Phase II Study of Erdafitinib in Patients With Tumors With Fibroblast Growth Factor Receptor Mutations or Fusions: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol K2.

PURPOSE: Subprotocol K2 (EAY131-K2) of the NCI-MATCH platform trial was an open-label, single-arm, phase II study designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 mutations or fusions. METHODS: Central confirmation of tumor FGFR1-4 mutations or fusions was required for outcome analysis. Patients with urothelial carcinoma were excluded. Enrolled subjects received oral erdafitinib at a starting dose of 8 mg daily continuously until intolerable toxicity or disease progression. The primary end point was objective response rate (ORR) with key secondary end points of safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. The median age was 61 years, and 52% of subjects had received ≥3 previous lines of therapy. The confirmed ORR was 16% (4 of 25 [90% CI, 5.7 to 33.0], P = .034 against the null rate of 5%). An additional seven patients experienced stable disease as best-confirmed response. Four patients had a prolonged PFS including two with recurrent WHO grade IV, IDH1-/2-wildtype glioblastoma. The median PFS and OS were 3.6 months and 11.0 months, respectively. Erdafitinib was manageable with no new safety signals. CONCLUSION: This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor-altered tumors outside of currently approved indications in a potentially tumor-agnostic manner.

Phase II Study of Erdafitinib in Patients With Tumors With FGFR Amplifications: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol K1.

PURPOSE: Despite fibroblast growth factor receptor (FGFR) inhibitors being approved in tumor types with select FGFR rearrangements or gene mutations, amplifications of FGFR represent the most common FGFR alteration across malignancies. Subprotocol K1 (EAY131-K1) of the National Cancer Institute-MATCH platform trial was designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 amplification. METHODS: EAY131-K1 was an open-label, single-arm, phase II study with central confirmation of presence of FGFR1-4 amplification in tumors. Patients with urothelial carcinoma were excluded. Enrolled patients received oral erdafitinib at a starting dose of 8 mg once daily continuously with escalation to 9 mg once daily continuously, on the basis of predefined time point assessments of phosphate levels, until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR), with key secondary end points being 6-month progression-free survival (PFS6), PFS, overall survival (OS), and safety. RESULTS: Thirty-five patients were enrolled into this study with 18 included in the prespecified primary efficacy analysis. The median age of the 18 patients was 60 years, and 78% had received ≥3 previous lines of therapy. There were no confirmed responses to erdafitinib; however, five patients experienced stable disease (SD) as best response. One patient with an FGFR1-amplified breast cancer had a prolonged PFS >168 days (5.5 months). The median PFS was 1.7 months (90% CI, 1.1 to 1.8 months) and the median OS was 4.2 months (90% CI, 2.3 to 9.3 months). The estimated PFS6 rate was 13.8% (90% CI, 3.3 to 31.6). The majority of toxicities were grade 1 to 2 in nature, although there was one grade 5 treatment-related adverse event. CONCLUSION: Erdafitinib did not meet its primary end point of efficacy as determined by ORR in treatment-refractory solid tumors harboring FGFR1-4 amplifications. Our findings support that rearrangements and gene mutations, but not amplifications, of FGFR remain the established FGFR alterations with approved indications for FGFR inhibition.

Recurrence of Glandular Odontogenic Cysts: A Systematic Review.

BACKGROUND: The glandular odontogenic cyst (GOC) is a benign developmental cyst of the jaws that is characterized by a high recurrence rate. METHODS: A systematic review is presented of reported cases, case series, and retrospective studies of recurrent cases of glandular odontogenic cysts, to determine the overall and detailed demographic features with documentation of the specific histologic features of the initial presentation of each cyst. Searches of detailed databases were carried out to identify articles published in the English language from 1988 to 2023. The variables were demographics, patient symptoms, cyst location, radiographic features, histopathological findings, type of treatment, and minimum eight months of follow-up. RESULTS: Eighteen cases were identified: with an equal gender presentation of 50% females and 50% males. The average age was 44.7. The mean size was 3.5 cm. The most common location was in the anterior mandible in 50% (n = 9) of cases, followed by the posterior mandible 27.8% (n = 5). Most patients were asymptomatic 55.6% (n = 10). The most common histologic features at first diagnosis were mucous cells in 88.9% (n = 16), variable thickness with 83.3% (n = 15), eosinophilic cuboidal cells 88.9% (n = 16), microcysts 83.3% (n = 15), and clear cells 77.8% (n = 14) cases. CONCLUSION: GOC has an aggressive behavior. Evidence was not conclusive to link any single or combination of histologic features to recurrence, and the strongest correlation for recurrence was the type of treatment. Since this is an uncommon cyst, more cases are needed. Follow-up should continue for at least five years, because recurrences were higher between years 3 and 5.

Trastuzumab and Pertuzumab in Patients with Non-Breast/Gastroesophageal HER2-Amplified Tumors: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol J.

PURPOSE: NCI-MATCH assigned patients with advanced cancer and progression on prior treatment, based on genomic alterations in pretreatment tumor tissue. Arm J (EAY131-J) evaluated the combination of trastuzumab/pertuzumab (HP) across HER2-amplified tumors. PATIENTS AND METHODS: Eligible patients had high levels of HER2 amplification [copy number (CN) ≥7] detected by central next-generation sequencing (NGS) or through NCI-designated laboratories. Patients with breast/gastroesophageal adenocarcinoma and those who received prior HER2-directed therapy were excluded. Enrollment of patients with colorectal cancer was capped at 4 based on emerging data. Patients received HP IV Q3 weeks until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: Thirty-five patients were enrolled, with 25 included in the primary efficacy analysis (CN ≥7 confirmed by a central lab, median CN = 28). Median age was 66 (range, 31-80), and half of all patients had ≥3 prior therapies (range, 1-11). The confirmed ORR was 12% [3/25 partial responses (colorectal, cholangiocarcinoma, urothelial cancers), 90% confidence interval (CI) 3.4%-28.2%]. There was one additional partial response (urothelial cancer) in a patient with an unconfirmed ERBB2 copy number. Median PFS was 3.3 months (90% CI 2.0-4.1), and median OS 9.4 months (90% CI 5.0-18.9). Treatment-emergent adverse events were consistent with prior studies. There was no association between HER2 CN and response. CONCLUSIONS: HP was active in a selection of HER2-amplified tumors (non-breast/gastroesophageal) but did not meet the predefined efficacy benchmark. Additional strategies targeting HER2 and potential resistance pathways are warranted, especially in rare tumors.

Segmental Odontomaxillary Dysplasia: A Case Report and Review of the Literature.

Segmental odontomaxillary dysplasia (SOD) is a rare and unusual nonhereditary developmental disorder that affects one side of the maxilla, impacting the hard tissue, soft tissue, and dentition in the affected area. It most frequently presents with enlargement of the gingival and osseous tissue of the affected side and hypodontia of the involved quadrant. Cutaneous irregularities of the impacted area are also common. We report a case of SOD arising in the right maxilla of a three-year-old female. Our report and review of the literature highlight the clinical, radiographic, and histopathologic characteristics of SOD, as well as the management of patients and the proposed etiologies of its pathogenesis.

Phase I study of sapanisertib (CB-228/TAK-228/MLN0128) in combination with ziv-aflibercept in patients with advanced solid tumors.

BACKGROUND: Sapanisertib is a potent ATP-competitive, dual inhibitor of mTORC1/2. Ziv-aflibercept is a recombinant fusion protein comprising human VEGF receptor extracellular domains fused to human immunoglobulin G1. HIF-1α inhibition in combination with anti-angiogenic therapy is a promising anti-tumor strategy. This Phase 1 dose-escalation/expansion study assessed safety/ tolerability of sapanisertib in combination with ziv-aflibercept in advanced solid tumors. METHODS: Fifty-five patients with heavily pre-treated advanced metastatic solid tumors resistant or refractory to standard treatment received treatment on a range of dose levels. RESULTS: Fifty-five patients were enrolled and treated across a range of dose levels. Forty were female (73%), median age was 62 (range: 21-79), and ECOG PS was 0 (9, 16%) or 1 (46, 84%). Most common tumor types included ovarian (8), colorectal (8), sarcoma (8), breast (3), cervical (4), and endometrial (4). Median number of prior lines of therapy was 4 (range 2-11). Sapanisertib 4 mg orally 3 days on and 4 days off plus 3 mg/kg ziv-aflibercept IV every 2 weeks on a 28-day cycle was defined as the maximum tolerated dose. Most frequent treatment-related grade ≥2 adverse events included hypertension, fatigue, anorexia, hypertriglyceridemia, diarrhea, nausea, mucositis, and serum lipase increase. There were no grade 5 events. In patients with evaluable disease (n = 50), 37 patients (74%) achieved stable disease (SD) as best response, two patients (4%) achieved a confirmed partial response (PR); disease control rate (DCR) (CR + SD + PR) was 78%. CONCLUSION: The combination of sapanisertib and ziv-aflibercept was generally tolerable and demonstrated anti-tumor activity in heavily pre-treated patients with advanced malignancies.

Automated sulfur-[18F]fluoride exchange radiolabelling of a prostate specific membrane antigen (PSMA) targeted ligand using the GE FASTlab™ cassette-based platform.

Sulfur-[18F]fluoride exchange radiochemistry is a rapid and convenient method for incorporating fluorine-18 into biologically active molecules. We report a fully automated radiolabelling procedure for the synthesis of a [18F]SO3F-bearing prostate specific membrane antigen (PSMA) targeted ligand ([18F]5) using the GE FASTLab™ cassette-based platform in a 25.0 ± 2.6% radiochemical yield (decay corrected). Uptake in vitro and in vivo correlated with PSMA expression, and the radioligand exhibited favourable biodistribution and pharmacokinetic profiles.

A novel FOXP3 knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell products.

Forkhead box P3 (FOXP3) is an essential transcription factor for regulatory T cell (Treg) function. Defects in Tregs mediate many immune diseases including the monogenic autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), which is caused by FOXP3 mutations. Treg cell products are a promising modality to induce allograft tolerance or reduce the use of immunosuppressive drugs to prevent rejection, as well as in the treatment of acquired autoimmune diseases. We have recently opened a phase I clinical trial for IPEX patients using autologous engineered Treg-like cells, CD4LVFOXP3. To facilitate the pre-clinical studies, a novel humanized-mouse (hu-mouse) model was developed whereby immune-deficient mice were transplanted with human hematopoietic stem progenitor cells (HSPCs) in which the FOXP3 gene was knocked out (FOXP3KO) using CRISPR-Cas9. Mice transplanted with FOXP3KO HSPCs had impaired survival, developed lymphoproliferation 10-12 weeks post-transplant and T cell infiltration of the gut, resembling human IPEX. Strikingly, injection of CD4LVFOXP3 into the FOXP3KO hu-mice restored in vivo regulatory functions, including control of lymphoproliferation and inhibition of T cell infiltration in the colon. This hu-mouse disease model can be reproducibly established and constitutes an ideal model to assess pre-clinical efficacy of human Treg cell investigational products.

Lifestyle patterns in European preschoolers: Associations with socio-demographic factors and body mass index.

BACKGROUND: Energy balance-related behaviours (EBRBs), that is, dietary intake, screen, outdoor play and sleep, tend to combine into 'lifestyle patterns', with potential synergistic influences on health. To date, studies addressing this theme mainly focused on school children and rarely accounted for sleep, with a cross-country perspective. OBJECTIVES: We aimed at comparing lifestyle patterns among preschool-aged children across Europe, their associations with socio-demographic factors and their links with body mass index (BMI). METHODS: Harmonized data on 2-5-year-olds participating in nine European birth cohorts from the EU Child Cohort Network were used (EBRBs, socio-demographics and anthropometrics). Principal component analysis and multivariable linear and logistic regressions were performed. RESULTS: The most consistent pattern identified across cohorts was defined by at least three of the following EBRBs: discretionary consumption, high screen time, low outdoor play time and low sleep duration. Consistently, children from low-income households and born to mothers with low education level had higher scores on this pattern compared to their socioeconomically advantaged counterparts. Furthermore, it was associated with higher BMI z-scores in the Spanish and Italian cohorts (ß = 0.06, 95% CI = [0.02; 0.10], both studies). CONCLUSION: These findings may be valuable in informing early multi-behavioural interventions aimed at reducing social inequalities in health at a European scale.

Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs.

Multicellular spheroids comprised of malignant cells, endothelial cells, and mesenchymal stem cells served as an in vitro model of human solid tumors to investigate the potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways. The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein; berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase; nedisertib or VX-984). A range of clinically achievable concentrations were tested up to the clinical Cmax, if known. Mechanistically, the types of DNA damage induced by temozolomide, topotecan, and trabectedin are distinct, which was apparent from the response of spheroids to combinations with various DNA repair inhibitors. Although most combinations resulted in additive cytotoxicity, synergistic activity was observed for temozolomide combined with PARP inhibitors as well as combinations of the ATM inhibitor AZD-1390 with either topotecan or trabectedin. These findings might provide guidance for the selection of anticancer agent combinations worthy of further investigation. Significance: Clinical efficacy of DNA-damaging anticancer drugs can be influenced by the DNA damage response in tumor cells. The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations.

Environmental exposures in early-life and general health in childhood.

BACKGROUND: Early-life environmental exposures are suspected to be involved in the development of chronic diseases later in life. Most studies conducted so far considered single or few exposures and single-health parameter. Our study aimed to identify a childhood general health score and assess its association with a wide range of pre- and post-natal environmental exposures. METHODS: The analysis is based on 870 children (6-12 years) from six European birth cohorts participating in the Human Early-Life Exposome project. A total of 53 prenatal and 105 childhood environmental factors were considered, including lifestyle, social, urban and chemical exposures. We built a general health score by averaging three sub-scores (cardiometabolic, respiratory/allergy and mental) built from 15 health parameters. By construct, a child with a low score has a low general health status. Penalized multivariable regression through Least Absolute Shrinkage and Selection Operator (LASSO) was fitted in order to identify exposures associated with the general health score. FINDINGS: The results of LASSO show that a lower general health score was associated with maternal passive and active smoking during pregnancy and postnatal exposure to methylparaben, copper, indoor air pollutants, high intake of caffeinated drinks and few contacts with friends and family. Higher child's general health score was associated with prenatal exposure to a bluespace near residency and postnatal exposures to pets, cobalt, high intakes of vegetables and more physical activity. Against our hypotheses, postnatal exposure to organochlorine compounds and perfluorooctanoate were associated with a higher child's general health score. CONCLUSION: By using a general health score summarizing the child cardiometabolic, respiratory/allergy and mental health, this study reinforced previously suspected environmental factors associated with various child health parameters (e.g. tobacco, air pollutants) and identified new factors (e.g. pets, bluespace) warranting further investigations.

Differences in birth weight between immigrants' and natives' children in Europe and Australia: a LifeCycle comparative observational cohort study.

OBJECTIVE: Research on adults has identified an immigrant health advantage, known as the 'immigrant health paradox', by which migrants exhibit better health outcomes than natives. Is this health advantage transferred from parents to children in the form of higher birth weight relative to children of natives? SETTING: Western Europe and Australia. PARTICIPANTS: We use data from nine birth cohorts participating in the LifeCycle Project, including five studies with large samples of immigrants' children: Etude Longitudinale Française depuis l'Enfance-France (N=12 494), the Raine Study-Australia (N=2283), Born in Bradford-UK (N=4132), Amsterdam Born Children and their Development study-Netherlands (N=4030) and the Generation R study-Netherlands (N=4877). We include male and female babies born to immigrant and native parents. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is birth weight measured in grams. Different specifications were tested: birth weight as a continuous variable including all births (DV1), the same variable but excluding babies born with over 4500 g (DV2), low birth weight as a 0-1 binary variable (1=birth weight below 2500 g) (DV3). Results using these three measures were similar, only results using DV1 are presented. Parental migration status is measured in four categories: both parents natives, both born abroad, only mother born abroad and only father born abroad. RESULTS: Two patterns in children's birth weight by parental migration status emerged: higher birth weight among children of immigrants in France (+12 g, p<0.10) and Australia (+40 g, p<0.10) and lower birth weight among children of immigrants in the UK (-82 g, p<0.05) and the Netherlands (-80 g and -73 g, p<0.001) compared with natives' children. Smoking during pregnancy emerged as a mechanism explaining some of the birth weight gaps between children of immigrants and natives. CONCLUSION: The immigrant health advantage is not universally transferred to children in the form of higher birth weight in all host countries. Further research should investigate whether this cross-national variation is due to differences in immigrant communities, social and healthcare contexts across host countries.

Role of foetal kidney size on kidney function in childhood: the born in bradford cohort renal study.

BACKGROUND: Foetal and early childhood development contributes to the risk of adult non-communicable diseases such as hypertension and cardiovascular disease. We aimed to investigate whether kidney size at birth is associated with markers of kidney function at 7-11 years. METHODS: Foetal kidney dimensions were measured using ultrasound scans at 34 weeks gestation and used to derive kidney volume (cm3) in 1802 participants in the Born in Bradford (BiB) birth cohort. Blood and urine samples were taken from those who participated in the BiB follow-up at 7-11 years (n = 630) and analysed for serum creatinine, cystatin C, urea, and urinary albumin to creatinine ratio (ACR), protein to creatinine ratio (PCR) and retinol binding protein (RBP). Estimated glomerular filtration rate (eGFR) was calculated using Schwartz creatinine only and combined with cystatin C, and cystatin C only Zappitelli and Filler equations. Linear regression was used to examine the association between foetal kidney volume and eGFR, ACR, PCR and blood pressure, unadjusted and adjusted for confounders. RESULTS: Kidney volume was positively associated in adjusted models with eGFR calculated using Schwartz combined (0.64 ml/min diff per unit increase in volume, 95% CI 0.25 to 1.02), Zappitelli (0.79, 95% CI 0.38 to 1.20) and Filler (2.84, 95% CI 1.40 to 4.28). There was an association with the presence of albuminuria but not with its level, or with other urinary markers or with blood pressure. CONCLUSION: Foetal kidney volume was associated with small increases in eGFR in mid-childhood. Longitudinal follow-up to investigate the relationship between kidney volume and markers of kidney function as children go through puberty is required.

The effect of maternal BMI, smoking and alcohol on congenital heart diseases: a Mendelian randomisation study.

BACKGROUND: Congenital heart diseases (CHDs) remain a significant cause of infant morbidity and mortality. Epidemiological studies have explored maternal risk factors for offspring CHDs, but few have used genetic epidemiology methods to improve causal inference. METHODS: Three birth cohorts, including 65,510 mother/offspring pairs (N = 562 CHD cases) were included. We used Mendelian randomisation (MR) analyses to explore the effects of genetically predicted maternal body mass index (BMI), smoking and alcohol on offspring CHDs. We generated genetic risk scores (GRS) using summary data from large-scale genome-wide association studies (GWAS) and validated the strength and relevance of the genetic instrument for exposure levels during pregnancy. Logistic regression was used to estimate the odds ratio (OR) of CHD per 1 standard deviation (SD) higher GRS. Results for the three cohorts were combined using random-effects meta-analyses. We performed several sensitivity analyses including multivariable MR to check the robustness of our findings. RESULTS: The GRSs associated with the exposures during pregnancy in all three cohorts. The associations of the GRS for maternal BMI with offspring CHD (pooled OR (95% confidence interval) per 1SD higher GRS: 0.95 (0.88, 1.03)), lifetime smoking (pooled OR: 1.01 (0.93, 1.09)) and alcoholic drinks per week (pooled OR: 1.06 (0.98, 1.15)) were close to the null. Sensitivity analyses yielded similar results. CONCLUSIONS: Our results do not provide robust evidence of an effect of maternal BMI, smoking or alcohol on offspring CHDs. However, results were imprecise. Our findings need to be replicated, and highlight the need for more and larger studies with maternal and offspring genotype and offspring CHD data.

Effect of common pregnancy and perinatal complications on offspring metabolic traits across the life course: a multi-cohort study.

BACKGROUND: Common pregnancy and perinatal complications are associated with offspring cardiometabolic risk factors. These complications may influence multiple metabolic traits in the offspring and these associations might differ with offspring age. METHODS: We used data from eight population-based cohort studies to examine and compare associations of pre-eclampsia (PE), gestational hypertension (GH), gestational diabetes (GD), preterm birth (PTB), small (SGA) and large (LGA) for gestational age (vs. appropriate size for gestational age (AGA)) with up to 167 plasma/serum-based nuclear magnetic resonance-derived metabolic traits encompassing lipids, lipoproteins, fatty acids, amino acids, ketones, glycerides/phospholipids, glycolysis, fluid balance, and inflammation. Confounder-adjusted regression models were used to examine associations (adjusted for maternal education, parity age at pregnancy, ethnicity, pre/early pregnancy body mass index and smoking, and offspring sex and age at metabolic trait assessment), and results were combined using meta-analysis by five age categories representing different periods of the offspring life course: neonates (cord blood), infancy (mean ages: 1.1-1.6 years), childhood (4.2-7.5 years); adolescence (12.0-16.0 years), and adulthood (22.0-67.8 years). RESULTS: Offspring numbers for each age category/analysis varied from 8925 adults (441 PTB) to 1181 infants (135 GD); 48.4% to 60.0% were females. Pregnancy complications (PE, GH, GD) were each associated with up to three metabolic traits in neonates (P≤0.001) with some evidence of persistence to older ages. PTB and SGA were associated with 32 and 12 metabolic traits in neonates respectively, which included an adjusted standardised mean difference of -0.89 standard deviation (SD) units for albumin with PTB (95% CI: -1.10 to -0.69, P=1.3×10-17) and -0.41 SD for total lipids in medium HDL with SGA (95% CI: -0.56 to -0.25, P=2.6×10-7), with some evidence of persistence to older ages. LGA was inversely associated with 19 metabolic traits including lower levels of cholesterol, lipoproteins, fatty acids, and amino acids, with associations emerging in adolescence, (e.g. -0.11 SD total fatty acids, 95% CI: -0.18 to -0.05, P=0.0009), and attenuating with older age across adulthood. CONCLUSIONS: These reassuring findings suggest little evidence of wide-spread and long-term impact of common pregnancy and perinatal complications on offspring metabolic traits, with most associations only observed for newborns rather than older ages, and for perinatal rather than pregnancy complications.

Rare diseases of ectoderm: Translating discovery to therapy.

Heritable conditions known as ectodermal dysplasias are rare and can be associated with marked morbidity, mortality, and a reduced quality of life. The diagnosis and care of individuals affected by one of the many ectodermal dysplasias presents myriad challenges due to their rarity and the diverse phenotypes. These conditions are caused by abnormalities in multiple genes and signaling pathways that are essential for the development and function of ectodermal derivatives. During a 2021 international conference focused on translating discovery to therapy, researchers and clinicians gathered with the goal of advancing the diagnosis and treatment of conditions affecting ectodermal tissues with an emphasis on skin, hair, tooth, and eye phenotypes. Conference participants presented a variety of promising treatment strategies including gene or protein replacement, gene editing, cell therapy, and the identification of druggable targets. Further, barriers that negatively influence the current development of novel therapeutics were identified. These barriers include a lack of accurate prevalence data for rare conditions, absence of an inclusive patient registry with deep phenotyping data, and insufficient animal models and cell lines. Overcoming these barriers will need to be prioritized in order to facilitate the development of novel treatments for genetic disorders of the ectoderm.

Aligning Small Datasets Using Domain Adversarial Learning: Applications in Automated in Vivo Oral Cancer Diagnosis.

Deep learning approaches for medical image analysis are limited by small data set size due to factors such as patient privacy and difficulties in obtaining expert labelling for each image. In medical imaging system development pipelines, phases for system development and classification algorithms often overlap with data collection, creating small disjoint data sets collected at numerous locations with differing protocols. In this setting, merging data from different data collection centers increases the amount of training data. However, a direct combination of datasets will likely fail due to domain shifts between imaging centers. In contrast to previous approaches that focus on a single data set, we add a domain adaptation module to a neural network and train using multiple data sets. Our approach encourages domain invariance between two multispectral autofluorescence imaging (maFLIM) data sets of in vivo oral lesions collected with an imaging system currently in development. The two data sets have differences in the sub-populations imaged and in the calibration procedures used during data collection. We mitigate these differences using a gradient reversal layer and domain classifier. Our final model trained with two data sets substantially increases performance, including a significant increase in specificity. We also achieve a significant increase in average performance over the best baseline model train with two domains (p = 0.0341). Our approach lays the foundation for faster development of computer-aided diagnostic systems and presents a feasible approach for creating a robust classifier that aligns images from multiple data centers in the presence of domain shifts.

Molecular Pathway-Based Classification of Ectodermal Dysplasias: First Five-Yearly Update.

To keep pace with the rapid advancements in molecular genetics and rare diseases research, we have updated the list of ectodermal dysplasias based on the latest classification approach that was adopted in 2017 by an international panel of experts. For this purpose, we searched the databases PubMed and OMIM for the term "ectodermal dysplasia", referring mainly to changes in the last 5 years. We also tried to obtain information about those diseases on which the last scientific report appeared more than 15 years ago by contacting the authors of the most recent publication. A group of experts, composed of researchers who attended the 8th International Conference on Ectodermal Dysplasias and additional members of the previous classification panel, reviewed the proposed amendments and agreed on a final table listing all 49 currently known ectodermal dysplasias for which the molecular genetic basis has been clarified, including 15 new entities. A newly reported ectodermal dysplasia, linked to the gene LRP6, is described here in more detail. These ectodermal dysplasias, in the strict sense, should be distinguished from syndromes with features of ectodermal dysplasia that are related to genes extraneous to the currently known pathways involved in ectodermal development. The latter group consists of 34 syndromes which had been placed on the previous list of ectodermal dysplasias, but most if not all of them could actually be classified elsewhere. This update should streamline the classification of ectodermal dysplasias, provide guidance to the correct diagnosis of rare disease entities, and facilitate the identification of individuals who could benefit from novel treatment options.

Multi-omics signatures of the human early life exposome.

Environmental exposures during early life play a critical role in life-course health, yet the molecular phenotypes underlying environmental effects on health are poorly understood. In the Human Early Life Exposome (HELIX) project, a multi-centre cohort of 1301 mother-child pairs, we associate individual exposomes consisting of >100 chemical, outdoor, social and lifestyle exposures assessed in pregnancy and childhood, with multi-omics profiles (methylome, transcriptome, proteins and metabolites) in childhood. We identify 1170 associations, 249 in pregnancy and 921 in childhood, which reveal potential biological responses and sources of exposure. Pregnancy exposures, including maternal smoking, cadmium and molybdenum, are predominantly associated with child DNA methylation changes. In contrast, childhood exposures are associated with features across all omics layers, most frequently the serum metabolome, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions, among others. Our comprehensive and unique resource of all associations ( https://helixomics.isglobal.org/ ) will serve to guide future investigation into the biological imprints of the early life exposome.

Characterisation of ethnic differences in DNA methylation between UK-resident South Asians and Europeans.

Ethnic differences in non-communicable disease risk have been described between individuals of South Asian and European ethnicity that are only partially explained by genetics and other known risk factors. DNA methylation is one underexplored mechanism that may explain differences in disease risk. Currently, there is little knowledge of how DNA methylation varies between South Asian and European ethnicities. This study characterised differences in blood DNA methylation between individuals of self-reported European and South Asian ethnicity from two UK-based cohorts: Southall and Brent Revisited and Born in Bradford. DNA methylation differences between ethnicities were widespread throughout the genome (n = 16,433 CpG sites, 3.4% sites tested). Specifically, 76% of associations were attributable to ethnic differences in cell composition with fewer effects attributable to smoking and genetic variation. Ethnicity-associated CpG sites were enriched for EWAS Catalog phenotypes including metabolites. This work highlights the need to consider ethnic diversity in epigenetic research.