PubMed · 13642377
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G DETRE. [Post-dysenteric colitis & appendicitis].. https://pubmed.ncbi.nlm.nih.gov/13642377/
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In order to determine the initial values and dynamic changes of EPO (erythropoietin) after therapy, 57 consecutively presenting, typical COPD (chronic obstructive pulmonary disease) patients with chronic hypoxia and acute exacerbated serum EPO levels were serially measured. Initial mean EPO levels were slightly above the normal range (41.4 +/- 83.5 units/l), but in the majority of patients the initial EPO levels were significantly reduced. Following the correction of hypoxaemia, mean EPO levels decreased to 14.1 +/- 16.9 units/l (P=0.0093). However, not all COPD patients showed this pattern; in an important subset of patients (36.8%), who had initially lower EPO levels and lower erythrocyte count, EPO levels were significantly increased (by more than 60%; P=0.0028) on the second day of treatment, despite correction of the hypoxaemia. This finding was unexpected and paradoxical when compared with physiological studies addressing the same issue. The data presented support previous reports of variable EPO levels in severely hypoxic COPD patients and suggest that the haematological response is already hampered at an early stage, at the level of EPO production, and much less likely at later steps in the haemopoietic response by failure to respond to elevated EPO levels. Our data are consistent with recent discoveries that the O2 sensing and regulation of EPO production is a complex process in which multiple factors, including cytokines and therapeutic agents, play a role by enhancing or inhibiting the response. We believe that further studies on this clinical condition are complementary to basic physiological research and may help to elucidate the role of cytokines and other individual factors in complex clinical hypoxic situations.
The progression of breast cancer is affected by multiple cellular and microenvironmental components. The monocyte chemoattractant MCP-1, IL-6 and matrix metalloproteinases (MMP) were suggested to promote, each on its own, breast cancer progression. We recently demonstrated that the high-tumorigenicity phenotype of the DA3 and CSML murine mammary adenocarcinoma cells is correlated with a high expression of MCP-1, IL-6 and MMP. This raised the possibility that common intrinsic tumor-derived factors regulate the concordant expression of these 3 components. The aim of the present study was to gain insight into the mode by which the secretion of MCP-1, IL-6 and MMP from murine mammary adenocarcinoma cells is regulated. This was investigated in cellular clones established from a highly malignant variant of the DA3 tumor (DA3-high). We also determined the secretion of the antimalignancy chemokine IP-10 from these cells. The results indicate that the secretion levels of IL-6, MMP and IP-10 varied between the clones. In contrast, all the clones secreted uniformly high levels of MCP-1, suggesting that MCP-1 constitutes an important feature of the malignancy phenotype of mammary carcinoma. In most of the clones, elevated levels of 1 of the 3 promalignancy factors did not correlate with a high expression of the other 2 factors and vice versa. These findings indicate that the 3 promalignancy factors are not coregulated by a common intrinsic tumor-derived factor. Rather, these results suggest that the individual capacities of the different clones to secrete these factors are summed up in the high-malignancy DA3 parental tumor population, which secretes relatively high levels of MCP-1, IL-6 and MMP as compared to DA3 cells expressing a low-malignancy phenotype. In contrast to the lack of coordinated intrinsic regulation of MCP-1, IL-6 and MMP, it was found that recombinant TNFalpha, a product of tumor-associated macrophages contributing to breast cancer progression, upregulated the secretion of MCP-1, IL-6 and MMP from all the clones. These results suggest a key role for this microenvironmental, monocyte-derived cytokine in the coordinated regulation of these 3 molecules. Furthermore, additional results demonstrated that monocytic cell-derived TNFalpha upregulated MCP-1 secretion from the tumor cells and that MCP-1 in turn promoted the secretion of TNFalpha from monocytic cells. This may result in a positive feedback loop, whereby the tumor cells and the monocytic cells at tumor site promote each other's ability to express and secrete promalignancy factors. We next attempted to assess the contribution of the promalignancy factors MCP-1, IL-6 and MMP and of the antimalignancy factor IP-10 to mammary adenocarcinoma progression. To this end, a preliminary formula was developed in which the net balance between secretion levels of the promalignancy factors and that of the antimalignancy IP-10 chemokine from different clones was related to their in vivo tumorigenicity profile. This formula suggests that a balance between the secretion levels of these factors plays an important role in determining the malignancy phenotype of mammary carcinomas. In all, our findings demonstrate that the mammary tumor cell population is composed of a heterogeneous assortment of clones whose individual characteristics are averaged in the whole population. The malignancy potential of such tumors is thus determined, inter alia, by a combinatorial effect of several promalignancy and antimalignancy factors secreted from each of the clones comprising these tumors. Our results also suggest that the expression of such factors is determined by several nonmutually exclusive regulatory mechanisms.
In a previous study we used gene expression arrays to identify genes that are more highly expressed by leukemic than by non-leukemic leukocytes from acute myelogenous leukemia patients. One of such genes was Phosphorylates tyrosine serine threonine 2 (PYST2), a dual-specificity Mitogen-activated protein (MAP) kinase (MAPK) phosphatase. In the present study, high levels of PYST2 mRNA were detected by RT-PCR and by Northern blotting in bone marrow (BM) leukocytes and in peripheral blood mononuclear cells from additional eight AML patients. No PYST2 mRNA was detected in nine out of twelve samples of Peripheral blood mononuclear cells (PBMC) from healthy blood bank donors and very low levels were detected by the same techniques in the other three PBMC samples from the healthy donors. Relatively high levels of PYST2 were detected in a variety of myeloid leukemia and other cancer cell lines. In view of the potential role played by PYST2 in MAPK signaling cascades we propose that an over expression of PYST2 in malignant cells may reflect a disrupted or an altered MAPK signaling pathway in malignancy processes.