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Τετάρτη 6 Ιουλίου 2022

Efficacy and safety of a single dose of casirivimab and imdevimab for the prevention of COVID-19 over an 8-month period: a randomised, double-blind, placebo-controlled trial

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Publication date: Available online 5 July 2022

Source: The Lancet Infectious Diseases

Author(s): Gary A Herman, Meagan P O'Brien, Eduardo Forleo-Neto, Neena Sarkar, Flonza Isa, Peijie Hou, Kuo-Chen Chan, Katharine J Bar, Ruanne V Barnabas, Dan H Barouch, Myron S Cohen, Christopher B Hurt, Dale R Burwen, Mary A Marovich, Bret J Musser, John D Davis, Kenneth C Turner, Adnan Mahmood, Andrea T Hooper, Jennifer D Hamilton

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Ocular proton therapy, pencil beam scanning high energy proton therapy or stereotactic radiotherapy for uveal melanoma; an in silico study

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Publication date: Available online 5 July 2022

Source: Cancer/Radiothérapie

Author(s): A. Gerard, M.L. Peyrichon, M. Vidal, C. Barnel, W. Sauerwein, A. Carnicer, G. Angellier, T.M. Mathis, K.K. Mishra, J. Thariat, J. Herault

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The Role of PARP‐1 and NF‐κB in Bile‐Induced DNA Damage and Oncogenic Profile in Hypopharyngeal Cells

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Objectives/Hypothesis

We recently documented that acidic bile, a gastroesophageal reflux content, can cause invasive hypopharyngeal squamous cell carcinoma, by inducing widespread DNA damage and promoting nuclear factor kappa B (NF-κB)-related oncogenic molecular events. Poly or adenosine diphosphate (ADP)-ribose polymerase-1 (PARP-1), a sensitive sensor of DNA damage, may interact with NF-κB. We hypothesized that PARP-1 is activated in hypopharyngeal cells (HCs) with marked DNA damage caused by acidic bile, hence there is an association between PARP-1 and NF-κB activation or its related oncogenic profile, in this process.

Study Design

In vitro study.

Methods

We targeted PARP-1 and NF-κB(p65), using pharmacologic inhibitors, 1.0 μM Rucaparib (AG014699) and 10 μM BAY 11–7082 {3-[4=methylphenyl)sulfonyl]-(2E)-propenenitrile}, respectively, or silencing their gene expression (siRNAs) and used immunofluorescence, luciferase, cell viability, direct enzyme-linked immunosorbent assays, and qPCR analysis to detect the effect of targeting PARP-1 or NF-κB in acidic bile-induced DNA damage, PARP-1, p-NF-κB, and B-cell lymphoma 2 (Bcl-2) expression, as well as NF-κB transcriptional activity, cell survival, and mRNA oncogenic phenotype in HCs.

Results

We showed that (i) PARP-1 is overexpressed by acidic bile, (ii) targeting NF-κB adequately prevents the acidic bile-induced DNA double-strand breaks (DSBs) by gamma H2A histone family member X (γH2AX), oxidative DNA/RNA damage, PARP-1 overexpression, anti-apoptotic mRNA phenotype, and cell survival, whereas (iii) targeting PARP-1 preserves elevated DNA damage, NF-κB activation, and anti-apoptotic phenotype.

Conclusion

We document for the first time that the activation of PARP-1 is an early event during bile reflux-related head and neck carcinogenesis and that NF-κB can mediate DNA damage and PARP-1 activation. Our data encourage further investigation into how acidic bile-induced activated NF-κB mediates DNA damage in hypopharyngeal carcinogenesis.

Level of Evidence

NA Laryngoscope, 2022

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Impact of Expanding Eligibility Criteria for Cochlear Implantation – Dynamic Modeling Study

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Impact of Expanding Eligibility Criteria for Cochlear Implantation – Dynamic Modeling Study

The aim of this study was to explore the impact of further expanding unilateral CI criteria in those with severe hearing loss (HL) (61–80 dBHL) in terms of number of CI recipients, costs, quality of life, and cost-effectiveness. Based on its outcomes, the described expansion appears to constitute a cost-effective use of healthcare resources. However, it would require a significant increase in diagnostic, operative and rehabilitative capacity. These quantitative estimates can serve as a basis for wider societal deliberation on the question wheter such an increase can and should be pursued.


Objectives

Eligibility criteria for cochlear implantation (CI) are shifting due to technological and surgical improvements. The aim of this study was to explore the impact of further expanding unilateral CI criteria in those with severe hearing loss (HL) (61–80 dBHL) in terms of number of CI recipients, costs, quality of life, and cost-effectiveness.

Methods

A dynamic population-based Markov model was constructed mimicking the Dutch population in three age categories over a period of 20 years. Health states included severe HL (61–80 dBHL), profound HL (>81 dBHL), CI recipients, and no-CI recipients. Model parameters were based on published literature, (national) databases, expert opinion, and model calibration.

Results

If persons with severe HL would qualify and opt for CI similar to those with profound HL now, this would lead to a 6–7 times increase of new CI recipients and an associated increase in costs (€550 million) and QALYs (54.000) over a 20-year period (incremental cost utility ratio: 10.771 euros/QALY [2.5–97.5 percentiles: 1.252–23.171]). One-way-sensitivity analysis indicated that model outcomes were most sensitive to regaining employment, utility associated with having a CI, and costs of surgery and testing.

Conclusion

Our findings suggest that expanding eligibility for CI to persons with severe HL could be a cost-effective use of resources. Clearly, however, it would require a significant increase in diagnostic, operative, and rehabilitative capacity. Our quantitative estimates can serve as a basis for a wider societal deliberation on the question whether such an increase can and should be pursued.

Level of Evidence

N/A Laryngoscope, 2022

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Stereotactic body radiotherapy extends the clinical benefit of PD-1 inhibitors in refractory recurrent/metastatic nasopharyngeal carcinoma

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Emerging evidence shows that immune checkpoint inhibitors lead to durable responses in a variety of cancers, including nasopharyngeal carcinoma (NPC), however, combination approaches (i.e., stereotactic body r...
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