Cancer-specific epigenome identifies oncogenic hijacking by nuclear factor I family proteins for medulloblastoma progression.

Normal cells coordinate proliferation and differentiation by precise tuning of gene expression based on the dynamic shifts of the epigenome throughout the developmental timeline. Although non-mutational epigenetic reprogramming is an emerging hallmark of cancer, the epigenomic shifts that occur during the transition from normal to malignant cells remain elusive. Here, we capture the epigenomic changes that occur during tumorigenesis in a prototypic embryonal brain tumor, medulloblastoma. By comparing the epigenomes of the different stages of transforming cells in mice, we identify nuclear factor I family of transcription factors, known to be cell fate determinants in development, as oncogenic regulators in the epigenomes of precancerous and cancerous cells. Furthermore, genetic and pharmacological inhibition of NFIB validated a crucial role of this transcription factor by disrupting the cancer epigenome in medulloblastoma. Thus, this study exemplifies how epigenomic changes contribute to tumorigenesis via non-mutational mechanisms involving developmental transcription factors.

Corrigendum: The effects of an acceptance and commitment-informed interdisciplinary rehabilitation program for chronic airway diseases on health status and psychological symptoms.

[This corrects the article DOI: 10.3389/fpsyg.2021.818659.].

Application of a dual mechanistic approach to support bilastine dose selection for older adults.

The objective of this study was to evaluate bilastine dosing recommendations in older adults and overcome the limitation of insufficient data from phase I studies in this underrepresented population. This was achieved by integrating bilastine physicochemical, in vitro and in vivo data in young adults and the effect of aging in the pharmacology by means of two alternative approaches: a physiologically-based pharmacokinetic (PBPK) model and a semi-mechanistic population pharmacokinetic (Senescence) model. Intestinal apical efflux and basolateral influx transporters were needed in the PBPK model to capture the observations from young adults after single i.v. (10 mg) and p.o. (20 mg) doses, supporting the hypothesis of involvement of gut transporters on secretion. The model was then used to extrapolate the pharmacokinetics (PKs) to elderly subjects considering their specific physiology. Additionally, the Senescence model was develop starting from a published population PK) model, previously applied for pediatrics, and incorporating declining functions on different physiological systems and changes in body composition with aging. Both models were qualified using observed data in a small group of young elderlies (N = 16, mean age = 68.69 years). The PBPK model was further used to evaluate the dose in older subjects (mean age = 80 years) via simulation. The PBPK model supported the hypothesis that basolateral influx and apical efflux transporters are involved in bilastine PK. Both, PBPK and Senescence models indicated that a 20 mg q.d. dose is safe and effective for geriatrics of any age. This approach provides an alternative to generate supplementary data to inform dosing recommendations in under-represented groups in clinical trials.

The Effects of an Acceptance and Commitment-Informed Interdisciplinary Rehabilitation Program for Chronic Airway Diseases on Health Status and Psychological Symptoms.

BACKGROUND: Chronic airway diseases are prevalent and costly conditions. Interdisciplinary rehabilitation programs that include Acceptance and Commitment-based (ACT) components could be important to tackle the vicious circle linking progression of the disease, inactivity, and psychopathological symptoms. METHODS: A retrospective evaluation of routinely collected data of an interdisciplinary rehabilitation program was performed. The program included group sessions including patient education, breathing exercise, occupational therapy and an ACT-based psychological treatment, and individual sessions of physical therapy. Demographic data, clinical characteristics of the patients and the values of outcome variables (health status, quality of life, anxiety, and depression) before treatment, at discharge, at 3 months, and at 6 months were extracted from medical records. Multiple imputation was employed to address missing data. Linear mixed models were employed to assess changes over time. Multivariable logistic regression was performed to assess predictors of a minimum clinically important change of health status from baseline to the 6-months follow-up. RESULTS: Data from 31 patients with chronic obstructive pulmonary disease (COPD) and 12 patients with bronchiectasis were extracted. Health status improved from baseline to discharge to the 3 months follow-up, but not to the 6 months follow-up. Anxiety and depression improved across all the time points. Quality of life did not improve over time. Having a worse health status at baseline and fewer depressive symptoms were significantly associated with achieving a minimum clinically important change of health status at 6 months. The effects of the interdisciplinary program were not different for patients with COPD or with bronchiectasis. DISCUSSION: Interdisciplinary programs including ACT-based components are promising treatments for the rehabilitation of patients with chronic airway diseases.

Case Report: Microfragmented Adipose Tissue Drug Delivery in Canine Mesothelioma: A Case Report on Safety, Feasibility, and Clinical Findings.

Mesothelioma is a rare lethal tumor of dogs and humans involving cavities of the body. Dogs are considered a model for new drugs and therapeutic methods since they present spontaneous diseases similar to humans. Microfragmented adipose tissue (MFAT) uploaded by paclitaxel (PTX) is a drug delivery medium providing slow release of chemotherapic drugs. A dog affected by pleural, pericardial, and peritoneal mesothelioma was treated by 17 intracavitary ultrasound-guided injections of MFAT-PTX over 22 months. A long-lasting improvement of general conditions was observed, treatment was well-tolerated, and no toxicity or hypersensitivity was reported. Pharmacokinetic (PK) data indicated low drug localization in the circulatory system and a tendency to enter or remain in the extravascular compartments of the body. Indeed, low levels of free-circulating drugs for a short time produced low toxicity, whereas, a higher intracavitary PTX concentration can have major pharmacological efficacy. To our knowledge, this is the first time that mesothelioma has been treated using such a procedure, and this should be considered as a novel therapeutic approach. The low systemic absorption suggests the possible role of MFAT-PTX for loco-regional/intratumoral therapy also useful in other types of tumors, and further investigation is warranted.

Using Acute Performance on a Comprehensive Neurocognitive, Vestibular, and Ocular Motor Assessment Battery to Predict Recovery Duration After Sport-Related Concussions.

BACKGROUND: A sport-related concussion (SRC) is a heterogeneous injury that requires a multifaceted and comprehensive approach for diagnosis and management, including symptom reports, vestibular/ocular motor assessments, and neurocognitive testing. PURPOSE: To determine which acute (eg, within 7 days) vestibular, ocular motor, neurocognitive, and symptom impairments predict the duration of recovery after an SRC. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: Sixty-nine patients with a mean age of 15.3 ± 1.9 years completed a neurocognitive, vestibular/ocular motor, and symptom assessment within 7 days of a diagnosed concussion. Patients were grouped by recovery time: ≤14 days (n = 27, 39.1%), 15-29 days (n = 25, 36.2%), and 30-90 days (n = 17, 24.6%). Multinomial regression was used to identify the best subset of predictors associated with prolonged recovery relative to ≤14 days. RESULTS: Acute visual motor speed and cognitive-migraine-fatigue symptoms were associated with an increased likelihood of recovery times of 30-90 days and 15-29 days relative to a recovery time of ≤14 days. A model with visual motor speed and cognitive-migraine-fatigue symptoms within the first 7 days of an SRC was 87% accurate at identifying patients with a recovery time of 30-90 days. CONCLUSION: The current study identified cognitive-migraine-fatigue symptoms and visual motor speed as the most robust predictors of protracted recovery after an SRC according to the Post-concussion Symptom Scale, Immediate Post-concussion Assessment and Cognitive Testing, and Vestibular/Ocular Motor Screening (VOMS). While VOMS components were sensitive in identifying a concussion, they were not robust predictors for recovery. Clinicians may consider particular patterns of performance on clinical measures when providing treatment recommendations and discussing anticipated recovery with patients.