Secondary Prevention of Cervical Cancer : ASCO Resource–Stratified Guideline Update

Q2Q2PURPOSE: To update resource-stratified, evidence-based recommendations on secondary prevention of cervical cancer globally. METHODS: American Society of Clinical Oncology convened a multidisciplinary, multinational Expert Panel to produce recommendations reflecting four resource-tiered settings. A review of existing guidelines, formal consensus-based process, and modified ADAPTE process to adapt existing guidelines was conducted. Other experts participated in formal consensus. RESULTS: This guideline update reflects changes in evidence since the previous update. Five existing guidelines were identified and reviewed, and adapted recommendations form the evidence base. Cost-effectiveness analyses provided indirect evidence to inform consensus, which resulted in ≥ 75% agreement. RECOMMENDATIONS: Human papillomavirus (HPV) DNA testing is recommended in all resource settings; visual inspection with acetic acid may be used in basic settings. Recommended age ranges and frequencies vary by the following setting: maximal: age 25-65 years, every 5 years; enhanced: age 30-65 years, if two consecutive negative tests at 5-year intervals, then every 10 years; limited: age 30-49 years, every 10 years; basic: age 30-49 years, one to three times per lifetime. For basic settings, visual assessment is used to determine treatment eligibility; in other settings, genotyping with cytology or cytology alone is used to determine treatment. For basic settings, treatment is recommended if abnormal triage results are obtained; in other settings, abnormal triage results followed by colposcopy is recommended. For basic settings, treatment options are thermal ablation or loop electrosurgical excision procedure; for other settings, loop electrosurgical excision procedure or ablation is recommended; with a 12-month follow-up in all settings. Women who are HIV-positive should be screened with HPV testing after diagnosis, twice as many times per lifetime as the general population. Screening is recommended at 6 weeks postpartum in basic settings; in other settings, screening is recommended at 6 months. In basic settings without mass screening, infrastructure for HPV testing, diagnosis, and treatment should be developed.https://orcid.org/0000-0001-7187-9946Revista Internacional - IndexadaCN

A soil fungus confers plant resistance against a phytophagous insect by disrupting the symbiotic role of its gut microbiota

Plants generate energy flows through natural food webs, driven by competition for resources among organisms, which are part of a complex network of multitrophic interactions. Here, we demonstrate that the interaction between tomato plants and a phytophagous insect is driven by a hidden interplay between their respective microbiotas. Tomato plants colonized by the soil fungus Trichoderma afroharzianum, a beneficial microorganism widely used in agriculture as a biocontrol agent, negatively affects the development and survival of the lepidopteran pest Spodoptera littoralis by altering the larval gut microbiota and its nutritional support to the host. Indeed, experiments aimed to restore the functional microbial community in the gut allow a complete rescue. Our results shed light on a novel role played by a soil microorganism in the modulation of plant-insect interaction, setting the stage for a more comprehensive analysis of the impact that biocontrol agents may have on ecological sustainability of agricultural systems

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

“I would rather be told than not know” - A qualitative study exploring parental views on identifying the future risk of childhood overweight and obesity during infancy

BACKGROUND: Risk assessment tools provide an opportunity to prevent childhood overweight and obesity through early identification and intervention to influence infant feeding practices. Engaging parents of infants is paramount for success however; the literature suggests there is uncertainty surrounding the use of such tools with concerns about stigmatisation, labelling and expressions of parental guilt. This study explores parents' views on identifying future risk of childhood overweight and obesity during infancy and communicating risk to parents. METHODS: Semi-structured qualitative interviews were conducted with 23 parents and inductive, interpretive and thematic analysis performed. RESULTS: Three main themes emerged from the data: 1) Identification of infant overweight and obesity risk. Parents were hesitant about health professionals identifying infant overweight as believed they would recognise this for themselves, in addition parents feared judgement from health professionals. Identification of future obesity risk during infancy was viewed positively however the use of a non-judgemental communication style was viewed as imperative. 2) Consequences of infant overweight. Parents expressed immediate anxieties about the impact of excess weight on infant ability to start walking. Parents were aware of the progressive nature of childhood obesity however, did not view overweight as a significant problem until the infant could walk as viewed this as a point when any excess weight would be lost due to increased energy expenditure. 3) Parental attributions of causality, responsibility, and control. Parents articulated a high level of personal responsibility for preventing and controlling overweight during infancy, which translated into self-blame. Parents attributed infant overweight to overfeeding however articulated a reluctance to modify infant feeding practices prior to weaning. CONCLUSION: This is the first study to explore the use of obesity risk tools in clinical practice, the findings suggest that identification, and communication of future overweight and obesity risk is acceptable to parents of infants. Despite this positive response, findings suggest that parents' acceptance to identification of risk and implementation of behaviour change is time specific. The apparent level of parental responsibility, fear of judgement and self-blame also highlights the importance of health professionals approach to personalised risk communication so feelings of self-blame are negated and stigmatisation avoided

Epithelial Cell Mitochondrial Dysfunction and PINK1 Are Induced by Transforming Growth Factor- Beta1 in Pulmonary Fibrosis

Background: Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial cell death and fibrosis. Methods: We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 (PINK1), in IPF lung tissues by Western blotting, transmission electron microscopy (TEM), and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-β1 (TGF-β1). Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung fibrosis. Results: Evaluation of IPF lung tissue demonstrated increased PINK1 expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-β1 induced mitochondrial depolarization, mitochondrial ROS, and PINK1 expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1-/- mice were more susceptible than control mice to bleomycin induced lung fibrosis. Conclusion: TGF-β1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, PINK1. PINK1 ameliorates epithelial cell death and may be necessary to limit fibrogenesis

Quantitative Analysis of Mechanisms That Govern Red Blood Cell Age Structure and Dynamics during Anaemia

Mathematical modelling has proven an important tool in elucidating and quantifying mechanisms that govern the age structure and population dynamics of red blood cells (RBCs). Here we synthesise ideas from previous experimental data and the mathematical modelling literature with new data in order to test hypotheses and generate new predictions about these mechanisms. The result is a set of competing hypotheses about three intrinsic mechanisms: the feedback from circulating RBC concentration to production rate of immature RBCs (reticulocytes) in bone marrow, the release of reticulocytes from bone marrow into the circulation, and their subsequent ageing and clearance. In addition we examine two mechanisms specific to our experimental system: the effect of phenylhydrazine (PHZ) and blood sampling on RBC dynamics. We performed a set of experiments to quantify the dynamics of reticulocyte proportion, RBC concentration, and erythropoietin concentration in PHZ-induced anaemic mice. By quantifying experimental error we are able to fit and assess each hypothesis against our data and recover parameter estimates using Markov chain Monte Carlo based Bayesian inference. We find that, under normal conditions, about 3% of reticulocytes are released early from bone marrow and upon maturation all cells are released immediately. In the circulation, RBCs undergo random clearance but have a maximum lifespan of about 50 days. Under anaemic conditions reticulocyte production rate is linearly correlated with the difference between normal and anaemic RBC concentrations, and their release rate is exponentially correlated with the same. PHZ appears to age rather than kill RBCs, and younger RBCs are affected more than older RBCs. Blood sampling caused short aperiodic spikes in the proportion of reticulocytes which appear to have a different developmental pathway than normal reticulocytes. We also provide evidence of large diurnal oscillations in serum erythropoietin levels during anaemia

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m$^{-}$$^{2}$ once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the dopamine D-2 receptor occupancy of olanzapine in rats

A mechanism-based PK-PD model was developed to predict the time course of dopamine D-2 receptor occupancy (D2RO) in rat striatum following administration of olanzapine, an atypical antipsychotic drug. A population approach was utilized to quantify both the pharmacokinetics and pharmacodynamics of olanzapine in rats using the exposure (plasma and brain concentration) and D2RO profile obtained experimentally at various doses (0.01-40 mg/kg) administered by different routes. A two-compartment pharmacokinetic model was used to describe the plasma pharmacokinetic profile. A hybrid physiology- and mechanism-based model was developed to characterize the D-2 receptor binding in the striatum and was fitted sequentially to the data. The parameters were estimated using nonlinear mixed-effects modeling . Plasma, brain concentration profiles and time course of D2RO were well described by the model; validity of the proposed model is supported by good agreement between estimated association and dissociation rate constants and in vitro values from literature. This model includes both receptor binding kinetics and pharmacokinetics as the basis for the prediction of the D2RO in rats. Moreover, this modeling framework can be applied to scale the in vitro and preclinical information to clinical receptor occupancy

Low Enzymatic Activity Haplotypes of the Human Catechol-O-Methyltransferase Gene: Enrichment for Marker SNPs

Catechol-O-methyltransferase (COMT) is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val158met) position, designated as low (LPS), average (APS), and high pain sensitive (HPS), are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions. APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively. In the present study, we investigated whether additional minor single nucleotide polymorphisms (SNPs), accruing in 1 to 5% of the population, situated in the COMT transcript region contribute to haplotype-dependent enzymatic activity. Computer analysis of COMT ESTs showed that one synonymous minor SNP (rs769224) is linked to the APS haplotype and three minor SNPs (two synonymous: rs6267, rs740602 and one nonsynonymous: rs8192488) are linked to the HPS haplotype. Results from in silico and in vitro experiments revealed that inclusion of allelic variants of these minor SNPs in APS or HPS haplotypes did not modify COMT function at the level of mRNA folding, RNA transcription, protein translation, or enzymatic activity. These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation. Thus, both minor synonymous and nonsynonymous SNPs in the coding region are markers of functional APS and HPS haplotypes rather than independent contributors to COMT activity