Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue tumors that occur either sporadically or in patients with Neurofibromatosis Type 1. The malignant transformation of the ...benign neurofibroma to MPNST is incompletely understood at the molecular level. We have determined the gene expression signature for benign and malignant PNSTs and found that the major trend in malignant transformation from neurofibroma to MPNST consists of the loss of expression of a large number of genes, rather than widespread increase in gene expression. Relatively few genes are expressed at higher levels in MPNSTs and these include genes involved in cell proliferation and genes implicated in tumor metastasis. In addition, a gene expression signature indicating p53 inactivation is seen in the majority of MPNSTs. Subsequent microRNA profiling of benign and malignant PNSTs indicated a relative downregulation of miR-34a in most MPNSTs compared to neurofibromas.
In vitro
studies using the cell lines MPNST-14 (NF1 mutant) and MPNST-724 (from a non-NF1 individual) show that exogenous expression of p53 or miR-34a promotes apoptotic cell death. In addition, exogenous expression of p53 in MPNST cells induces miR-34a and other miRNAs. Our data shows that p53 inactivation and subsequent loss of expression of miR-34a may significantly contribute to the MPNST development. Collectively, our findings suggests that deregulation of miRNAs have a potential role in the malignant transformation process in peripheral nerve sheath tumors.
Medications may lessen core symptoms of attention deficit hyperactivity disorder (ADHD), yet families continue to report stress and have a low quality of life. Primary care providers manage almost ...half of all children with ADHD but do not have a brief measure to assess ADHD impacts on family in the context of everyday family life. The IMPACT (Impact Measure of Parenting-Related ADHD Challenges and Treatment) 1.0 Scale was codeveloped with input from parent advisors and administered to 79 parents of children with ADHD. Exploratory factor analysis, correlations with validated instruments, and test-retest reliability were examined. Exploratory factor analysis resulted in 4 subscales (Misbehavior, Siblings, Time, School), which demonstrated moderate to high test-retest reliability. Scale domains were related to severity and change in ADHD symptoms. Significant correlations were found between IMPACT scores, adaptive functioning in the home, and ADHD-related quality of life. The IMPACT 1.0 Scale provides a novel, reliable, and valid method to assess family impact of ADHD.
Cohesin subunits are frequently mutated in cancer, but how they function as tumor suppressors is unknown. Cohesin mediates sister chromatid cohesion, but this is not always perturbed in cancer cells. ...Here, we identify a previously unknown role for cohesin. We find that cohesin is required to repress transcription at DNA double-strand breaks (DSBs). Notably, cohesin represses transcription at DSBs throughout interphase, indicating that this is distinct from its known role in mediating DNA repair through sister chromatid cohesion. We identified a cancer-associated SA2 mutation that supports sister chromatid cohesion but is unable to repress transcription at DSBs. We further show that failure to repress transcription at DSBs leads to large-scale genome rearrangements. Cancer samples lacking SA2 display mutational patterns consistent with loss of this pathway. These findings uncover a new function for cohesin that provides insights into its frequent loss in cancer.
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•Cohesin and PBAF repress gene transcription near DNA double-strand breaks (DSBs)•Transcriptional repression at DSBs requires cohesin and PBAF throughout interphase•Loss of DSB-induced gene repression leads to more large-scale genome alterations
Meisenberg et al. show that, in response to DNA double strand breaks (DSBs), cohesin is required to repress nearby transcription. This happens throughout interphase, regardless of whether a sister chromatid is present. Failure to repress transcription near a DNA DSB results in an increase in large-scale chromosome rearrangements.
"Treatable traits" have been proposed as a new paradigm for the management of airway diseases, particularly complex disease, which aims to apply personalised medicine to each individual to improve ...outcomes. Moving new treatment approaches from concepts to practice is challenging, but necessary. In an effort to accelerate progress in research and practice relating to the treatable traits approach, the Treatable Traits Down Under International Workshop was convened in Melbourne, Australia in May 2018. Here, we report the key concepts and research questions that emerged in discussions during the meeting. We propose a programme of research that involves gaining international consensus on candidate traits, recognising the prevalence of traits, and identifying a potential hierarchy of traits based on their clinical impact and responsiveness to treatment. We also reflect on research methods and designs that can generate new knowledge related to efficacy of the treatable traits approach and consider multidisciplinary models of care that may aid its implementation into practice.
Objective: Preterm delivery remains the leading cause of neonatal morbidity and mortality leading to a burden lasting well beyond the inherent costs of caring for the premature neonate. ...Physician-scientists, scientists, and clinicians have intensively studied associations, scoured every aspect to determine modifiable risk factors, and trialed prospective interventions to generate best practices. We aimed to generate a useful review for clinicians for the identification of women at risk for preterm birth along with modifiable factors and treatments to help reduce preterm delivery. Mechanism: We performed a literature search for preterm birth prevention to facilitate compilation of a narrative review. Findings in Brief: The PROLONG study found that Makena did not significantly reduce the risk of preterm birth (PTB) <35 weeks among those with a history of PTB <37 weeks; the PTB rate was 11.5% in the placebo group and 11.0% in the 17 alpha-hydroxyprogesterone caproate (17-OHP) group, (relative risk (RR) 0.95, 95% confidence interval (95% CI) 0.71–1.26, p = 0.72) and led to the American College of Obstetricians and Gynecologists to no longer recommend use of Makena for prevention of preterm birth. Nonetheless, a number of tools for screening and behavior modification remain for clinicians to utilize in patient care: (1) alabama Preterm Prevention project showed high negative predictive value of a cervical length in excess of 2.0 cm for delivery preterm birth, particularly in women with prior preterm birth less than 34 weeks (hazard ratio (HR) 2.8, p < 0.0001; RR 2.1, p < 0.0001); (2) treatment of infections; e.g., antibiotic treatment of urinary tract infections may be associated with a reduction in preterm birth (RR 0.34, 95% CI 0.13–0.88); (3) discontinuation of tobacco and illicit drug use given the association of use with preterm birth; and (4) identification of vaginal dysbiosis or pathologic alterations in vaginal flora poses as opportunity to reduce preterm delivery (e.g., bacterial vaginosis confers 2.9 fold increased risk of preterm birth). Conclusions: Many associations and modifiable behaviors and conditions have been identified for the care of the patient at risk for preterm birth. Evidence-based therapeutic intervention includes identification and treatment of nutritional deficits, infections, short cervix, and cervical insufficiency. Future studies on alteration of vaginal microbiome may identify additional therapy to reduce incidence of preterm birth.
Aims and Objectives
To determine the frequency, timing, and duration of post‐acute sequelae of SARS‐CoV‐2 infection (PASC) and their impact on health and function.
Background
Post‐acute sequelae of ...SARS‐CoV‐2 infection is an emerging major public health problem that is poorly understood and has no current treatment or cure. PASC is a new syndrome that has yet to be fully clinically characterised.
Design
Descriptive cross‐sectional survey (n = 5163) was conducted from online COVID‐19 survivor support groups who reported symptoms for more than 21 days following SARS‐CoV‐2 infection.
Methods
Participants reported background demographics and the date and method of their covid diagnosis, as well as all symptoms experienced since onset of covid in terms of the symptom start date, duration, and Likert scales measuring three symptom‐specific health impacts: pain and discomfort, work impairment, and social impairment. Descriptive statistics and measures of central tendencies were computed for participant demographics and symptom data.
Results
Participants reported experiencing a mean of 21 symptoms (range 1–93); fatigue (79.0%), headache (55.3%), shortness of breath (55.3%) and difficulty concentrating (53.6%) were the most common. Symptoms often remitted and relapsed for extended periods of time (duration M = 112 days), longest lasting symptoms included the inability to exercise (M = 106.5 days), fatigue (M = 101.7 days) and difficulty concentrating, associated with memory impairment (M = 101.1 days). Participants reported extreme pressure at the base of the head, syncope, sharp or sudden chest pain, and “brain pressure” among the most distressing and impacting daily life.
Conclusions
Post‐acute sequelae of SARS‐CoV‐2 infection can be characterised by a wide range of symptoms, many of which cause moderate‐to‐severe distress and can hinder survivors' overall well‐being.
Relevance to Clinical Practice
This study advances our understanding of the symptoms of PASC and their health impacts.
Abstract
Long-haul COVID-19, also called post-acute sequelae of SARS-CoV-2 (PASC), is a new illness caused by SARS-CoV-2 infection and characterized by the persistence of symptoms. The purpose of ...this cross-sectional study was to identify a distinct and significant temporal pattern of PASC symptoms (symptom type and onset) among a nationwide sample of PASC survivors (n = 5652). The sample was randomly sorted into two independent samples for exploratory (EFA) and confirmatory factor analyses (CFA). Five factors emerged from the EFA: (1) cold and flu-like symptoms, (2) change in smell and/or taste, (3) dyspnea and chest pain, (4) cognitive and visual problems, and (5) cardiac symptoms. The CFA had excellent model fit (
x
2
= 513.721, df = 207,
p
< 0.01, TLI = 0.952, CFI = 0.964, RMSEA = 0.024). These findings demonstrate a novel symptom pattern for PASC. These findings can enable nurses in the identification of at-risk patients and facilitate early, systematic symptom management strategies for PASC.
Using pan-cancer data from The Cancer Genome Atlas (TCGA), we investigated how patterns in copy number alterations in cancer cells vary both by tissue type and as a function of genetic alteration. We ...find that patterns in both chromosomal ploidy and individual arm copy number are dependent on tumour type. We highlight for example, the significant losses in chromosome arm 3p and the gain of ploidy in 5q in kidney clear cell renal cell carcinoma tissue samples. We find that specific gene mutations are associated with genome-wide copy number changes. Using signatures derived from non-negative factorisation, we also find gene mutations that are associated with particular patterns of ploidy change. Finally, utilising a set of machine learning classifiers, we successfully predicted the presence of mutated genes in a sample using arm-wise copy number patterns as features. This demonstrates that mutations in specific genes are correlated and may lead to specific patterns of ploidy loss and gain across chromosome arms. Using these same classifiers, we highlight which arms are most predictive of commonly mutated genes in kidney renal clear cell carcinoma (KIRC).
A genomic basis of vocal rhythm in birds Sebastianelli, Matteo; Lukhele, Sifiso M; Secomandi, Simona ...
Nature communications,
04/2024, Volume:
15, Issue:
1
Journal Article
Peer reviewed
Open access
Vocal rhythm plays a fundamental role in sexual selection and species recognition in birds, but little is known of its genetic basis due to the confounding effect of vocal learning in model systems. ...Uncovering its genetic basis could facilitate identifying genes potentially important in speciation. Here we investigate the genomic underpinnings of rhythm in vocal non-learning Pogoniulus tinkerbirds using 135 individual whole genomes distributed across a southern African hybrid zone. We find rhythm speed is associated with two genes that are also known to affect human speech, Neurexin-1 and Coenzyme Q8A. Models leveraging ancestry reveal these candidate loci also impact rhythmic stability, a trait linked with motor performance which is an indicator of quality. Character displacement in rhythmic stability suggests possible reinforcement against hybridization, supported by evidence of asymmetric assortative mating in the species producing faster, more stable rhythms. Because rhythm is omnipresent in animal communication, candidate genes identified here may shape vocal rhythm across birds and other vertebrates.
ABSTRACT
The prevalence of fat‐soluble vitamin (FSV) deficiency in children undergoing total pancreatectomy with islet autotransplantation (TPIAT) for chronic pancreatitis (CP) is unknown. We ...quantified FSV deficiency in 100 children (age ≤18) undergoing TPIAT. FSV levels (vitamins A, E, D) and clinical history were ed from medical records. Vitamin A was low in 4% before and 7% at 1 year after TPIAT, vitamin E in 17% and 18%, and vitamin D in 22% and 24%, respectively, regardless of pancreatic enzyme or vitamin supplement dosing. Longer duration of CP was associated with pre‐TPIAT vitamin D insufficiency (P = 0.0002). This remained significant in a multivariate regression model (adjusted P = 0.01). On multivariate analysis, there were no significant predictors of low FSV levels post‐TPIAT. FSV deficiencies are common among children undergoing TPIAT and patients who have had longer disease duration may be at increased risk. All children should be monitored for FSV deficiency after TPIAT.
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