While for most cancers incidence and mortality are decreasing, those of non-Hodgkin's lymphoma (NHL) are steadily increasing. Research to define reasons for this increase is extensive, but has not yet resolved them. We have conducted a literature analysis on trends regarding changes in the incidence, geographic distribution, and etiologic factors of NHL. From our own and previous analyses, an increasing NHL incidence at a rate of 3-4% per year was observed for the 1970s and 1980s. This stabilized in the 1990s, nevertheless still with an annual rise of 1-2%, resulting in almost a doubling of the NHL incidence. This rise has been noted worldwide, particularly in elderly persons >55 years. Concerning gender subgroups, a male predominance throughout all age groups is apparent. Although the NHL incidence has historically been higher in whites than blacks, disproportional increases have recently been observed in the latter group. Increases in high-grade NHL and extranodal disease are predominant. Differences in geographic distribution are striking for follicular lymphoma, which is more common in Western countries than elsewhere. Asians have higher rates of aggressive NHL, T-cell lymphomas, and extranodal disease. In the Middle East, high rates of intestinal extranodal disease are observed, whereas in Africa, endemic Burkitt's lymphoma accounts for a substantial proportion. Risks for developing NHL include immunosuppression and a causal link between infectious agents, and lymphomagenesis has also been determined, particularly for human T-cell leukemia/lymphoma virus type 1 (HTLV-1), Epstein-Barr virus (EBV), and Helicobacter pylori infections. Exposure to environmental agents and occupational risks have been studied; however, their significance is as yet uncertain.

Rationale: Fibrosis is mediated partly by extracellular matrix–depositing fibroblasts in the heart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functional consequence of this heterogeneity is unknown. Objective: We sought to validate a panel of surface markers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiac fibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates of each developmental subset of fibroblasts after pressure overload injury. Methods and Results: We showed that Thy1 + CD45 − CD31 − CD11b − Ter119 − cells constitute the majority of cardiac fibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy, and transcriptional profiling (using reverse transcription polymerase chain reaction and RNA-seq). We used lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblasts derive from the epicardium, a minority arises from endothelial cells, and a small fraction from Pax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulating cells. Interestingly, proliferation rates of fibroblast subsets on injury were identical, and the relative abundance of each lineage remained the same after injury. The anatomic distribution of fibroblast lineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstrated that Tie2-derived and Tbx18-derived fibroblasts within each operation group exhibit similar gene expression profiles. Conclusions: The cellular expansion of cardiac fibroblasts after transaortic constriction surgery was not restricted to any single developmental subset. The parallel proliferation and activation of a heterogeneous population of fibroblasts on pressure overload could suggest that common signaling mechanisms stimulate their pathological response.

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Antibody-dependent cell-mediated cytotoxicity (ADCC), which is largely mediated by natural killer (NK) cells, is thought IntroductionMonoclonal antibodies (mAbs) have revolutionized the treatment of cancer. The first approved mAb for this purpose, rituximab, a murine-human chimeric immunoglobulin G1 (IgG1) antibody against CD20, has become a standard treatment for patients with B-cell lymphomas.Despite tumor response rates to rituximab of up to 90% and decreased risk of death by as much as 36%, the majority of patients with advanced lymphoma still die of their disease, including 19 000 patients in the United States in 2009 alone. [1][2][3][4] Enhancing the efficacy of rituximab represents an opportunity to improve patient outcome. We have developed a strategy to enhance the antitumor activity of rituximab by augmenting antibody-induced cell killing.Several mechanisms of rituximab's antitumor action have been proposed, including direct induction of apoptosis, complementdependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC), and, possibly, induction of an adaptive immune response (a "vaccinal" effect). 5 Among these mechanisms, ADCC is believed to be of importance, particularly to the initial antitumor response. In vitro studies have shown that rituximab can induce ADCC of human lymphoma cell lines. 6 In murine xenotransplant lymphoma models, a role for ADCC in rituximab's efficacy was confirmed in studies using FcR-␥-chain-deficient mice, 7 as well as a neutralizing antibody against murine Fc␥R. 8 Further murine studies using CD20 mAbs have confirmed that monocyte-mediated ADCC is the primary, if not exclusive, mechanism through which normal and malignant B cells are depleted in vivo. 9-13 Finally, clinical results have shown that patients harboring an Fc␥RIIIA polymorphism with higher affinity for IgG1 have better responses to rituximab, further supporting the hypothesis that ADCC is an important in vivo mechanism of rituximab action in patients with lymphoma. 14,15 Natural killer (NK) cells are known to be important effector cells mediating ADCC. Binding of the NK-cell Fc receptor (Fc␥RIII, CD16) to the constant region of an antibody induces NK-cell activation. On activation, NK cells release cytotoxic granules, promoting tumor cell killing, and up-regulate the expression of several activation markers, including CD137. 16 In this study, we hypothesized that rituximab-induced ADCC could be specifically increased by using an anti-CD137 agonistic mAb to enhance NK-cell function.CD137 (4-1BB) is a surface glycoprotein that belongs to the tumor-necrosis factor receptor superfamily. 17 CD137 is an inducible costimulatory molecule expressed on a variety of immune cells, including activated CD4 and CD8 T cells, NK cells, monocytes, and dendritic cells. 18,19 On T cells specifically, CD137 functions as a costimulatory receptor induced on T-cell receptor stimulation. In this context, ligation of CD137 leads to increased T-cell proliferation, cytokine production, functional maturation, and prolonged ...