 ± 0.38 % vs. 22.38 ± 1.95 %, p = 0.002) in the crypt-like HAMs vs. flat HAMs, while no difference was found for the quiescence marker CEBPD (22.99 ± 2.96% vs. 30.49 ± 3.33 %, p = 0.17). Most of the cells stained negative for the corneal epithelial differentiation marker KRT3/12, and some were positive for N-cadherin in the crypt-like structures, but there was no difference in staining for E-cadherin and CX43 in crypt-like HAMs vs. flat HAMs. This novel HAM preparation method enhanced the number of progenitor cells expanded in the crypt-like HAM compared to cultures on the conventional flat HAM.