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Inherited genetic variations in the melanocortin-1 receptor (MC1R) responsible for human red hair color (RHC) variants are associated with impaired DNA damage repair and increased melanoma risk. MC1R signaling is critically dependent on palmitoylation, primarily mediated by the protein acyltransferase zinc finger DHHC-type palmitoyltransferase 13 (ZDHHC13). A better understanding of how ZDHHC13 is physiologically activated could help identify approaches to prevent melanomagenesis in redheads. Here, we report that AMP-activated protein kinase (AMPK) phosphorylates ZDHHC13 at S208 to strengthen the interaction between ZDHHC13 and MC1R-RHC, leading to enhanced MC1R palmitoylation in redheads. Consequently, phosphorylation of ZDHHC13 by AMPK increased MC1R-RHC downstream signaling. AMPK activation and MC1R palmitoylation repressed UVB-induced transformation of human melanocytes in vitro and delayed melanomagenesis in vivo in C57BL/6J-MC1R-RHC mice. The importance of AMPK to MC1R signaling was validated in human melanomas where AMPK upregulation correlated with expression of factors downstream from MC1R signaling and with prolonged patient survival. These findings suggest AMPK activation as a promising strategy to reduce melanoma risk, especially for individuals with red hair. Significance: Phosphorylation of ZDHHC13 by AMPK at S208 promotes MC1R activation and suppresses melanocyte transformation, indicating activation of AMPK as a potential approach to prevent melanoma in people with red hair.

Natural disasters have a significant impact on the environment and economies of all countries around the world, and a large amount of multi-source heterogeneous geographic information data is generated every day. However, due to a lack of knowledge transformation capabilities, these nations continue to struggle with the issue of "a large amount of data and little knowledge". Therefore, it is of great significance how to extract geographic knowledge related to disasters from the vast data and construct a geographic knowledge graph integrating disaster information. Based on the theory related to knowledge extraction, this paper proposes a method to construct a natural disaster knowledge graph integrating geographic information. The core of this knowledge graph is to construct the association relationship between natural disaster concepts, research areas, and spatial data. The vocabulary and relationships associated with disaster concepts are primarily transformed by an existing word list of geographic narratives, which then provide rich semantic relationships of domain concepts for the entire knowledge graph. The research areas and spatial data types are mainly obtained through knowledge entity extraction and disambiguation methods. This disaster knowledge graph can support applications well such as natural disaster visualization and analysis, data recommendation systems, and intelligent Q&A systems, which can further improve the intelligence of natural disaster knowledge services and is expected to promote the sharing and reuse of domain knowledge graphs to a certain extent.

The analysis of natural hazards is still lacking in real-time and comprehensiveness. To enhance the intelligent analysis of disasters, reduce natural disasters, and provide more timely and accurate disaster warnings. The method of constructing a natural disaster research event graph using the abstracts of research literature related to natural disaster analysis as the data source is proposed. First, a rule-based matching algorithm combined with syntactic analysis is used to extract the events of the disaster analysis process and spatio-temporal information from the abstract; Then build an event storage model based on Neo4j to store the event chain and related information; Then use Word2vec to convert events into word vectors, and define the event similarity as a linear sum of the object similarity and predicate similarity of the two events, combine event similarity setting equation to calculate core nodes and perform event generalization and fusion of graphs. Based on the above method, soil erosion is used as an example to construct an event graph and provide the basis for decision making services for intelligent analysis of natural disasters.

Advances in molecular profiling have led to improved understanding of glioma heterogeneity. Results have been used to inform diagnostic classification and targeted treatment strategies. Validation of these tests is necessary in the development of biomarkers that can aid in treatment decision, allowing for personalized medicine in neuro-oncologic diseases. Although not all populations have benefitted equally from awareness of and access to testing, opportunities arise regarding incorporating this testing into the standard of care for patients with glioma.

Purpose:Multiple myeloma is a malignancy of plasma cells. Extensive genetic and transcriptional characterization of myeloma has identified subtypes with prognostic and therapeutic implications. In contrast, relatively little is known about the myeloma epigenome.Experimental Design:CD138+CD38+ myeloma cells were isolated from fresh bone marrow aspirate or the same aspirate after freezing for 1–6 months. Gene expression and chromatin accessibility were compared between fresh and frozen samples by RNA sequencing (RNA-seq) and assay for transpose accessible chromatin sequencing (ATAC-seq). Chromatin accessible regions were used to identify regulatory RNA expression in more than 700 samples from newly diagnosed patients in the Multiple Myeloma Research Foundation CoMMpass trial (NCT01454297).Results:Gene expression and chromatin accessibility of cryopreserved myeloma recapitulated that of freshly isolated samples. ATAC-seq performed on a series of biobanked specimens identified thousands of chromatin accessible regions with hundreds being highly coordinated with gene expression. More than 4,700 of these chromatin accessible regions were transcribed in newly diagnosed myelomas from the CoMMpass trial. Regulatory element activity alone recapitulated myeloma gene expression subtypes, and in particular myeloma subtypes with immunoglobulin heavy chain translocations were defined by transcription of distal regulatory elements. Moreover, enhancer activity predicted oncogene expression implicating gene regulatory mechanisms in aggressive myeloma.Conclusions:These data demonstrate the feasibility of using biobanked specimens for retrospective studies of the myeloma epigenome and illustrate the unique enhancer landscapes of myeloma subtypes that are coupled to gene expression and disease progression.

Enrichment of transcription factor consensus binding motifs in regulatory elements predictive of gene expression associated with poor overall survival.

Correlation of regulatory element transcription and gene expression in CoMMpass specimens.

ATAC-seq data for Emory patients.

Correlation of chromatin accessibility and gene expression for the 5% most variably expressed genes.

Regulatory elements predictive of gene expression for genes prognostic of overall survival in CoMMpass.

Regulatory element transcription in newly diagnosed myelomas from CoMMpass.

Gene set enrichment analysis of transcribed regulatory elements in CoMMpass.

Supplementary Table 1 from Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas

Supplementary Table 2 from Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas

Malignant astrocytomas are a deadly solid tumor in children. Limited understanding of their underlying genetic basis has contributed to modest progress in developing more effective therapies. In an effort to identify such alterations, we performed a genome-wide search for DNA copy number aberrations (CNA) in a panel of 33 tumors encompassing grade 1 through grade 4 tumors. Genomic amplifications of 10-fold or greater were restricted to grade 3 and 4 astrocytomas and included the MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13), and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26), and TP53 (17p3.1) were evident among grade 2 to 4 tumors. BRAF gene rearrangements that were indicated in three tumors prompted the discovery of KIAA1549-BRAF fusion transcripts expressed in 10 of 10 grade 1 astrocytomas and in none of the grade 2 to 4 tumors. In contrast, an oncogenic missense BRAF mutation (BRAFV600E) was detected in 7 of 31 grade 2 to 4 tumors but in none of the grade 1 tumors. BRAFV600E mutation seems to define a subset of malignant astrocytomas in children, in which there is frequent concomitant homozygous deletion of CDKN2A (five of seven cases). Taken together, these findings highlight BRAF as a frequent mutation target in pediatric astrocytomas, with distinct types of BRAF alteration occurring in grade 1 versus grade 2 to 4 tumors. Cancer Res; 70(2); 512–9

Supplementary Figure 1 from Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas

Introduction Given the high morbidity and mortality of stroke, there remains a demand for techniques that provide rapid and safe intervention while improving time to recanalization. The direct aspiration first-pass technique (ADAPT) uses force and aspiration for clot removal without the aid of separators or retrievers. In this study, we compare the force and aspiration qualities of commercially available catheters. Methods Four different catheters with varying inner diameters were set up in a bench top model to test catheter tip pressure and flow rate. Catheter tip pressure was measured by attaching the catheter to a vacuum pressure gauge and an aspiration pump. The flow rate was calculated by measuring the volume of room temperature water aspirated through each catheter over a given time. Results The Microvention Sofia catheter generated the greatest tip force (21.32 g), and the Stryker AXS Catalyst 6 catheter generated the smallest tip force (15.88 g). The Penumbra ACE 068 catheter and Medtronic ARC catheter measured 20.87 g and 16.78 g respectively. The ACE 068 had highest rate of aspiration at 289 mL/min, and the Catalyst 6 catheter had the lowest rate at 214. The Microvention Sofia catheter had the second highest rate while the ARC had the third highest rate, measuring 285 mL/min and 256 mL/min, respectively. Conclusions When using the ADAPT technique, knowledge of the tip force and catheter flow rate of newer catheters with larger distal inner diameters may guide selection of aspiration catheters. While this study demonstrates differences in tip force and flow rate of different commercially available catheters, clinical translation will require further testing and evaluation.

PURPOSE CALGB 40603 ( NCT00861705 ), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points. PATIENTS AND METHODS The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing. RESULTS Among baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P < .0001) and overall survival (87.9% v 63.4%, P < .0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS. CONCLUSION Despite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival.

The geodetic method of positional data processing is usually not one of position estimation only, nor one of model testing only, but usually one where estimation and testing are combined. The DIA-estimator captures the statistical intricacies of this combination, thus providing a unifying framework for the rigorous analyses of positional integrity and quality control procedures. However, to be able to establish fit-for-purpose quality control, not only solutions for the forward problem (quality of control) need to be available, but also for the inverse problem (control of quality). With the DIA-estimator and its multimodal probability density function (PDF), we have solutions available for the forward problem, but not so for the inverse problem. That is, no objective methods and strategies are currently available that allow one to design DIA-estimators specifically for explicitly formulated fit-for-purpose quality criteria. In this invited contribution we present and illustrate some of the underlying design and computational challenges that are brought forward by the complexities of the inverse problem. This relates, amongst others, to the DIA-variables, such as the chosen partitionings of the misclosure spaces, and to the ‘winner-takes-all’ structure of the DIA-class estimators currently employed. For an underpinning of the design and computational challenges various numerical and graphical examples will be provided. The challenges that will be provided represent samples of fertile grounds for the typical researcher interested in geodetic data processing and modelling, and eager to take up a difficult challenge and/or looking for research opportunities that can make a difference., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

Purpose: Programmed death ligand 1 [PD-(L)1]-targeted therapies have shown modest survival benefit in triple-negative breast cancer (TNBC). PD-L1+ microenvironments in TNBC are not well characterized and may inform combinatorial immune therapies. Herein, we characterized clinicopathologic features, RNA-based immune signatures, and spatially defined protein-based tumor–immune microenvironments (TIME) in early-stage PD-L1+ and PD-L1− TNBC. Experimental Design: From a large cohort of chemotherapy-naïve TNBC, clinicopathologic features, deconvoluted RNA immune signatures, and intraepithelial and stromal TIME (Nanostring GeoMX) were identified in subsets of PD-L1+ and PD-L1− TNBC, as defined by FDA-approved PD-L1 companion assays. Results: 228 of 499 (46%) TNBC were PD-L1+ (SP142: ≥1% immune cells-positive). Using PD-L1 22C3, 46% had combined positive score (CPS) ≥ 1 and 16% had CPS ≥10. PD-L1+ TNBC were higher grade with higher tumor-infiltrating lymphocytes (TIL; P < 0.05). PD-L1 was not associated with improved survival following adjustment for TILs and other variables. RNA profiles of PD-L1+ TNBC had increased dendritic cell, macrophage, and T/B cell subset features; and decreased myeloid-derived suppressor cells. PD-L1+ stromal and intraepithelial TIMEs were highly enriched in IDO-1, HLA-DR, CD40, and CD163 compared with PD-L1-TIME, with spatially specific alterations in CTLA-4, Stimulator of Interferon Genes (STING), and fibronectin. Macrophage- and antigen presentation–related proteins correlated most strongly with PD-L1 protein. Conclusions: In this early-stage TNBC cohort, nearly 50% were PD-L1+ (SP142 companion assay) while 16% were PD-L1+ with the 22C3 companion assay. PD-L1+ TNBC had specific myeloid-derived and lymphoid features. Spatially defined PD-L1+ TIME were enriched in several clinically actionable immune proteins. These data may inform future studies on combinatorial immunotherapies for patients with PD-L1+ TNBC. See related commentary by Symmans, p. 5446

Animals are under constant selective pressure from a myriad of diverse pathogens. Microsporidia are ubiquitous animal parasites, but the influence they exert on shaping animal genomes is mostly unknown. Using multiplexed competition assays, we measured the impact of four different species of microsporidia on 22 wild isolates ofCaenorhabditis elegans. This resulted in the identification and confirmation of 13 strains with significantly altered population fitness profiles under infection conditions. One of these identified strains, JU1400, is sensitive to an epidermal-infecting species by lacking tolerance to infection. JU1400 is also resistant to an intestinal-infecting species and can specifically recognize and destroy this pathogen. Genetic mapping of JU1400 demonstrates that these two opposing phenotypes are caused by separate loci. Transcriptional analysis reveals the JU1400 sensitivity to epidermal microsporidia infection results in a response pattern that shares similarity to toxin-induced responses. In contrast, we do not observe JU1400 intestinal resistance being regulated at the transcriptional level. The transcriptional response to these four microsporidia species is conserved, withC. elegansstrain-specific differences in potential immune genes. Together, our results show that phenotypic differences to microsporidia infection amongstC. elegansare common and that animals can evolve species-specific genetic interactions.

Purpose: Multiple myeloma is a malignancy of plasma cells. Extensive genetic and transcriptional characterization of myeloma has identified subtypes with prognostic and therapeutic implications. In contrast, relatively little is known about the myeloma epigenome. Experimental Design: CD138+CD38+ myeloma cells were isolated from fresh bone marrow aspirate or the same aspirate after freezing for 1–6 months. Gene expression and chromatin accessibility were compared between fresh and frozen samples by RNA sequencing (RNA-seq) and assay for transpose accessible chromatin sequencing (ATAC-seq). Chromatin accessible regions were used to identify regulatory RNA expression in more than 700 samples from newly diagnosed patients in the Multiple Myeloma Research Foundation CoMMpass trial (NCT01454297). Results: Gene expression and chromatin accessibility of cryopreserved myeloma recapitulated that of freshly isolated samples. ATAC-seq performed on a series of biobanked specimens identified thousands of chromatin accessible regions with hundreds being highly coordinated with gene expression. More than 4,700 of these chromatin accessible regions were transcribed in newly diagnosed myelomas from the CoMMpass trial. Regulatory element activity alone recapitulated myeloma gene expression subtypes, and in particular myeloma subtypes with immunoglobulin heavy chain translocations were defined by transcription of distal regulatory elements. Moreover, enhancer activity predicted oncogene expression implicating gene regulatory mechanisms in aggressive myeloma. Conclusions: These data demonstrate the feasibility of using biobanked specimens for retrospective studies of the myeloma epigenome and illustrate the unique enhancer landscapes of myeloma subtypes that are coupled to gene expression and disease progression.

Animals are under constant selective pressure from a myriad of diverse pathogens. Microsporidia are ubiquitous animal parasites, but the influence they exert on shaping animal genomes is mostly unknown. Using multiplexed competition assays, we measured the impact of four different species of microsporidia on 22 wild isolates of Caenorhabditis elegans. This resulted in the identification and confirmation of 13 strains with significantly altered population fitness profiles under infection conditions. One of these identified strains, JU1400, is sensitive to an epidermal-infecting species by lacking tolerance to infection. JU1400 is also resistant to an intestinal-infecting species and can specifically recognize and destroy this pathogen. Genetic mapping of JU1400 demonstrates that these two opposing phenotypes are caused by separate loci. Transcriptional analysis reveals the JU1400 sensitivity to epidermal microsporidia infection results in a response pattern that shares similarity to toxin-induced responses. In contrast, we do not observe JU1400 intestinal resistance being regulated at the transcriptional level. The transcriptional response to these four microsporidia species is conserved, with C. elegans strain-specific differences in potential immune genes. Together, our results show that phenotypic differences to microsporidia infection amongst C. elegans are common and that animals can evolve species-specific genetic interactions.

Alzheimer’s disease (AD) is an aging-related neurodegenerative disease, leading to the progressive loss of memory and other cognitive functions. As there is still no cure for AD, the growth in the number of susceptible individuals represents a major emerging threat to public health. Currently, the pathogenesis and etiology of AD remain poorly understood, while no efficient treatments are available to slow down the degenerative effects of AD. Metabolomics allows the study of biochemical alterations in pathological processes which may be involved in AD progression and to discover new therapeutic targets. In this review, we summarized and analyzed the results from studies on metabolomics analysis performed in biological samples of AD subjects and AD animal models. Then this information was analyzed by using MetaboAnalyst to find the disturbed pathways among different sample types in human and animal models at different disease stages. We discuss the underlying biochemical mechanisms involved, and the extent to which they could impact the specific hallmarks of AD. Then we identify gaps and challenges and provide recommendations for future metabolomics approaches to better understand AD pathogenesis.

PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) –targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival. PATIENTS AND METHODS Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples. RESULTS One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS. CONCLUSION In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.

Cancer biomarker discoveries typically involve utilizing patient specimens. In practice, there is often strong desire to preserve high quality biospecimens for studies that are most likely to yield useful information. Previously, we proposed a two-stage adaptive design for binary endpoints which terminates the biomarker study in a futility interim if the model performance is unsatisfactory. In this work, we extend the two-stage design framework to accommodate time-to-event endpoints. The first stage of the procedure involves testing whether the measure of discrimination for survival models (C-index) exceeds a pre-specified threshold. We describe the computation of cross-validated C-index and evaluation of the statistical significance using re-sampling techniques. The second stage involves an independent model validation. Our simulation studies show that under the null hypothesis, the proposed design maintains type I error at the nominal level and has high probabilities of terminating the study early. Under the alternative hypothesis, power of the design is a function of the true event proportion, the sample size, and the targeted improvement in the discriminant measure. We apply the method to design of a prognostic biomarker study in patients with triple-negative breast cancer. Some practical aspects of the proposed method are discussed.

PURPOSE To determine the effectiveness of office-based vergence/accommodative therapy for improving accommodative amplitude and accommodative facility in children with symptomatic convergence insufficiency and accommodative dysfunction. METHODS We report changes in accommodative function following therapy among participants in the Convergence Insufficiency Treatment Trial - Attention and Reading Trial with decreased accommodative amplitude (115 participants in vergence/accommodative therapy; 65 in placebo therapy) or decreased accommodative facility (71 participants in vergence/accommodative therapy; 37 in placebo therapy) at baseline. The primary analysis compared mean change in amplitude and facility between the vergence/accommodative and placebo therapy groups using analyses of variance models after 4, 8, 12 and 16 weeks of treatment. The proportions of participants with normal amplitude and facility at each time point were calculated. The average rate of change in amplitude and facility from baseline to week 4, and from weeks 4 to 16, were determined in the vergence/accommodative therapy group. RESULTS From baseline to 16 weeks, the mean improvement in amplitude was 8.6 dioptres (D) and 5.2 D in the vergence/accommodative and placebo therapy groups, respectively (mean difference = 3.5 D, 95% confidence interval (CI): 1.5 to 5.5 D; p = 0.01). The mean improvement in facility was 13.5 cycles per minute (cpm) and 7.6 cpm in the vergence/accommodative and placebo therapy groups, respectively (mean difference = 5.8 cpm, 95% CI: 3.8 to 7.9 cpm; p

Background: TNBC is the most aggressive sub-type of breast cancer and has limited targeted therapies. Atezolizumab was recently FDA-approved for patients with advanced PD-L1+ TNBC. In a well-characterized cohort of patients with early-stage TNBC, we used the FDA-approved PD-L1 SP142 companion assay for atezolizumab to score whole tumor sections for PD-L1 expression. We determined the frequency and scoring distribution of PD-L1 in these tumors and evaluated PD-L1 status for associations with clinicopathologic variables and outcomes. Methods: Whole tumor sections from 498 women with surgically-treated, non-(distant) metastatic TNBC (ER/PR 15% (80%). 228/498 (46%) tumors were PD-L1+, distributed as IC score 1-5%: 21%, 6-10%: 13%, 11-20%: 5% and >20%: 7%. 270/498 (54%) were PD-L1-. 43 (8.6%) of tumors had PD-L1 staining in TC (all but 1 were also IC+). PD-L1 IC expression was associated with larger tumor size (p = 0.005), higher nodal stage (≥pN1: 43% vs. 31%, p < 0.001), higher grade (grade 3: 95% vs. 86%, p< 0.001), higher Ki-67 PI (>15%: 88% vs. 69%, p Citation Format: Jodi M Carter, Mei-Yin C Polley, Jason P Sinnwell, Roberto A Leon-Ferre, Fergus J Couch, Krishna R Kalari, Judy C Boughey, Minetta C Liu, Daniel W Visscher, Matthew P Goetz. Frequency, characteristics and prognostic factors of PD-L1+ triple negative breast cancer using the PD-L1 SP142 companion assay [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-08.

Hydrophilic polymer coatings on intravascular devices lower friction between the device and vasculature, thereby reducing trauma during interventional procedures. Polymer coating embolism-the detachment and downstream embolism of polymer particles-has been reported as an iatrogenic complication of coated interventional devices affecting the vasculature and various organs. The Food and Drug Administration (FDA) acknowledges this complication and continues to work with stakeholders to close gaps in performance testing and standards related to polymer coating integrity. Recent innovations within interventional technologies have led to development of new hydrophilic-coated devices with expanded indications for use. The 2018 FDA draft guidance for intravascular guidewires expands the application of particulate generation testing to most devices and recommends labeling changes to increase industry awareness. This article highlights current procedural trends where the phenomenon of polymer coating embolism may be more prevalent. It describes the mechanisms of polymer separation, reported clinical sequelae, and risk factors for relevant indications. These procedural trends and associated risk factors articulate the need for particulate testing and support the FDA's draft guidance recommendations for performance testing of applied coatings. If standardized, particulate assessments may allow characterization and comparisons of coating integrity among devices from various manufacturers, and are an important foundation for setting particulate limits. As hydrophilic coatings enable endovascular treatment for a range of patient populations, setting particulate limits or finding alternative solutions without compromise to device function may be essential. Particulate testing is relevant to physicians, regulators, and manufacturers for the purposes of product development and quality improvement of interventional devices.

Obesity is a global public health threat. Although studies have suggested that the built environment is related to obesity, scholars have paid less attention to the pathways from the built environment to young adults' obesity. To bridge this gap, we employed path analysis to examine whether food intake, exercise, and active travel mediate the association between the campus-based built environment and body mass index (BMI), based on a nationwide sample of 15,503 Chinese undergraduates mostly aged 18–23 years old. Our results showed that unhealthy food intake mediated the association. A higher number of points of interest, more green space, and fewer restaurants were negatively related to body mass index by inhibiting unhealthy food intake. Neither the duration of exercise nor active travel distance mediated the built environment-BMI association, although both were directly associated with the campus-based built environment. These findings suggest that improving the campus-based environment could contribute to a reduction in obesity risk among undergraduates by improving their diets.

Applications in early-phase cancer trials have motivated the development of many statistical designs since the late 1980s, including dose-finding methods, futility screening, treatment selection, and early stopping rules. These methods are often proposed to address the conventional cytotoxic therapeutics for neoplastic diseases and cancer. Recent advances in precision medicine have motivated novel trial designs, most notably the idea of master protocol (eg, platform trial, basket trial, umbrella trial, N-of-1 trial), for the evaluation of molecularly targeted cancer therapies. In this article, we review the concepts and methodology of early-phase cancer trial designs with a focus on dose finding and treatment screening and put these methods in the context of platform trials of molecularly targeted cancer therapies. Because most cancer trial designs have been developed for cytotoxic agents, we will discuss how these time-tested design principles hold relevance for targeted cancer therapies, and we will delineate how a master protocol may serve as an efficient platform for safety and efficacy evaluations of novel targeted therapies.

Background: Patients with HER2+ breast cancer who have residual disease after neoadjuvant anti-HER2 plus chemotherapy have a high risk of recurrence and benefit from adjuvant trastuzumab emtansine (T-DM1). We hypothesize that endocrine-responsive residual tumors after neoadjuvant treatments may have good outcomes among patients receiving only adjuvant endocrine therapy plus trastuzumab. Using paired pre- and post-treatment samples from CALGB 40601 and other neoadjuvant cohorts that did not include adjuvant T-DM1, we investigated survival by pretreatment and residual disease ESR1 and PgR gene expression in CALGB 40601, and by estrogen receptor (ER) and progesterone receptor (PR) immunohistochemistry (IHC) in the other cohorts. We considered endocrine-responsive tumors those with ER and/or PR expression by gene expression or IHC. Methods: CALGB 40601 is a randomized neoadjuvant trial of single vs. dual HER2-targeting (trastuzumab and/or lapatinib added to paclitaxel). We only included those patients who had not suffered from disease progression or death during their preoperative treatments. In total, 77 patients with paired pretreatment and residual disease tumors were profiled by mRNA sequencing and studied. Cutoffs for ESR1 and PgR mRNA expression mimicking clinical positivity were obtained using 265 pretreatment CALGB 40601 tumors (and 1,045 TCGA samples for ESR1). We also examined ER and PR IHC in paired tumors from 202 patients treated at 4 different collaborating institutions; all had residual disease after neoadjuvant HER2 targeting plus chemotherapy. We considered ER- or PR-positive as ≥10% positively staining cells. The primary endpoint was EFS, defined as the time from randomization to event in CALGB 40601 and from the first systemic therapy to event in the 4-institution validation cohort. Results: In 77 patients from CALGB 40601 with paired (pretreatment/residual disease) specimens, 38 (49.3%) had ESR1+/ESR1+ tumors. The EFS was superior in the ESR1+/ESR1+ (n=38) group than in the remaining others (the log-rank test, p=0.011). The 5- and 7-year EFS rates for the ESR1+/ESR1+ (n=38) were 92.1% and 89.2%, whereas the rates were uniformly < 70% in the others. In particular, the 5-year EFS rate among 11 patients with ESR1+/ESR1- tumors was 61.4%. This remained significant in multivariable analysis with clinical stage and treatment arm; the hazard ratio (HR) for EFS in ESR1+/ESR1+ versus all others was 0.29 (95% CI, 0.09-0.90). In ESR1+/ESR1+ tumors, 5-year EFS rates were high for those whose residual disease and also being PgR+ (n=32) or PAM50 LumA or Normal-like (n=34) (93.8% and 97.1%, respectively). In the institutional validation cohort, pretreatment /residual disease ER(+)/ER(+) tumors (n=113) had superior 3-year EFS versus all others (p=0.010). At a median follow-up of 35.9 months, the 3-year EFS rates for ER(+)/ER(+) and all other groups were 96.6% and 82.6%, respectively. This remained strongly significant in multivariable analysis with clinical stage; the HR for EFS in ER(+)/ER(+) versus all other groups was 0.28 (95% CI, 0.09-0.88). Among 46 who also had PR+ in the residual disease, the 3-year EFS was 100.0%. Conclusions: HER2+ patients with ER+ pretreatment and ER+ residual disease after neoadjuvant chemotherapy + HER2-targeting have a very good survival outcome despite not receiving additional anti-HER2 targeting with T-DM1. This may provide a simple mechanism to better tailor therapy within residual disease patients using serial ER measurements. Citation Format: Sung Gwe Ahn, Aranzazu Fernandez-Martinez, Mei-Yin C. Polley, Soong June Bae, Seho Park, Núria Chic, Fara Brasó-Maristany, Benedetta Conte, Valentina Guarneri, Maria Vittoria Dieci, Gaia Griguolo, PierFranco Conte, Joon Jeong, Aleix Prat, Lisa A. Carey, Charles M Perou. A good prognosis of endocrine-dependent tumors among residual invasive cancer after anti-HER2 therapy: CALGB 40601 (Alliance) and validation studies [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-02.

Epithelial-mesenchymal transition (EMT) and its reversal, mesenchymal-epithelial transition (MET) drive tissue reorganization critical for early development. In carcinomas, processing through EMT, MET or partial states promotes migration, invasion, dormancy, and metastatic colonization. As a reversible process, EMT is inherently regulated at epigenetic and epigenomic levels. To understand the epigenomic nature of reversible EMT and its partial states, we characterized chromatin accessibility dynamics, transcriptomic output, protein expression, and cellular phenotypes during stepwise reversible EMT. We found that the chromatin insulating protein machinery, including CTCF, is suppressed and re-expressed, coincident with broad alterations in chromatin accessibility, during EMT/MET and is lower in triple-negative breast cancer cell lines with EMT features. Through analysis of chromatin accessibility using ATAC-seq, we identify that early phases of EMT are characterized by enrichment for AP-1 family member binding motifs but also by diminished enrichment for CTCF binding motifs. Through loss-of-function analysis we demonstrate that suppression of CTCF alters cellular plasticity, facilitating entrance into a partial EMT state. These findings are indicative of a role of CTCF and chromatin reorganization for epithelial-mesenchymal plasticity.

PURPOSE Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma. PATIENTS AND METHODS Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety. RESULTS Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; P = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; P = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common ( P < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% v 10.7%, respectively), febrile neutropenia (35.0% v 17.7%, respectively), mucositis (8.4% v 2.1%, respectively), and neuropathy (18.6% v 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm. CONCLUSION In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.

The epithelial-to-mesenchymal transition (EMT) reversible cellular reprogramming event, used repeatedly throughout development, is hypothesized to be involved in the cell migration and consequently metastasis that ultimately contributes to most breast cancer-related fatalities. In this process, cuboidal epithelial cells, marked by the presence of tight junction proteins and cell-cell adhesions, lose their apicobasal polarity and acquire a spindle-like morphology and migratory traits. EMT was originally regarded to have only two states, with cells exhibiting either epithelial or mesenchymal phenotypes; however, recently, researchers have demonstrated the existence of a dual epithelial/mesenchymal state, termed hybrid- or partial-EMT. Due to its inherent plasticity, it is believed that EMT and its reversal mesenchymal-to-epithelial transition (MET) is, at least, partly regulated by epigenetic means such as alterations in chromatin structure. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) is a novel technique that employs the use of a mutant Tn5 transposase to cleave nucleosome-free DNA regions in a non-biased manner. In this investigation, we induced MCF10A mammary epithelial cells to undergo a short-term (4 days) EMT. Addition and withdrawal of exogenous TGFβ1 produced partial- or full-EMT and MET conditions which were interrogated by ATAC- and RNA-seq. Hierarchical clustering of ATAC cleavage peaks revealed that pre-EMT and short- and long-term MET conditions demonstrate similar chromatin accessibility profiles with cleavage sites enriched for specific binding motifs. Notably, transcription factors typically not associated with EMT displayed dynamic enrichment in the accessible chromatin at various timepoints in our assay. Correlation with RNA-seq data reveals highly dynamic changes in gene expression suggesting dynamic and reversible use of regulatory programs. Importantly, partial-EMT cells were characterized by unique accessibility patterns, motif enrichment, and gene expression supporting the conclusion that this is not merely an intermediate but a unique state. Citation Format: Johnson KS, Hussein S, Lin Y, Taube JH. Defining chromatin accessibility profiles of partial and reversible EMT [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-08-04.

SIGNIFICANCE Clinicians can better diagnose and manage vision problems of autism spectrum disorder (ASD) children by establishing a standard of care for this population. Results also reinforce the importance of a comprehensive binocular vision evaluation in all patients with ASD. PURPOSE The purposes of this study were to compare near-point and ocular motility test findings in ASD children and typically developing (TD) peers and to compare findings among ASD children by level of verbal communication. METHODS Sixty-one children and adolescents (ASD, 34; TD, 27) aged 9 to 17 years completed an eye examination protocol including tests of distance and near phoria, near point of convergence, near fusional convergence and divergence, accommodative response, and Northeastern State University College of Optometry oculomotor testing. Testing was completed through refractive correction. Parents of ASD children provided information regarding subjects' verbal communication level (nonverbal, uses short words, verbal). RESULTS Distance phoria did not differ significantly between groups. Near phoria of ASD subjects was more exophoric (difference, 2.8 prism diopters). Mean near point of convergence break and recovery were 7.0 and 8.02 cm, respectively, in ASD subjects and 2.19 and 3.99 cm in TD subjects. Near fusional divergence and convergence showed no significant difference. Autism spectrum disorder subjects had significantly poorer stereoacuity (P < .0001) and, on Northeastern State University College of Optometry Oculomotor Testing, reduced fixation, poorer accuracy and stamina/ability, and increased head and body movement. Monocular estimation method retinoscopy results did not differ significantly between ASD and TD subjects. No significant differences in phoria, near point of convergence, and near fusional divergence or convergence were observed between ASD subgroups (nonverbal, uses short words, verbal). CONCLUSIONS Autism spectrum disorder children are more likely to show receded near point of convergence, poor fixation, inaccurate saccades, erratic pursuits, and exophoric posture. These differences occur, regardless of reported verbal communication level.

In early-stage HER2-positive breast cancer, biomarkers that guide deescalation and/or escalation of systemic therapy are needed. CelTIL score is a novel, combined biomarker based on stromal tumor-infiltrating lymphocytes and tumor cellularity and is determined in tumor biopsies at week 2 of anti-HER2 therapy only. We evaluated the prognostic value of CelTIL in 196 patients with early-stage HER2-positive disease treated with standard trastuzumab-based chemotherapy in the NeoALTTO phase III trial. Using a prespecified CelTIL cutoff, a better 5-year event-free survival and overall survival was observed between CelTIL-high and CelTIL-low score with a 76.4% (95% confidence interval [CI] = 68.0% to 85.0%) vs 59.7% (95% CI = 50.0% to 72.0%) (hazard ratio = 0.40, 95% CI = 0.17 to 0.94) and 86.4% (95% CI = 80.0% to 94.0%) vs 73.5% (95% CI = 64.0% to 84.0%) (hazard ratio = 0.43, 95% CI = 0.20 to 0.92), respectively. Statistical significance was maintained after adjusting for baseline tumor-infiltrating lymphocytes, hormone receptor status, pretreatment tumor size and nodal status, type of surgery, treatment arm, and pathological complete response. Further studies to support CelTIL as an early readout biomarker to help deescalate or escalate systemic therapy in HER2-positive breast cancer seem warranted.

PURPOSE: Endocrine therapy (ET) is an effective strategy to treat hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer (ABC) but nearly all patients eventually progress. Our goal was to develop and validate a web-based clinical calculator for predicting disease outcomes in women with HR+ABC who are candidates for receiving first-line single-agent ET. METHODS: The meta-database comprises 891 patient-level data from the control arms of five contemporary clinical trials where patients received first-line single-agent ET (either aromatase inhibitor or fulvestrant) for ABC. Risk models were constructed for predicting 24-months progression-free survival (PFS-24) and 24-months overall survival (OS-24). Final models were internally validated for calibration and discrimination using ten-fold cross-validation. RESULTS: Higher number of sites of metastases, measurable disease, younger age, lower body mass index, negative PR status, and prior endocrine therapy were associated with worse PFS. Final PFS and OS models were well-calibrated and associated with cross-validated time-dependent area under the curve (AUC) of 0.61 and 0.62, respectively. CONCLUSIONS: The proposed ABC calculator is internally valid and can accurately predict disease outcomes. It may be used to predict patient prognosis, aid planning of first-line treatment strategies, and facilitate risk stratification for future clinical trials in patients with HR+ABC. Future validation of the proposed models in independent patient cohorts is warranted.

Epigenetic landscapes can provide insight into regulation of gene expression and cellular diversity. Here, we examined the transcriptional and epigenetic profiles of seven human blood natural killer (NK) cell populations, including adaptive NK cells. The BCL11B gene, encoding a transcription factor (TF) essential for T cell development and function, was the most extensively regulated, with expression increasing throughout NK cell differentiation. Several Bcl11b-regulated genes associated with T cell signaling were specifically expressed in adaptive NK cell subsets. Regulatory networks revealed reciprocal regulation at distinct stages of NK cell differentiation, with Bcl11b repressing RUNX2 and ZBTB16 in canonical and adaptive NK cells, respectively. A critical role for Bcl11b in driving NK cell differentiation was corroborated in BCL11B-mutated patients and by ectopic Bcl11b expression. Moreover, Bcl11b was required for adaptive NK cell responses in a murine cytomegalovirus model, supporting expansion of these cells. Together, we define the TF regulatory circuitry of human NK cells and uncover a critical role for Bcl11b in promoting NK cell differentiation and function.

Polymer coating emboli have been affiliated with persisting brain lesions after endovascular procedures.1–6 Patient symptoms include headaches, fevers, chills (ie, constitutional symptoms), neurological presentations of focal weakness, sensory and visual deficits, and seizures. Follow-up imaging highlights distinct areas of contrast enhancement in slightly different locations, with some lesions increasing in number and size (see figure 1). Polymer particles from various coating compositions have different rates of degradation, absorption, and metabolism or excretion (DAM/E). These varied rates of DAM/E may have impacts on persisting brain lesions, recurrent patient symptoms, and adverse event outcomes. Figure 1 Characteristic MRI of patients with persisting brain lesions. T1 postcontrast images highlighting an increase in the number and size of lesions (white arrows) over a 12 month period. Also note formation of new enhancing lesions. Images used with permission by Williams and Wilkins Co. (license ID: 1100407-1). Degradation is the chemical breakdown of a polymer by hydrolysis, oxidation, or enzymatic processes. A faster degradation rate may result in less obstruction within blood vessels or reduced presence …

Supplemental material, sj-pdf-5-hpq-10.1177_13591053211018806 for Scaling up research on discrimination and health: The abridged Explicit Discrimination Scale by João L Bastos, Michael E Reichenheim and Yin C Paradies in Journal of Health Psychology

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Supplemental material, sj-pdf-2-hpq-10.1177_13591053211018806 for Scaling up research on discrimination and health: The abridged Explicit Discrimination Scale by João L Bastos, Michael E Reichenheim and Yin C Paradies in Journal of Health Psychology

Supplemental material, sj-pdf-4-hpq-10.1177_13591053211018806 for Scaling up research on discrimination and health: The abridged Explicit Discrimination Scale by João L Bastos, Michael E Reichenheim and Yin C Paradies in Journal of Health Psychology

Supplemental material, sj-pdf-5-hpq-10.1177_13591053211018806 for Scaling up research on discrimination and health: The abridged Explicit Discrimination Scale by João L Bastos, Michael E Reichenheim and Yin C Paradies in Journal of Health Psychology

Supplemental material, sj-pdf-3-hpq-10.1177_13591053211018806 for Scaling up research on discrimination and health: The abridged Explicit Discrimination Scale by João L Bastos, Michael E Reichenheim and Yin C Paradies in Journal of Health Psychology

Supplemental material, sj-pdf-4-hpq-10.1177_13591053211018806 for Scaling up research on discrimination and health: The abridged Explicit Discrimination Scale by João L Bastos, Michael E Reichenheim and Yin C Paradies in Journal of Health Psychology