Isoforms of Neuropilin-2 Denote Unique Tumor-Associated Macrophages in Breast Cancer.

Tumor-associated macrophages (TAMs) exert profound influence over breast cancer progression, promoting immunosuppression, angiogenesis, and metastasis. Neuropilin-2 (NRP2), consisting of the NRP2a and NRP2b isoforms, is a co-receptor for heparin-binding growth factors including VEGF-C and Class 3 Semaphorins. Selective upregulation in response to environmental stimuli and independent signaling pathways endow the NRP2 isoforms with unique functionality, with NRP2b promoting increased Akt signaling via receptor tyrosine kinases including VEGFRs, MET, and PDGFR. Although NRP2 has been shown to regulate macrophage/TAM biology, the role of the individual NRP2a/NRP2b isoforms in TAMs has yet to be evaluated. Using transcriptional profiling and spectral flow cytometry, we show that NRP2 isoform expression was significantly higher in TAMs from murine mammary tumors. NRP2a/NRP2b levels in human breast cancer metastasis were dependent upon the anatomic location of the tumor and significantly correlated with TAM infiltration in both primary and metastatic breast cancers. We define distinct phenotypes of NRP2 isoform-expressing TAMs in mouse models of breast cancer and within malignant pleural effusions from breast cancer patients which were exclusive of neuropilin-1 expression. Genetic depletion of either NRP2 isoform in macrophages resulted in a dramatic reduction of LPS-induced IL-10 production, defects in phagosomal processing of apoptotic breast cancer cells, and increase in cancer cell migration following co-culture. By contrast, depletion of NRP2b, but not NRP2a, inhibited production of IL-6. These results suggest that NRP2 isoforms regulate both shared and unique functionality in macrophages and are associated with distinct TAM subsets in breast cancer.

Experimental respiratory exposure to putative Gulf War toxins promotes persistent alveolar macrophage recruitment and pulmonary inflammation.

AIMS: Respiratory disorders are a prominent component of Gulf War Illness. Although much of the underlying mechanisms of Gulf War Illness remain undefined, chronic immune dysfunction is a consistent feature of this multi-symptomatic, multi-organ disorder. Alveolar macrophages represent the predominant mononuclear phagocytes of the pulmonary mucosa, orchestrating the host response to pathogens and environmental stimuli. Herein, we sought to characterize the innate immune response of the pulmonary mucosa, with a focus on macrophages, to experimental respiratory exposure to two putative Gulf War Toxins (GWTs). MATERIALS AND METHODS: Utilizing commercially available instrumentation, we evaluated the effect of aerosolized exposure to the pesticide malathion and diesel exhaust particulate (DEP) on the immune composition and inflammatory response of the lung in FVB/N mice using multiparametric spectral cytometry, cytokine analysis, and histology. KEY FINDINGS: Aerosolized GWTs induced gross pulmonary pathology with transient recruitment of neutrophils and sustained accumulation of alveolar macrophages to the lung for up to two weeks after exposure cessation. High-dimensional cytometry and unbiased computational analysis identified novel myeloid subsets recruited to the lung post-exposure driven by an influx of peripheral monocyte-derived progenitors. DEP and malathion, either alone or in combination, induced soluble mediators in bronchoalveolar lavage indicative of oxidative stress (PGF2α), inflammation (LTB4, TNFα, IL-12), and immunosuppression (IL-10), that were sustained or increased two weeks after exposures concluded. SIGNIFICANCE: These findings indicate that macrophage accumulation and pulmonary inflammation induced by GWTs continue in the absence of toxin exposure and may contribute to the immunopathology of respiratory Gulf War Illness.

HMGB1 Promotes Myeloid Egress and Limits Lymphatic Clearance of Malignant Pleural Effusions.

Pleural effusions, when benign, are attributed to cardiac events and suffusion of fluid within the pleural space. When malignant, lymphatic obstruction by tumor and failure to absorb constitutively produced fluid is the predominant formulation. The prevailing view has been challenged recently, namely that the lymphatics are only passive vessels, carrying antigenic fluid to secondary lymphoid sites. Rather, lymphatic vessels can be a selective barrier, efficiently coordinating egress of immune cells and factors within tissues, limiting tumor spread and immune pathology. An alternative explanation, offered here, is that damage associated molecular pattern molecules, released in excess, maintain a local milieu associated with recruitment and retention of immune cells associated with failed lymphatic clearance and functional lymphatic obstruction. We found that levels of high mobility group box 1 (HMGB1) were equally elevated in both benign and malignant pleural effusions (MPEs) and that limited diversity of T cell receptor expressing gamma and delta chain were inversely associated with these levels in MPEs. Acellular fluid from MPEs enhanced γδ T cell proliferation in vitro, while inhibiting cytokine production from γδ T cells and monocytes as well as restricting monocyte chemotaxis. Novel therapeutic strategies, targeting HMGB1 and its neutralization in such effusions as well as direct delivery of immune cells into the pleural space to reconstitute normal physiology should be considered.

Pancreatic islet transplantation.

Pancreatic islet transplantation is a minimally invasive treatment that has the potential to prevent diabetes after total pancreatectomy for benign disease (islet autotransplantation) and to reverse diabetes in those with type 1 diabetes (islet allotransplantation). In both scenarios, the treatment involves extracting sufficient numbers of pancreatic islets from the resected or donor pancreas and infusing these through the portal vein into the patient's liver. The results for both forms of this treatment have been encouraging over recent years, with up to 85% of adult patients remaining insulin independent for at least 1 year after transplantation. However, there are a number of challenges that need to be overcome before these treatments can be used routinely in children. The aim of this review is to outline the rationale, methodology, and current results of islet allotransplantation, and to discuss the potential new developments that could enable this important treatment to be widely applicable to children. Although islet autotransplantation is not discussed in detail, the overall rationale and methods are similar. However, as the procedure involves the transplantation of the patient's own islets, and the indication for the procedure is not for autoimmune disease, there are none of the difficult immune challenges of allotransplantation.

Haematuria and the retro-aortic left renal vein.

The authors present the case of a 10-year-old boy with a 2-year history of intermittent macroscopic haematuria. After exclusion of other causes of haematuria through history, examination and a number of investigations, MRI revealed the finding of a retro-aortic left renal vein, which appeared to be compressed between the aorta and the L3 vertebral body. The retro-aortic left renal vein or 'posterior nutcracker syndrome" is a rare but important cause of haematuria and other manifestations of left renal vein hypertension. A discussion about the implications of this finding in children with symptoms consistent with left renal vein hypertension, and the potential options for management is undertaken.

Removing the bedroom television set: a possible method for decreasing television viewing time in overweight and obese adults.

U.S. adults watch television (TV) for an average of 5 hours per day, an amount associated with increased obesity risk. Studies in children have found bedroom TV sets, which result in greater time spent by watching TV and shorter sleep durations, both of which increase a child's odds of becoming overweight. The authors examined associations between bedroom TV viewing time (BTVT), Body Mass Index (BMI), sleep time, non-BTVT, and total TV viewing time in 39 overweight and obese adults with and without a bedroom TV set. No significant correlations are found between BTVT and BMI or sleep time. BTVT is positively associated with non-BTVT (Spearman's rho = 0.37, p = .076; n = 24). Participants with a bedroom TV tend to watch significantly more TV (5.4 hours per day +/- 2.7; p = .057; n = 28) than do participants without a bedroom TV (3.6 +/- 1.9 hours per day, p = .057; n = 11). This article suggested that taking the TV out of the bedroom may help to reduce overweight and obese adults can decrease their TV viewing time.

Effects of television viewing reduction on energy intake and expenditure in overweight and obese adults: a randomized controlled trial.

BACKGROUND: The average adult watches almost 5 hours of television (TV) per day, an amount associated with increased risks for obesity. This trial examines the effects of TV reduction on energy intake (EI), energy expenditure (EE), energy balance, body mass index (BMI), (calculated as weight in kilograms divided by height in meters squared), and sleep in overweight and obese adults. METHODS: Randomized controlled trial of 36 adults with a BMI of 25 to 50 who self-reported a minimum of 3 h/d of TV viewing. Participants were enrolled in home-based protocols from January through July 2008. After a 3-week observation phase, participants were stratified by BMI and randomized to an observation-only control group (n = 16) or an intervention group (n = 20) for 3 additional weeks. The intervention consisted of reducing TV viewing by 50% of each participant's objectively measured baseline enforced by an electronic lock-out system. RESULTS: Although not statistically significant, both groups reduced their EI (-125 kcal/d [95% CI, -303 to 52] vs -38 [95% CI, -265 to 190]) (P = .52) for intervention and control group participants, respectively, where CI indicates confidence interval. The intervention group significantly increased EE (119 kcal/d [95% CI, 23 to 215]) compared with controls (-95 kcal/d [95% CI, -254 to 65]) (P = .02). Energy balance was negative in the intervention group between phases (-244 kcal/d [95% CI, -459 to -30]) but positive in controls (57 kcal/d [95% CI, -216 to 330]) (P = .07). The intervention group showed a greater reduction in BMI (-0.25 [95% CI, -0.45 to -0.05] vs -0.06 [95% CI, -0.43 to 0.31] in controls) (P = .33). There was no change in sleep. CONCLUSION: Reducing TV viewing in our sample produced a statistically significant increase in EE but no apparent change in EI after 3 weeks of intervention. Trial Registration clinicaltrials.gov Identifier: NCT00622050.

The relationship between motor proficiency and physical activity in children.

OBJECTIVES: Youth with better motor abilities may find it easier to be physically active and may be more likely to engage in physical activity compared with peers with poorer motor competence. The purpose of this study was to examine the relationship between motor proficiency and physical activity in 8- to 10-year-old children. Self-efficacy toward physical activity was also assessed. METHODS: Sixty-five children (34 girls and 31 boys) were studied. Children's physical activity was assessed by the Manufacturing Technologies Incorporated/Computer Science and Applications Incorporated model 7164 accelerometer, and their motor proficiency was determined by the Bruininks-Oseretsky Test of Motor Proficiency. The Children's Self-Perceptions of Adequacy in and Predilection for Physical Activity scale measured children's self-perceptions of adequacy in performing and desire to participate in physical activities. RESULTS: Children's motor proficiency was positively associated with activity counts and percentage of time in moderate and moderate-to-vigorous intensity physical activity and inversely related to percentage of time in sedentary activity. Children in the greatest quartile of motor proficiency were the most physically active compared with children with lower levels of motor proficiency who had similar levels of physical activity. Children with greater standardized BMI were less physically active, more sedentary, and had poorer motor proficiency compared with children with a lower standardized BMI. Children's Self-Perceptions of Adequacy in and Predilection for Physical Activity scores were positively associated with Bruininks-Oseretsky Test of Motor Proficiency standard score for boys. Children's motor proficiency explained an additional 8.7% of the variance in physical activity in multiple linear regression after controlling for factors that may influence physical activity. CONCLUSIONS: Motor proficiency is positively associated with physical activity and inversely associated with sedentary activity in children, but there may be a threshold of motor proficiency above which children may be the most physically active. Children's motor proficiency may be an appropriate target for increasing physical activity in youth.