Citations

Male and female glioblastomas are biologically distinct, and improving outcomes may require sex-specific approaches to treatment.

Abstract We present serial bone scintigraphy examinations in a 38-year-old woman who presented with posterior left rib pain in the setting of adrenal insufficiency secondary to pituitary damage as a result of radiation treatment for orbital sarcoma.

Extensive mammographic density (MD), a well‐established breast cancer risk factor, is a radiological representation of stromal and epithelial breast tissue content. In studies conducted predominantly among Caucasian women, histologic measures of reduced terminal duct lobular unit (TDLU) involution have been correlated with extensive MD, but independently associated with breast cancer risk. We therefore examined associations between TDLU measures and MD among Chinese women, a low‐risk population but with high prevalence of dense breasts. Diagnostic pre‐treatment digital mammograms were obtained from 144 breast cancer cases at a tertiary hospital in Beijing and scored using the Breast Imaging Reporting and Data System (BI‐RADS) density classification. TDLU features were assessed using three standardized measures (count/100 mm2, span [μm], and acini count/TDLU) in benign tissues.Associations between each of TDLU measures and MD were examined using generalized linear models for TDLU count and span and polytomous logistic regression for acini count with adjustment for potential confounders stratified by age. Among women ≥50 years, 63% had dense breasts; cases with dense breasts (BI‐RADS, c‐d) had greater TDLU count (21.1 [SE = 2.70] vs. 9.0 [SE = 1.83]; p = 0.0004), longer span (480.6 μm [SE = 24.6] vs. 393.8 μm [SE = 31.8]; p = 0.03), and greater acini count (ORtrend = 16.1; 95%CI = 4.08–63.1; ptrend < 0.0001) compared to those with non‐dense breasts (BI‐RADS, a‐b). Among women <50 years, 91% had dense breasts, precluding our ability to detect associations. Our findings are consistent with previously reported associations between extensive MD and reduced TDLU involution, supporting the hypothesis that breast cancer risk associated with extensive MD may be related to the amount of “at‐risk” epithelium.

Abstract DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P &lt; 7.94 × 10−7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

Abstract Rationale Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that stromal cells comprising the COPD lung contain pathological gene expression programs supporting oncogenesis. Objectives To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer. Methods Study subjects included patients with COPD with (n = 30) or without (n = 30) lung cancer across a spectrum of COPD severity. We conducted multi-omics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. Results Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation impacting protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms driving these procancer translation programs differed on the basis of COPD severity. In mild or no COPD, the mammalian target of rapamycin pathway served as an upstream driver; whereas in advanced COPD, pathways downstream of pathological extracellular matrix emerged. Both the mammalian target of rapamycin and extracellular matrix gene expression programs paralleled activation of previously identified secretomes that can be independently induced and promote cancer initiation in mouse models. These included the senescence secretome in mild to no COPD and the ETS2 (erythroblast transformation-specific 2) secretome in moderate to severe COPD. Furthermore, in situ examination of COPD lung tissue documented stromal fibroblasts expressing key cancer-associated proteins from procancer secretomes including IL-6 (senescence secretome) in mild COPD and bone morphogenetic protein-1 (ETS2 secretome) in advanced COPD. Conclusions Two distinct stromal gene expression programs promoting cancer initiation are activated in patients with lung cancer depending on the severity of COPD as measured by lung function. Our work has implications both for screening strategies and personalized approaches to prevent cancer in COPD.

INTRODUCTION The human cerebral cortex has undergone an extraordinary increase in size and complexity during mammalian evolution. Cortical cell lineages are specified in the embryo, and genetic and epidemiological evidence implicates early cortical development in the etiology of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disabilities, and schizophrenia. Most of the disease-implicated genomic variants are located outside of genes, and the interpretation of noncoding mutations is lagging behind owing to limited annotation of functional elements in the noncoding genome. RATIONALE We set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human cortical development, focusing on enhancers, which carry most of the weight upon regulation of gene expression. We longitudinally modeled human brain development using human induced pluripotent stem cell (hiPSC)–derived cortical organoids and compared organoids to isogenic fetal brain tissue. RESULTS Fetal fibroblast–derived hiPSC lines were used to generate cortically patterned organoids and to compare oganoids’ epigenome and transcriptome to that of isogenic fetal brains and external datasets. Organoids model cortical development between 5 and 16 postconception weeks, thus enabling us to study transitions from cortical stem cells to progenitors to early neurons. The greatest changes occur at the transition from stem cells to progenitors. The regulatory landscape encompasses a total set of 96,375 enhancers linked to target genes, with 49,640 enhancers being active in organoids but not in mid-fetal brain, suggesting major roles in cortical neuron specification. Enhancers that gained activity in the human lineage are active in the earliest stages of organoid development, when they target genes that regulate the growth of radial glial cells. Parallel weighted gene coexpression network analysis (WGCNA) of transcriptome and enhancer activities defined a number of modules of coexpressed genes and coactive enhancers, following just six and four global temporal patterns that we refer to as supermodules, likely reflecting fundamental programs in embryonic and fetal brain. Correlations between gene expression and enhancer activity allowed stratifying enhancers into two categories: activating regulators (A-regs) and repressive regulators (R-regs). Several enhancer modules converged with gene modules, suggesting that coexpressed genes are regulated by enhancers with correlated patterns of activity. Furthermore, enhancers active in organoids and fetal brains were enriched for ASD de novo variants that disrupt binding sites of homeodomain, Hes1, NR4A2, Sox3, and NFIX transcription factors. CONCLUSION We validated hiPSC-derived cortical organoids as a suitable model system for studying gene regulation in human embryonic brain development, evolution, and disease. Our results suggest that organoids may reveal how noncoding mutations contribute to ASD etiology. Summary of the study, analyses, and main results. Data were generated for iPSC-derived human telencephalic organoids and isogenic fetal cortex. Organoids modeled embryonic and early fetal cortex and show a larger repertoire of enhancers. Enhancers could be divided into activators and repressors of gene expression. We derived networks of modules and supermodules with correlated gene and enhancer activities, some of which were implicated in autism spectrum disorders (ASD).

AbstractBackgroundCardiac resynchronization therapy (CRT) reverses left ventricular remodeling and improves left ventricular systolic function. However, little is known about whether CRT improves ventricular conduction.ObjectiveTo determine the relationship between CRT response and QRS narrowing.MethodsThe study included consecutive patients who underwent CRT with defibrillator (CRT‐D) implantation between January 2002 and December 2012 and had subsequent generator replacement (GR). At the time of GR, super‐responder was defined as those who had left ventricular ejection fraction (LVEF) of 50% or more; patients who had an LVEF of 36–49% with an increase of more than 5% were considered responders, and the others were nonresponders. All patients were assessed 6 months after CRT‐D implantation and at the time of GR.ResultsOf 114 study patients, 58 (50.9%) were nonresponders, 29 (25.4%) responders, and 27 (23.7%) super‐responders. QRS narrowing at 6 months was significant in super‐responders (175.4 ± 21.4 to 159.7 ± 20.7 ms, P = 0.001) and responders (169.0 ± 21.3 to 157.7 ± 17.6 ms, P = 0.008). At time of GR, only super‐responders had further QRS narrowing (159.7 ± 20.7 to 146.3 ± 19.2 ms, P < 0.001). QRS duration change after 6 months was independently associated with super‐response (hazard ratio: 1.20 for every 5 ms QRS duration narrowing; 95% confidence interval, 1.06–1.38; P = 0.005), and QRS narrowing of 10 ms or more was associated with lower risk of all‐cause mortality after GR.ConclusionContinuous QRS narrowing after CRT, as an electrical marker, is associated with a super‐response to CRT. Further QRS narrowing 6 months after CRT implantation was associated with lower risk of mortality after GR.

Abstract Background The use of mesenchymal stem cells (MSCs) in clinical applications for the treatment of musculoskeletal disease is steadily increasing in office-based practice. The so-called “first generation” of MSCs is defined as autologous stem cells that have undergone minimal manipulation and are used for a homologous purpose. Systematic reviews of the clinical trials completed to date of such MSCs enable practitioners to better understand what is currently known about the outcomes and side effects of such treatments. Study Design A systematic review of human clinical studies of office-based MSC therapy for the treatment of painful degenerative musculoskeletal conditions. Methods A search of the Ovid MEDLINE, EMBASE, and Scopus databases was conducted from 2006 through September 2016. Seven hundred sixty-one records were identified from database searching, and two records from reference review of included papers. Studies with human subjects that evaluated treatment of musculoskeletal disease with minimally manipulated MSCs were included. Results Eight studies were included in this review based on selection criteria. A total of 941 patients were included, 841 of whom received cellular products, and no significant adverse events were reported. Symptomatology generally improved, though no differences were seen over controls where present. Conclusion Support in the literature is strongest for the use of bone marrow aspirate concentrate (BMAC) injections for the treatment of knee pain, but applications of the use of BMAC and peripheral blood–derived MSCs for the treatment of hip pain, tendon pain, and disc pain have all been reported. Further research is required, with large randomized controlled trials.