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. 相似文献
Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction. 相似文献
This reflection describes a life‐limiting case of oral squamous cell carcinoma (SCC) that required thoughtful management facilitated by an advance care plan (ACP). A 70‐year‐old female was diagnosed with a T4aN2bM0 biopsy‐proven invasive, well‐differentiated keratinizing SCC. Surgical wide‐local excision included teeth #11‐16 with left unilateral neck dissection, levels I‐V. She was rehabilitated with maxillary obturator prosthesis and underwent chemoradiation therapy. Her course was complicated by dysphagia and trismus. She experienced multiple recurrences. At a certain point, negative margins could not be achieved without facial disfigurement. The patient, her husband, and providers decided together that further management would be palliative. Before the additional surgical procedures, she communicated a thorough ACP with her husband and providers who were prepared to facilitate difficult care decisions on her behalf. The patient passed away at home with hospice care at the age of 74. This motivated patient with oral SCC and impactful postmanagement complications appreciated the clarity of an ACP. Her values and goals of care were incorporated with ongoing communication and documentation of this plan, which was instrumental in facilitating her person‐centered care. The providers apply lessons learned here in future practice and education of residents and students. 相似文献
The location and angle of scaphoid fractures are important attributes which guide management. We used a 3 dimensional scaphoid model, generated from CT scans, to map scaphoid fracture planes. The point at which the fracture plane crossed the central axis of the scaphoid was noted. The angle of the fracture planes with regard to the central axis was also noted. This allowed calculation of the location of the fracture and the angle of the 379 fractures. The mean point of intersection for fractures with the scaphoid axis was 50% along the scaphoid. Sixty percent of all fractures were found around the central 20% of the scaphoid. The mean angle between the scaphoid axis and the fracture plane was 63 degrees). On comparing angle with location, as fractures move away from the scaphoid waist, they become less perpendicular to the scaphoid axis (p?.01). Older patients are more likely to have proximal fractures (p?.01). Men are more at risk of proximal scaphoid fractures than women (p?.001). Proximal fractures increases risk of progressing to non-union (p?=?.018). There was no link between fracture plane angles and age, sex and union status. Most fractures occur at the centre of the scaphoid. There is a link between the location and angle of scaphoid fractures. It also identifies older patients and males are more likely to have more proximal scaphoid fractures. 相似文献
Depressive symptoms are associated with poor HIV viral control and immune recovery among people living with HIV. However, no prior studies assessed this association exclusively among people co-infected with HIV-hepatitis C virus (HCV). While people with HIV only and those with HIV-HCV co-infection share many characteristics, co-infected people may become more susceptible to the effects of depressive symptoms on health outcomes. We assessed this association exclusively among people co-infected with HIV-HCV in Canada using data from the Food Security &; HIV-HCV Sub-Study (FS Sub-Study) of the Canadian Co-Infection Cohort (CCC). Stabilized inverse probability weighted marginal structural model was used to account for potential time-varying confounders. A total of 725 participants were enrolled between 2012 and 2015. At baseline, 52% of participants reported depressive symptoms, 75% had undetectable HIV viral load, and median CD4 count was 466 (IQR 300–665). People experiencing depressive symptoms had 1.32 times (95% CI: 1.07, 1.63) the risk of having detectable HIV viral load, but had comparable CD4 count to people who did not experience depressive symptoms (fold change of CD4?=?0.96, 95% CI: 0.91, 1.03). Presence of depressive symptoms is a risk factor for incomplete short-term HIV viral suppression among people co-infected with HIV-HCV. Therefore, depressive symptoms screening and related counseling may improve HIV related health outcomes and reduce HIV transmission. 相似文献
Calcineurin, a serine-threonine-specific, Ca2+-calmodulin-activated protein phosphatase, conserved from yeast to humans, plays a key role in regulating cardiac development, hypertrophy, and pathological remodeling. Recent studies demonstrate that calcineurin regulates cardiomyocyte ion channels and receptors in a manner which often entails direct interaction with these target proteins. Here, we review the current state of knowledge of calcineurin-mediated regulation of ion channels in the myocardium with emphasis on the transient outward potassium current (Ito) and L-type calcium current (ICa,L). We go on to discuss unanswered questions that surround these observations and provide perspective on future directions in this exciting field. 相似文献