Childhood Cancers and Systems Medicine

Despite major advances in treatment, pediatric cancers in the 5-16 age group remain the most common cause of disease death, and one out of eight children with cancer will not survive. Among children that do survive, some 60% suffer from late effects such as cancer recurrence and increased risk of obesity. This paper will provide a broad overview of pediatric oncology in the context of systems medicine. Systems medicine utilizes an integrative approach that relies on patient information gained from omics technology. A major goal of a systems medicine is to provide personalized medicine that optimizes positive outcomes while minimizing deleterious short and long-term sideeffects. There is an ever increasing development of effective cancer drugs, but a major challenge lies in picking the most effective drug for a particular patient. As detailed below, high-throughput omics technology holds the promise of solving this problem. Omics includes genomics, epigenomics, and proteomics. System medicine integrates omics information and provides detailed insights into disease mechanisms which can then inform the optimal treatment strategy

The clinical and laboratory spectrum of Hb C [β6(A3)Glu→Lys, GAG\u3eAAG] disease

Newborn screening (NBS) provides early diagnosis of sickle hemoglobinopathies. After Hb S [β6(A3)Glu→Val, GAG\u3eGTG], Hb C [β6(A3)Glu→Lys, GAG\u3eAAG] is the most common hemoglobin (Hb) abnormality identified in the United States (1,2). Published data regarding children with Hb C disease are limited. This study was conducted to summarize a single institution\u27s clinical and laboratory data for patients with Hb C disease, specifically homozygous Hb CC and its variants over a 10-year period. Forty-seven patients, whose mean age at diagnosis was 2.9 years (range 0.04 to 23 years), were identified. Twenty-nine had Hb CC and the remainder had compound heterozygous variants [10 Hb C/β;+-thalassemia (β;+-thal), four Hb C/β;0-thal, and one each with Hb C/Hb Hope or β136(H14)Gly→Asp (GGT\u3eGAT), Hb C/Hb Lepore (a hybrid δβ-globin gene), Hb C/HPFH (hereditary persistence of fetal Hb) [probably a ;Gγ HPFH-2 (the Ghanaian type)], and Hb C/Osu-Christiansborg or β52(D3)Asp→Asn (GAT\u3eAAT)]. All patients had mild microcytic anemia with reticulocytosis and frequent target cells on peripheral smear. Splenomegaly or cholelithiasis occurred in 2.6% of patients \u3c8 years of age, however, these symptoms were more common (71.0%) in patients \u3e8 years of age. No patient had serious infections or painful events resembling vasoocclusion. Accurate diagnosis and understanding of Hb C-related disorders helped to avoid confusion with sickle hemoglobinopathies and aided in proper clinical management. © 2013 Informa Healthcare USA, Inc

AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model

Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by recessive, loss-of-function mutations in FIG4, encoding a phosphoinositol(3,5)P2-phosphatase. CMT4J patients have both neuron loss and demyelination in the peripheral nervous system, with vacuolization indicative of endosome/lysosome trafficking defects. Although the disease is highly variable, the onset is often in childhood and FIG4 mutations can dramatically shorten life span. There is currently no treatment for CMT4J. Here, we present the results of preclinical studies testing a gene-therapy approach to restoring FIG4 expression. A mouse model of CMT4J, the Fig4–pale tremor (plt) allele, was dosed with a single-stranded adeno-associated virus serotype 9 (AAV9) to deliver a codon-optimized human FIG4 sequence. Untreated, Fig4(plt/plt) mice have a median survival of approximately 5 weeks. When treated with the AAV9-FIG4 vector at P1 or P4, mice survived at least 1 year, with largely normal gross motor performance and little sign of neuropathy by neurophysiological or histopathological evaluation. When mice were treated at P7 or P11, life span was still significantly prolonged and peripheral nerve function was improved, but rescue was less complete. No unanticipated adverse effects were observed. Therefore, AAV9-mediated delivery of FIG4 is a well-tolerated and efficacious strategy in a mouse model of CMT4J

AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model.

Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by recessive, loss-of-function mutations in FIG4, encoding a phosphoinositol(3,5)P2-phosphatase. CMT4J patients have both neuron loss and demyelination in the peripheral nervous system, with vacuolization indicative of endosome/lysosome trafficking defects. Although the disease is highly variable, the onset is often in childhood and FIG4 mutations can dramatically shorten life span. There is currently no treatment for CMT4J. Here, we present the results of preclinical studies testing a gene-therapy approach to restoring FIG4 expression. A mouse model of CMT4J, the Fig4-pale tremor (plt) allele, was dosed with a single-stranded adeno-associated virus serotype 9 (AAV9) to deliver a codon-optimized human FIG4 sequence. Untreated, Fig4plt/plt mice have a median survival of approximately 5 weeks. When treated with the AAV9-FIG4 vector at P1 or P4, mice survived at least 1 year, with largely normal gross motor performance and little sign of neuropathy by neurophysiological or histopathological evaluation. When mice were treated at P7 or P11, life span was still significantly prolonged and peripheral nerve function was improved, but rescue was less complete. No unanticipated adverse effects were observed. Therefore, AAV9-mediated delivery of FIG4 is a well-tolerated and efficacious strategy in a mouse model of CMT4J

Urinary Excretion of Sodium, Potassium, and Chloride, but Not Iodine, Varies by Timing of Collection in a 24-Hour Calibration Study

Because of the logistic complexity, excessive respondent burden, and high cost of conducting 24-h urine collections in a national survey, alternative strategies to monitor sodium intake at the population level need to be evaluated. We conducted a calibration study to assess the ability to characterize sodium intake from timed-spot urine samples calibrated to a 24-h urine collection. In this report, we described the overall design and basic results of the study. Adults aged 18–39 y were recruited to collect urine for a 24-h period, placing each void in a separate container. Four timed-spot specimens (morning, afternoon, evening, and overnight) and the 24-h collection were analyzed for sodium, potassium, chloride, creatinine, and iodine. Of 481 eligible persons, 407 (54% female, 48% black) completed a 24-h urine collection. A subsample (n = 133) collected a second 24-h urine 4–11 d later. Mean sodium excretion was 3.54 6 1.51 g/d for males and 3.09 6 1.26 g/d for females. Sensitivity analysis excluding those who did not meet the expected creatinine excretion criterion showed the same results. Day-to-day variability for sodium, potassium, chloride, and iodine was observed among those collecting two 24-h urine samples (CV = 16–29% for 24-h urine samples and 21–41% for timed-spot specimens). Among all race-gender groups, overnight specimens had larger volumes (P This article is from Journal of Nutrition 143 (2013): 1276, doi: 10.3945/jn.113.175927.</p