The accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts is a hallmark of malignancy-associated inflammation and a major mediator for the induction of T cell suppression in cancer. MDSC can be divided phenotypically into granulocytic (G-MDSC) and monocytic (Mo-MDSC) subgroups. Several mechanisms mediate the induction of T cell anergy by MDSC; however, the specific role of these pathways in the inhibitory activity of MDSC subpopulations remains unclear. Therefore, we aimed to determine the effector mechanisms by which subsets of tumor-infiltrating MDSC block T cell function. We found that G-MDSC had a higher ability to impair proliferation and expression of effector molecules in activated T cells, as compared to Mo-MDSC. Interestingly, both MDSC subgroups inhibited T cells through nitric oxide (NO)-related pathways, but expressed different effector inhibitory mechanisms. Specifically, G-MDSC impaired T cells through the production of peroxynitrites (PNT), while Mo-MDSC suppressed by the release of NO. The production of PNT in G-MDSC depended on the expression of gp91phox and endothelial NO synthase (eNOS), while inducible NO synthase (iNOS) mediated the generation of NO in Mo-MDSC. Deletion of eNOS and gp91phox or scavenging of PNT blocked the suppressive function of G-MDSC and induced anti-tumoral effects, without altering Mo-MDSC inhibitory activity. Furthermore, NO-scavenging or iNOS knockdown prevented Mo-MDSC function, but did not affect PNT production or suppression by G-MDSC. These results suggest that MDSC subpopulations utilize independent effector mechanisms to regulate T cell function. Inhibition of these pathways is expected to specifically block MDSC subsets and overcome immune suppression in cancer.

Barth syndrome (BTHS); MIM accession # 302060) is a rare X‐linked recessive cardioskeletal mitochondrial myopathy with features of cardiomyopathy, neutropenia, and growth abnormalities. The objectives of this study were to further elucidate the natural history, clinical disease presentation, and course, and describe growth characteristics for males with BTHS. Patients with a confirmed genetic diagnosis of BTHS are referred to the BTHS Registry through the Barth Syndrome Foundation, self‐referral, or physician referral. This study is based on data obtained from 73 subjects alive at the time of enrollment that provided self‐reported and/or medical record abstracted data. The mean age at diagnosis of BTHS was 4.04 ± 5.45 years. While the vast majority of subjects reported a history of cardiac dysfunction, nearly 6% denied any history of cardiomyopathy. Although most subjects had only mildly abnormal cardiac function by echocardiography reports, 70% were recognized as having cardiomyopathy in the first year of life and 12% have required cardiac transplantation. Of the 73 enrolled subjects, there have been five deaths. Growth curves were generated demonstrating a shift down for weight, length, and height versus the normative population with late catch up in height for a significant percentage of cases. This data also confirms a significant number of patients with low birth weight, complications in the newborn period, failure to thrive, neutropenia, developmental delay of motor milestones, and mild learning difficulties. However, it is apparent that the disease manifestations are variable, both over time for an individual patient and across the BTHS population. © 2012 Wiley Periodicals, Inc.

Enzymatic depletion of the non-essential amino acid L-Arginine (L-Arg) in cancer patients by the administration of a pegylated form of the catabolic enzyme arginase I (peg-Arg I) has shown some promise as a therapeutic approach. However, L-Arg deprivation also suppresses T-cell responses in tumors. In this study, we sought to reconcile these observations by conducting a detailed analysis of the effects of peg-Arg I on normal T-cells. Strikingly, we found that peg-Arg I blocked proliferation and cell cycle progression in normal activated T-cells without triggering apoptosis or blunting T-cell activation. These effects were associated with an inhibition of aerobic glycolysis in activated T-cells, but not with significant alterations in mitochondrial oxidative respiration, which thereby regulated survival of T-cells exposed to peg-Arg I. Further mechanistic investigations showed that addition of citrulline, a metabolic precursor for L-Arg, rescued the anti-proliferative effects of peg-Arg I on T-cells in vitro. Moreover, serum levels of citrulline increased after in vivo administration of peg-Arg I. In support of the hypothesis that peg-Arg I acted indirectly to block T-cell responses in vivo, peg-Arg I inhibited T-cell proliferation in mice by inducing accumulation of myeloid-derived suppressor cells (MDSC). MDSC induction by peg-Arg I occurred through the general control non-repressed-2 eIF2α kinase. Moreover, we found that peg-Arg I enhanced the growth of tumors in mice in a manner that correlated with higher MDSC numbers. Taken together, our results highlight the risks of the L-Arg-depleting therapy for cancer treatment and suggest a need for co-targeting MDSC in such therapeutic settings.

Background Time‐to‐antibiotic (TTA) administration is a widely used quality‐of‐care measure for children with cancer and febrile neutropenia (FN). We sought to determine whether TTA is associated with outcomes of FN. Procedure A single‐center, retrospective cohort study was conducted of 1,628 FN admissions from 653 patients from 2001 to 2009. Outcome variables included (1) an adverse event (AE) composite of in‐hospital mortality, pediatric intensive care unit (PICU) admission within 24 hours of presentation, and/or fluid resuscitation ≥40 ml/kg within 24 hours of presentation and (2) length of stay (LOS). TTA was measured as a continuous variable and in 60‐minute intervals. Mixed regression models were constructed to evaluate associations of TTA with the outcome variables after adjusting for relevant covariates including cancer diagnosis, degree of myelosuppression, and presence of bacteremia. Results The composite AE outcome occurred in 11.1% of admissions including 0.7% in‐hospital mortality, 4.7% PICU admission, and 10.1% fluid resuscitation. In univariate analysis, TTA was associated with the composite AE outcome (Odds Ratio [OR] 1.29, 95% CI 1.02–1.64) but not LOS. In multivariate analysis, after adjustment for relevant covariates, 60‐minute TTA intervals were associated with the composite AE outcome (61–120 minutes vs. ≤60 minutes, OR 1.81, 95% CI 1.01–3.26). Unexpectedly, admission from the emergency department (ED) was also independently associated with the composite AE outcome (ED vs. clinic, OR 3.15, 95% CI 1.95–5.09). Conclusions TTA and presentation to the ED are independently associated with poor outcomes of FN. Pediatr Blood Cancer 2013;60:1299–1306. © 2013 Wiley Periodicals, Inc.

The efficacy of low-molecular-weight heparin as a prophylactic agent was A single injection of low-molecular-weight heparin daily is a convenient way of preventing deep vein thrombosis in high-risk patients undergoing major abdominal surgery.