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Purpose: Glioblastoma is the most common type of primary brain malignancy and has a poor prognosis. The standard treatment strategy is based on maximal safe surgical resection followed by radiotherapy and chemotherapy. Surgical resection can be optimized by using 5-delta-aminolevulinic acid (5-ALA)-induced fluorescence, which is the current mainstay. Although 5-ALA-induced fluorescence has gained general acceptance, it is also limited by inter-observer variability and non-standardized fluorescence parameters. We present a new software for processing images analysis to better recognize the tumor infiltration margins using an intraoperative immediate safety map of 5-ALA-induced fluorescence. We tested this in a brain model using a commercial surgical exoscope., Methods: A dedicated software GLIOVIS (ACQuF-II, Advanced Colorimetry-based Quantification of Fluorescence) was designed for processing analysis of images taken on the Intraoperative Orbital Camera Olympus Orbeye (IOC) to determine the relative quantification of Protoporphyrin IX (5-ALA metabolite) fluorescence. The software allows to superpose the new fluorescence intensity map and the safety margins over the original images. The software was tested on gel-based brain models., Results: Two surrogate models were developed: PpIX agarose gel-integrated in gelatin-based brain model at different scales (1:25 and 1:1). The images taken with the IOC were then processed using GLIOVIS. The intensity map and safety margins could be obtained for all available models., Conclusions: GLIOVIS for 5-ALA-guided surgery image processing was validated on various gelatin-based brain models. Different levels of fluorescence could be qualitatively digitalized using this technique. These results need to be further confirmed and corroborated in vivo and validated clinically in order to define a new standard of care for glioblastoma resection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mazevet, Oberli, Marinelli, Zaed, Bauer, Kaelin-Lang, Marchi, Gardenghi, Reinert and Cardia.)

Purpose: Dental students learn knowledge and practical skills to provide oral health care to the population. Practical skills must be maintained or continuously developed throughout a professional career. This cross-sectional survey aimed to evaluate the perception of practical skills of dental students and dental-school graduates by national dental associations (NDAs) in international comparison in the European Regional Organization of the FDI World Dental Federation (ERO-FDI) zone., Materials and Methods: A questionnaire of 14 items collected information on pre-/postgraduate areas., Results: A total of 25 countries participated (response rate: 69.4%), with 80.0% having minimum requirements for practical skills acquisition and 64.0% starting practical training in the 3rd year of study. In countries where clinical practical work on patients begins in the 2nd year of study, practical skills of graduates are perceived as average, starting in the 3rd year of study as mainly good, starting in the 4th as varying widely from poor to very good. In total, 76.0% of respondents feel that improvements are needed before entering dental practice. Improvements could be reached by treating more patients in dental school (32.0%), increasing the quantity of clinical training (20.0%), or having more clinical instructors (12.0%). In 56.0% of the countries, it is possible to open one's own dental practice immediately after graduation, and in 16.0%, prior vocational training is mandatory., Conclusions: All participating countries in the ERO-FDI zone reported practical training in dental school, most starting in the 3rd year of study. The perception of practical skills of dental students and dental-school graduates among NDAs is very heterogeneous. Reasons for the perceived deficiencies should be further explored.

Activation of the KRAS oncogene is a source of replication stress, but how this stress is generated and how it is tolerated by cancer cells remain poorly understood. Here we show that induction of KRAS G12V expression in untransformed cells triggers H3K27me3 and HP1-associated chromatin compaction in an RNA transcription dependent manner, resulting in replication fork slowing and cell death. Furthermore, elevated ATR expression is necessary and sufficient for tolerance of KRAS G12V -induced replication stress to expand replication stress-tolerant cells (RSTCs). PrimPol is phosphorylated at Ser255, a potential Chk1 substrate site, under KRAS G12V -induced replication stress and promotes repriming to maintain fork progression and cell survival in an ATR/Chk1-dependent manner. However, ssDNA gaps are generated at heterochromatin by PrimPol-dependent repriming, leading to genomic instability. These results reveal a role of ATR-PrimPol in enabling precancerous cells to survive KRAS-induced replication stress and expand clonally with accumulation of genomic instability., (© 2023. Springer Nature Limited.)

Anthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the exchange protein directly activated by cAMP (EPAC) in Dox-induced cardiotoxicity and the potential cardioprotective effects of EPAC inhibition. We show that Dox induces DNA damage and cardiomyocyte cell death with apoptotic features. Dox also led to an increase in both cAMP concentration and EPAC1 activity. The pharmacological inhibition of EPAC1 (with CE3F4) but not EPAC2 alleviated the whole Dox-induced pattern of alterations. When administered in vivo , Dox-treated WT mice developed a dilated cardiomyopathy which was totally prevented in EPAC1 knock-out (KO) mice. Moreover, EPAC1 inhibition potentiated Dox-induced cell death in several human cancer cell lines. Thus, EPAC1 inhibition appears as a potential therapeutic strategy to limit Dox-induced cardiomyopathy without interfering with its antitumoral activity., Competing Interests: MM, AB, MR, DD, AL, ML, TB, PM, MG, FL, JC, CB, CR, FL, BC, JB, MV, RF, AG, CL, EM No competing interests declared, (© 2023, Mazevet et al.)

The SWI/SNF chromatin remodeling complex regulates transcription through the control of chromatin structure and is increasingly thought to play an important role in human cancer. Lung adenocarcinoma (LADC) patients frequently harbor mutations in SMARCA4, a core component of this multisubunit complex. Most of these mutations are loss-of-function mutations, which disrupt critical functions in the regulation of chromatin architecture and can cause DNA replication stress. This study reports that LADC cells deficient in SMARCA4 showed increased DNA replication stress and greater sensitivity to the ATR inhibitor (ATRi) in vitro and in vivo . Mechanistically, loss of SMARCA4 increased heterochromatin formation, resulting in stalled forks, a typical DNA replication stress. In the absence of SMARCA4, severe ATRi-induced single-stranded DNA, which caused replication catastrophe, was generated on nascent DNA near the reversed forks around heterochromatin in an Mre11-dependent manner. Thus, loss of SMARCA4 confers susceptibility to ATRi, both by increasing heterochromatin-associated replication stress and by allowing Mre11 to destabilize reversed forks. These two mechanisms synergistically increase susceptibility of SMARCA4-deficient LADC cells to ATRi. These results provide a preclinical basis for assessing SMARCA4 defects as a biomarker of ATRi efficacy., (© The Author(s) 2020. Published by Oxford University Press on behalf of NAR Cancer.)

This CariesCare practice guide is derived from the International Caries Classification and Management System (ICCMS) and provides a structured update for dentists to help them deliver optimal caries care and outcomes for their patients. This '4D cycle' is a practice-building format, which both prevents and controls caries and can engage patients as long-term health partners with their practice. CariesCare International (CCI™) promotes a patient-centred, risk-based approach to caries management designed for dental practice. This comprises a health outcomes-focused system that aims to maintain oral health and preserve tooth structure in the long-term. It guides the dental team through a four-step process (4D system), leading to personalised interventions: 1st D: Determine Caries Risk; 2nd D: Detect lesions, stage their severity and assess their activity status; 3rd D: Decide on the most appropriate care plan for the specific patient at that time; and then, finally, 4th D: Do the preventive and tooth-preserving care which is needed (including risk-appropriate preventive care; control of initial non-cavitated lesions; and conservative restorative treatment of deep dentinal and cavitated caries lesions). CariesCare International has designed this practice-friendly consensus guide to summarise best practice as informed by the best available evidence. Following the guide should also increase patient satisfaction, involvement, wellbeing and value, by being less invasive and more health-focused. For the dentist it should also provide benefits at the professional and practice levels including improved medico-legal protection.

Cardiac failure is a common complication in cancer survivors treated with anthracyclines. Here we followed up cardiac function and excitation-contraction (EC) coupling in an in vivo doxorubicin (Dox) treated mice model (iv, total dose of 10 mg/Kg divided once every three days). Cardiac function was evaluated by echocardiography at 2, 6 and 15 weeks after the last injection. While normal at 2 and 6 weeks, ejection fraction was significantly reduced at 15 weeks. In order to evaluate the underlying mechanisms, we measured [Ca 2+ ] i transients by confocal microscopy and action potentials (AP) by patch-clamp technique in cardiomyocytes isolated at these times. Three phases were observed: 1/depression and slowing of the [Ca 2+ ] i transients at 2 weeks after treatment, with occurrence of proarrhythmogenic Ca 2+ waves, 2/compensatory state at 6 weeks, and 3/depression on [Ca 2+ ] i transients and cell contraction at 15 weeks, concomitant with in-vivo defects. These [Ca 2+ ] i transient alterations were observed without cellular hypertrophy or AP prolongation and mirrored the sarcoplasmic reticulum (SR) Ca 2+ load variations. At the molecular level, this was associated with a decrease in the sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a) expression and enhanced RyR2 phosphorylation at the protein kinase A (PKA, pS2808) site (2 and 15 weeks). RyR2 phosphorylation at the Ca 2+ /calmodulin dependent protein kinase II (CaMKII, pS2814) site was enhanced only at 2 weeks, coinciding with the higher incidence of proarrhythmogenic Ca 2+ waves. Our study highlighted, for the first time, the progression of Dox treatment-induced alterations in Ca 2+ handling and identified key components of the underlying Dox cardiotoxicity. These findings should be helpful to understand the early-, intermediate-, and late- cardiotoxicity already recorded in clinic in order to prevent or treat at the subclinical level., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target., Methods: The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes., Results: In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca(2+) transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals., Conclusion: Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The issue of toxicity is a primary concern for chest irradiation, because it is a dose-limiting toxicity and because in some circumstances it can alleviate the survival benefit of radiation therapy. Potential acute and delayed side effects can compromise the patients' prognosis and generate significant morbidity. Here we review on chest complications of radiation therapy, with focus on cardiac and pulmonary radio-induced side effects. Most radiographic changes associated with thoracic irradiation are asymptomatic. However, chest irradiation generated by treatment of breast cancer, bronchopulmonary malignancies, or mediastinal lymphoma has been associated with a risk of acute radiation pneumonitis and late lung fibrosis. An increasing number of clinical studies suggest that some dosimetric factors (e.g. V20, V30, mean lung dose) should be considered for limiting the risk of lung toxicity. Improvements in radiation techniques as well as changes in indications, volumes and prescribed doses of radiation therapy should help to better spare lungs from irradiation and thus decreasing the risk of subsequent toxicity. Numerous other contributing factors should also be considered, such as chemotherapeutic agents, smoking, tumor topography, or intrinsic sensitivity. Cardiac toxicity is another clinically relevant issue in patients receiving radiation therapy for breast cancer or for lymphoma. This life threatening toxicity should be analyzed in the light of dosimetric factors (including low doses) but also associated systemic agents which almost carry a potential for additive toxicity toward myocardium or coronaries. A long-term follow-up of patients as well as an increasing knowledge of the underlying biological pathways involved in cardiac toxicity should help designing effective preventing strategies., (Copyright © 2013. Published by Elsevier Masson SAS.)

Anthracyclines, discovered 50 years ago, are antibiotics widely used as antineoplastic agents and are among the most successful anticancer therapies ever developed to treat a wide range of cancers, including hematological malignancies, soft tissue sarcomas and solid tumors. However, some anthracyclines, including doxorubicin, exhibit major signs of cardiotoxicity that may ultimately lead to heart failure (HF). Despite intensive research on doxorubicine-induced cardiotoxicity, the underlying mechanisms responsible for doxorubicin-induced cardiotoxicity have not been fully elucidated yet. Published literature so far has focused mostly on mitochondria dysfunction with consequent oxidative stress, Ca(2+) overload, and cardiomyocyte death as doxorubicin side effects, leading to heart dysfunction. This review focuses on the current understanding of the molecular mechanisms underlying doxorubicin-induced cardiomyocyte death (i.e.: cardiomyocyte death, mitochondria metabolism and bioenergetic alteration), but we will also point to new directions of possible mechanisms, suggesting potent prior or concomitant alterations of specific signaling pathways with molecular actors directly targeted by the anticancer drugs itself (i.e. calcium homeostasis or cAMP signaling cascade). The mechanisms of anticancer cardiac toxicity may be more complex than just mitochondria dysfunction. Partnership of both basic and clinical research is needed to promote new strategies in diagnosis, therapies with concomitant cardioprotection in order to achieve cancer treatment with acceptable cardiotoxicity along life span., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)