Rationale:Patients with acute coronary syndrome (ACS) predisposed to recurrent coronary events have an expansion of a distinctive T-cell subset, the CD4 ؉ CD28 null T cells. These cells are highly inflammatory and cytotoxic in spite of lacking the costimulatory receptor CD28, which is crucial for optimal T cell function. The mechanisms that govern CD4 ؉ CD28null T cell function are unknown.Objective: Our aim was to investigate the expression and role of alternative costimulatory receptors in CD4 ؉ CD28 null T cells in ACS. Methods and Results: Expression of alternative costimulatory receptors (inducible costimulator, OX40, 4 -1BB,cytotoxic T lymphocyte associated antigen-4, programmed death-1) was quantified in CD4 ؉ CD28 null T cells from circulation of ACS and stable angina patients. Strikingly, in ACS, levels of OX40 and 4-1BB were significantly higher in circulating CD4 ؉ CD28null T cells compared to classical CD4 ؉ CD28 ؉ T lymphocytes. This was not observed in stable angina patients. Furthermore, CD4؉ CD28 null T cells constituted an important proportion of CD4 ؉ T lymphocytes in human atherosclerotic plaques and exhibited high levels of OX40 and 4-1BB. In addition, the ligands for OX40 and 4-1BB were present in plaques and also expressed on monocytes in circulation. Importantly, blockade of OX40 and 4-1BB reduced the ability of CD4 ؉ CD28null T cells to produce interferon-␥ and tumor necrosis factor-␣ and release perforin. Key Words: atherosclerosis Ⅲ coronary disease Ⅲ immune system Ⅲ lymphocytes Ⅲ receptors C oronary artery disease continues to be the leading cause of death in the developed world. Recent research has demonstrated that coronary artery disease results from an uncontrolled immune response and T lymphocytes have a central role in the development and progression of the disease. 1,2 Detailed analysis of CD4 ϩ T cells in coronary artery disease unveiled an increased frequency of a distinctive subset of lymphocytes called CD4 ϩ CD28 Conclusions: Costimulatory pathways are altered in CD4؉null T cells. 3 These cells are characterized by the lack of CD28, the main costimulatory receptor that regulates the response of T lymphocytes to antigen. 4 The CD4 ϩ CD28null T cell subset is present in low frequencies in healthy individuals and has also been shown to increase in patients with chronic inflammatory diseases such as autoimmunity. 5 In coronary artery disease, the frequency of CD4 The proinflammatory features of CD4 ϩ CD28 null T lymphocytes are surprising, as the activation and survival of T cells depends on costimulatory signals delivered via the CD28 receptor. 4 The activation of T cells requires not only the recognition of antigen, but also a second signal delivered by the interaction of the CD28 costimulatory receptor on T cells with its ligands on antigen presenting cells. 4 CD28 signaling controls the expression of interleukin-2 receptors and the production of interleukin-2 by activated T cells, which enable their proliferation, differentiation into effectors and survival. 12 Indeed, in th...

BackgroundArtesunate is an antimalarial agent with broad anti-cancer activity in in vitro and animal experiments and case reports. Artesunate has not been studied in rigorous clinical trials for anticancer effects.AimTo determine the anticancer effect and tolerability of oral artesunate in colorectal cancer (CRC).MethodsThis was a single centre, randomised, double-blind, placebo-controlled trial. Patients planned for curative resection of biopsy confirmed single primary site CRC were randomised (n = 23) by computer-generated code supplied in opaque envelopes to receive preoperatively either 14 daily doses of oral artesunate (200 mg; n = 12) or placebo (n = 11). The primary outcome measure was the proportion of tumour cells undergoing apoptosis (significant if > 7% showed Tunel staining). Secondary immunohistochemical outcomes assessed these tumour markers: VEGF, EGFR, c-MYC, CD31, Ki67 and p53, and clinical responses.Findings20 patients (artesunate = 9, placebo = 11) completed the trial per protocol. Randomization groups were comparable clinically and for tumour characteristics. Apoptosis in > 7% of cells was seen in 67% and 55% of patients in artesunate and placebo groups, respectively. Using Bayesian analysis, the probabilities of an artesunate treatment effect reducing Ki67 and increasing CD31 expression were 0.89 and 0.79, respectively. During a median follow up of 42 months 1 patient in the artesunate and 6 patients in the placebo group developed recurrent CRC.InterpretationArtesunate has anti-proliferative properties in CRC and is generally well tolerated.

Dietary supplementation with EPA significantly increases levels of this fatty acid in colonic mucosa, associated with significantly reduced proliferation and increased mucosal apoptosis. Further studies are needed to assess the potential efficacy of EPA supplementation in preventing polyps in the chemoprevention of colorectal cancer.

The interstitial cells of Cajal (ICC) are thought to play an important role in the control of gut motility. The regional and transmural pattern of distribution of ICC in the normal human colon and rectum was evaluated with immunohistochemistry using an anti-c- kit antibody. The transmural distribution of ICC was constant throughout the whole colon, the density of ICC was significantly greater at the myenteric plexus than at either the longitudinal or circular muscle layers, and in the rectum the transmural distribution was more even. Regionally, at the myenteric plexus, the transverse colon had a significantly greater density of ICC compared with the right colon ( P = 0.038), left colon ( P = 0.006), and rectum ( P = 0.008). The pattern of distribution of ICC identified in this study is consistent with the proposed roles of ICC as colorectal pacemakers, intermediaries of the neural control of muscle activity, and coordinators of colorectal muscle activity. The highest density of ICC was at the myenteric plexus of the transverse colon, which is the proposed region of pacemaking activity.

These data suggest that extranodal deposit is a distinct form of metastatic disease in patients with rectal cancer. The association with vascular invasion and earlier development of metastases probably infers that a significant proportion of extranodal deposits may represent blood-borne spread. These tumor foci should be considered as indicators of poor prognosis.