Identification of molecular phenotypic descriptors of breast capsular contracture formation using informatics analysis of the whole genome transcriptome.

Breast capsular contracture formation following silicone implant augmentation/reconstruction is a common complication that remains poorly understood. The aim of this study was to identify potential biomarkers implicated in breast capsular contracture formation by using, for the first time, whole genome arrays. Biopsy samples were taken from 18 patients (23 breast capsules) with Baker Grade I-II (Control) and Baker Grade III-IV (Contracted). Whole genome microarrays were performed and six significantly dysregulated genes were selected for further validation with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Hematoxylin and eosin was also carried out to compare the histological characteristics of control and contracted samples. Microarray results showed that aggrecan, tissue inhibitor of metalloproteinase 4 (TIMP4), and tumor necrosis factor superfamily (ligand) member 11 were significantly down-regulated in contracted capsules; while matrix metallopeptidase 12, serum amyloid A 1, and interleukin 8 (IL8) were significantly up-regulated. The dysregulation of aggrecan, tumor necrosis factor superfamily (ligand) member 11, TIMP4, and IL8 was validated by quantitative reverse transcriptase polymerase chain reaction (p < 0.05). Immunohistochemistry confirmed an increased protein expression for IL8 and matrix metallopeptidase 12 in contracted capsules (p < 0.05), and decreased protein expression of TIMP4 (p < 0.05). This study has shown, for the first time, a number of unique biomarkers of significance in capsular contracture formation. IL8 and TIMP4 may serve as potential key diagnostic, therapeutic, and prognostic biomarkers in capsular contracture formation.

Identification of biomarkers in sequential biopsies of patients with chronic wounds receiving simultaneous acute wounds: a genetic, histological, and noninvasive imaging study.

Chronic wounds are common and lead to significant patient morbidity. A better understanding of their pathogenesis and relevant biomarkers are required. We compared acute and chronic wounds in the same individual using noninvasive imaging including spectrophotometric intracutaneous analysis (SIAscopy) and full-field laser perfusion imaging. Gene expression analysis was also performed on sequential biopsies. Whole genome gene expression microarray analysis (44k), quantitative polymerase chain reaction, and immunohistochemistry were carried out to determine gene expression levels in tissue biopsies. Fifteen Caucasian patients with chronic venous ulcers had biopsies of the wound edges and simultaneously had an acute wound created on their upper arm on days 0, 7, and 14. SIAscopy revealed increased levels of melanin (p < 0.001), reduced levels of collagen (p < 0.001), and hemoglobin (p = 0.022) in chronic wounds. Microarray and subsequent quantitative polymerase chain reaction analysis confirmed an overall differential expression in acute and chronic wounds for several genes. Significantly higher levels of inhibin, beta A (INHBA) expression were confirmed in the dermis of chronic wounds (p < 0.05). Additionally, INHBA and thrombospondin 1 messenger RNA levels significantly correlated with SIAscopy measurements (p < 0.05). This unique study has showed aberrant expression of INHBA in chronic wounds using a sequential biopsy model of chronic vs. acute wounds in the same individual.

Hyaluronan, TSG-6, and inter-α-inhibitor in periprosthetic breast capsules: reduced levels of free hyaluronan and TSG-6 expression in contracted capsules.

BACKGROUND: The exact mechanism of capsular contracture (CC) is still unknown. The covalent modification of hyaluronan (HA) with the heavy chains (HC) of inter-α-inhibitor (IαI) has been identified as an important pathway in inflammation and tissue remodeling, where HC·HA formation is catalyzed by TSG-6 (the protein product of tumor necrosis factor stimulated gene-6). OBJECTIVE: The authors quantitatively assess the correlation between severity of CC (measured by Baker grade) and expression of HA, TSG-6, and IαI (ie, the polypeptides HC1, HC2, and bikunin) in periprosthetic breast capsules. METHODS: Immunofluorescent staining for HA, TSG-6, HC1, HC2, and bikunin was carried out on periprosthetic breast capsules (n = 7) of each Baker grade from four anatomical locations. Quantitative analysis was performed to identify differences in staining intensity. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to determine differences in TSG-6 gene expression levels. RESULTS: Severity of contracture was associated with reduced staining for both free HA (Pearson correlation coefficient, r = -0.645, P < .001) and TSG-6 (r = -0.642, P = .002). RT-qPCR showed a significant negative correlation between severity of contracture and TSG-6 gene expression levels (r = -0.750, P = .001). CONCLUSIONS: The negative correlation between TSG-6 expression levels and severity of CC suggests a possible protective role for TSG-6 in the context of CC formation, and this may have a clinically relevant role in prevention of breast CC.