PurposeThe present study aimed to determine the prevalence of self-reported oral problems and the oral health-related quality of life (OHRQoL) in childhood cancer survivors (CCS).MethodsPatient and... Show morePurposeThe present study aimed to determine the prevalence of self-reported oral problems and the oral health-related quality of life (OHRQoL) in childhood cancer survivors (CCS).MethodsPatient and treatment characteristics of CCS have been collected in a cross-sectional study, part of the multidisciplinary DCCSS-LATER 2 Study. To assess self-reported oral health problems and dental problems, CCS filled out the 'Toegepast-Natuurwetenschappelijk Onderzoek' (TNO) oral health questionnaire. OHRQoL was assessed by the Dutch version of the Oral Health Impact Profile-14 (OHIP-14). Prevalences were compared with two comparison groups from the literature. Univariable and multivariable analyses were performed.ResultsA total of 249 CCS participated in our study. The OHIP-14 total score had a mean value of 1.94 (sd 4.39), with a median score of 0 (range 0-29). The oral problems 'oral blisters/aphthae' (25.9%) and 'bad odor/halitosis' (23.3%) were significantly more often reported in CCS than in comparison groups (12% and 12%, respectively). The OHIP-14 score was significantly correlated with the number of self-reported oral health problems (r = .333, p<0.0005) and dental problems (r = .392, p <0.0005). In multivariable analysis, CCS with a shorter time since diagnosis (10-19 years vs. >= 30 years) had a 1.47-fold higher risk of >= 1 oral health problem.ConclusionThough the perceived oral health is relatively good, oral complications following childhood cancer treatment are prevalent in CCS. This underlines that attention to impaired oral health and awareness on this topic is mandatory and regular visits to the dentist should be a part of long-term follow-up care. Show less
Schultheis, M.; Zhao, H.; Zwitter, T.; Bailer-Jones, C.A.L.; Carballo, R.; Sordo, R.; ... ; Meichsner, J. et al. 2023
Cutaneous T-cell lymphomas (CTCLs) are a subset of T-cell malignancies presenting in the skin. The treatment options for CTCL, in particular in advanced stages, are limited. One of the emerging... Show moreCutaneous T-cell lymphomas (CTCLs) are a subset of T-cell malignancies presenting in the skin. The treatment options for CTCL, in particular in advanced stages, are limited. One of the emerging therapies for CTCL is treatment with histone deacetylase (HDAC) inhibitors. We recently discovered an evolutionarily conserved crosstalk between HDAC1, one of the targets of HDAC inhibitors, and the histone methyltransferase DOT1L. HDAC1 negatively regulates DOT1L activity in yeast, mouse thymocytes, and mouse thymic lymphoma. Here we studied the functional relationship between HDAC inhibitors and DOT1L in two human CTCL cell lines, specifically addressing the question whether the crosstalk between DOT1L and HDAC1 observed in mouse T cells plays a role in the therapeutic effect of clinically relevant broad-acting HDAC inhibitors in the treatment of human CTCL. We confirmed that human CTCL cell lines were sensitive to treatment with pan-HDAC inhibitors. In contrast, the cell lines were not sensitive to DOT1L inhibitors. Combining both types of inhibitors did neither enhance nor suppress the inhibitory effect of HDAC inhibitors on CTCL cells. Thus our in vitro studies suggest that the effect of commonly used pan-HDAC inhibitors in CTCL cells relies on downstream effects other than DOT1L misregulation. Show less
Mazzone, E.; Dell'Oglio, P.; Grivas, N.; Wit, E.; Donswijk, M.; Briganti, A.; ... ; Poel, H. van der 2021
Despite good sensitivity and a good negative predictive value, the implementation of sentinel node biopsy (SNB) in robot-assisted radical prostatectomy with extended pelvic lymph node dissection ... Show moreDespite good sensitivity and a good negative predictive value, the implementation of sentinel node biopsy (SNB) in robot-assisted radical prostatectomy with extended pelvic lymph node dissection (ePLND) for prostate cancer is still controversial. For this reason, we aimed to define the added value of SNB (with different tracer modalities) to ePLND in the identification of nodal metastases. Complication rates and oncologic outcomes were also assessed. Methods: From January 2006 to December 2019, prospectively collected data were retrospectively analyzed from a single-institution database regarding prostate cancer patients treated with robot-assisted radical prostatectomy and ePLND with or without additional use of SNB, either with the hybrid tracer indocyanine green (ICG)-Tc-99m-nanocolloid or with free ICG. Multivariable logistic and Cox regression models tested the impact of adding SNB (either with the hybrid tracer or with free ICG) on lymph nodal invasion detection, complications, and oncologic outcomes. Results: Overall, 1,680 patients were included in the final analysis: 1,168 (69.5%) in the non-SNB group, 161 (9.6%) in the ICG-SNB group, and 351 (20.9%) in the hybrid-SNB group. The hybrid-SNB group (odds ratio, 1.61; 95%CI, 1.18-2.20; P = 0.002) was an independent predictor of nodal involvement, whereas the ICG-SNB group did not reach independent predictor status when compared with the non-SNB group (odds ratio, 1.35; 95%CI, 0.89-2.03; P = 0.1). SNB techniques were not associated with higher rates of complications. Lastly, use of hybrid SNB was associated with lower rates of biochemical recurrence (0.79; 95%CI, 0.63-0.98) and of clinical recurrence (hazard ratio, 0.76, P = 0.035) than were seen in the non-SNB group. Conclusion: The implementation of hybrid-SNB technique with ICG-Tc-99m-nanocolloid in prostate cancer improves detection of positive nodes and potentially lowers recurrence rates with subsequent optimization of patient management, without harming patient safety. Show less
Kollenstart, L.; Horst, S.C. van der; Vreeken, K.; Janssen, G.M.C.; Martino, F.; Vlaming, H.; ... ; Attikum, H. van 2021
The collection of known posttranslational modifications (PTMs) has expanded rapidly with the identification of various non-acetyl histone lysine acylations, such as crotonylation, succinylation and... Show moreThe collection of known posttranslational modifications (PTMs) has expanded rapidly with the identification of various non-acetyl histone lysine acylations, such as crotonylation, succinylation and butyrylation, yet their regulation is still not fully understood. Through an unbiased chromatin immunoprecipitation (ChIP)-based approach called Epigenetics-IDentifier (Epi-ID), we aimed to identify regulators of crotonylation, succinylation and butyrylation in thousands of yeast mutants simultaneously. However, highly correlative results led us to further investigate the specificity of the pan-K-acyl antibodies used in our Epi-ID studies. This revealed cross-reactivity and lack of specificity of pan-K-acyl antibodies in various assays. Our findings suggest that the antibodies might recognize histone acetylation in vivo, in addition to histone acylation, due to the vast overabundance of acetylation compared to other acylation modifications in cells. Consequently, our Epi-ID screen mostly identified factors affecting histone acetylation, including known (e.g. GCN5, HDA1, and HDA2) and unanticipated (MET7, MTF1, CLB3, and RAD26) factors, expanding the repertoire of acetylation regulators. Antibody-independent follow-up experiments on the Gcn5-Ada2-Ada3 (ADA) complex revealed that, in addition to acetylation and crotonylation, ADA has the ability to butyrylate histones. Thus, our Epi-ID screens revealed limits of using pan-K-acyl antibodies in epigenetics research, expanded the repertoire of regulators of histone acetylation, and attributed butyrylation activity to the ADA complex. Show less
Dell'Oglio, P.; Mazzone, E.; Grivas, N.; Wit, E.; Donswijk, M.; Briganti, A.; ... ; Poel, H. van der 2021
Despite good sensitivity and a good negative predictive value, the implementation of sentinel node biopsy (SNB) in robot-assisted radical prostatectomy with extended pelvic lymph node dissection ... Show moreDespite good sensitivity and a good negative predictive value, the implementation of sentinel node biopsy (SNB) in robot-assisted radical prostatectomy with extended pelvic lymph node dissection (ePLND) for prostate cancer is still controversial. For this reason, we aimed to define the added value of SNB (with different tracer modalities) to ePLND in the identification of nodal metastases. Complication rates and oncologic outcomes were also assessed. Methods: From January 2006 to December 2019, prospectively collected data were retrospectively analyzed from a single-institution database regarding prostate cancer patients treated with robot-assisted radical prostatectomy and ePLND with or without additional use of SNB, either with the hybrid tracer indocyanine green (ICG)–99mTc-nanocolloid or with free ICG. Multivariable logistic and Cox regression models tested the impact of adding SNB (either with the hybrid tracer or with free ICG) on lymph nodal invasion detection, complications, and oncologic outcomes. Results: Overall, 1,680 patients were included in the final analysis: 1,168 (69.5%) in the non-SNB group, 161 (9.6%) in the ICG-SNB group, and 351 (20.9%) in the hybrid-SNB group. The hybrid-SNB group (odds ratio, 1.61; 95%CI, 1.18–2.20; P = 0.002) was an independent predictor of nodal involvement, whereas the ICG-SNB group did not reach independent predictor status when compared with the non-SNB group (odds ratio, 1.35; 95%CI, 0.89–2.03; P = 0.1). SNB techniques were not associated with higher rates of complications. Lastly, use of hybrid SNB was associated with lower rates of biochemical recurrence (0.79; 95%CI, 0.63–0.98) and of clinical recurrence (hazard ratio, 0.76, P = 0.035) than were seen in the non-SNB group. Conclusion: The implementation of hybrid-SNB technique with ICG–99mTc-nanocolloid in prostate cancer improves detection of positive nodes and potentially lowers recurrence rates with subsequent optimization of patient management, without harming patient safety. Show less
Zande, H.J.P. van der; Gonzalez, M.A.; Ruiter, K. de; Wilbers, R.H.P.; Garcia-Tardon, N.; Huizen, M. van; ... ; Guigas, B. 2021
Type 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta-inflammation and insulin resistance. Infection with the helminth... Show moreType 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta-inflammation and insulin resistance. Infection with the helminth parasite Schistosoma mansoni and treatment with its soluble egg antigens (SEA) induce a type 2 immune response in metabolic organs and improve insulin sensitivity and glucose tolerance in obese mice, yet, a causal relationship remains unproven. Here, we investigated the effects and underlying mechanisms of the T2 ribonuclease omega-1 (omega 1), one of the major S mansoni immunomodulatory glycoproteins, on metabolic homeostasis. We show that treatment of obese mice with plant-produced recombinant omega 1, harboring similar glycan motifs as present on the native molecule, decreased body fat mass, and improved systemic insulin sensitivity and glucose tolerance in a time- and dose-dependent manner. This effect was associated with an increase in white adipose tissue (WAT) type 2 T helper cells, eosinophils, and alternatively activated macrophages, without affecting type 2 innate lymphoid cells. In contrast to SEA, the metabolic effects of omega 1 were still observed in obese STAT6-deficient mice with impaired type 2 immunity, indicating that its metabolic effects are independent of the type 2 immune response. Instead, we found that omega 1 inhibited food intake, without affecting locomotor activity, WAT thermogenic capacity or whole-body energy expenditure, an effect also occurring in leptin receptor-deficient obese and hyperphagic db/db mice. Altogether, we demonstrate that while the helminth glycoprotein omega 1 can induce type 2 immunity, it improves whole-body metabolic homeostasis in obese mice by inhibiting food intake via a STAT6-independent mechanism. Show less
Starreveld, D.E.J.; Habers, G.E.A.; Valdimarsdottir, H.; Kessels, R.; Daniels, L.; Leeuwen, F. van; Bleiker, E. 2021
Differentiation of naive peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B-cell fate remain... Show moreDifferentiation of naive peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B-cell fate remain unclear. Here, we identified a role for the histone H3K79 methyltransferase DOT1L in controlling B-cell differentiation. Mouse B cells lacking Dot1L failed to establish germinal centers (GC) and normal humoral immune responses in vivo. In vitro, activated B cells in which Dot1L was deleted showed aberrant differentiation and prematurely acquired plasma cell characteristics. Similar results were obtained when DOT1L was chemically inhibited in mature B cells in vitro. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative, pro-GC program. In addition, DOT1L indirectly supports the repression of an anti-proliferative plasma cell differentiation program by maintaining the repression of Polycomb Repressor Complex 2 (PRC2) targets. Our findings show that DOT1L is a key modulator of the core transcriptional and epigenetic landscape in B cells, establishing an epigenetic barrier that warrants B-cell naivety and GC B-cell differentiation. Show less
Riello, M.; De Angeli, F.; Evans, D.W.; Montegriffo, P.; Carrasco, J.M.; Busso, G.; ... ; Yoldas, A. 2021
