Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the ...hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies.
Obesity is associated with adipose inflammation, defined by macrophages encircling dead adipocytes, as well as extracellular matrix (ECM) remodeling and increased risk of breast cancer. Whether ECM ...affects macrophage phenotype in obesity is uncertain. A better understanding of this relationship could be strategically important to reduce cancer risk or improve outcomes in the obese. Using clinical samples, computational approaches, and in vitro decellularized ECM models, this study quantified the relative abundance of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages in human breast adipose tissue, determined molecular similarities between obesity and tumor-associated macrophages, and assessed the regulatory effect of obese versus lean ECM on macrophage phenotype. Our results suggest that breast adipose tissue contains more M2- than M1-biased macrophages across all body mass index categories. Obesity further increased M2-biased macrophages but did not affect M1-biased macrophage density. Gene Set Enrichment Analysis suggested that breast tissue macrophages from obese versus lean women are more similar to tumor-associated macrophages. These changes positively correlated with adipose tissue interstitial fibrosis, and in vitro experiments indicated that obese ECM directly stimulates M2-biased macrophage functions. However, mammographic density cannot be used as a clinical indicator of these changes. Collectively, these data suggest that obesity-associated interstitial fibrosis promotes a macrophage phenotype similar to tumor-associated macrophages, which may contribute to the link between obesity and breast cancer.
We report a brittle Mg-based bulk metallic glass which approaches the ideal brittle behavior. However, a dimple structure is observed at the fracture surface by high resolution scanning electron ...microscopy, indicating some type of "ductile" fracture mechanism in this very brittle glass. We also show, from the available data, a clear correlation between the fracture toughness and plastic process zone size for various glasses. The results indicate that the fracture in brittle metallic glassy materials might also proceed through the local softening mechanism but at different length scales.
MicroRNA (miRNA) microarray analysis has consistently found altered expression of miRNAs in thyroid tumors, suggesting their roles in thyroid carcinogenesis. To explore whether this differential ...expression can be used as a diagnostic tool in surgical pathology and fine-needle aspirate (FNA) specimens, the expression of selected miRNA was evaluated by quantitative RT-PCR, using total RNA from 84 formalin-fixed paraffin-embedded tissues and 40 ex vivo aspirate specimens. miRNA from all paraffin-embedded tissues and all but one FNA sample were found to be analyzable, with paraffin sections yielding better miRNA quality. Preliminary analysis of 6 miRNAs in 10 papillary thyroid carcinoma and 10 follicular adenoma identified significant overexpression of miR-146b, -221, and -222 in papillary thyroid carcinoma (P<0.02), but not miR-146a, -155, or -187 (P>0.08). The expression of these first three miRNAs was examined in a series of 5 normal thyroid, 11 hyperplastic nodules, 24 follicular adenoma, 27 classical papillary thyroid carcinoma, 5 follicular variant papillary thyroid carcinoma, 2 follicular carcinoma, and 10 encapsulated follicular lesions with partial nuclear features of papillary carcinoma. Results showed miR-146b to be most consistently overexpressed in both classical papillary carcinoma and follicular variants, whereas all other groups showed lower expression at a similar level (P<0.001 for pair-wise comparisons between papillary carcinoma and all other groups). Follicular lesions with partial features of papillary carcinoma all showed low miR-146b levels similar to other non-papillary carcinoma groups, suggesting that they are biologically distinctive from papillary carcinoma. miR-221 and miR-222 also showed higher expression in papillary carcinoma, but with substantial overlaps with the other groups. When applied to 40 FNA samples of various lesions, only miR-146b and miR-222 persisted as distinguishing markers for papillary carcinoma. We concluded that miRNAs, particularly miR-146b, might potentially be adjunct markers for diagnosing papillary thyroid carcinoma in both FNA and surgical pathology specimens.
Inflammation and oxidative stress are involved in age-related macular degeneration (AMD) and possibly associated with an activation of neuronal apoptosis inhibitor protein/class II transcription ...activator of the Major Histocompatibility Complex (MHC)/heterokaryon incompatibility/telomerase-associated protein 1, leucine-rich repeat or nucleotide-binding domain, leucine-rich repeat-containing family, and pyrin domain-containing 3 (NLRP3) inflammasome. In the present study, we used a translational approach to address this hypothesis. In patients with AMD, we observed increased mRNA levels of NLRP3, pro-interleukin-1 beta (IL-1β) and pro-IL-18 in AMD lesions of the retinal pigment epithelium (RPE) and photoreceptor. In vitro, a similar increase was evoked by oxidative stress or lipopolysaccharide (LPS) stimulation in the adult retinal pigment epithelium (ARPE-19) cell line, and the increase was reduced in siRNA transfected cells to knockdown NLRP3. Ultrastructural studies of ARPE-19 cells showed a swelling of the cytoplasm, mitochondrial damage, and occurrence of autophagosome-like structures. NLRP3 positive dots were detected within autophagosome-like structures or in the extracellular space. Next, we used a mouse model of AMD, Ccl2/Cx3cr1 double knockout on rd8 background (DKO rd8) to ascertain the in vivo relevance. Ultrastructural studies of the RPE of these mice showed damaged mitochondria, autophagosome-like structures, and cytoplasmic vacuoles, which are reminiscent of the pathology seen in stressed ARPE-19 cells. The data suggest that the NLRP3 inflammasome may contribute in AMD pathogenesis.
Calcitonin gene-related peptide (CGRP) can bias the outcome of Ag presentation to responsive T cells in vitro away from Th1-type immunity and toward the Th2 and Th17 poles through actions on ...endothelial cells (ECs). To test the in vivo significance of this observation, we engineered a mouse lacking functional CGRP receptors on ECs (EC receptor activity modifying protein 1 RAMP1 knockout mice). On percutaneous immunization to 1-fluoro-2,4-dinitrobenzene, stimulated CD4
T cells from draining lymph nodes showed significantly reduced IL-17A expression with significantly increased IFN-γ, IL-4, and IL-22 expression at the protein and mRNA levels compared with control mice. Retinoic acid receptor-related orphan receptor γ t mRNA was significantly reduced, while mRNAs for T-box expressed in T cells and GATA binding protein 3 were significantly increased. In addition, EC RAMP1 knockout mice had significantly reduced contact hypersensitivity responses, and systemic administration of a CGRP receptor antagonist similarly inhibited contact hypersensitivity in wild-type mice. These observations provide compelling evidence that CGRP is a key regulator of cutaneous immunity through effects on ECs and suggest a novel pathway for potential therapeutic manipulation.
Sympathetic ophthalmia is a rare bilateral granulomatous inflammation that follows accidental or surgical insult to the uvea of one eye. Onset of sympathetic ophthalmia can be insidious or acute, ...with recurrent periods of exacerbation. Clinical presentation shows mutton-fat keratic precipitates, choroidal infiltrations, and Dalen-Fuchs nodules. Histopathology reveals diffuse or nodular granulomatous inflammation of the uvea. Prevention and treatment strategies for sympathetic ophthalmia are currently limited to two modalities, enucleation of the injured eye and immunosuppressive therapy, aimed at controlling inflammation. The etiology and pathophysiology of the disease is still unclear but is largely thought to be autoimmune in nature. Recent insight on the molecular pathology of the disease as well as developments in imaging technology have furthered both the understanding on the autoimmune process in sympathetic ophthalmia and the targeting of prevention and treatment strategies for the future.
Three-line array stereo aerial survey camera is a typical mapping equipment of aerial photogrammetry. As one of the airborne equipment, it can quickly obtain a large range of basic geographic ...information with high precision. At present, typical three-line array stereoscopic aerial survey cameras, such as Leica ADS40 and 80, have the disadvantages of small field of view and low resolution, which makes it difficult to meet the demand of large-scale topographic mapping for economic construction. For the urgent need of domestic three linear array aerial mapping camera in our project, we developed the AMS-3000 camera system. Camera features include a large field of view, high resolution, low distortion and high environmental adaptability. The AMS-3000 system has reached the international advanced level on both software and hardware aspects.
Cancer/testis (CT) antigens are protein antigens normally expressed only in germ cells of testis, and yet are expressed in a proportion of a wide variety of human cancers. CT antigens can elicit ...spontaneous immune responses in cancer patients with CT-positive cancers, and CT antigen-based therapeutic cancer vaccine trials are ongoing for "CT-rich" tumors. Although some previous studies found breast cancer to be "CT-poor", our recent analysis identified increased CT mRNA transcripts in the ER-negative subset of breast cancer.
In this study, we performed a comprehensive immunohistochemical study to investigate the protein expression of eight CT genes in 454 invasive ductal carcinomas, including 225 ER/PR/HER2-negative (triple-negative) carcinomas. We found significantly more frequent expression of all eight CT antigens in ER-negative cancers, and five of them--MAGEA, CT7, NY-ESO-1, CT10 and CT45, were expressed in 12-24% of ER-negative cancers, versus 2-6% of ER-positive cancers (p<0.001 to 0.003). In comparison, GAGE, SAGE1 and NXF2 were only expressed in 3-5% of ER-negative and 0-2% of ER-positive cancers. ER-negative cancers were also more likely to simultaneously co-express multiple CT antigens, with 27% (34/125) of ER-negative, CT-positive tumors expressing three or more CT antigens. HER2 status had no consistent effect on CT expression, and triple-negative carcinomas showed similar frequencies of MAGEA and NY-ESO-1 expression as ER-negative/HER2-positive carcinomas. More frequent CT expression was also found in tumors with higher nuclear grade (p<0.001 to p = 0.01) and larger in size (>2 cm).
CT antigens are preferentially expressed in hormone receptor-negative and high-grade breast cancer. Considering the limited treatment options for ER/PR/HER2 triple-negative breast cancer, the potential of CT-based immunotherapy should be explored.
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