bluuebunny/crossref_metadata_2025 huggingface dataset:
Occupational Factors and Socioeconomic Differences in Breast Cancer Risk and Stage at Diagnosis in Swiss Working Women
Authors: Bulliard Jean-Luc , Bovio Nicolas , Arveux Patrick , Bergeron Yvan , Chiolero Arnaud , Fournier Evelyne , Germann Simon , Konzelmann Isabelle , Maspoli Manuela , Rapiti Elisabetta , Canu Irina Guseva
Published: August 2022

Socioeconomic differences in breast cancer (BC) incidence are driven by differences in lifestyle, healthcare use and occupational exposure. Women of high socioeconomic status (SES) have a higher risk of BC, which is diagnosed at an earlier stage, than in low SES women. As the respective effects of occupation and SES remain unclear, we examined the relationships between occupation-related variables and BC incidence and stage when considering SES. Female residents of western Switzerland aged 18–65 years in the 1990 or 2000 census, with known occupation, were linked with records of five cancer registries to identify all primary invasive BC diagnosed between 1990 and 2014 in this region. Standardized incidence ratios (SIRs) were computed by occupation using general female population incidence rates, with correction for multiple comparisons. Associations between occupation factors and BC incidence and stage at diagnosis were analysed by negative binomial and multinomial logistic regression models, respectively. The cohort included 381,873 women-years and 8818 malignant BC, with a mean follow-up of 14.7 years. Compared with reference, three occupational groups predominantly associated with a high socioprofessional status had SIRs > 1: legal professionals (SIR = 1.68, 95%CI: 1.27–2.23), social science workers (SIR = 1.29; 95%CI: 1.12–1.49) and some office workers (SIR = 1.14; 95%CI: 1.09–1.20). Conversely, building caretakers and cleaners had a reduced incidence of BC (SIR = 0.69, 95%CI: 0.59–0.81). Gradients in BC risk with skill and socioprofessional levels persisted when accounting for SES. A higher incidence was generally associated with a higher probability of an early-stage BC. Occupation and SES may both contribute to differences in risk and stage at diagnosis of BC.
Trimodal Therapy in Esophageal Squamous Cell Carcinoma: Role of Adjuvant Therapy Following Neoadjuvant Chemoradiation and Surgery
Authors: Li Xiaokun , Luan Siyuan , Yang Yushang , Zhou Jianfeng , Shang Qixin , Fang Pinhao , Xiao Xin , Zhang Hanlu , Yuan Yong
Published: August 2022

Background: The aim of this study was to determine the role of adjuvant therapy after neoadjuvant chemoradiotherapy and esophagectomy for esophageal squamous cell carcinoma (ESCC). Methods: The study retrospectively reviewed 447 ESCC patients who underwent neoadjuvant chemoradiotherapy and esophagectomy. Patients were divided into an adjuvant therapy group and no adjuvant therapy group. Propensity score matching was used to adjust the confounding factors. Results: 447 patients with clinical positive lymph nodes and no distant metastasis treated with neoadjuvant chemoradiotherapy and esophagectomy were eligible for analysis. After propensity score matching, there were 120 patients remaining in each group. Patients receiving adjuvant therapy had a significantly shorter post-resection overall survival (OS) and disease-free survival (DFS) when compared to patients not receiving adjuvant therapy (log-rank, OS: p = 0.046, DFS: p < 0.001). Receiving adjuvant therapy is not an independently prognostic factor for OS (hazard ratio (HR): 1.270, HR: 0.846–1.906, p = 0.249) but a significantly unfavorable independent prognostic factor for DFS (HR: 2.061, HR: 1.436–2.958, p < 0.001). Conclusions: The results of our study indicate that adjuvant therapy after neoadjuvant chemoradiotherapy and surgery could reduce the OS and DFS in patients with ESCC. Therefore, adjuvant therapy is not recommended for ESCC patients after neoadjuvant chemoradiotherapy and esophagectomy, especially patients without nodal metastases after neoadjuvant therapy.
Peripheral Blood Biomarkers Predictive of Efficacy Outcome and Immune-Related Adverse Events in Advanced Gastrointestinal Cancers Treated with Checkpoint Inhibitors
Authors: Zhang Zhening , Xie Tong , Qi Changsong , Zhang Xiaotian , Shen Lin , Peng Zhi
Published: August 2022

Background: Gastrointestinal cancers constitute a major burden of global cancer mortalities. In recent years, the advent of immune checkpoint inhibitors has greatly improved the survival of patients with advanced gastrointestinal cancers, while predictive biomarkers of treatment efficacy and toxicities are still unmet demands. Methods: In our retrospective study, patients with advanced gastrointestinal cancers who received single or double immune checkpoint inhibitors in the Department of Gastrointestinal Oncology in Peking University Cancer Hospital between July 2016 and February 2022 were enrolled. Records of clinicopathological information, survival parameters, safety data, and baseline and posttreatment peripheral blood constituents were retrieved. Cox regression analysis and logistic regression analysis were performed to identify the predictive factors of treatment outcomes and immune-related adverse events. Results: We demonstrated that early treatment lines, the presence of immune-related adverse events, and a lower C2 neutrophil-to-lymphocyte ratio were independent factors predicting a superior objective response rate and progression-free survival in patients treated with immunotherapy. Lower ECOG PS, higher baseline albumin, and lower C2 neutrophil-to-lymphocyte ratios were independent risk factors for the onset of immune-related adverse events. Patients who succumbed to immune-related adverse events during immunotherapy presented better survival. Conclusion: Our results indicate that peripheral blood markers have potential for predicting treatment outcomes and immune-related adverse events in patients with advanced gastrointestinal cancer. Prospective validations are warranted.
Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy
Authors: Hersh Andrew M. , Gaitsch Hallie , Alomari Safwan , Lubelski Daniel , Tyler Betty M.
Published: August 2022

Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival.
Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer
Authors: Mao Yifeng , Yang Gaowei , Li Yingbang , Liang Guowu , Xu Wangwang , Hu Mingqiu
Published: August 2022

Despite aggressive treatment and androgen-deprivation therapy, most prostate cancer patients ultimately develop castration-resistant prostate cancer (CRPC), which is associated with high mortality rates. However, the mechanisms governing the development of CRPC are poorly understood, and androgen receptor (AR) signaling has been shown to be important in CRPC through AR gene mutations, gene overexpression, co-regulatory factors, AR shear variants, and androgen resynthesis. A growing number of non-AR pathways have also been shown to influence the CRPC progression, including the Wnt and Hh pathways. Moreover, non-coding RNAs have been identified as important regulators of the CRPC pathogenesis. The present review provides an overview of the relevant literature pertaining to the mechanisms governing the molecular acquisition of castration resistance in prostate cancer, providing a foundation for future, targeted therapeutic efforts.
Integration of p16/HPV DNA Status with a 24-miRNA-Defined Molecular Phenotype Improves Clinically Relevant Stratification of Head and Neck Cancer Patients
Authors: Hess Julia , Unger Kristian , Maihoefer Cornelius , Schüttrumpf Lars , Weber Peter , Marschner Sebastian , Wintergerst Ludmila , Pflugradt Ulrike , Baumeister Philipp , Walch Axel , Woischke Christine , Kirchner Thomas , Werner Martin , Sörensen Kristin , Baumann Michael , Tinhofer Ingeborg , Combs Stephanie E. , Debus Jürgen , Schäfer Henning , Krause Mechthild , Linge Annett , von der Grün Jens , Stuschke Martin , Zips Daniel , Canis Martin , Lauber Kirsten , Ganswindt Ute , Henke Michael , Zitzelsberger Horst , Belka Claus
Published: August 2022

Human papillomavirus (HPV)-driven head and neck squamous cell carcinomas (HNSCC) generally have a more favourable prognosis. We hypothesized that HPV-associated HNSCC may be identified by an miRNA-signature according to their specific molecular pathogenesis, and be characterized by a unique transcriptome compared to HPV-negative HNSCC. We performed miRNA expression profiling of two p16/HPV DNA characterized HNSCC cohorts of patients treated by adjuvant radio(chemo)therapy (multicentre DKTK-ROG n = 128, single-centre LMU-KKG n = 101). A linear model predicting HPV status built in DKTK-ROG using lasso-regression was tested in LMU-KKG. LMU-KKG tumours (n = 30) were transcriptome profiled for differential gene expression and miRNA-integration. A 24-miRNA signature predicted HPV-status with 94.53% accuracy (AUC: 0.99) in DKTK-ROG, and 86.14% (AUC: 0.86) in LMU-KKG. The prognostic values of 24-miRNA- and p16/HPV DNA status were comparable. Combining p16/HPV DNA and 24-miRNA status allowed patient sub-stratification and identification of an HPV-associated patient subgroup with impaired overall survival. HPV-positive tumours showed downregulated MAPK, Estrogen, EGFR, TGFbeta, WNT signaling activity. miRNA-mRNA integration revealed HPV-specific signaling pathway regulation, including PD−L1 expression/PD−1 checkpoint pathway in cancer in HPV-associated HNSCC. Integration of clinically established p16/HPV DNA with 24-miRNA signature status improved clinically relevant risk stratification, which might be considered for future clinical decision-making with respect to treatment de-escalation in HPV-associated HNSCC.
Activated Carbon-Loaded Titanium Dioxide Nanoparticles and Their Photocatalytic and Antibacterial Investigations
Authors: Parvathiraja Chelliah , Katheria Snehlata , Siddiqui Masoom Raza , Wabaidur Saikh Mohammad , Islam Md Ataul , Lai Wen-Cheng
Published: August 2022

Activated carbon doping TiO2 nanoparticles were synthesised by zapota leaf extract using the co-precipitation method. The bio-constituents of plant compounds were used in the reactions of stabilization and reductions. The carbon loading on the TiO2 nanoparticles was characterised by XRD, FTIR, UV-DRS, SEM with EDX, and TEM analysis. The loading of activated carbon onto the TiO2 nanoparticles decreased the crystallite size and optical bandgap, and their doping improved the surface structure of AC/TiO2 nanoparticles. Mesoporous/microporous instability was remodified from the activated carbon, which was visualised using SEM and TEM analysis, respectively. The photocatalytic dye degradation of Rh-B dye was degraded in TiO2 and AC/TiO2 nanoparticles under visible light irradiation. The degradation efficiencies of TiO2 and AC/TiO2 nanoparticles were 73% and 91%, respectively. The bacterial abilities of TiO2 and AC/TiO2 nanoparticles were examined by E. coli and S. aureus. The water reclamation efficiency and bactericidal effect of TiO2 and AC/TiO2 nanoparticles were examined via catalytic dye degradation and bacterial efficiency of activated carbon-doped titanium dioxide nanoparticles.
Photo-Oxidation of Glycerol Catalyzed by Cu/TiO2
Authors: Avilés-García Osmín , Mendoza-Zepeda Arisbeht , Regalado-Méndez Alejandro , Espino-Valencia Jaime , Martínez-Vargas Sandra L. , Romero Rubi , Natividad Reyna
Published: August 2022

In the present study, glycerol was oxidized by photocatalysis to glyceraldehyde, formaldehyde, and formic acid. Copper-doped TiO2 was synthesized by the evaporation-induced self-assembly approach and it was used as catalyst during the glycerol photo-oxidation reactions. The prepared mesoporous material exhibited high specific surface area (242 m2/g) and band gap energy reduction of 2.55 eV compared to pure titania (3.2 eV) by the synthesis method due to the presence of copper cations (Cu2+ identified by XPS). The catalyst showed only anatase crystalline phase with nanocrystals around 8 nm and irregular agglomerates below 100 μm. The selectivity and formation rate of the products were favored towards formaldehyde and glyceraldehyde. The variables studied were catalyst amount, reaction temperature, and initial glycerol concentration. The response surface analysis was used to evaluate the effect of the variables on the product’s concentration. The optimized conditions were 0.4 g/L catalyst, 0.1 mol/L glycerol, and temperature 313.15 K. The response values under optimal conditions were 3.23, 8.17, and 1.15 mM for glyceraldehyde, formaldehyde, and formic acid, respectively. A higher selectivity towards formaldehyde was observed when visible light was used as the radiation source. This study is useful to evaluate the best reaction conditions towards value-added products during the oxidation of glycerol by photocatalysis using Cu/TiO2.
N-Heterocyclic Carbene Gold Complexes Active in Hydroamination and Hydration of Alkynes
Authors: Mariconda Annaluisa , Sirignano Marco , Troiano Rubina , Russo Simona , Longo Pasquale
Published: August 2022

Until the year 2000, gold compounds were considered catalytically inert. Subsequently, it was found that they are able to promote the nucleophilic attack on unsaturated substrates by forming an Au–π-system. The main limitation in the use of these catalytic systems is the ease with which they decompose, which is avoided by stabilization with an ancillary ligand. N-heterocyclic carbenes (NHCs), having interesting σ-donor capacities, are able to stabilize the gold complexes (Au (I/III) NHC), favoring the exploration of their catalytic activity. This review reports the state of the art (years 2007–2022) in the nucleophilic addition of amines (hydroamination) and water (hydration) to the terminal and internal alkynes catalyzed by N-heterocyclic carbene gold (I/III) complexes. These reactions are particularly interesting both because they are environmentally sustainable and because they lead to the production of important intermediates in the chemical and pharmaceutical industry. In fact, they have an atom economy of 100%, and lead to the formation of imines and enamines, as well as the formation of ketones and enols, all important scaffolds in the synthesis of bioactive molecules, drugs, heterocycles, polymers, and bulk and fine chemicals.
GhWRKY33 Interacts with GhTIFY10A to Synergistically Modulate Both Ageing and JA-Mediated Leaf Senescence in Arabidopsis
Authors: Wu Songguo , Zhang Huimin , Wang Ruling , Chang Guimei , Jing Yifen , Li Zhifang , Chen Ligang
Published: August 2022

WRKY transcription factors play critical roles in the modulation of transcriptional changes during leaf senescence, but the underlying mechanisms controlled by them in this progress still remain enigmatic. In this study, Gossypium hirsutum WRKY DNA-binding protein 33 (GhWRKY33) was characterized as a negative regulator of both ageing and JA-mediated leaf senescence. The overexpression of GhWRKY33 in Arabidopsis greatly delayed leaf senescence, as determined by elevated chlorophyll content, lower H2O2 content, and reduced expression of several senescence-associated genes (SAGs). An electrophoretic mobility shift assay (EMSA) and transient dual–luciferase reporter assay revealed that GhWRKY33 could bind to the promoters of both AtSAG12 and Ghcysp and suppress their expression. Yeast two-hybrid (Y2H) and firefly luciferase complementation imaging (LUC) assays showed that GhWRKY33 could interact with GhTIFY10A. Similarly, the overexpression of GhTIFY10A in Arabidopsis also dramatically delayed leaf senescence. Furthermore, both GhWRKY33 and GhTIFY10A negatively regulate JA-mediated leaf senescence. In addition, a transientdual-luciferase reporter assay indicated that GhWRKY33 and GhTIFY10A could function synergistically to inhibit the expression of both AtSAG12 and Ghcysp. Thus, our work suggested that GhWRKY33 may function as a negative regulator to modulate both ageing and JA-mediated leaf senescence and also contributes to a basis for further functional studies on cotton leaf senescence.
Tensin Regulates Fundamental Biological Processes by Interacting with Integrins of Tonsil-Derived Mesenchymal Stem Cells
Authors: Park Gi Cheol , Kim Ji Min , Shin Sung-Chan , Cheon Yong-il , Sung Eui-Suk , Lee Minhyung , Lee Jin-Choon , Lee Byung-Joo
Published: August 2022

Human tonsil-derived mesenchymal stem cells (TMSCs) have a superior proliferation rate and differentiation potential compared to adipose-tissue-derived MSCs (AMSCs) or bone-marrow-derived MSCs (BMSCs). TMSCs exhibit a significantly higher expression of the tensin3 gene (TNS3) than AMSCs or BMSCs. TNS is involved in cell adhesion and migration by binding to integrin beta-1 (ITG β1) in focal adhesion. Here, we investigated the roles of four TNS isoforms, including TNS3 and their relationship with integrin in various biological processes of TMSCs. Suppressing TNS1 and TNS3 significantly decreased the cell count. The knockdown of TNS1 and TNS3 increased the gene and protein expression levels of p16, p19, and p21. TNS1 and TNS3 also have a significant effect on cell migration. Transfecting with siRNA TNS3 significantly reduced Oct4, Nanog, and Sox-2 levels. Conversely, when TNS4 was silenced, Oct4 and Sox-2 levels significantly increase. TNS1 and TNS3 promote osteogenic and adipogenic differentiation, whereas TNS4 inhibits adipogenic differentiation of TMSCs. TNS3 is involved in the control of focal adhesions by regulating integrin. Thus, TNS enables TMSCs to possess a higher proliferative capacity and differentiation potential than other MSCs. Notably, TNS3 plays a vital role in TMSC biology by regulating ITGβ1 activity.
The Outcomes and Quality of Pancreatic Islet Cells Isolated from Surgical Specimens for Research on Diabetes Mellitus
Authors: Oh Ju Yun , Kim Yang Hee , Lee Song , Lee Yu Na , Go Han Se , Hwang Dae Wook , Song Ki Byung , Lee Jae Hoon , Lee Woohyung , So Seongjun , Kang Eunju , Jun Eunsung , Shim In Kyong , Kim Song Cheol
Published: August 2022

Isolating a large quantity of high-quality human islets is a prerequisite for diabetes research. Human islets are typically isolated from the pancreases of brain-dead donors, making research difficult due to low availability. Pancreas tissue discarded after surgical resection may be a good alternative source of islet cells. To test this hypothesis, we isolated islets from discarded surgical specimens and evaluated the islet yield and quality as well as islet cell preparations. Eighty-two segmental pancreases were processed using the Ricordi automated method, and islet yield and quality were investigated. The mean age of patients was 54.6, and the cohort included 32 diabetes patients. After purification, partially resected pancreases yielded an average of 59,593 ± 56,651 islet equivalents (IEQs) and 2546 IEQ/g of digested pancreas, with 71.5 ± 21% purity. Multivariate analysis revealed that diabetes (p = 0.0046) and the lobe used (p = 0.0156) significantly altered islet yield. Islets transplanted into diabetic mice displayed good viability and in vitro glucose responses, DNA/RNA quality, mitochondrial function, and glucose control, even though these results were dependent on islet quality. Isolated cells also maintained high viability and function even after cryopreservation. Our findings indicate that pancreatic tissue discarded after surgery can be a valuable source of islets for diabetes research.
TGF-β Superfamily Signaling in the Eye: Implications for Ocular Pathologies
Authors: Hachana Soumaya , Larrivée Bruno
Published: August 2022

The TGF-β signaling pathway plays a crucial role in several key aspects of development and tissue homeostasis. TGF-β ligands and their mediators have been shown to be important regulators of ocular physiology and their dysregulation has been described in several eye pathologies. TGF-β signaling participates in regulating several key developmental processes in the eye, including angiogenesis and neurogenesis. Inadequate TGF-β signaling has been associated with defective angiogenesis, vascular barrier function, unfavorable inflammatory responses, and tissue fibrosis. In addition, experimental models of corneal neovascularization, diabetic retinopathy, proliferative vitreoretinopathy, glaucoma, or corneal injury suggest that aberrant TGF-β signaling may contribute to the pathological features of these conditions, showing the potential of modulating TGF-β signaling to treat eye diseases. This review highlights the key roles of TGF-β family members in ocular physiology and in eye diseases, and reviews approaches targeting the TGF-β signaling as potential treatment options.
A Comparative Analysis of Mucus Immunomodulatory Properties from Seven Marine Gastropods from the Mediterranean Sea
Authors: Sansone Clementina , Balestra Cecilia , Pistelli Luigi , Del Mondo Angelo , Osca David , Brunet Christophe , Crocetta Fabio
Published: August 2022

The treatment of inflammatory and immune-related diseases due to dysfunctioning of the immune system necessitates modulation of the immune response through immunomodulatory compounds. Marine environments are considered as a new frontier for health benefit product implementations. Marine biodiversity is still a low explored resource, despite it is expected to represent an important platform for chemical bioactive compounds. Within the phylum Mollusca, gastropods are known to synthetize mucus, the latter presenting relevant bioactive properties, e.g., related to immunomodulant molecules able to activate the innate and acquired immune system. This study proposes a bioprospecting of the immunomodulant activity of mucus isolated from seven common gastropod species from the Gulf of Naples (Mediterranean Sea). Results showed that not all mucus displayed a significant cytotoxic activity on the two human cancer cell lines A549 and A2058. On the other hand, the mucus from Bolinus brandaris was strongly bioactive and was therefore thoroughly investigated at cellular, molecular, and protein levels on the human monocytes U937 line. It can conclusively induce monocyte differentiation in vitro and significantly stimulate natural immunity response.
The Impact of Oulema melanopus—Associated Bacteria on the Wheat Defense Response to the Feeding of Their Insect Hosts
Authors: Wielkopolan Beata , Frąckowiak Patryk , Wieczorek Przemysław , Obrępalska-Stęplowska Aleksandra
Published: August 2022

Wheat production is threatened by the destructive effects of numerous pests, including Oulema melanopus (cereal leaf beetle, CLB). Both adults and larvae of CLB damage grain crops, but the target of insecticide treatments are the larvae. Insect-associated bacteria are important for many of the insects’ life processes and may also modulate plant defense responses to feeding of their insect host. The aim of our study was to elucidate the early wheat plants’ reaction to this herbivore feeding and to disclose the CLB-associated bacteria modulation of the wheat-insect interactions. Transcriptome analyses were performed for the leaves wounded mechanically and by feeding of the CLB larvae as well as for the distal leaves to study both, the plant’s local and systemic response. Comparative transcriptome analysis indicated that 24 h after the plant treatment, a much larger number of up-regulated DEGs in damaged leaves was noted, especially those on which larvae were fed. It may suggest that at the analysed time point, the local response was stronger than the systemic one. In the leaves on which larvae with natural bacterial flora were fed (local response), the number of up- and down-regulated differentially expressed genes (DEGs) was 7136 and 7411, respectively, in comparison to the dataset obtained for the leaves wounded by larvae with a reduced number of bacteria. In the distal leaves, 3015 up- and 2372 down-regulated DEGs were noted. CLB-associated bacteria were found to affect many aspects of the physiology of wheat plants, especially in wounded leaves, including the expression of genes related to primary metabolism, phytohormone signaling and photosynthesis. We also observed that CLB-associated bacteria mitigated numerous anti-herbivore processes and pathways associated with the synthesis of metabolites and proteins, potentially harmful to the insects. The bacteria also reversed the expression of some genes involved, inter alia, in the phosphorylation of proteins, oxidative stress, cell wall organization, and biogenesis. Understanding the role of CLB-associated bacteria in the plant’s defense response will be important to the fields of pest control and herbivore and its host ecology and evolution.
Hydrophobic Bile Salts Induce Pro-Fibrogenic Proliferation of Hepatic Stellate Cells through PI3K p110 Alpha Signaling
Authors: Zimny Sebastian , Koob Dennis , Li Jingguo , Wimmer Ralf , Schiergens Tobias , Nagel Jutta , Reiter Florian Paul , Denk Gerald , Hohenester Simon
Published: August 2022

Bile salts accumulating during cholestatic liver disease are believed to promote liver fibrosis. We have recently shown that chenodeoxycholate (CDC) induces expansion of hepatic stellate cells (HSCs) in vivo, thereby promoting liver fibrosis. Mechanisms underlying bile salt-induced fibrogenesis remain elusive. We aimed to characterize the effects of different bile salts on HSC biology and investigated underlying signaling pathways. Murine HSCs (mHSCs) were stimulated with hydrophilic and hydrophobic bile salts. Proliferation, cell mass, collagen deposition, and activation of signaling pathways were determined. Activation of the human HSC cell line LX 2 was assessed by quantification of α-smooth muscle actin (αSMA) expression. Phosphatidyl-inositol-3-kinase (PI3K)-dependent signaling was inhibited both pharmacologically and by siRNA. CDC, the most abundant bile salt accumulating in human cholestasis, but no other bile salt tested, induced Protein kinase B (PKB) phosphorylation and promoted HSC proliferation and subsequent collagen deposition. Pharmacological inhibition of the upstream target PI3K-inhibited activation of PKB and pro-fibrogenic proliferation of HSCs. The PI3K p110α-specific inhibitor Alpelisib and siRNA-mediated knockdown of p110α ameliorated pro-fibrogenic activation of mHSC and LX 2 cells, respectively. In summary, pro-fibrogenic signaling in mHSCs is selectively induced by CDC. PI3K p110α may be a potential therapeutic target for the inhibition of bile salt-induced fibrogenesis in cholestasis.
Human Milk Extracellular Vesicles: A Biological System with Clinical Implications
Authors: Chutipongtanate Somchai , Morrow Ardythe L. , Newburg David S.
Published: August 2022

The consumption of human milk by a breastfeeding infant is associated with positive health outcomes, including lower risk of diarrheal disease, respiratory disease, otitis media, and in later life, less risk of chronic disease. These benefits may be mediated by antibodies, glycoproteins, glycolipids, oligosaccharides, and leukocytes. More recently, human milk extracellular vesicles (hMEVs) have been identified. HMEVs contain functional cargos, i.e., miRNAs and proteins, that may transmit information from the mother to promote infant growth and development. Maternal health conditions can influence hMEV composition. This review summarizes hMEV biogenesis and functional contents, reviews the functional evidence of hMEVs in the maternal–infant health relationship, and discusses challenges and opportunities in hMEV research.
Roles of Epigenetics in Cardiac Fibroblast Activation and Fibrosis
Authors: Shao Jingrong , Liu Jiao , Zuo Shengkai
Published: August 2022

Cardiac fibrosis is a common pathophysiologic process associated with numerous cardiovascular diseases, resulting in cardiac dysfunction. Cardiac fibroblasts (CFs) play an important role in the production of the extracellular matrix and are the essential cell type in a quiescent state in a healthy heart. In response to diverse pathologic stress and environmental stress, resident CFs convert to activated fibroblasts, referred to as myofibroblasts, which produce more extracellular matrix, contributing to cardiac fibrosis. Although multiple molecular mechanisms are implicated in CFs activation and cardiac fibrosis, there is increasing evidence that epigenetic regulation plays a key role in this process. Epigenetics is a rapidly growing field in biology, and provides a modulated link between pathological stimuli and gene expression profiles, ultimately leading to corresponding pathological changes. Epigenetic modifications are mainly composed of three main categories: DNA methylation, histone modifications, and non-coding RNAs. This review focuses on recent advances regarding epigenetic regulation in cardiac fibrosis and highlights the effects of epigenetic modifications on CFs activation. Finally, we provide some perspectives and prospects for the study of epigenetic modifications and cardiac fibrosis.
Immunorthodontics: PD-L1, a Novel Immunomodulator in Cementoblasts, Is Regulated by HIF-1α under Hypoxia
Authors: Yong Jiawen , Gröger Sabine , von Bremen Julia , Meyle Joerg , Ruf Sabine
Published: August 2022

Recent studies have revealed that hypoxia alters the PD-L1 expression in periodontal cells. HIF-1α is a key regulator for PD-L1. As hypoxia presents a hallmark of an orthodontically induced microenvironment, hypoxic stimulation of PD-L1 expression may play vital roles in immunorthodontics and orthodontically induced inflammatory root resorption (OIIRR). This study aims to investigate the hypoxic regulation of PD-L1 in cementoblasts, and its interaction with hypoxia-induced HIF-1α expression. The cementoblast (OCCM-30) cells (M. Somerman, NIH, NIDCR, Bethesda, Maryland) were cultured in the presence and absence of cobalt (II) chloride (CoCl2). Protein expression of PD-L1 and HIF-1α as well as their gene expression were evaluated by Western blotting and RT-qPCR. Immunofluorescence was applied to visualize the localization of the proteins within cells. The HIF-1α inhibitor (HY-111387, MedChemExpress) was added, and CRISPR/Cas9 plasmid targeting HIF-1α was transferred for further investigation by flow cytometry analysis. Under hypoxic conditions, cementoblasts undergo an up-regulation of PD-L1 expression at protein and mRNA levels. Silencing of HIF-1α using CRISPR/Cas9 indicated a major positive correlation with HIF-1α in regulating PD-L1 expression. Taken together, these findings show the influence of hypoxia on PD-L1 expression is modulated in a HIF-1α dependent manner. The HIF-1α/PD-L1 pathway may play a role in the immune response of cementoblasts. Thus, combined HIF-1α/PD-L1 inhibition could be of possible therapeutic relevance for OIIRR prevention.
Regulation of the Cancer Stem Phenotype by Long Non-Coding RNAs
Authors: Gutierrez-Cruz Jose Adan , Maldonado Vilma , Melendez-Zajgla Jorge
Published: August 2022

Cancer stem cells are a cell population within malignant tumors that are characterized by the ability to self-renew, the presence of specific molecules that define their identity, the ability to form malignant tumors in vivo, resistance to drugs, and the ability to invade and migrate to other regions of the body. These characteristics are regulated by various molecules, such as lncRNAs, which are transcripts that generally do not code for proteins but regulate multiple biological processes through various mechanisms of action. LncRNAs, such as HOTAIR, H19, LncTCF7, LUCAT1, MALAT1, LINC00511, and FMR1-AS1, have been described as key regulators of stemness in cancer, allowing cancer cells to acquire this phenotype. It has been proposed that cancer stem cells are clinically responsible for the high recurrence rates after treatment and the high frequency of metastasis in malignant tumors, so understanding the mechanisms that regulate the stem phenotype could have an impact on the improvement of cancer treatments.
Chronic AMPK Activation Reduces the Expression and Alters Distribution of Synaptic Proteins in Neuronal SH-SY5Y Cells
Authors: Yang Alex J. T. , Mohammad Ahmad , Tsiani Evangelia , Necakov Aleksandar , MacPherson Rebecca E. K.
Published: August 2022

Neuronal growth and synaptic function are dependent on precise protein production and turnover at the synapse. AMPK-activated protein kinase (AMPK) represents a metabolic node involved in energy sensing and in regulating synaptic protein homeostasis. However, there is ambiguity surrounding the role of AMPK in regulating neuronal growth and health. This study examined the effect of chronic AMPK activation on markers of synaptic function and growth. Retinoic-acid-differentiated SH-SY5Y human neuroblastoma cells were treated with A-769662 (100 nM) or Compound C (30 nM) for 1, 3, or 5 days before AMPK, mTORC1, and markers for synapse function were examined. Cell morphology, neuronal marker content, and location were quantified after 5 days of treatment. AMPK phosphorylation was maintained throughout all 5 days of treatment with A-769662 and resulted in chronic mTORC1 inhibition. Lower total, soma, and neuritic neuronal marker contents were observed following 5 d of AMPK activation. Neurite protein abundance and distribution was lower following 5 days of A-769662 treatment. Our data suggest that chronic AMPK activation impacts synaptic protein content and reduces neurite protein abundance and distribution. These results highlight a distinct role that metabolism plays on markers of synapse health and function.
Innate, High Tolerance to Zinc and Lead in Violets Confirmed at the Suspended Cell Level
Authors: Miszczak Szymon , Sychta Klaudia , Dresler Sławomir , Kurdziel Agnieszka , Hanaka Agnieszka , Słomka Aneta
Published: August 2022

Many species of the Viola L. genus (violets) colonize areas with high concentrations of trace elements in the soil, e.g., nickel, cadmium, zinc, and lead. Although tolerance to heavy metals is a common phenomenon in violets, it is not clear whether this is the result of gradual microevolutionary processes as a part of the adaptation to the specific conditions, or whether the tolerance was inherited from the ancestor(s). We developed cell suspension cultures of five plant species: two non-metallophytes—Arabidopsis thaliana (Col-0) and Viola · wittrockiana, and three metallophytes—V. philippica, V. tricolor, and Silene vulgaris subsp. humilis for tolerance tests. The aim of the study was to measure the level of tolerance of violets in comparison with species from the other genera to verify the hypothesis of the high, innate tolerance of the former. We measured cell viability, non-enzymatic antioxidant content, and the accumulation of heavy metals after cell treatment with Zn or Pb. The results indicate they are innate and independent on the ecological status (metallophyte vs. non-metallophyte) and high in comparison with other species tolerance to Zn and Pb in violets. Viability of the cells after Zn and Pb (1000 μM) exposure for 72 h was the highest in violets. Antioxidant content, after heavy metal treatment, increased significantly, particularly in metallophyte violets, indicating their high responsivity to metals. In all species, lead was detected in the protoplasm of the cells, not in the vacuole or cell wall. All violets were characterized by the accumulation capacity of lead. Here, we clearly show that the physiological and biochemical studies conducted with the use of heavy metals on plant cells translate into the heavy metal tolerance of the species.
Sweat Proteomics in Cystic Fibrosis: Discovering Companion Biomarkers for Precision Medicine and Therapeutic Development
Authors: Burat Bastien , Reynaerts Audrey , Baiwir Dominique , Fléron Maximilien , Gohy Sophie , Eppe Gauthier , Leal Teresinha , Mazzucchelli Gabriel
Published: August 2022

In clinical routine, the diagnosis of cystic fibrosis (CF) is still challenging regardless of international consensus on diagnosis guidelines and tests. For decades, the classical Gibson and Cooke test measuring sweat chloride concentration has been a keystone, yet, it may provide normal or equivocal results. As of now, despite the combination of sweat testing, CFTR genotyping, and CFTR functional testing, a small fraction (1–2%) of inconclusive diagnoses are reported and justifies the search for new CF biomarkers. More importantly, in the context of precision medicine, with a view to early diagnosis, better prognosis, appropriate clinical follow-up, and new therapeutic development, discovering companion biomarkers of CF severity and phenotypic rescue are of utmost interest. To date, previous sweat proteomic studies have already documented disease-specific variations of sweat proteins (e.g., in schizophrenia and tuberculosis). In the current study, sweat samples from 28 healthy control subjects and 14 patients with CF were analyzed by nanoUHPLC-Q-Orbitrap-based shotgun proteomics, to look for CF-associated changes in sweat protein composition and abundance. A total of 1057 proteins were identified and quantified at an individual level, by a shotgun label-free approach. Notwithstanding similar proteome composition, enrichment, and functional annotations, control and CF samples featured distinct quantitative proteome profiles significantly correlated with CF, accounting for the respective inter-individual variabilities of control and CF sweat. All in all: (i) 402 sweat proteins were differentially abundant between controls and patients with CF, (ii) 68 proteins varied in abundance between F508del homozygous patients and patients with another genotype, (iii) 71 proteins were differentially abundant according to the pancreatic function, and iv) 54 proteins changed in abundance depending on the lung function. The functional annotation of pathophysiological biomarkers highlighted eccrine gland cell perturbations in: (i) protein biosynthesis and trafficking, (ii) CFTR proteostasis and membrane stability, and (iii) cell-cell adherence, membrane integrity, and cytoskeleton crosstalk. Cytoskeleton-related biomarkers were of utmost interest because of the consistency between variations observed here in CF sweat and variations previously documented in other CF tissues. From a clinical stance, nine candidate biomarkers of CF diagnosis (CUTA, ARG1, EZR, AGA, FLNA, MAN1A1, MIA3, LFNG, SIAE) and seven candidate biomarkers of CF severity (ARG1, GPT, MDH2, EML4 (F508del homozygous), MGAT1 (pancreatic insufficiency), IGJ, TOLLIP (lung function impairment)) were deemed suitable for further verification.
Ti/Cu/Kovar Multilayer Interlayer PTLP Diffusion Bonding Si3N4/Ht250
Authors: Zhang Deku , Zhang Lian , Zhou Ning , Wang Kehong , Li Xiaopeng
Published: August 2022

In this paper, partial transient liquid phase (PTLP) diffusion bonding between Si3N4 ceramics and Ht250 cast iron was carried out by using an Ti/Cu/Kovar/Cu/Ti interlayer. The effects of the heating temperature and holding time on the microstructure, formation mechanism, and mechanical properties of Si3N4/Ht250 cast iron joints were studied. The results show that the maximum shear strength of the joint is 112 MPa when the welding temperature is 1000 °C and the holding time is 1 h. In addition, the problems of Ti/Cu/Ti intermetallic compound formation and Cu/Si3N4 ceramic residual thermal stress in the joint can be effectively alleviated.
The Impact of the Functional Layer Composition of Glucose Test-Strips on the Stability of Electrochemical Response
Authors: Zolotukhina Ekaterina V. , Gerasimova Ekaterina V. , Sorokin Vladislav V. , Levchenko Maria G. , Freiman Alisa S. , Silina Yuliya E.
Published: August 2022

Herein, the impact of the chemical stability of RedOx mediator ferricyanide, K3[Fe(CN)6] (FC), a type of buffer solution used for bioreceptor preparation, gel composition (carboxymethylcellulose, CMC, Aerosile, AS, and alginate, ALG) on the long term stability of glucose test-strips and their analytical performance was examined. By simple addition of ALG to the functional gel aiming to improve its viscosity, we managed to enhance the sensitivity of conventional CMC-containing amperometric glucose test-strips from 3.3 µA/mM to 3.9 µA/mM and extend their shelf life from 8 months to 1.7 years. Moreover, during the course of investigations, it was revealed that the activity of enzyme in dependence with the used buffer did not linearly correlate with its activity in a dried functional layer, and the entire long-term electrochemical signal of glucose test-strips was determined by RedOx mediator FC chemical stability. The most stable and sensitive test-strips were obtained by the screen-printing approach from a gel containing 24 mg/mL GOx prepared in citrate buffer with pH 6, 200 mg/mL of FC and 10 mg/mL of CMC supplemented with 25 mg/mL of ALG.
Effect of Vagus Nerve Stimulation on Blood Inflammatory Markers in Children with Drug-Resistant Epilepsy: A Pilot Study
Authors: Baro Valentina , Bonavina Maria Vittoria , Saettini Francesco , D’Amico Giovanna , Trezza Andrea , Denaro Luca , Grioni Daniele , Landi Andrea
Published: August 2022

Background: Since one of the suggested mechanisms of action of VNS on epilepsy is the reduction of central inflammation, we carried out a comprehensive analysis of blood inflammatory markers in children considered for VNS surgery. Materials and methods: Five pediatric patients were studied. An extensive analysis of blood inflammatory markers was performed before surgery (T0) and six weeks after VNS implantation (T1). An epileptological outcome was obtained according to the McHugh score. Results: The variations of IgA, IgE, IgG, CD19, and PTX3 displayed a tendency toward a positive statistical correlation between T0 and T1. According to McHugh score, the patients were divided into Group 1 (i.e., Class I) and Group 2 (i.e., Classes II and III). IL-1β and PTX-3 tended to decrease more in Group 1, while TNF-α decreased in Group 2 (−56.65%) and slightly increased (+3.61%) in Group 1 at T1 without statistical correlation. Conclusions: The variation of IL-1β and PTX-3 seem to be related to a better outcome; thus, they do not reach statistical significance. A larger series of patients is needed to determine whether biochemical changes could relay with the clinical improvement of epilepsy.
Attitude of Midwives towards Fluoride Recommendations and Oral Prevention in Infants and Young Children
Authors: Geiken Antje , Holtmann Louise , Doerfer Christof E. , Schwarz Christiane , Graetz Christian
Published: August 2022

Early childhood caries is a challenge. Early dental screening flanked by multidisciplinary preventions by pediatricians, dentists, and midwives (MWs) may be helpful. New recommendations for dental screening in children (FUs) and fluoride have been introduced in Germany. The aim of this study was to investigate whether midwives consider FUs useful and implement early childhood caries prevention, as well as fluoride recommendations. The survey was conducted using an online questionnaire. Demographic data, including 11 items on early childhood dental prophylaxis and fluoride, were requested. Agreement was recorded using Likert scales. The data were analyzed descriptively. Two hundred and seventeen female MWs participated (age: 44.1 (11.04) years). One hundred and four (47.9%) participants knew about the FUs. Of the MWs, 30.7% found a referral from the first tooth to be very important (important/neutral/unimportant: 27%/27.9%/14.4%), compared with 84.8% for the entire primary dentition (11.8%/2.8%/0.5%). Of the MWs, 41.7% always recommended fluoride toothpaste from the first tooth (often/occasionally/rarely/never: 22.7%/12.4%/7.9%/15.3%) and 48.1% completely rejected fluoride-free toothpaste (always/often/occasionally/rarely: 9.8%/8.9%/17.3%/15.9%). In addition, 54.8% never recommended the use of fluoride tablets (always/often/occasionally/rarely: 9.2%/7.4%/10.2%/18.4%). The FUs are not yet well-known among MWs, and only less than one-third recommended dental check-ups, starting with the first tooth. This contrasts with the high uptake of fluoridated toothpaste. More educational work should be carried out to convince more MWs of the benefits of the FUs.
Does Friend Support Matter? The Association between Gender Role Attitudes and School Bullying among Male Adolescents in China
Authors: Chen Binli , Wang Xiying , Gao Yutong
Published: August 2022

This study investigated the association between gender role attitudes, perceived friend support, and school bullying among male adolescents from 11 schools in two cities in China. A total of 3172 Chinese adolescents between 12 and 20 years of age (48.80% girls and 51.20% boys) completed questionnaires that included measures of bullying, gender role attitudes, and perceived social support. In terms of outcome measures, the Chinese version of the Illinois Bully Scale (IBS), Attitudes toward Women Scale for Adolescents (AWSA), and Multidimensional Scale of Perceived Social Support (MSPSS) were used to assess bullying perpetration, gender role attitudes, and perceived friend support, respectively. Based on masculinity theories and the stress-buffering theory, the study found that male adolescents held more traditional gender role attitudes (t = 30.78, p < 0.001) and reported higher prevalence of bullying behaviors (36.02%) than girls (31.20%). In addition, boys’ bullying behaviors were significantly predicted by gender role attitudes through perceived friend support. That is, male youth with more conservative gender role attitudes reported less perceived friend support (adjusted OR = 1.055; SE = 0.013), which elevated their risks of bullying perpetration (adjusted OR = 2.082; SE = 0.302). These findings have critical implications for bullying intervention and prevention through gender equity education.