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Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor suppressor neurofibromin, a negative regulator of RAS signaling. Patients with NF1 present with a wide range of clinical manifestations, and the tumor with highest prevalence is cutaneous neurofibroma (cNF). Most patients harboring cNF suffer greatly from the burden of those tumors, which have no effective medical treatment. Ironically, none of the numerous NF1 mouse models developed so far recapitulate cNF. Here, we discovered that HOXB7 serves as a lineage marker to trace the developmental origin of cNF neoplastic cells. Ablating Nf1 in the HOXB7 lineage faithfully recapitulates both human cutaneous and plexiform neurofibroma. In addition, we discovered that modulation of the Hippo pathway acts as a “modifier” for neurofibroma tumorigenesis. This mouse model opens the doors for deciphering the evolution of cNF to identify effective therapies, where none exist today.Significance:This study provides insights into the developmental origin of cNF, the most common tumor in NF1, and generates the first mouse model that faithfully recapitulates both human cutaneous and plexiform neurofibroma. The study also demonstrates that the Hippo pathway can modify neurofibromagenesis, suggesting that dampening the Hippo pathway could be an attractive therapeutic target.This article is highlighted in the In This Issue feature, p. 1

Epidemiologic research has shown convincingly that certain phenotypic attributes are associated with increased relative risks of melanoma. Although such findings have intrinsic utility, there have been few attempts to translate such knowledge into estimates of disease burden suitable for framing public health policy. We aimed to estimate the population attributable fraction (PAF) for melanoma associated with melanocytic nevi using relative risk estimates derived from a systematic review and meta-analysis. We identified eligible studies using citation databases, followed by manual review of retrieved references. Of 49 studies identified, 25 and 23, respectively, were included in meta-analyses of atypical and common nevi. For people with ≥1 atypical nevi, the summary relative risk was 3.63 (95% confidence interval, 2.85-4.62), with a PAF of 0.25. The relative risk increased by 1.017 (95% confidence interval, 1.014-1.020) for each common nevus; however, significant heterogeneity in risk estimates was observed. We estimated that 42% of melanomas were attributable to having ≥25 common nevi (PAF 25-49 nevi = 0.15; PAF ≥50 nevi = 0.27), whereas PAFs for low nevus counts were modest (PAF 0-10 nevi = 0.04; PAF 11-24 nevi = 0.07). We modeled PAF under scenarios of varying nevus prevalence; the highest melanoma burden was always among those with high nevus counts (PAF range of 0.31-0.62 for ≥25 common nevi). Patients with ≥25 common nevi and/or ≥1 atypical nevi are a high-risk group, which might be targeted for identification, screening, and education. This work is the necessary first step in designing targeted preventive strategies for melanoma, which must now be overlaid with information about cost and utility. Cancer Prev Res; 3(2); 233–45

Supplementary Table S2, provided as a separate Excel file. Contains a list of custom designed probes for expression profiling of prognostic long non-coding RNAs with the nCounter assay

Supplementary Figures and Tables

Supplementary Data, which contains text, tables and figures supportive of the results reported in the main manuscript. Text includes details about clinical trials protocols, RNA extraction techniques and statistical analyses. Tables include a list of prognostic long non-coding RNAs that are measured by the custom-designed nCounter assay and a list of mRNA transcripts that significantly associate with unfavorable lncRNA scores. Figures include scatterplots depicting the correlation of nCounter results in repeated measurements of samples of patients.

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with cytogenetic and molecular factors and patient demographics (e.g., age and race). We compared survival of 25,523 non-Hispanic Black and White adults with AML using Surveillance Epidemiology and End Results (SEER) Program data and performed mutational profiling of 1,339 patients with AML treated on frontline Alliance for Clinical Trials in Oncology (Alliance) protocols. Black patients had shorter survival than White patients, both in SEER and in the setting of Alliance clinical trials. The disparity was especially pronounced in Black patients NPM1 and more IDH2 mutations in younger Black patients. Overall survival of younger Black patients was adversely affected by IDH2 mutations and FLT3-ITD, but, in contrast to White patients, was not improved by NPM1 mutations.Significance:We show that young Black patients have not benefited as much as White patients from recent progress in AML treatment in the United States. Our data suggest that both socioeconomic factors and differences in disease biology contribute to the survival disparity and need to be urgently addressed.See related commentary by Vyas, p. 540.This article is highlighted in the In This Issue feature, p. 521

We have previously shown that expression levels of 48 long noncoding RNAs (lncRNA) can generate a prognostic lncRNA score that independently associates with outcome of older patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the techniques used to identify and measure prognostic lncRNAs (i.e., RNA sequencing and microarrays) are not tailored for clinical testing. Herein, we report on an assay (based on the nCounter platform) that is designed to produce targeted measurements of prognostic lncRNAs in a clinically applicable manner. We analyzed a new cohort of 76 older patients with CN-AML and found that the nCounter assay yielded reproducible measurements and that the lncRNA score retained its prognostic value; patients with high lncRNA scores had lower complete remission (CR) rates (P = 0.009; 58% vs. 87%), shorter disease-free (P = 0.05; 3-year rates: 0% vs. 21%), overall (OS; P = 0.02, 3-year rates: 10% vs. 29%), and event-free survival (EFS; P = 0.002, 3-year rates: 0% vs. 18%) than patients with low lncRNA scores. In multivariable analyses, the lncRNA score independently associated with CR rates (P = 0.02), OS (P = 0.02), and EFS (P = 0.02). To gain biological insights, we examined our initial cohort of 71 older patients with CN-AML, previously analyzed with RNA sequencing. Genes involved in immune response and B-cell receptor signaling were enriched in patients with high lncRNA scores. We conclude that clinically applicable lncRNA profiling is feasible and potentially useful for risk stratification of older patients with CN-AML. Furthermore, we identify potentially targetable molecular pathways that are active in the high-risk patients with high lncRNA scores.

Supplementary Table 1 from Estimating the Attributable Fraction for Cancer: A Meta-analysis of Nevi and Melanoma

Background In acute ischemic stroke (AIS), fluid-attenuated inversion recovery (FLAIR) is used for treatment decisions when onset time is unknown. Synthetic FLAIR could be generated with deep learning from information embedded in diffusion-weighted imaging (DWI) and could replace acquired FLAIR sequence (real FLAIR) and shorten MRI duration. Purpose To compare performance of synthetic and real FLAIR for DWI-FLAIR mismatch estimation and identification of patients presenting within 4.5 hours from symptom onset. Materials and Methods In this retrospective study, all pretreatment and early follow-up (48 hours after symptom onset) MRI data sets including DWI (

Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML), which may give insights into the basis for its poor prognosis, have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and miRNA expression profiles were also determined using paired RNA and small RNA sequencing data. Notably, gene mutations were detected in all the major AML-associated functional groups, which include activated signaling, chromatin remodeling, cohesin complex, methylation, NPM1, spliceosome, transcription factors, and tumor suppressors. Gene mutations in the chromatin remodeling groups were relatively more frequent in patients SMARCA2 gene. In patients ≥60 years of age, the presence of spliceosome mutations associated with a lower complete remission rate (P = 0.03). RNA sequencing revealed distinct gene and miRNA expression patterns between the sole -7 and non -7 AML cases, with reduced expression, as expected, of many genes and miRNAs mapped to chromosome 7, and overexpression of ID1, MECOM, and PTPRM, among others. Overall, our findings illuminate a number of molecular features of the underlying aggressive pathobiology in -7 AML patients. Cancer Res; 77(1); 207–18. ©2016 AACR.

Supplementary Methods, Supplementary References Supplementary Table S1: Inherited regions of homozygosity in >1% of 1,798 non-leukemic individuals Supplementary Table S2: Acquired uniparental disomies detected in 425 cytogenetically normal AML patients Supplementary Table S3. Associations between recurrent UPDs with pretreatment patient characteristics for patients with cytogenetically normal acute myeloid leukemia Supplementary Table S5. Variant allele fraction of gene mutations that co-occurred with UPDs Supplementary Table S6. Allelic ratio of FLT3 internal tandem duplications that co-occurred with UPDs Supplementary Table S7: Copy number gains and losses in 425 patients with cytogenetically normal acute myeloid leukemia

Purpose:Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML.Experimental Design: We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with de novo CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years.Results:We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with FLT3-internal tandem duplication (FLT3-ITD; P < 0.001), and 11p UPD with WT1 mutations (P = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including FLT3-ITD and WT1 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS.Conclusions:LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.

Supplementary Figure S1. Unsupervised clustering of the sole -7 AML cohort and the complete TCGA AML patient data set. Supplementary Figure S2. SMARCA2 mutations in AML patients with sole -7. Supplementary Figure S3. Heatmap depicting the differential gene expression of AML patients with sole -7. Supplementary Figure S4. Heatmap visualizing the gene ontology (GO) analyses of the predicted target genes of the miRs upregulated in AML patients with sole -7. Supplementary Figure S5. Heatmap visualizing the gene ontology (GO) analyses of the predicted target genes of the miRs downregulated in AML patients with sole -7. Tables: Supplementary Table S1. Gene mutations detected in 36 patients with acute myeloid leukemia (AML) and sole -7 (DNA sequencing of 81 genes). Supplementary Table S2. Mutation analysis in paired germline-leukemic samples of 10 sole -7 patients. Supplementary Table S3. Genes significantly downregulated in 31 AML patients with sole -7 compared with gene expression of 136 AML patients from the TCGA cohort (14) who had other chromosome abnormalities that did not include abnormalities of chromosome 7 or a complex karyotype. Supplementary Table S4. Genes significantly upregulated in 31 AML patients with sole -7 compared with gene expression of 136 AML patients from the TCGA cohort (14) who had other chromosome abnormalities that did not include abnormalities of chromosome 7 or a complex karyotype. Supplementary Table S5. MicroRNAs (miRs) significantly downregulated in 31 AML patients with sole -7 compared with gene expression of 136 AML patients from the TCGA cohort who had other chromosome abnormalities that did not include abnormalities of chromosome 7 or a complex karyotype. Supplementary Table S6. MicroRNAs (miRs) significantly upregulated in 31 AML patients with sole -7 compared with gene expression of 136 AML patients from the TCGA cohort who had other chromosome abnormalities that did not include abnormalities of chromosome 7 or a complex karyotype. Supplementary Table S7. Gene ontogeny analyses of significantly downregulated genes located on chromosome 7 in 31 AML patients with sole -7.

Peritoneal metastasis of high-grade serous ovarian cancer (HGSOC) occurs when tumor cells suspended in ascites adhere to mesothelial cells. Despite the strong relationship between metastatic burden and prognosis in HGSOC, there are currently no therapies specifically targeting the metastatic process. We utilized a coculture model and multivariate analysis to examine how interactions between tumor cells, mesothelial cells, and alternatively-activated macrophages (AAM) influence the adhesion of tumor cells to mesothelial cells. We found that AAM-secreted MIP-1β activates CCR5/PI3K signaling in mesothelial cells, resulting in expression of P-selectin on the mesothelial cell surface. Tumor cells attached to this de novo P-selectin through CD24, resulting in increased tumor cell adhesion in static conditions and rolling underflow. C57/BL6 mice treated with MIP-1β exhibited increased P-selectin expression on mesothelial cells lining peritoneal tissues, which enhanced CaOV3 adhesion ex vivo and ID8 adhesion in vivo. Analysis of samples from patients with HGSOC confirmed increased MIP-1β and P-selectin, suggesting that this novel multicellular mechanism could be targeted to slow or stop metastasis in HGSOC by repurposing anti-CCR5 and P-selectin therapies developed for other indications.Significance: This study reports novel insights on the peritoneal dissemination occurring during progression of ovarian cancer and has potential for therapeutic intervention.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3560/F1.large.jpg. Cancer Res; 78(13); 3560–73. ©2018 AACR.

Materials and Methods: Participating institutions. List of all institutions that participated in the study. Patients and treatments. Detailed information about patients included in the study and their treatments. Mutational profiling. Detailed information about the techniques used to perform the mutational profiling. Definition of clinical endpoints. Statistical definition of the used end point terms . Univariable outcome analysis. Listing of all parameters that were included in the univariable outcome analysis.

Mutations detected in 425 CN-AML patients

Trisomy 21, the genetic cause of Down syndrome (DS), is the most common congenital chromosomal anomaly. It is associated with a 20-fold increased risk of acute lymphoblastic leukemia (ALL) during childhood and results in distinctive leukemia biology. To comprehensively define the genomic landscape of DS-ALL, we performed whole genome sequencing and whole-transcriptome sequencing (RNA-Seq) on 295 cases. Our integrated genomic analyses identified 15 molecular subtypes of DS-ALL, with marked enrichment of CRLF2-r, IGH::IGF2BP1, and C/EBP altered (C/EBPalt) subtypes compared to 2257 non-DS-ALL cases. We observed abnormal activation of the CEBPD, CEBPA, and CEBPE genes in 10.5% of DS-ALL cases, via a variety of genomic mechanisms, including chromosomal rearrangements and noncoding mutations leading to enhancer hijacking. 42.3% of C/EBP-activated DS-ALL also have concomitant FLT3 point mutation or indel, relative to 4.1% in other subtypes (P=7.2×10-6). CEBPD overexpression enhanced the differentiation of mouse hematopoietic progenitor cells into pro-B cells in vitro, particularly in a DS genetic background. Notably, RAG-mediated somatic genomic abnormalities were common in DS-ALL, accounting for a median of 27.5% of structural alterations, compared to 7.7% in non-DS-ALL (P=2.1×10-12). Unsupervised hierarchical clustering analyses of CRLF2-rearranged DS-ALL identified substantial heterogeneity within this group, with the BCR::ABL1-like subset linked to an inferior event-free survival (hazard ratio=5.27, P=9.3×10-8), even after adjusting for known clinical risk factors (hazard ratio=4.32; P=0.0020). These results provide important insights into the biology of DS-ALL and point to opportunities for targeted therapy and treatment individualization.

Supplemental File contains 8 Figures: SF1 shows a schematic of the co-culture device, SF2 shows additional details of PLSR model and validation of MIP-1β, SF3 shows validation of MIP-1β impact on SELP/P-selectin in mesothelial cell lines, SF4 shows CD24 expression in HGSOC lines, SF5 shows additional CD24 data for HGSOC lines and validation of CD24 siRNA knockdown, SF6 shows additional IHC of in vivo tissues for P-selectin, SF7 shows the impact of ascites on additional HGSOC lines, and SF8 shows additional immunofluorescent images of P-selectin in HGSOC patients. There are also 4 Tables: ST1 lists genes differentially expressed in LP-9 with AAM co-culture, ST2 lists soluble factors in Bioplex arrays that were not detected, ST3 provides CCR1 and CCR5 qRT-PCR results, and ST4 details the prognostic impact of CD24 in HGSOC patients.

Importance of serine as a metabolic regulator is well known in tumors and raising attention also in degenerative diseases. Recent data indicate thatde novoserine biosynthesis is an integral component of metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-drivende novoserine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles and enhanced mitochondrial integrated stress response (ISRmt),in vivo,in skeletal muscle and in cultured cells. Our evidence indicates thatde novoserine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activatingde novoserine synthesis may protect against mitochondrial failure in the skeletal muscle.Bullet pointsSerine becomes an essential amino acid in mitochondrial translation defectsBlockingde novoserine biosynthesis promotes progression of mitochondrial diseaseDe novoserine biosynthesis maintains phospholipid homeostasis upon mitochondrial insultSerine biosynthesis sustains redox-balance and mitochondrial translation in disease

Not available.

Polygenic risk scores (PRS) are rapidly emerging as aggregated measures of disease-risk associated with many genetic variants. Understanding the interplay of PRS with environmental factors is critical for interpreting and applying PRS in a wide variety of settings. We develop an efficient method for simultaneously modeling gene-environment correlations and interactions using PRS in case-control studies. We use a logistic-normal regression modeling framework to specify the disease risk and PRS distribution in the underlying population and propose joint inference across the two models using the retrospective likelihood of the case-control data. Extensive simulation studies demonstrate the flexibility of the method in trading-off bias and efficiency for the estimation of various model parameters compared to the standard logistic regression or a case-only analysis for gene-environment interactions, or a control-only analysis for gene-environment correlations. Finally, using simulated case-control datasets within the UK Biobank study, we demonstrate the power of the proposed method for its ability to recover results from the full prospective cohort for the detection of an interaction between long-term oral contraceptive use and PRS on the risk of breast cancer. This method is computationally efficient and implemented in a user-friendly R package.

Although animal research implicates a central role for dopamine in motor skill learning, a direct causal link has yet to be established in neurotypical humans. Here, we tested if a pharmacological manipulation of dopamine alters motor learning, using a paradigm which engaged explicit, goal-directed strategies. Participants (27 females, 11 males, aged 18-29 years) first consumed either 100mg of Levodopa (n=19), a dopamine precursor that increases dopamine availability, or placebo (n=19). Then, during training, participants learnt the explicit strategy of aiming away from presented targets by instructed angles of varying sizes. Targets shifted mid-movement by the instructed aiming angle. Task success was thus contingent upon aiming accuracy. The effect of the dopamine manipulations on skill learning was assessed during training, and at an overnight follow-up. Increasing dopamine availability improved aiming accuracy and lengthened reaction times, particularly for larger, more difficult aiming angles, both at training, and at follow-up. Results support the proposal that dopamine is important in decisions to engage instrumental motivation to optimise performance, particularly when learning to execute goal-directed strategies in motor skill learning.

Background: Quantitative susceptibility mapping (QSM) is a measure of iron content, and ≥6% increase in QSM has been correlated with new hemorrhage in previously stable cavernous angiomas. Longitudinal changes in QSM are not known in cavernous angiomas with symptomatic hemorrhage (CASH) with high rates of rebleeding and are the targets of novel pharmacotherapies. In a prospective multisite Trial Readiness project (clinicaltrials.gov NCT03652181), QSM is longitudinally assessed. Methods: Trial eligible subjects with CASH in the prior year and not undergoing lesion resection or radiation, were enrolled. Mean QSM of CASH lesion was acquired at baseline and at 1 and 2 year planned follow-ups. Relative change in mean lesional QSM during each follow-up year was assessed, and any symptomatic hemorrhage (SH), asymptomatic changes (AC; defined as subclinical bleed or growth) in the lesion during the same epoch. Results: Paired QSM assessments were completed to date in 99 CASH lesions (67 year 1, and 32 year 2) and are reported herein. Four SH and 6 ACs occurred during 1 st follow-up year, and 3 SH during 2 nd year. QSM increased in 54 lesion-years, decreased in 44, and remained stable in 1. The % lesional QSM change in year 1 was significantly higher than that observed in year 2 (mean +9.33, SD 37.52 vs. +5.20; SD= 24.86; p=0.05; Spearman correlation ρ -0.36). CAs with clinical SH or AC had a significantly higher % QSM change than lesions without (mean +28.03, SD 17.77 vs. +4.97, SD= 34.75; p=0.0014). All 13 lesions with SH/AC demonstrated a QSM increase ≥6% while 31 of 86 (36%) lesions with no clinical events had a ≥6% QSM increase. Conclusion: QSM change of ≥6% is present in every CASH lesion manifesting a new SH or AC (100% specificity), and is more common than clinical events (3.4X higher sensitivity). The biomarker can hence be used as a more sensitive categorical outcome than SH or AC in clinical trials of novel therapies aimed at bleeding in CASH lesions. Effect of an intervention on % QSM change may also be proposed as a time-averaged difference between 2 arms using a repeated measures analysis implemented as an unadjusted linear mixed model. These results are the basis of application for certification by the U.S F.D.A. of QSM as a monitoring biomarker of drug effect in CASH.

Purpose: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.Methods: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells.Results: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme alpha-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C > T:p.(Pro189Leu) and c.890C > A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G > A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells.Conclusion: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities.(c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license

Acute pulmonary embolism (PE) leads to an abrupt increase in pulmonary vascular resistance and right ventricular afterload, and when significant enough, can result in hemodynamic instability. High-risk PE is a dire cardiovascular emergency and portends a poor prognosis. Traditional therapeutic options to rapidly reduce thrombus burden like systemic thrombolysis and surgical pulmonary endarterectomy have limitations, both with regards to appropriate candidates and efficacy, and have limited data demonstrating their benefit in high-risk PE. There are growing percutaneous treatment options for acute PE that include both localized thrombolysis and mechanical embolectomy. Data for such therapies with high-risk PE are currently limited. However, given the limitations, there is an opportunity to improve outcomes, with percutaneous treatments options offering new mechanisms for clot reduction with a possible improved safety profile compared with systemic thrombolysis. Additionally, mechanical circulatory support options allow for complementary treatment for patients with persistent instability, allowing for a bridge to more definitive treatment options. As more data develop, a shift toward a percutaneous approach with mechanical circulatory support may become a preferred option for the management of high-risk PE at tertiary care centers.

Background: Increases in mean lesional iron content (≥6%) measurement by QSM and vascular permeability (≥40%) assessed by DCEQP MRI have been associated with new bleeding, and are used as monitoring biomarkers in NINDS funded 1st clinical trial of pharmacotherapy (clinicaltrials.gov NCT02603328) in cavernous angiomas with symptomatic hemorrhage (CASH). Plasma protein levels previously associated with CASH in diagnostic and prognostic contexts have never been compared to lesional QSM and DCEQP in the same subjects. Methods: Plasma samples and MRI sequences were simultaneously acquired during 1 year-epochs of prospective follow-up of CASH patients. Plasma levels of 16 proteins were assayed by ELISA and correlated with lesional QSM and DCEQP during the same epochs. Univariate correlations were followed by multivariate analyses combining multiple protein levels to minimize Akaike Information Criterion (AIC) and increase R 2 . Accuracy (AUC on receiver operating curves) and sum of squared error (SSE) are reported for associations achieving statistical significance with FDR correction. Results: None of the proteins individually correlated with QSM/DCEQP (continuous or categorical). Relative change of angiopoietin2, and absolute change of the combination (endoglin+IL1B+IL16) had the highest accuracy (AUC 78.7%, SD 0.062 and 98.4%, SD 0.013 respectively) for lesional QSM increase ≥6%. Relative change of endoglin+IL1B, and absolute change of angiopoetin2+endoglin+thromobomodulin+VEGF, had the highest accuracy (AUC 64.6%, SD 0.057 and 93.2%, SD 0.040 respectively) for lesional DCEQP increase ≥40%. Relative change in angiopoetin1 had the lowest SSE (8.87) with QSM change as a continuous variable, and relative change in lipopolysaccharide binding protein had the lowest SSE (469.06) with DCEQP change as continuous variable. Conclusion: Circulating proteins reflect changes in lesional iron content and permeability in CASH during prospective follow-up. Results are a proof of concept that blood tests could replace more complex and costly imaging biomarkers in the monitoring of hemorrhage in cavernous angiomas. Additional mechanistic plasma molecules (miRNAs and metabolites) may further enhance the accuracy of these monitoring biomarkers.

This study presents the role of 5d orbitals in the bonding, and electronic and magnetic structure of Ce imido and oxo complexes synthesized with a tris(hydroxylaminato) [((2- t BuNO)C6H4CH2)3N]3- (TriNO x 3-) ligand framework, including the reported synthesis and characterization of two new alkali metal-capped Ce oxo species. X-ray spectroscopy measurements reveal that the imido and oxo materials exhibit an intermediate valent ground state of the Ce, displaying hallmark features in the Ce LIII absorption of partial f-orbital occupancy that are relatively constant for all measured compounds. These spectra feature a double peak consistent with other formal Ce(iv) compounds. Magnetic susceptibility measurements reveal enhanced levels of temperature-independent paramagnetism (TIP). In contrast to systems with direct bonding to an aromatic ligand, no clear correlation between the level of TIP and f-orbital occupancy is observed. CASSCF calculations defy a conventional van Vleck explanation of the TIP, indicating a single-reference ground state with no low-lying triplet excited state, despite accurately predicting the measured values of f-orbital occupancy. The calculations do, however, predict strong 4f/5d hybridization. In fact, within these complexes, despite having similar f-orbital occupancies and therefore levels of 4f/5d hybridization, the d-state distributions vary depending on the bonding motif (Ce[double bond, length as m-dash]O vs. Ce[double bond, length as m-dash]N) of the complex, and can also be fine-tuned based on varying alkali metal cation capping species. This system therefore provides a platform for understanding the characteristic nature of Ce multiple bonds and potential impact that the associated d-state distribution may have on resulting reactivity.

Catfish have the ability to inflict stings on their victims through spines located on their dorsal and pectoral fins. The stings of catfish can release toxins that have dermonecrotic, edemogenic, and vasospastic factors. In this case, a 56-year-old man suffered a catfish sting to his right thumb, which resulted in acute hand compartment syndrome and resultant hand fasciotomies. His hospital course was complicated by multiple irrigation and debridements, finger amputations, hand fluid cultures positive for Vibrio damsela, and eventual wrist disarticulation. The combination of envenomation, infection, and delayed presentation for treatment ultimately led to a hand amputation.

Honey bees obtain lipids from pollen or commercial supplements. These supplements do not fully support colony health. We tested the hypothesis that supplements are deficient because they lack essential fatty acids (EFAs). The five supplements we tested had low linolenic (⍵3) acid and were unbalanced (⍵6:⍵3 > 6) compared to natural pollen. We selected two of these supplements for further study because they had different levels of individual EFAs and different ⍵6:⍵3 ratios. Bees from hives fed these different supplements had equivalent tissue EFA levels. In choice assays, hives fed these different supplements were presented with flours with various absolute and relative levels of EFAs. We saw no difference in foraging preference. Rather, all hives preferred flours with small grain size and high protein to lipid ratios. We conclude that bees balance their internal EFAs and that differential colony nutrition does not affect foraging preference. The data also argue for more linolenic (⍵3) acid in commercial supplements.