Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion.

Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme activity have shown chemopreventive activity in carcinogen-induced and transgenic rodent tumor models and clinically for colon cancer. However, the mechanism(s) by which COX-2 inhibitors reduce carcinogenesis remains controversial. We report herein that administration of the selective COX-2 inhibitor, celecoxib, significantly reduces the number of Gr1(+)CD11b(+) immature myeloid suppressor cells (IMSCs) during chemoprevention of 1,2-dimethylhydrazine diHCl-(1,2-DMH-) induction of large intestinal tumors in Swiss mice. Celecoxib administration also increased splenic lymphatic number and tumor infiltration by lymphocytes. The 1,2-DMH induction of large intestinal tumors was associated with a four-fold increase in IMSCs, and a decrease in splenic T cell number and function. Concordant with the changes in the IMSC frequency, messenger ribonucleic acid (mRNA) levels of inducible nitric oxide synthase (NOS-2) and arginase (Arg) were increased in the spleen of the tumor-bearing mice and normalized by celecoxib administration. In addition to delaying tumor induction, reducing tumor number, and increasing lymphocyte infiltration of tumors, celecoxib therapy reversed CD4(+) T cell loss, decreased IMSC numbers and increased mRNA levels of NOS-2 and Arg in the spleen. In summary, our results suggest that celecoxib chemoprevention of autochthonous intestinal tumors can regulate IMSCs and CD4(+) T cell numbers.

Risk factors for systemic Candida infections in pediatric small bowel transplant recipients.

BACKGROUND: Fungal infections are an important cause of morbidity and mortality after small bowel transplantation (SBT). Little information about risk factors for Candida infections in pediatric SBT is available. METHODS: We performed a 1:1 matched retrospective case-control study including 23 Candida culture-positive patients (cases) and 23 culture-negative patients (controls), matched based on age and time of transplantation. Patients' characteristics were compared using Wilcoxon rank-sum, χ, or Fisher exact tests. McNemar test was used to assess discordance between pretransplant and posttransplant fungemia. Univariate and multivariable conditional logistic regression analyses were performed to identify risk factors. RESULTS: The median age of the group was 1.87 years (range, 0.87-17.60); 59% patients were male. Within 1 month before transplant, 8.7% cases had fungemia and within 1-6 months before transplant, 30.4% cases had fungemia, compared with 69.6% within the 12 months after transplantation (P = 0.0001 and P = 0.02). By univariate analysis, total parenteral nutrition (TPN) (odds ratio [OR], 17.0 [95% confidence interval: 2.12, 2198]; P = 0.003) and antibiotic administration (OR, 18.99 [2.42, 2449]; P = 0.002) were risk factors for fungal infections. By multivariable analysis, both remained independent risk factors (TPN: OR, 10.86 [1.23, 1425], P = 0.03; antibiotic administration: OR, 12.83 [1.52, 1672], P = 0.01). CONCLUSIONS: Fungemia was significantly more frequent after SBT than before transplantation. Patients receiving TPN and antibiotic treatment had, respectively, 11 and 13 times higher risk of developing Candida infections after SBT.

Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells.

The tumor microenvironment is heterogeneous for the expansion and infiltration by myeloid derived suppressor cells (MDSCs) which has been hypothesized to be dependent on tumor burden. We report a relationships between tumor size, MDSCs and T-cells; using four murine mammary tumors to assess tumor growth, infiltration and gene expression. Our analysis of cellular infiltration into tumors and gene expression used collagenase dissociated tumors and density gradient isolation of non-parenchymal cells (NPCs). The frequency of splenic and peripheral blood (PB) MDSCs was tumor dependent resulting in a significantly increased number of MDSCs. The MDSC frequency inversely correlated with the frequency of CD3+ lymphocytes in the spleen, independent of the tumor studied and directly correlated with tumor burden. Tumor growth up-regulated cyclooxygenase-2 (COX-2), vascular endothelial growth factor-A (VEGF-A), granulocyte (G-) and granulocyte-monocyte-colony stimulating factor (GM-CSF), arginase-1 (ARG-1), and nitric oxide synthase-2 (NOS-2) transcription in the tumor and spleens (not VEGF-A). The frequency of splenic MDSCs directly correlated with splenic COX-2, NOS-2, and ARG-1 message levels, while COX-2 and NOS-2 transcript levels inversely correlated with splenic CD3+ cell frequency. COX-2 mRNA levels also directly correlated with the ARG-1 and NOS-2 transcript levels from tumor-infiltrating leukocytic cells, supporting prostaglandin E2 as a regulator of ARG-1 and NOS-2 transcription. In summary, MDSC numbers in the spleen and tumor microenvironment are tumor dependent, directly correlating with tumor size and inversely correlating with T-cell number. MDSCs are also directly associated with VEGF-A and G-CSF transcript levels suggesting multiple mechanisms for MDSC regulation and COX-2, NOS-2 and ARG-1 supporting multiple mechanisms of T-cell suppression.