bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Profiling Reveals HPV Integration Pattern and Activated Carcinogenic Pathways in Penile Squamous Cell Carcinoma
Authors: Huang Kang-Bo , Guo Sheng-Jie , Li Yong-Hong , Zhang Xin-Ke , Chen Dong , Spiess Philippe E. , Li Zai-Shang , Deng Chuang-Zhong , Chen Jie-Ping , Zhou Qiang-Hua , Hu Zheng , Ma Xin , Jin Jie-Tian , Cao Yun , Luo Jun-Hang , Wang Xiao-Bin , Zhou Fang-Jian , Liu Ran-Yi , Han Hui
Published: December 2021

Human papillomavirus (HPV) is a significant etiologic driver of penile squamous cell carcinoma (PSCC). The integration pattern of HPV and its carcinogenic mechanism in PSCC remain largely unclear. We retrospectively reviewed 108 PSCC cases who received surgery between 2008 and 2017. Using high-throughput viral integration detection, we identified 35 HPV-integrated PSCCs. Unlike cervical cancer, the HPV E2 oncogene was not prone to involvement in integration. Eleven of the 35 (31.4%) HPV-integrated PSCCs harbored intact HPV E2; these tumors had lower HPV E6 and E7 expression and higher expression of p53 and pRb proteins than those with disrupted E2 did (p < 0.001 and p = 0.024). Integration breakpoints are preferentially distributed in or near host genes, including previously reported hotspots (KLF5, etc.) and newly identified hotspots (CADM2, etc.), which are mainly involved in oncogenic signaling pathways (MAPK, JAK/STAT, etc.). Regarding the phosphorylation levels of JNK, p38 was higher in HPV-positive tumors with MAPK-associated integration than those in HPV-positive tumors with other integration and those in HPV-negative tumors. In vitro, KLF5 knockdown inhibited proliferation and invasion of PSCC cells, while silencing CADM2 promoted migration and invasion. In conclusion, this study enhances our understanding of HPV-induced carcinogenesis in PSCC, which may not only rely on the E6/E7 oncogenes, but mat also affect the expression of critical genes and thus activate oncogenic pathways.
Deep Proteomic Analysis on Biobanked Paraffine-Archived Melanoma with Prognostic/Predictive Biomarker Read-Out
Authors: Szadai Leticia , Velasquez Erika , Szeitz Beáta , Almeida Natália Pinto de , Domont Gilberto , Betancourt Lazaro Hiram , Gil Jeovanis , Marko-Varga Matilda , Oskolas Henriett , Jánosi Ágnes Judit , Boyano-Adánez Maria del Carmen , Kemény Lajos , Baldetorp Bo , Malm Johan , Horvatovich Peter , Szász A. Marcell , Németh István Balázs , Marko-Varga György
Published: December 2021

The discovery of novel protein biomarkers in melanoma is crucial. Our introduction of formalin-fixed paraffin-embedded (FFPE) tumor protocol provides new opportunities to understand the progression of melanoma and open the possibility to screen thousands of FFPE samples deposited in tumor biobanks and available at hospital pathology departments. In our retrospective biobank pilot study, 90 FFPE samples from 77 patients were processed. Protein quantitation was performed by high-resolution mass spectrometry and validated by histopathologic analysis. The global protein expression formed six sample clusters. Proteins such as TRAF6 and ARMC10 were upregulated in clusters with enrichment for shorter survival, and proteins such as AIFI1 were upregulated in clusters with enrichment for longer survival. The cohort’s heterogeneity was addressed by comparing primary and metastasis samples, as well comparing clinical stages. Within immunotherapy and targeted therapy subgroups, the upregulation of the VEGFA-VEGFR2 pathway, RNA splicing, increased activity of immune cells, extracellular matrix, and metabolic pathways were positively associated with patient outcome. To summarize, we were able to (i) link global protein expression profiles to survival, and they proved to be an independent prognostic indicator, as well as (ii) identify proteins that are potential predictors of a patient’s response to immunotherapy and targeted therapy, suggesting new opportunities for precision medicine developments.
Gastrin-Releasing Peptide Receptor Antagonist [68Ga]RM2 PET/CT for Staging of Pre-Treated, Metastasized Breast Cancer
Authors: Michalski Kerstin , Kemna Lars , Asberger Jasmin , Grosu Anca L. , Meyer Philipp T. , Ruf Juri , Sprave Tanja
Published: December 2021

Background: Positron emission tomography (PET)/computed tomography (CT) using the gastrin-releasing peptide receptor antagonist [68Ga]RM2 has shown to be a promising imaging method for primary breast cancer (BC) with positive estrogen receptor (ER) status. This study assessed tumor visualization by [68Ga]RM2 PET/CT in patients with pre-treated ER-positive BC and suspected metastases. Methods: This retrospective pilot study included eight female patients with initial ER-positive, pre-treated BC who underwent [68Ga]RM2 PET/CT. Most of these patients (seven out of eight; 88%) were still being treated with or had received endocrine therapy. [68Ga]RM2 PET/CTs were visually analyzed by two nuclear medicine specialists in consensus. Tumor manifestations were rated qualitatively (i.e., RM2-positive or RM2-negative) and quantitatively using the maximum standardized uptake value (SUVmax). SUVmax values were compared between the two subgroups (RM2-positive vs. RM2-negative). Results: Strong RM2 binding was found in all metastatic lesions of six patients (75%), whereas tracer uptake in all metastases of two patients (25%) was rated negative. Mean SUVmax of RM2-positive metastases with the highest SUVmax per patient (in lymph node and bone metastases; 15.8 ± 15.1 range: 3.7–47.8) was higher than mean SUVmax of the RM2-negative metastases with the highest SUVmax per patient (in bone metastases; 1.6 ± 0.1, range 1.5–1.7). Conclusions: Our data suggest that RM2 binding is maintained in the majority of patients with advanced disease stage of pre-treated ER-positive BC. Thus, [68Ga]RM2 PET/CT could support treatment decision in these patients, radiotherapy planning in oligometastatic patients or selection of patients for RM2 radioligand therapy. Further studies with larger patient cohorts are warranted to confirm these findings.
A Comprehensive Survey on Deep-Learning-Based Breast Cancer Diagnosis
Authors: Mridha Muhammad Firoz , Hamid Md. Abdul , Monowar Muhammad Mostafa , Keya Ashfia Jannat , Ohi Abu Quwsar , Islam Md. Rashedul , Kim Jong-Myon
Published: December 2021

Breast cancer is now the most frequently diagnosed cancer in women, and its percentage is gradually increasing. Optimistically, there is a good chance of recovery from breast cancer if identified and treated at an early stage. Therefore, several researchers have established deep-learning-based automated methods for their efficiency and accuracy in predicting the growth of cancer cells utilizing medical imaging modalities. As of yet, few review studies on breast cancer diagnosis are available that summarize some existing studies. However, these studies were unable to address emerging architectures and modalities in breast cancer diagnosis. This review focuses on the evolving architectures of deep learning for breast cancer detection. In what follows, this survey presents existing deep-learning-based architectures, analyzes the strengths and limitations of the existing studies, examines the used datasets, and reviews image pre-processing techniques. Furthermore, a concrete review of diverse imaging modalities, performance metrics and results, challenges, and research directions for future researchers is presented.
Induction of Apoptosis in Human Pancreatic Cancer Stem Cells by the Endoplasmic Reticulum-Targeted Alkylphospholipid Analog Edelfosine and Potentiation by Autophagy Inhibition
Authors: Gajate Consuelo , Gayet Odile , Fraunhoffer Nicolas A. , Iovanna Juan , Dusetti Nelson , Mollinedo Faustino
Published: December 2021

Pancreatic cancer is one of the most lethal malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio. Pancreatic cancer remains an incurable malignancy, and current therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1 pancreatic cancer cell line as CD44+CD24+EpCAM+ cells. These CSCs form pancreatic cancer spheres or spheroids and develop tumors in SCID mice after subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog edelfosine inhibited CSC pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0/G1 region by means of flow cytometry, indicative of DNA breakdown and apoptosis. This correlated with an increase in caspase-3 activity and PARP breakdown, as a major substrate of caspase-3, following PANC-1 CSC treatment with edelfosine. The antitumor ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation. Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors, chloroquine or bafilomycin A1, enhanced edelfosine-induced apoptosis. Primary cultures from pancreatic cancer patients were sensitive to edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and pancreatic cancer patients are sensitive to edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.
First-Line Pharmacotherapies and Survival among Patients Diagnosed with Non-Resectable NSCLC: A Real-Life Setting Study with Gender Prospective
Authors: Spini Andrea , Gini Rosa , Rosellini Pietro , Singier Allison , Bellan Cristiana , Pascucci Alessandra , Leoncini Lorenzo , Mathieu Clément , Martellucci Ignazio , Furiesi Folco , Giorgi Silvano , Donnini Sandra , Roberto Giuseppe , Ziche Marina , Salvo Francesco
Published: December 2021

(1) Purpose: To describe first-line pharmacotherapy and overall survival in non-resectable non-small cell lung cancer (nrNSCLC) patients by gender. (2) Methods: Incident cases of nrNSCLC recorded between 2009 and 2019 (cohort entry) in the pathology registry of the regional administrative healthcare database of Tuscany were identified. Records of antineoplastic therapies delivered up to 4 months following cohort entry were classified as chemotherapy, target therapies, immunotherapies, and undefined monoclonal antibodies. First-line treatment and survival of patients receiving drug treatment was described. Analyses were stratified according to histology, gender, and cohort entry year. (3) Results: 4393 incident cases of nrNSCLC were included. Women with non-squamous-NSCLC received target-therapy more frequently than men (14.9% vs. 6.5%). Immunotherapy incidence of use varied between 3.8% (2017) and 9.1% (2019). The 2-year survival rate increased over time: for non-squamous-NSCLC, it was 22.3% (2009–2011) and 30.6% (2018–2019), while for squamous-NSCLC, it was 13.5% and 22.5%, respectively. After multivariate analysis, a low reduction in mortality risk in 2018–2019 vs. 2009–2011 was found (non-squamous: HR: 0.95 CI95%: 0.92–0.98; squamous: HR: 0.94 CI95%: 0.90–0.98). Among non-squamous NSCLC, median survival was longer in women than in men (389 vs. 276 days). (4) Conclusion: In light of sex-related biomolecular differences, among non-squamous NSCLC, women received target-therapy more frequently than men. Survival seemed to slightly improve over the study period for both histologies, despite a poor reduction in mortality risk was still observed.
Impact of Prostate Size on the Outcomes of Radical Prostatectomy: A Systematic Review and Meta-Analysis
Authors: Fahmy Omar , Alhakamy Nabil A. , Ahmed Osama A. A. , Khairul-Asri Mohd Ghani
Published: December 2021

Background: The impact of prostate size on the radical prostatectomy outcome is not clear. Several published reports have shown conflicting results. Objectives: To investigate the effect of prostate size on the surgical, functional and oncological results of radical prostatectomy. Methods: A systematic review and meta-analysis were carried out in accordance with the PRISMA criteria. Finally, we investigated the research that reported on the impact of prostate size on radical prostatectomy outcome. The Review Manager (RevMan) software version 5.4 was utilized for statistical analysis. Results: Eighteen studies including 12,242 patients were included. Estimated blood loss was significantly less with smaller prostates (Z = 3.01; p = 0.003). The complications rate was 17% with larger prostates, compared to 10% for smaller prostates (Z = 5.73; p < 0.00001). Seventy-three percent of patients with a smaller prostate were continent within one month, compared to 64% with a larger prostate (Z = 1.59; p = 0.11). The rate of positive surgical margins was significantly higher with smaller prostates (20.2% vs. 17.8%). (Z = 2.52; p = 0.01). The incidence of biochemical recurrence was higher with smaller prostates (7.8% vs. 4.9%) (Z = 1.87; p = 0.06). Conclusion: Larger prostate size is associated with more blood loss and a higher rate of complications. However, the oncological outcome is better, compared to that in patients with smaller prostates. The impact of the size on the functional outcome is not clear.
Pretreatment Albumin-to-Alkaline Phosphatase Ratio Is a Prognostic Marker in Lung Cancer Patients: A Registry-Based Study of 7077 Lung Cancer Patients
Authors: Sandfeld-Paulsen Birgitte , Aggerholm-Pedersen Ninna , Winther-Larsen Anne
Published: December 2021

The albumin-to-alkaline phosphatase ratio (AAPR) is a novel promising prognostic marker in cancer patients. However, the evidence for its significance in lung cancer is scarce. Therefore, we assessed the prognostic value of the AAPR in a large cohort of lung cancer patients. Data on lung cancer patients diagnosed from January 2009 to June 2018 were extracted from the Danish Lung Cancer Registry and combined with data on the pretreatment serum AAPR level extracted from the clinical laboratory information system (LABKA). AAPR tertiles were applied as cutoffs. Cox proportional hazard models assessed the prognostic value of the AAPR. In total, 5978 non-small cell lung cancer (NSCLC) patients and 1099 small cell lung cancer (SCLC) patients were included. Decreasing AAPR level was significantly associated with declining median overall survival (OS) in NSCLC patients (medium vs. low AAPR, adjusted HR = 0.73 (95% confidence interval (CI) 0.68–0.79); high vs. low AAPR, adjusted HR = 0.68 (95% CI 0.62–0.73)) and in SCLC patients (medium vs. low AAPR, adjusted HR = 0.62 (95% CI 0.52–0.74); high vs. low, adjusted HR = 0.59 (95% CI 0.50–0.70)). In conclusion, the AAPR was an independent prognostic factor in NSCLC and SCLC patients. The correlation seems to be level dependent, with reducing survival found to be associated with decreasing AAPR level.
Chiral Quaternary Ammoniums Derived from Dehydroabietylamine: Synthesis and Application to Alkynylation of Isatin Derivatives Catalyzed by Silver
Authors: Jiang Guanyu , Sun Xinduo , Zhou Fanrui , Liang Kun , Chen Qian
Published: December 2021

Abietic acid and its derivatives have broadly been used in fine chemicals and are renewable resources. Its inherent chiral rigid tricyclic phenanthrene skeleton is unique. Its utilities in asymmetric catalysis remain to be explored. A series new amide-type chiral quaternary ammoniums bearing dehydroabietylamine were designed, and prepared by two convenient steps. Acylation of dehydroabietylamine with bromoacetyl chloride afforded amide holding bromoacetyl group in higher yields using triethyl amine as base. Subsequent quaternization reaction gave the desired amide-type chiral quaternary ammoniums. The new chiral quaternary ammoniums can be used as phase-transfer catalyst (PTC) for the transition metal-catalysed alkynylation of isatin derivatives.
Cytosine Palladium Complex Supported on Ordered Mesoporous Silica as Highly Efficient and Reusable Nanocatalyst for One-Pot Oxidative Esterification of Aldehydes
Authors: Rajabi Fatemeh , Chia Chin Hua , Sillanpää Mika , Voskressensky Leonid G. , Luque Rafael
Published: December 2021

The synthesis of esters is one of the most fundamental and significant subjects in organic chemistry and chemical industry because they are used in high-value products such as cosmetics, biofuel, pharmaceuticals, surfactants, and food ingredients. In this study, an efficient, economic, sustainable, and green protocol for oxidative esterification reaction has been developed. A one-pot direct transformation of aliphatic, aromatic, and unsaturated aldehydes into esters in the presence of oxygen has been carried out over mesoporous organosilica-supported palladium nanocatalyst (Pd-Cyt@SBA-15) under ambient conditions. Pd-Cyt@SBA-15 efficiently catalyzed selectively large-scale conversion of aldehydes into esters in high yields and large turnover numbers (TON = 98,000). Pd-Cyt@SBA-15 nanocatalyst demonstrated excellent reusability and stability and could be recycled up to ten times without loss of significant reactivity. ICP-AES analysis showed that no leaching of active palladium species occurred during the recycling process of the heterogeneous Pd-Cyt@SBA-15 nanocatalyst.
1H NMR Analysis of the Metathesis Reaction between 1-Hexene and (E)-Anethole Using Grubbs 2nd Generation Catalyst: Effect of Reaction Conditions on (E)-1-(4-Methoxyphenyl)-1-hexene Formation and Decomposition
Authors: Swart Marthinus Rudi , Marais Charlene , Erasmus Elizabeth
Published: December 2021

The metathesis of 1-hexene and (E)-anethole in the presence of Grubbs 2nd generation catalyst was monitored by in situ 1H NMR spectroscopy at different temperatures (15 °C, 25 °C, and 45 °C) and anethole mol fractions (XAnethole ≈ 0.17, 0.29, 0.5, 0.71, 0.83). Time traces confirmed the instantaneous formation of (E)-1-(4-methoxyphenyl)-1-hexene, the cross-metathesis product. A maximum concentration of (E)-1-(4-methoxyphenyl)-1-hexene is reached fairly fast (the time depending on the reaction conditions), and this is followed by a decrease in the concentration of (E)-1-(4-methoxyphenyl)-1-hexene due to secondary metathesis. The maximum concentration of (E)-1-(4-methoxyphenyl)-1-hexene was more dependent on the XAnethole than the temperature. The highest TOF (3.46 min−1) was obtained for the reaction where XAnethole was 0.16 at 45 °C. The highest concentration of the cross-metathesis product was however achieved after 6 min with an anethole mol fraction of 0.84 at 25 °C. A preliminary kinetic study indicated that the secondary metathesis reaction followed first order kinetics.
Performance of Liquid Eversa on Fatty Acid Ethyl Esters Production by Simultaneous Esterification/Transesterification of Low-to-High Acidity Feedstocks
Authors: Vieira Ana Carolina , Cansian Ana Bárbara Moulin , Guimarães José Renato , Vieira Angelica Marquettotti Salcedo , Fernandez-Lafuente Roberto , Tardioli Paulo Waldir
Published: December 2021

Liquid Eversa was evaluated in hydrolysis of acylglycerols from soybean oil deodorizer distillate (SODD), as well as simultaneous esterification/transesterification of SODD with low-to-high free fatty acids (FFAs) content using ethanol as acyl acceptor. Hydrolysis of SODD at mild temperature (37 °C) and without pH control (water:SODD mass ratio of 4:1) increased its FFAs content from 17.2 wt.% to 72.5 wt.% after 48 h reaction. A cold saponification of SODD allowed a saponification phase (SODD-SP) to be recovered with 93 wt.% saponification index and 2.25 wt.% FFAs content, which was used to find the experimental conditions for simultaneous esterification/transesterification reactions by experimental design. Temperature of 35 °C, enzyme concentration of 8.36 wt.%, and molar ratio of 3.64:1 (ethanol:SODD-SP) were found as the best conditions for fatty acid ethyl esters (FAEEs) production from SODD-SP (86.56 wt.% ester yield after 23 h reaction). Under the same reaction conditions, crude SODD (17.2 wt.% FFAs) and hydrolyzed SODD (72.5 wt.% FFAs) yielded products containing around 80 wt.% FAEEs. Caustic treatment could increase the ester content to around 90 wt.% and reduce the FFAs content to less than 1 wt.%. Our results show the good performance of liquid Eversa in aqueous (hydrolysis reactions) and organic (esterification/transesterification reactions) media.
Steps toward Rationalization of the Enantiomeric Excess of the Sakurai–Hosomi–Denmark Allylation Catalyzed by Biisoquinoline N,N’-Dioxides Using Computations
Authors: Morgante Pierpaolo , Deluca Coty , Jones Tegla E. , Aldrich Gregory J. , Takenaka Norito , Peverati Roberto
Published: December 2021

Allylation reactions of aldehydes are chemical transformations of fundamental interest, as they give direct access to chiral homoallylic alcohols. In this work, we focus on the full computational characterization of the catalytic activity of substituted biisoquinoline-N,N’-dioxides for the allylation of 2-naphthaldehyde. We characterized the structure of all transition states as well as identified the π stacking interactions that are responsible for their relative energies. Motivated by disagreement with the experimental results, we also performed an assessment of 34 different density functional methods, with the goal of assessing DFT as a general tool for understanding this chemistry. We found that the DFT results are generally consistent as long as functionals that correctly account for dispersion interactions are used. However, agreement with the experimental results is not always guaranteed. We suggest the need for a careful synergy between computations and experiments to correctly interpret the data and use them as a design tool for new and improved asymmetric catalysts.
Formation and Functioning of Nickel Bis-(acetylacetonate)-Based Multicomponent Catalytic Systems for Di- and Oligomerization of Ethylene: New Mechanistic Aspects
Authors: Titova Yuliya , Schmidt Fedor
Published: December 2021

The paper summarizes new information on the formation and functioning of Ni(acac)2-based multicomponent (Ziegler) systems for oligo- and polymerization of ethylene. It turns out that catalytically active sites formed in these systems are deposited on nickel-containing nanoparticles generated via the interaction of the starting components directly in the reaction system. It is shown that the activity, productivity, and composition of the target products depend on the water content in the initial solvent, all other things being equal. A model of nanosized nickel-containing particles formed during the interaction of Ni(acac)2 and diethylaluminum chloride or ethylaluminum sesquichloride is presented.
Maresin-1 Prevents Liver Fibrosis by Targeting Nrf2 and NF-κB, Reducing Oxidative Stress and Inflammation
Authors: Rodríguez María José , Sabaj Matías , Tolosa Gerardo , Herrera Vielma Francisca , Zúñiga María José , González Daniel R. , Zúñiga-Hernández Jessica
Published: December 2021

Liver fibrosis is a complex process characterized by the excessive accumulation of extracellular matrix (ECM) and an alteration in liver architecture, as a result of most types of chronic liver diseases such as cirrhosis, hepatocellular carcinoma (HCC) and liver failure. Maresin-1 (MaR1) is derivative of ω-3 docosahexaenoic acid (DHA), which has been shown to have pro-resolutive and anti-inflammatory effects. We tested the hypothesis that the application of MaR1 could prevent the development of fibrosis in an animal model of chronic hepatic damage. Sprague-Dawley rats were induced with liver fibrosis by injections of diethylnitrosamine (DEN) and treated with or without MaR1 for four weeks. In the MaR1-treated animals, levels of AST and ALT were normalized in comparison with DEN alone, the hepatic architecture was improved, and inflammation and necrotic areas were reduced. Cell proliferation, assessed by the mitotic activity index and the expression of Ki-67, was increased in the MaR1-treated group. MaR1 attenuated liver fibrosis and oxidative stress was induced by DEN. Plasma levels of the pro-inflammatory mediators TNF-α and IL-1β were reduced in MaR1-treated animals, whereas the levels of IL-10, an anti-inflammatory cytokine, increased. Interestingly, MaR1 inhibited the translocation of the p65 subunit of NF-κB, while increasing the activation of Nrf2, a key regulator of the antioxidant response. Finally, MaR1 treatment reduced the levels of the pro-fibrotic mediator TGF-β and its receptor, while normalizing the hepatic levels of IGF-1, a proliferative agent. Taken together, these results suggest that MaR1 improves the parameters of DEN-induced liver fibrosis, activating hepatocyte proliferation and decreasing oxidative stress and inflammation. These results open the possibility of MaR1 as a potential therapeutic agent in fibrosis and other liver pathologies.
Biomarkers of Central Nervous System Involvement from Epithelial Ovarian Cancer
Authors: Scotto Giulia , Borella Fulvio , Turinetto Margherita , Tuninetti Valentina , Valsecchi Anna , Giannone Gaia , Cosma Stefano , Benedetto Chiara , Valabrega Giorgio
Published: December 2021

Epithelial ovarian cancer (EOC) is the leading cause of death among women affected by gynaecological malignancies. Most patients show advanced disease at diagnosis (FIGO stage III-IV) and, despite the introduction of new therapeutic options, most women experience relapses. In most cases, recurrence is abdominal-pelvic; however, EOC can occasionally metastasize to distant organs, including the central nervous system. The incidence of brain metastases (BMs) from EOC is low, but it has grown over time; currently, there are no follow-up strategies available. In the last decade, a few biomarkers able to predict the risk of developing BMs from OC or as potential therapeutic targets have been investigated by several authors; to date, none have entered clinical practice. The purpose of this review is to offer a summary on the role of the most relevant predictors of central nervous system (CNS) involvement (hormone receptors; BRCA; MRD1; PD-1/PD-L1) and to highlight possible therapeutic strategies for the management of metastatic brain disease in EOC
Nestin-Expressing Cells in the Lung: The Bad and the Good Parts
Authors: Jaramillo-Rangel Gilberto , Chávez-Briones María-de-Lourdes , Ancer-Arellano Adriana , Ortega-Martínez Marta
Published: December 2021

Nestin is a member of the intermediate filament family, which is expressed in a variety of stem or progenitor cells as well as in several types of malignancies. Nestin might be involved in tissue homeostasis or repair, but its expression has also been associated with processes that lead to a poor prognosis in various types of cancer. In this article, we review the literature related to the effect of nestin expression in the lung. According to most of the reports in the literature, nestin expression in lung cancer leads to an aggressive phenotype and resistance to chemotherapy as well as radiation treatments due to the upregulation of phenomena such as cell proliferation, angiogenesis, and metastasis. Furthermore, nestin may be involved in the pathogenesis of some non-cancer-related lung diseases. On the other hand, evidence also indicates that nestin-positive cells may have a role in lung homeostasis and be capable of generating various types of lung tissues. More research is necessary to establish the true value of nestin expression as a prognostic factor and therapeutic target in lung cancer in addition to its usefulness in therapeutic approaches for pulmonary diseases.
The Fusion Protein rFlaA:Betv1 Modulates DC Responses by a p38-MAPK and COX2-Dependent Secretion of PGE2 from Epithelial Cells
Authors: Lin Yen-Ju , Flaczyk Adam , Wolfheimer Sonja , Goretzki Alexandra , Jamin Annette , Wangorsch Andrea , Vieths Stefan , Scheurer Stephan , Schülke Stefan
Published: December 2021

Developing new adjuvants/vaccines and better understanding their mode-of-action is an important task. To specifically improve birch pollen allergy treatment, we designed a fusion protein consisting of major birch pollen allergen Betv1 conjugated to the TLR5-ligand flagellin (rFlaA:Betv1). This study investigates the immune-modulatory effects of rFlaA:Betv1 on airway epithelial cells. LA-4 mouse lung epithelial cells were stimulated with rFlaA:Betv1 in the presence/absence of various inhibitors with cytokine- and chemokine secretion quantified by ELISA and activation of intracellular signaling cascades demonstrated by Western blot (WB). Either LA-4 cells or LA-4-derived supernatants were co-cultured with BALB/c bone marrow-derived myeloid dendritic cells (mDCs). Compared to equimolar amounts of flagellin and Betv1 provided as a mixture, rFlaA:Betv1 induced higher secretion of IL-6 and the chemokines CCL2 and CCL20 from LA-4 cells and a pronounced MAPK- and NFκB-activation. Mechanistically, rFlaA:Betv1 was taken up more strongly and the induced cytokine production was inhibited by NFκB-inhibitors, while ERK- and p38-MAPK-inhibitors only suppressed IL-6 and CCL2 secretion. In co-cultures of LA-4 cells with mDCs, rFlaA:Betv1-stimulated LA-4 cells p38-MAPK- and COX2-dependently secreted PGE2, which modulated DC responses by suppressing pro-inflammatory IL-12 and TNF-α secretion. Taken together, these results contribute to our understanding of the mechanisms underlying the strong immune-modulatory effects of flagellin-containing fusion proteins.
Central Suppression of the GH/IGF Axis and Abrogation of Exercise-Related mTORC1/2 Activation in the Muscle of Phenotype-Selected Male Marathon Mice (DUhTP)
Authors: Brenmoehl Julia , Walz Christina , Caffier Caroline , Brosig Elli , Walz Michael , Ohde Daniela , Trakooljul Nares , Langhammer Martina , Ponsuksili Siriluck , Wimmers Klaus , Zettl Uwe K. , Hoeflich Andreas
Published: December 2021

The somatotropic axis is required for a number of biological processes, including growth, metabolism, and aging. Due to its central effects on growth and metabolism and with respect to its positive effects on muscle mass, regulation of the GH/IGF-system during endurance exercise is of particular interest. In order to study the control of gene expression and adaptation related to physical performance, we used a non-inbred mouse model, phenotype-selected for high running performance (DUhTP). Gene expression of the GH/IGF-system and related signaling cascades were studied in the pituitary gland and muscle of sedentary males of marathon and unselected control mice. In addition, the effects of three weeks of endurance exercise were assessed in both genetic groups. In pituitary glands from DUhTP mice, reduced expression of Pou1f1 (p = 0.002) was accompanied by non-significant reductions of Gh mRNA (p = 0.066). In addition, mRNA expression of Ghsr and Sstr2 were significantly reduced in the pituitary glands from DUhTP mice (p ≤ 0.05). Central downregulation of Pou1f1 expression was accompanied by reduced serum concentrations of IGF1 and coordinated downregulation of multiple GH/IGF-signaling compounds in muscle (e.g., Ghr, Igf1, Igf1r, Igf2r, Irs1, Irs2, Akt3, Gskb, Pik3ca/b/a2, Pten, Rictor, Rptor, Tsc1, Mtor; p ≤ 0.05). In response to exercise, the expression of Igfbp3, Igfbp 4, and Igfbp 6 and Stc2 mRNA was increased in the muscle of DUhTP mice (p ≤ 0.05). Training-induced specific activation of AKT, S6K, and p38 MAPK was found in muscles from control mice but not in DUhTP mice (p ≤ 0.05), indicating a lack of mTORC1 and mTORC2 activation in marathon mice in response to physical exercise. While hormone-dependent mTORC1 and mTORC2 pathways in marathon mice were repressed, robust increases of Ragulator complex compounds (p ≤ 0.001) and elevated sirtuin 2 to 6 mRNA expression were observed in the DUhTP marathon mouse model (p ≤ 0.05). Activation of AMPK was not observed under the experimental conditions of the present study. Our results describe coordinated downregulation of the somatotropic pathway in long-term selected marathon mice (DUhTP), possibly via the pituitary gland and muscle interaction. Our results, for the first time, demonstrate that GH/IGF effects are repressed in a context of superior running performance in mice.
High-Throughput Functional Analysis of CFTR and Other Apically Localized Proteins in iPSC-Derived Human Intestinal Organoids
Authors: Xia Sunny , Bozóky Zoltán , Di Paola Michelle , Laselva Onofrio , Ahmadi Saumel , Jiang Jia Xin , Pitstick Amy L. , Jiang Chong , Rotin Daniela , Mayhew Christopher N. , Jones Nicola L. , Bear Christine E.
Published: December 2021

Induced Pluripotent Stem Cells (iPSCs) can be differentiated into epithelial organoids that recapitulate the relevant context for CFTR and enable testing of therapies targeting Cystic Fibrosis (CF)-causing mutant proteins. However, to date, CF-iPSC-derived organoids have only been used to study pharmacological modulation of mutant CFTR channel activity and not the activity of other disease-relevant membrane protein constituents. In the current work, we describe a high-throughput, fluorescence-based assay of CFTR channel activity in iPSC-derived intestinal organoids and describe how this method can be adapted to study other apical membrane proteins. Specifically, we show how this assay can be employed to study CFTR and ENaC channels and an electrogenic acid transporter in the same iPSC-derived intestinal tissue. This phenotypic platform promises to expand CF therapy discovery to include strategies that target multiple determinants of epithelial fluid transport.
Therapeutic Potential of Annexin A1 Modulation in Kidney and Cardiovascular Disorders
Authors: Mozaffari Mahmood S.
Published: December 2021

Renal and cardiovascular disorders are very prevalent and associated with significant morbidity and mortality. Among diverse pathogenic mechanisms, the dysregulation of immune and inflammatory responses plays an essential role in such disorders. Consequently, the discovery of Annexin A1, as a glucocorticoid-inducible anti-inflammatory protein, has fueled investigation of its role in renal and cardiovascular pathologies. Indeed, with respect to the kidney, its role has been examined in diverse renal pathologies, including acute kidney injury, diabetic nephropathy, immune-mediated nephropathy, drug-induced kidney injury, kidney stone formation, and renal cancer. Regarding the cardiovascular system, major areas of investigation include the role of Annexin A1 in vascular abnormalities, atherosclerosis, and myocardial infarction. Thus, this review briefly describes major structural and functional features of Annexin A1 followed by a review of its role in pathologies of the kidney and the cardiovascular system, as well as the therapeutic potential of its modulation for such disorders.
A Novel Boron Lipid to Modify Liposomal Surfaces for Boron Neutron Capture Therapy
Authors: Shirakawa Makoto , Zaboronok Alexander , Nakai Kei , Sato Yuhki , Kayaki Sho , Sakai Tomonori , Tsurubuchi Takao , Yoshida Fumiyo , Nishiyama Takashi , Suzuki Minoru , Tomida Hisao , Matsumura Akira
Published: December 2021

Boron neutron capture therapy (BNCT) is a cancer treatment with clinically demonstrated efficacy using boronophenylalanine (BPA) and sodium mercaptododecaborate (BSH). However, tumor tissue selectivity of BSH and retention of BPA in tumor cells is a constant problem. To ensure boron accumulation and retention in tumor tissues, we designed a novel polyethylene glycol (PEG)-based boron-containing lipid (PBL) and examined the potency of delivery of boron using novel PBL-containing liposomes, facilitated by the enhanced permeability and retention (EPR) effect. PBL was synthesized by the reaction of distearoylphosphoethanolamine and BSH linked by PEG with Michael addition while liposomes modified using PBL were prepared from the mixed lipid at a constant molar ratio. In this manner, novel boron liposomes featuring BSH in the liposomal surfaces, instead of being encapsulated in the inner aqueous phase or incorporated in the lipid bilayer membrane, were prepared. These PBL liposomes also carry additional payload capacity for more boron compounds (or anticancer agents) in their inner aqueous phase. The findings demonstrated that PBL liposomes are promising candidates to effect suitable boron accumulation for BNCT.
Angiotensin-Converting Enzyme 2 (ACE2) As a Novel Biorecognition Element in A Cell-Based Biosensor for the Ultra-Rapid, Ultra-Sensitive Detection of the SARS-CoV-2 S1 Spike Protein Antigen
Authors: Mavrikou Sofia , Tsekouras Vasileios , Hatziagapiou Kyriaki , Tsalidou Asimina , Bakakos Petros , Rovina Nikoletta , Koutsoukou Antonia , Michos Athanasios , Nikola Olti , Koniari Eleni , Papaparaskevas Joseph , Chrousos George P. , Kanaka-Gantenbein Christina , Kintzios Spyridon
Published: December 2021

Antigen screening for the SARS-CoV-2 S1 spike protein is among the most promising tools for the mass monitoring of asymptomatic carriers of the virus, especially in limited resource environments. Herewith, we report on the possible use of the angiotensin-converting enzyme 2 (ACE2), the natural receptor and entry point of the virus, as a biorecognition element for the detection of the S1 antigen combined with an established bioelectric biosensor based on membrane-engineered cells. The working principle of our approach is based on the measurable change of the electric potential of membrane-engineered mammalian cells bearing ACE2 after attachment of the respective viral protein. We demonstrate that sensitive and selective detection of the S1 antigen is feasible in just three min, with a limit of detection of 20 fg/mL. In a preliminary clinical application, positive patient-derived samples were identified with a 87.9% score compared to RT-PCR. No cross-reactivity was observed against a wide range of nucleocapsid protein concentrations. The novel biosensor is embedded in a commercially ready-to-use testing platform, complete with the consumable immobilized cell–electrode interface and a portable read-out device operable through smartphone or tablet. In addition, the possible application of the system for the high throughput screening of potential pharmacological inhibitors of the ACE2 receptor-S1 RBD interaction is discussed.
Carbon Dioxide Sensing with Langmuir–Blodgett Graphene Films
Authors: Andrić Stevan , Sarajlić Milija , Frantlović Miloš , Jokić Ivana , Vasiljević-Radović Dana , Spasenović Marko
Published: December 2021

Graphene has become a material of choice for an increasing number of scientific and industrial applications. It has been used for gas sensing due to its favorable properties, such as a large specific surface area, as well as the sensitivity of its electrical parameters to adsorption processes occurring on its surface. Efforts are ongoing to produce graphene gas sensors by using methods that are compatible with scaling, simple deposition techniques on arbitrary substrates, and ease of use. In this paper, we demonstrate the fabrication of carbon dioxide gas sensors from Langmuir–Blodgett thin films of sulfonated polyaniline-functionalized graphene that was obtained by using electrochemical exfoliation. The sensor was tested within the highly relevant concentration range of 150 to 10,000 ppm and 0% to 100% at room temperature (15 to 35 °C). The results show that the sensor has both high sensitivity to low analyte concentrations and high dynamic range. The sensor response times are approximately 15 s. The fabrication method is simple, scalable, and compatible with arbitrary substrates, which makes it potentially interesting for many practical applications. The sensor is used for real-time carbon dioxide concentration monitoring based on a theoretical model matched to our experimental data. The sensor performance was unchanged over a period of several months.
Changes in Breathing Patterns after Surgery in Severe Laryngomalacia
Authors: Cialente Fabrizio , Meucci Duino , Tropiano Maria Luisa , Salvati Antonio , Torsello Miriam , Savignoni Ferdinando , Landolfo Francesca , Dotta Andrea , Trozzi Marilena
Published: December 2021

Background: Most of the studies regarding the surgical treatment of severe laryngomalacia (LM) have been aimed at describing the efficacy of the treatment in terms of improvement of clinical symptoms or anatomical findings. There are no studies specifically aimed at analyzing the changes in breathing patterns following surgical treatment for severe LM. Objective: To review the breathing pattern changes before and after corrective surgery in infants with severe LM. Study design: A series of retrospective cases at a tertiary referral children’s hospital. Methods: Retrospective chart review of 81 infants who underwent supra-glottoplasty (SGP) for severe laryngomalacia between 2011 and 2020 at Bambino Gesù Children’s Hospital of Rome, Italy. Among the patients, 47 (58%) were male and 34 (42%) were female. Twenty-one patients (26%) had one or more comorbidities condition. The data collected included age, symptoms, a polysomnography/pulse oximetry study, growth rate, the findings from flexible endoscopy, pre- and post-supra-glottoplasty (SGP) pulmonary function tests (PFTs) and, when indicated, 24 h pH-metry. Breathing patterns were studied during restful, normal sleep, using an ultrasonic flow-meter (Exhalyzer, Viasys) which measured: Tidal Volume (Vt), Respiratory Rate (RR), time to peak expiratory flow/expiratory time ratio (tPTEF/Te, an index of the patency of the lower airways) and mean expiratory/mean inspiratory flow ratio (MEF/MIF, an index of the patency of the upper airways) evaluated before surgical procedure (T1) and 3–6 weeks after (T2). Pre- and post-operative mean data were calculated and comparisons made with a Student T-test. Results: The surgical procedure was well tolerated by all infants and no intraoperative or post-operatory long-term complications were noted. In T1, breathing patterns were characterized by low tidal volume and high tPTEF/Te and MEF/MIF ratios, suggesting a severe reduction in the patency of the upper airways in all patients. After surgery (T2), all the previously mentioned variables significantly improved, reaching normal values for the child’s age. Conclusions: Supra-glottoplasty, as already described in several studies, is a safe and efficient procedure to treat severe laryngomalacia during infancy. The improvement in breathing patterns after surgery was reliably confirmed by a lung function test in our study, which showed the diagnostic value of testing respiratory functionality in the laryngomalacia and comparing them to clinical and endoscopic data. Moreover, considering the results obtained, we also propose the use of this available, dependable test to verify its therapeutic effects (post-surgery) and to monitor future respiratory development in these infants. Moreover, we believe that further studies will provide detailed grading guidelines for gravity of the LM, based on these functional lung tests.
Reducing the Burden of Care: Multidisciplinary Management of Late-Manifested Crouzon Syndrome—A Case Report
Authors: Achterrath Sarah , Kruse Teresa , Neuschulz Julia , Graf Isabelle , Zöller Joachim , Braumann Bert
Published: December 2021

The therapy of patients with Crouzon syndrome involves a multidisciplinary team. In most cases, this therapy is extensive, time-consuming, and exhausting for the patient. This case report illustrates a temporally coordinated therapy plan that succeeds in reducing the burden of care. Showing typical extraoral characteristics of Crouzon syndrome, the patient had a frontal and left-sided crossbite, and impaction of the maxillary canines. Multidisciplinary therapy included the extraction of multiple teeth, midface distraction at Le Fort III level, and alignment of the impacted teeth. Before starting, during, and after completion of the treatment, the patient’s oral health-related quality of life was assessed using COHIP-19. The combination of different treatment steps significantly reduced the duration of therapy. The therapy improved not only the patient’s oro- and craniofacial function, but also the patient’s facial appearance in a short treatment period. The patient’s quality of life improved considerably during this time. In the treatment of severe craniofacial anomalies, the highest priority should be given to keeping the burden of care low. All measures should encourage young patients’ appropriate psychosocial development despite extensive therapies, ensuring at the same time medically satisfactory treatment results.
Psychometric Properties of the Strengths and Difficulties Questionnaire-Dysregulation Profile in Italian Early Adolescents
Authors: Levantini Valentina , Cei Eleonora , Pirri Gennarina , Muratori Pietro
Published: December 2021

Emotional dysregulation is of great cause for concern because it is associated with severe outcomes. Currently, the identification of youths with signs of emotional and behavioral dysregulation is obtained through the assessment of a Dysregulation Profile (DP), including the Strengths and Difficulties Questionnaire-DP (SDQ-DP). Despite its increasingly frequent use in research, studies exploring the SDQ-DP properties are still limited, and no study with Italian samples is currently available. The current study aimed to explore the psychometric properties of the SDQ-DP parent-report and its association with difficulties in the school context in a sample of 332 Italian early adolescents. Results showed that the SDQ-DP parent-report is a single-factor measure with good internal consistency. Also, in both males and females, the SDQ-DP parent-report was associated with higher teacher-reported Internalizing (e.g., anxious symptoms) and Externalizing Problems (e.g., hyperactivity, conduct problems) and lower Prosocial Behavior. This study added further evidence about the utility of the SDQ-DP in the assessment, prevention, and treatment of emotional dysregulation.
Health-Related Quality of Life Assessed in Children with Chronic Rhinitis and Sinusitis
Authors: Chmielik Lechosław Paweł , Mielnik-Niedzielska Grażyna , Kasprzyk Anna , Stankiewicz Tomasz , Niedzielski Artur
Published: December 2021

Introduction: Quality of life (QoL) can be simply defined as an area of human life that directly affects people which they consider to be important. This can be defined in greater detail as ‘an individual perception of an individual’s life position within a cultural context, value system and in relation to their tasks, expectations and standards determined by environmental conditions’. The health-related quality of life (HRQoL) more specifically focuses on how the QoL affects health (including both medical and non-medical issues). Limitations in well-being will, by association, also occur in those children suffering with sinus diseases. Study aim: To compare the quality of life in children–adolescents suffering from some of the most commonly occurring childhood diseases of chronic rhinitis and sinusitis on a group of healthy children–adolescents. Test materials and methods: Subjects were children–adolescents with at least one of the aforementioned conditions afflicting the upper respiratory tract. Admission criteria were: ages 5 to 18 years in the presence of a chronic disease such as chronic rhinitis and paranasal sinusitis. The Child Health Questionnaire-Parent Form 50 CHQ-PF-50 (CHQ-PF50) was used, which is a general-purpose research instrument based on psychometric testing designed for assessing physical and mental well-being in children–adolescents aged 5 to 18 years. Results: Wellbeing significantly deteriorated in sick children within the following areas: current health status of the child (STAND), physical fitness (PF), social functioning resulting from behaviour or emotional state (REB), the impact of physical health on limitations in social functioning (RP), pain and discomfort (BP), behaviour (BE), mental health (MH), self-esteem (SE), general health perception (GH), influence of the child’s health condition on parental emotions (PE), limitations on parental leisure time due to the child’s health (PT) and restrictions on joint family activities (FA). Conclusions: The greatest impairment to well-being in children with chronic rhinitis and paranasal sinusitis was on the impact of the child’s health status on parents’ emotions, pain and discomfort and general perception of health. This study confirms that parents of healthy children attach great importance to their health and health-related quality of life.