Citations

Abstract Lapatinib (GW572016) is a selective inhibitor of both epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases. Here, we explore the therapeutic potential of lapatinib by testing its effect on tumor cell growth in a panel of 31 characterized human breast cancer cell lines, including trastuzumab-conditioned HER-2-positive cell lines. We further characterize its activity in combination with trastuzumab and analyze whether EGFR and HER-2 expression or changes induced in the activation of EGFR, HER-2, Raf, AKT, or extracellular signal-regulated kinase (ERK) are markers of drug activity. We report that concentration-dependent antiproliferative effects of lapatinib were seen in all breast cancer cell lines tested but varied significantly between individual cell lines with up to 1,000-fold difference in the IC50s (range, 0.010-18.6 μmol/L). Response to lapatinib was significantly correlated with HER-2 expression and its ability to inhibit HER-2, Raf, AKT, and ERK phosphorylation. Long-term in vivo lapatinib studies were conducted with human breast cancer xenografts in athymic mice. Treatment over 77 days resulted in a sustained and significant reduction in xenograft volume compared with untreated controls. For the combination of lapatinib plus trastuzumab, synergistic drug interactions were observed in four different HER-2-overexpressing cell lines. Moreover, lapatinib retained significant in vitro activity against cell lines selected for long-term outgrowth (>9 months) in trastuzumab-containing (100 μg/mL) culture medium. These observations provide a clear biological rationale to test lapatinib as a single agent or in combination with trastuzumab in HER-2-overexpressing breast cancer and in patients with clinical resistance to trastuzumab. (Cancer Res 2006; 66(3): 1630-9)

Non-exercise activity thermogenesis (NEAT) is the energy expenditure of all physical activities other than volitional sporting-like exercise. NEAT includes all the activities that render us vibrant, unique, and independent beings such as working, playing, and dancing. Because people of the same weight have markedly variable activity levels, it is not surprising that NEAT varies substantially between people by up to 2000 kcal per day. Evidence suggests that low NEAT may occur in obesity but in a very specific fashion. Obese individuals appear to exhibit an innate tendency to be seated for 2.5 hours per day more than sedentary lean counterparts. If obese individuals were to adopt the lean “NEAT-o-type,” they could potentially expend an additional 350 kcal per day. Obesity was rare a century ago and the human genotype has not changed over that time. Thus, the obesity epidemic may reflect the emergence of a chair-enticing environment to which those with an innate tendency to sit, did so, and became obese. To reverse obesity, we need to develop individual strategies to promote standing and ambulating time by 2.5 hours per day and also re-engineer our work, school, and home environments to render active living the option of choice.

Purpose Results of a prospective randomized trial conducted by the Intergroupe Francais du Myélome (IFM 90) indicated that autologous hematopoietic cell–supported high-dose therapy (HDT) effected higher complete response rates and extended progression-free survial (PFS) and overall survival (OS) compared with standard-dose therapies (SDT) for patients with multiple myeloma (MM). Patients and Methods In 1993, three North American cooperative groups launched a prospective randomized trial (S9321) comparing HDT (melphalan [MEL] 140 mg/m 2 plus total-body irradiation 12 Gy) with SDT using the vincristine, carmustine, MEL, cyclophosphamide, and prednisone regimen. Responders on both arms (≥ 75%) were randomly assigned to interferon (IFN) or no maintenance treatment. Results With a median follow-up time of 76 months, no differences were observed in response rates between the two study arms (HDT, n = 261 patients; SDT, n = 255 patients). Similarly, PFS and OS durations did not differ between the HDT and SDT arms, with 7-year estimates of PFS of 17% and 16%, respectively, and OS of 37% and 42%, respectively. Of 242 patients achieving at least 75% tumor reduction, no difference was observed in PFS or OS among the 121 patients randomly assigned to IFN and the 121 patients randomly assigned to no maintenance therapy. Among 157 patients relapsing on SDT, 87 received a salvage autotransplantation; their median survival time of 30 months was only slightly better than the survival time of the remaining patients who were managed with further SDT (23 months; P = .13). Conclusion The HDT and SDT regimens used in S9321 yielded comparable response rates and PFS and OS durations. IFN maintenance therapy did not benefit patients who achieved ≥ 75% tumor reduction on either arm.

CD4 T cells, through the release of cytokines as well as direct effector functions, have been implicated in promoting inflammation of the atherosclerotic plaque. Plaque-infiltrating CD4 T cells include a specialized subset of CD4 + CD28 − T cells that express a unique profile of regulatory receptors and are responsive to novel microenvironmental cues. Here we report that CD4 + CD28 − T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation. CD4 + CD28 − IL-12R + cells responded to IL-12 stimulation with the upregulation of the chemokine receptor CCR5 and the C-type lectin receptor CD161, both implicated in regulating tissue homing of effector T cells. IL-12 treatment of CD4 + CD28 − T cells enhanced their chemotaxis and transendothelial migration toward the chemokine CCL5. In vivo relevance for the role of IL-12 in regulating the recruitment of CD4 + CD28 − T cells into the atheroma was examined in human atheroma-SCID mouse chimeras. Exposure of nonstimulated CD4 + CD28 − T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, CD4 + CD28 − T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12–inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions.

Acute coronary syndromes (ACS) are precipitated by a rupture of the atherosclerotic plaque, often at the site of T cell and macrophage infiltration. Here, we show that plaque-infiltrating CD4 T cells effectively kill vascular smooth muscle cells (VSMC). VSMCs sensitive to T cell–mediated killing express the death receptor DR5 (TNF-related apoptosis-inducing ligand [TRAIL] receptor 2), and anti-TRAIL and anti-DR5 antibodies block T cell–mediated apoptosis. CD4 T cells that express TRAIL upon stimulation are expanded in patients with ACS and more effectively induce VSMC apoptosis. Adoptive transfer of plaque-derived CD4 T cells into immunodeficient mice that are engrafted with human atherosclerotic plaque results in apoptosis of VSMCs, which was prevented by coadministration of anti-TRAIL antibody. These data identify that the death pathway is triggered by TRAIL-producing CD4 T cells as a direct mechanism of VSMC apoptosis, a process which may lead to plaque destabilization.