Small Molecule-mediated Disruption of Ribosome Biogenesis Synergizes With FGFR Inhibitors to Suppress Glioma Cell Growth

alexandrossfakianakis shared this article with you from Inoreader Small Molecule-mediated Disruption of Ribosome Biogenesis Synergizes With FGFR Inhibitors to Suppress Glioma Cell Growth via Neuro-Oncology Advance Access Abstract Background High-grade gliomas are malignant brain tumors characterized by aggressiveness and resistance to chemotherapy. Prognosis remains dismal, highlighting the need to identify novel molecular dependencies and targets. Ribosome biogenesis (RiBi), taking place in the nucleolus, represents a promising target as several cancer types rely on high RiBi rates to sustain proliferation. Publicly available transcriptomics data of glioma patients revealed a positive correlation between RiBi rates and histological grades. We, therefore, hypothesized that glioma cells could be susceptible to RiBi inhibition. Methods Transcriptomics data from glioma patients were analyzed for RiBi-related processes. BMH-21, a small molecule inhibitor of RNA polI transcription, was tested in adult and pediatric high-grade glioma cell lines and a zebrafish transplant model. Cellular phenotypes were evaluated by transcriptomics, cell cycle analysis, and vi ability assays. A chemical synergy screen was performed to identify drugs potentiating BMH-21-mediated effects. Results BMH-21 reduced glioma cell viability, induced apoptosis, and impaired the growth of transplanted glioma cells in zebrafish. Combining BMH-21 with TMZ potentiated cytotoxic effects. Moreover, BMH-21 synergized with FGFR inhibitor Erdafitinib, a top hit in the chemical synergy screen. RiBi inhibition using BMH-21, POLR1A siRNA, or Actinomycin D revealed engagement of the FGFR-FGF2 pathway. BMH-21 downregulated FGFR1 and SOX2 levels, whereas FGF2 was induced and released from the nucleolus. Conclusions This study conceptualizes the implementation of RiBi inhibition as a viable future therapeutic strategy for glioma and reveals an FGFR connection to the cellular response upon RiBi inhibition with potential translational value. View on Web

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Wnt Signaling Regulates MFSD2A-dependent Drug Delivery through Endothelial Transcytosis in Glioma

alexandrossfakianakis shared this article with you from Inoreader Wnt Signaling Regulates MFSD2A-dependent Drug Delivery through Endothelial Transcytosis in Glioma via Neuro-Oncology Advance Access Abstract Background Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed. Methods Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient and Mfsd2a EC specific inducible mice were developed to study the underlying molecular mechanisms. Results We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MSFD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice. Conclusions These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ deli very through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment. View on Web

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H‐Type Tracheoesophageal Fistula Cannulation for Rapid Intraoperative Localization

alexandrossfakianakis shared this article with you from Inoreader H‐Type Tracheoesophageal Fistula Cannulation for Rapid Intraoperative Localization via The Laryngoscope Various techniques for tracheoesophageal fistula cannulation have been reported. In this case, we created a loop using a plastic catheter. The loop allowed us to create traction for rapid intraoperative localization and to pull a difficult-to-reach fistula, superiorly into the neck, to be reached through a cervical approach. Laryngoscope, 2022 View on Web

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Inflammatory profile of apical periodontitis exacerbated by cigarette smoke inhalation: histological and immunohistochemical analysis in rats

alexandrossfakianakis shared this article with you from Inoreader Inflammatory profile of apical periodontitis exacerbated by cigarette smoke inhalation: histological and immunohistochemical analysis in rats via International Endodontic Journal Abstract Aim To evaluate the effects of cigarette smoke inhalation (CSI) on inflammation, proinflammatory mediators and haematological parameters in rats with induced apical periodontitis (AP). Methodology Thirty-two 3-month-old male Wistar rats were divided into four experimental groups (n=8): C - Control; S - rats with CSI; AP - rats with AP; and SAP - rats with CSI + AP. Animals in groups S and SAP inhaled cigarette smoke by remaining inside a smoking chamber for 8 minutes, 3 times daily, for 50 days. After 20 days of smoke inhalation, animals in AP and SAP groups had the pulps of the lower right first molar exposed to oral environment for 30 days to induce AP. In these subsequent 30 days, animals in group S and SAP continued with CSI. On day 50th, animals were euthanized and mandibles were histologically processed to assess inflammatory infiltrate, immunohistochemical interleukins (IL-1β, IL-6 and TNF-α), and blood sample collected for laboratory analysis. The Mann–Whitney test was performed for nonparametric data and the pairwise analyses of Student's t-test for parametric data, with a significance level of P<0.050. Results Inflammatory infiltrate was moderate in AP group and more severe in the SAP (P=0.010). The interleukins IL-6, IL-1β and TNF-α were higher in SAP group (P<0.001) when compared with the AP group. A greater number of red blood cells (P=0.010), haemoglobin (P=0.007), and neutrophils (P=0.014) were observed in the SAP group in comparison with the AP group. Conclusion Cigarette smoke inhalation induced a more severe inflammatory infiltrate, with increased levels of proinflammatory cytokines and changes in haematological parameters in rats with induced AP. Thus, cigarette smoke inhalation aggravated AP, exacerbating the inflammatory response. View on Web

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Prognostic significance of head and neck spindle cell carcinoma

alexandrossfakianakis shared this article with you from Inoreader Prognostic significance of head and neck spindle cell carcinoma via Head & Neck Abstract Background Our study investigates the prognostic significance of spindle cell histology on overall survival (OS) of conventional head and neck squamous cell carcinoma (HNSCC). Methods The 2004 to 2017 National Cancer Database was queried for patients with head and neck spindle cell carcinoma (HNSpCC) (n = 1572) or HNSCC (n = 242 697) of the oral cavity, major salivary glands, sinonasal tract, oropharynx, hypopharynx, and larynx treated with curative intent. Results Patients with HNSpCC presented more frequently with higher-grade tumors and cN0 disease than those with HNSCC (p < 0.001). In the oral cavity, the HR for death for SpCC compared with SCC was 1.33 (p < 0.001). In the oropharynx, the HR for death for SpCC compared with SCC was 1.47 (p = 0.028). Conclusions After adjusting for patient, tumor, and treatment characteristics, SpCC histology had an independent adverse prognostic effect on OS in the oral cavity and oropharynx. SpCC histology does not necessarily portend poorer survival in all HNSCC. Level of Evidence: 4. View on Web

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Clinical evaluation and patient related outcomes of one‐ and two‐piece zirconia implants at five years of loading: A case series study

alexandrossfakianakis shared this article with you from Inoreader Clinical evaluation and patient related outcomes of one‐ and two‐piece zirconia implants at five years of loading: A case series study via Journal of Esthetic and Restorative Dentistry Abstract Objective The objective of this study was to investigate the survival and biological and mechanical complications of one-piece and two-piece zirconia implants at five years of loading. Materials and Methods Consecutive patients receiving zirconia implants were studied, collecting data at five years of loading on their clinical history, peri-implant health status, mechanical complications, esthetic results, and patient related outcomes. Results The study included 18 patients with 29 implants. The survival rate was 86% in implant-based analysis and 78% in patient-based analysis. There were no cases of peri-implantitis, but mucositis was present in 53% of implants. A mean of 4.1 ± 0.81 mm was obtained for probing depth and 1.6 ± 0.9 mm for crestal bone loss (radiographic assessment). There were no implant fractures. Major (10%) and minor (10%) prosthesis complications were observed. The esthetic outcome was moderate to almost perfect, with a high level of patient satisfaction. No significant association was found between survival rate and the presence of mucositis around one- or two-piece implants or any other study variable. Conclusions The survival rate is low for one- and two-piece zirconia implants. Both types of implants demonstrated a low mechanical complication rate. The incidence of periimplantitis is low but mucositis is present in 50%. Patient satisfaction related to esthetics and function is moderate to high. They represent a good option for patients requiring an alternative to titanium implants. Clinical Relevance Zirconia implants appear to be an alternative to the titanium option and may be indicated for patients requiring "metal-free" restorations. View on Web

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DSCS, a New Cell Line Developed in vitro From Human Stem Cells of the Apical Papilla

alexandrossfakianakis shared this article with you from Inoreader DSCS, a New Cell Line Developed in vitro From Human Stem Cells of the Apical Papilla via International Endodontic Journal Abstract Aim To establish and fully characterize a new cell line from human stem cells of the apical papilla (SCAPs) through immortalization with an SV40 large T antigen. Methodology Human SCAPs were isolated and transfected with an SV40 large T antigen and treated with puromycin to select the infected population. Expression of human mesenchymal surface markers CD73, CD90 and CD105 was assessed in the new cell line named Dental Stem Cells SV40 (DSCS) by flow cytometry at early and late passages. Cell and proliferation were also analysed. To evaluate trilineage differentiation; quantitative polymerase chain reaction and histological staining were performed. Results DSCS cell flow cytometry confirmed expression of mesenchymal surface markers even in late passages (100% positive for CD73 and CD90 and 98.9% for CD105 at passage (P) 25). Fewer than 0.5% were positive for haematopoietic cell markers (CD45 and CD34). DSCS cells also showed increased proliferation when compared with the primary culture after 48 h, with a doubling time of 23.46 h for DSCS cells and 40.31 h for SCAPs, and retained the capacity to grow for >45 passages (150 population doubling) and their spindle shape morphology. Trilineage differentiation potential was confirmed through histochemical staining and gene expression of the chondrogenic markers SOX9 and COL2A1, adipogenic markers CEBPA and LPL, and osteogenic markers COL1A1 and ALPL. Conclusions The new cell line derived from human SCAPs has multipotency, retains its morphology and expression of mesenchymal surface markers, and shows higher proliferative capacity even at late passages (P45). DSCS cells can be used for in vitro study of root development and to achieve better understanding of the regenerative mechanisms. View on Web

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Three‐point sectional‐cast digital method for transferring the interocclusal relationship for full‐mouth rehabilitation of worn dentition

alexandrossfakianakis shared this article with you from Inoreader Three‐point sectional‐cast digital method for transferring the interocclusal relationship for full‐mouth rehabilitation of worn dentition via Journal of Prosthodontics Abstract For full-mouth rehabilitation of worn dentition, "diagnostic" interim restorations are required to reestablish the interocclusal relationship. It is important but challenging to transfer the interocclusal relationship, and to map the basic form and contour of interim restorations to the final restorations. Alignment of interim restorations and working casts is difficult when using digital workflows because of a lack of consistent hard tissue reference points. The digital workflow presented in this study used a "3-point sectional-cast digital cross-mounting method" to transfer the interocclusal relationship during full-mouth rehabilitation. An intermediate cast was made with 3 interim restorations: 1 on an incisor and 2 on molars. The interocclusal relationship and occlusal morphologies of the diagnostic interim prostheses were transferred and aligned to working casts using the 3-point sectional casts. This article is protected by copyright. All rights reserved View on Web

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SARS-CoV-2 infection history and antibody response to three COVID-19 mRNA vaccine doses

alexandrossfakianakis shared this article with you from Inoreader SARS-CoV-2 infection history and antibody response to three COVID-19 mRNA vaccine doses via Clinical Infectious Diseases Advance Access ABSTRACT Background Three doses of coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines produce robust antibody responses, but data are limited among individuals previously infected with SARS-CoV-2. From a cohort of health care personnel (75.5%), first responders (4.6%), and other frontline workers (19.8%) in 6 US states, we longitudinally assessed antibody waning after dose-2, and response to dose-3, according to SARS-CoV-2 infection history. Methods Participants submitted sera every three months, after SARS-CoV-2 infection, and after each COVID-19 vaccine dose. Sera were tested for antibodies and reported quantitatively as area under the serial dilution curve (AUC). Changes in the AUC values over time were compared as fold-changes using a linear mixed model. Results Analysis included 388 participants who received dose-3 by November 2021. Three comparison groups: (1) vaccine only with no known prior SARS-CoV-2 inf ection (n = 224); (2) infection prior to dose-1 (n = 123); and (3) infection after dose 2 and before dose-3 (n = 41). The interval from dose 2 and dose 3 was approximately 8-months. After dose-3, antibody levels rose 2.5-fold (95%CI = 2.2-3.0) in group 2, and 2.9-fold (95%CI = 2.6-3.3) in group 1. Those infected within 90 days before dose-3 (and median 233 days (IQR = 213-246) after dose-2) did not increase significantly after dose-3. Conclusions A third dose of mRNA vaccine typically elicited a robust humoral immune response among those with primary vaccination regardless of SARS-CoV-2 infection >3 months prior to boosting. Those with infection < 3 months prior to boosting did not have a significant increase in antibody concentrations in response to a booster. View on Web

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Topical Adenosine Inhibits Inflammation and Mucus Production in Viral Acute Rhinosinusitis

alexandrossfakianakis shared this article with you from Inoreader Topical Adenosine Inhibits Inflammation and Mucus Production in Viral Acute Rhinosinusitis via The Laryngoscope Topical adenosine treatment inhibits inflammation and mucus production in a mouse model of viral acute rhinosinusitis. It may be an effective treatment for viral ARS. Original work created with Biorender.com. Objective Viral acute rhinosinusitis (ARS) is the leading cause of work and school absence and antibiotic over-prescription. There are limited treatment options available to ameliorate the symptoms caused by viral ARS. We have previously demonstrated that topical adenosine treatment enhances mucociliary clearance in the sino-nasal tract. Here, we assessed the therapeutic potential of topical adenosine in a mouse model of viral ARS. Methods The effect of topical adenosine on inflammatory response and mucin gene expression was examined in a mouse model of viral ARS induced by respiratory syncytial virus (RSV) nasal-only infection. We also investigated the inflammatory effect of both endogenous and exogenous adenosine in the sino-nasal tract. Results Topical adenosine significantly inhibited the expression of pro-inflammatory cytokines, goblet hyperplasia, mucin expression, and cell damage in the nose of mice with viral ARS. This treatment did not prolong virus clearance. This inhibitory effect was primarily mediated by the A2A adenosine receptor (AR). Although previous studies have shown that adenosine induces a robust inflammatory response in the lungs, neither endogenous nor exogenous adenosine produced inflammation in the sino-nasal tract. Instead, exogenous adenosine inhibited the baseline expression of TNF and IL-1β in the nose. Additionally, baseline expression of ARs was lower in the nose than that in the trachea and lungs. Conclusion We demonstrated that intranasal adenosine administration effectively decreased inflammation and mucus production in a mouse model of viral ARS. Level of Evidence N/A Laryngoscope, 2022 View on Web

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