Hedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia

Introduction: The Hedgehog (HH) pathway constitutes a collection of signaling molecules which critically influence embryogenesis. In adults, however, the HH pathway remains integral to the proliferation, maintenance, and apoptosis of adult stem cells including hematopoietic stem cells.

Areas covered: We discuss the current understanding of the HH pathway as it relates to normal hematopoiesis, the pathology of acute myeloid leukemia (AML), the rationale for and data from combination therapies including HH pathway inhibitors, and ultimately the prospects that might offer promise in targeting this pathway in AML.

Expert opinion: Efforts to target the HH pathway have been focused on impeding this disposition and restoring chemosensitivity to conventional myeloid neoplasm therapies. The year 2018 saw the first approval of a HH pathway inhibitor (glasdegib) for AML, though for an older population and in combination with an uncommonly-used therapy. Several other clinical trials with agents targeting modulators of HH signaling in AML and MDS are underway. Further study and understanding of the interplay between the numerous aspects of HH signaling and how it relates to the augmented survival of AML will provide a more reliable substrate for therapeutic strategies in patients with this poor-risk disease.     

Oocyte maturation arrest produced by TUBB8 mutations: impact of genetic disorders in infertility treatment

Abstract

Oocyte maturation defect is a challenging situation in the management of infertility, the etiology may be related to endocrine causes, protocols used in ovarian stimulation, oocyte intrinsic defects or procedures in embryology laboratory. We report three Mexican females in treatment for primary infertility with non-mature oocytes after ovary stimulation and oocyte capture in whom a genetic diagnosis of TUBB8-oocyte maturation defect was revealed by exome sequencing. Two couples achieved pregnancies though oocyte donation after establishing the genetic etiology. Our results expand the role of TUBB8-disorders in patients of non-Asian ethnicity. Oocyte maturation defects of monogenic origin are a growing group of disorders that endocrinologists and reproductive medicine specialists should be aware in order to provide referral to genetics for establish a correct and opportune diagnosis.     

Spike‐associated networks and intracranial electrographic findings

Aims. Functional connectivity is providing new insights into the network nature of epilepsy with growing clinical applications. Our objective was to validate a novel magnetoencephalography‐based method to non‐invasively measure the epileptic network. Methods. We retrospectively identified pediatric and adult patients with refractory focal epilepsy who underwent pre‐surgical magnetoencephalography with subsequent intracranial electrographic monitoring. Magnetoencephalography tracings were visually reviewed, and interictal epileptiform discharges (“spikes”) were individually marked. We then evaluated differences in whole‐brain connectivity during brief epochs preceding the spikes and during the spikes using the Network‐Based Statistic to test differences at the network level. Results. In six patients with statistically‐significant network differences, we observed substantial overlap between the spike‐associated networks and electrographically active areas identified during intracranial monitoring (the spike‐associated network was 78% and 83% sensitive for intracranial electroencephalography‐defined regions in the irritative and seizure onset zones, respectively). Conclusion. These findings support the neurobiological validity of the spike‐associated network method. Assessment of spike‐associated networks has the potential to improve surgical planning in epilepsy surgery patients by identifying components of the epileptic network prior to implantation.     

Prosthetic treatment in the adult French population: Prevalence and relation with demographic,socioeconomic and medical characteristics

BackgroundThe aim of this study was to estimate the prevalence of dental prosthetic treatment and to investigate the demographic, social, economic and medical factors associated with the use of fixed and removable dentures in a representative sample of adults living in France.MethodsThe data were obtained from the 2002–2003 Decennial Health Survey, a cross-sectional study of a representative sample of the population living in France, which included 29,679 adults. Information was collected by interview. The variables collected were fixed denture, removable denture, age, gender, number of children, area of residence, nationality, educational attainment, family social status, employment status, annual household income per capita, supplementary insurance, chronic disease, eyesight problems/glasses, hearing problems/hearing aids. Multinomial logistic regression models were used to study the relationship between prosthetic treatment and demographic, socioeconomic and medical characteristics unadjusted, adjusted for age and adjusted for all the characteristics.ResultsThe prevalence of prosthetic treatment was 34.6% (95% confidence interval (CI): [34.1; 35.2]) for fixed prosthetic dentures and 13.8% (95% CI: [13.4; 14.2]) for removable prosthetic dentures. We showed a gradient between educational attainment and removable dentures; the odds ratio adjusted for all the variables (aOR) associated with no or primary education compared to post-secondary education was 2.56; 95% CI: [2.09; 3.13]. When annual household income per capita was low, subjects were less likely to report fixed dentures (aOR = 0.68; 95% CI: [0.62; 0.75]) than those with high annual household income per capita. Individuals without insurance less often reported fixed dentures than those with private insurance. Those reporting chronic disease were less likely to report fixed dentures (aOR = 0.87; 95% CI: [0.79; 0.95]) but more likely to report removable dentures (aOR = 1.29; 95% CI: [1.17; 1.43]) than those without chronic disease.ConclusionThis study reveals social, economic and medical inequalities in fixed and removable prosthetic treatment among adults in France.     

“T” is for “transgender”: an analysis of children’s picture books featuring transgender protagonists and narrators

ABSTRACT

This project examined 55 picture books featuring transgender, gender expansive or genderqueer protagonists or narrators published between 2008 and 2018. The purpose of the study was to determine how this genre of children’s literature supports and challenges four gender assumptions: the gender binary, gender essentialism, sex/gender congruency and gender stability. Additionally, this critical analysis explored misgendering within this genre and themes of social rejection and acceptance. Protagonists and narrators were permitted a degree of gender nonconformity, however, the majority of picture books missed opportunities for a more complete exploration of gender possibilities.