Reactive oxygen species (ROS) play a pivotal role in the orchestration of the normal wound-healing response. They act as secondary messengers to many immunocytes and non-lymphoid cells, which are involved in the repair process, and appear to be important in coordinating the recruitment of lymphoid cells to the wound site and effective tissue repair. ROS also possess the ability to regulate the formation of blood vessels (angiogenesis) at the wound site and the optimal perfusion of blood into the wound-healing area. ROS act in the host's defence through phagocytes that induce an ROS burst onto the pathogens present in wounds, leading to their destruction, and during this period, excess ROS leakage into the surrounding environment has further bacteriostatic effects. In light of these important roles of ROS in wound healing and the continued quest for therapeutic strategies to treat wounds in general and chronic wounds, such as diabetic foot ulcers, venous and arterial leg ulcers and pressure ulcers in particular, the manipulation of ROS represents a promising avenue for improving wound-healing responses when they are stalled. This article presents a review of the evidence supporting the critical role of ROS in wound healing and infection control at the wound site, and some of the new emerging concepts associated with ROS modulation and its potential in improving wound healing are discussed.

Membrane-presented CD40 agonists can induce apoptosis in carcinoma, but not normal homologous epithelial cells, whereas soluble agonists are growth inhibitory but not proapoptotic unless protein synthesis is blocked. Here we demonstrate that membrane-presented CD40 ligand (CD154) (mCD40L), but not soluble agonists, triggers cell death in malignant human urothelial cells via a direct mechanism involving rapid upregulation of TNFR-associated factor (TRAF)3 protein, without concomitant upregulation of TRAF3 mRNA, followed by activation of the c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) pathway and induction of the caspase-9/caspase-3-associated intrinsic apoptotic machinery. TRAF3 knockdown abrogated JNK/AP-1 activation and prevented CD40-mediated apoptosis, whereas restoration of CD40 expression in CD40-negative carcinoma cells restored apoptotic susceptibility via the TRAF3/AP-1-dependent mechanism. In normal human urothelial cells, mCD40L did not trigger apoptosis, but induced rapid downregulation of TRAF2 and 3, thereby paralleling the situation in Blymphocytes. Thus, TRAF3 stabilization, JNK activation and caspase-9 induction define a novel pathway of CD40-mediated apoptosis in carcinoma cells.

We have examined the possibility that the E7 proteins of the high-risk human papillomavirus (HPV) type 16 and 18 and the oncogenic adenovirus (Ad) type 12 E1A protein share the ability to down-regulate the expression of components of the antigen processing and presentation pathway, as a common strategy in the evasion of immune surveillance during the induction of cell transformation. Expression of the HPV 18 E7 oncoprotein, like Ad 12 E1A, resulted in repression of the major histocompatibility complex (MHC) class I heavy chain promoter, as well as repression of a bidirectional promoter that regulates expression of the genes encoding the transporter associated with antigen processing subunit 1 (TAP1) and a proteasome subunit, low molecular weight protein 2 (LMP2). HPV 16 E7 also caused a reduction in class I heavy chain promoter activity, however it did not have any signi®cant e ect on the activity of the bidirectional promoter. Interestingly, expression of the low-risk HPV 6b E7 protein resulted in an increase in MHC class I heavy chain promoter activity, while repressing the TAP1/LMP2 promoter. Interference with the class I pathway could also explain the ability of low-risk HPVs in inducing benign lesions. Oncogene (2000) 19, 4930 ± 4935.

No abstract

A close connectivity between autoimmune and tumor rejection responses is known to exist in the case of melanoma immunotherapy. However, relatively little is known about selfantigens on other types of normal cells, their relation to the development of autoimmune disease, and their possible coexistence as potential tumor rejection antigens on associated tumors. In the current study, we induced inflammatory killing of normal prostate tissue in situ using a fusogenic membrane glycoprotein along with the immune adjuvant hsp70. We show here that, in the prostate, hsp70 induces interleukin (IL)-6, which triggers a CD4-and CD8-dependent progressive autoimmune reactivity, associated with IL-17 expression. This autoimmune response was also able to induce the rejection of established prostate tumors, but not other histologic types of tumors, growing elsewhere in the animal. These data show that the intimate connectivity between autoimmune and tumor rejection responses extends beyond the classic melanoma paradigm and may be clinically valuable for the treatment of established metastatic disease of the prostate. [Cancer Res 2007;67(24):11970-9]

No abstract

Chemotherapy-induced alopecia (CIA) represents perhaps the most distressing side effect of chemotherapeutic agents and is of huge concern to the majority of patients. Scalp cooling is currently the only safe option to combat CIA. Clinical and biological evidence suggests improvements can be made, including efficacy in delivering adequately low temperature to the scalp and patient-specific cap design. The increased use of scalp cooling, an understanding of how to deliver it most effectively, and biological evidence-based approaches to improve its efficacy have enormous potential to ease the psychological burden of CIA, as this could lead to improvements in treatment and patient quality-of-life.

Bladder cancer is the fifth most common cancer in the UK, yet human bladder carcinogenesis remains poorly understood and the response of bladder tumours to radio- and chemo-therapy is unpredictable. The aims of this article are to review human bladder carcinogenesis and appraise the different in vitro and in vivo approaches that have been developed to study the process. The review considers how in vitro models based on normal human urothelial (NHU) cells can be applied to human bladder cancer research. We conclude that recent advances in NHU cell culture offer novel approaches for defining urothelial tissue-specific responses to genotoxic and non-genotoxic carcinogens and elucidating the role of specific genes involved in the mechanisms of bladder carcinogenesis and malignant progression.