Correlation between Multiparametric MR Imaging and Molecular Genetics in Pontine Pediatric High-Grade Glioma.

BACKGROUND AND PURPOSE: Molecular profiling is a crucial feature in the "integrated diagnosis" of CNS tumors. We aimed to determine whether radiomics could distinguish molecular types of pontine pediatric high-grade gliomas that have similar/overlapping phenotypes on conventional anatomic MR images. MATERIALS AND METHODS: Baseline MR images from children with pontine pediatric high-grade gliomas were analyzed. Retrospective imaging studies included standard precontrast and postcontrast sequences and DTI. Imaging analyses included median, mean, mode, skewness, and kurtosis of the ADC histogram of the tumor volume based on T2 FLAIR and enhancement at baseline. Histone H3 mutations were identified through immunohistochemistry and/or Sanger or next-generation DNA sequencing. The log-rank test identified imaging factors prognostic of survival from the time of diagnosis. Wilcoxon rank-sum and Fisher exact tests compared imaging predictors among groups. RESULTS: Eighty-three patients had pretreatment MR imaging and evaluable tissue sampling. The median age was 6 years (range, 0.7-17 years); 50 tumors had a K27M mutation in H3-3A, and 11, in H3C2/3. Seven tumors had histone H3 K27 alteration, but the specific gene was unknown. Fifteen were H3 wild-type. Overall survival was significantly higher in H3C2/3- compared with H3-3A-mutant tumors (P = .003) and in wild-type tumors compared with any histone mutation (P = .001). Lower overall survival was observed in patients with enhancing tumors (P = .02) compared with those without enhancement. H3C2/3-mutant tumors showed higher mean, median, and mode ADC_total values (P < .001) and ADC_enhancement (P < .004), with lower ADC_total skewness and kurtosis (P < .003) relative to H3-3A-mutant tumors. CONCLUSIONS: ADC histogram parameters are correlated with histone H3 mutation status in pontine pediatric high-grade glioma.

Quantifying the Antifungal Activity of Peptides Against Candida albicans.

Traditional methods for performing antifungal susceptibility testing for Candida albicans are time-consuming and lack quantitative results. For example, a common approach relies on plating cells treated with different concentrations of antifungal molecules on agar plates and then counting the colonies to determine the relationship between molecule concentration and growth inhibition. This method requires many plates and substantial time to count the colonies. Another common approach eliminates the plates and counting of colonies by visually inspecting cultures treated with antifungal agents to identify the minimum concentration required to inhibit growth; however, visual inspection produces only qualitative results, and information on growth at subinhibitory concentrations is lost. This protocol describes a method for measuring the susceptibility of C. albicans to antifungal peptides. By relying on optical density measurements of cultures, the method reduces the time and materials needed to obtain quantitative results on culture growth at different peptide concentrations. The incubation of the fungus with peptides is performed in a 96-well plate using an appropriate buffer, with controls representing no growth inhibition and complete growth inhibition. Following the incubation with the peptide, the resulting cell suspensions are diluted to reduce peptide activity and then grown overnight. After overnight growth, the optical density of each well is measured and compared to the positive and negative controls to calculate the resulting growth inhibition at each peptide concentration. The results using this assay are comparable to the results using the traditional method of plating the cultures on agar plates, but this protocol reduces plastic waste and the time spent on counting colonies. Although the applications of this protocol have focused on antifungal peptides, the method will also be applicable to testing other molecules with known or suspected antifungal activity.

The effect on the T-14 paediatric throat disorders outcome score of delaying adenotonsillectomy surgery due to COVID-19.

INTRODUCTION: Adenotonsillectomy is commonly performed for recurrent tonsillitis and obstructive sleep apnoea. These conditions may improve with age. The COVID-19 pandemic led to all UK elective surgery being suspended. This study aimed to determine whether delaying surgery had any effect on a patient's symptoms using the validated T-14 paediatric throat disorders outcome test. METHODS: Patients completed a T-14 questionnaire when the child was listed for surgery; this was repeated on the revised surgery date and a paired t test was used to compare the responses. RESULTS: Questionnaires were completed by 29 patients a mean of 6.4 months apart. There was a significant improvement in scores (p<0.02) for five domains: eating habits, visits to a doctor/A&E, antibiotics for less than 2 weeks, chronic infections and school missed due to sore throats. CONCLUSIONS: This study demonstrates that following delays resulting from the COVID-19 pandemic, paediatric patients experienced an improvement in some aspects of their quality of life while awaiting tonsillectomy and/or adenoidectomy. This was most apparent in quality-of-life measures relating to recurrent tonsillitis, namely visits to a doctor/A&E, antibiotics for less than 2 weeks, chronic infections and school missed due to sore throats. Patients may experience an improvement in some of their individual symptoms, in particular their infective symptoms, during an observation period.

Exposure to Anti-Tobacco Messaging and Quit Attempts among Adolescent and Young Adult in Lagos, Nigeria: A Population-based Study.

BACKGROUND: Health behavior theories suggest that knowledge about the health risks of the behavior precedes behavior change. Tobacco control messages aim to promote knowledge of health risks associated with tobacco use and encourage smoking cessation behaviors such as quit attempts and intention to quit. This study assessed the relationship between exposure to Anti-Tobacco Messaging (ATM) and quit attempts among adolescents and young adults in Lagos, Nigeria. METHODS: This was an online cross-sectional survey of 947 participants aged between 15-35 years. The survey obtained sociodemographic information, smoking status, exposure to ATM, intention to quit and quit attempts in the past 12-months. Logistic regression analysis was used to identify the relationship between exposure to ATM and quit attempts; pvalues <0.05 were considered significant. Statistical analysis was done using STATA-15.0 software. RESULTS: The mean age of respondents was 23.4 years (SD:4.0). Less than one-third of the respondents were smokers (23.4%). The most common source of ATM were digital sources (online and social media - 29.6%). Based on the multivariable logistic regression model, younger age (p:0.03) and an intention to quit (p: <0.001) were significantly associated with a quit attempt. Exposure to ATM in the past 12 months was also significantly associated with higher odds of a quit attempt (OR:5.33; 95% CI: 1.26,22.60; p: 0.02). CONCLUSION: Our findings suggest an association between exposure to ATM and quit attempts among adolescent and young adult smokers in Lagos State, Nigeria. Policymakers should consider measures aimed at promoting tobacco control education and improving access to smoking cessation services.

CONTEXTE: Les théories du comportement en matière de santé suggèrent que la connaissance des risques sanitaires du comportement précède le changement de comportement. Les messages de lutte contre le tabagisme visent à promouvoir la connaissance des risques pour la santé associés au tabagisme et à encourager les comportements de renoncement au tabac tels que les tentatives d'abandon et l'intention d'abandonner. Cette étude a évalué la relation entre l'exposition aux messages antitabac (MTA) et les tentatives d'arrêt du tabac chez les adolescents et les jeunes adultes de Lagos, au Nigeria. MÉTHODES: Il s'agissait d'une enquête transversale en ligne auprès de 947 participants âgés de 15 à 35 ans. L'enquête a permis d'obtenir des informations sociodémographiques, le statut tabagique, l'exposition au MTA, l'intention d'arrêter et les tentatives d'arrêt au cours des 12 derniers mois. Une analyse de régression logistique a été utilisée pour identifier la relation entre l'exposition à la GTA et les tentatives d'abandon ; les valeurs p <0,05 ont été considérées comme significatives. L'analyse statistique a été réalisée à l'aide du logiciel STATA-15.0. RÉSULTATS: L'âge moyen des répondants était de 23,4 ans (écarttype:4,0). Moins d'un tiers des répondants étaient fumeurs (23,4%). La source de DAB la plus courante était les sources numériques (médias en ligne et sociaux-29, 6%). D'après le modèle de régression logistique multivariable, un âge plus jeune (p: 0,03) et une intention d'arrêter de fumer (p:<0,001) étaient significativement associés à une tentative d'arrêt. L'exposition à la GTA au cours des 12 derniers mois était également associée de manière significative à une probabilité plus élevée de tentative d'abandon (OR:5,33;IC à 95%: 1,26,22,60; p:0,02). CONCLUSION: Nos résultats suggèrent une association entre l'exposition à la GTA et les tentatives d'arrêt chez les fumeurs adolescents et jeunes adultes de l'État de Lagos, au Nigeria. Les décideurs politiques devraient envisager des mesures visant à promouvoir l'éducation à la lutte antitabac et à améliorer l'accès aux services d'aide au sevrage tabagique. Mots clés: Adolescent, Intention d'arrêter de fumer, Tentative d'arrêt du tabac, Jeunes, Tabac.

Surgical and functional outcomes of two types of transcutaneous bone conduction implants.

OBJECTIVE: This study aimed to evaluate surgical and functional outcomes, in a tertiary referral centre, of two different types of semi-implantable transcutaneous bone conduction devices. METHOD: This study involved prospective data collection and review of patients implanted between November 2014 and December 2016. Glasgow Hearing Aid Inventory (Glasgow Hearing Aid Benefit Profile or Glasgow Hearing Aid Difference Profile) and Client Oriented Scale of Improvement were completed where appropriate. Surgical and audiological outcomes were recorded in the surgical notes. RESULTS: Glasgow Hearing Aid Difference Profile and Glasgow Hearing Aid Benefit Profile showed similar mean score in the active and the passive transcutaneous bone conduction devices. Client Oriented Scale of Improvement showed improvements in listening situations. Post-operative speech reception threshold showed better mean threshold in the active transcutaneous bone conduction devices group when compared with the passive transcutaneous bone conduction devices group. No device failures or surgical complications existed in either group, with the surgical time being less in the passive transcutaneous bone conduction devices group. CONCLUSION: Both devices are reliable semi-implantable transcutaneous bone conduction devices with excellent surgical and functional outcomes and patient satisfaction. Overall surgical time was much less in the passive transcutaneous bone conduction devices group with no necessity for pre-planning. This is much easier to remove with the possibility of conversion to other devices in the manufacturer's portfolio and wide-ranging wireless accessories. Further studies are needed to assess the longer-term results in a bigger population.

Intensive nutrition counseling as part of a multi-component weight loss intervention improves diet quality and anthropometrics in older adults with obesity.

BACKGROUND AND AIMS: Obesity significantly impacts older adults. Intensive nutrition counseling can aid in weight reduction and improve diet quality, but data are sparse in this population. The objective of this intervention is to determine how intensive nutrition counseling affects diet quality and anthropometric measures during a multi-component weight loss intervention in rural older adults with obesity. METHODS: A series of 12-week, single-arm feasibility pilots were conducted in fall 2017 and winter/spring 2018 in a community aging center in rural Northern New England. Adults were eligible if ≥ 65 years old with a Body Mass Index (BMI) ≥30 kg/m2. Exclusion criteria included dementia/cognitive impairment, uncontrolled psychiatric illness, weight-loss surgery, weight loss >5% in previous 6-months, life-threatening illness, palliative/hospice services, current participation in another weight-loss study/program, obesogenic medications, or presence of major chronic conditions. Participants received once-weekly nutrition counseling by a registered dietitian nutritionist (RDN), and twice-weekly exercise sessions by a physical therapist (PT). Primary outcomes were diet quality changes measured by total Rapid Eating and Activity Assessment for Patients-Short Version (REAP-S) and Automated Self-Administered 24-h dietary recall (ASA-24). Secondary outcome measures were changes in weight (kilograms) and waist circumference (centimeters). McNemar test was conducted for all paired categorical data while paired t-tests were conducted for all paired continuous data. All analyses were conducted in R; p-value<0.05 was significant. RESULTS: Total n = 23. Mean age was 72.2 (5.8) years (73.9% female); mean BMI was 35.9 ± 5.0 kg/m2. At 12 weeks, diet quality significantly improved. REAP-S scores increased by 3.53 ± 3.13 points (p < 0.001). Kilocalories, grams fat, grams saturated fat, milligrams sodium, grams added sugar, and grams alcohol via ASA-24 significantly decreased (all p < 0.05). Significant reductions in weight (-5.22 ± 3.13 kg) and waist circumference (-6.88 ± 5.67 cm) were observed (both p < 0.001). CONCLUSION: Intensive nutrition counseling significantly enhances diet quality and reduces weight and waist circumference in rural older adults with obesity.

Concomitant botanical medicine use among patients participating in commercial prostate cancer trials.

OBJECTIVES: Patients with cancer frequently use botanical medications. The concomitant use of such medications by patients on commercial trials has not been well-described, despite the importance of these trials for evaluating the safety and efficacy of new agents. We sought to describe the use of botanical medications taken by patients with prostate cancer enrolled on global commercial trials. DESIGN: Retrospective study. SETTING: Regulatory repository of commercial clinical trial data. INTERVENTIONS: Anti-cancer therapy. MAIN OUTCOME MEASURES: Botanical and medication use data were pooled across six international commercial randomized trials for metastatic prostate cancer with detailed information on medication and indications. Botanical products were considered to have potential for drug interaction if they led to a change in drug exposure in human trials. Potential for interaction was ascertained by PubMed review. Descriptive statistics were used for analysis. RESULTS: Of 7318 enrolled patients, 700 (10 %) reported botanical use at any time and 653 (9%) reported use of botanical products while on trial. Nearly half of botanical product types were not classified by plant (43 %). The highest proportion of botanical use was among patients in Asian countries (32 %), followed by patients in North America (13 %). Eighty-six different types of botanical products were used; of these, nineteen had a patient-reported anti-cancer indication. CONCLUSIONS: Botanical medicine use among patients with prostate cancer in commercial trials is moderate, although it varies by region. Practitioners should be aware of the use of botanical interventions in a clinical trial context.

MR Imaging Correlates for Molecular and Mutational Analyses in Children with Diffuse Intrinsic Pontine Glioma.

BACKGROUND AND PURPOSE: Recent advances in molecular techniques have characterized distinct subtypes of diffuse intrinsic pontine gliomas. Our aim was the identification of MR imaging correlates of these subtypes. MATERIALS AND METHODS: Initial MRIs from subjects with diffuse intrinsic pontine gliomas recruited for a prospective clinical trial before treatment were analyzed. Retrospective imaging analyses included FLAIR/T2 tumor volume, tumor volume enhancing, the presence of cyst and/or necrosis, median, mean, mode, skewness, kurtosis of ADC tumor volume based on FLAIR, and enhancement at baseline. Molecular subgroups based on EGFR and MGMT mutations were established. Histone mutations were also determined (H3F3A, HIST1H3B, HIST1H3C). Univariate Cox proportional hazards regression was used to test the association of imaging predictors with overall and progression-free survival. Wilcoxon rank sum, Kruskal-Wallis, and Fisher exact tests were used to compare imaging measures among groups. RESULTS: Fifty patients had biopsy and MR imaging. The median age at trial registration was 6 years (range, 3.3-17.5 years); 52% were female. On the basis of immunohistochemical results, 48 patients were assigned to 1 of 4 subgroups: 28 in MGMT-/epidermal growth factor receptor (EGFR)-, 14 in MGMT-/EGFR+, 3 in MGMT+/EGFR-, and 3 in MGMT+/EGFR+. Twenty-three patients had histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HIST1H3C. Enhancing tumor volume was near-significantly different across molecular subgroups (P = .04), after accounting for the false discovery rate. Tumor volume enhancing, median, mode, skewness, and kurtosis ADC T2-FLAIR/T2 were significantly different (P ≤ .048) between patients with H3F3A and HIST1H3B/C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters are correlated with molecular subgroups and mutations in children with diffuse intrinsic pontine gliomas.

Rapid suppression of bone formation marker in response to sleep restriction and circadian disruption in men.

We describe the time course of bone formation marker (P1NP) decline in men exposed to ~ 3 weeks of sleep restriction with concurrent circadian disruption. P1NP declined within 10 days and remained lower with ongoing exposure. These data suggest even brief exposure to sleep and circadian disruptions may disrupt bone metabolism. INTRODUCTION: A serum bone formation marker (procollagen type 1 N-terminal, P1NP) was lower after ~ 3 weeks of sleep restriction combined with circadian disruption. We now describe the time course of decline. METHODS: The ~ 3-week protocol included two segments: "baseline," ≥ 10-h sleep opportunity/day × 5 days; "forced desynchrony" (FD), recurring 28 h day (circadian disruption) with sleep restriction (~ 5.6-h sleep per 24 h). Fasted plasma P1NP was measured throughout the protocol in nine men (20-59 years old). We tested the hypothesis that PINP would steadily decline across the FD intervention because the magnitude of sleep loss and circadian misalignment accrued as the protocol progressed. A piecewise linear regression model was used to estimate the slope (ß) as ΔP1NP per 24 h with a change point mid-protocol to estimate the initial vs. prolonged effects of FD exposure. RESULTS: Plasma P1NP levels declined significantly within the first 10 days of FD ([Formula: see text] = - 1.33 µg/L per 24 h, p < 0.0001) and remained lower than baseline with prolonged exposure out to 3 weeks ([Formula: see text] = - 0.18 µg/L per 24 h, p = 0.67). As previously reported, levels of a bone resorption marker (C-telopeptide (CTX)) were unchanged. CONCLUSION: Sleep restriction with concurrent circadian disruption induced a relatively rapid decline in P1NP (despite no change in CTX) and levels remained lower with ongoing exposure. These data suggest (1) even brief sleep restriction and circadian disruption can adversely affect bone metabolism, and (2) there is no P1NP recovery with ongoing exposure that, taken together, could lead to lower bone density over time.

Implementation and evaluation of nationwide scale-up of the Surgical Safety Checklist.

BACKGROUND: The WHO Surgical Safety Checklist improves surgical outcomes, but evidence and theoretical frameworks for successful implementation in low-income countries remain lacking. Based on previous research in Madagascar, a nationwide checklist implementation in Benin was designed and evaluated longitudinally. METHODS: This study had a longitudinal embedded mixed-methods design. The well validated Consolidated Framework for Implementation Research (CFIR) was used to structure the approach and evaluate the implementation. Thirty-six hospitals received 3-day multidisciplinary training and 4-month follow-up. Seventeen hospitals were sampled purposively for evaluation at 12-18 months. The primary outcome was sustainability of checklist use at 12-18 months measured by questionnaire. Secondary outcomes were CFIR-derived implementation outcomes, measured using the WHO Behaviourally Anchored Rating Scale (WHOBARS), safety questionnaires and focus groups. RESULTS: At 12-18 months, 86·0 per cent of participants (86 of 100) reported checklist use compared with 31·1 per cent (169 of 543) before training and 88·8 per cent (158 of 178) at 4 months. There was high-fidelity use (median WHOBARS score 5·0 of 7; use of basic safety processes ranged from 85·0 to 99·0 per cent), and high penetration shown by a significant improvement in hospital safety culture (adapted Human Factors Attitude Questionnaire scores of 76·7, 81·1 and 82·2 per cent before, and at 4 and 12-18 months after training respectively; P < 0·001). Acceptability, adoption, appropriateness and feasibility scored 9·6-9·8 of 10. This approach incorporated 31 of 36 CFIR implementation constructs successfully. CONCLUSION: This study shows successfully sustained nationwide checklist implementation using a validated implementation framework.

The estrogen receptor α-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice: potential molecular mechanisms

The authors and journal apologise for an error in the above paper, which appeared in volume 199 part 2, pages 275­286. The error relates to Fig. 10, given on page 283.

Correction: The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation.

Since the publication of the above article, the authors have noted that the input data in Fig. 6E is incorrect. The correct data are included in the below Fig. 6E. The mistake does not affect the conclusions of the paper as the levels of input proteins remain similar between samples. We apologise for any inconvenience caused by this error.

Survival times in dogs with presumptive intracranial gliomas treated with oral lomustine: A comparative retrospective study (2008-2017).

Intracranial gliomas are a common malignancy in dogs, and are associated with a poor prognosis due to their aggressive nature and a lack of clinically effective treatments. The efficacies of various treatment modalities for canine brain tumours have been previously described, though little data exist on the use of cytotoxic chemotherapy. A comparative retrospective study, including 40 cases from 5 northeastern US veterinary hospitals, from 2008 to 2017, was conducted. Variables analysed in this study with relation to overall survival and prognostic significance included: age, sex, clinical signs, clinical sign duration, tumour location and treatment protocol used. Dogs with presumptive intracranial gliomas treated with lomustine chemotherapy lived longer (median, 138 days) than those treated exclusively with symptomatic care (median, 35 days; P = .0026 log-rank, 0.0138 Wilcoxon). Additionally, a duration of clinical signs ≥16 days prior to diagnosis (median, 109 days) was associated with a longer survival than a duration <16 days prior (median, 25 days; P = .0100 log-rank, 0.0322 Wilcoxon). Lomustine-associated side effects included neutropenia in 46% of dogs, anaemia in 15% and thrombocytopenia in 15%. Potential renal and hepatotoxicity based on increased BUN and/or creatinine and ALT values were reported in 15% and 50% of dogs, respectively. This study provides evidence that lomustine therapy may be effective in prolonging survival in dogs with intracranial gliomas and should be considered as a potential treatment option. Although lomustine-related toxicities are fairly common, they are rarely life threatening and often do not result in discontinuation of therapy.

A multicentre study of long-term follow-up and owner satisfaction following enucleation in horses.

BACKGROUND: Horses are reported to return to a variety of disciplines following unilateral enucleation; however, owners of horses with ocular disease are frequently reluctant to consider the procedure. There is little published information investigating owners' attitudes towards, and satisfaction following, enucleation. OBJECTIVES: To investigate the hypotheses: 1) horses return to their previous level of work following unilateral enucleation and 2) their owners are satisfied with the post-operative outcome. STUDY DESIGN: Retrospective case series with cross-sectional survey. METHODS: Clinical records from eight equine referral centres in the United Kingdom were reviewed to identify horses that underwent enucleation between August 2006 and March 2015. Owner questionnaires were completed to corroborate information provided by medical records and obtain information on client perceptions. RESULTS: A total of 170 cases were identified and 119 owner questionnaires completed. The most frequent primary uses of horses in the study were pleasure/leisure riding, showjumping and dressage, with 25.2% (n = 30) of horses used for competition. Following enucleation, 77.3% (n = 92) of horses were performing at an equivalent or higher level than prior to enucleation and 60.0% (n = 18/30) of competition horses were competing at an equivalent or higher level. Complications related to the surgical site (predominantly mild post-operative swelling) were reported in 3.7% of cases and nonocular complications in 3.7% of cases. Of owners who reported being concerned or very concerned about certain factors prior to surgery, ≥86.8% reported that these factors caused little or no issue post-surgery. Most owners, 90.8% (n = 108) were pleased with the outcome following surgery, with 21.3% (n = 23/108) wishing the procedure had been undertaken sooner. MAIN LIMITATIONS: Retrospective data collection from clinical records and the potential for recall bias. CONCLUSIONS: Horses can return successfully to a variety of disciplines following enucleation. Owners are satisfied with the outcome and pleased that enucleation was performed.

Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial-mesenchymal transition.

This corrects the article DOI: 10.1038/onc.2015.365.

Expression of sex steroid hormone receptors in human skeletal muscle during the menstrual cycle.

AIM: Variations in sex hormone levels during the menstrual cycle may affect neuromuscular performance and the risk of sustaining musculoskeletal injury in women. The aim of this study was to investigate mRNA and protein levels for sex steroid hormone receptors in skeletal muscle in three distinct phases of the menstrual cycle. METHODS: Fifteen, healthy women with regular menstrual cycles participated in the study. Muscle biopsies from the vastus lateralis were obtained in three hormonally verified phases of the menstrual cycle for each individual, that is the follicular phase, the ovulatory phase and the luteal phase. mRNA and protein levels of oestrogen (ERα and ERß), progesterone (PR) and androgen (AR) receptors were analysed. RESULTS: There was an overall significant variation in mRNA and protein levels of ERα and PR across the menstrual cycle. mRNA and protein levels of ERα were highest in the follicular phase when oestradiol levels were low, whereas protein levels of PR were highest in the luteal phase when progesterone levels were high. mRNA levels of PR were highest in the ovulatory phase. No significant variation in AR levels was detected across the menstrual cycle. ERß levels were very low in all three phases of the menstrual cycle. CONCLUSION: Significant variations in mRNA and protein levels of ERα and PR were detected in skeletal muscle during three confirmed phases of the menstrual cycle. These results may have an impact on effects of muscular training and sports injuries in women.

Effect of MTA particle size on periapical healing.

AIM: To examine the effect of reduction in MTA particle size on dento-alveolar and osseous healing in dogs. METHODOLOGY: Root canals of 24 mandibular premolars in four 2-year-old beagles were prepared and filled with gutta-percha and sealer. Two to four weeks later, during periapical surgery, the root-end cavity preparations in these teeth were filled with either grey ProRoot MTA or modified (reduced particle sizes with faster setting time) MTA. The animals were sacrificed 4 months later. Degrees of inflammation, type of inflammatory cells, fibrous connective tissue adjacent to the root-end filling materials, cementum formation over the resected roots and root-end filling materials and bone healing were examined. Data were analysed using the McNemar test. RESULTS: No significant differences in healing of periapical tissues were found when comparing ProRoot MTA to a modified MTA containing reduced particle sizes. CONCLUSION: Reducing the particle sizes of MTA did not impact its biological properties.

Translational Pharmacokinetic-Pharmacodynamic Modeling and Simulation: Optimizing 5-Fluorouracil Dosing in Children With Pediatric Ependymoma.

We previously investigated novel therapies for pediatric ependymoma and found 5-fluorouracil (5-FU) i.v. bolus increased survival in a representative mouse model. However, without a quantitative framework to derive clinical dosing recommendations, we devised a translational pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation approach. Results from our preclinical PK-PD model suggested tumor concentrations exceeded the 1-hour target exposure (in vitro IC90), leading to tumor growth delay and increased survival. Using an adult population PK model, we scaled our preclinical PK-PD model to children. To select a 5-FU dosage for our clinical trial in children with ependymoma, we simulated various 5-FU dosages for tumor exposures and tumor growth inhibition, as well as considering tolerability to bolus 5-FU administration. We developed a pediatric population PK model of bolus 5-FU and simulated tumor exposures for our patients. Simulations for tumor concentrations indicated that all patients would be above the 1-hour target exposure for antitumor effect.

RING finger protein 31 promotes p53 degradation in breast cancer cells.

The atypical E3 ubiquitin ligase RNF31 is highly expressed in human breast cancer, the most frequent neoplastic lethality among women. Here, RNF31 depletion in breast cancer cells in combination with global gene expression profiling revealed p53 (TP53) signaling as a potential RNF31 target. Interestingly, RNF31 decreased p53 stability, whereas depletion of RNF31 in breast cancer cells caused cell cycle arrest and cisplatin-induced apoptosis in a p53-dependent manner. Furthermore, RNF31 associated with the p53/MDM2 complex and facilitated p53 polyubiquitination and degradation by stabilizing MDM2, suggesting a molecular mechanism by which RNF31 regulates cell death. Analysis of publically available clinical data sets displayed a negative correlation between RNF31 and p53 target genes, including IGFBP3 and BTG1, consistent with RNF31 regulating p53 function in vivo as well. Together, our findings suggest RNF31 as a potential therapeutic target to restore p53 function in breast cancer.