McColley S.A.,Northwestern University |
McColley S.A.,Stanley Manne Childrens Research Institute |
McColley S.A.,Clinical Translational Science Institute
Expert Opinion on Drug Safety | Year: 2016
Introduction: Ivacaftor is indicated for treatment of cystic fibrosis (CF) mediated by 10 mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that causes gating or partial function abnormalities. In placebo-controlled and open-label studies, ivacaftor-treated subjects showed improved pulmonary function, nutrition and quality of life measures. This article reviews ivacaftor safety.Areas covered: Safety findings in ivacaftor clinical trials, and reported subsequently, were accessed by a PubMed search using key words "VX-770" or "ivacaftor". Additional information was accessed via Google Search. Transaminitis was noted in ivacaftor and combination lumacaftor-ivacaftor trials. Ivacaftor was associated with cataracts in juvenile rat pups in pre-clinical studies; non-congenital cataracts have been found in children taking ivacaftor. Ivacaftor is a CYP3A substrate; CYP3A inhibitors and inducers should be avoided during its administration. Ivacaftor and its M1 metabolite may inhibit CYP3A and P-gp; therefore, ivacaftor may increase systemic exposure to drugs which are substrates of CYP3A and/or P-gp, increasing the potential for adverse events.Expert opinion: Ivacaftor therapy may be associated with ocular and hepatic side effects; specific recommendations for monitoring are available. Potential drug interactions should be evaluated in patients taking ivacaftor. High clinical efficacy suggests that the risk benefit ratio of ivacaftor favors therapy. © 2016 Informa UK Limited, trading as Taylor & Francis Group.
Khalkhali-Ellis Z.,Stanley Manne Childrens Research Institute |
Hendrix M.J.C.,Northwestern University
European Journal of Physical and Health Education | Year: 2014
Since its discovery as a lysosomal hydrolase, Cathepsin D (CatD) has been the subject of intensive scrutiny by numerous scientists. Those accumulated efforts have defined its biosynthetic pathway, structure, and companion proteins in the context of its perceived "house keeping" function. However, in the past two decades CatD has emerged as a multifunctional enzyme, involved in myriad biological processes beyond its original "housekeeping" role. CatD is responsible for selective and limited cleavage (quite distinct from non-specific protein degradation) of particular substrates vital to proper cellular function. These proteolytic events are critical in the control of biological processes, including cell cycle progression, differentiation and migration, morphogenesis and tissue remodeling, immunological processes, ovulation, fertilization, neuronal outgrowth, angiogenesis, and apoptosis. Consistent with the biological relevance of CatD, its deficiency, altered regulation or post-translational modification underlie important pathological conditions such as cancer, atherosclerosis, neurological and skin disorders. Specifically, deregulated synthesis, post-translational modifications and hyper-secretion of CatD, along with its mitogenic effects, are established hallmarks of cancer. More importantly, but less studied, is its significance in regulating the sensitivity to anticancer drugs. This review outlines CatD's post-translational modifications, cellular trafficking, secretion and protein binding partners in normal mammary gland, and restates the "site-specific" function of CatD which is most probably dictated by its post-translational modifications and binding partners. Noteworthy, CatD's association with one of its binding partners in the context of drug sensitivity is highlighted, with the optimism that it could contribute to the development of more effective chemotherapeutic agent(s) tailored for individual patients. © 2014 Ellis, et al.
Lavigne J.V.,Northwestern University |
Gouze K.R.,Stanley Manne Childrens Research Institute |
Hopkins J.,Illinois Institute of Technology |
Bryant F.B.,Loyola University Chicago
Development and Psychopathology | Year: 2015
The present study examined a cascade model of age 4 and 5 contextual, parent, parenting, and child factors on symptoms of oppositional defiant disorder (ODD) at age 6 in a diverse community sample of 796 children. Contextual factors include socioeconomic status, family stress, and conflict; parent factors included parental depression; parenting factors included parental hostility, support, and scaffolding skills; child factors included child effortful control (EC), negative affect (NA), and sensory regulation. Direct effects of age 5 conflict, hostility, scaffolding, EC, and NA were found. Significant indirect, cascading effects on age 6 ODD symptom levels were noted for age 4 socioeconomic status via age 5 conflict and scaffolding skills; age 4 parental depression via age 5 child NA; age 4 parental hostility and support via age 5 EC; age 4 support via age 5 EC; and age 4 attachment via age 5 EC. Parenting contributed to EC, and the age 5 EC effects on subsequent ODD symptom levels were distinct from age 5 parental contributions. Scaffolding and ODD symptoms may have a reciprocal relationship. These results highlight the importance of using a multidomain model to examine factors associated with ODD symptoms early in the child's grammar school years. Copyright © Cambridge University Press 2015
McColley S.A.,Northwestern University |
McColley S.A.,Stanley Manne Childrens Research Institute
Expert Opinion on Orphan Drugs | Year: 2016
Introduction: Cystic fibrosis (CF) is a life-shortening autosomal recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, causing pancreatic insufficiency, progressive bronchiectasis that leads to respiratory failure, and other organ system disease. Ivacaftor, the first commercially available therapy that improves CFTR function, has been available for patients with "gating" CFTR mutations since 2012. Lumacaftor combined with ivacaftor was recently demonstrated to improve lung function and reduce pulmonary exacerbation frequency in CF patients who are homozygous for the F508del mutation, the most prevalent CFTR mutation worldwide.Areas covered: This article discusses basic discoveries leading to the development of lumacaftor-ivacaftor combination therapy, and results of phase 2 and 3 clinical trials. Articles were accessed via PubMed using the search terms VX-809 and lumacaftor; supplemental information was accessed using Google Search and the United States National Institutes of Health clinical trials website.Expert opinion: Combination lumacaftor and ivacaftor therapy confers benefit in the treatment of F508del homozygous cystic fibrosis, most notably in reduction of pulmonary exacerbation. The pulmonary function and nutritional benefits are modest compared to ivacaftor monotherapy in CF patients with gating mutations, and efforts are underway to optimize CFTR correction. © 2016 Taylor & Francis.
Sredni S.T.,Ann and Robert H. Lurie Childrens Hospital of Chicago |
Sredni S.T.,Northwestern University |
Sredni S.T.,Stanley Manne Childrens Research Institute |
Tomita T.,Ann and Robert H. Lurie Childrens Hospital of Chicago |
Tomita T.,Northwestern University
Pediatric and Developmental Pathology | Year: 2015
Rhabdoid tumors (RT), or malignant rhabdoid tumors, are among the most aggressive and lethal forms of human cancer. They can arise in any location in the body but are most commonly observed in the brain, where they are called atypical teratoid/rhabdoid tumors (AT/RT), and in the kidneys, where they are called rhabdoid tumors of the kidney. The vast majority of rhabdoid tumors present with a loss of function in the SMARCB1 gene, also known as INI1, BAF47, and hSNF5, a core member of the SWI/SNF chromatin-remodeling complex. Recently, mutations in a 2nd locus of the SWI/SNF complex, the SMARCA4 gene, also known as BRG1, were found in rhabdoid tumors with retention of SMARCB1 expression. Familial cases may occur in a condition known as rhabdoid tumor predisposition syndrome (RTPS). In RTPS, germline inactivation of 1 allele of a gene occurs. When the mutation occurs in the SMARCB1 gene, the syndrome is called RTPS1, and when the mutation occurs in the SMARCA4 gene it is called RTPS2. Children presenting with RTPS tend to develop tumors at a younger age, but the impact that germline mutation has on survival remains unclear. Adults who carry the mutation tend to develop multiple schwannomas. The diagnosis of RTPS should be considered in patients with RT, especially if they have multiple primary tumors, and/or in individuals with a family history of RT. Because germline mutations result in an increased risk of carriers developing RT, genetic counseling for families with this condition is recommended. © 2015 Society for Pediatric Pathology.