Deleterious inflammation is a primary feature of breast cancer. Accumulating evidence demonstrates that macrophages, the most abundant leukocyte population in mammary tumors, have a critical role at ...each stage of cancer progression. Such tumor-associated macrophages facilitate neoplastic transformation, tumor immune evasion and the subsequent metastatic cascade. Herein, we discuss the dynamic process whereby molecular and cellular features of the tumor microenvironment act to license tissue-repair mechanisms of macrophages, fostering angiogenesis, metastasis and the support of cancer stem cells. We illustrate how tumors induce, then exploit trophic macrophages to subvert innate and adaptive immune responses capable of destroying malignant cells. Finally, we discuss compelling evidence from murine models of cancer and early clinical trials in support of macrophage-targeted intervention strategies with the potential to dramatically reduce breast cancer morbidity and mortality.
Immunization education for physicians-in-training is crucial to address vaccine concerns in clinical practice. Vaccine education is not standardized across residency programs. The Collaboration for ...Vaccination Education and Research (CoVER) team developed an online curriculum for pediatric (Peds) and family medicine (FM) residents.
A cluster randomized controlled trial (RCT) was performed during the 2017–2018 academic year to evaluate the CoVER curriculum. A convenience sample of residency institutions were randomly allocated to the intervention or control group, with stratification by residency type. The intervention, the CoVER curriculum, consisted of four online modules and an in-person training guide. Control sites continued with their standard vaccine education. Pre-intervention and post-intervention surveys were emailed to residents in both groups. The primary outcomes compared between groups were changes in “vaccine knowledge,” “vaccine attitudes/hesitancy,” and “self-confidence” in immunization communication. The team assessing outcomes was unblinded to assignments. Hierarchical general linear model was used to adjust for residency type and residency year; residency site was modeled as a random effect.
Overall, 1444 residents from 31 residency programs were eligible to participate (734 intervention, 710 control). The pre-intervention response rate was 730 (51%) and post-intervention was 526 (36%). Average knowledge scores increased from pre-intervention (control 53%; CoVER 53%) to post-intervention (control 58%; CoVER 60%). Increases in vaccine knowledge among FM residents were greater for CoVER compared to controls (p = 0.041). Vaccine hesitancy was more common among FM (23%) than Peds (10%) residents. In all three residency years, residents in the CoVER group showed greater increases in self-confidence in ability to discuss vaccines with parents/patients (p < 0.03) compared to control group.
The CoVER curriculum is an effective model to standardize immunization education of physicians-in-training. This RCT demonstrated the effectiveness of the CoVER curriculum to improve resident confidence in their ability to discuss vaccines with parents and patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To determine whether population-specific normative data should be employed when screening neurocognitive functioning as part of physician fitness for duty evaluations. If so, to provide such norms ...based on the evidence currently available.
A comparison of published data from four sources was analyzed. Data from the two physician samples were then entered into a meta-analysis to obtain full information estimates and generate provisional norms for physicians.
Two-way analysis of variance (Study x Index) revealed a significant main effect and an interaction. Results indicate differences in mean levels of performance and standard deviation for physicians.
Reliance on general population normative data results in under-identification of potential neuropsychological difficulties. Population specific normative data are needed to effectively evaluate practicing physicians.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although somatic cell activation of the embryonic stem cell (ESC) pluripotency factor OCT4 has been reported, this previous work has been controversial and has not demonstrated a functional role for ...OCT4 in somatic cells. Here we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 in Apoe(-/-) mice resulted in increased lesion size and changes in lesion composition that are consistent with decreased plaque stability, including a thinner fibrous cap, increased necrotic core area, and increased intraplaque hemorrhage. Results of SMC-lineage-tracing studies showed that these effects were probably the result of marked reductions in SMC numbers within lesions and SMC investment within the fibrous cap, which may result from impaired SMC migration. The reactivation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was hypoxia inducible factor-1α (HIF-1α, encoded by HIF1A) and Krüppel-like factor-4 (KLF4)-dependent. These results provide the first direct evidence that OCT4 has a functional role in somatic cells, and they highlight the potential role of OCT4 in normal and diseased somatic cells.
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IJS, NUK, SBMB, UL, UM, UPUK
Depression affects women nearly twice as often as men, but the neurobiological underpinnings of this discrepancy are unclear. Preclinical studies in male mice suggest that activity of ventral ...hippocampus (vHPC) neurons projecting to the nucleus accumbens (NAc) regulates mood-related behavioral responses to stress. We sought to characterize this circuit in both sexes and to investigate its role in potential sex differences in models of depression.
We used male and female adult C57BL/6J mice in the subchronic variable stress model to precipitate female-specific reduction in sucrose preference and performed gonadectomies to test the contributions of gonadal hormones to this stress response. In addition, ex vivo slice electrophysiology of transgenic Cre-inducible Rosa-eGFP-L10a mice in combination with retrograde viral tracing to identify circuits was used to test contributions of gonadal hormones to sex differences in vHPC afferents. Finally, we used an intersecting viral DREADD (designer receptor exclusively activated by designer drugs) strategy to manipulate vHPC-NAc excitability directly in awake behaving mice.
We show a testosterone-dependent lower excitability in male versus female vHPC-NAc neurons and corresponding testosterone-dependent male resilience to reduced sucrose preference after subchronic variable stress. Importantly, we show that long-term DREADD stimulation of vHPC-NAc neurons causes decreased sucrose preference in male mice after subchronic variable stress, whereas DREADD inhibition of this circuit prevents this effect in female mice.
We demonstrate a circuit-specific sex difference in vHPC-NAc neurons that is dependent on testosterone and causes susceptibility to stress in female mice. These data provide a substantive mechanism linking gonadal hormones to cellular excitability and anhedonia—a key feature in depressive states.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Virus neutralization by antibodies is an important prognostic factor in many viral diseases. To easily and rapidly measure titers of neutralizing antibodies in serum or plasma, we developed ...pseudovirion particles composed of the spike glycoprotein of SARS-CoV-2 incorporated onto murine leukemia virus capsids and a modified minimal murine leukemia virus genome encoding firefly luciferase. This assay design is intended for use in laboratories with biocontainment level 2 and therefore circumvents the need for the biocontainment level 3 that would be required for replication-competent SARS-CoV-2 virus. To validate the pseudovirion assay, we set up comparisons with other available antibody tests including those from Abbott, Euroimmun and Siemens, using archived, known samples.
11 out of 12 SARS-CoV-2-infected patient serum samples showed neutralizing activity against SARS-CoV-2-spike pseudotyped MLV viruses, with neutralizing titers-50 (NT
) that ranged from 1:25 to 1:1,417. Five historical samples from patients hospitalized for severe influenza infection in 2016 tested negative in the neutralization assay (NT
< 25). Three serum samples with high neutralizing activity against SARS-CoV-2/MLV pseudoviruses showed no detectable neutralizing activity (NT
< 25) against SARS-CoV-1/MLV pseudovirions. We also compared the semiquantitative Siemens SARS-CoV-2 IgG test, which measures binding of IgG to recombinantly expressed receptor binding domain of SARS-CoV-2 spike glycoprotein with the neutralization titers obtained in the pseudovirion assay and the results show high concordance between the two tests (R
= 0.9344).
SARS-CoV-2 spike/MLV pseudovirions provide a practical means of assessing neutralizing activity of antibodies in serum or plasma from infected patients under laboratory conditions consistent with biocontainment level 2. This assay offers promise also in evaluating immunogenicity of spike glycoprotein-based candidate vaccines in the near future.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human activities have doubled the pre-industrial supply of reactive nitrogen on Earth, and future rates of increase are expected to accelerate. Yet little is known about the capacity of the biosphere ...to buffer increased nitrogen influx. Past changes in global ecosystems following deglaciation at the end of the Pleistocene epoch provide an opportunity to understand better how nitrogen cycling in the terrestrial biosphere responded to changes in carbon cycling. We analysed published records of stable nitrogen isotopic values (δ(15)N) in sediments from 86 lakes on six continents. Here we show that the value of sedimentary δ(15)N declined from 15,000 years before present to 7,056 ± 597 years before present, a period of increasing atmospheric carbon dioxide concentrations and terrestrial carbon accumulation. Comparison of the nitrogen isotope record with concomitant carbon accumulation on land and nitrous oxide in the atmosphere suggests millennia of declining nitrogen availability in terrestrial ecosystems during the Pleistocene-Holocene transition around 11,000 years before present. In contrast, we do not observe a consistent change in global sedimentary δ(15)N values during the past 500 years, despite the potential effects of changing temperature and nitrogen influx from anthropogenic sources. We propose that the lack of a single response may indicate that modern increases in atmospheric carbon dioxide and net carbon sequestration in the biosphere have the potential to offset recent increased supplies of reactive nitrogen in some ecosystems.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acts of extraordinary, costly altruism, in which significant risks or costs are assumed to benefit strangers, have long represented a motivational puzzle. But the features that consistently ...distinguish individuals who engage in such acts have not been identified. We assess six groups of real-world extraordinary altruists who had performed costly or risky and normatively rare (<0.00005% per capita) altruistic acts: heroic rescues, non-directed and directed kidney donations, liver donations, marrow or hematopoietic stem cell donations, and humanitarian aid work. Here, we show that the features that best distinguish altruists from controls are traits and decision-making patterns indicating unusually high valuation of others' outcomes: high Honesty-Humility, reduced Social Discounting, and reduced Personal Distress. Two independent samples of adults who were asked what traits would characterize altruists failed to predict this pattern. These findings suggest that theories regarding self-focused motivations for altruism (e.g., self-enhancing reciprocity, reputation enhancement) alone are insufficient explanations for acts of real-world self-sacrifice.
Emerging evidence shows correlation between the presence of neutralization antibodies (nAbs) and protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently ...available commercial serology assays lack the ability to specifically identify nAbs. An enzyme-linked immunosorbent assay-based nAb assay (GenScript cPass neutralization antibody assay) has recently received emergency use authorization from the Food and Drug Administration.
To evaluate the performance characteristics of this assay and compare and correlate it with the commercial assays that detect SARS-CoV-2-specific immunoglobulin G (IgG).
Specimens from SARS-COV-2 infected patients (n = 124), healthy donors obtained prepandemic (n = 100), and patients with non-coronavirus disease 2019 (COVID-19) respiratory infections (n = 92) were analyzed using this assay. Samples with residual volume were also tested on 3 commercial serology platforms (Abbott, Euroimmun, Siemens). Twenty-eight randomly selected specimens from patients with COVID-19 and 10 healthy controls were subjected to a plaque reduction neutralization test.
The cPass assay exhibited 96.1% (95% CI, 94.9%-97.3%) sensitivity (at >14 days post-positive PCR), 100% (95% CI, 98.0%-100.0%) specificity, and zero cross-reactivity for the presence of non-COVID-19 respiratory infections. When compared with the plaque reduction assay, 97.4% (95% CI, 96.2%-98.5%) qualitative agreement and a positive correlation (R2 = 0.76) was observed. Comparison of IgG signals from each of the commercial assays with the nAb results from plaque reduction neutralization test/cPass assays displayed greater than 94.7% qualitative agreement and correlations with R2 = 0.43/0.68 (Abbott), R2 = 0.57/0.85 (Euroimmun), and R2 = 0.39/0.63 (Siemens), respectively.
The combined data support the use of cPass assay for accurate detection of the nAb response. Positive IgG results from commercial assays associated reasonably with nAbs presence and can serve as a substitute.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely ...understood, hindering development of novel treatments. Because of its projections to brain regions regulating reward and anxiety, the ventral hippocampus is uniquely poised to translate the experience of stress into altered brain function and pathological mood, though the cellular and molecular mechanisms of this process are not fully understood. Here, we use a novel method of circuit-specific gene editing to show that the transcription factor ΔFosB drives projection-specific activity of ventral hippocampus glutamatergic neurons causing behaviorally diverse responses to stress. We establish molecular, cellular, and circuit-level mechanisms for depression- and anxiety-like behavior in response to stress and use circuit-specific gene expression profiling to uncover novel downstream targets as potential sites of therapeutic intervention in depression.
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