bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline Eosinophil Count as a Potential Clinical Biomarker for Clinical Complexity in EGPA: A Real-Life Experience
Authors: Matucci Andrea , Vivarelli Emanuele , Perlato Margherita , Mecheri Valentina , Accinno Matteo , Cosmi Lorenzo , Parronchi Paola , Rossi Oliviero , Vultaggio Alessandra
Published: October 2022

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a small-vessel necrotizing vasculitis with multiple organ involvement. Despite improvements in clinical management, biomarkers for organ involvement and disease prognosis are still an unmet need. Methods: EGPA patients referred to our immunology clinic were retrospectively reviewed. Demographic/clinical features, eosinophils, ANCA status, eosinophil cationic protein (ECP) and total serum IgE were evaluated at the baseline. Eosinophils, total serum IgE, ECP and ANCA were studied as possible biomarkers for lung and extrapulmonary disease. Results: In total, 167 EGPA patients were recruited for our study. A positive association between eosinophils and peripheral nervous system (PNS) involvement was demonstrated (p <0.001; chi-squared test). Receiver operating characteristic (ROC) curves using the eosinophil count or percentage as predictors of PNS involvement yielded AUC values of 0.75 and 0.67, respectively. ANCA positivity was associated with PNS involvement, while no correlations with clinical parameters were found for ECP and total serum IgE. Patients without extrapulmonary involvement had lower eosinophils (eosinophils: 2844.7 ± 1698 vs. 6373 ± 5468, p < 0.001; eosinophil percentage: 24.6 ± 10% vs. 36.2 ± 15.8, p < 0.001) and were less likely to be ANCA+ (p < 0.001, chi-squared test). Conclusion: Eosinophils in EGPA are an important biomarker and are associated with extrapulmonary involvement. These findings could strengthen the role of anti-eosinophilic drugs in improving extrapulmonary disease.
Probing Subcellular Iron Availability with Genetically Encoded Nitric Oxide Biosensors
Authors: Sevimli Gulsah , Alston Amy , Funk Felix , Flühmann Beat , Malli Roland , Graier Wolfgang , Eroglu Emrah
Published: October 2022

Cellular iron supply is required for various biochemical processes. Measuring bioavailable iron in cells aids in obtaining a better understanding of its biochemical activities but is technically challenging. Existing techniques have several constraints that make precise localization difficult, and the lack of a functional readout makes it unclear whether the tested labile iron is available for metalloproteins. Here, we use geNOps; a ferrous iron-dependent genetically encoded fluorescent nitric oxide (NO) biosensor, to measure available iron in cellular locales. We exploited the nitrosylation-dependent fluorescence quenching of geNOps as a direct readout for cellular iron absorption, distribution, and availability. Our findings show that, in addition to ferrous iron salts, the complex of iron (III) with N,N’-bis (2-hydroxybenzyl)ethylenediamine-N,N’-diacetic acid (HBED) can activate the iron (II)-dependent NO probe within intact cells. Cell treatment for only 20 min with iron sucrose was also sufficient to activate the biosensor in the cytosol and mitochondria significantly; however, ferric carboxymaltose failed to functionalize the probe, even after 2 h of cell treatment. Our findings show that the geNOps approach detects available iron (II) in cultured cells and can be applied to assay functional iron (II) at the (sub)cellular level.
Sex and Sexuality in Autism Spectrum Disorders: A Scoping Review on a Neglected but Fundamental Issue
Authors: Maggio Maria Grazia , Calatozzo Patrizia , Cerasa Antonio , Pioggia Giovanni , Quartarone Angelo , Calabrò Rocco Salvatore
Published: October 2022

ASD consists of a set of permanent neurodevelopmental conditions, which are studded with social and communication differences, limited interests, and repetitive behaviors. Individuals with ASD have difficulty reading eye gestures and expressions, and may also have stereotyped or repetitive language, excessive adherence to routines, fixed interests, and rigid thinking. However, sexuality in adolescents and young adults with ASD is still a poorly studied and neglected issue. This review aims to evaluate sexual function and behavior in individuals with ASD to foster a greater understanding of this important, although often overlooked, issue. This review was conducted by searching peer-reviewed articles published between 01 June 2000 and 31 May 2022 using the following databases: PubMed, Embase, Cochrane Database, and Web of Science. A comprehensive search was conducted using the terms: “Autism” OR “ASD” AND “Sexuality” OR “Romantic relation” OR “sexual behavior” AND/OR “sexual awareness”. After an accurate revision of 214 full manuscripts, 11 articles satisfied the inclusion/exclusion criteria. This review found that, although individuals with ASD may have sexual functioning, their sexuality is characterized by higher prevalence rates of gender dysphoria and inappropriate sexual behavior. Furthermore, sexual awareness is reduced in this patient population, and the prevalence of other variants of sexual orientation (i.e., homosexuality, asexuality, bisexuality, etc.) is higher in adolescents with ASD than in non-autistic peers. Sexual health and education should be included in the care path of patients with ASD in order to improve their quality of life and avoid/reduce inappropriate and risky behaviors.
Sustainable Construction through Resource Planning Systems Incorporation into Building Information Modelling
Authors: Junussova Tokzhan , Nadeem Abid , Kim Jong R. , Azhar Salman , Khalfan Malik , Kashyap Mukesh
Published: October 2022

The latest industrial revolution 4 enabled significant performance improvement through technological advancements. Simultaneously, the industry is setting high-level expectations for changing business practices toward long-term benefits in all three sustainability dimensions. The concept of sustainability embraces all production and operation processes in the Architecture, Engineering, and Construction (AEC) industry. This study systematically explores the literature on sustainability with Enterprise Resource Planning (ERP) and Building Information Modelling (BIM) technologies in the AEC industry and the sustainability vision for their integration. The different types of ERP and BIM implementations have similarities in addressing the broad scope of functionalities. The emergence and proliferation of ERP and BIM have brought crucial changes to the business environment. Further evolution to cloud-based operations is transforming companies from technology-oriented practices to data-centric decision-making smart infrastructures. The narrative literature review investigates the sustainability insights and ideas in ERP and BIM solutions, presenting state of the art on systems integration topics. The relevant literature was retrieved to achieve the research objectives which were qualitatively analyzed to generate the basis for further research.
Exploring the Renovation Status and Flexible Strategies of Urban Housing in China Based on Two Surveys of Residents and Architects
Authors: Huang Jie , Zhou Jingmin , Gao Song , Liu Xiao
Published: October 2022

Housing renovations have become an important part of the construction of living environments in China, and improving residential flexibility is an important way to facilitate renovations. This study focused on the adjustments of interior space and living function from the perspective of the application of flexible design strategies through two-stage surveys. The renovation contents and needs of 439 residents were statistically analyzed, an evaluation of design strategies was performed by 226 architects, and a correlation analysis was carried out based on the data. The results showed that the distribution of renovations was positively related to the renovation difficulty and could be summarized into four parts, viz., functional arrangement, device and pipeline, furniture and storage, and decorative details, while the willingness to renovate was related to living requirements. Twenty design strategies for improving housing flexibility were evaluated, and a statistical analysis was carried out on the flexibility assessment and adoption willingness provided by architects. In 14 of these strategies, the flexibility assessment affected the architects’ willingness to adopt the design (p < 0.05); however, the adoption willingness was affected by external factors in the other six strategies, such as cost control. In addition, the architects’ adoption willingness score was generally lower than their assessment score for the same strategy; thus, top-level guidance to promote the application of flexible strategies should be strengthened.
Performance of Polyethylene Vapor Barrier Systems in Temperate Climates
Authors: Rasmussen Torben Valdbjørn , Hansen Tessa Kvist , Shashoua Yvonne , Ottosen Lisbeth M. , Pedersen Louise Green , Nielsen Jens Kromann , Steenstrup Frederik R.
Published: October 2022

The performance of nine different vapor barrier systems comprising polyethylene (PE) membranes were assessed. The vapor barrier systems comprised membranes of virgin PE, 100% new PE, regenerated PE and multilayered virgin and regenerated PE. Membranes were joined either with tape suited to the individual system or an adhesive base on butyl rubber. The vapor barrier systems were evaluated and compared using standard laboratory tests. Chemical analytical techniques and physicomechanical tests were used. Mechanical properties were assessed using laboratory tests recommended by the harmonized standard EN 1385. Chemical analyses followed standard laboratory protocols performed with specialized equipment and visual examination. Chemical and mechanical properties were determined before and after exposure to an aging regime comprising 168 days at 70 °C in total. The chemical stability of the plastic present in each membrane was further evaluated after an additional exposure to an aging regime comprising 50 days followed by another 30 days at 70 °C. Additional aging indicated chemical changes in the membrane material with time. However, it was not possible to distinguish between aging properties for membranes containing virgin PE, 100% new PE, regenerated PE or multilayered virgin and regenerated PE.
Investigation of Process Parameters of Phosphogypsum for Preparing Calcium Sulfoaluminate Cement
Authors: Zhang Ping , Zhang Bingxin , Chang Jun , Wang Tong , Zhang Jixin , Li Li
Published: October 2022

Preparing calcium sulfoaluminate cement (CAS) from solid waste phosphogypsum (PG) instead of natural gypsum is an effective way to utilize solid waste. In this paper, CAS clinker was successfully prepared from PG and the mineral content of calcium sulfoaluminate (C4A3S¯) in the sample was above 65%. The effects of raw material ratio, calcination temperature, and time on clinker composition were investigated. The mechanical properties of different samples were tested. The optimum ratio for preparing CAS using PG was 42.23% limestone, 17.43% PG, and 40.34% bauxite. The optimal calcination conditions are a high temperature of 1250 °C for 45 min. The 3-day compressive strengths of the laboratory-prepared CAS were all above 50 MPa. It was found that as the calcination temperature increased, the amount of C4A3S¯ produced gradually increased. Temperatures above 1300 °C resulted in the decomposition of C4A3S¯. The calcination time did not significantly affect the mineral composition of the clinker or the strength of the cement. C4A3S¯ was observed to be rounded and hexagonal platelets with crystal sizes of 1 to 2 μm, a relatively small size that is favorable to the hydration of C4A3S¯, as observed by SEM images. In addition, the high calcination temperature affected the particle morphology of C4A3S¯, changing it from a well-defined polygonal structure to a molten state. The test results provide helpful information for improving PG utilization and applying PG in CAS production.
Experiment and Design Method of Cold-Formed Thin-Walled Steel Double-Lipped Equal-Leg Angle under Axial Compression
Authors: Yao Xingyou , Liu Yafei , Zhang Shile , Guo Yanli , Hu Chengli
Published: October 2022

The cold-formed steel (CFS) double-lipped equal-leg angle is widely used in modular container houses and cold-formed steel buildings. To study the buckling behavior and bearing capacity design method of the cold-formed steel (CFS) double-lipped equal-leg angle under axial compression, 24 CFS double-lipped equal-leg angles with different sections and slenderness ratios the axial compression were conducted. The test results showed that the distortional buckling occurs for specimens with a small width-to-thickness ratio and small slenderness ratio. The buckling interactive with distortional and global flexural buckling was observed for the specimens with small width-to-thickness ratios and large slenderness ratios. The specimens with large width-to-thickness ratios and small slenderness ratios showed interactive buckling with local and distortion buckling. The specimens with large width-to-thickness ratios and large slenderness ratio developed interactive buckling with local, distortional, and global flexural buckling. The finite element model established by ABAQUS software was used to simulate and analyze the test. The buckling modes and the load-carrying capacities analyzed by the finite element model agreed with the test results, which showed that the developed finite element model was feasible to analyze the buckling and bearing capacity of the CFS double-lipped equal-leg angles. The experimental results were compared with those calculated by the direct strength method in the North American standard and the effective width method in the Chinese standard. The comparisons indicated that the calculated results are very conservative with maximum value 36% and 51% for direct strength method and effective width method, respectively. The coefficient of variation was 0.276 and 0.397, respectively. Finally, the modified direct strength method and the modified effective width method were proposed based on the experimental results. The comparison on the ultimate strength between test results and calculated results by using the modified method showed a good agreement. The modified method can be as a proposed desigh method for the ultimate strength of the CFS double-lipped equal-leg angles under axial compression.
A Comparative Study on the Influence of Different Decoration Styles on Subjective Evaluation of Hotel Indoor Environment
Authors: Xu Jian , Li Muchun , Huang Dandan , Wei Yuxin , Zhong Sijia
Published: October 2022

The purpose of this study is to explore the occupants’ subjective evaluation of the indoor environmental quality (IEQ) of hotels with the same physical environment and different decoration styles, and to reveal the influence of different decoration styles on the subjective evaluation of the indoor environmental quality. The study found a hotel with three mainstream styles of modern simple style, British pastoral style, and modern Japanese style, and adopted standard rooms with the same area, pattern, lighting, orientation, and decoration cost. The only variable controlled was the decoration style, and the subjective feelings of customers on the physical environment were investigated. Based on the literature and 604 online comments, the researchers designed a questionnaire and collected 710 effective questionnaires for empirical analysis. The analysis results of KH coder and SPSS software (Chicago, IL, USA) show that ➀ the light environment in the indoor environment (including indoor natural lighting, lighting and other influencing factors) and non-light visual factors (including indoor color matching, plant layout, closeness to nature, decoration texture, space materials, decoration atmosphere and other factors) has the greatest impact on the subjective evaluation of decoration style, especially on the subjective evaluation of modern simple indoor environment. ➁ Light environment, air quality and non-light visual factors play a key role in the subjective evaluation of the indoor environment of the British pastoral-style hotels. ➂ The light environment, thermal environment and non-light visual factors are the most sensitive to the subjective evaluation of the indoor environment of modern Japanese-style hotels. ➃ Thermal environment, light environment, acoustic environment, air quality environment and non-light visual factors have the greatest impact on the subjective evaluation of the hotel indoor environment. Based on the findings, this study puts forward some suggestions to improve the interior environment of the hotel with different decoration styles to improve the quality and attractiveness of the hotel.
Mechanical and Microstructural Properties of Ultra-High Performance Concrete with Lightweight Aggregates
Authors: Alanazi Hani , Elalaoui Oussama , Adamu Musa , Alaswad Saleh O. , Ibrahim Yasser E. , Abadel Aref A. , Al Fuhaid Abdulrahman Fahad
Published: October 2022

Although ultra-high-performance concrete (UHPC) presents superior mechanical properties and durability compared to conventional concrete; its spalling resistance to elevated temperatures is much lower compared to conventional concrete due to the high compactness and absence of capillary pores. This paper investigated the influence of lightweight aggregate (LWA) on the strength properties and microstructure of UHPC to enhance its resistance to elevated temperatures. UHPC specimens prepared with LWA as a partial replacement of silica sand were produced. The study evaluated the compressive and flexural strengths, failure mode, mass loss, and microstructure of the specimens, using SEM. The results showed that the compressive strength of the UHPC specimen was reduced with increasing the content of LWA at ambient temperature, but the compressive strength of the UHPC specimens prepared with LWA improved when exposed to elevated temperatures. The replacement of 10% of the silica sand with LWA led to an increase in the compressive strength from 100 MPa to 110 MPa after exposure to 200 °C; however, the flexural strength decreased from 23.6 MPa to 18.3 MPa. On the contrary, the flexural strength of UHPC increased with the inclusion of LWA at an ambient temperature but reduced with high-temperature exposure. The failure mode of UHPC was not significantly affected by the variation in LWA content and temperature. In addition, the SEM result confirms that LWA is an effective internal curing material for enhancing the microstructure and compressive strength of UHPC
“Intestinal-Type” Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group
Authors: Dellino Miriam , Cicogna Stefania , Falcone Francesca , Mitidieri Marco , Mazzeo Roberta , Pignata Sandro , Mangili Giorgia , Cormio Gennaro
Published: October 2022

Intestinal-type adenocarcinoma (VAIt) represents a sporadic variant of vulvar carcinoma. It appears frequently localized to epithelial glands in the vulvar region, and it probably derives from cloacal remnants persisting in the adult. We performed a systematic review of the limited cases reported in the literature, with the intent to assess the specific peculiarities of this rare neoplasia and to state consistent management recommendations. The principal histological VAIt characteristic is that it resembles mucinous colonic carcinomas. Therefore, immunohistochemical workup, with different tumor markers including CK20, CDX2, and CK7 staining, is needed. To confirm vulvar origin, a thorough diagnostic, and radiological examination is required to rule out other primary malignancies. The gold standard of treatment for VAIt is surgery, with local excision with tumor-free margins. Lymph node staging is an option advised if the tumor size is >2 cm or if lymph node metastases are suspected on imaging. On the other hand, the role of neoadjuvant therapy is still in doubt, but a good response to adjuvant chemotherapy treatments has been described in both advanced and recurrent diseases. Sometimes, VAIt behavior can be unpredictable, with relapses even after many years, so more experiences and longer follow-up periods are needed to elucidate the best therapeutic management and its long-term prognosis.
Trends in Melanoma Phase 3 Clinical Trials since 2010: Is there Hope for Advanced Melanoma Therapies beyond Approved Treatment Mechanisms?
Authors: Kakish Hanna H. , Ahmed Fasih Ali , Elshami Mohamedraed , Loftus Alexander W. , Hoehn Richard S. , Ammori John B. , Ocuin Lee M. , Winter Jordan M. , Bordeaux Jeremy S. , Mangla Ankit , Rothermel Luke D.
Published: October 2022

Background: Several drugs and treatment modalities are under investigation to improve current melanoma therapy options. This review profiles the trends in clinical trial investment in late-stage melanoma, and anticipates what changes are expected in melanoma treatment, with a focus on exploratory drug mechanisms. Methods: We reviewed nine international clinical trial databases for registered, interventional, and phase 3 cutaneous melanoma clinical trials since 2010. Results: 73 trials studied drug therapies in late-stage (stage III and IV) melanoma. Exploratory mechanisms were investigated in 32% (23/73) of the late-stage melanoma drug therapy trials. Most exploratory drug trials include immunotherapy drug mechanisms (15/23 trials). Two exploratory mechanisms showed promise: the anti-LAG3 antibody, relatlimab, and the hapten modified vaccine, MVax. Many (52%) trials of exploratory mechanisms are ongoing including the use of adoptive cell transfer immunotherapies, dendritic cell vaccine therapy, and histone deacetylase (HDAC) inhibitors, among others. Conclusions: Since most clinical trials focus on previously approved drug mechanisms, it is likely that paradigm-changing treatments will involve these therapies being used in new treatment contexts or combinations. Only 2 exploratory drug mechanisms studied since 2010 have achieved promising results in the phase 3 setting, though many other trials are ongoing at this time.
A Novel Strategy to Model Age-Related Cancer for Elucidation of the Role of Th17 Inflammaging in Cancer Progression
Authors: Zhang Qiuyang , Jazwinski S. Michal
Published: October 2022

Cancer is a disease of aging, but most studies on cancer are in young but not aged animal models, and cancer clinical trials are rarely performed in older adults. Recognition of the connections between aging and cancer and improvement of treatment for elderly cancer patients has become one of the most critical medical issues with the global increase in the elderly population. Mouse models are essential experimental tools for understanding the molecular mechanisms of complex processes and related gene pathways of biological aging. However, few mouse models can be used to understand the role of aging in cancer development and the underlying mechanisms. One of the hallmarks of aging is chronic inflammation, often called inflammaging. This is our rationale for examining the role of aging-related inflammation in prostate cancer, a major aging malignancy. We have now developed a novel method to generate age-related cancer models in mice to better understand how age impacts cancer initiation and progression in the natural aging process. We discuss its application to elucidate some of the contributing mechanisms.
A Whole New Comprehension about ncRNA-Encoded Peptides/Proteins in Cancers
Authors: Chen Qinnan , Shen Hongyu , Nie Fengqi , Sun Ming
Published: October 2022

It is generally considered that non-coding RNAs do not encode proteins; however, more recently, studies have shown that lncRNAs and circRNAs have ORFs which are regions that code for peptides/protein. On account of the lack of 5′cap structure, translation of circRNAs is driven by IRESs, m6A modification or through rolling amplification. An increasing body of evidence have revealed different functions and mechanisms of ncRNA-encoded peptides/proteins in cancers, including regulation of signal transduction (Wnt/β-catenin signaling, AKT-related signaling, MAPK signaling and other signaling), cellular metabolism (Glucose metabolism and Lipid metabolism), protein stability, transcriptional regulation, posttranscriptional regulation (regulation of RNA stability, mRNA splicing and translation initiation). In addition, we conclude the existing detection technologies and the potential of clinical applications in cancer therapy.
Luminal and Tumor-Associated Gut Microbiome Features Linked to Precancerous Lesions Malignancy Risk: A Compositional Approach
Authors: Romanov Vladimir A. , Karasev Ivan A. , Klimenko Natalia S. , Koshechkin Stanislav I. , Tyakht Alexander V. , Malikhova Olga A.
Published: October 2022

Colorectal cancer is the third most commonly diagnosed cancer worldwide. Human gut microbiome plays important roles in protecting against it, as well as contributing to its onset and progression. Identification of specific bacterial taxa associated with early stages of colorectal cancer may help develop effective microbiome-based diagnostics. For precancerous lesions, links of their characteristics to luminal and tumor-associated microbiome composition are to be elucidated. Paired stool and tumor brush biopsy samples were collected from 50 patients with precancerous lesions and early forms of colon cancer; their microbial communities were profiled using high-throughput 16S rRNA sequencing. We showed that the microbiome differences between stool and biopsy samples can be to a high extent computationally corrected. Compositionality-aware statistical analysis of microbiome composition revealed its associations with the number of lesions, lesion type, location and malignization pathway. A major determinant of precancerous lesions malignancy risk—the number of lesions—was positively associated with the abundance of H2S-producing taxa. Our results contribute to the basis for developing early non-invasive colorectal cancer diagnostics via identifying microorganisms likely participating in early stages of cancer pathogenesis.
Cellular Plasticity and Heterotypic Interactions during Breast Morphogenesis and Cancer Initiation
Authors: Ingthorsson Saevar , Traustadottir Gunnhildur Asta , Gudjonsson Thorarinn
Published: October 2022

The human breast gland is a unique organ as most of its development occurs postnatally between menarche and menopause, a period ranging from 30 to 40 years. During this period, the monthly menstruation cycle drives the mammary gland through phases of cell proliferation, differentiation, and apoptosis, facilitated via a closely choreographed interaction between the epithelial cells and the surrounding stroma preparing the gland for pregnancy. If pregnancy occurs, maximal differentiation is reached to prepare for lactation. After lactation, the mammary gland involutes to a pre-pregnant state. These cycles of proliferation, differentiation, and involution necessitate the presence of epithelial stem cells that give rise to progenitor cells which differentiate further into the luminal and myoepithelial lineages that constitute the epithelial compartment and are responsible for the branching structure of the gland. Maintaining homeostasis and the stem cell niche depends strongly on signaling between the stem and progenitor cells and the surrounding stroma. Breast cancer is a slowly progressing disease whose initiation can take decades to progress into an invasive form. Accumulating evidence indicates that stem cells and/or progenitor cells at different stages, rather than terminally differentiated cells are the main cells of origin for most breast cancer subgroups. Stem cells and cancer cells share several similarities such as increased survival and cellular plasticity which is reflected in their ability to switch fate by receiving intrinsic and extrinsic signals. In this review, we discuss the concept of cellular plasticity in normal breast morphogenesis and cancer, and how the stromal environment plays a vital role in cancer initiation and progression.
Viral Integration Plays a Minor Role in the Development and Prognostication of Oral Squamous Cell Carcinoma
Authors: Satgunaseelan Laveniya , Strbenac Dario , Tadi Sahithi , Nguyen Kevin , Wykes James , Palme Carsten E. , Low Tsu-Hui (Hubert) , Yang Jean Y. H. , Clark Jonathan R. , Gupta Ruta
Published: October 2022

Viruses are well known drivers of several human malignancies. A causative factor for oral cavity squamous cell carcinoma (OSCC) in patients with limited exposure to traditional risk factors, including tobacco use, is yet to be identified. Our study aimed to comprehensively evaluate the role of viral drivers in OSCC patients with low cumulative exposure to traditional risk factors. Patients under 50 years of age with OSCC, defined using strict anatomic criteria were selected for WGS. The WGS data was interrogated using viral detection tools (Kraken 2 and BLASTN), together examining >700,000 viruses. The findings were further verified using tissue microarrays of OSCC samples using both immunohistochemistry and RNA in situ hybridisation (ISH). 28 patients underwent WGS and comprehensive viral profiling. One 49-year-old male patient with OSCC of the hard palate demonstrated HPV35 integration. 657 cases of OSCC were then evaluated for the presence of HPV integration through immunohistochemistry for p16 and HPV RNA ISH. HPV integration was seen in 8 (1.2%) patients, all middle-aged men with predominant floor of mouth involvement. In summary, a wide-ranging interrogation of >700,000 viruses using OSCC WGS data showed HPV integration in a minority of male OSCC patients and did not carry any prognostic significance.
Inhibition of IκB Kinase Is a Potential Therapeutic Strategy to Circumvent Resistance to Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer Cells
Authors: Yi Yong Weon , You Kyu Sic , Han Sanghee , Ha In Jin , Park Jeong-Soo , Lee Seok-Geun , Seong Yeon-Sun
Published: October 2022

Triple-negative breast cancer (TNBC) remains as an intractable malignancy with limited therapeutic targets. High expression of epidermal growth factor receptor (EGFR) has been associated with a poor prognosis of TNBC; however, EGFR targeting has failed with unfavorable clinical outcomes. Here, we performed a combinatorial screening of fifty-five protein kinase inhibitors with the EGFR inhibitor gefitinib in the TNBC cell line MDA-MB-231 and identified the IκB kinase (IKK) inhibitor IKK16 as a sensitizer of gefitinib. Cell viability and clonogenic survival assays were performed to evaluate the antiproliferative effects of the gefitinib and IKK16 (Gefitinib + IKK16) combination in TNBC cell lines. Western blot analyses were also performed to reveal the potential mode of action of this combination. In addition, next-generation sequencing (NGS) analysis was performed in Gefitinib+IKK16-treated cells. The Gefitinib+IKK16 treatment synergistically reduced cell viability and colony formation of TNBC cell lines such as HS578T, MDA-MB-231, and MDA-MB-468. This combination downregulated p-STAT3, p-AKT, p-mTOR, p-GSK3β, and p-RPS6. In addition, p-NF-κB and the total NF-κB were also regulated by this combination. Furthermore, NGS analysis revealed that NF-κB/RELA targets including CCL2, CXCL8, EDN1, IL-1β, IL-6, and SERPINE1 were further reduced and several potential tumor suppressors, such as FABP3, FADS2, FDFT1, SEMA6A, and PCK2, were synergistically induced by the Gefitinib-+IKK16 treatment. Taken together, we identified the IKK/NF-κB pathway as a potential target in combination of EGFR inhibition for treating TNBC.
Asymmetric Hydroarylation Reactions Catalyzed by Transition Metals: Last 10 Years in a Mini Review
Authors: De Angelis Martina , Iazzetti Antonia , Serraiocco Andrea , Ciogli Alessia
Published: October 2022

Hydroarylation reactions play a pivotal role in organic chemistry due to their versatility and efficiency. In the last 10 years, the scientific production around this reaction has been very high, but in its asymmetric version, the results are less. In this mini review, selected literature examples are considered to draw attention to directions of the asymmetric hydroarylation reaction mediated by transition metal catalysts. The selected works were grouped in two main sections. In the first, we reported examples relating the narrower definition of hydroarylation, namely the metal-catalyzed processes where inactivated aryl moiety undergoes a direct functionalization via insertion of an unsaturated compound. In the second part, hydroarylation reactions take place with the use of pre-activated aryl substrates, usually aryl-iodides or aryl-boronated.
Abundant Oxygen Vacancies Induced by the Mechanochemical Process Boost the Low-Temperature Catalytic Performance of MnO2 in NH3-SCR
Authors: Dong Yuanyuan , Jin Baofang , Liu Shaomian , Gao Jiajian , Wang Kangjun , Su Fabing
Published: October 2022

Manganese oxides (MnOx) have attracted particular attention in the selective catalytic reduction of NOx with NH3 (NH3-SCR) because of their excellent low-temperature activity. Herein, we prepared a highly efficient MnO2 (MnO2-M) catalyst through a facile ball milling-assisted redox strategy. MnO2-M shows a 90% NOx conversion in a wide operating temperature window of 75–200 °C under a gas hourly space velocity of 40,000 h−1, which is much more active than the MnO2 catalyst prepared by the redox method without the ball-milling process. Moreover, MnO2-M exhibits better H2O and SO2 resistance. The enhanced catalytic properties of MnO2-M originated from the high surface area, abundant oxygen vacancies, more acid sites, and higher Mn4+ content induced by the ball-milling process. In situ DRIFTS studies probed the reaction intermediates, and the SCR reaction was deduced to proceed via the typical Eley–Rideal mechanism. This work provides a facile method to enhance the catalytic performance of Mn-based catalysts for low-temperature denitrification and deep insights into the NH3-SCR reaction process.
Synthesis of Novel Key Chromophoric Intermediates via C-C Coupling Reactions
Authors: Nhari Laila M. , Bifari Elham N. , Al-Marhabi Aisha R. , Al-Ghamdi Huda A. , Al-Ghamdi Sameera N. , Al-Zahrani Fatimah A. M. , Al-Footy Khalid O. , El-Shishtawy Reda M.
Published: October 2022

The fundamentals of Pd-catalyzed Csp2−Csp2 Miyaura borylation, Suzuki cross-coupling, and Stille cross-coupling reactions for a variety of borylated precursors based on phenothiazine (PTZ), phenoxazine (POZ), carbazole (Cz), and quinoxaline (QX) units have been explored. Three palladium-based catalysts were chosen for this study: Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2, applying different reaction conditions. Around 16 desired chromophores were successfully designed and synthesized using C-C cross-coupling reactions in moderate to excellent yields, including PTZ, POZ, and Cz units coupled with QX, indolinium iodide, thienyl, phenyl, or triphenylamine moieties. Additionally, PTZ, POZ, and Cz have been employed in synthesizing various pinacol boronate ester derivatives in good to moderate yields. Interestingly, Pd(dppf)Cl2 was found to be the best catalyst for borylation, and C-C cross-coupling reactions occurred in as little as 30 min, with an excellent yield exceeding 98%. Pd(PPh3)4 and Pd(PPh3)2Cl2 catalyzed the reaction to obtain the desired products in moderate to good yields after a long time (20–24 h). On the other hand, the Suzuki-Miyaura cross-coupling between N-(2-methyl)hexyl carbazole pinacol boronate ester derivative 10c and three halogenated quinoxaline derivatives—4-(3-(5-bromothiophen-2-yl)quinoxalin-2-yl)benzaldehyde (27), 4-(5-(3-(5-bromothiophen-2-yl)quinoxalin-2-yl)thiophen-2-yl)benzaldehyde (30), and 4-(3-chloroquinoxalin-2-yl)benzaldehyde (25) catalyzed by Pd(PPh3)4—afforded three carbazole-quinoxaline chromophores (28, 30, and 31, respectively) in 2–3 h, with good to excellent yields reaching 86%. The electron-deficient QX couplers proved to be coupled efficiently using the Stille coupling reaction, which involves the coupling between electron-rich orgaostannane and electron-deficient halide. The synthesized precursors and desired chromophores were characterized by FTIR, 1H-NMR, 13C-NMR, and HRMS.
Acid-Modified Sepiolite-Supported Pt (Noble Metal) Catalysts for HCHO Oxidation at Ambient Temperature
Authors: Zhou Yidi , Min Xin , Wang Lijuan , Zhao Yajing , Yang Bozhi , Wu Xiaoxian , Zhang Dan , Hou Xifeng , Liu Yan’gai , Fang Minghao , Huang Zhaohui
Published: October 2022

The critical need to enhance the quality of indoor air leads to the improvement of catalyst activity for the removal of formaldehyde. Sepiolite can be utilized in catalytic reactions for its unique structure, composition and high surface area. The adhesion between sepiolite fibers and the blocked microporous channel (by impurities) demands the activation of natural sepiolite through acid treatment. This treatment successfully produces acid-modified sepiolite Pt-supported samples. The impacts of different acid concentrations, Pt loading content and calcination temperature on catalytic activity for formaldehyde (HCHO) oxidation are studied. The catalytic activity of HCHO is characterized and evaluated by techniques including specific surface area, X-ray diffraction, Fourier transform infrared spectrum, X-ray photoelectron spectroscopy and transmission electron microscopy. The results show the maximum specific area of sepiolite at the optimized 0.06 M acid concentration. Among all the prepared samples, the 0.02Pt/Sep catalyst calcined at 500 °C exhibits the highest catalytic activity for the oxidation of HCHO.
Inhibition of the Cell Uptake of Delta and Omicron SARS-CoV-2 Pseudoviruses by N-Acetylcysteine Irrespective of the Oxidoreductive Environment
Authors: La Maestra Sebastiano , Garibaldi Silvano , Balansky Roumen , D’Agostini Francesco , Micale Rosanna T. , De Flora Silvio
Published: October 2022

The binding of SARS-CoV-2 spikes to the cell receptor angiotensin-converting enzyme 2 (ACE2) is a crucial target both in the prevention and in the therapy of COVID-19. We explored the involvement of oxidoreductive mechanisms by investigating the effects of oxidants and antioxidants on virus uptake by ACE2-expressing cells of human origin (ACE2-HEK293). The cell uptake of pseudoviruses carrying the envelope of either Delta or Omicron variants of SARS-CoV-2 was evaluated by means of a cytofluorimetric approach. The thiol N-acetyl-L-cysteine (NAC) inhibited the uptake of both variants in a reproducible and dose-dependent fashion. Ascorbic acid showed modest effects. In contrast, neither hydrogen peroxide (H2O2) nor a system-generating reactive oxygen species (ROS), which play an important role in the intracellular alterations produced by SARS-CoV-2, were able to affect the ability of either Delta or Omicron SARS-CoV-2 pseudoviruses to be internalized into ACE2-expressing cells. In addition, neither H2O2 nor the ROS generating system interfered with the ability of NAC to inhibit that mechanism. Moreover, based on previous studies, a preventive pharmacological approach with NAC would have the advantage of decreasing the risk of developing COVID-19, irrespective of its variants, and at the same time other respiratory viral infections and associated comorbidities.
Therapeutic Targeting of NF-κB in Acute Lung Injury: A Double-Edged Sword
Authors: Millar Michelle Warren , Fazal Fabeha , Rahman Arshad
Published: October 2022

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating disease that can be caused by a variety of conditions including pneumonia, sepsis, trauma, and most recently, COVID-19. Although our understanding of the mechanisms of ALI/ARDS pathogenesis and resolution has considerably increased in recent years, the mortality rate remains unacceptably high (~40%), primarily due to the lack of effective therapies for ALI/ARDS. Dysregulated inflammation, as characterized by massive infiltration of polymorphonuclear leukocytes (PMNs) into the airspace and the associated damage of the capillary-alveolar barrier leading to pulmonary edema and hypoxemia, is a major hallmark of ALI/ARDS. Endothelial cells (ECs), the inner lining of blood vessels, are important cellular orchestrators of PMN infiltration in the lung. Nuclear factor-kappa B (NF-κB) plays an essential role in rendering the endothelium permissive for PMN adhesion and transmigration to reach the inflammatory site. Thus, targeting NF-κB in the endothelium provides an attractive approach to mitigate PMN-mediated vascular injury, not only in ALI/ARDS, but in other inflammatory diseases as well in which EC dysfunction is a major pathogenic mechanism. This review discusses the role and regulation of NF-κB in the context of EC inflammation and evaluates the potential and problems of targeting it as a therapy for ALI/ARDS.
NRF2 Regulates Viability, Proliferation, Resistance to Oxidative Stress, and Differentiation of Murine Myoblasts and Muscle Satellite Cells
Authors: Bronisz-Budzyńska Iwona , Kozakowska Magdalena , Pietraszek-Gremplewicz Katarzyna , Madej Magdalena , Józkowicz Alicja , Łoboda Agnieszka , Dulak Józef
Published: October 2022

Increased oxidative stress can slow down the regeneration of skeletal muscle and affect the activity of muscle satellite cells (mSCs). Therefore, we evaluated the role of the NRF2 transcription factor (encoded by the Nfe2l2 gene), the main regulator of the antioxidant response, in muscle cell biology. We used (i) an immortalized murine myoblast cell line (C2C12) with stable overexpression of NRF2 and (ii) primary mSCs isolated from wild-type and Nfe2l2 (transcriptionally)-deficient mice (Nfe2l2tKO). NRF2 promoted myoblast proliferation and viability under oxidative stress conditions and decreased the production of reactive oxygen species. Furthermore, NRF2 overexpression inhibited C2C12 cell differentiation by down-regulating the expression of myogenic regulatory factors (MRFs) and muscle-specific microRNAs. We also showed that NRF2 is indispensable for the viability of mSCs since the lack of its transcriptional activity caused high mortality of cells cultured in vitro under normoxic conditions. Concomitantly, Nfe2l2tKO mSCs grown and differentiated under hypoxic conditions were viable and much more differentiated compared to cells isolated from wild-type mice. Taken together, NRF2 significantly influences the properties of myoblasts and muscle satellite cells. This effect might be modulated by the muscle microenvironment.
Paracrine Senescence of Mesenchymal Stromal Cells Involves Inflammatory Cytokines and the NF-κB Pathway
Authors: Chou Lun-Yin , Ho Chun-Te , Hung Shih-Chieh
Published: October 2022

It has been known that senescence-associated secretory phenotype (SASP) triggers senescence of the surrounding normal cells. However, SASP signaling regarding mesenchymal stromal cell aging remains to be fully elucidated. Therefore, the present study aimed to clarify the molecular mechanism of late (passage) MSC-induced paracrine SASP-mediated senescence of early (passage) MSCs during ex vivo expansion. Here, we conducted an extensive characterization of senescence features in bone-marrow (BM)-derived MSCs from healthy human donors. Late MSCs displayed an enlarged senescent-like morphology, induced SASP-related proinflammatory cytokines (IL-1α and IL-8), and reduced clonogenic capacity and osteogenic differentiation when compared to early MSCs. Of note, paracrine effects of SASP-related IL-1α and IL-8 from late MSCs induced cellular senescence of early MSCs via an NF-κB-dependent manner. Moreover, cellular senescence of early MSCs was promoted by the synergistic action of IL-1α and IL-8. However, inhibition of NF-κB by shRNA transfection or using inhibitors in early MSCs blocked early MSCs cellular senescence caused by paracrine SASP of late MSCs. In conclusion, these findings reveal that late MSCs display features of senescence and that, during ex vivo expansion, SASP-related proinflammatory cytokines contribute to activate a cellular senescence program in early MSCs that may ultimately impair their functionality.
High-Dimensional Cytometry Dissects Immunological Fingerprints of Idiopathic Inflammatory Myopathies
Authors: Nelke Christopher , Pawlitzki Marc , Schroeter Christina B. , Huntemann Niklas , Räuber Saskia , Dobelmann Vera , Preusse Corinna , Roos Andreas , Allenbach Yves , Benveniste Olivier , Wiendl Heinz , Lundberg Ingrid E. , Stenzel Werner , Meuth Sven G. , Ruck Tobias
Published: October 2022

Chronic inflammation of skeletal muscle is the common feature of idiopathic inflammatory myopathies (IIM). Given the rarity of the disease and potential difficulty of routinely obtaining target tissue, i.e., standardized skeletal muscle, our understanding of immune signatures of the IIM spectrum remains incomplete. Further insight into the immune topography of IIM is needed to determine specific treatment targets according to clinical and immunological phenotypes. Thus, we used high-dimensional flow cytometry to investigate the immune phenotypes of anti-synthetase syndrome (ASyS), dermatomyositis (DM) and inclusion-body myositis (IBM) patients as representative entities of the IIM spectrum and compared them to healthy controls. We studied the CD8, CD4 and B cell compartments in the blood aiming to provide a contemporary overview of the immune topography of the IIM spectrum. ASyS was characterized by altered CD4 composition and expanded T follicular helper cells supporting B cell-mediated autoimmunity. For DM, unsupervised clustering identified expansion of distinct B cell subtypes highly expressing immunoglobulin G4 (IgG4) and CD38. Lastly, terminally differentiated, cytotoxic CD8 T cells distinguish IBM from other IIM. Interestingly, these terminally differentiated CD8 T cells highly expressed the integrin CD18 mediating cellular adhesion and infiltration. The distinct immune cell topography of IIM might provide the framework for targeted treatment approaches potentially improving therapeutic outcomes.
Induced Pluripotent Stem Cells, a Stepping Stone to In Vitro Human Models of Hearing Loss
Authors: Durán-Alonso María Beatriz , Petković Hrvoje
Published: October 2022

Hearing loss is the most prevalent sensorineural impairment in humans. Yet despite very active research, no effective therapy other than the cochlear implant has reached the clinic. Main reasons for this failure are the multifactorial nature of the disorder, its heterogeneity, and a late onset that hinders the identification of etiological factors. Another problem is the lack of human samples such that practically all the work has been conducted on animals. Although highly valuable data have been obtained from such models, there is the risk that inter-species differences exist that may compromise the relevance of the gathered data. Human-based models are therefore direly needed. The irruption of human induced pluripotent stem cell technologies in the field of hearing research offers the possibility to generate an array of otic cell models of human origin; these may enable the identification of guiding signalling cues during inner ear development and of the mechanisms that lead from genetic alterations to pathology. These models will also be extremely valuable when conducting ototoxicity analyses and when exploring new avenues towards regeneration in the inner ear. This review summarises some of the work that has already been conducted with these cells and contemplates future possibilities.