NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors.

Meningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow-up (median 9.9 years; range 15 days-43 years), we performed extensive molecular characterization including genome-wide DNA methylation profiling (n = 80) and targeted TERT promoter mutation testing (n = 98). Associations were examined with NAB2::STAT6 fusion status (n = 101 cases; 51 = ex5-7::ex16-17, 26 = ex4::ex2-3; 12 = ex2-3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. NAB2::STAT6 fusion breakpoints (fusion type) were significantly associated with metastasis-free survival (MFS) (p = 0.03) and, on multivariate analysis, disease-specific survival (DSS) when adjusting for CNS WHO grade (p = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (n = 38), Cluster 2 (n = 22), and Cluster 3 (n = 20). Methylation clusters were significantly associated with fusion type (p < 0.001), with Cluster 2 harboring ex4::ex2-3 fusion in 16 (of 20; 80.0%), nearly all TERT promoter mutations (7 of 8; 87.5%), and predominantly an "SFT" histologic phenotype (15 of 22; 68.2%). Clusters 1 and 3 were less distinct, both dominated by tumors having ex5-7::ex16-17 fusion (respectively, 25 of 33; 75.8%, and 12 of 18; 66.7%) and with variable histological phenotypes. Methylation clusters were significantly associated with MFS (p = 0.027), but not overall survival (OS). In summary, NAB2::STAT6 fusion type was significantly associated with MFS and DSS, suggesting that tumors with an ex5::ex16-17 fusion may have inferior patient outcomes. Methylation clusters were significantly associated with fusion type, TERT promoter mutation status, histologic phenotype, and MFS.

Prognostic value of DNA methylation subclassification, aneuploidy, and CDKN2A/B homozygous deletion in predicting clinical outcome of IDH mutant astrocytomas.

BACKGROUND: Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS: We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS: There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534). CONCLUSIONS: The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.

Predicting methylation class from diffusely infiltrating adult gliomas using multimodality MRI data.

Background: Radiogenomic studies of adult-type diffuse gliomas have used magnetic resonance imaging (MRI) data to infer tumor attributes, including abnormalities such as IDH-mutation status and 1p19q deletion. This approach is effective but does not generalize to tumor types that lack highly recurrent alterations. Tumors have intrinsic DNA methylation patterns and can be grouped into stable methylation classes even when lacking recurrent mutations or copy number changes. The purpose of this study was to prove the principle that a tumor's DNA-methylation class could be used as a predictive feature for radiogenomic modeling. Methods: Using a custom DNA methylation-based classification model, molecular classes were assigned to diffuse gliomas in The Cancer Genome Atlas (TCGA) dataset. We then constructed and validated machine learning models to predict a tumor's methylation family or subclass from matched multisequence MRI data using either extracted radiomic features or directly from MRI images. Results: For models using extracted radiomic features, we demonstrated top accuracies above 90% for predicting IDH-glioma and GBM-IDHwt methylation families, IDH-mutant tumor methylation subclasses, or GBM-IDHwt molecular subclasses. Classification models utilizing MRI images directly demonstrated average accuracies of 80.6% for predicting methylation families, compared to 87.2% and 89.0% for differentiating IDH-mutated astrocytomas from oligodendrogliomas and glioblastoma molecular subclasses, respectively. Conclusions: These findings demonstrate that MRI-based machine learning models can effectively predict the methylation class of brain tumors. Given appropriate datasets, this approach could generalize to most brain tumor types, expanding the number and types of tumors that could be used to develop radiomic or radiogenomic models.

Telehealth and CFTR modulators: Accelerating innovative models of cystic fibrosis care.

Better health and longer survival for many people with cystic fibrosis (PwCF) compels the continued evolution of the CF care model. Designed to deliver specialized care for a complex chronic condition, the model is organized around interdisciplinary healthcare teams at dedicated care centers. Introduction of CFTR modulators and the COVID-19 pandemic have catalyzed the model's evolution. Many PwCF on modulator therapies are experiencing better health and considering changes in their daily care routines. Some of the growing number of adults with CF are experiencing age-associated co-morbidities, requiring coordination with new specialists. The pandemic accelerated the use of telehealth, revealing tradeoffs from new configurations of care delivery. Herein we review the implications of these recent shifts and offer recommendations to improve the quality of care coordinated across the interdisciplinary teams and an expanding field of subspecialists, while supporting the ability of the patient to take on greater responsibility in disease management.

Comprehensive study of semi-supervised learning for DNA methylation-based supervised classification of central nervous system tumors.

BACKGROUND: Precision medicine for cancer treatment relies on an accurate pathological diagnosis. The number of known tumor classes has increased rapidly, and reliance on traditional methods of histopathologic classification alone has become unfeasible. To help reduce variability, validation costs, and standardize the histopathological diagnostic process, supervised machine learning models using DNA-methylation data have been developed for tumor classification. These methods require large labeled training data sets to obtain clinically acceptable classification accuracy. While there is abundant unlabeled epigenetic data across multiple databases, labeling pathology data for machine learning models is time-consuming and resource-intensive, especially for rare tumor types. Semi-supervised learning (SSL) approaches have been used to maximize the utility of labeled and unlabeled data for classification tasks and are effectively applied in genomics. SSL methods have not yet been explored with epigenetic data nor demonstrated beneficial to central nervous system (CNS) tumor classification. RESULTS: This paper explores the application of semi-supervised machine learning on methylation data to improve the accuracy of supervised learning models in classifying CNS tumors. We comprehensively evaluated 11 SSL methods and developed a novel combination approach that included a self-training with editing using support vector machine (SETRED-SVM) model and an L2-penalized, multinomial logistic regression model to obtain high confidence labels from a few labeled instances. Results across eight random forest and neural net models show that the pseudo-labels derived from our SSL method can significantly increase prediction accuracy for 82 CNS tumors and 9 normal controls. CONCLUSIONS: The proposed combination of semi-supervised technique and multinomial logistic regression holds the potential to leverage the abundant publicly available unlabeled methylation data effectively. Such an approach is highly beneficial in providing additional training examples, especially for scarce tumor types, to boost the prediction accuracy of supervised models.

Comprehensive molecular characterization of pediatric radiation-induced high-grade glioma.

Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. We performed DNA methylation profiling, RNA-seq, and DNA sequencing on 32 RIG tumors and an in vitro drug screen in two RIG cell lines. We report that based on DNA methylation, RIGs cluster primarily with the pediatric receptor tyrosine kinase I high-grade glioma subtype. Common copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, and Ch. 13q and Ch. 14q loss; focal alterations include PDGFRA and CDK4 gain and CDKN2A and BCOR loss. Transcriptomically, RIGs comprise a stem-like subgroup with lesser mutation burden and Ch. 1p loss and a pro-inflammatory subgroup with greater mutation burden and depleted DNA repair gene expression. Chromothripsis in several RIG samples is associated with extrachromosomal circular DNA-mediated amplification of PDGFRA and CDK4. Drug screening suggests microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors, as potentially effective therapies.

Clinical and Genetic Risk Factors of Recurrent Nonalcoholic Fatty Liver Disease After Liver Transplantation.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has been increasingly reported among recipients of liver transplantation (LT). We aimed to identify clinical and genetic risk factors responsible for the development of early recurrent NAFLD in nonalcoholic steatohepatitis transplant recipients. METHODS: Forty-six total single nucleotide polymorphisms with known association with NAFLD were tested among both recipient and donor liver samples in 66 LT recipients with nonalcoholic steatohepatitis to characterize influences on NAFLD recurrence at ∼1 year post-LT (median interval from LT to biopsy: 377 days). RESULTS: Recurrent NAFLD was identified in 43 (65.2%) patients, 20 (30.3%) with mild recurrence, and 23 (34.8%) with moderate to severe NAFLD. On adjusted analysis, change in the body mass index (BMI) (ΔBMI) was significantly associated with NAFLD recurrence, whereas post-LT diabetes mellitus was associated with increased severity of NAFLD recurrence. ADIPOR1 rs10920533 in the recipient was associated with increased risk of moderate to severe NAFLD recurrence, whereas the minor allele of SOD2 rs4880 in the recipient was associated with reduced risk. Similar reduced risk was noted in the presence of donor SOD2 rs4880 and HSD17B13 rs6834314 polymorphism. DISCUSSION: Increased BMI post-LT is strongly associated with NAFLD recurrence, whereas post-LT diabetes mellitus was associated with increased severity of NAFLD recurrence. Both donor and recipient SOD2 rs4880 and donor HSD17B13 rs6834314 single nucleotide polymorphisms may be associated with reduced risk of early NAFLD recurrence, whereas presence of the minor allele form of ADIPOR1 rs10920533 in the recipient is associated with increased severity NAFLD recurrence.

Differences in biomarkers of inflammation and immune responses in chronic smokers and moist snuff users.

BACKGROUND: Cigarette smoking is a major risk factor for cancer and other diseases. While smoking induces chronic inflammation and aberrant immune responses, the effects of smokeless tobacco products (STPs) on immune responses is less clear. Here we evaluated markers related to immune regulation in smokers (SMK), moist snuff consumers (MSC) and non-tobacco consumers (NTC) to better understand the effects of chronic tobacco use. MATERIALS AND METHODS: Several markers associated with immune regulation were measured in peripheral blood mononuclear cells (PBMCs) from SMK (n = 40), MSC (n = 40), and NTC (n = 40) by flow cytometry. RESULTS: Relative to NTC, seven markers were significantly suppressed in SMK, whereas in MSC, only one marker was significantly suppressed. In a logistic regression model, markers including granzyme B+ lymphocytes, perforin+ lymphocytes, granzyme B+ CD8+T cells, and KLRB1+ CD8+ T cells remained as statistically significant predictors for classifying the three cohorts. Further, cell-surface receptor signaling pathways and cell-cell signaling processes were downregulated in SMK relative to MSC; chemotaxis and LPS-mediated signaling pathways, were upregulated in SMK compared to MSC. A network of the tested markers was constructed to visualize the immunosuppression in SMK relative to MSC. CONCLUSION: Moist snuff consumption is associated with significantly fewer perturbations in inflammation and immune function biomarkers relative to smoking. IMPACT: This work identifies several key immunological biomarkers that differentiate the effects of chronic smoking from the use of moist snuff. Additionally, a molecular basis for aberrant immune responses that could render smokers more susceptible for infections and cancer is provided.

Biology and grading of pleomorphic xanthoastrocytoma-what have we learned about it?

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma predominantly affecting children and young adults. We performed comprehensive genomic characterization on a cohort of 67 patients with histologically defined PXA (n = 53, 79%) or anaplastic PXA (A-PXA, n = 14, 21%), including copy number analysis (ThermoFisher Oncoscan, n = 67), methylation profiling (Illumina EPIC array, n = 43) and targeted next generation sequencing (n = 32). The most frequent alterations were CDKN2A/B deletion (n = 63; 94%) and BRAF p.V600E (n = 51, 76.1%). In 7 BRAF p.V600 wild-type cases, alternative driver alterations were identified involving BRAF, RAF1 and NF1. Downstream phosphorylation of ERK kinase was uniformly present. Additional pathogenic alterations were rare, with TERT, ATRX and TP53 mutations identified in a small number of tumors, predominantly A-PXA. Methylation-based classification of 46 cases utilizing a comprehensive reference tumor allowed assignment to the PXA methylation class in 40 cases. A minority grouped with the methylation classes of ganglioglioma or pilocytic astrocytoma (n = 2), anaplastic pilocytic astrocytoma (n = 2) or control tissues (n = 2). In 9 cases, tissue was available from matched primary and recurrent tumors, including 8 with anaplastic transformation. At recurrence, two tumors acquired TERT promoter mutations and the majority demonstrated additional non-recurrent copy number alterations. Methylation class was preserved at recurrence. For 62 patients (92.5%), clinical follow-up data were available (median follow-up, 5.4 years). Overall survival was significantly different between PXA and A-PXA (5-year OS 80.8% vs. 47.6%; P = 0.0009) but not progression-free survival (5-year PFS 59.9% vs. 39.8%; P = 0.05). WHO grade remained a strong predictor of overall survival when limited to 38 cases defined as PXA by methylation-based classification. Our data confirm the importance of WHO grading in histologically and epigenetically defined PXA. Methylation-based classification may be helpful in cases with ambiguous morphology, but is largely confirmatory in PXA with well-defined morphology.

Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition.

Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.

Hemoptysis from the perspective of people with cystic fibrosis.

INTRODUCTION: People with cystic fibrosis (CF) are living longer, thus complications associated with age, such as hemoptysis, are increasing. The Institute of Medicine has emphasized the importance of patient-centeredness. Although guidelines about hemoptysis in people with CF are available, these focus on management of the complication and not the patient perspective. OBJECTIVE: We sought to understand hemoptysis from the point of view of those who have experienced it. METHODS: We fielded an 11-question survey to adults with CF and asked those who had hemoptysis to respond. Four questions had open-ended options: (1) the person's first experience with hemoptysis, (2) how that experience affected the way they approach their CF, (3) how they deal with hemoptysis when it occurs outside the home and (4) a free text box for general comments. RESULTS: Thirty-one of 132 adults with CF who were sent a survey completed it (23% response rate); 63% F), indicated that they had experienced hemoptysis and described their triggers. In response to open questioning, 77% of respondents found their first experience with hemoptysis to be 'scary,' 'frightening,' 'worrying' or 'jarring.' Half of respondents reported quality of life being negatively affected by worsening stress or anxiety, fear of bleeding in public or other life impacts. CONCLUSIONS: Focusing on how to cope with future episodes of hemoptysis and the associated anxiety can be helpful to patients. Proactive communication and sensitivity to patient experience may deepen physician-patient rapport, increase self-efficacy to cope with future episodes and lead to more comprehensive care of hemoptysis.

Time-resolved characterization of the mechanisms of toxicity induced by silica and amino-modified polystyrene on alveolar-like macrophages.

Macrophages play a major role in the removal of foreign materials, including nano-sized materials, such as nanomedicines and other nanoparticles, which they accumulate very efficiently. Because of this, it is recognized that for a safe development of nanotechnologies and nanomedicine, it is essential to investigate potential effects induced by nano-sized materials on macrophages. To this aim, in this work, a recently established model of primary murine alveolar-like macrophages was used to investigate macrophage responses to two well-known nanoparticle models: 50 nm amino-modified polystyrene, known to induce cell death via lysosomal damage and apoptosis in different cell types, and 50 nm silica nanoparticles, which are generally considered non-toxic. Then, a time-resolved study was performed to characterize in detail the response of the macrophages following exposure to the two nanoparticles. As expected, exposure to the amino-modified polystyrene led to cell death, but surprisingly no lysosomal swelling or apoptosis were detected. On the contrary, a peculiar mitochondrial membrane hyperpolarization was observed, accompanied by endoplasmic reticulum stress (ER stress), increased cellular reactive oxygen species (ROS) and changes of metabolic activity, ultimately leading to cell death. Strong toxic responses were observed also after exposure to silica, which included mitochondrial ROS production, mitochondrial depolarization and cell death by apoptosis. Overall, these results showed that exposure to the two nanoparticles led to a very different series of intracellular events, suggesting that the macrophages responded differently to the two nanoparticle models. Similar time-resolved studies are required to characterize the response of macrophages to nanoparticles, as a key parameter in nanosafety assessment.

Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis.

Astroblastoma (AB) is a rare CNS tumor demonstrating abundant astroblastomatous pseudorosettes. Its molecular features have not been comprehensively studied and its status as a tumor entity is controversial. We analyzed a cohort of 27 histologically-defined ABs using DNA methylation profiling, copy number analysis, FISH and site-directed sequencing. Most cases demonstrated mutually exclusive MN1 rearrangements (n = 10) or BRAFV600E mutations (n = 7). Two additional cases harbored RELA rearrangements. Other cases lacked these specific genetic alterations (n = 8). By DNA methylation profiling, tumors with MN1 or RELA rearrangement clustered with high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1) and RELA-fusion ependymoma, respectively. In contrast, BRAFV600E-mutant tumors grouped with pleomorphic xanthoastrocytoma (PXA). Six additional tumors clustered with either supratentorial pilocytic astrocytoma and ganglioglioma (LGG-PA/GG-ST), normal or reactive cerebrum, or with no defined DNA methylation class. While certain histologic features favored one genetic group over another, no group could be reliably distinguished by histopathology alone. Survival analysis between genetic AB subtypes was limited by sample size, but showed that MN1-rearranged AB tumors were characterized by better overall survival compared to other genetic subtypes, in fact, significantly better than BRAFV600E-mutant tumors (P = 0.013). Our data confirm that histologically-defined ABs are molecularly heterogeneous and do not represent a single entity. They rather encompass several low- to higher-grade glial tumors including neuroepithelial tumors with MN1 rearrangement, PXA-like tumors, RELA ependymomas, and possibly yet uncharacterized lesions. Genetic subtyping of tumors exhibiting AB histology, particularly determination of MN1 and BRAFV600E status, is necessary for important prognostic and possible treatment implications.

DNA Methylation Profiling Reveals Prognostically Significant Groups in Pediatric Adrenocortical Tumors: A Report From the International Pediatric Adrenocortical Tumor Registry.

PURPOSE: Pediatric adrenocortical carcinomas (ACCs) are aggressive; the overall survival of patients with ACCs is 40%-50%. Appropriate staging and histologic classification are crucial because children with incomplete resections, metastases, or relapsed disease have a dismal prognosis. The clinical course of pediatric adrenocortical tumors (ACTs) is difficult to predict using the current classification schemas, which rely on subjective microscopic and gross macroscopic variables. Recent advances in adult ACT studies have revealed distinct DNA methylation patterns with prognostic significance that have not been systematically interrogated in the pediatric population. PATIENTS AND METHODS: We performed DNA methylation analyses on 48 newly diagnosed ACTs from the International Pediatric Adrenocortical Tumor Registry and 12 pediatric adrenal controls to evaluate for distinct methylation groups. Pediatric methylation data were also compared systematically with the adult ACC cohort from The Cancer Genome Atlas (TCGA). RESULTS: Two pediatric ACT methylation groups were identified and showed differences in selected clinicopathologic and outcome characteristics. The A1 group was enriched for CTNNB1 variants and unfavorable outcome. The A2 group was enriched for TP53 germline variants, younger age at onset, and favorable outcome. Pediatric ACT methylation groups were maintained when International Pediatric Adrenocortical Tumor Registry cohort data were combined with TCGA cohort data. The CpG-island hypermethylator phenotype characterizing the TCGA cohort was not identified in the pediatric patients. When methylome findings were combined with independent histopathologic review using the Wieneke criteria, a high-risk population was identified with uniform fatal outcome. CONCLUSION: Our results indicate DNA methylation analysis can enhance current diagnostic algorithms. A combination of methylation and histologic classification produced the strongest prediction model and may prove useful in future risk-adapted therapeutic trials.

Genetic and Epigenetic Culprits in the Pathogenesis of Nonalcoholic Fatty Liver Disease.

Nonalcoholic Fatty Liver Disease (NAFLD) constitutes a wide spectrum of liver pathology with hepatic steatosis at the core of this pathogenesis. Variations of certain genetic components have demonstrated increased susceptibility for hepatic steatosis. Therefore, these inciting variants must be further characterized in order to ultimately provide effective, targeted therapies for NAFLD and will be the focus of this review. Several genetic variants revealed an association with NAFLD through Genome-wide Association Study, meta-analyses, and retrospective case-control studies. PNPLA3 rs738409 and TM6SF2 rs58542926 are the two genetic variants providing the strongest evidence for association with NAFLD. However, it remains to be determined if these genetic variants serve as the primary culprit which induces the pathogenesis of NAFLD. Prospective and intervention studies are urgently needed to firmly establish a cause-and-effect relationship between the presence of certain genetic variants and risk of NAFLD development and progression.

Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons.

Background: The inability to analyze gene expression in living neurons from Angelman (AS) and Duplication 15q (Dup15q) syndrome subjects has limited our understanding of these disorders at the molecular level. Method: Here, we use dental pulp stem cells (DPSC) from AS deletion, 15q Duplication, and neurotypical control subjects for whole transcriptome analysis. We identified 20 genes unique to AS neurons, 120 genes unique to 15q duplication, and 3 shared transcripts that were differentially expressed in DPSC neurons vs controls. Results: Copy number correlated with gene expression for most genes across the 15q11.2-q13.1 critical region. Two thirds of the genes differentially expressed in 15q duplication neurons were downregulated compared to controls including several transcription factors, while in AS differential expression was restricted primarily to the 15q region. Here, we show significant downregulation of the transcription factors FOXO1 and HAND2 in neurons from 15q duplication, but not AS deletion subjects suggesting that disruptions in transcriptional regulation may be a driving factor in the autism phenotype in Dup15q syndrome. Downstream analysis revealed downregulation of the ASD associated genes EHPB2 and RORA, both genes with FOXO1 binding sites. Genes upregulated in either Dup15q cortex or idiopathic ASD cortex both overlapped significantly with the most upregulated genes in Dup15q DPSC-derived neurons. Conclusions: Finding a significant increase in both HERC2 and UBE3A in Dup15q neurons and significant decrease in these two genes in AS deletion neurons may explain differences between AS deletion class and UBE3A specific classes of AS mutation where HERC2 is expressed at normal levels. Also, we identified an enrichment for FOXO1-regulated transcripts in Dup15q neurons including ASD-associated genes EHPB2 and RORA indicating a possible connection between this syndromic form of ASD and idiopathic cases.

Pharmacogenomics of Chemically Distinct Classes of Keap1-Nrf2 Activators Identify Common and Unique Gene, Protein, and Pathway Responses In Vivo.

The Kelch-like erythroid-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) signaling pathway is the subject of several clinical trials evaluating the effects of Nrf2 activation on the prevention of cancer and diabetes and the treatment of chronic kidney disease and multiple sclerosis. 3H-1,2-dithiole-3-thione (D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are representative members of two distinct series of Nrf2 chemical activators. Previous reports have described activator-specific effects on Nrf2-dependent gene regulation and physiologic outcomes. Here we used a robust chemical genomics approach to characterize expression profiles between D3T and CDDO-Im in livers from wild-type and Nrf2-null mice. At equally efficacious doses in wild-type mice, 406 genes show common RNA responses to both treatments. These genes enriched the Nrf2-regulated pathways of antioxidant defense and xenobiotic metabolism. In addition, 197 and 745 genes were regulated uniquely in response to either D3T or CDDO-Im, respectively. Functional analysis of the D3T-regulated set showed a significant enrichment of Nrf2-regulated enzymes involved in cholesterol biosynthesis. This result was supported by Nrf2-dependent increases in lanosterol synthase and CYP51 protein expression. CDDO-Im had no effect on cholesterol biosynthesis regardless of the dose tested. However, unlike D3T, CDDO-Im resulted in Nrf2-dependent elevation of peroxisome proliferator α and Kruppel-like factor 13, as well as the coactivator peroxisome proliferator γ coactivator 1ß, together indicating regulation of ß-oxidation and lipid metabolic pathways. These findings provide novel insights into the pharmacodynamic action of these two activators of Keap1-Nrf2 signaling. Although both compounds modify Keap1 to affect canonical cytoprotective gene expression, additional unique sets of Nrf2-dependent genes were regulated by each agent with enrichment of selective metabolic pathways.

The Primary Results of the Treating Adult Smokers at Risk for Weight Gain with Interactive Technology (TARGIT) Study.

OBJECTIVE: To evaluate whether a behavioral weight management program combined with a smoking cessation program delivered via interactive technology could prevent postcessation weight gain. METHODS: Three hundred and thirty young adult smokers, age 18 to 35 years, were randomized to a smoking cessation program alone (comparison group), which included behavioral counseling and nicotine replacement, or to a behavioral weight management program adapted from the Look AHEAD trial plus the same smoking cessation program (intervention group). RESULTS: The Treating Adult Smokers at Risk for Weight Gain with Interactive Technology study randomized 164 participants to the comparison group and 166 participants to the intervention group. On average, the participants gained 0.91 kg after 24 months in the trial (comparison group + 1.45 kg and intervention group + 0.32; P = 0.157). The only variable systematically affecting weight change over time was smoking abstinence, in which those who were abstinent, on average, gained 0.14 kg more per month compared with those who continued to smoke (P < 0.001). In exploratory analyses, the intervention participants who were abstinent at 6 months had numerically smaller weight gains compared with abstinent participants in the comparison group, but these differences were not statistically significant. CONCLUSIONS: Providing an intensive weight gain prevention program combined with a smoking cessation program via interactive technology was not associated with greater long-term weight gain prevention.