Therapies targeting oncogene addiction have had a tremendous impact on tumor growth and patient outcome, but drug resistance continues to be problematic. One approach to deal with the challenge of ...resistance entails extending anticancer treatments beyond targeting cancer cells by additionally altering the tumor microenvironment. Understanding how the tumor microenvironment contributes to the evolution of diverse resistance pathways could aid in the design of sequential treatments that can elicit and take advantage of a predictable resistance trajectory. Tumor-associated macrophages often support neoplastic growth and are frequently the most abundant immune cell found in tumors. Here, we used clinically relevant in vivo Braf-mutant melanoma models with fluorescent markers to track the stage-specific changes in macrophages under targeted therapy with Braf/Mek inhibitors and assessed the dynamic evolution of the macrophage population generated by therapy pressure-induced stress. During the onset of a drug-tolerant persister state, Ccr2+ monocyte-derived macrophage infiltration rose, suggesting that macrophage influx at this point could facilitate the onset of stable drug resistance that melanoma cells show after several weeks of treatment. Comparison of melanomas that develop in a Ccr2-proficient or -deficient microenvironment demonstrated that lack of melanoma infiltrating Ccr2+ macrophages delayed onset of resistance and shifted melanoma cell evolution towards unstable resistance. Unstable resistance was characterized by sensitivity to targeted therapy when factors from the microenvironment were lost. Importantly, this phenotype was reversed by coculturing melanoma cells with Ccr2+ macrophages. Overall, this study demonstrates that the development of resistance may be directed by altering the tumor microenvironment to improve treatment timing and the probability of relapse.
Ccr2+ melanoma macrophages that are active in tumors during the drug-tolerant persister state following targeted therapy-induced regression are key contributors directing melanoma cell reprogramming toward specific therapeutic resistance trajectories.
Successful immunity to infection, malignancy, and tissue damage requires the coordinated recruitment of numerous immune cell subsets to target tissues. Once within the target tissue, effector T cells ...rely on local chemotactic cues and structural cues from the tissue matrix to navigate the tissue, interact with antigen‐presenting cells, and release effector cytokines. This highly dynamic process has been “caught on camera” in situ by intravital multiphoton imaging. Initial studies revealed a surprising randomness to the pattern of T cell migration through inflamed tissues, behavior thought to facilitate chance encounters with rare antigen‐bearing cells. Subsequent tissue‐wide visualization has uncovered a high degree of spatial preference when it comes to T cell activation. Here, we discuss the basic tenants of a successful effector T cell activation niche, taking cues from the dynamics of Tfh positioning in the lymph node germinal center. In peripheral tissues, steady‐state microanatomical organization may direct the location of “pop‐up” de novo activation niches, often observed as perivascular clusters, that support early effector T cell activation. These perivascular activation niches appear to be regulated by site‐specific chemokines that coordinate the recruitment of dendritic cells and other innate cells for local T cell activation, survival, and optimized effector function.
Correct positioning of T cells within infected tissues is critical for T cell activation and pathogen control. Upon tissue entry, effector T cells must efficiently locate antigen-presenting cells ...(APC) for peripheral activation. We reveal that tissue entry and initial peripheral activation of Th1 effector T cells are tightly linked to perivascular positioning of chemokine-expressing APCs. Dermal inflammation induces tissue-wide de novo generation of discrete perivascular CXCL10+ cell clusters, enriched for CD11c+MHC-II+ monocyte-derived dendritic cells. These chemokine clusters are “hotspots” for both Th1 extravasation and activation in the inflamed skin. CXCR3-dependent Th1 localization to the cluster micro-environment prolongs T-APC interactions and boosts function. Both the frequency and range of these clusters are enhanced via a T helper 1 (Th1)-intrinsic, interferon-gamma (IFNγ)-dependent positive-feedback loop. Thus, the perivascular CXCL10+ clusters act as initial peripheral activation niches, optimizing controlled activation broadly throughout the tissue by coupling Th1 tissue entry with enhanced opportunities for Th1-APC encounter.
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•CXCL10 expression is limited to discrete perivascular niches in the inflamed skin•The CXCL10+ niches are hotspots or preferred sites of Th1 tissue entry•The niche is enriched for MHC-II+ moDCs and supports prolonged Th1:APC interactions•IFNγ enhances niche availability, boosting opportunities for Th1:APC encounter
Prizant et. al. identify a perivascular peripheral activation niche for T cells, defined by myeloid cell expression of the chemokine CXCL10. These CXCL10+ perivascular clusters serve as hotspots for T cell entry into the inflamed skin and a niche for early activation.
Abstract
Pathogen control requires T-cells to locate and make direct contact with antigen-presenting cells (APCs) for peripheral reactivation and delivery of effector molecules. The signals that ...orchestrate T-cell-APC interactions are poorly understood in inflamed peripheral tissues. Using intravital imaging (IVI), we have found that Th1 cell entry into the inflamed dermis is nucleated by perivascular CXCL10+ cellular clusters enriched for APCs. Th1 cells form more stable interactions with APCs within these clusters compared to outer regions. CXCL10+ clusters are amplified in a IFNγ-dependent manner, where CD4+ T-cell IFNγ release increases APC recruitment and CXCL10 expression. We hypothesize that these chemokine clusters serve as CXCL10 Peripheral Activation (PAC-10) niches, where Th1 cells achieve early peripheral activation away from the pathogen modulated milieu. We seek to determine the relationship between these spatially restricted PAC-10 niches, infection foci, and pathogen clearance. Using a combination of IVI, flow cytometry, and transcriptomics we characterized niche specific Th1 cells and niche cellular composition to determine if PAC-10 niches modulate Th1 cells for pathogen control. Initial studies reveal that niche specific Th1 cells have increased CD69 and IFNγ expression compared to non-niche counterparts. PAC-10 niches appear to have a spatially distinct innate cell population, likely with enhanced ability to support Th1 activation. Future studies will characterize the functional status of niche specific Th1 cells and evaluate the necessity of PAC-10 niches for pathogen control. These studies will inform therapeutic strategies to boost T-cell activation in infection or hinder activation in autoimmunity.
Supported by NIH NIAID P01 AI02851 NIH NIAID R01 AI070826
Atopic dermatitis (AD) lesional skin is often colonized with S. aureus, and the load of S. aureus correlates with disease severity. However, a causative and mechanistic link between S. aureus skin ...colonization and severity of AD is not well established. We made use of well-established mouse model of AD elicited by epicutaneous sensitization of tape stripped skin with ovalbumin to investigate the relationship between allergic skin inflammation and cutaneous S. aureus colonization. Topical application of S aureus exacerbated allergic skin inflammation induced by epicutaneous sensitization with ovalbumin, whereas allergic skin inflammation generated a permissive environment for S. aureus persistence. Our results establish a mutually reinforcing role of allergic skin inflammation and S. aureus skin colonization.
•Topical application of S aureus exacerbated allergic skin inflammation.•Allergic skin inflammation generated a permissive environment for S. aureus persistence.•IL-4 and IL-13 impair S. aureus clearance from sites of allergic skin inflammation.
The COVID-19 Pandemic has had an unprecedented impact on how employees and employers operate. Employees, directly affected by workplace changes, may provide information regarding future efficiencies. ...As a result, crowdsourced employee satisfaction (ES) reviews mentioning the COVID-19 Pandemic may contain useful information regarding the future profitability of these firms. We utilize crowdsourced COVID-19 Pandemic specific ES obtained from Glassdoor.com to determine the impact on abnormal stock returns for public firms from March–December 2020. We find evidence that higher COVID-19 ES is related to higher abnormal stock returns. While non-COVID ES is found not to be related to abnormal stock returns.
Abstract Combat exposure is associated with increased rates of mental health problems such as post-traumatic stress disorder, depression, and anxiety when Soldiers return home. Another important ...health consequence of combat exposure involves the potential for increased risk-taking propensity and unsafe behavior among returning service members. Survey responses regarding 37 different combat experiences were collected from 1252 US Army Soldiers immediately upon return home from combat deployment during Operation Iraqi Freedom. A second survey that included the Evaluation of Risks Scale (EVAR) and questions about recent risky behavior was administered to these same Soldiers 3 months after the initial post-deployment survey. Combat experiences were reduced to seven factors using principal components analysis and used to predict post-deployment risk-propensity scores. Although effect sizes were small, specific combat experiences, including greater exposure to violent combat, killing another person, and contact with high levels of human trauma, were predictive of greater risk-taking propensity after homecoming. Greater exposure to these combat experiences was also predictive of actual risk-related behaviors in the preceding month, including more frequent and greater quantities of alcohol use and increased verbal and physical aggression toward others. Exposure to violent combat, human trauma, and having direct responsibility for taking the life of another person may alter an individual’s perceived threshold of invincibility and slightly increase the propensity to engage in risky behavior upon returning home after wartime deployment. Findings highlight the importance of education and counseling for returning service members to mitigate the public health consequences of elevated risk-propensity associated with combat exposure.
Category:
Ankle Arthritis; Midfoot/Forefoot
Introduction/Purpose:
Midfoot osteoarthritis affects over 16% of adults over the age of 50, interfering with activities of daily living and leisure. ...Non-operative management includes anti-inflammatory, carbon fiber shank/custom orthotics, and cortico-steroid injections. To improve accuracy, these injections are often done under fluoroscopic guidance. Operative intervention with midfoot fusions is sometimes performed, though non-union rates and continued pain after surgery can be challenging. Sometimes, there can be difficulty in determining exactly which midfoot joints are most arthritic/symptomatic based on radiographs. This study aims to quantify how well surgeons are able to diagnose midfoot and transverse tarsal joint arthritis on standing radiographs versus advanced imaging.
Methods:
We reviewed the records of 113 patients (144 feet) with midfoot arthritis, who were treated from 2015 to 2019 at an academic medical center by a single fellowship trained foot and ankle surgeon. The mean age was 63.0 years, the average BMI was 31.5, and 7 patients eventually underwent surgery. Each patient underwent both plain radiographs, according to a standardized protocol, and either a CT or MRI scan. Radiographs and advanced images were graded separately for the presence of joint space narrowing, subchondral cysts, and other signs of arthritis in the following joints: 1st tarsometatarsal (TMT), 2nd TMT, 3rd TMT, 4th TMT, 5th TMT, naviculocuneiforms (NC), talonavicular (TN), calcaneocuboid (CC), subtalar (ST), and 1st metatarsophalangeal (MTP). The sensitivity, specificity, precision, negative predictive value, and overall accuracy of radiographs compared to CT scans was calculated for each joint. Statistical significance was assessed using a paired t-test.
Results:
The most common joints affected by arthritis were the 2nd TMT (radiograph=75.7%, CT=79.9%) and 3rd TMT (radiograph=65.5%, CT=70.4%). Advanced imaging showed a significantly higher rate of arthritis in the 1st TMT (P<0.01), 4th TMT (P<0.01), and 5th TMT (P<0.01), as compared to radiograph. Only 16.9% of patients' radiographs had a direct correlation with the results of their CT scan. A CT scan showed one or two additional affected joints by 19.7% and 13.0 %, respectively; and rarely showed one or two less joints affected by arthritis (8.1% and 3.2%, respectively). We found radiographic sensitivity and specificity to be highly variable (1st TMT=61.3% & 92.3%, 3rd TMT=79.5% & 69.3%).
Conclusion:
Radiographs vary drastically in their sensitivities and specificities in diagnosing arthritic joints in the midfoot and transverse tarsal joints. When treating midfoot osteoarthritis surgically, we recommend obtaining advanced imaging preoperatively, rather than relying on plain radiographs alone to determine which joints may need to be managed surgically.
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