High Healthcare Resource Use in Hospitalized Patients with a Diagnosis of Spinal Muscular Atrophy Type 1 (SMA1): Retrospective Analysis of the Kids' Inpatient Database (KID).

BACKGROUND: Patients with spinal muscular atrophy (SMA) have high healthcare resource use (HRU) due to respiratory and nutritional complications resulting from progressive muscle atrophy. While previous studies estimate the direct costs to be US$113,000 to US$121,682 per year in the US, they potentially understate costs for type 1 SMA (SMA1). This study analyzed HRU in hospitalizations with a diagnosis of SMA1 and compared it with hospitalizations with complex chronic conditions (CCC) other than SMA1 or those with no CCC. METHODS: This retrospective analysis of a defined subset of the 2012 Kids' Inpatient Database (KID) compared a nationally estimated number of hospitalizations of children (aged < 3 years) categorized into three groups: (1) SMA1 (n = 237 admissions), (2) no CCC (n = 632,467 admissions), and (3) other CCC (n = 224,953 admissions). RESULTS: Mean total charges were higher for SMA1 admissions compared with admissions with no CCC (US$150,921 vs US$19,261 per admission, respectively; costs: US$50,190 vs $5862 per admission, respectively; both p < 0.0001). A larger proportion of SMA1 admissions were billed for one or more procedure codes (81.9%) than in the no CCC group (39.4%) or other CCC group (70.1%; both p ≤ 0.0003). SMA1 admissions had a longer length of stay compared with admissions with no CCC (15.1 vs 3.4, respectively; p < 0.0001). CONCLUSIONS: The average total charges for a single SMA1 admission were higher than those of the no CCC group. Because most infants with SMA1 require multiple hospitalizations per year, previous estimates may dramatically underestimate the direct costs associated with HRU. Further studies are required to determine the indirect costs and societal impacts of SMA1.

Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease. METHODS: Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×1013 vg per kilogram of body weight), and 12 received a high dose (2.0×1014 vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts). RESULTS: As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone. CONCLUSIONS: In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).

Improving access and provision of preventive oral health care for very young, poor, and low-income children through a new interdisciplinary partnership.

OBJECTIVES: We provided oral health care services at 2 sites using a nurse practitioner-dietitian team to increase dental workforce capacity and improve access to care for low-income preschool children. METHODS: Our team provided oral health assessments and education, fluoride varnish application, and dentist referrals. The primary endpoint was participants' access to oral health care. Secondary endpoints included increasing the practice scope of registered dietitians through training programs for oral health assessment and the application of fluoride varnishes for children. The oral health and hygiene and dietary habits of the participants were also determined. RESULTS: From 2010 to 2013, 4360 children received fluoride varnishes in 7195 total visits. Although the proportion of children with dental caries at the first visit was greater at the urban site, both sites were similar by visits 2 and 3. The number of caries declined with increased program visits, which coincided with an increase in the proportion of participants visiting a dentist. CONCLUSIONS: Progress toward eliminating dental health disparities requires addressing barriers to dental care access. We showed that expanding access to oral health services through nurse practitioner-dietitian cooperation improved access to preventive fluoride varnishing use in low-income children.

Vitamin C Transporters, Recycling and the Bystander Effect in the Nervous System: SVCT2 versus Gluts.

Vitamin C is an essential micronutrient in the human diet; its deficiency leads to a number of symptoms and ultimately death. After entry into cells within the central nervous system (CNS) through sodium vitamin C transporters (SVCTs) and facilitative glucose transporters (GLUTs), vitamin C functions as a neuromodulator, enzymatic cofactor, and reactive oxygen species (ROS) scavenger; it also stimulates differentiation. In this review, we will compare the molecular and structural aspects of vitamin C and glucose transporters and their expression in endothelial or choroid plexus cells, which form part of the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier, respectively. Additionally, we will describe SVCT and GLUT expression in different cells of the brain as well as SVCT2 distribution in tanycytes and astrocytes of the hypothalamic region. Finally, we will describe vitamin C recycling in the brain, which is mediated by a metabolic interaction between astrocytes and neurons, and the role of the "bystander effect" in the recycling mechanism of vitamin C in both normal and pathological conditions.

VDR activity is differentially affected by Hic-5 in prostate cancer and stromal cells.

UNLABELLED: Patients with prostate cancer treated with androgen deprivation therapy (ADT) eventually develop castrate-resistant prostate cancer (CRPC). 1,25-Dihydroxyvitamin D3 (1,25D3/calcitriol) is a potential adjuvant therapy that confers antiproliferative and pro-differentiation effects in vitro, but has had mixed results in clinical trials. The impact of the tumor microenvironment on 1,25D3 therapy in patients with CRPC has not been assessed. Transforming growth factor ß (TGFß), which is associated with the development of tumorigenic "reactive stroma" in prostate cancer, induced vitamin D3 receptor (VDR) expression in the human WPMY-1 prostate stromal cell line. Similarly, TGFß enhanced 1,25D3-induced upregulation of CYP24A1, which metabolizes 1,25D3 and thereby limits VDR activity. Ablation of Hic-5, a TGFß-inducible nuclear receptor coregulator, inhibited basal VDR expression, 1,25D3-induced CYP24A1 expression and metabolism of 1,25D3 and TGFß-enhanced CYP24A1 expression. A Hic-5-responsive sequence was identified upstream (392-451 bp) of the CYP24A1 transcription start site that is occupied by VDR only in the presence of Hic-5. Ectopic expression of Hic-5 sensitized LNCaP prostate tumor cells to growth-inhibitory effects of 1,25D3 independent of CYP24A1. The sensitivity of Hic-5-expressing LNCaP cells to 1,25D3-induced growth inhibition was accentuated in coculture with Hic-5-ablated WPMY-1 cells. Therefore, these findings indicate that the search for mechanisms to sensitize prostate cancer cells to the antiproliferative effects of VDR ligands needs to account for the impact of VDR activity in the tumor microenvironment. IMPLICATIONS: Hic-5 acts as a coregulator with distinct effects on VDR transactivation, in prostate cancer and stromal cells, and may exert diverse effects on adjuvant therapy designed to exploit VDR activity in prostate cancer.

The Public Health Impact of Herbs and Nutritional Supplements.

Dietary supplement use has increased exponentially in recent years despite the lack of regulatory oversight and in the face of growing safety concerns. This paper provides an overview of the public health implications and safety concerns associated with dietary supplement use, especially by cancer patients. Botanical research is actively pursued at the Memorial Sloan-Kettering Cancer Center (MSKCC) Integrative Medicine department. Work of the MSKCC Center for the Study of Botanical Immunomodulators is described, and guidelines for cancer patients' use of dietary supplements outlined. Herbs and other botanicals are complex, physiologically active agents, but little is known about most of the popular, widely available dietary supplements. Herb-drug interactions, a major concern, are exacerbated in the cancer setting. Biologically active agents may interfere with chemotherapy and other prescription medications. They may exert anti-coagulant activity at rather inconvenient times such as during surgery, and create other serious problems. Research on the bioavailability, effective dosage, safety and benefits of these complex agents is sorely needed. Oncology professionals and other healthcare providers should educate themselves and their patients about these issues. Probably the largest, continuously-updated free information resource is MSKCC's AboutHerbs website (www.mskcc.org/AboutHerbs).

Coactivators and nuclear receptor transactivation.

A variety of coregulator proteins serve as partners for nuclear receptors orchestrating the molecular events required for receptor-dependent transcriptional regulation. Some coregulators directly interact with nuclear receptors and provide a platform for recruitment of other factors that provide distinct biochemical activities that influence transcriptional efficiency. Coregulators can influence chromatin structure and activity via direct modification of histone proteins or by facilitating ATP-dependent chromatin remodeling. They also have the capacity to impact multiple steps in the transcription process including initiation, elongation, and mRNA splicing. Genetic analysis in humans and animal models are revealing the important cell and tissue-type specific actions of nuclear receptor coregulators as well and their role in human physiology and disease.

Glucocorticoid receptor physiology.

Glucocorticoid action in cells is mediated by a specific receptor protein, the glucocorticoid receptor (GR). GR is a member of a superfamily of ligand-inducible transcription factors that control a variety of physiological functions; such as, metabolism, development, and reproduction. Unliganded GR is predominantly localized within the cytoplasm but rapidly and efficiently translocates to the nucleus following hormone binding. This review will focus on the intracellular signaling pathway utilized by the GR including the mechanisms that control its intracellular trafficking, hormone binding and transcriptional regulation. Many receptor-interacting proteins are involved in distinct steps in GR signal transduction, each with a unique mechanism to regulate receptor action and providing potential drug targets for the manipulation of cellular responses to glucocorticoids.

Hic-5/ARA55: a prostate stroma-specific AR coactivator.

Growth factors and cytokines mediate communication between the epithelial and stromal compartments of the prostate. In prostate cancer (PCa), changes in the spatial arrangements of the two compartments (i.e. basement membrane invasion), DNA mutations, or cellular dedifferentiation (i.e. myofibroblasts) leads to significant changes in gene expression within both compartments. This results in altered cytokine and/or growth factor signaling in PCa. Recently, a stromal-specific androgen receptor (AR) coactivator, Hic-5/ARA55, has been identified that may play a role in regulating expression of the growth factor and/or cytokine expression in the prostate. Specifically, Hic-5/ARA55 expression influences androgen-induced keratinocyte growth factor (KGF) expression in WPMY-1 prostate stromal cells. Because Hic-5/ARA55's expression is also altered in PCa, it may play a role in the differential cellular signaling events that occur during tumor progression.

Hic-5, an adaptor-like nuclear receptor coactivator.

In recent years, numerous nuclear receptor-interacting proteins have been identified that influence nuclear transcription through their direct modification of chromatin. Along with coactivators that possess histone acetyltransferase (HAT) or methyltransferase activity, other coactivators that lack recognizable chromatin-modifying activity have been discovered whose mechanism of action is largely unknown. The presence of multiple protein-protein interaction motifs within mechanistically undefined coactivators suggests that they function as adaptor molecules, either recruiting or stabilizing promoter-specific protein complexes. This perspective will focus on a family of nuclear receptor coactivators (i.e., group III LIM domain proteins related to paxillin) that appear to provide a scaffold to stabilize receptor interactions with chromatin-modifying coregulators.

Hic-5/ARA55, a LIM domain-containing nuclear receptor coactivator expressed in prostate stromal cells.

Prostate gland development and growth requires both androgen action and epithelial-stromal communications. In fact, androgen signaling through the androgen receptor (AR) may be important in both stromal and epithelial cells of the prostate. Because interaction of AR with the coactivator, Hic-5/ARA55, results in enhanced androgen-induced transcription, we analyzed Hic-5/ARA55 expression in prostate tissue sections from normal human donors and prostate cancer patients. In each sample, Hic-5/ARA55 expression was confined to the stromal compartment of the prostate. Furthermore, a prostate stromal cell line, WPMY-1 cells, expresses Hic-5/ARA55, which is localized both at focal adhesion complexes and within the soluble cytoplasmic compartment. The ability of Hic-5/ARA55 to shuttle between the nuclear and cytoplasmic compartments was revealed on inhibition of nuclear export with leptomycin B. Small interfering RNA ablation experiments established endogenous Hic-5/ARA55 as a coactivator for both viral and endogenous cellular AR-regulated genes. Finally, the mechanism of Hic-5/ARA55 coactivator activity in WPMY-1 cells was revealed by chromatin immunoprecipitation analysis that showed its androgen-dependent recruitment to the promoter of the stromal androgen-responsive keratinocyte growth factor gene. These data provide the first demonstration of a stromal-specific AR coactivator that has an effect on an androgen-regulated growth factor that is essential for stromal/epithelial cell communication in the prostate.