Progression through the various stages of skin tumorigenesis is correlated with an altered expression of the integrin α3β1, suggesting that it plays an important role in the tumorigenic process. Using epidermis-specific Itga3 KO mice subjected to the 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate two-stage skin carcinogenesis protocol, we demonstrate that efficient tumor development is critically dependent on the presence of α3β1. In the absence of α3β1, tumor initiation is dramatically decreased because of increased epidermal turnover, leading to a loss of DMBA-initiated label-retaining keratinocytes. Lineage tracing revealed emigration of α3-deficient keratinocytes residing in the bulge of the hair follicle toward the interfollicular epidermis. Furthermore, tumor growth and cell proliferation were strongly reduced in mice with an epidermis-specific deletion of Itga3. However, the rate of progression of α3β1-null squamous cell carcinomas to undifferentiated, invasive carcinomas was increased. Therefore, α3β1 critically affects skin carcinogenesis with opposing effects early and late in tumorigenesis.skin cancer | cell adhesion | cell migration | laminin receptor | hair cycling S kin cancer is the most common form of cancer among white populations, with basal cell carcinomas and squamous cell carcinomas (SSCs) being the most common subtypes. Although early detection and surgical resection can prevent most complications associated with this disease, SCCs frequently metastasize and then cannot be effectively treated. Understanding the molecular basis of skin tumorigenesis is a prerequisite for future prevention and therapy. The well-characterized 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) protocol models the multistep nature of human skin carcinogenesis in mice. Oncogenic mutations (e.g., Hras), induced by a single treatment with the carcinogen DMBA confer growth advantage to the initiated cells, which form benign papillomas under repetitive tumorpromoting treatments with the phorbol ester TPA. Subsequent progression to SCCs involves mutation of Trp53 and trisomization of chromosomes 6 and 7 (1-5).Integrins are αβ heterodimeric adhesion receptors that play an important role in maintaining epithelial integrity. In the skin, the major integrins α2β1, α3β1, and α6β4 connect the cytoskeleton of basal keratinocytes to the underlying basement membrane (6). Besides their key function in skin physiology, these integrins also have been implicated in the development and progression of SCCs (7). Mouse models in which different integrins are either overexpressed in the suprabasal epidermis or mutated in the whole animal showed altered susceptibilities to chemically induced skin tumorigenesis (8-10). Increased expression of α2β1, α3β1, and α6β4 has been observed in hyperproliferating human cancers of the head and neck (11). Integrins thus seem to play a role in initiation and promotion of tumors. Surprisingly, the role of α3β1 in basal keratinocytes in skin tumorigene...
Background In order to improve adherence to treatment guidelines and performance indicators advocating tight control of disease activity in rheumatoid arthritis (RA), it is important to gain insight into the factors influencing rheumatologists’ decisions whether or not to escalate care. Objective To determine the influence of specific attributes relative to a validated measure of disease activity (DAS) on rheumatologists’ decision to escalate care. Methods We used a computer-based choice-based conjoint (CBC) analysis survey to determine the relative importance of six attributes on rheumatologists’ decisions related to escalation of care in RA. We administered the survey in a convenience sample of rheumatologists attending the 2008 ACR national meeting. Utilities were calculated using hierarchical Bayes modeling and these results were used to calculate the relative importance of each attribute. Results Rheumatologists assigned the most importance to the DAS score (relative importance of 30.7%) in their decision to escalate care. The age of the patient (21.5%) and erosions (20.5%) were rated as equally important in this decision. The decision to escalate care was least influenced by change in symptoms reported by the patient (11.1%), current treatment (8.9%) and disease duration (7.4%). Conclusion Our findings suggest that rheumatologists endorse the DAS as a means to guide decision making in RA. We also found that age and erosions are important influences on rheumatologists’ decision to escalate care in RA. Our results add to the literature supporting age bias in RA and suggest that further research is needed to determine how age affects quality of care in clinical practice.
A heterogeneous set of factors highlights the complexity of prescribing ICTS for early RA in daily clinical practice. Future improvement strategies should stimulate the facilitators while at the same time addressing the barriers. The generalizability of these findings to other health care systems needs further examination.
Altered expression of the tetraspanin CD151 is associated with skin tumorigenesis; however, whether CD151 is causally involved in the tumorigenic process is not known. To evaluate its role in tumor formation, we subjected epidermis-specific Cd151 knockout mice to chemical skin carcinogenesis. Mice lacking epidermal Cd151 developed fewer and smaller tumors than wild-type mice following DMBA/TPA treatment. Furthermore, Cd151-null epidermis showed a reduced hyperproliferative response to short-term treatment with TPA compared to that of wild-type skin, while epidermal turnover was increased. Tumors were formed in equal numbers following DMBA only treatment. We suggest that DMBA-initiated keratinocytes lacking Cd151 leave their niches in the epidermis and hair follicles in response to TPA treatment and subsequently are lost by differentiation. Because genetic ablation of Itga3 also reduced skin tumor formation, we tested whether reduced expression of α3 could further suppress tumor formation in epidermis-specific Cd151 knockout mice. Although the response to DMBA/TPA-induced formation of skin tumors was similar in compound heterozygotes for Cd151 and Itga3 to that in wild-type mice, heterozygosity for Itga3 on a Cd151-null background diminished tumorigenesis suggesting genetic interaction between the two genes. We thus identify CD151 as a critical factor in TPA-dependent skin carcinogenesis.
Background In the current recommendations for early rheumatoid arthritis (RA) management, the focus is set to achieve clinical remission as soon as possible with an early and intensive treatment. Our previous research indicated that rheumatologists’ perception of patients’ concerns at initation influenced their prescription behaviour of intensive combination treatment strategies (ICTS). Understanding patients’ perspectives on ICTS is necessary to identify opportunities to improve early RA care. Objectives To explore early RA patients’ perceptions of and experiences with ICTS at an early stage in their care process. Methods A qualitative study was carried out using individual semi-structured interviews with early RA patients who agreed to ICTS within the CareRA trial four months earlier. The CareRA trial is a multicentre RCT across Flanders comparing different ICTS for early RA with conventional DMARDs plus step-down glucocorticoids. Data saturation was reached after 26 interviews. Each interview was recorded, transcribed literally and thematically coded using the constant comparative method. Results Patients indicated that when ICTS was advised they were afraid of the side-effects in the short term and of the health consequences of the treatment in the long-term. At the same time, many patients reported that it was confronting to hear what the treatment entailed just after being burdened with the diagnosis of RA. Motivations for the decision to agree with intensive treatment initiation were faith in the treatment and healthcare team and knowing the medication would be phased out eventually. Patients who initiated ICTS reported that their negative feelings disappeared and that ICTS was easily incorporated into their daily life. Conclusions Despite their concerns when ICTS was advised, most patients had positive experiences with ICTS once initiated. The study findings may be helpful for healthcare professionals to understand patients’ concerns and to support them in their decision-making process to initiate ICTS. References Meyfroidt S, van Hulst L, De Cock D, Van der Elst K, Joly J, Westhovens R, Hulscher M, and Verschueren P. (2012) Intensive combination treatment strategies for early rheumatoid arthritis: a qualitative study of rheumatologists’ and nurses’ experiences and views. Manuscript submitted for publication. Acknowledgements The authors thank the healthcare professionals and their patients for their participation in this study. Disclosure of Interest None Declared
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