Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview

Introduction: Epigenetic mechanisms of gene regulatory control play fundamental roles in developmental morphogenesis, and, as more recently appreciated, are heavily implicated in the onset and progression of neoplastic disease, including cancer. Many epigenetic mechanisms are therapeutically targetable, providing additional incentive for understanding of their contribution to cancer and other types of neoplasia.

Areas covered: The Jumonji-domain histone demethylase (JHDM) family exemplifies many of the above traits. This review summarizes the current state of knowledge of the functions and pharmacologic targeting of JHDMs in cancer and other neoplastic processes, with an emphasis on diseases affecting the pediatric population.

Expert opinion: To date, the JHDM family has largely been studied in the context of normal development and adult cancers. In contrast, comparatively few studies have addressed JHDM biology in cancer and other neoplastic diseases of childhood, especially solid (non-hematopoietic) neoplasms. Encouragingly, the few available examples support important roles for JHDMs in pediatric neoplasia, as well as potential roles for JHDM pharmacologic inhibition in disease management. Further investigations of JHDMs in cancer and other types of neoplasia of childhood can be expected to both enlighten disease biology and inform new approaches to improve disease outcomes.     

Does prenylation predict progression in NAFLD?

Non-alcoholic fatty liver disease (NAFLD) often develops in concert with related metabolic diseases, such as obesity, dyslipidemia and insulin resistance. Prolonged lipid accumulation and inflammation can progress to non-alcoholic steatohepatitis (NASH). Although factors associated with the development of NAFLD are known, triggers for the progression of NAFLD to NASH are poorly understood. Recent findings published in The Journal of Pathology reveal the possible regulation of NASH progression by metabolites of the mevalonate pathway. Mevalonate can be converted into the isoprenoids farnesyldiphosphate (FPP) and geranylgeranyl diphosphate (GGPP). GGPP synthase (GGPPS), the enzyme that converts FPP to GGPP, is dysregulated in humans and mice during NASH. Both FPP and GGPP can be conjugated to proteins through prenylation, modifying protein function and localization. Deletion or knockdown of GGPPS favors FPP prenylation (farnesylation) and augments the function of liver kinase B1, an upstream kinase of AMP-activated protein kinase (AMPK). Despite increased AMPK activation, livers in Ggpps-deficient mice on a high-fat diet poorly oxidize lipids due to mitochondrial dysfunction. Although work from Liu et al provides evidence as to the potential importance of the prenylation portion of the mevalonate pathway during NAFLD, future studies are necessary to fully grasp any therapeutic or diagnostic potential. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Association of gray matter volumes with general and specific dimensions of psychopathology in children

Childhood is an important time for the manifestation of psychopathology. Psychopathology is characterized by considerable comorbidity which is mirrored in the underlying neural correlates of psychopathology. Both common and dissociable variations in brain volume have been found across multiple mental disorders in adult and youth samples. However, the majority of these studies used samples with broad age ranges which may obscure developmental differences. The current study examines associations between regional gray matter volumes (GMV) and psychopathology in a large sample of children with a narrowly defined age range. We used data from 9607 children 9–10 years of age collected as part of the Adolescent Brain Cognitive Development^SM Study (ABCD Study^®). A bifactor model identified a general psychopathology factor that reflects common variance across disorders and specific factors representing internalizing symptoms, ADHD symptoms, and conduct problems. Brain volume was acquired using 3T MRI. After correction for multiple testing, structural equation modeling revealed nearly global inverse associations between regional GMVs and general psychopathology and conduct problems, with associations also found for ADHD symptoms (p_fdr-values ≤ 0.048). Age, sex, and race were included as covariates. Sensitivity analyses including total GMV or intracranial volume (ICV) as covariates support this global association, as a large majority of region-specific results became nonsignificant. Sensitivity analyses including income, parental education, and medication use as additional covariates demonstrate largely convergent results. These findings suggest that globally smaller GMVs are a nonspecific risk factor for general psychopathology, and possibly for conduct problems and ADHD as well.Subject terms: Human behaviour, Risk factors, Neuroscience     

Anatomic structures at risk in anteroposterior screw fixation of posterior malleolar fractures: A cadaver study

IntroductionPercutaneous anterior-posterior (AP) screw is an option for posterior malleolus fracture fixation when the fracture fragment can be reduced indirectly by the mean of ligamentotaxis. However, anterior anatomic structures could be injured during screw placement.Materials and methodsEleven below-knee cadavers were employed for the placement of AP screws in an attempt of fixing assumed Haraguchi Type-I posterior malleolar fractures. Three entry points were selected as medial to the anterior tibial tendon (ATT), lateral to the ATT, and lateral to the extensor digitorum longus (EDL). Three AP screws were placed under guidance of fluoroscopy. After dissection, measurements were made (mm) from each screw to nearby structures. Distances were calculated and damage to structures was documented.ResultsMean, minimum, and maximum distances from the medial screw to the greater saphenous vein, TA, EHL, anterior tibial artery (ATA), and deep peroneal nerve (DPN), were 18.1 (12–25) mm, 2.0 (0–5) mm, 13.6 (9–20) mm, 16.6 (9–25) mm, and 20.1 (12–27) mm. From the middle screw to the ATA, DPN, TA, EHL, and EDL, were 1.2 (0–3) mm, 4.9 (3–9) mm, 3.8 (1–7) mm, 0.4 (0–2) mm, and 13.6 (10–18) mm. From the lateral screw to the superficial peroneal nerve (SPN), EDL, DPN, and ATA, were 10.8 (0–16) mm, 1.2 (0–4) mm, 15.9 (11–25) mm, 19 (15–27) mm. The SPN was found partially cut by the lateral screw on 1 specimen.ConclusionsLateral and middle percutaneous AP screw placement put certain anatomic structures at-risk of injury. Medial screw placement did not result in appreciable damage to adjacent structures. Entry point of AP screws should be selected with respect to posterior malleolar fracture and anatomic structures.Level of evidenceIV.     

Beyond Self-report: Brain Imaging at the Threshold of Odor Perception

Odorants exert their effects at many levels. Most often, these stimuli are well above detection threshold and allow the investigator to use self-report or behavioral techniques to evaluate odor effects. There are, however, considerable data demonstrating effects for odor stimuli that are below sensory thresholds or are undetected by subjects. In these cases, self-report is of little use, and brain imaging has been very effective in helping to explain these findings. This paper reviews the problem of low-intensity odors and the application of a wide variety of brain imaging techniques to research on this phenomenon. Finally, a model of undetected odor effects and brain imaging is presented to help simplify the variations in nomenclature that are used to describe this field.     

Clinical Impact of a Dedicated Trauma Hybrid Operating Room

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Post-Publication Discussion: Invitation for Reply

Annals of Surgical Oncology -     

Sensitivity and specificity of patient-entered red flags for lower back pain

Background Context

Red flags are questions typically ascertained by providers to screen for serious underlying spinal pathologies. The utility of patient-reported red flags in guiding clinical decision-making for spine care, however, has not been studied.