In vivo analysis of fracture toughness of thyroid gland tumors

BackgroundHuman solid tumors that are hard or firm on physical palpation are likely to be cancerous, a clinical maxim that has been successfully applied to cancer screening programs, such as breast self-examination. However, the biological relevance or prognostic significance of tumor hardness remains poorly understood. Here we present a fracture mechanics based in vivo approach for characterizing the fracture toughness of biological tissue of human thyroid gland tumors.MethodsIn a prospective study, 609 solid thyroid gland tumors were percutaneously probed using standard 25 gauge fine needles, their tissue toughness ranked on the basis of the nature and strength of the haptic force feedback cues, and subjected to standard fine needle biopsy. The tumors' toughness rankings and final cytological diagnoses were combined and analyzed. The interpreting cytopathologist was blinded to the tumors' toughness rankings.ResultsOur data showed that cancerous and noncancerous tumors displayed remarkable haptically distinguishable differences in their material toughness.ConclusionThe qualitative method described here, though subject to some operator bias, identifies a previously unreported in vivo approach to classify fracture toughness of a solid tumor that can be correlated with malignancy, and paves the way for the development of a mechanical device that can accurately quantify the tissue toughness of a human tumor

High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids.

BackgroundPatients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors. High levels of leptin and low levels of adiponectin are associated with both atherosclerosis and immunomodulatory functions in the general population.ObjectiveTo examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis.MethodsCarotid ultrasonography was performed in 250 women with SLE and 122 controls. Plasma leptin and adiponectin levels were measured. Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed.ResultsLeptin levels were significantly higher in patients with SLE than in controls (23.7±28.0 vs 13.3±12.9 ng/ml, p<0.001). Leptin was also higher in the 43 patients with SLE with plaque than without plaque (36.4±32.3 vs 20.9±26.4 ng/ml, p=0.002). After multivariate analysis, the only significant factors associated with plaque in SLE were leptin levels in the highest quartile (≥29.5 ng/ml) (OR=2.8, p=0.03), proinflammatory HDL (piHDL) (OR=12.8, p<0.001), age (OR=1.1, p<0.001), tobacco use (OR=7.7, p=0.03) and hypertension (OR=3.0, p=0.01). Adiponectin levels were not significantly associated with plaque in our cohort. A significant correlation between leptin and piHDL function (p<0.001), Lp(a) (p=0.01) and OxPL/apoB100 (p=0.02) was also present.ConclusionsHigh leptin levels greatly increase the risk of subclinical atherosclerosis in SLE, and are also associated with an increase in inflammatory biomarkers of atherosclerosis such as piHDL, Lp(a) and OxPL/apoB100. High leptin levels may help to identify patients with SLE at risk of atherosclerosis

Fracture Toughness of Human Solid Cancers

Human solid cancers typically are harder and firmer than surrounding normal tissue upon clinical palpation. This characteristic has been linked to the presence of abundant collagen in the tumor stroma, referred to as the desmoplastic reaction. Recent evidence indicates that tumor-associated desmoplastic stroma is critical to cancer’s growth and progression. However, how best to measure, interpret, and/or model the mechanical attributes of tumor microenvironment in vivo remain unclear. 

During routine sonographically-guided fine needle biopsy of solid tumors of the human thyroid gland, it was serendipitously observed by the lead author that the nature and strength of the haptic force feedback cues varied among tumors [See Movie:http://www.jbioleng.org/imedia/6538834542236038/supp1.mov]. Note the apparent ease with which the needle travels through a non-cancerous tumor. In contrast, a cancerous tumor offers substantial resistance to needle insertion and penetration. To further investigate this phenomenon and to assess the relationship between tumor hardness and cytological diagnosis, a clinical study was designed and implemented incorporating the principles of fracture mechanics with haptic modality. 

In this prospective study, 609 solid thyroid gland tumors were percutaneously probed using standard 25-gauge fine needles, their tissue toughness ranked on the basis of the nature and strength of the haptic force feedback cues, and subjected to standard fine needle biopsy. Ranked tumors were placed in one of two groups: Group 1 [N = 134]: tumors exhibiting penetration resistance with a distinctive force-feedback cue, as if cutting through an unripe pear; and Group 2 [N = 475]: tumors exhibiting no resistance, as if cutting through jelly. The results were dramatic: 64% of Group 1 tumors were cancerous while 95% of Group 2 tumors were noncancerous.
 
This qualitative method, though subject to some operator bias, identifies a previously unreported in vivo approach for characterizing the fracture toughness of human solid tumors that can be correlated with malignancy. Our results when validated by quantitative measurement data are likely to provide a new framework for understanding the mechanical attributes of the tumor microenvironment. We anticipate our method to be a starting point for the development of a mechanical device that can quantify a tumor’s toughness in vivo using the principles of fracture mechanics. [Journal of Biological Engineering 2008;2:12 doi:10.1186/1754-1611-2-12]
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Association of Paraoxonase 1 Gene Polymorphism and Enzyme Activity With Carotid Plaque in Rheumatoid Arthritis

ObjectiveTo investigate the relationship of genetic and biochemical determinants of paraoxonase 1 activity to carotid plaque as a surrogate marker of cardiovascular (CV) risk in patients with rheumatoid arthritis (RA).MethodsThe relationships between paraoxonase 1 activity, PON1 genotype (for the functional polymorphism at position 192), and carotid plaque presence were determined in 168 RA patients. After an overnight fast, blood was collected for lipoprotein analysis, and paraoxonase 1 activity was measured using paraoxon as the substrate. The PON1 Q192R genotype was determined for all patients. Lipoprotein cholesterol levels, traditional CV risk factors, medication use, and RA disease characteristics were assessed for all patients.ResultsParaoxonase 1 activity values in the RA patients were highest for the RR genotype, intermediate for the QR genotype, and lowest for the QQ genotype (P < 0.0001). Compared to patients with either the QQ genotype or the QR genotype, patients with the RR genotype demonstrated decreased risk of carotid plaque on multivariate analysis, controlling for traditional CV risk factors, high-sensitivity C-reactive protein levels, prednisone use, and cholesterol-lowering medication use (P < 0.05). Additional multivariate logistic regression analysis controlling for the above factors also revealed a significant association of plasma paraoxonase 1 activity with carotid plaque in RA patients. Lower plasma paraoxonase 1 activity was associated with increased risk of carotid plaque (P < 0.05).ConclusionThe current findings suggest a relationship of the genetic determinants and activity of paraoxonase 1 to CV risk in RA patients, as assessed by the presence or absence of carotid plaque. Further CV outcome studies are warranted to validate the utility of paraoxonase 1 as a biomarker of CV risk in patients with RA

A Panel of Biomarkers Associates With Increased Risk for Cardiovascular Events in Women With Systemic Lupus Erythematosus.

ObjectiveThe increase in cardiovascular events (CVEs) in systemic lupus erythematosus (SLE) is not fully explained by traditional risk factors. We previously identified four biomarkers (proinflammatory high-density lipoprotein, leptin, soluble TNF-like weak inducer of apoptosis (sTWEAK), and homocysteine) that we combined with age and diabetes to create the predictors of risk for elevated flares, damage progression, and increased cardiovascular diseasein patients with SLE (PREDICTS) risk profile. PREDICTS more accurately identified patients with SLE at risk for progression of subclinical atherosclerosis than any individual variable. We examined whether PREDICTS can also identify patients with SLE at risk for future CVEs.MethodsA total of 342 patients with SLE and 155 matched control subjects participated in this longitudinal prospective study. A high PREDICTS score was defined as three or more predictors or diabetes + one or more predictor. The biomarkers were measured at baseline using published methods. All major adverse CVEs (MACEs) were confirmed by medical record review.ResultsDuring 116 months of follow-up, 5% of patients with SLE died, 12% had a cerebrovascular event, and 5% had a cardiac event. Overall, 20% of patients with lupus experienced any new MACE compared with 5% of control subjects (P < 0.0001). More patients with SLE with a new MACE had high PREDICTS score at baseline (77%) versus patients with no new events (34%) (P < 0.0001). High baseline PREDICTS score also associated with cerebrovascular (P < 0.0001) and cardiac events (P < 0.0001) in SLE. Using Cox regression, a baseline high PREDICTS score associated with a 3.7-fold increased hazard ratio (HR) for a new MACE (P < 0.0001) in SLE. Hypertension (HR = 2.1; P = 0.006) was also a risk.ConclusionA high PREDICTS score and hypertension confer increased risk for new MACEs in patients with SLE

High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids.

BackgroundPatients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors. High levels of leptin and low levels of adiponectin are associated with both atherosclerosis and immunomodulatory functions in the general population.ObjectiveTo examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis.MethodsCarotid ultrasonography was performed in 250 women with SLE and 122 controls. Plasma leptin and adiponectin levels were measured. Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed.ResultsLeptin levels were significantly higher in patients with SLE than in controls (23.7±28.0 vs 13.3±12.9 ng/ml, p<0.001). Leptin was also higher in the 43 patients with SLE with plaque than without plaque (36.4±32.3 vs 20.9±26.4 ng/ml, p=0.002). After multivariate analysis, the only significant factors associated with plaque in SLE were leptin levels in the highest quartile (≥29.5 ng/ml) (OR=2.8, p=0.03), proinflammatory HDL (piHDL) (OR=12.8, p<0.001), age (OR=1.1, p<0.001), tobacco use (OR=7.7, p=0.03) and hypertension (OR=3.0, p=0.01). Adiponectin levels were not significantly associated with plaque in our cohort. A significant correlation between leptin and piHDL function (p<0.001), Lp(a) (p=0.01) and OxPL/apoB100 (p=0.02) was also present.ConclusionsHigh leptin levels greatly increase the risk of subclinical atherosclerosis in SLE, and are also associated with an increase in inflammatory biomarkers of atherosclerosis such as piHDL, Lp(a) and OxPL/apoB100. High leptin levels may help to identify patients with SLE at risk of atherosclerosis