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We describe how K-12 students played Jenga to learn about the connections between health living habits, disease, and community well-being and resilience.

The high levels of biodiversity supported by mountains suggest a possible link between geologic processes and biological evolution. Freshwater biodiversity is high not only in tectonically active settings but also in tectonically quiescent montane regions such as the Appalachian Mountains. We show that erosion through different rock types drove allopatric divergence between lineages of the Greenfin Darter ( Nothonotus chlorobranchius ), a fish species endemic to rivers draining metamorphic rocks in the Tennessee River basin in the United States. In the past, metamorphic rock preferred by N. chlorobranchius was more widespread, but as erosion exposed other rock types, lineages of this species were progressively isolated in tributaries farther upstream, where metamorphic rock remained. Our results suggest a geologic mechanism for initiating allopatric diversification in mountains long after tectonic activity ceases.

Background: Diabetic dyslipidemia is associated with atherosclerosis risk factors and cardiovascular disease. Saroglitazar is a dual PPAR α and γ agonist approved initially for diabetic dyslipidemia and later for managing non-alcoholic steatohepatitis and hyperglycemia in T2DM. This study was conducted to estimate the association of studied PPAR α and γ gene polymorphisms among patients with diabetic dyslipidemia at baseline and with triglyceride response to saroglitazar administration. Methods: A total of 54 diabetic dyslipidemia patients who are not controlled i.e., triglycerides (TG)>200 mg/dl with moderate intensity of atorvastatin (≥10 mg) were recruited to the study. All the patients were given saroglitazar 4 mg once daily for 12 weeks. PPARα single nucleotide polymorphisms (SNPs) rs1800206, rs4253778, rs135542 and those of PPARγ gene rs3856806, rs10865710, rs1805192 were genotyped by real-time PCR. Results: 54 patients (67% female) with a mean age of 48.01±6.73 years were given saroglitazar 4 mg once daily for 12 weeks. There was a significant decrease in TG (36.9%) from baseline of 292.33±83.81mg/dl (mean±SD) to 184.46±95.90 mg/dl (

Purpose This investigation provides a rigorous systematic review of the postoperative outcomes of patients with and without chronic hepatitis C who underwent total hip arthroplasty (THA) and total knee arthroplasty (TKA). Methods We queried PubMed, Embase, Cochrane Database of Systematic Reviews, Scopus, Web of Science and the ‘gray’ literature, including supplemental materials, conference abstracts and proceedings as well as commentary published in various peer-reviewed journals from 1992 to present to evaluate studies that compared the postoperative outcomes of patients with and without chronic hepatitis C who underwent primary THA or TKA. This investigation was registered in the PROSPERO international prospective register of systematic reviews and follows the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. In our literature search, we identified 14 articles that met our inclusion criteria and were included in our fixed-effects meta-analysis. The postoperative outcomes analyzed included periprosthetic joint infection (PJI), aseptic revision, non-homebound discharge and inpatient mortality. Results Our statistical analysis demonstrated a statistically significant increase in postoperative complications of patients with chronic hepatitis C who underwent primary THA or TKA including PJI (odds ratio (OR): 1.98, 95% CI: 1.86 – 2.10), aseptic revision (OR: 1.58, 95% CI: 1.50 – 1.67), non-homebound discharge (OR: 1.31, 95% CI: 1.28– 1.34) and inpatient mortality (OR: 9.37, 95% CI: 8.17 – 10.75). Conclusion This meta-analysis demonstrated a statistically significant increase in adverse postoperative complications in patients with chronic hepatitis C who underwent primary THA or TKA compared to patients without chronic hepatitis C.

Specific ion effects govern myriad biological phenomena, including protein-ligand interactions and enzyme activity. Despite recent advances, detailed understanding of the role of ion hydrophobicity in specific ion effects, and the intersection with hydrotropic effects, remains elusive. Short chain fatty acid sodium salts are simple amphiphiles which play an integral role in our gastrointestinal health. We hypothesise that increasing a fatty acid's hydrophobicity will manifest stronger salting-out behaviour.Here we study the effect of these amphiphiles on an exemplar thermoresponsive polymer brush system, conserving the carboxylate anion identity while varying anion hydrophobicity via the carbon chain length. Ellipsometry and quartz crystal microbalance with dissipation monitoring were used to characterise the thermoresponse and viscoelasticity of the brush, respectively, whilst neutron reflectometry was used to reveal the internal structure of the brush. Diffusion-ordered nuclear magnetic resonance spectroscopy and computational investigations provide insight into polymer-ion interactions.Surface sensitive techniques unveiled a non-monotonic trend in salting-out ability with increasing anion hydrophobicity, revealing the bundle-like morphology of the ion-collapsed system. An intersection between ion-specific and hydrotropic effects was observed both experimentally and computationally; trending from good anti-hydrotrope towards hydrotropic behaviour with increasing anion hydrophobicity, accompanying a change in hydrophobic hydration.

Long-lasting sepsis-induced immunoparalysis has been principally studied in primary (1°) memory CD8 T cells; however, the impact of sepsis on memory CD8 T cells with a history of repeated cognate Ag encounters is largely unknown but important in understanding the role of sepsis in shaping the pre-existing memory CD8 T cell compartment. Higher-order memory CD8 T cells are crucial in providing immunity against common pathogens that reinfect the host or are generated by repeated vaccination. In this study, we analyzed peripheral blood from septic patients and show that memory CD8 T cells with defined Ag specificity for recurring CMV infection proliferate less than bulk populations of central memory CD8 T cells. Using TCR-transgenic T cells to generate 1° and higher-order (quaternary [4°]) memory T cells within the same host, we demonstrate that the susceptibility and loss of both memory subsets are similar after sepsis induction, and sepsis diminished Ag-dependent and -independent (bystander) functions of these memory subsets equally. Both the 1° and 4° memory T cell populations proliferated in a sepsis-induced lymphopenic environment; however, due to the intrinsic differences in baseline proliferative capacity, expression of receptors (e.g., CD127/CD122), and responsiveness to homeostatic cytokines, 1° memory T cells become overrepresented over time in sepsis survivors. Finally, IL-7/anti–IL-7 mAb complex treatment early after sepsis induction preferentially rescued the proliferation and accumulation of 1° memory T cells, whereas recovery of 4° memory T cells was less pronounced. Thus, inefficient recovery of repeatedly stimulated memory cells after polymicrobial sepsis induction leads to changes in memory T cell pool composition, a notion with important implications in devising strategies to recover the number and function of pre-existing memory CD8 T cells in sepsis survivors.

Determining the tools and equipment use in Radio Television and Global System Mobile Servicing at Vocational Centers in Gombe State, Nigeria, was the major goal of the study. The study used a descriptive survey research approach and was carried out in Gombe State, Nigeria. 55 respondents made up the study's population, including 42 teachers and 13 administrators (principals). There was no sampling because the population was of a manageable size, hence the entire population was employed for the study. A structured questionnaire called the "Tools and Equipment Utilization Questionnaire (TEUQ)" was the instrument used to gather the data. The instrument was evaluated by three professionals, and Cronbach Alpha yielded a reliability value of 0.72. The mean statistics were utilized to answer the research questions, and the null hypotheses were tested using a t-test with a 0.05 threshold of significance. Equipment in RTV and GSM servicing trade workshops at the Vocational Training Centers in Gombe State, including workstations, multimeters-digital, multimeters-analog, Booster meters, white lights, various phone panels, Tornados (soft wire boxes), television training modules, probe/logic pulsar, oscilloscopes, pattern generators, picture tube testers, isolation transformers, vector scopes, signal strength meters, black and white television, colored television, and TV. The study also showed that the tools used in the RTV and GSM servicing Trade workshop at the Vocational Training Centers in Gombe State, including (Set of flat Screwdrivers, (large, medium, and small), Asterics, a Set of Allen keys, Set of Star Screwdrivers, Set of Spanners and Soldering Iron) is sufficient. It was suggested that in order for the schools to succeed, the Gombe State Ministry of Education should supply them with the necessary training materials and apparatus. Additionally, the government has to provide all trainers with greater technical training so they can use new technology in the workshop.

RESUMO Uma revisão sistemática da literatura foi realizada para avaliar o impacto da pandemia de COVID-19 na incidência de depressão pós-parto. A revisão incluiu estudos publicados entre janeiro de 2020 e março de 2023 e examinou a prevalência e fatores de risco para DPP durante a pandemia. Os resultados indicam que a pandemia aumentou a incidência de DPP em todo o mundo, com um aumento de cerca de 30% em comparação com as taxas pré-pandêmicas. A falta de suporte social e emocional, restrições ao acesso aos serviços de saúde, mudanças nas rotinas diárias e o aumento do estresse financeiro e emocional foram identificados como fatores de risco específicos associados à pandemia que podem aumentar a probabilidade de desenvolvimento de DPP. A revisão destacou intervenções eficazes para prevenir e tratar a DPP durante a pandemia, incluindo o uso de telemedicina, terapia online, grupos de apoio virtual e intervenções baseadas emmindfulness. A revisão enfatizou a importância de fornecer apoio psicológico e emocional às mães durante a pandemia, especialmente aquelas em áreas de alto risco.

Erosion degrades soils and undermines agricultural productivity. For agriculture to be sustainable, soil erosion rates must be low enough to maintain fertile soil. Hence, quantifying both pre-agricultural and agricultural erosion rates is vital for determining whether farming practices are sustainable. However, there have been few measurements of pre-agricultural erosion rates in major farming areas where soils form from Pleistocene deposits. We quantified pre-agricultural erosion rates in the midwestern United States, one of the world's most productive agricultural regions. We sampled soil profiles from 14 native prairies and used in situ–produced 10Be and geochemical mass balance to calculate physical erosion rates. The median pre-agricultural erosion rate of 0.04 mm yr–1 is orders of magnitude lower than agricultural values previously measured in adjacent fields, as is a site-averaged diffusion coefficient (0.005 m2 yr–1) calculated from erosion rate and topographic curvature data. The long-term erosion rates are also one to four orders of magnitude lower than the assumed 1 mm yr–1 soil loss tolerance value assigned to these locations by the U.S. Department of Agriculture. Hence, quantifying long-term erosion rates using cosmogenic nuclides provides a means for more robustly defining rates of tolerable erosion and for developing management guidelines that promote soil sustainability.

Purpose: Over the past decade, the need for improved teaching and learning approaches that enhance entrepreneurial competencies has been a critical agenda in Tanzania. Despite its importance, the process of realizing entrepreneurial competencies through education, suffers from various shortcomings especially in relation to teaching and learning approaches. This paper assesses the effects of teaching and learning approaches on graduates’ entrepreneurial competencies for self-employment in Tanzania. Methodology: The study used a cross-sectional case study research design with the aid of snowball sampling. A sample of 202 respondents was picked from selected universities of Sokoine and St. Augustine of Tanzania. Data were collected using a structured questionnaire which included a Likert scale, key informant interviews and documentary reviews. While content analysis was used to analyze qualitative data, statistical package for social sciences (SPSS) was used to analyze quantitative data. Findings: The results showed that a theoretical active participation approach (with the mean 3.8614) was used to develop capacity that empowered graduates with entrepreneurial competencies indicating a shift from rote learning that previous studies established. Most of the practical teaching and learning approaches ascribing to entrepreneurial framework were, however, not applied to yield greater effect on graduates’ self-employment. Based on the results, the paper concludes that universities used only fragments of a student-centered approach as opposed to incorporating the holistic approach recommended for educating for entrepreneurship. Recommendations: The paper recommends that university instructors should apply holistic teaching and learning approaches that would increase graduates’ confidence and commitment to seek self-employment in Tanzania.

Spin defects in foils of hexagonal boron nitride are an attractive platform for magnetic field imaging, since the probe can be placed in close proximity to the target. However, as a III-V material the electron spin coherence is limited by the nuclear spin environment, with spin echo coherence times of ∽100 ns at room temperature accessible magnetic fields. We use a strong continuous microwave drive with a modulation in order to stabilize a Rabi oscillation, extending the coherence time up to ∽ 4μs, which is close to the 10 μs electron spin lifetime in our sample. We then define a protected qubit basis, and show full control of the protected qubit. The coherence times of a superposition of the protected qubit can be as high as 0.8 μs. This work establishes that boron vacancies in hexagonal boron nitride can have electron spin coherence times that are competitive with typical nitrogen vacancy centres in small nanodiamonds under ambient conditions.

Sara Moradi Tuchayi,1 Ying Wang,1 Isaac J Pence,1 Alex Fast,1 Anat Stemmer-Rachamimov,2 Conor L Evans,1 R Rox Anderson,1 Lilit Garibyan1 1Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA, USA; 2Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, MA, USACorrespondence: Lilit Garibyan, Wellman Center for Photomedicine, Massachusetts General Hospital, 50 Blossom Street-Thier 2, Boston, MA, 02114, USA, Tel +1 617-726-2005, Email lgaribyan@mgh.harvard.eduBackground: Cryoneurolysis uses tissue cooling as an opioid-sparing, long-lasting treatment for peripheral nerve pain. A nerve-selective method for cryoneurolysis by local injection of ice-slurry was developed to allow cryoneurolysis to be performed with a standard needle and syringe, similar to peripheral nerve blocks. Since the treatment of patients with chronic pain may require repeated injections, we investigated the safety and tolerance of repeated treatments in a rat model.Methods: Three repeated ice-slurry treatments, given 6 weeks apart were performed around the rat sciatic nerve. Nerve and surrounding tissues were collected up to 4 months after the third treatment for analysis. Coherent anti-Stokes Raman scattering (CARS) microscopy was used to study effects on myelin sheaths and axon structure. Immunofluorescence (IF) staining was used to study effects on axon density. Hematoxylin and Eosin (H&E) staining was used to examine histologic effects on sciatic nerve and surrounding tissue.Results: Histologic and CARS image analysis of nerve tissue collected months after three injections demonstrated recovery of nerve structure, myelin organization and axon density to baseline levels, without any residual inflammation, scarring or neuroma formation. No inflammation or scarring was detected in surrounding skin and muscle tissues.Conclusion: Repeated ice-slurry injections cause temporary, nerve-selective and reversible changes in the peripheral nerve. There was no histologic damage to surrounding skin and muscle tissues. Repeated treatments with injectable ice-slurry for cryoneurolysis appear to be safe and well tolerated. Clinical studies for patients with chronic pain are warranted.Keywords: pain treatment, slurry, cooling, multiple treatments

© Copyright 2022. Sociedad Meteorológica Estadounidense (AMS). Para obtener permiso para reutilizar cualquier parte de este Trabajo, comuníquese con permisos@ametsoc. org . Cualquier uso del material en este Trabajo que se determine como "uso justo" según la Sección 107 de la Ley de derechos de autor de EE. UU. (17 Código de EE. UU. § 107) o que cumpla las condiciones especificadas en la Sección 108 de la Ley de derechos de autor de EE. ) no requiere el permiso de la AMS. La republicación, la reproducción sistemática, la publicación en forma electrónica, como en un sitio web o en una base de datos de búsqueda, u otros usos de este material, excepto los exentos de la declaración anterior, requieren un permiso por escrito o una licencia de la AMS. Todas las publicaciones periódicas y monográficas de AMS están registradas en el Centro de Autorización de Derechos de Autor (https://www.copyright.com ). Se proporcionan detalles adicionales en la declaración de política de derechos de autor de AMS, disponible en el sitio web de AMS ( https://www.ametsoc.org/PUBSCopyrightPolicy ) ., In 2021, both social and economic activities began to return towards the levels preceding the COVID-19 pandemic for some parts of the globe, with others still experiencing restrictions. Meanwhile, the climate has continued to respond to the ongoing increase in greenhouse gases and resulting warming. La Niña, a phenomenon which tends to depress global temperatures while changing rainfall patterns in many regions, prevailed for all but two months of the year. Despite this, 2021 was one of the six-warmest years on record as measured by global mean surface temperature with an anomaly of between +0.21° and +0.28°C above the 1991–2020 climatology., Lake surface water temperatures from satellite data have been generated within the GloboLakes project funded by the UK National Environment Research Council (NE/J023345/2), with extensions funded by the EU Copernicus Climate Change Service (C3S) programme...

Fluorescence microscopy with fluorescent reporters that respond to environmental cues is a powerful method for interrogating biochemistry and biophysics in living systems. Photoinduced electron transfer (PeT) is commonly used as a trigger to modulate fluorescence in response to changes in the biological environment. PeT-based indicators rely on PeT either into the excited state (acceptor PeT) or out of the excited state (donor PeT). Our group has been developing voltage-sensitive fluorophores (VF dyes) that respond to changes in biological membrane potential (

Sepsis, an amplified immune response to systemic infection that leads to life-threatening organ dysfunction, affects >125,000 people/day worldwide with 20% mortality. Modest therapeutic progress for sepsis has been made, in part because of the lack of therapeutic translatability between mouse-based experimental models and humans. One potential reason for this difference stems from the extensive use of immunologically naive specific pathogen-free mice in preclinical research. To address this issue, we used sequential infections with well-defined BSL-2 pathogens to establish a novel immune-experienced mouse model (specific pathogen experienced [SPexp]) to determine the extent to which immunological experience and/or inflammation influences the host capacity to respond to subsequent infections, including sepsis. Consistent with their immunological experience, SPexp inbred or outbred mice had significant changes in the composition and activation status of multiple leukocyte populations known to influence the severity of cecal ligation and puncture–induced sepsis. Importantly, by varying the timing of sepsis induction, we found the level of basal inflammation controls sepsis-induced morbidity and mortality in SPexp mice. In addition, although a beneficial role of NK cells in sepsis was recently demonstrated in specific pathogen-free mice, NK cell depletion before cecal ligation and puncture induction in SPexp mice lead to diminished mortality, suggesting NK cells may have beneficial or detrimental roles in the response to septic insult dependent on host immune status. Thus, data highlight the importance of utilizing immune-experienced models for preclinical studies to interrogate the cellular/molecular mechanism(s) that could be therapeutically exploited during severe and dysregulated infection-induced inflammatory responses, such as sepsis.

The visualization of photosynthesis-derived reactive oxygen species has been experimentally limited to pH-sensitive probes, unspecific redox dyes, and whole-plant phenotyping. Recent emergence of probes that circumvent these limitations permit advanced experimental approaches to investigate in situ plastid redox properties. Despite growing evidence of heterogeneity in photosynthetic plastids, investigations have not addressed the potential for spatial variation in redox and/or reactive oxygen dyamics. To study the dynamics of H2O2 in distinct plastid types, we targeted the pH-insensitive, highly specific probe HyPer7 to the plastid stroma in Arabidopsis (Arabidopsis thaliana). Using HyPer7 and glutathione redox potential (EGSH) probe for redox-active green fluorescent protein 2 (roGFP2) genetically fused to the redox enzyme human glutaredoxin-1 (Grx1-roGFP2) with live cell imaging and optical dissection of cell types, we report heterogeneities in H2O2 accumulation and redox buffering within distinct epidermal plastids in response to excess light and hormone application. Our observations suggest that plastid types can be differentiated by their physiological redox features. These data underscore the variation in photosynthetic plastid redox dynamics and demonstrate the need for cell type-specific observations in future plastid phenotyping.

Cumulative incidence of all-cause mortality, breast cancer-specific mortality, and breast cancer recurrence among women diagnosed with invasive breast cancer in the Pathways Study, according to tertiles of the 2-year post-diagnosis lifestyle score, 2006–2018

Hazard ratios (HR) and 95% confidence intervals (95% CI) for the association of 2-year post-diagnosis lifestyle with all-cause mortality, breast cancer-mortality, and breast cancer recurrence among women diagnosed with stage I–III breast cancer.

Supplementary text providing additional information regarding methods.

Background:Lifestyle habits can impact breast cancer development, but its impact on breast cancer prognosis remains unclear. We investigated associations of post-diagnosis lifestyle with mortality and recurrence in 1,964 women with invasive breast cancer enrolled in the Kaiser Permanente Northern California Pathways Study shortly after diagnosis with lifestyle information at baseline (2005–2013) and the 2-year follow-up.Methods:We calculated a post-diagnosis lifestyle score (range, 0–18) based on 9 diet, physical activity, and body weight recommendations from the American Cancer Society/American Society of Clinical Oncology (ACS/ASCO) using follow-up data (body weight also included baseline data); higher scores indicate greater guideline concordance. Similarly, we calculated a pre-diagnosis lifestyle score using baseline data to investigate pre- to post-diagnosis changes. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazard models, with follow-up through December 2018 (observing 290 deaths and 176 recurrences).Results:The 2-year post-diagnosis lifestyle score was inversely associated with all-cause mortality (ACM; HR per 2-point increase = 0.90; 95% CI, 0.82–0.98), and breast cancer–related mortality (HR, 0.79; 95% CI, 0.67–0.95), but not recurrence. Relative to women who maintained low concordance with recommendations at both time points, women who maintained high concordance had a lower risk of ACM (HR, 0.61, 95% CI, 0.37–1.03). Improved concordance with some specific recommendations (particularly PA) may be associated with a lower hazard of ACM (HRPA, 0.52; 95% CI, 0.35–0.78).Conclusions:Results suggest that women with breast cancer may benefit from a post-diagnosis lifestyle aligned with ACS/ASCO guidelines.Impact:This information may potentially guide lifestyle recommendations for breast cancer survivors to reduce mortality risk.

The concept of truth is at the core of science, journalism, law, and many other pillars of modern society. Yet, given the imprecision of natural language, deciding what information should count as true is no easy task, even with access to the ground truth. How do people decide whether a given claim of fact qualifies as true or false? Across two studies (N = 1181; 16,248 observations), participants saw claims of fact alongside the ground truth about those claims. Participants classified each claim as true or false. Although participants knew precisely how accurate the claims were, participants classified claims as false more often when they judged the information source to be intending to deceive (versus inform) their audience, and classified claims as true more often when they judged the information source to be intending to provide an approximate (versus precise) account. These results suggest that, even if people have access to the same set of facts, they might disagree about the truth of claims if they attribute discrepant intentions to information sources. Such findings may shed light on the robust and persistent disagreements over claims of fact that have arisen in the “post-truth era”.

Supplemental Table 1. Overall cohort characteristics of AAPC whole exome sequencing cohort (n=102) Supplemental Table 2. Clinical and pathological characteristics of AAPC WES discovery cohort (n=102) Supplemental Table 3. Comparison of numbers of tumors by Gleason grade between the TCGA and AAPC cohorts Supplemental Table 4. Germline pathogenic variants in genes in the DNA repair pathway and list of 20 DNA repair genes assessed in targeted analysis Supplemental Table 5. Alteration file of somatic variants detected in the AAPC WES discovery cohort (n=102) Supplemental Table 6. Focal deletion and amplification peaks and genes located within peaks by GISTIC2.0 analysis of AAPC WES cohort Supplemental Table 7. ERF deletions and mutations in prostate tumors of the Weill Cornell Precision Medicine cohort Supplemental Table 8. Clinical and pathological characteristics of AAPC targeted sequencing extension cohort Supplemental Table 9. List of genes and intronic regions targeted with hybrid capture bait set used for AAPC extension cohort Supplemental Table 10. Alteration file of somatic variants detected in the AAPC extension cohort (n=90) using the targeted sequencing panel Supplemental Table 11. ERF mutation frequencies across published prostate cancer cohorts Supplemental Table 12. Germline ERF variant detected in the AAPC WES cohort Supplemental Table 13. Mutations in cytochrome P450 genes in the AAPC exome discovery cohort Supplemental Table 14. ERF oligonucleotides used for RNA in situ hybridization Supplemental Table 15. Gene sets shERF_VCAP_UP_LnCAP_UP_overlap_UP and shERF_vs_CNTRL.LHSAR_UP Supplemental Table 16. Tumor purity estimates for AAPC exome discovery cohort

Supplemental Methods

Supplemental Figure Legends

Supplementary tables 1s-4s. Supplementary Table 1s. Concordance of variant calls. Supplementary Table 2s. Breast cancer-related genes from the Cancer Gene Consensus database. Supplementary Table 3s. Concordance of variant calls in known breast cancer genes. Supplementary Table 4s. Discordant variant calls in breast cancer-related genes.

PDF file - 114K, Suppl Table 1 - List of the 517 genes whose expression was measured by DASL microarray analysis of RNA from FFPE specimens. Supplemental Table 2. Mean difference and t-test p-value between the computed DDCt from EAM minus the computed DDCt from AAM from the validation sample of 16 AAM and 16 EAM. Supplemental Figure 1. Plot of the first 2 principal components, computed from all 517 genes on 163 patient tumor samples (80 AAM, 83 EAM) with the corresponding matched normal samples.

Supplementary Figure 3 from Context-Dependent Role of Angiopoietin-1 Inhibition in the Suppression of Angiogenesis and Tumor Growth: Implications for AMG 386, an Angiopoietin-1/2–Neutralizing Peptibody

Background: Despite more aggressive screening across all demographics and gradual declines in mortality related to prostate cancer (PCa) in the United States, disparities among populations persist. A substantial proportion of African American men (AAM) have a higher overall incidence, earlier age of onset, increased proportion of clinically advanced disease, and increased bone metastases and mortality from PCa compared to European American men (EAM). Limited early evidence indicates that underlying causes for disparities may be observed in tumor-specific gene expression programs.Methods: This study used microarray-based methods to measure expression levels for 517 genes that were previously associated with PCa in archived formalin-fixed paraffin embedded (FFPE) specimens; testing the hypothesis that gene expression features of functional consequence to cancer distinguish PCa from AAM and EAM. A t test was conducted comparing AAM to EAM expression levels for each probe on the array.Results: Analysis of 639 tumor samples (270 AAM, 369 EAM) showed that 95 genes were overexpressed specifically in PCa from AAM relative to EAM and 132 were overexpressed in PCa from EAM relative to AAM. Furthermore, systems-level analyses highlight the relevant signaling pathways and functions associated with the EAM- or AAM-specific overexpressed gene sets, for example, inflammation and lipid metabolism.Conclusions: Results here bring further understanding to the potential for molecular differences for PCa in AAM versus EAM.Impact: The results support the notion that therapeutic benefits will be realized when targeted treatments are designed to acknowledge and address a greater spectrum of PCa subtypes and molecular distinctions. Cancer Epidemiol Biomarkers Prev; 22(5); 891–7. ©2013 AACR.

AMG 386 is an investigational first-in-class peptide-Fc fusion protein (peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 (Ang1) and Ang2 with their receptor, Tie2. Although the therapeutic value of blocking Ang2 has been shown in several models of tumorigenesis and angiogenesis, the potential benefit of Ang1 antagonism is less clear. To investigate the consequences of Ang1 neutralization, we have developed potent and selective peptibodies that inhibit the interaction between Ang1 and its receptor, Tie2. Although selective Ang1 antagonism has no independent effect in models of angiogenesis-associated diseases (cancer and diabetic retinopathy), it induces ovarian atrophy in normal juvenile rats and inhibits ovarian follicular angiogenesis in a hormone-induced ovulation model. Surprisingly, the activity of Ang1 inhibitors seems to be unmasked in some disease models when combined with Ang2 inhibitors, even in the context of concurrent vascular endothelial growth factor inhibition. Dual inhibition of Ang1 and Ang2 using AMG 386 or a combination of Ang1- and Ang2-selective peptibodies cooperatively suppresses tumor xenograft growth and ovarian follicular angiogenesis; however, Ang1 inhibition fails to augment the suppressive effect of Ang2 inhibition on tumor endothelial cell proliferation, corneal angiogenesis, and oxygen-induced retinal angiogenesis. In no case was Ang1 inhibition shown to (a) confer superior activity to Ang2 inhibition or dual Ang1/2 inhibition or (b) antagonize the efficacy of Ang2 inhibition. These results imply that Ang1 plays a context-dependent role in promoting postnatal angiogenesis and that dual Ang1/2 inhibition is superior to selective Ang2 inhibition for suppression of angiogenesis in some postnatal settings. Mol Cancer Ther; 9(10); 2641–51. ©2010 AACR.

Background: Whole-exome sequencing (WES) has recently emerged as an appealing approach to systematically study coding variants. However, the requirement for a large amount of high-quality DNA poses a barrier that may limit its application in large cancer epidemiologic studies. We evaluated the performance of WES with low input amount and saliva DNA as an alternative source material.Methods: Five breast cancer patients were randomly selected from the Pathways Study. From each patient, four samples, including 3 μg, 1 μg, and 0.2 μg blood DNA and 1 μg saliva DNA, were aliquoted for library preparation using the Agilent SureSelect Kit and sequencing using Illumina HiSeq2500. Quality metrics of sequencing and variant calling, as well as concordance of variant calls from the whole exome and 21 known breast cancer genes, were assessed by input amount and DNA source.Results: There was little difference by input amount or DNA source on the quality of sequencing and variant calling. The concordance rate was about 98% for single-nucleotide variant calls and 83% to 86% for short insertion/deletion calls. For the 21 known breast cancer genes, WES based on low input amount and saliva DNA identified the same set variants in samples from a same patient.Conclusions: Low DNA input amount, as well as saliva DNA, can be used to generate WES data of satisfactory quality.Impact: Our findings support the expansion of WES applications in cancer epidemiologic studies where only low DNA amount or saliva samples are available. Cancer Epidemiol Biomarkers Prev; 24(8); 1207–13. ©2015 AACR.