Myeloid-derived suppressor cells: general characteristics and relevance to clinical management of pancreatic cancer.

Recent studies describe a heterogeneous population of cells of the myeloid lineage, termed myeloid derived suppressor cells (MDSC), which are observed with increased prevalence in the peripheral blood and tumor microenvironment of cancer patients, including pancreatic cancer. Accumulation of MDSC in the peripheral circulation has been related to extent of disease, and correlates with stage. MDSC have primarily been implicated in promoting tumor growth by suppressing antitumor immunity. There is also compelling evidence MDSC are also involved in angiogenesis and metastatic spread. Two main subsets of MDSC have been identified in cancer patients: a monocytic subset, characterized by expression of CD14, and a granulocytic subset characterized by expression of CD15. Both subsets of MDSC actively suppress host immunity through a variety of mechanisms including production of reactive oxygen species and arginase. Just as in humans, accumulation of monocytic and granulocytic MDSC has been noted in the bone marrow, spleen, peripheral circulation, and tumors of tumor bearing mice. Successful targeting of MDSC in mice is associated with improved immune responses, delayed tumor growth, improved survival, and increased efficacy of vaccine therapy. By further elucidating mechanisms of MDSC recruitment and maintenance in the tumor environment, strategies could be developed to reverse immune tolerance to tumor. We discuss here what is currently known about MDSC as well as some potential strategies targeting MDSC in the context of our work on pancreatic cancer and recent literature. Due to the number of new reports on MDSC, the most pertinent ones have been selected.

RNA splicing capability of live neuronal dendrites.

Dendrites are specialized extensions of the neuronal soma that contain components of the cellular machinery involved in RNA and protein metabolism. Several dendritically localized proteins are associated with the precursor-mRNA (pre-mRNA) splicing complex, or spliceosome. Although some spliceosome-related, RNA-binding proteins are known to subserve separate cytoplasmic functions when moving between the nucleus and cytoplasm, little is known about the pre-mRNA splicing capacity of intact dendrites. Here, we demonstrate the presence and functionality of pre-mRNA-splicing components in dendrites. When isolated dendrites are transfected with a chicken delta-crystallin pre-mRNA or luciferase reporter pre-mRNA, splicing junctions clustered at or near expected splice sites are observed. Additionally, in vitro synaptoneurosome experiments show that this subcellular fraction contains a similar complement of splicing factors that is capable of splicing chicken delta-crystallin pre-mRNA. These observations suggest that pre-mRNA-splicing factors found in the dendroplasm retain the potential to promote pre-mRNA splicing.

Leukotriene C4 production by normal-density and low-density eosinophils of atopic individuals and other patients with eosinophilia.

With the use of a percoll gradient separation procedure, eosinophils of individuals with asthma and with allergy could be separated into normal- and low-density cell fractions. The presence of low-density eosinophils possibly reflects an ongoing process of activation of these cells induced by the allergic reaction. Ca-ionophore-induced leukotriene (LT) C4 production, in the absence of added substrates, demonstrated a decreased potency for LT generation by low-density eosinophils compared with the LT generation of normal-density cells (57 +/- 33 ng and 103 +/- 44 ng per 10(6) cells, respectively). In contrast with the Ca-ionophore-induced LT formation, incubations with serum-treated zymosan in the presence of glutathione demonstrated higher productions of LTC4 with the low-density eosinophilic subpopulation compared with normal-density cells. This is compatible with a possibly higher expression of complement C3b receptors on the low-density eosinophils. Total arylsulfatase contents demonstrated that low-density eosinophils are not degranulated with respect to their small granules. Although release of the large granules by low-density eosinophils cannot be excluded, electron-microscopy studies indicated that degranulation is not the only (or major) factor that determines the density of the various eosinophilic subpopulations.