Looking back at the TEDDY study: lessons and future directions.

The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed.

The mouse metabolic phenotyping center (MMPC) live consortium: an NIH resource for in vivo characterization of mouse models of diabetes and obesity.

The Mouse Metabolic Phenotyping Center (MMPC)Live Program was established in 2023 by the National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) to advance biomedical research by providing the scientific community with standardized, high quality phenotyping services for mouse models of diabetes and obesity. Emerging as the next iteration of the MMPC Program which served the biomedical research community for 20 years (2001-2021), MMPCLive is designed as an outwardly-facing consortium of service cores that collaborate to provide reduced-cost consultation and metabolic, physiologic, and behavioral phenotyping tests on live mice for U.S.

Nutrition's checkpoint inhibition: The impact of nutrition on immunotherapy outcomes.

Objectives: To determine if nutritional status effects response to immunotherapy in women with gynecologic malignancies.

Methods: A retrospective chart review was conducted on gynecologic cancer patients who received immunotherapy at a single institution between 2015 and 2022. Immunotherapy included checkpoint inhibitors and tumor vaccines.

Early appearance of thyroid autoimmunity in children followed from birth for type 1 diabetes risk.

Purpose: Autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) define pre-clinical autoimmune thyroid disease (AITD) which can progress to either clinical hypo- or hyperthyroidism. We determined the age at seroconversion in children genetically at risk for type 1 diabetes.

Methods: TPOAb and TgAb seropositivity were determined in 5066 healthy children with HLA DR3 or DR4 containing haplogenotypes from The Environmental Determinants of Diabetes in the Young (TEDDY) Study.

The Influence of Pubertal Development on Autoantibody Appearance and Progression to Type 1 Diabetes in the TEDDY Study.

Context: The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty.

Objective: We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes.

Methods: The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Serum Proteomic Signatures in Cervical Cancer: Current Status and Future Directions.

In 2020, the World Health Organization (WHO) reported 604,000 new diagnoses of cervical cancer (CC) worldwide, and over 300,000 CC-related fatalities. The vast majority of CC cases are caused by persistent human papillomavirus (HPV) infections. HPV-related CC incidence and mortality rates have declined worldwide because of increased HPV vaccination and CC screening with the Papanicolaou test (PAP test).

Intake of B vitamins and the risk of developing islet autoimmunity and type 1 diabetes in the TEDDY study.

Purpose: The aim was to study the association between dietary intake of B vitamins in childhood and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D) by the age of 10 years.

Methods: We followed 8500 T1D-susceptible children born in the U.S.

Ovarian recurrence risk assessment using machine learning, clinical information, and serum protein levels to predict survival in high grade ovarian cancer.

In ovarian cancer, there is no current method to accurately predict recurrence after a complete response to chemotherapy. Here, we develop a machine learning risk score using serum proteomics for the prediction of early recurrence of ovarian cancer after initial treatment. The developed risk score was validated in an independent cohort with serum collected prospectively during the remission period.

High serum levels of inflammatory markers are associated with early recurrence in patients with high-grade serous ovarian cancer after platinum therapy.

Objective: To determine if inflammatory biomarkers can predict the long-term outcome of platinum therapy in patients with high-grade serous ovarian cancer.

Methods: Women diagnosed with high-grade serous epithelial ovarian cancer (n = 70) at a single institution were enrolled in a prospective serum collection study between 2005 and 2020. Seventeen markers of inflammation and oxidative stress were measured in serum samples on a chemistry analyzer.

Dietary Intake and Body Mass Index Influence the Risk of Islet Autoimmunity in Genetically At-Risk Children: A Mediation Analysis Using the TEDDY Cohort.

Background/objective: Growth and obesity have been associated with increased risk of islet autoimmunity (IA) and progression to type 1 diabetes. We aimed to estimate the effect of energy-yielding macronutrient intake on the development of IA through BMI.

Research Design And Methods: Genetically at-risk children ( = 5,084) in Finland, Germany, Sweden, and the USA, who were autoantibody negative at 2 years of age, were followed to the age of 8 years, with anthropometric measurements and 3-day food records collected biannually.

HLA Genotype and Probiotics Modify the Association Between Timing of Solid Food Introduction and Islet Autoimmunity in the TEDDY Study.

Objective: To study the interaction among HLA genotype, early probiotic exposure, and timing of complementary foods in relation to risk of islet autoimmunity (IA).

Research Design And Methods: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes. We used a Cox proportional hazards regression model adjusting for potential confounders to study early feeding and the risk of IA in a sample of 7,770 children.

Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes.

The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high-risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8.

Physical Activity and the Development of Islet Autoimmunity and Type 1 Diabetes in 5- to 15-Year-Old Children Followed in the TEDDY Study.

Objective: This study investigated physical activity and its association with the development of islet autoimmunity and type 1 diabetes in genetically at-risk children aged 5-15 years.

Research Design And Methods: As part of the longitudinal Environmental Determinants of Diabetes in the Young (TEDDY) study, annual assessment of activity using accelerometry was conducted from age 5 years. Time-to-event analyses using Cox proportional hazard models were used to assess the association between time spent in moderate to vigorous physical activity per day and the appearance of one or several autoantibodies and progression to type 1 diabetes in three risk groups: 1) 3,869 islet autoantibody (IA)-negative children, of whom 157 became single IA positive; 2) 302 single IA-positive children, of whom 73 became multiple IA positive; and 3) 294 multiple IA-positive children, of whom 148 developed type 1 diabetes.

Rising Hemoglobin A1c in the Nondiabetic Range Predicts Progression of Type 1 Diabetes As Well As Oral Glucose Tolerance Tests.

Objective: Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies.

Research Design And Methods: Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA1c measurements were followed to diabetes or median age 11.1 years.

A novel network based linear model for prioritization of synergistic drug combinations.

Drug combination therapies can improve drug efficacy, reduce drug dosage, and overcome drug resistance in cancer treatments. Current research strategies to determine which drug combinations have a synergistic effect rely mainly on clinical or empirical experience and screening predefined pools of drugs. Given the number of possible drug combinations, the speed, and scope to find new drug combinations are very limited using these methods.

Persistent STAT5 activation reprograms the epigenetic landscape in CD4 T cells to drive polyfunctionality and antitumor immunity.

The presence of polyfunctional CD4 T cells is often associated with favorable antitumor immunity. We report here that persistent activation of signal transducer and activator of transcription 5 (STAT5) in tumor-specific CD4 T cells drives the development of polyfunctional T cells. We showed that ectopic expression of a constitutively active form of murine STAT5A (CASTAT5) enabled tumor-specific CD4 T cells to undergo robust expansion, infiltrate tumors vigorously, and elicit antitumor CD8 T cell responses in a CD4 T cell adoptive transfer model system.

Frequent HPV-independent p16/INK4A overexpression in head and neck cancer.

Objectives: p16 (p16) is the most widely used clinical biomarker for Human Papillomavirus (HPV) in head and neck squamous cell cancer (HNSCC). HPV is a favourable prognostic marker in HNSCC and is used for patient stratification. While p16 is a relatively accurate marker for HPV within the oropharynx, recent reports suggest it may be unsuitable for use in other HNSCC subsites, where a smaller proportion of tumors are HPV-driven.

The Geropathology Research Network: An Interdisciplinary Approach for Integrating Pathology Into Research on Aging.

Geropathology is the study of aging and age-related lesions and diseases in the form of whole necropsies/autopsies, surgical biopsies, histology, and molecular biomarkers. It encompasses multiple subspecialties of geriatrics, anatomic pathology, molecular pathology, clinical pathology, and gerontology. In order to increase the consistency and scope of communication in the histologic and molecular pathology assessment of tissues from preclinical and clinical aging studies, a Geropathology Research Network has been established consisting of pathologists and scientists with expertise in the comparative pathology of aging, the design of aging research studies, biostatistical methods for analysis of aging data, and bioinformatics for compiling and annotating large sets of data generated from aging studies.

The same self-peptide selects conventional and regulatory CD4⁺ T cells with identical antigen receptors.

The role of the T-cell receptor (TCR) in commitment of thymocytes to regulatory CD4(+)Foxp3(+) and conventional CD4(+)Foxp3(-) T-cell lineages remains controversial. According to the prevailing view, commitment to the former lineage, in contrast to the latter, requires that high affinity TCRs bind rare class II MHC/peptide complexes presented in 'thymic niches', which could explain differences between their TCR repertoires. Here we challenge this view and show that the binding of identical TCRs to the same ubiquitously expressed MHC/peptide complex often directs thymocytes to both CD4(+) lineages, indicating that the TCR affinity does not play the instructive role, and that restricted presentation of peptides in 'thymic niches' is not necessary for selection of CD4(+)Foxp3(+) T cells.

Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota.

Peripheral mechanisms preventing autoimmunity and maintaining tolerance to commensal microbiota involve CD4(+) Foxp3(+) regulatory T (Treg) cells generated in the thymus or extrathymically by induction of naive CD4(+) Foxp3(-) T cells. Previous studies suggested that the T-cell receptor repertoires of thymic Treg cells and induced Treg cells are biased towards self and non-self antigens, respectively, but their relative contribution in controlling immunopathology, such as colitis and other untoward inflammatory responses triggered by different types of antigens, remains unresolved. The intestine, and especially the colon, is a particularly suitable organ to study this question, given the variety of self-, microbiota- and food-derived antigens to which Treg cells and other T-cell populations are exposed.

Research resource: dkCOIN, the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) consortium interconnectivity network: a pilot program to aggregate research resources generated by multiple research consortia.

The National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) supports multiple basic science consortia that generate high-content datasets, reagent resources, and methodologies, in the fields of kidney, urology, hematology, digestive, and endocrine diseases, as well as metabolic diseases such as diabetes and obesity. These currently include the Beta Cell Biology Consortium, the Nuclear Receptor Signaling Atlas, the Diabetic Complications Consortium, and the Mouse Metabolic Phenotyping Centers. Recognizing the synergy that would accrue from aggregating information generated and curated by these initiatives in a contiguous informatics network, we created the NIDDK Consortium Interconnectivity Network (dkCOIN; www.

Gene expression profiling of early-phase Sjögren's syndrome in C57BL/6.NOD-Aec1Aec2 mice identifies focal adhesion maturation associated with infiltrating leukocytes.

Purpose: Despite considerable efforts, the molecular and cellular events in lacrimal gland tissues initiating inflammatory responses leading to keratoconjunctivitis sicca (KCS), autoimmunity, and Sjögren's syndrome (SjS) have yet to be defined. To determine whether altered glandular homeostasis occurs before the onset of autoimmunity, a temporal transcriptome study was carried out in an animal model of primary SjS.

Methods: Using oligonucleotide microarrays, gene expression profiles were generated for lacrimal glands of C57BL/6.

Hepatic gene expression profiling reveals key pathways involved in leptin-mediated weight loss in ob/ob mice.

Background: Leptin, a cytokine-like protein, plays an important role in the regulation of body weight through inhibition of food intake and stimulation of energy expenditure. Leptin circulates in blood and acts on the brain, which sends downstream signals to regulate body weight. Leptin therapy has been successful in treating leptin deficient obese patients.

ParaSAM: a parallelized version of the significance analysis of microarrays algorithm.

Motivation: Significance analysis of microarrays (SAM) is a widely used permutation-based approach to identifying differentially expressed genes in microarray datasets. While SAM is freely available as an Excel plug-in and as an R-package, analyses are often limited for large datasets due to very high memory requirements.

Summary: We have developed a parallelized version of the SAM algorithm called ParaSAM to overcome the memory limitations.