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Background/Objective: The present case demonstrates the successful preservation of a severely inflamed dental pulp despite uncontrolled bleeding occurring during pulpotomy. This novel therapeutic approach was developed when a 7-year-old boy presented for endodontic treatment one week after sustaining a crown-root fracture in an immature incisor. The tooth exhibited slight hypersensitivity to cold testing, with no tenderness to percussion or palpation. An exposed pulp was present; however, when he could avoid contact with the exposed pulp tissue, the patient reported no symptoms. Methods: The critical determinant of success when uncontrolled pulpal bleeding occurred following pulpotomy was the stepwise treatment in two visits and the bacteria-tight seal of the access cavity. The seal was achieved through the incremental application of the temporary filling material. A calcium hydroxide preparation was applied as interappointment topical pulp dressing. Four weeks after the initial visit the pulpotomy could be accomplished. Results: During 3.5 years of follow-up, the patient remained without symptoms and the tooth showed ongoing root growth in length and width combined with positive reaction to electric pulp testing. Conclusions: In summary, this case demonstrates that, despite persistent bleeding following pulpotomy, pulpal vitality can be preserved, thereby promoting continued root development.

Hydraulic calcium silicate cements (HCSCs) are contemporary materials in vital pulp therapy (VPT) and regenerative endodontic therapy (RET) due to their favorable effects on pulpal and periodontal cells, including cell differentiation and hard tissue formation. Recent studies also indicated the involvement of several S100A proteins in inflammatory, differentiation, and mineralization processes of the pulp. The aim of the present study was to investigate the effects of HCSCs on S100A gene expression in human dental pulp stem cells (hDPSCs). Human DPSCs were isolated and characterized by multi-lineage stem-cell markers and differentiation protocols. In stimulation experiments hDPSCs were exposed to ProRoot®MTA, Biodentine®, IL-1β, and dexamethasone. Cell viability was determined by XTT assay. IL-6 and IL-8 mRNA expression was measured to analyze proinflammatory response. In addition, odontogenic differentiation and biomineralization assays were conducted (DSPP- and ALP-mRNA expression, ALP activity, and Alizarin Red staining). Differential expression of 13 S100A genes was examined using qPCR. Low concentrations of HCSCs enhanced the proliferation of hDPSCs, whereas higher concentrations exhibited cytotoxic effects. HCSCs induced a pro-inflammatory response and led to odontogenic differentiation and biomineralization. This was accompanied by significant alterations in the expression levels of various S100A genes. ProRoot®MTA and Biodentine® significantly affect the expression of several S100A genes in hDPSCs, supporting their role in inflammation, differentiation, and mineralization. These findings indicate a link between the effects of HCSCs on human pulp cells during VPT or RET and S100A proteins.

ObjectivesThis in vitro study aimed to modify TLR-2-mediated effects on the paracrine, proliferative, and differentiation potentials of human dental pulp–derived cells using histone acetyltransferase (HAT) and histone deacetylase (HDAC) inhibitors.Materials and methodsCell viability was assessed using the XTT assay. Cells were either treated with 10 μg/ml Pam3CSK4 only, or pre-treated with valproic acid (VPA) (3 mM), trichostatin A (TSA) (3 μM), and MG-149 (3 μM) for a total of 4 h and 24 h. Control groups included unstimulated cells and cells incubated with inhibitors solvents only. Transcript levels for NANOG, OCT3-4, FGF-1 and 2, NGF, VEGF, COL-1A1, TLR-2, hβD-2 and 3, BMP-2, DSPP, and ALP were assessed through qPCR.ResultsAfter 24 h, TSA pre-treatment significantly upregulated the defensins and maintained the elevated pro-inflammatory cytokines, but significantly reduced healing and differentiation genes. VPA significantly upregulated the pro-inflammatory cytokine levels, while MG-149 significantly downregulated them. Pluripotency genes were not significantly affected by any regimen.ConclusionsAt the attempted concentrations, TSA upregulated the defensins gene expression levels, and MG-149 exerted a remarkable anti-inflammatory effect; therefore, they could favorably impact the immunological profile of hDPCs.Clinical relevanceTargeting hDPC nuclear function could be a promising option in the scope of the biological management of inflammatory pulp diseases.

Objectives Narrowed radicular pulp spaces are frequently observed in teeth wearing extended restorations. The present study investigates whether the narrowing of particularly the radicular pulp space can be attributed to coronal restorations. Materials and methods The study is based on an anonymized copy of the cone-beam computed tomography (CBCT) database from the Center of Dental Medicine of the University of Zurich. One hundred CBCT scans were selected out of 7317 data sets to match either a crowned (group A; n  = 50) or a filled tooth (group B; n  = 50) with a contralateral healthy, unrestored, and caries-free control tooth at the same position, respectively. Cross-sectional images were adjusted in the coronal, middle, and apical root third of each subjected tooth. Screenshots were taken in that position and analyzed. The area occupied by the pulp space was determined as percentage area of the whole root diameter on each cross section. The resulting values were compared between restored and control teeth. Results In both groups (crowned and filled teeth) and in all the three root thirds, the radicular pulp space was significantly narrower in the restored teeth compared to the control teeth. The strongest narrowing effect was observed in the coronal root third and it decreased towards the apical root third (both groups). Conclusions Teeth with coronal restorations show within the limitations of the present study a significant narrowing of their radicular pulp space. Clinical relevance The asserted narrowing could have a complicating effect if root canal treatment becomes necessary in those teeth.

The aim of this study was to assess the effect of body temperature (37 °C) on the cyclic fatigue resistance of three endodontic single-file systems using a new testing setup. One Shape® new generation (OS), WaveOne™ (WO) and WaveOne® GOLD (WOG), which are made from different NiTi alloys and operated in different motions (rotation/reciprocation), were evaluated. The study design included four groups. Each group comprised 30 files, 10 files of each of the three file systems, tested at 20 ± 2 °C (group 1 and 3) and at 37 ± 1 °C (group 2 and 4). All files were tested in a custom-made metal block with artificial canals of 60° angle, and a 5 mm and 3 mm radius of curvature, respectively. A heating element was attached to replicate a temperature of 37 °C. Files were introduced 18 mm into the canals and operated until failure. Transformation temperatures of five samples of each of the tested file systems were determined via the bend and free recovery (BFR) method. With the exception of WOG in canals with a 3 mm radius of curvature (p = 0.075), all the tested file systems showed statistically significantly less time needed to fracture when operated at 37 ± 1 °C compared to at 20 ± 2 °C in canals with a 5 mm and 3 mm radius of curvature using Mann–Whitney U test (p < 0.05). All file systems showed transformation temperatures below the body temperature. We concluded that body temperature directly affects the cyclic fatigue resistance of all tested file systems. Bend and free recovery can be suitable for the determination of austenite finish temperatures (Af) of endodontic instruments as it allows testing a longer portion of the instrument.

Objectives The aim of this series of studies was the development and validation of a new model for evaluation of dentinal hypersensitivity (DH) therapies. Materials and methods Roots from extracted human teeth were sealed with a flowable composite. In the cervical area, a 3-mm-wide circular window was ground through the seal 1 mm deep into dentine. The pulp lumen was connected to a reservoir of artificial dentinal fluid (ADF) containing protein, mineral salts and methylene blue. At increased pulpal pressure, the ADF released through the said window was collected in containers each with 20 ml of physiologic saline for a consecutive series of 30-min intervals and ADF concentration (absorption) was determined photometrically. The model was verified by three experiments. In experiment 1, the lower limit of quantification (LLoQ, coefficient of variation = 20 % and difference of 5 standard deviations (SD) from blank) of ADF in physiologic saline was determined by measuring the absorption of 15 dilutions of ADF in physiologic saline (containing 0.625 ng to 12.5 μg methylene blue/ml) photometrically for ten times. In experiment 2, long-term linearity of ADF perfusion/outflow was investigated using 11 specimens. The ADF released through the window was collected in the said containers separately for each consecutive interval of 30 min for up to 240 min. Absorption was determined and analysed by linear regression over time. In experiment 3, perfusion before (2×) and after single treatment according to the following three groups was measured: BisGMA-based sealant (Seal&Protect®), an acidic fluoride solution (elmex fluid®) and control (no treatment). Results In experiment 1, the LLoQ was 0.005 μg methylene blue/ml. In experiment 2, permeability was different within the specimens and decreased highly linearly with time, allowing the prediction of future values. In experiment 3, Seal&Protect® completely occluded dentinal tubules. elmex fluid® increased tubular permeability by about 30 % compared to control. Conclusions A model comprising the use of artificial dentinal fluid was developed and validated allowing screening of therapeutic agents for the treatment of DH through reliable measurement of permeability of cervical root dentine. Clinical relevance The described in vitro model allows evaluation of potential agents for the treatment of DH at the clinically relevant cervical region of human teeth.

The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions. Immune response during breast cancer progression remains to be explored. Here, the characterisation of sequential and parallel multiregion samples of an index patient and a cohort of metastatic triple-negative breast cancers reveals convergent immune evasion mechanisms and an increase in tumor genomic heterogeneity.

•Since 2017, a number of clinical studies in centronuclear myopathies have taken place.•Focus groups were held with members of patient organizations in different countries.•The results provide insights in trial experiences and recommendations for future trials.•The acknowledgment of the patient perspective was strongly appreciated.•Efficient communication is expected to improve future clinical studies. Since 2014, several clinical studies focusing on centronuclear myopathies have been conducted, including a prospective natural history study, a gene transfer clinical trial and a clinical trial using an antisense oligonucleotide. Dedicated patient organizations have played an important role in this process. The experience of members of these organizations, either as a study participant, parent or as a patient organization member communicating with the sponsors are potentially very informative for future trial design. We investigated the burden of and the lessons learned from the first natural history studies and clinical trials from a patient perspective using a qualitative approach. We arranged 4 focus groups with a total of 37 participants from 3 large international patient organizations: ZNM-ZusammenStark!, the Myotubular Trust, and the MTM-CNM Family Connection. 4 themes, based on a systematic literature search were discussed: Expectations and preparation, Clinical study participation, Communication and Recommendations for future clinical trials. The focus group recordings were transcribed, anonymized, and uploaded to Atlas-ti version 8.1 software. The data were analyzed using a thematic content analysis. Overall, participants were realistic in their expectations, hoping for small improvements of function and quality of life. The realization that trial participation does not equate to a treatment was challenging. Participating in a clinical study had a huge impact on many aspects of daily life, both for patients and their immediate families. First-hand insights into the burden of the design and its possible effect on performance were provided, resulting in numerous compelling recommendations for future clinical studies. Furthermore, participants stressed the importance of clear communication, which was considered to be especially vital in cases of severe adverse events. Finally, while patients were understanding of the importance of adhering to the regulations of good clinical practice, they indicated that they would strongly appreciate a greater understanding and/or acknowledgment of the patient perspective and a reflection of this perspective in future clinical trial design. The acknowledgment and inclusion of patients’ perspectives and efficient and effective communication is expected to improve patient recruitment and retention in future clinical studies, as well as more accurate assessment of the patient performance related to suitable planning of the study visits.

The cancer-testis (CT) family of antigens is expressed in a variety of malignant neoplasms. In most cases, no CT antigen is found in normal tissues, except in testis, making them ideal targets for cancer immunotherapy. A comprehensive analysis of CT antigen expression has not yet been reported in prostate cancer. MAGE-C2/CT-10 is a novel CT antigen. The objective of this study was to analyze extent and prognostic significance of MAGE-C2/CT10 protein expression in prostate cancer. 348 prostate carcinomas from consecutive radical prostatectomies, 29 castration-refractory prostate cancer, 46 metastases, and 45 benign hyperplasias were immunohistochemically analyzed for MAGE-C2/CT10 expression using tissue microarrays. Nuclear MAGE-C2/CT10 expression was identified in only 3.3% primary prostate carcinomas. MAGE-C2/CT10 protein expression was significantly more frequent in metastatic (16.3% positivity) and castration-resistant prostate cancer (17% positivity; p<0.001). Nuclear MAGE-C2/CT10 expression was identified as predictor of biochemical recurrence after radical prostatectomy (p = 0.015), which was independent of preoperative PSA, Gleason score, tumor stage, and surgical margin status in multivariate analysis (p<0.05). MAGE-C2/CT10 expression in prostate cancer correlates with the degree of malignancy and indicates a higher risk for biochemical recurrence after radical prostatectomy. Further, the results suggest MAGE-C2/CT10 as a potential target for adjuvant and palliative immunotherapy in patients with prostate cancer.

TRANSVAC represents a long-running effort to accelerate the development of novel vaccines by integrating institutions from across Europe under a single collaborative framework. This initiative has empowered the global vaccine community since 2009 including contributing toward the development and optimization of vaccine candidates as well as the provision of new adjuvants, research protocols, and technologies. Scientific services were provided in support of 88 different vaccine development projects, and 400 professionals attended TRANSVAC training events on various vaccine-related topics. Here, we review the accomplishments of the TRANSVAC consortia and analyze the continued needs of academic and industrial vaccine developers in Europe. The findings highlight the benefits of coordination across different sectors, both through research infrastructures such as TRANSVAC and other mechanisms, to address the current and future global health challenges and ensure that European vaccine developers have the support required to successfully compete in the global market.