IntroductionThus far, 3 subsets of proinflammatory helper T cells have been described: Th1, Th2, and Th17 cells. 1 Naive T cells exposed to interleukin-12 1 (IL-12) differentiate into Th1 cells, resulting in expression of Tbet and STAT4, and secretion of interferon (IFN)-␥. 2 Th1 cells are essential for the clearance of intracellular bacteria and negatively regulate the development of Th2 and Th17 cells. 2 IL-4 activates a Th2 program, characterized by expression of STAT6 and GATA3 and secretion of IL-4, IL-5, and IL-13, which is important for humoral immunity. 2 Finally, naive T cells exposed to TGF-␤, IL-6, and IL-21 differentiate into Th17 cells by activating ROR␥t, ROR␣, STAT3, STAT4, and IRF4 transcription factors. [3][4][5][6] Th17 cells produce high levels of IL-17A (IL-17), IL-17F, IL-21, and IL-22, and have been shown to contribute to mucosal immunity. [7][8][9] Specifically, IL-17 is important in the control or clearance of various pathogens, including Klebsiella pneumoniae, 10 Citrobacter rodentium, 3 Borrelia burgdorferi, 11 and Candida albicans. 12 In addition, Th17 cells have been implicated in allograft rejection of solid organs [13][14][15] and several autoimmune diseases. 1,[16][17][18][19] IL-17, otherwise known as IL-17A, is the bestcharacterized member of the IL-17 family (IL-17A through F). IL-17 is a disulfide-linked homodimeric glycoprotein consisting of 155 amino acids with a molecular weight of 35 kDa. 20 IL-17F shares the greatest homology with IL-17 (55%). Th17 cells produce IL-17 and IL-17F while innate immune cells produce other IL-17 family members. IL-17 and IL-17F can exist as homodimers or heterodimers. 21 IL-17 homodimers are efficient at inducing chemokine production by epithelial cells. The IL-17 receptor (IL-17RA) is a type 1 transmembrane protein, and its mRNA is expressed in the lungs, kidneys, liver, and spleen as well as in isolated fibroblasts, epithelial cells, mesothelial cells, and various myeloid cells in rats and mice. 20 Th17 cells have been identified as the primary source of IL-22, an IL-10 family member. 8,22 IL-22 can stimulate proliferation, abnormal differentiation, and migration of various epithelial cells. 23 Its up-regulation has been associated with several autoimmune diseases, including psoriasis, Crohn's disease, and ulcerative colitis, as well as murine models of inflammatory bowel disease. [24][25][26][27] Allogeneic bone marrow transplantation (BMT) is a potentially curative therapy for various hematopoietic malignancies and immunologic diseases. 28,29 GVHD is a major complication of allogeneic BMT and causes significant morbidity and mortality. GVHD is the result of alloreactive donor T cells recognizing alloantigens on normal host tissues and mounting an attack against the host. 28,30 During GVHD, donor T cells specifically target the intestines, skin, and liver, 28 however, alloreactive T cells also contribute to graft-versus-tumor (GVT) activity, which may prevent tumor relapse. 28 During the early stages after BMT, alloreactive CD4 ϩ T cells sec...

Cancer cells acquire drug resistance as a result of selection pressure dictated by unfavorable microenvironments. This survival process is facilitated through efficient control of oxidative stress originating from mitochondria that typically initiates programmed cell death. We show this critical adaptive response in cancer cells to be linked to uncoupling protein-2 (UCP2), a mitochondrial suppressor of reactive oxygen species (ROS). UCP2 is present in drug-resistant lines of various cancer cells and in human colon cancer. Overexpression of UCP2 in HCT116 human colon cancer cells inhibits ROS accumulation and apoptosis after exposure to chemotherapeutic agents. Tumor xenografts of UCP2-overexpressing HCT116 cells retain growth in nude mice receiving chemotherapy. Augmented cancer cell survival is accompanied by altered NH 2 -terminal phosphorylation of the pivotal tumor suppressor p53 and induction of the glycolytic phenotype (Warburg effect). These findings link UCP2 with molecular mechanisms of chemoresistance. Targeting UCP2 may be considered a novel treatment strategy for cancer. [Cancer Res 2008;68(8):2813-9]

We identified substantial variability in the withdrawal of life-sustaining treatment across world regions and countries. Similar variability existed between ICUs within countries and even between providers within the same ICU. Further study is necessary, and could lead to interventions to improve end-of-life care in the ICU.