Matrix metalloproteinases as biomarkers in premalignant and malignant tumors of the human skin

The incidence of non-melanoma skin cancer is increasing worldwide. Basal cell carcinoma followed by squamous cell carcinoma and malignant melanoma are the most frequent skin tumors. Immunosuppressed patients have an increased risk of neoplasia, of which non-melanoma skin cancer is the most common. Matrix metalloproteinases (MMPs) are proteolytic enzymes that collectively are capable of degrading virtually all components of the extracellular matrix. MMPs can also process substrates distinct from extracellular matrix proteins and influence cell proliferation, differentiation, angiogenesis, and apoptosis. MMP activity is regulated by their natural inhibitors, tissue inhibitors of metallopro-teinases (TIMPs). In this study, the expression patterns of MMPs, TIMPs, and certain cancer-related molecules were investigated in premalignant and malignant lesions of the human skin. As methods were used immunohistochemisty, in situ hybridization, and reverse transcriptase polymerase chain reaction (RT-PCR) from the cell cultures. Our aim was to evaluate the expression pattern of MMPs in extramammary Paget's disease in order to find markers for more advanced tumors, as well as to shed light on the origin of this rare neoplasm. Novel MMPs -21, -26, and -28 were studied in melanoma cell culture, in primary cutaneous melanomas, and their sentinel nodes. The MMP expression profile in keratoacanthomas and well-differentiated squamous cell carcinomas was analyzed to find markers to differentiate benign keratinocyte hyperproliferation from malignantly transformed cells. Squamous cell carcinomas of immunosuppressed organ transplant recipients were compared to squamous cell carcinomas of matched immunocompetent controls to investigate the factors explaining their more aggressive nature. We found that MMP-7 and -19 proteins are abundant in extramammary Paget's disease and that their presence may predict an underlying adenocarcinoma in these patients. In melanomas, MMP-21 was upregulated in early phases of melanoma progression, but disappeared from the more aggressive tumors with lymph node metastases. The presence of MMP-13 in primary melanomas and lymph node metastases may relate to more aggressive disease. In keratoacanthomas, the expression of MMP-7 and -9 is rare and therefore should raise a suspicion of well-differentiated squamous cell carcinomas. Furthermore, MMP-19 and p16 were observed in benign keratinocyte hyperproliferation of keratoacanthomas, whereas they were generally lost from malignant keratinocytes of SCCs. MMP-26 staining was significantly stronger in squamous cell carcinomas and Bowen s disease samples of organ transplant recipients and it may contribute to the more aggressive nature of squamous cell carcinomas in immunosuppressed patients. In addition, the staining for MMP-9 was significantly stronger in macrophages surrounding the tumors of the immunocompetent group and in neutrophils of those patients on cyclosporin medication. In conclusion, based on our studies, MMP-7 and -19 might serve as biomarkers for more aggressive extramammary Paget's disease and MMP-21 for malignant transformation of melanocytes. MMP -7, -9, and -26, however, could play an important role in the pathobiology of keratinocyte derived malignancies.

Experimental investigation on lateral impact response of concrete-filled double-skin tube columns using horizontal-impact-testing system

This paper presents an experimental investigation on the lateral impact performance of axially loaded concrete-filled double-skin tube (CFDST) columns. These columns have desirable structural and constructional properties and have been used as columns in building, legs of off shore platforms and as bridge piers. Since they could be vulnerable to impact from passing vessels or vehicles, it is necessary to understand their behaviour under lateral impact loads. With this in mind, an experimental method employing an innovative instrumented horizontal impact testing system (HITS) was developed to apply lateral impact loads whilst the column maintained a static axial pre-loading to examine the failure mechanism and key response parameters of the column. These included the time histories of impact force, reaction forces, global lateral deflection and permanent local buckling profile. Eight full scale columns were tested for key parameters including the axial load level and impact location. Based on the test data, the failure mode, peak impact force, impact duration, peak reaction forces, reaction force duration, column maximum and residual global deflections and column local buckling length, depth and width under varying conditions are analysed and discussed. It is evident that the innovative HITS can successfully test structural columns under the combination of axial pre-loading and impact loading. The findings on the lateral impact response of the CFDST columns can serve as a benchmark reference for their future analysis and design.

The Risk of Cancer Associated with Immunosuppressive Therapy for Skin Diseases

The possible carcinogenic risk of immunosuppressive therapies is an important issue in everyday clinical practise. Carcinogenesis is a slow multi step procedure, thus a long latency period is needed before cancer develops. PUVA therapy is used for many skin diseases including psoriasis, early stage cutaneous T cell lymphoma, atopic dermatitis, palmoplantar pustulosis and chronic eczema. There has been concern about the increased melanoma risk associated to PUVA therapy, which has previously been associated with an increased risk on non-melanoma skin cancer, especially squamous cell carcinoma. The increased risk of basal cell carcinoma (BCC) is also documented but it is modest compared to squamous cell carcinoma (SCC). This thesis evaluated melanoma and noncutaneous cancer risk associated to PUVA, and the persistence of nonmelanoma cancer risk after the cessation of PUVA treatment. Also, the influence of photochemotherapy to the development of secondary cancers in cutaneous T cell lymphoma and the role of short term cyclosporine in later cancer development in inflammatory skin diseases were evaluated. The first three studies were performed on psoriasis patients. The risk of melanoma started to increase 15 years after the first treatment with PUVA. The risk was highest among persons who had received over 250 treatments compared to those under 250 treatments. In noncutaneous cancer, the overall risk was not increased (RR=1.08,95% CI=0.93-1.24), but significant increases in risk were found in thyroid cancer, breast cancer and in central nervous system neoplasms. These cancers were not associated to PUVA. The increased risk of SCC was associated to high cumulative UVA exposure in the PUVA regimen. The patients with high risk had no substantial exposure to other carcinogens. In BCC there was a similar but more modest tendency. In the two other studies, the risk of all secondary cancers (SIR) in CTCL patients was 1.4 (95% CI=1.0-1.9). In separate sites, the risk of lung cancer, Hodgkin and non-Hodgkin lymphomas were increased. PUVA seemed not to contribute to any extent to the appearance of these cancers. The carcinogenity of short-term cyclosporine was evaluated in inflammatory skin diseases. No increased risk for any type of cancer including the skin cancers was detected. To conclude, our studies confirm the increased skin cancer risk related to PUVA treatment in psoriasis patients. In clinical practice, this has led to a close and permanent follow-up of patients treated with PUVA. In CTCL patients, PUVA treatment did not contribute to the development of secondary cancers. We could not detect any increase in the risk of cancer in patients treated with short term cyclosporine, unlike in organ transplant patients under such long-term therapy.

Topical tacrolimus in atopic dermatitis : Effects of long-term treatment on skin and respiratory symptoms

Objective: Patients with atopic dermatitis often have a poor long-term response to conventional topical or systemic treatments. Staphylococcal superinfections, skin atrophy due to corticosteroid use, and asthma and allergic rhinitis are common. Only a few, usually short-term, studies have addressed the effects of different treatments on these problems. Tacrolimus ointment is the first topical compound suitable for long-term treatment. The aim of this thesis was to evaluate the effects of long-term topical tacrolimus treatment on cutaneous staphylococcal colonization, collagen synthesis, and symptoms and signs of asthma and allergic rhinitis. Methods: Patients with moderate-to-severe atopic dermatitis were treated with intermittent 0.1% tacrolimus ointment in prospective, open studies lasting for 6 to 48 months. In Study I, cutaneous staphylococcal colonization was followed for 6 to 12 months. In Study II, skin thickness and collagen synthesis were followed by skin ultrasound and procollagen I and III propeptide concentrations of suction blister fluid samples for 12 to 24 months and compared with a group of corticosteroid-treated atopic dermatitis patients and with a group of healthy subjects. Study III was a cross-sectional study of the occurrence of respiratory symptoms, bronchial hyper-responsiveness, and sputum eosinophilia in atopic dermatitis patients and healthy controls. In Study V, the same parameters as in Study III were assessed in atopic dermatitis patients before and after 12 to 48 months of topical tacrolimus treatment. Study IV was a retrospective follow-up of the effect of tacrolimus 0.03% ointment on severe atopic blepharoconjunctivitis and conjunctival cytology. Results: The clinical response to topical tacrolimus was very good in all studies (p≤0.008). Staphylococcal colonization decreased significantly, and the effect was sustained throughout the study (p=0.01). Skin thickness (p<0.001) and markers of collagen synthesis (p<0.001) increased in the tacrolimus-treated patients significantly, whereas they decreased or remained unchanged in the corticosteroid-treated controls. Symptoms of asthma and allergic rhinitis (p<0.0001), bronchial hyper-responsiveness (p<0.0001), and sputum eosinophilia (p<0.0001) were significantly more common in patients with atopic dermatitis than in healthy controls, especially in subjects with positive skin prick tests or elevated serum immunoglobulin E. During topical tacrolimus treatment the asthma and rhinitis (p=0.005 and p=0.002) symptoms and bronchial hyper-responsiveness (p=0.02) decreased significantly, and serum immunoglobulin E and sputum eosinophils showed a decreasing trend in patients with the best treatment response. Treatment of atopic blepharoconjunctivitis resulted in a marked clinical response and a significant decrease in eosinophils, lymphocytes, and neutrophils in the conjunctival cytology samples. No significant adverse effects or increase in skin infections occurred in any study. Conclusions: The studies included in this thesis, except the study showing an increase in skin collagen synthesis in tacrolimus-treated patients, were uncontrolled, warranting certain reservations. The results suggest, however, that tacrolimus ointment has several beneficial effects in the long-term intermittent treatment of atopic dermatitis. Tacrolimus ointment efficiently suppresses the T cell-induced inflammation of atopic dermatitis. It has a normalizing effect on the function of the skin measured by the decrease in staphylococcal colonization. It does not cause skin atrophy as do corticosteroids but restores the skin collagen synthesis in patients who have used corticosteroids. Tacrolimus ointment has no marked systemic effect, as the absorption of the drug is minimal and decreases along with skin improvement. The effects on the airway: decrease in bronchial hyper-responsiveness and respiratory symptoms, can be speculated to be caused by the decrease in T cell trafficking from the skin to the respiratory tissues as the skin inflammation resolves, as well as inhibition of epicutaneous invasion of various antigens causing systemic sensitization when the skin barrier is disrupted as in atopic dermatitis. Patients with moderate-to-severe atopic dermatitis seem to benefit from efficient long-term treatment with topical tacrolimus.

The skin safety model: Reconceptualizing skin vulnerability in older patients

Purpose: To develop a unique skin safety model (SSM) that offers a new and unified perspective on the diverse yet interconnected antecedents that contribute to a spectrum of potential iatrogenic skin injuries in older hospitalized adults. Organizing Construct: Discussion paper. Methods: A literature search of electronic databases was conducted for published articles written in English addressing skin integrity and iatrogenic skin injury in elderly hospital patients between 1960 and 2014. Findings: There is a multiplicity of literature outlining the etiology, prevention, and management of specific iatrogenic skin injuries. Complex and interrelated factors contribute to iatrogenic skin injury in the older adult, including multiple comorbidities, factors influencing healthcare delivery, and acute situational stressors. A range of injuries can result when these factors are com- plicated by skin irritants, pressure, shear, or friction; however, despite skin injuries sharing multiple ntecedents, no unified overarching skin safety conceptual model has been published. Conclusions: The SSM presented in this article offers a new, unified framework that encompasses the spectrum of antecedents to skin vulnerability as well as the spectrum of iatrogenic skin injuries that may be sustained by older acute care patients. Current skin integrity frameworks address prevention and management of specific skin injuries. In contrast, the SSM recognizes the complex interplay of patient and system factors that may result in a range of iatrogenic skin injuries. Skin safety is reconceptualized into a single model that has the potential for application at the individual patient level, as well as health-care systems and governance levels. Clinical Relevance: Skin safety is concerned with keeping skin safe from any iatrogenic skin injury, and remains an ongoing challenge for healthcare providers. A conceptual framework that encompasses all of the factors that may contribute to a range of iatrogenic skin injuries is essential, and guides the clinician in maintaining skin integrity in the vulnerable older patient.

Concrete-filled double skin tube columns subjected to lateral impact loading: Experimental and numerical study

This research treats the lateral impact behaviour of composite columns, which find increasing use as bridge piers and building columns. It offers (1) innovative experimental methods for testing structural columns, (2) dynamic computer simulation techniques as a viable tool in analysis and design of such columns and (3) significant new information on their performance which can be used in design. The research outcomes will enable to protect lives and properties against the risk of vehicular impacts caused either accidentally or intentionally.

Experimental study on behaviour of concrete filled double skin tube columns under lateral impact loading

This paper presents an experimental investigation on the lateral impact response of axially loaded concrete filled double skin tube (CFDST) columns. A total of four test series are being conducted at Queensland University of Technology using a novel horizontal impact-testing rig. The test results reported in this paper are from the first test series, where the columns are pinned at both ends and impacted at mid-span. In the next three series, effects of support conditions, impact location and repeated impact will be treated. The main objectives of the current paper are to describe the innovative testing procedure and provide some insight into the lateral impact behavior and failure of simply supported axially pre-loaded CFDST columns. The results include time histories of impact forces, reaction forces, axial force and global lateral deflection. Based on the test data, the failure mode, peak impact force, peak reaction forces, maximum deflection and residual deflection, with and without axial load, are analyzed and discussed. The findings of this study will serve as a benchmark reference for future analysis and design of CFDST columns.

Reflections from East Asia's ageing population: An interaction designers' challenge

As Asia experiences the demographic imbalance between working and ageing populations, the need for attention in this area is highlighted. The shift of a country's age structure that results from people having small families and living long lives, where previously they had large families and lived short lives, results in more workers and fewer dependents creating economic growth, known as the demographic dividend. However for a generation after this bulge and dividend, a disproportionate number of older people must be supported by a smaller working population, a current concern in Asia with its rapidly growing number of older adults. This extended abstract draws practical and unique insights from three of the oldest and richest nations in Asia - Japan, South Korea and China, on the perspective of interactive technology design for older adults. ICT has powerful potential to ameliorate the imbalance in the population demographic through its potential to leverage various kinds of support. As HCI researchers, this is a challenge we embrace; a challenge for the ageing society of unique individuals to exploit the technologies that they have helped to create. The paper draws lessons from key sample studies, one from each country, which aimed to understand their ageing population. The insights for interaction designers are presented in the form of a practical set of reflections to guide the authors, who are in the early stages of research on technology design for older adults.

The effect of ageing on microstructure and nanoindentation behaviour of dc magnetron sputter deposited nickel rich NiTi films

Nickel rich NiTi films were sputter deposited on p-doped Si left angle bracket1 0 0right-pointing angle bracket substrates maintained at 300 °C. The films were subsequently solution treated at 700 °C for 30 min followed by ageing at 400 and 500 °C for 5 h. The microstructure of the films was examined by TEM and these studies revealed that the NiTi films were mostly amorphous in the as-deposited condition. The subsequent solution treatment and ageing resulted in crystallization of the films with the film aged at 400 °C exhibiting nanocrystalline grains and three phases viz. B2 (austenite), R and Ni3Ti2 whereas the film aged at 500 °C shows micron sized grains and two phases viz. R and Ni3Ti2. Nanoindentation studies revealed that the nature of the load versus indentation depth response for the films aged at 400 and 500 °C was different. For the same load, the indenter penetrated to a much greater depth for the film aged at 400 °C as compared to the film aged at 500 °C. Also the ratio of the residual indentation depth (hf) to maximum indentation depth (hmax) is lower for the film aged at 400 °C as compared to the film aged at 500 °C. This was attributed to the occurrence of stress induced martensitic transformation of the B2 phase present in the film aged at 400 °C during indentation loading which results in a transformation strain in addition to the normal elastic and plastic strains and its subsequent recovery on unloading. The hardness and elastic modulus measured using the Oliver and Pharr analysis was also found to be lower for the film aged at 400 °C as compared to the film aged at 500 °C which was also primarily attributed to the same effect.

Ageing and learning in Australia: Arguing an evidence base for informed and equitable policy

Given Australia’s population ageing and predicted impacts related to health, productivity, equity and enhancing quality of life outcomes for senior Australians, lifelong learning has been identified as a pathway for addressing the risks associated with an ageing population. To date Australian governments have paid little attention to addressing these needs and thus, there is an urgent need for policy development for lifelong learning as a national priority. The purpose of this article is to explore the current lifelong learning context in Australia and to propose a set of factors that are most likely to impact learning in later years.

Ageing and learning as conceptualized by senior adults in two cultures: Hong Kong and Australia

This paper is about a study aimed to understand what successful ageing and later life learning mean to older adults in two cultures: Hong Kong and Australia. Findings from the study were reported in this paper to shed light on: (1) the meaning of ageing and learning as conceptualized by elders in Hong Kong and Australia; (2) the reasons for participation in later life learning, as well as, barriers for non-participation; (3) their learning interests and instructional preferences, and finally (4) the correlation between learning and successful ageing, and between learning and other well-being variables, including health, happiness and satisfaction of elders in Hong Kong and Australia. Two large samples of elders from Hong Kong (n=519) and Queensland, Australia (n=421) participated in the study. Within group analysis of the data from the two locations indicated that there are more similarities, rather than differences, between elders in Hong Kong and Australia with respect to background characteristics, meanings of ageing and learning, reasons for participation, barriers for non-participation, learning interests and instructional preferences.

Studies on the ageing behaviour of Polyvinylchloride/ammonium perchlorate composite solid propellant

The effects of ageing on the properties of a complete polyvinyl chloride — dibutyl phthalate — ammonium perchlorate solid propellant have been studied by measurements of burning rates, thermal decomposition rates (by thermogravimetry and DTA) and calorimetric values. Ageing leads to loss of HCl by dehydrochlorination and a corresponding increase in heat of combustion.