Jenise C. Wong

The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin

WT1 encodes a zinc finger transcription factor implicated in kidney differentiation and tumorigenesis. In reporter assays, WT1 represses transcription from GC- and TC-rich promoters, but its physiological targets remain uncertain. We used hybridization to high-density oligonucleotide arrays to search for native genes whose expression is altered following inducible expression of WT1. The major target of WT1 was amphiregulin, a member of the epidermal growth factor family. The WT1(-KTS) isoform binds directly to the amphiregulin promoter, resulting in potent transcriptional activation. The in vivo expression profile of amphiregulin during fetal kidney development mirrors the highly specific pattern of WT1 itself, and recombinant Amphiregulin stimulates epithelial branching in organ cultures of embryonic mouse kidney. These observations suggest a model for WT1 as a transcriptional regulator during kidney differentiation.

Real-time continuous glucose monitoring among participants in the T1D Exchange clinic registry.

OBJECTIVE To assess the frequency of continuous glucose monitoring (CGM) device use, factors associated with its use, and the relationship of CGM with diabetes outcomes (HbA1c, severe hypoglycemia [SH], and diabetic ketoacidosis [DKA]). RESEARCH DESIGN AND METHODS Survey questions related to CGM device use 1 year after enrollment in the T1D Exchange clinic registry were completed by 17,317 participants. Participants were defined as CGM users if they indicated using real-time CGM during the prior 30 days. RESULTS Nine percent of participants used CGM (6% of children <13 years old, 4% of adolescents 13 to <18 years, 6% of young adults 18 to <26 years, and 21% of adults ≥26 years). CGM use was more likely with higher education, higher household income, private health insurance, longer duration of diabetes, and use of insulin pump (P < 0.01 all factors). CGM use was associated with lower HbA1c in children (8.3% vs. 8.6%, P < 0.001) and adults (7.7% vs. 7.9%, P < 0.001). In adults, more frequent use of CGM (≥6 days/week) was associated with lower mean HbA1c. Only 27% of users downloaded data from their device at least once per month, and ≤15% of users reported downloading their device at least weekly. Among participants who used CGM at baseline, 41% had discontinued within 1 year. CONCLUSIONS CGM use is uncommon but associated with lower HbA1c in some age-groups, especially when used more frequently. Factors associated with discontinuation and infrequent use of retrospective analysis of CGM data should be considered in developing next-generation devices and education on CGM use.

Severe hypoglycemia and diabetic ketoacidosis among youth with type 1 diabetes in the T1D Exchange clinic registry

Severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) are common serious acute complications of type 1 diabetes (T1D). The aim of this study was to determine the frequency of SH and DKA and identify factors related to their occurrence in the T1D Exchange pediatric and young adult cohort.

A low, adaptive dose of gamma-rays reduced the number and altered the spectrum of S1− mutants in human-hamster hybrid AL cells

We examined the effects of a low, adaptive dose of 137Cs-gamma-irradiation (0.04 Gy) on the number and kinds of mutants induced in AL human-hamster hybrid cells by a later challenge dose of 4 Gy. The yield of S1- mutants was significantly less (by 53%) after exposure to both the adaptive and challenge doses compared to the challenge dose alone. The yield of hprt- mutants was similarly decreased. Incubation with cycloheximide (CX) or 3-aminobenzamide largely negated the decrease in mutant yield. The adaptive dose did not perturb the cell cycle, was not cytotoxic, and did not of itself increase the mutant yield above background. The adaptive dose did, however, alter the spectrum of S1- mutants from populations exposed only to the adaptive dose, as well as affecting the spectrum of S1- mutants generated by the challenge dose. The major change in both cases was a significant increase in the proportion of complex mutations compared to small mutations and simple deletions.

A contrast between children and adolescents with excellent and poor control: the T1D exchange clinic registry experience

Optimizing glycemic control in pediatric type 1 diabetes (T1D) is essential to minimizing long‐term risk of complications. We used the T1D Exchange database from 58 US diabetes clinics to identify differences in diabetes management characteristics among children categorized as having excellent vs. poor glycemic control.

Induction of the interleukin-2/15 receptor β-chain by the EWS–WT1 translocation product

EWS–WT1 is a chimeric transcription factor resulting from fusion of the N-terminal domain of the Ewing sarcoma gene EWS to the three C-terminal zinc fingers of the Wilms tumor suppressor WT1. This translocation underlies desmoplastic small round cell tumor (DSRCT), which is noted for the abundance of reactive stroma surrounding islets of tumor cells, suggestive of paracrine signals contributing to tumor cell proliferation. Hybridization to high-density oligonucleotide microarrays can be used to identify targets of EWS–WT1. Expression of EWS–WT1 from a tetracycline-regulated promoter leads to the induction of growth-associated genes, of which the most remarkable is the beta-chain of the interleukin-2/15 receptor (IL-2/15Rβ). Potent transcriptional activation by the chimeric protein maps to two bindings sites within the IL-2/15Rβ promoter. Analysis of primary DSRCT tumor specimens demonstrates high levels of IL-2/15Rβ within the tumor cells, along with expression of IL-2 and IL-15 by the abundant hyperplastic endothelial cells within the reactive stroma. Activation of this cytokine signaling pathway is consistent with the nuclear localization of its downstream effectors, phosphorylated STAT3 and STAT5. These observations suggest that the transcriptional induction of a cytokine receptor by a tumor-associated translocation product enables a proliferative response of epithelial cancer cells to ligands secreted by the surrounding stroma.

A Minority of Patients with Type 1 Diabetes Routinely Downloads and Retrospectively Reviews Device Data

Abstract Background: In type 1 diabetes (T1D), periodic review of blood glucose and insulin dosing should be performed, but it is not known how often patients review these data on their own. We describe the proportion of patients with T1D who routinely downloaded and reviewed their data at home. Materials and Methods: A cross-sectional survey of 155 adults and 185 caregivers of children with T1D at a single academic institution was performed. “Routine Downloaders” (downloaded four or more times in the past year) were also considered “Routine Reviewers” if they reviewed their data most of the time they downloaded from devices. Logistic regression was used to identify factors associated with being a Routine Reviewer. Results: Only 31% of adults and 56% of caregivers reported ever downloading data from one or more devices, whereas 20% and 40%, respectively, were considered Routine Downloaders. Only 12% of adults and 27% of caregivers were Routine Reviewers. Mean hemoglobin A1c was lower in Routine Reviewers compared with non-Routine Reviewers (7.2±1.0% vs. 8.1±1.6% [P=0.03] in adults and 7.8±1.4% vs. 8.6±1.7% [P=0.001] in children). In adjusted analysis of adults, the odds ratio of being a Routine Reviewer of one or more devices for every 10-year increase in age was 1.5 (95% confidence interval, 1.1, 2.1 [P=0.02]). For every 10 years since diabetes diagnosis, the odds ratio of being a Routine Reviewer was 1.7 (95% confidence interval, 1.2, 2.4 [P=0.01]). For caregivers, there were no statistically significant factors associated with being a Routine Reviewer. Conclusions: A minority of T1D patients routinely downloads and reviews data from their devices on their own. Further research is needed to understand obstacles, provide better education and tools for self-review, and determine if patient self-review is associated with improved glycemic control.

Insulin pump use and glycemic control in adolescents with type 1 diabetes: Predictors of change in method of insulin delivery across two years.

Few studies have explored durability of insulin pump use, and none have explored the link between depression and pump discontinuation. To examine the relationship between depressive symptoms [measured by the Childrens Depression Inventory (CDI)], method of insulin delivery, and hemoglobin A1c (A1c), mixed models were used with data from 150 adolescents with type 1 diabetes (T1D) and visits every 6 months for 2 years. Of the 63% who used a pump, compared with multiple daily injections (MDI) at baseline, there were higher proportions who were non‐minorities, had caregivers with a college degree, private insurance, and two caregivers in the home (p ≤ 0.01). After adjusting for time, sex, age, T1D duration, frequency of blood glucose monitoring, ethnicity, insurance, and caregiver number and education, baseline pump use was associated with −0.79% lower mean A1c [95% confidence interval (CI): −1.48, −0.096; p = 0.03]. For those using a pump at baseline, but switching to MDI during the study (n = 9), mean A1c was 1.38% higher (95% CI: 0.68, 2.08; p < 0.001) than that for those who did not switch method of delivery. A 10‐point increase in CDI was associated with a 0.39% increase in A1c (95% CI: 0.16, 0.61; p = 0.001), independent of pump use. Regarding the temporal relationship between CDI score and changing method of insulin delivery, prior higher CDI score was associated with switching from pump to MDI (odds ratio = 1.21; 95% CI: 1.05, 1.39; p = 0.007). Clinicians should be aware of the associations between depressive symptoms, change in insulin delivery method, and the effect on glycemic control.

A case study in open source innovation: developing the Tidepool Platform for interoperability in type 1 diabetes management

Objective Develop a device-agnostic cloud platform to host diabetes device data and catalyze an ecosystem of software innovation for type 1 diabetes (T1D) management. Materials and Methods An interdisciplinary team decided to establish a nonprofit company, Tidepool, and build open-source software. Results Through a user-centered design process, the authors created a software platform, the Tidepool Platform, to upload and host T1D device data in an integrated, device-agnostic fashion, as well as an application (“app”), Blip, to visualize the data. Tidepool’s software utilizes the principles of modular components, modern web design including REST APIs and JavaScript, cloud computing, agile development methodology, and robust privacy and security. Discussion By consolidating the currently scattered and siloed T1D device data ecosystem into one open platform, Tidepool can improve access to the data and enable new possibilities and efficiencies in T1D clinical care and research. The Tidepool Platform decouples diabetes apps from diabetes devices, allowing software developers to build innovative apps without requiring them to design a unique back-end (e.g., database and security) or unique ways of ingesting device data. It allows people with T1D to choose to use any preferred app regardless of which device(s) they use. Conclusion The authors believe that the Tidepool Platform can solve two current problems in the T1D device landscape: 1) limited access to T1D device data and 2) poor interoperability of data from different devices. If proven effective, Tidepool’s open source, cloud model for health data interoperability is applicable to other healthcare use cases.

Evaluation of Pump Discontinuation and Associated Factors in the T1D Exchange Clinic Registry

Background: The objectives of this study were to examine factors associated with insulin pump discontinuation among children and adults followed longitudinally for 1 year in the multicenter T1D Exchange clinic registry, and to provide participant-reported reasons for stopping pump therapy. Methods: We longitudinally followed 8935 participants of all ages using an insulin pump at the time of registry enrollment. Logistic regressions were used to identify demographic and clinical factors associated with pump discontinuation. Pump discontinuation was self-reported by participants on a first annual follow-up survey. Results: The overall frequency of pump discontinuation was 3%. Discontinuation was higher in adolescents (4%) and young adults (4%) than in younger children (3%) or older adults (1%). In multivariate analysis of children between 6 and <13 and 13 and <18 years, participants who discontinued pump use were more likely to have higher HbA1c levels at baseline (adjusted P < .001 for both). The top participant-reported reasons for discontinuing the pump included problems with wearability (57%), disliking the pump or feeling anxious (44%), and problems with glycemic control (30%). Conclusions: In T1D Exchange registry participants, insulin pump discontinuation is uncommon, but more prevalent among adolescents and young adults, and youth with poor glycemic control. Given the known benefits of pump therapy, these populations should be targeted for support and education on troubleshooting pump use. Common reasons for discontinuation should also be considered in future device design and technological improvement.