Temporal Trends of Great Lakes Legacy Contaminants: Ecological and Biological Considerations Applying the Age-Trend Model.

The USEPA Great Lakes Fish Monitoring and Surveillance Program (GLFMSP) has been monitoring top predator lake trout and walleye contaminant concentrations since the early 1970s. Our research revealed that select legacy contaminant groups (∑PCBs, ∑DDTs, ∑chlordanes, and ∑5PBDEs) have similar t1/2 and k2 values across the Great Lakes, with the exception of both Lake Erie sites and the Lake Superior─Keweenaw Point site. The slower halving times determined at both Lake Erie sites are consistent with legacy contaminant remobilization due to extreme weather climate effects and past remedial actions on the Detroit River, whereas the Lake Superior─Keweenaw Point site demonstrates contaminant halving times approaching the exponential minimum. Overall, Great Lakes select contaminant groupings have decreased between 25.8 and 97.9% since 2004. An age-normalized Great Lakes Contaminant Index (GLCI) was devised, indicating both Lake Michigan sites as the most highly impacted. The mean absolute deviation statistic was applied, documenting the need to age-correct contaminant trends due to highly variable age profiles. With the noted exceptions, the uniformity of age-corrected trend modeling suggests that a combination of the fundamental biological and physicochemical mechanisms of natural contaminant sequestration, declining dissolved water concentrations, accumulation/metabolism/depuration, and the overall reduction of legacy contaminant loading are driving the generally consistent rates of declines in the Great Lakes. Many of the biological and ecological stressors currently associated with climate change appear to be accounted for by the age-trend model.

Polychlorinated Naphthalenes across the Great Lakes: Lake Trout and Walleye Concentrations, Trends, and TEQ Assessment-2004-2018.

Polychlorinated naphthalenes (PCNs) were measured in lake trout and walleye over the period 2004-2018, utilizing isotope dilution techniques with high-resolution gas chromatography/high-resolution mass spectrometry to assess concentrations and toxic equivalence (TEQ). An age-trend model was applied to mitigate the effect of a changing lake trout age structure. Most Great Lakes Fish Monitoring and Surveillance Program sampling sites demonstrated significant half-life and percent decreases for lake trout total PCNs and total TEQ over the 2004-2018 period, the exceptions being Lake Erie lake trout and walleye which illustrated increasing concentrations. Great Lakes total PCN concentrations ranged between 5701 and 100 pg/g ww, whereas total PCN TEQ concentrations ranged between 8.89 and 0.13 pg-TEQ/g ww. Based on the average number of chlorines per naphthalene, we determined that the overall lake trout and walleye PCN congener distribution has significantly shifted to a lower-chlorinated composition in the Great Lakes (5.33 to 4.48 Cl/CN) and has resulted in a substantial 59.1% reduction of the overall total PCN TEQ burden. A prominent PCN concentration trend breakpoint was observed in Lake Ontario lake trout over the 2012-2016 period likely associated with hazardous waste cleanups, channel dredging, and spoils disposal in the Detroit River and western-basin of Lake Erie.

The fundamental thermodynamic bounds on finite models.

The minimum heat cost of computation is subject to bounds arising from Landauer's principle. Here, I derive bounds on finite modeling-the production or anticipation of patterns (time-series data)-by devices that model the pattern in a piecewise manner and are equipped with a finite amount of memory. When producing a pattern, I show that the minimum dissipation is proportional to the information in the model's memory about the pattern's history that never manifests in the device's future behavior and must be expunged from memory. I provide a general construction of a model that allows this dissipation to be reduced to zero. By also considering devices that consume or effect arbitrary changes on a pattern, I discuss how these finite models can form an information reservoir framework consistent with the second law of thermodynamics.

Extreme Dimensionality Reduction with Quantum Modeling.

Effective and efficient forecasting relies on identification of the relevant information contained in past observations-the predictive features-and isolating it from the rest. When the future of a process bears a strong dependence on its behavior far into the past, there are many such features to store, necessitating complex models with extensive memories. Here, we highlight a family of stochastic processes whose minimal classical models must devote unboundedly many bits to tracking the past. For this family, we identify quantum models of equal accuracy that can store all relevant information within a single two-dimensional quantum system (qubit). This represents the ultimate limit of quantum compression and highlights an immense practical advantage of quantum technologies for the forecasting and simulation of complex systems.

Embracing the complexity of modifiable risk reduction: A registry of modifiable risks for 0-12 month infants.

Despite relatively high medical expenditures, the United States performs poorly on population health indicators relative to many other countries. A key step in addressing this situation involves determining impactful and cost-effective interventions for at-risk populations. This requires an understanding of medical, social, behavioral health and safety domains of risk. Of immediate interest are those risks that are modifiable at the individual and family levels and could be reduced through intervention and broader care coordination efforts. Unfortunately, a comprehensive list of such risks does not exist in the published literature. Using multiple interrelated methods, including clinical, social, and care coordination experience, expert elaboration and validation, and reviews of existing assessments and literature, we present what we believe to be the most comprehensive listing of individually modifiable risk factors (IMRFs), relevant to care coordination, available for individuals aged 0-12 months. The list addresses IMRFs within four broad domains of risk (medical, social, behavioral health, and safety). Comprehensive risk registries such as the one presented here can enhance our collective efforts to identify and mitigate risks for specific populations. Such registries can also support research to build understandings of the impact of risks, individually and in interconnected signature combinations. The risk registry presented here and the enhanced understandings flowing from it may yield useful insights for clinicians, social service providers and researchers seeking a whole person approach to care, as well as for payers and policymakers seeking to enable health policy and payment reforms to improve population health.

Concentrations, toxic equivalence, and age-corrected trends of legacy organic contaminants in Lake Champlain lake trout: 2012-2018.

Our study is the first comprehensive, multi-year assessment of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), organochlorine pesticides (OCPs), polychlorinated naphthalenes (PCNs), polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans (PCDD/Fs) lake trout concentrations and trends in Lake Champlain (LC). Lake trout whole-fish, fillets, and eggs were collected over the 2012-2018 study period. Total PCB concentrations (395.7 ng/g wet weight (ww)) were the highest average concentration of any contaminant grouping reported in this study. Whole-fish lake trout modeling revealed highly significant (p < 0.05) log-linear correlations for all dioxin-like contaminants measured. Overall contaminant decreases for the 2012-2018 period ranged from 20.9% (total PCNs) to 39.3% (2378-TCDD). Contaminant decreases for total PCBs and total-5-PBDEs were 30.9% and 48.3%, respectively. Of particular significance were the measured total PBDE concentrations (74.3 ng/g ww) found in LC whole-fish lake trout. Log-linear forecasting indicates that whole-fish lake trout TEQs will be below the guidelines protective of wildlife thresholds during the periods 2035-2047 (TRGbird) and 2062-2088 (TRGmammal). Based on current USEPA guidelines, all lake trout fillets from Lake Champlain analyzed for this study exceed the human health cancer screening value of 0.15 pg-TEQ/g ww by a substantial margin (average = 8.61 pg-TEQ/g ww). Dioxin-like trend data collected for Lake Champlain indicates that the mechanisms of contaminant uptake, trends, and yearly percent decline reflect those found in the Great Lakes.

Do Subspecialists Ask About and Refer Families with Psychosocial Concerns? A Comparison with General Pediatricians.

Objectives Calls for pediatricians to tend to children's psychosocial concerns have existed for decades because they are known to negatively impact child health. Children with chronic illnesses frequently have child- and family-level psychosocial concerns that complicate the care provided by their pediatric subspecialists. This study compares pediatricians who exclusively practice general pediatrics with subspecialists regarding their inquiring/screening and referring for psychosocial concerns. Physician and practice characteristics associated with these behaviors were examined. Methods We conducted a cross-sectional study using the 2013 American Academy of Pediatrics Periodic Survey of Fellows. Respondents included 304 pediatricians who exclusively practice general pediatrics and 147 subspecialists. The primary analysis compared the current practices of generalists vs. subspecialists with regard to inquiring/screening and referring children with 10 different psychosocial concerns. Covariates included socio-demographics, practice characteristics, and training experiences. Weighted univariate, bivariate and multivariable analyses were performed. Results Less than half of all pediatricians in the sample reported routinely inquiring/screening for most psychosocial concerns, and 2/3 of subspecialists failed to routinely inquire/screen for most of these conditions. Pediatricians who practice general pediatrics exclusively were more likely to inquire/screen (incident rate ratio (IRR) 1.41, p < .05) and refer (IRR 1.59, p < .001) for a greater number of psychosocial concerns than subspecialists, after adjusting for provider and practice characteristics. Having attended a child or adolescent mental health (MH) lecture/conference in the past 2 years was also related to inquiring/screening (IRR 1.24, p < .05). Conclusions Pediatricians infrequently inquire/screen and refer psychosocial concerns, with subspecialists addressing these concerns even less frequently.

Association Between Health Literacy and Parental Self-Efficacy among Parents of Newborn Children.

OBJECTIVE: To determine whether health literacy was associated with parental self-efficacy in a diverse sample of parents of newborns. We hypothesized that parents with lower health literacy would have lower parental self-efficacy. STUDY DESIGN: We conducted a cross-sectional analysis of baseline surveys from 253 English and Spanish speaking parents >18 years old with newborns <28 days old enrolled in a trial testing a multisite primary care-based parenting intervention. Surveys assessed parental, child, and environmental characteristics, and used validated instruments to measure health literacy and parental self-efficacy (total and 4 subtypes). Bivariate analyses identified parental, child, and environmental characteristics associated with parental self-efficacy. Multivariable linear regression models examined the associations between health literacy and parental self-efficacy, adjusting for covariates. RESULTS: Parents (median age, 29 years) were 92.1% female, 54.5% black/African American, and 29.6% Hispanic/Latino. More than one-half (58.9%) had completed some college education or more, 49.0% spoke mostly English, and 16.2% had low health literacy. In bivariate analyses, parental self-efficacy was significantly lower in parents with fewer household residents. In multivariable analyses, parents with low compared with high health literacy had significantly lower parental self-efficacy scores (total and 4 subtypes including caretaking procedures, evoking behaviors, reading behaviors and signaling, and situational beliefs). CONCLUSIONS: Lower health literacy was associated with lower parental self-efficacy in parents of newborns. To maximize impact on positive parenting behaviors and child outcomes, interventions assisting parents with low parental self-efficacy should consider strategies to address low health literacy.

Age-Corrected Trends and Toxic Equivalence of PCDD/F and CP-PCBs in Lake Trout and Walleye from the Great Lakes: 2004-2014.

Our research reports polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and coplanar polychlorinated biphenyls (CP-PCBs) concentrations and age-corrected trends for lake trout and walleye in the Great Lakes over the 2004-2014 period. We determined that age-contaminant corrections are required to accurately report contaminant trends due to significant lake trout age structure changes. The age-trend model (ATM) described here uses a lake-specific age-contaminant regression to mitigate the effect of a fluctuating lake trout age structure to directly improve the log-linear regression model. ATM results indicate that half-life (t1/2) and percent decreases for PCDD/Fs, CP-PCBs, and toxic equivalence (TEQ) (average -56 to 70%) were fairly uniform and consistent across the Great Lakes over the 2004-2014 period. The vast majority of TEQ associated with all Great Lakes lake trout and walleye samples is due to the nonortho CP-PCBs (average = 79%) as compared with PCDD/Fs (average = 21%). On average, CP-PCB_126 individually accounted for over 95% of the total CP-PCB TEQ. A retrospective analysis (1977-2014) of 2378-TCDF and 2378-TCDD raw concentrations in Lake Ontario lake trout revealed decreases of 94% and 96%, respectively. Tissue residue guidelines for wildlife protection based on lake trout and walleye total TEQ were uniformly exceeded in all the Great Lakes.

Guaranteed energy-efficient bit reset in finite time.

Landauer's principle states that it costs at least kBTln2 of work to reset one bit in the presence of a heat bath at temperature T. The bound of kBTln2 is achieved in the unphysical infinite-time limit. Here we ask what is possible if one is restricted to finite-time protocols. We prove analytically that it is possible to reset a bit with a work cost close to kBTln2 in a finite time. We construct an explicit protocol that achieves this, which involves thermalizing and changing the system's Hamiltonian so as to avoid quantum coherences. Using concepts and techniques pertaining to single-shot statistical mechanics, we furthermore prove that the heat dissipated is exponentially close to the minimal amount possible not just on average, but guaranteed with high confidence in every run. Moreover, we exploit the protocol to design a quantum heat engine that works near the Carnot efficiency in finite time.

Atmospheric concentrations and potential sources of dioxin-like contaminants to Acadia National Park.

Acadia National Park (ANP) is located on Mt. Desert Island, ME on the U.S. Atlantic coast. ANP is routinely a top-ten most popular National Park with over four million visits in 2022. The overall contribution and negative effects of long-range atmospheric transport and local sources of dioxin-like contaminants endangering natural and wildlife resources is unknown. Dioxin-like (DL) contaminants polychlorinated dibenzo-p-dioxins (∑PCDD) and polychlorinated dibenzofurans (∑PCDF), non-ortho coplanar PCBs (∑CP4), and polychlorinated naphthalenes (∑PCNs) were measured at the McFarland Hill air monitoring station (44.37°N, 68.26°W). On a mass/volume basis, total PCNs averaged 90.9 % (788 fg/m3) of DL contaminants measured annually, with 92.9 % of the collected total in the vapor-phase. Alternatively, total dioxin/furans (∑PCDD/Fs) represented 71.6 % of the total toxic equivalence (∑TEQ) (1.018 fg-TEQ/m3), with 69.7 % in the particulate-phase. Maximum concentrations measured for individual sampling events for ∑PCDD/F, ∑CP4, and ∑PCN were 159 (winter), 139 (summer), and 2100 (autumn), fg/m3 respectively. Whereas the maximum ∑TEQ concentrations for individual sampling events for ∑PCDD/F, ∑CP4, and ∑PCN were 2.8 (autumn), 0.38 (summer), and 0.71 (autumn), fg-TEQ/m3 respectively. Pearson correlations were calculated for ∑PCDD/Fs and ∑PCN particulate/vapor-phase air concentrations and PM2.5 wood smoke "indicator" species. The most significant correlations were observed in autumn for particulate-phase ∑PCDD/Fs suggesting a relationship between visitation-generated combustion sources (campfires and/or waste burning) or climate-change mediated forest fires. Significant Clausius-Clapeyron (C-C) correlations observed for particulate-phase ∑PCDDs (r2 = 0.567) as ambient temperatures decreased suggests a connection between localized domestic heating sources or visitor-based burning of wood/trash resources. Alternatively, highly significant C-C vapor-phase ∑CP4-PCBs correlations (r2 = 0.815) implies that the majority of ∑CP4-PCB loading to ANP is from long-range atmospheric transport processes. Based on these findings, Acadia National Park should be classified as a remote site with minor depositional impacts from ∑PCDD/Fs, ∑CP4-PCBs, and ∑PCN atmospheric transport or local diffuse sources.

An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2R206H. In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2R206H inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2R206H binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2R206H with high affinity, inhibiting signaling from ALK2R206H and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2R206H mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2R206H mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2R206H mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.

Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma.

Background and Aims: Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as a driver of FLC pathogenesis. We aimed to assess whether FLC tumors maintain dependency on this gene fusion and determine if PRKACA is a viable therapeutic target. Methods: FLC patient-derived xenograft (PDX) shRNA cell lines were implanted subcutaneously into female NOD-SCID mice and tumors were allowed to develop prior to randomization to doxycycline (to induce knockdown) or control groups. Tumor development was assessed every 2 days. To assess the effect of treatment with novel selective PRKACA small molecule kinase inhibitors, BLU0588 and BLU2864, FLC PDX tumor cells were implanted subcutaneously into NOD-SCID mice and tumors allowed to develop. Mice were randomized to treatment (BLU0588 and BLU2864, orally, once daily) or control groups and tumor size determined as previously. Results: Knockdown of DNAJB1-PRKACA reversed a FLC-specific gene signature and reduced PDX tumor growth in mice compared to the control group. Furthermore, FLC PDX tumor growth was significantly reduced with BLU0588 and BLU2864 treatment vs control (P = .003 and P = .0005, respectively). Conclusion: We demonstrated, using an inducible knockdown and small molecule approaches, that FLC PDX tumors were dependent upon DNAJB1-PRKACA fusion activity. In addition, this study serves as a proof-of-concept that PRKACA is a viable therapeutic target for FLC and warrants further investigation.

Toward Measurement for a Whole Child Health Policy: Validity and National and State Prevalence of the Integrated Child Risk Index.

OBJECTIVE: To develop, validate and estimate national and across state prevalence on a multidimensional index that assesses the complex medical, social, and relational health risks experienced by United States children. METHODS: Data from the National Survey of Children's Health were used to construct the Integrated Child Risk Index (ICRI) which includes medical health risk (MHR), social health risk (SHR) and relational health risk (RHR) domains. Confirmatory factor analysis and logistic regression analyses were employed to assess construct and predictive validity. Validity outcomes were child flourishing, school engagement/readiness, emergency room utilization and forgone care. RESULTS: Confirmatory factor analysis confirmed the ICRI 3-domain structure and greater correlation between MHR and RHR than MHR and SHR. Logistic regressions confirmed strong predictive validity of the ICRI for all study outcomes and ICRI scoring approaches. Nearly two-thirds of children (64.3%) with MHR also experienced SHR and/or RHR. Nearly one-third of United States children experienced risks on 2 or more ICRI domains and 15% of publicly insured children had risks on all domains (16.2%; 9.0%-25.7% across states). Significant variations were observed across states and by age, race/ethnicity, health insurance and household income. CONCLUSIONS: The ICRI is a valid national and state level index associated with children's flourishing and educational preparedness and emergency and forgone care. National child health policies and Medicaid risk stratification and payment models should consider children's RHR in addition to SHR and MHR. Results call for integrated systems of care with the capacity to address medical, social and relational health risks and promote well-being. Substate and clinical applications require research.

Social and Relational Health Risks and Common Mental Health Problems Among US Children: The Mitigating Role of Family Resilience and Connection to Promote Positive Socioemotional and School-Related Outcomes.

Nearly 70% (67.6%) of US children with mental, emotional, and behavioral problems (MEB) experienced significant social health risks (SHR) and/or relational health risks (RHR). Shifts are needed in child mental health promotion, prevention, diagnosis, and treatment to address both RHR and SHR. Public health approaches are needed that engage families, youth, and the range of child-serving professionals in collaborative efforts to prevent and mitigate RHR and SHR and promote positive mental health at a community level. Building strong family resilience and connection may improve SR and, in turn, academic and social outcomes among all US children with or without MEB.

Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer.

While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound 30) is a potent, reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.

The discovery of benzanilides as c-Met receptor tyrosine kinase inhibitors by a directed screening approach.

A directed screen of a relatively small number of compounds, selected for kinase ATP pocket binding potential, yielded a novel series of hit compounds (1). Hit explosion on two binding residues identified compounds 27 and 43 as the best leads for an optimization program having reduced secondary metabolism, as measured by in vitro rat hepatocytes incubation, leading to oral bio-availability. Structure-activity relationships and molecular modeling have suggested a binding mode for the most potent inhibitor 12.

Preventing Childhood Toxic Stress: Partnering With Families and Communities to Promote Relational Health.

By focusing on the safe, stable, and nurturing relationships (SSNRs) that buffer adversity and build resilience, pediatric care is on the cusp of a paradigm shift that could reprioritize clinical activities, rewrite research agendas, and realign our collective advocacy. Driving this transformation are advances in developmental sciences as they inform a deeper understanding of how early life experiences, both nurturing and adverse, are biologically embedded and influence outcomes in health, education, and economic stability across the life span. This revised policy statement on childhood toxic stress acknowledges a spectrum of potential adversities and reaffirms the benefits of an ecobiodevelopmental model for understanding the childhood origins of adult-manifested disease and wellness. It also endorses a paradigm shift toward relational health because SSNRs not only buffer childhood adversity when it occurs but also promote the capacities needed to be resilient in the future. To translate this relational health framework into clinical practice, generative research, and public policy, the entire pediatric community needs to adopt a public health approach that builds relational health by partnering with families and communities. This public health approach to relational health needs to be integrated both vertically (by including primary, secondary, and tertiary preventions) and horizontally (by including public service sectors beyond health care). The American Academy of Pediatrics asserts that SSNRs are biological necessities for all children because they mitigate childhood toxic stress responses and proactively build resilience by fostering the adaptive skills needed to cope with future adversity in a healthy manner.

Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations.

Recent clinical data indicates that the emergence of mutant drug-resistant kinase alleles may be particularly relevant for targeted kinase inhibitors. In order to explore how different classes of targeted therapies impact upon resistance mutations, we performed EGFR (epidermal-growth-factor receptor) resistance mutation screens with erlotinib, lapatinib and CI-1033. Distinct mutation spectra were generated with each inhibitor and were reflective of their respective mechanisms of action. Lapatinib yielded the widest variety of mutations, whereas mutational variability was lower in the erlotinib and CI-1033 screens. Lapatinib was uniquely sensitive to mutations of residues located deep within the selectivity pocket, whereas mutation of either Gly(796) or Cys(797) resulted in a dramatic loss of CI-1033 potency. The clinically observed T790M mutation was common to all inhibitors, but occurred with varying frequencies. Importantly, the presence of C797S with T790M in the same EGFR allele conferred complete resistance to erlotinib, lapatinib and CI-1033. The combination of erlotinib and CI-1033 effectively reduced the number of drug-resistant clones, suggesting a possible clinical strategy to overcome drug resistance. Interestingly, our results also indicate that co-expression of ErbB2 (v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2) has an impact upon the EGFR resistance mutations obtained, suggesting that ErbB2 may play an active role in the acquisition of drug-resistant mutations.

Trends of polychlorinated dioxins, polychlorinated furans, and dioxin-like polychlorinated biphenyls in Chinook and Coho salmonid eggs from a Great Lakes tributary.

Eggs from mature Chinook (Oncorhynchus tshawytscha) and Coho (Oncorhynchus kisutch) salmon were collected between 2004 and 2014 from the Salmon River fish hatchery in Altmar, New York. The egg samples were analyzed for seventeen polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), as well as four dioxin-like polychlorinated biphenyls (DL-PCBs) using USEPA methods 1613 and 1668. Salmonid eggs were chosen as a tissue of interest since salmon feed at all trophic levels of the food web as they grow, and spawn in a narrow range of ages providing consistent, representative, and temporal samples of contaminant exposure. First-order decay models indicate decreasing trends for all select contaminants in both species, expressed by a toxic equivalence (TEQ) half-life (t1/2) of 11 years in Chinook and Coho eggs. No significant statistical difference in contaminant elimination rates were noted between species. TEQ elimination rates for Coho and Chinook eggs were not significantly different (p > 0.05) when compared with published Lake Ontario whole-fish lake trout elimination rates. Our research demonstrates that salmonid eggs are an effective means to assess PCDD, PCDF, and DL-PCB exposures and long-term trends in the Great Lakes.