While adjuvant therapy with anti-programmed cell death protein-1 (anti-PD1) for patients with resected stage III/IV melanoma has been shown to improve recurrence-free survival, the overall survival ...benefit remains uncertain. This study aims to evaluate the impact of adjuvant anti-PD1 therapy on the health-related quality of life (HRQOL) of patients with resected stage III/IV melanoma
Data was used from two melanoma registries in Australia and the Netherlands. Patients with resected stage III/IV melanoma treated with adjuvant anti-PD1 who completed a baseline and at least one post-baseline HRQOL assessment were included. HRQOL was assessed using the EORTC QLQ-C30 at baseline, 3, 6, and 12 months. Established thresholds were used for interpreting changes in QLQ-C30 scores.
92 patients were included. Mean symptom and functioning scores improved or remained stable at 12 months compared to baseline. However, a substantial proportion of patients experienced a clinically significant decline in role (39%, μ = −50.8), social (41%, μ = −32.7), or emotional (50%, μ = −25.1) functioning at 12 months compared to baseline. Younger patients were more likely to experience clinically significant deteriorations in role (OR=1.07, 95% CI: 1.02–1.13, p < 0.01) and social (OR=1.06, 95% CI: 1.01–1.11, p = 0.013) functioning.
A significant proportion of patients with resected stage III/IV melanoma who received adjuvant anti-PD1 experienced clinically significant declines in role, social and emotional functioning at 12 months compared to baseline. This highlights the HRQOL issues that may arise during adjuvant anti-PD1 therapy which may require supportive care intervention.
•We assessed HRQOL in stage III/IV melanoma patients treated with adjuvant anti-PD1•Many patients’ emotional and social functioning deteriorated after adjuvant therapy.•Younger patients experienced more role and social functioning deterioration.•Our study highlights the value of conducting a more detailed analysis of HRQOL data.
It is widely accepted that the intestinal microbiome is connected to obesity, as key mediator of the diet impact on the host metabolic and immunological status. To investigate whether the individual ...gut microbiome has a potential in predicting the onset and progression of diseases, here we characterized the faecal microbiota of 70 children in a two-time point prospective study, within a four-year window. All children had normal weight at the beginning of this study, but 36 of them gained excessive weight at the subsequent check-up. Microbiome data were analysed together with the hosts' diet information, physical activity, and inflammatory parameters. We find that the gut microbiota structures were stratified into a discrete number of groups, characterized by different biodiversity that correlates with inflammatory markers and dietary habits, regardless of age, gender, and body weight. Collectively, our data underscore the importance of the microbiome-host-diet configuration as a possible predictor of obesity.
Muscular and cardiorespiratory fitness (MF and CRF) have been related to inflammation. Thus, the aim of this study was to assess the relationship between fitness and high-sensitivity C-reactive ...protein (hs-CRP) in European children both in the cross-sectional and longitudinal analysis.
Three hundred and fifty-seven children (46.2% males) aged 2-9 years with hs-CRP measured, data from MF and CRF, diet quality, objectively measured physical activity (PA) and screen time at baseline and follow-up after 2 years were included. Body mass index z-score (zBMI), waist circumference (WC) and fat mass index (FMI) were assessed. MF and CRF were also dichotomized as follows: low-medium quartiles (Q1-Q3) and highest quartile (Q4).
At follow-up, children with the highest CRF (Q4) showed a lower probability of having high hs-CRP. In the longitudinal analysis, children who improved their CRF over time showed a significantly lower probability (p < 0.05) of being in the highest hs-CRP category at follow-up, independently of the body composition index considered: odds ratio (OR) = 0.22 for zBMI, OR = 0.17 for WC, and OR = 0.21 for FMI.
Improving CRF during childhood reduces the odds of an inflammatory profile, independently of body composition and lifestyle behaviours. These highlight the importance of enhancing fitness, especially CRF, to avoid an inflammatory state in children.
Improvements in the cardiorespiratory profile during childhood could reverse an unfavourable inflammatory status. There is a longitudinal and inverse association between CRF and inflammation in children. This is the first longitudinal study assessing the relationship between fitness and inflammation during childhood that takes also into account the lifestyle behaviours. Results from the present study suggest a protective role of fitness already in childhood. Efforts to improve fitness in children should be aimed at as inflammation could trigger future cardiovascular disease.
PRC2 is thought to be the histone methyltransferase (HMTase) responsible for H3‐K27 trimethylation at Polycomb target genes. Here we report the biochemical purification and characterization of a ...distinct form of Drosophila PRC2 that contains the Polycomb group protein polycomblike (Pcl). Like PRC2, Pcl‐PRC2 is an H3‐K27‐specific HMTase that mono‐, di‐ and trimethylates H3‐K27 in nucleosomes in vitro. Analysis of Drosophila mutants that lack Pcl unexpectedly reveals that Pcl‐PRC2 is required to generate high levels of H3‐K27 trimethylation at Polycomb target genes but is dispensable for the genome‐wide H3‐K27 mono‐ and dimethylation that is generated by PRC2. In Pcl mutants, Polycomb target genes become derepressed even though H3‐K27 trimethylation at these genes is only reduced and not abolished, and even though targeting of the Polycomb protein complexes PhoRC and PRC1 to Polycomb response elements is not affected. Pcl‐PRC2 is thus the HMTase that generates the high levels of H3‐K27 trimethylation in Polycomb target genes that are needed to maintain a Polycomb‐repressed chromatin state.
Polycomb group (PcG) proteins are transcriptional repressors that control processes ranging from the maintenance of cell fate decisions and stem cell pluripotency in animals to the control of ...flowering time in plants. In Drosophila, genetic studies identified more than 15 different PcG proteins that are required to repress homeotic (HOX) and other developmental regulator genes in cells where they must stay inactive. Biochemical analyses established that these PcG proteins exist in distinct multiprotein complexes that bind to and modify chromatin of target genes. Among those, Polycomb repressive complex 1 (PRC1) and the related dRing-associated factors (dRAF) complex contain an E3 ligase activity for monoubiquitination of histone H2A (refs 1-4). Here we show that the uncharacterized Drosophila PcG gene calypso encodes the ubiquitin carboxy-terminal hydrolase BAP1. Biochemically purified Calypso exists in a complex with the PcG protein ASX, and this complex, named Polycomb repressive deubiquitinase (PR-DUB), is bound at PcG target genes in Drosophila. Reconstituted recombinant Drosophila and human PR-DUB complexes remove monoubiquitin from H2A but not from H2B in nucleosomes. Drosophila mutants lacking PR-DUB show a strong increase in the levels of monoubiquitinated H2A. A mutation that disrupts the catalytic activity of Calypso, or absence of the ASX subunit abolishes H2A deubiquitination in vitro and HOX gene repression in vivo. Polycomb gene silencing may thus entail a dynamic balance between H2A ubiquitination by PRC1 and dRAF, and H2A deubiquitination by PR-DUB.
This systematic scoping review compares the toxicities experienced by patients receiving immune checkpoint inhibitors (ICIs) or targeted therapy (TT) for stage III (resected and unresectable) and ...stage IV melanoma.
OVID Medline, Embase, and PsycInfo were searched to identify Phase III trials reporting toxicities of FDA-approved ICIs and TT for advanced melanoma. AEs that were reported by ≥ 10% of patients in the evaluated trials were included.
Toxicity profiles of 11208 patients from 24 studies were reviewed. The rate of AEs was lower with ICIs compared to TT. However, ICIs were associated with higher rates of long-term or permanent AEs compared to TT, where toxicities generally were shortterm and reversible with treatment discontinuation.
The toxicity profiles of ICIs and TT vary substantially. Whilst the rate of AEs was lower with ICIs than during TT, it was also associated with higher rates of potentially chronic AEs.
•The use of targeted therapy (TT) was associated with higher rates of AEs than the use of immune-checkpoint inhibitors (ICIs).•ICIs were associated with higher rates of long-term AEs compared to TT, where toxicities were short-term and reversible.•Resected melanoma patients experienced more AEs during ICIs than unresectable or metastatic melanoma patients.•For TT, vemurafenib was associated with the highest rates of AEs of all evaluated mono and combination treatments.•Varying toxicity reporting methods are a serious problem when comparing toxicity results from melanoma trials.
The present study aims to examine the cross‐sectional and longitudinal association between self‐reported nocturnal sleep duration, blood pressure, and hypertension in European children, aged ...2‐9.9 years, participating in the IDEFICS project. Blood pressure (BP) and the main anthropometric indices were measured according to standardized procedures. Childhood elevated BP and hypertension were defined according to the European Society of Hypertension Guidelines for children and adolescents. Parents reported lifestyle and socio‐demographic data. Nocturnal sleep duration was assessed as part of a parental 24‐h recall and categorized as follows: (a) ≤9 hours/night; (b) >9 hours to ≤10 hours/night; (c) >10 hours to ≤11 hours/night; and (d) >11 hours/night. A complete set of variables included in the present analysis was provided by 7974 participants (boys/girls = 4049/3925) at the baseline survey (T0). Of them, 5656 were re‐examined 2 years later at follow‐up (T1). Children reporting shorter sleep duration at T0 had significantly higher BP values (P for trend < 0.001) compared to those who slept more. Prospective analyses showed that shorter sleep duration at baseline predicted, over the 2‐year follow‐up, higher increases in systolic blood pressure and diastolic blood pressure, after adjustment for age, sex, country of origin, BMI z‐score, parental education, physical activity, screen time, and T0 value of the examined outcome variables (P for trend < 0.001). Our findings reveal that shorter sleep duration is associated with higher BP in childhood, suggesting that sleep may be a potential risk factor for hypertension later in life.
Purpose
The use of Patient-Reported Outcome Measures (PROMs) for individual patient management within clinical practice is becoming increasingly important. New evidence about graphic visualization ...formats for PROMs scores has become available. This systematic literature review evaluated evidence for graphic visualization formats of PROMs data in clinical practice for patients and clinicians, for both individual and group level PROMs data.
Methods
Studies published between 2000 and 2020 were extracted from CINAHL, PubMed, PsychInfo, and Medline. Studies included patients ≥ 18 years old in daily clinical practice. Papers not available in English, without full-text access, or that did not specifically describe visualization of PROMs data were excluded. Outcomes were: visualization preferences; interpretation accuracy; guidance for clinical interpretation.
Results
Twenty-five out of 789 papers were included for final analysis. Most frequently studied formats were: bar charts, line graphs, and pie charts. Patients preferred bar charts and line graphs as these were easy and quick for retrieving information about their PROMs scores over time. Clinicians’ interpretation accuracy and preferences were similar among graphic visualization formats. Scores were most often compared with patients’ own previous scores; to further guide clinical interpretation, scores were compared to norm population scores. Different ‘add-ons’ improved interpretability for patients and clinicians, e.g. using colors, descriptions of measurement scale directionality, descriptive labels, and brief definitions.
Conclusion
There was no predominant graphical visualization format approach in terms of preferences or interpretation accuracy for both patients and clinicians. Detailed clarification of graph content is essential.
Plain English summary
Patient-Reported Outcome Measures (PROMs) capture patients' self-reported health through the use of questionnaires. PROMs measure health related quality of life, daily functioning, and symptom experience, which are becoming increasingly important to incorporate in clinical practice for individual patient management. To present PROMs within clinical practice, raw or summarized PROMs scores can be visualized in graphical formats. To be useful during clinical encounters, both patients and clinicians ought to interpret such formats correctly. New evidence about graphic visualization formats for PROMs scores has become available. Therefore, we systematically reviewed the literature to evaluate evidence for graphic visualization formats of PROMs data in clinical practice. In 25 included papers, most studies used graphical formats like bar charts, line graphs, and pie charts for presenting PROMs scores. There was no predominant graphical visualization format approach in terms of preferences or interpretation accuracy for both patients and clinicians. Patients preferred bar charts and line graphs as these were easy and quick for retrieving information about their PROMs scores over time. Clinicians’ interpretation accuracy and preferences were similar among graphic visualization formats. The graphical interpretation of PROMs data for patients and clinicians can be improved by using colors, descriptions of measurement scale directionality, descriptive labels, and brief definitions.
Polycomb group (PcG) protein complexes repress developmental regulator genes by modifying their chromatin. How different PcG proteins assemble into complexes and are recruited to their target genes ...is poorly understood. Here, we report the crystal structure of the core of the Drosophila PcG protein complex Pleiohomeotic (Pho)-repressive complex (PhoRC), which contains the Polycomb response element (PRE)-binding protein Pho and Sfmbt. The spacer region of Pho, separated from the DNA-binding domain by a long flexible linker, forms a tight complex with the four malignant brain tumor (4MBT) domain of Sfmbt. The highly conserved spacer region of the human Pho ortholog YY1 binds three of the four human 4MBT domain proteins in an analogous manner but with lower affinity. Comparison of the Drosophila Pho:Sfmbt and human YY1:MBTD1 complex structures provides a molecular explanation for the lower affinity of YY1 for human 4MBT domain proteins. Structure-guided mutations that disrupt the interaction between Pho and Sfmbt abolish formation of a ternary Sfmbt:Pho:DNA complex in vitro and repression of developmental regulator genes in Drosophila. PRE tethering of Sfmbt by Pho is therefore essential for Polycomb repression in Drosophila. Our results support a model where DNA tethering of Sfmbt by Pho and multivalent interactions of Sfmbt with histone modifications and other PcG proteins create a hub for PcG protein complex assembly at PREs.
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