Human SRMAtlas: A Resource of Targeted Assays to Quantify the Complete Human Proteome.

The ability to reliably and reproducibly measure any protein of the human proteome in any tissue or cell type would be transformative for understanding systems-level properties as well as specific pathways in physiology and disease. Here, we describe the generation and verification of a compendium of highly specific assays that enable quantification of 99.7% of the 20,277 annotated human proteins by the widely accessible, sensitive, and robust targeted mass spectrometric method selected reaction monitoring, SRM. This human SRMAtlas provides definitive coordinates that conclusively identify the respective peptide in biological samples. We report data on 166,174 proteotypic peptides providing multiple, independent assays to quantify any human protein and numerous spliced variants, non-synonymous mutations, and post-translational modifications. The data are freely accessible as a resource at http://www.srmatlas.org/, and we demonstrate its utility by examining the network response to inhibition of cholesterol synthesis in liver cells and to docetaxel in prostate cancer lines.

Evaluation of methods for characterizing the fine particulate matter emissions from aircraft and other diffusion flame combustion aerosol sources.

The U. S. Environmental Protection Agency in collaboration with the U. S. Air Force Arnold Engineering Development Complex conducted the VAriable Response In Aircraft nvPM Testing (VARIAnT) 3 and 4 test campaigns to compare nonvolatile particulate matter (nvPM) emissions measurements from a variety of diffusion flame combustion aerosol sources (DFCASs), including a Cummins diesel engine, a diesel powered generator, two gas turbine start carts, a J85-GE-5 turbojet engine burning multiple fuels, and a Mini-CAST soot generator. The VARIAnT research program was devised to understand reported variability in the ARP6320A sampling system nvPM measurements. The VARIAnT research program has conducted four test campaigns to date with the VARIAnT 3 and 4 campaigns devoted to: (1) assessing the response of three different black carbon mass analyzers to particles of different size, morphology, and chemical composition; (2) characterizing the particles generated by 6 different combustion sources according to morphology, effective density, and chemical composition; and (3) assessing any significant difference between black carbon as determined by the 3 mass analyzers and the total PM determined via other techniques. Results from VARIAnT 3 and 4 campaigns revealed agreement of about 20% between the Micro-Soot Sensor, the Cavity Attenuated Phase Shift (CAPS PMSSA) monitor and the thermal-optical reference method for elemental carbon (EC) mass, independent of the calibration source used. For the LII-300, the measured mass concentrations in VARIAnT 3 fall within 18% and in VARIAnT 4 fall within 27% of the reference EC mass concentration when calibrated on a combustor rig in VARIAnT 3 and on an LGT-60 start cart in VARIAnT 4, respectively. It was also found that the three mass instrument types (MSS, CAPS PMSSA, and LII-300) can exhibit different BC to reference EC ratios depending on the emission source that appear to correlate to particle geometric mean mobility diameter, morphology, or some other parameter associated with particle geometric mean diameter (GMD) with the LII-300 showing a slightly stronger apparent trend with GMD. Systematic differences in LII-300 measured mass concentrations have been reduced by calibrating with a turbine combustion as a particle source (combustor or turbine engine). With respect to the particle size measurements, the sizing instruments (TSI SMPS, TSI EEPS, and Cambustion DMS 500) were found to be in general agreement in terms of size distributions and concentrations with some exceptions. Gravimetric measurements of the total aerosol mass produced by the various DFCAs differed from the reference EC, BC and integrated particle size distribution measured aerosol masses. The measurements of particle size distributions and single particle analysis performed using the miniSPLAT indicated the presence of larger particles (≳150 nm) having more compact morphologies, higher effective density, and a composition dominated by OC and containing ash. This increased large particle fraction is also associated with higher values of single scattering albedo measured by the CAPS PMSSA instrument and higher OC measurements. These measurements indicate gas turbine engine emissions can be a more heterogeneous mix of particle types beyond the original E-31 assumption that engine exit exhaust particles are mainly composed of black carbon.

The Plasma Membrane Monoamine Transporter is Highly Expressed in Neuroblastoma and Functions as an mIBG Transporter.

Neuroblastoma (NB) is a pediatric cancer with low survival rates in high-risk patients. 131I-mIBG has emerged as a promising therapy for high-risk NB and kills tumor cells by radiation. Consequently, 131I-mIBG tumor uptake and retention are major determinants for its therapeutic efficacy. mIBG enters NB cells through the norepinephrine transporter (NET), and accumulates in mitochondria through unknown mechanisms. Here we evaluated the expression of monoamine and organic cation transporters in high-risk NB tumors and explored their relationship with MYCN amplification and patient survival. We found that NB mainly expresses NET, the plasma membrane monoamine transporter (PMAT), and the vesicular membrane monoamine transporter 1/2 (VMAT1/2), and that the expression of these transporters is significantly reduced in MYCN-amplified tumor samples. PMAT expression is the highest and correlates with overall survival in high-risk NB patients without MYCN amplification. Immunostaining showed that PMAT resides intracellularly in NB cells and co-localizes with mitochondria. Using cells expressing PMAT, mIBG was identified as a PMAT substrate. In mitochondria isolated from NB cell lines, mIBG uptake was reduced by ∼50% by a PMAT inhibitor. Together, our data suggest that PMAT is a previously unrecognized transporter highly expressed in NB and could impact intracellular transport and therapeutic response to 131I-mIBG. SIGNIFICANCE STATEMENT: This study identified that plasma membrane monoamine transporter (PMAT) is a novel transporter highly expressed in neuroblastoma and its expression level is associated with overall survival rate in high-risk patients without MYCN amplification. PMAT is expressed intracellularly in neuroblastoma cells, transports meta-iodobenzylguanidine (mIBG) and thus could impact tumor retention and response to 131I-mIBG therapy. These findings have important clinical implications as PMAT could represent a novel molecular marker to help inform disease prognosis and predict response to 131I-mIBG therapy.

The Evolution of Drug Metabolism and Disposition: A Perspective From the Editors.

This article was solicited to commemorate the 50th anniversary of Drug Metabolism and Disposition (DMD) and features perspectives from five former editors spanning the years 1994 to 2020. During that time frame the journal underwent significant changes in manuscript submission and processing as well as multiple generational changes in the composition of the editorial board and associate editors. A constant, however, has been the commitment to be the premier journal for publications of articles in the areas of drug metabolism, absorption, distribution, excretion, and pharmacokinetics. Advances in some of those areas during the past 3 decades have been monumental. Two cases in point involve cytochromes P450 and drug transporters. In 1994 rigorous characterization of human cytochrome P450 enzymes was in its infancy, there were no proven selective inhibitors, and the idea of solving a human P450 X-ray crystal structure was just a fantasy. Likewise, little was known about individual drug transporters. Today, detailed knowledge of individual human P450 enzymes and drug transporters is integral in drug design and drug discovery and in avoiding drug interactions. In the face of these huge advances in knowledge, each editor has been charged with maintaining the caliber and significance of the journal and its financial solvency while serving the needs of individual authors. We present 5 individual perspectives on the challenges and rewards of serving as DMD editor and hope that, by humanizing the job, we will encourage others to assume positions of responsibility in publication of society journals. SIGNIFICANCE STATEMENT: The 5 most recent former editors of DMD describe their experiences and perspectives on the position in the context of constantly changing scientific emphases, technology, and publishing practices. The article offers subscribers, authors, and future editors and editorial board members valuable insights into the inner workings of the journal.

Four Decades of Cytochrome P450 2B Research: From Protein Adducts to Protein Structures and Beyond.

This article features selected findings from the senior author and colleagues dating back to 1978 and covering approximately three-fourths of the 60 years since the discovery of cytochrome P450. Considering the vast number of P450 enzymes in this amazing superfamily and their importance for so many fields of science and medicine, including drug design and development, drug therapy, environmental health, and biotechnology, a comprehensive review of even a single topic is daunting. To make a meaningful contribution to the 50th anniversary of Drug Metabolism and Disposition, we trace the development of the research in a single P450 laboratory through the eyes of seven individuals with different backgrounds, perspectives, and subsequent career trajectories. All co-authors are united in their fascination for the structural basis of mammalian P450 substrate and inhibitor selectivity and using such information to improve drug design and therapy. An underlying theme is how technological advances enable scientific discoveries that were impossible and even inconceivable to prior generations. The work performed spans the continuum from: 1) purification of P450 enzymes from animal tissues to purification of expressed human P450 enzymes and their site-directed mutants from bacteria; 2) inhibition, metabolism, and spectral studies to isothermal titration calorimetry, deuterium exchange mass spectrometry, and NMR; 3) homology models based on bacterial P450 X-ray crystal structures to rabbit and human P450 structures in complex with a wide variety of ligands. Our hope is that humanizing the scientific endeavor will encourage new generations of scientists to make fundamental new discoveries in the P450 field. SIGNIFICANCE STATEMENT: The manuscript summarizes four decades of work from Dr. James Halpert's laboratory, whose investigations have shaped the cytochrome P450 field, and provides insightful perspectives of the co-authors. This work will also inspire future drug metabolism scientists to make critical new discoveries in the cytochrome P450 field.

Biological and behavioral predictors of relative energy intake after acute exercise.

Energy intake in the post-exercise state is highly variable and compensatory eating - i.e., (over-) compensation of the expended energy via increased post-exercise energy intake - occurs in some individuals but not others. We aimed to identify predictors of post-exercise energy intake and compensation. In a randomized crossover design, 57 healthy participants (21.7 [SD = 2.5] years; 23.7 [SD = 2.3] kg/m2, 75% White, 54% female) completed two laboratory-based test-meals following (1) 45-min exercise and (2) 45-min rest (control). We assessed associations between biological (sex, body composition, appetite hormones) and behavioral (habitual exercise via prospective exercise log, eating behavior traits) characteristics at baseline and total energy intake, relative energy intake (intake - exercise expenditure), and the difference between post-exercise and post-rest intake. We found a differential impact of biological and behavioral characteristics on total post-exercise energy intake in men and women. In men, only fasting (baseline) concentrations of appetite-regulating hormones (peptide YY [PYY, ß = 0.88, P < 0.001] and adiponectin [ß = 0.66, P = 0.005] predicted total post-exercise energy intake, while in women, only habitual exercise (ß = -0.44, P = 0.017) predicted total post-exercise energy intake. Predictors of relative intake were almost identical to those of total intake. The difference in energy intake between exercise and rest was associated with VO2peak (ß = -0.45, P = 0.020), fasting PYY (ß = 0.53, P = 0.036), and fasting adiponectin (ß = 0.57, P = 0.021) in men but not women (all P > 0.51). Our results show that biological and behavioral characteristics differentially affect total and relative post-exercise energy intake in men and women. This may help identify individuals who are more likely to compensate for the energy expended in exercise. Targeted countermeasures to prevent compensatory energy intake after exercise should take the demonstrated sex differences into account.

Particle emissions from mobile sources: Discussion of ultrafine particle emissions and definition.

There is no universally agreed upon definition for ultrafine particles (UFP). Commonly used definitions for UFP are either particle number below 100 nm or total particle number, but without an agreed upon lower cut point. For example, a lower cut point of 3 nm compared to 10 nm could result in a substantially higher count. Another definition for UFP is total particle mass but without a commonly agreed upon aerodynamic diameter upper cut point, e.g., below 100 nm, 200 nm, 300 nm, etc. Yet another definition is lung deposited surface area weighted by lung deposition fraction, found mainly in the particle mobility diameter range from 20 to 400 nm. It is clear from these definitions that there are inconsistencies in the way UFP is used and defined in the literature. Sometimes these metrics are well correlated, sometimes not. In this paper we suggest three exposure metrics: UFP-N, UFP-M, and UFP-S, that we believe will add clarity. These metrics represent total number, mass, and surface area below 500 nm, respectively. For surface area and mass, the 500 nm cut point can be either aerodynamic or mobility diameter depending upon measurement methodology. For all metrics, this cut point captures nearly all of the primary particle emissions from mobile sources. Furthermore, UFP-N would include a lower cut point of 3-6 nm and would not require an upper size cut point because there is very little particle number above 500 nm or even above 100 nm. Thus, our definition of UFP-N is consistent with the current definition of ultrafine number except for, importantly, the specification of a lower cut point. These exposure metrics can help facilitate consistency in the characterization of both short- and long-term UFP ambient exposures and associated health effects in epidemiological studies.

Analysis of high-risk pedigrees identifies 11 candidate variants for Alzheimer's disease.

INTRODUCTION: Analysis of sequence data in high-risk pedigrees is a powerful approach to detect rare predisposition variants. METHODS: Rare, shared candidate predisposition variants were identified from exome sequencing 19 Alzheimer's disease (AD)-affected cousin pairs selected from high-risk pedigrees. Variants were further prioritized by risk association in various external datasets. Candidate variants emerging from these analyses were tested for co-segregation to additional affected relatives of the original sequenced pedigree members. RESULTS: AD-affected high-risk cousin pairs contained 564 shared rare variants. Eleven variants spanning 10 genes were prioritized in external datasets: rs201665195 (ABCA7), and rs28933981 (TTR) were previously implicated in AD pathology; rs141402160 (NOTCH3) and rs140914494 (NOTCH3) were previously reported; rs200290640 (PIDD1) and rs199752248 (PIDD1) were present in more than one cousin pair; rs61729902 (SNAP91), rs140129800 (COX6A2, AC026471), and rs191804178 (MUC16) were not present in a longevity cohort; and rs148294193 (PELI3) and rs147599881 (FCHO1) approached significance from analysis of AD-related phenotypes. Three variants were validated via evidence of co-segregation to additional relatives (PELI3, ABCA7, and SNAP91). DISCUSSION: These analyses support ABCA7 and TTR as AD risk genes, expand on previously reported NOTCH3 variant identification, and prioritize seven additional candidate variants.

Dog and owner characteristics predict training success.

Teaching owners how to train their dogs is an important part of maintaining the health and safety of dogs and people. Yet we do not know what behavioral characteristics of dogs and their owners are relevant to dog training or if owner cognitive abilities play a role in training success. The aim of this study is to determine which characteristics of both dogs and owners predict success in completing the American Kennel Club Canine Good Citizen training program. Before the first session of a dog training course, owners completed surveys evaluating the behavior and cognition of their dog and themselves. Additionally, we collected the dogs' initial training levels via behavioral tasks. We then examined what factors predicted whether the dogs passed the Canine Good Citizen test after the class ended. In terms of dog characteristics, we found that, while dog age, sex and neuter status did not predict success, owner-rated levels of disobedience did predict completion of the program. In terms of owner characteristics, owners who scored higher on cognitive measures were more likely to have their dogs complete the program. Finally, dog-owner characteristics such as the time spent training predicted success. Thus, characteristics of the dogs, owners, and how they interact seem to predict training success. These findings suggest that there are some owner, dog, and dog-owner characteristics that can facilitate or hinder dog training.

Assessment of a regulatory measurement system for the determination of the non-volatile particulate matter emissions from commercial aircraft engines.

The SAE International has published Aerospace Information Report (AIR) 6241 which outlined the design and operation of a standardized measurement system for measuring non-volatile particulate matter (nvPM) mass and number emissions from commercial aircraft engines. Prior to this research, evaluation of this system by various investigators revealed differences in nvPM mass emissions measurement on the order of 15-30% both within a single sampling system and between two systems operating in parallel and measuring nvPM mass emissions from the same source. To investigate this issue, the U. S. Environmental Protection Agency in collaboration with the U. S. Air Force's Arnold Engineering Development Complex initiated the VAriable Response In Aircraft nvPM Testing (VARIAnT) research program to compare nvPM measurements within and between AIR-compliant sampling systems used for measuring combustion aerosols generated both by a 5201 Mini-CAST soot generator and a J85-GE-5 turbojet engine burning multiple fuels. The VARIAnT research program has conducted four test campaigns to date. The first campaign (VARIAnT 1) compared two essentially identical commercial versions of the sampling system while the second campaign (VARIAnT 2) compared a commercial system to the custom-designed Missouri University of Science and Technology's North American Reference System (NARS) built to the same specifications. Comparisons of nvPM particle mass (i.e., black carbon), number, and size were conducted in both campaigns. Additionally, the sensitivity to variation in system operational parameters was evaluated in VARIAnT 1. Results from both campaigns revealed agreement of about 12% between the two sampling systems, irrespective of manufacturer, in all aspects except for black carbon determination. The major source of measurement differences (20-70%) was due to low BC mass measurements made by the Artium Technologies LII-300 as compared to the AVL 483 Micro-Soot Sensor, the Aerodyne Cavity Attenuated Phase Shift (CAPS PMSSA) monitor, and the thermal-optical reference method for elemental carbon (EC) determination, which was used as the BC reference.

Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants.

BACKGROUND: Longevity as a phenotype entails living longer than average and typically includes living without chronic age-related diseases. Recently, several common genetic components to longevity have been identified. This study aims to identify additional genetic variants associated with longevity using unique and powerful analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB). METHODS: From an existing biorepository of Utah pedigrees, six independent cousin pairs were selected from four extended pedigrees that exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on two elderly individuals from each pedigree who were either first cousins or first cousins once removed. Rare (<.01 population frequency) variants shared by at least one elderly cousin pair in a region likely to be identical by descent were identified as candidates. Ingenuity Variant Analysis was used to prioritize putative causal variants based on quality control, frequency, and gain or loss of function. The variant frequency was compared in healthy cohorts and in an Alzheimer's disease cohort. Remaining variants were filtered based on their presence in genes reported to have an effect on the aging process, aging of cells, or the longevity process. Validation of these candidate variants included tests of segregation on other elderly relatives. RESULTS: Fifteen rare candidate genetic variants spanning 17 genes shared within cousins were identified as having passed prioritization criteria. Of those variants, six were present in genes that are known or predicted to affect the aging process: rs78408340 (PAM), rs112892337 (ZFAT), rs61737629 (ESPL1), rs141903485 (CEBPE), rs144369314 (UTP4), and rs61753103 (NUP88 and RABEP1). ESPL1 rs61737629 and CEBPE rs141903485 show additional evidence of segregation with longevity in expanded pedigree analyses (p-values = .001 and .0001, respectively). DISCUSSION: This unique pedigree analysis efficiently identified several novel rare candidate variants that may affect the aging process and added support to seven genes that likely contribute to longevity. Further analyses showed evidence for segregation for two rare variants, ESPL1 rs61737629 and CEBPE rs141903485, in the original longevity pedigrees in which they were initially observed. These candidate genes and variants warrant further investigation.

Differential relationship between physical activity and intake of added sugar and nutrient-dense foods: A cross-sectional analysis.

A curvilinear relationship exists between physical activity (PA) and dietary energy intake (EI), which is reduced in moderately active when compared to inactive and highly active individuals, but the impact of PA on eating patterns remains poorly understood. Our goal was to establish the relationship between PA and intake of foods with varying energy and nutrient density. Data from the 2009-2010 United States National Health and Nutrition Examination Survey were used to include a Dietary Screener Questionnaire for estimated intakes of added sugar, fruits and vegetables, whole grains, fiber, and dairy. Participants (n = 4766; 49.7% women) were divided into sex-specific quintiles based on their habitual PA. After adjustment for age, body mass index, household income, and education, intakes were compared between PA quartiles, using the lowest activity quintile (Q1) as reference. Women in the second to fourth quintile (Q2-Q4) consumed less added sugar from sugary foods (+2 tsp/day) and from sweetened beverages (+2 tsp/day; all p < 0.05 vs. Q1). In men, added sugar intake was elevated in the highest activity quintile (Q5: +3 ± 1 tsp/day, p = 0.007 vs. Q1). Fruit and vegetable intake increased (women: Q1-Q4 +0.3 ± 0.1 cup eq/day; p < 0.001; men: Q1-Q3 +0.3 ± 0.1 cup eq/day, p = 0.002) and stagnated in higher quintiles. Dairy intake increased with PA only in men (Q5: +0.3 ± 0.1 cup eq/day, p < 0.001 vs. Q1). Results demonstrate a differential relationship between habitual PA and dietary intakes, whereby moderate but not necessarily highest PA levels are associated with reduced added sugar and increased nutrient-dense food consumption. Future research should examine specific mechanisms of food choices at various PA levels to ensure dietary behaviors (i.e., increased sugary food intake) do not negate positive effects of PA.

Social contact patterns can buffer costs of forgetting in the evolution of cooperation.

Analyses of the evolution of cooperation often rely on two simplifying assumptions: (i) individuals interact equally frequently with all social network members and (ii) they accurately remember each partner's past cooperation or defection. Here, we examine how more realistic, skewed patterns of contact-in which individuals interact primarily with only a subset of their network's members-influence cooperation. In addition, we test whether skewed contact patterns can counteract the decrease in cooperation caused by memory errors (i.e. forgetting). Finally, we compare two types of memory error that vary in whether forgotten interactions are replaced with random actions or with actions from previous encounters. We use evolutionary simulations of repeated prisoner's dilemma games that vary agents' contact patterns, forgetting rates and types of memory error. We find that highly skewed contact patterns foster cooperation and also buffer the detrimental effects of forgetting. The type of memory error used also influences cooperation rates. Our findings reveal previously neglected but important roles of contact pattern, type of memory error and the interaction of contact pattern and memory on cooperation. Although cognitive limitations may constrain the evolution of cooperation, social contact patterns can counteract some of these constraints.

Tumor Dose Response in Yttrium-90 Resin Microsphere Embolization for Neuroendocrine Liver Metastases: A Tumor-Specific Analysis with Dose Estimation Using SPECT-CT.

PURPOSE: To evaluate dose-response relationship in yttrium-90 (90Y) resin microsphere radioembolization for neuroendocrine tumor (NET) liver metastases using a tumor-specific dose estimation based on technetium-99m-labeled macroaggregated albumin (99mTc MAA) single photon emission computed tomography (SPECT)-CT. MATERIALS AND METHODS: Fifty-five tumors (mean size 3.9 cm) in 15 patients (10 women; mean age 57 y) were evaluated. Tumor-specific absorbed dose was estimated using a partition model. Initial (median 2.3 months) follow-up data were available for all tumors; last (median 7.6 months) follow-up data were available for 45 tumors. Tumor response was evaluated using Modified Response Evaluation Criteria in Solid Tumors (mRECIST) on follow-up CT. Tumors with complete or partial response were considered responders. Mean tumor absorbed dose was 231.4 Gy ± 184.3, and mean nontumor liver absorbed dose was 39.0 Gy ± 18.0. RESULTS: Thirty-six (65.5%) and 30 (66.7%) tumors showed response at initial and last follow-up, respectively. Mean absorbed doses in responders and nonresponders at initial and last follow-up were 285.8 Gy ± 191.1 and 128.1 Gy ± 117.1 (P = .0004) and 314.3 Gy ± 195.8 and 115.7 Gy ± 117.4 (P = .0001). Cutoff value of ≥ 191.3 Gy for tumor-specific absorbed dose predicted tumor response with 93% specificity, whereas < 72.8 Gy predicted nonresponse with 100% specificity at last follow-up. Estimated mean absorbed tumor dose per patient was significantly higher in responders versus nonresponders over the follow-up period (224.5 Gy ± 90.3 vs 70.0 Gy ± 28.0; P = .007). CONCLUSIONS: Tumor-specific absorbed dose, estimated with a partition model, was significantly associated with tumor response in NET liver metastases. An estimated dose ≥ 191.3 Gy predicted treatment response with high sensitivity and specificity.

Mass cytometry: a highly multiplexed single-cell technology for advancing drug development.

Advanced single-cell analysis technologies (e.g., mass cytometry) that help in multiplexing cellular measurements in limited-volume primary samples are critical in bridging discovery efforts to successful drug approval. Mass cytometry is the state-of-the-art technology in multiparametric single-cell analysis. Mass cytometers (also known as cytometry by time-of-flight or CyTOF) combine the cellular analysis principles of traditional fluorescence-based flow cytometry with the selectivity and quantitative power of inductively coupled plasma-mass spectrometry. Standard flow cytometry is limited in the number of parameters that can be measured owing to the overlap in signal when detecting fluorescently labeled antibodies. Mass cytometry uses antibodies tagged to stable isotopes of rare earth metals, which requires minimal signal compensation between the different metal tags. This unique feature enables researchers to seamlessly multiplex up to 40 independent measurements on single cells. In this overview we first present an overview of mass cytometry and compare it with traditional flow cytometry. We then discuss the emerging and potential applications of CyTOF technology in the pharmaceutical industry, including quantitative and qualitative deep profiling of immune cells and their applications in assessing drug immunogenicity, extensive mapping of signaling networks in single cells, cell surface receptor quantification and multiplexed internalization kinetics, multiplexing sample analysis by barcoding, and establishing cell ontologies on the basis of phenotype and/or function. We end with a discussion of the anticipated impact of this technology on drug development lifecycle with special emphasis on the utility of mass cytometry in deciphering a drug's pharmacokinetics and pharmacodynamics relationship.

Evolutionary pressures on primate intertemporal choice.

From finding food to choosing mates, animals must make intertemporal choices that involve fitness benefits available at different times. Species vary dramatically in their willingness to wait for delayed rewards. Why does this variation across species exist? An adaptive approach to intertemporal choice suggests that time preferences should reflect the temporal problems faced in a species's environment. Here, I use phylogenetic regression to test whether allometric factors relating to body size, relative brain size and social group size predict how long 13 primate species will wait in laboratory intertemporal choice tasks. Controlling for phylogeny, a composite allometric factor that includes body mass, absolute brain size, lifespan and home range size predicted waiting times, but relative brain size and social group size did not. These findings support the notion that selective pressures have sculpted intertemporal choices to solve adaptive problems faced by animals. Collecting these types of data across a large number of species can provide key insights into the evolution of decision making and cognition.

Radiation-induced liver disease as a mimic of liver metastases at serial PET/CT during neoadjuvant chemoradiation of distal esophageal cancer.

PURPOSE: To determine the frequency and appearance of radiation-induced liver disease on PET/CT in patients undergoing serial imaging during neoadjuvant chemoradiation of distal esophageal cancer. MATERIALS AND METHODS: In this IRB-approved, HIPAA-compliant retrospective analysis, we identified 112 patients with distal esophageal cancer treated by neoadjuvant chemoradiation who had serial PET/CT imaging available for review. Two readers reviewed all studies in consensus and recorded those cases where new foci of visually detectable increased FDG avidity appeared in the liver during therapy. The etiology of such foci was determined from corresponding findings at CT or MRI, by hepatic biopsy during surgery, by characteristic evolution on post-operative imaging, or by a combination of these methods. RESULTS: New foci of FDG avidity developed in the liver during neoadjuvant therapy in 10 of 112 (9%) patients, of whom nine (8%) were determined to have radiation-induced liver disease based on further imaging and/or biopsy and one of whom had developed interval metastatic disease based on biopsy. In the cases of radiation-induced liver disease, the abnormal foci were found only in the caudate and left hepatic lobes, near the primary tumor, while the patient who developed interval metastatic disease had involvement of the inferior right hepatic lobe, remote from the radiation therapy field. CONCLUSION: New foci of increased FDG avidity are commonly seen in the caudate and left hepatic lobes of the liver during neoadjuvant chemoradiation of distal esophageal cancer, and these findings generally reflect radiation-induced liver disease rather than metastatic disease.

Impulsivity as a trait in domestic dogs (Canis familiaris): A systematic review and meta-analysis.

Impulsivity is a critical component of dog (Canis familiaris) behavior that owners often want to curtail. Though studies of dog impulsivity have examined their inability to wait and to inhibit inappropriate behaviors, it is not clear whether impulsivity is a behavioral trait with consistent characteristics across contexts. For this project, we conducted a systematic review and meta-analysis to investigate whether impulsivity exists as a behavioral trait in domestic dogs. Under a preregistered protocol, we processed over 10,000 bibliographic database records to uncover 13 articles with multiple impulsivity tasks assessed in the same subjects. Across 31 pairs of impulsivity tasks, 28 failed to detect a correlation in performance between tasks and three detected a correlation. For 15 correlations of impulsivity tasks with the owner's perception of their dog's impulsivity, 10 were not correlated, while five were correlated. A formal meta-analysis on one pair of tasks (A-not-B task and cylinder task) tested across seven different studies showed no overall correlation between the tasks. Our systematic review and meta-analysis found little indication of consistent relationships between impulsivity levels across tasks for dogs. Therefore, at the moment, we do not have good evidence of impulsivity as a behavioral trait that transfers across contexts, suggesting that perhaps we should focus on the context-specific nature of impulsivity in dogs. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Looking beyond year 1 in the molecular era of pediatric brain tumor diagnosis: confirmatory testing of germline variants found on tumor sequencing.

Purpose: Somatic molecular profiling of pediatric brain tumors aids with the diagnosis and treatment of patients with a variety of high- and low-grade central nervous system neoplasms. Here, we report follow-up targeted germline evaluation for patients with possible germline variants following tumor only testing in the initial year in which somatic molecular testing was implemented at a single institution. Patients and Methods: Somatic testing was completed for all tumors of the central nervous system (CNS) undergoing diagnostic workup at Seattle Children's Hospital during the study period of November 2015 to November 2016. Sequencing was performed in a College of American Pathologists-accredited, Clinical Laboratory Improvements Amendments-certified laboratory using UW-OncoPlex™ assay (version 5), a DNA-based targeted next generation sequencing panel validated to detect genetic alterations in 262 cancer-related genes. We tracked subsequent clinical evaluation and testing on a subgroup of this cohort found to have potential germline variants of interest. Results: Molecular sequencing of 88 patients' tumors identified 31 patients with variants that warranted consideration of germline testing. To date, 19 (61%) patients have been tested. Testing confirmed germline variants for ten patients (31% of those identified for testing), one with two germline variants (NF1 and mosaic TP53). Eight (26%) patients died before germline testing was sent. One patient (13%) has not yet had testing. Conclusion: Clinically validated molecular profiling of pediatric brain tumors identifies patients who warrant further germline evaluation. Despite this, only a subset of these patients underwent the indicated confirmatory sequencing. Further work is needed to identify barriers and facilitators to this testing, including the role of genetic counseling and consideration of upfront paired somatic-germline testing.