14 research outputs found
The presenting characteristics of erythema migrans vary by age, sex, duration, and body location.
PURPOSE: The erythema migrans (EM) skin lesion is often the first clinical sign of Lyme disease. Significant variability in EM presenting characteristics such as shape, color, pattern, and homogeneity, has been reported. We studied associations between these presenting characteristics, as well as whether they were associated with age, sex, EM duration, body location, and initiation of antibiotics.
METHODS: Two hundred and seventy one adult participants with early Lyme disease who had a physician-diagnosed EM skin lesion ofââ„â5 cm in diameter andââ€â72 h of antibiotic treatment were enrolled. Participant demographics, clinical characteristics, and characteristics of their primary EM lesion were recorded.
RESULTS: After adjusting for potential confounders, EM size increased along with increasing EM duration to a peak of 14 days. Male EM were found to be on average 2.18 cm larger than female EM. The odds of a red (vs blue/red) EM were 65% lower in males compared to females, and were over 3 times as high for EM found on the pelvis, torso, or arm compared to the leg. Age remained a significant predictor of central clearing in adjusted models; for every 10-year increase in age, the odds of central clearing decreased 25%.
CONCLUSIONS: Given that EM remains a clinical diagnosis, it is essential that both physicians and the general public are aware of its varied manifestations. Our findings suggest possible patterns within this variability, with implications for prompt diagnosis and treatment initiation, as well as an understanding of the clinical spectrum of EM
Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma
Inhibition of melanoma cell-intrinsic Tim-3 stimulates MAPK-dependent tumorigenesis.
T-cell immunoglobulin and mucin domain 3 (Tim-3) is an immune checkpoint receptor that dampens effector functions and causes terminal exhaustion of cytotoxic T-cells. Tim-3 inhibitors are under investigation in immuno-oncology (IO) trials, because blockade of T-cell-Tim-3 enhances antitumor immunity. Here, we identify an additional role for Tim-3 as a growth-suppressive receptor intrinsic to melanoma cells. Inhibition of melanoma cell-Tim-3 promoted tumor growth in both immunocompetent and immunocompromised mice, while melanoma-specific Tim-3 overexpression attenuated tumorigenesis. Antibody (Ab)-mediated Tim-3 blockade inhibited growth of immunogenic murine melanomas in T-cell-competent hosts, consistent with established antitumor effects of T-cell Tim-3 inhibition. In contrast, Tim-3 Ab administration stimulated tumorigenesis of both highly and lesser immunogenic murine and human melanomas in T-cell-deficient mice, confirming growth-promoting effects of melanoma-Tim-3 antagonism. Melanoma-Tim-3 activation suppressed, while its blockade enhanced, phosphorylation of pro-proliferative downstream mitogen-activated protein kinase (MAPK) signaling mediators. Finally, pharmacologic MAPK inhibition reversed unwanted Tim-3 Ab-mediated tumorigenesis in T-cell-deficient mice and promoted desired antitumor activity of Tim-3 interference in T-cell-competent hosts. These results identify melanoma-Tim-3 blockade as a mechanism that antagonizes T-cell-Tim-3-directed IO therapeutic efficacy. They further reveal MAPK targeting as a combination strategy for circumventing adverse consequences of unintended melanoma-Tim-3 inhibition
Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth
Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy
A Network Approach to Define Modularity of Components in Complex Products
Modularity has been defined at the product and system levels. However, little effort has gone into defining and quantifying modularity at the component level. We consider complex products as a network of components that share technical interfaces (or connections) in order to function as a whole and define component modularity based on the lack of connectivity among them. Building upon previous work in graph theory and social network analysis, we define three measures of component modularity based on the notion of centrality. Our measures consider how components share direct interfaces with adjacent components, how design interfaces may propagate to nonadjacent components in the product, and how components may act as bridges among other components through their interfaces. We calculate and interpret all three measures of component modularity by studying the product architecture of a large commercial aircraft engine. We illustrate the use of these measures to test the impact of modularity on component redesign. Our results show that the relationship between component modularity and component redesign depends on the type of interfaces connecting product components. We also discuss directions for future work