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BackgroundTumor-associated macrophages (TAMs) exert profound influence over breast cancer progression, promoting immunosuppression, angiogenesis, and metastasis.1 Neuropilin-2 (NRP2), consisting of 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.2 3 We have shown that the two isoforms of NRP2 endow opposing functionality to tumor cells due to distinct signaling pathways, with NRP2b promoting metastatic behavior.3 Although NRPs have been shown to regulate macrophage/TAM biology, the role of NRP2 isoforms in TAM functionality has yet to be evaluated.MethodsTo assess the contribution of NRP2 isoforms to macrophage biology, conditional NRP2a and NRP2b knockout mice and stable shRNA knockdown of NRP2a or NRP2b in Raw264.7 macrophages were generated. Phagocytosis, lysosomal processing of phagocytosed cargo, cytokine production, and influence on tumor cell migration were assessed in vitro using NRP2 isoform knockdown macrophages. NRP2 isoform expression was evaluated on TAMs from murine 4T1 and EO771 mammary carcinoma models using spectral cytometry and single-cell qPCR. NRP2 isoforms and approximated immune composition were evaluated in paired primary tumors and distant metastasis using RNAseq in a cohort of 99 breast cancer patients. High-dimensional myeloid phenotyping was performed on malignant pleural effusions (MPEs) from breast cancer patients or effusions of benign origin using 33-color spectral cytometry and unbiased computational analysis.ResultsNRP2 isoform expression was significantly increased in TAMs from murine tumors compared to macrophages from healthy mammary glands. NRP2 isoforms in human primary and metastatic breast cancer were strongly correlated with one another and positively correlated with increased TAMs. Distinct phenotypes of NRP2 isoform-expressing TAMs in were present in 4T1 and EO771 mouse breast cancers and within MPEs from breast cancer patients which were associated with high levels of activation and potential response to a hypoxic tumor niche. Genetic depletion of either NRP2 isoform resulted in 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, inhibition of IL-6 production was specific in NRP2b knockdown cells while phagocytic uptake of labeled particulates was inhibited only by NPR2a knockdown.ConclusionsThese results demonstrate that NRP2 isoforms regulate both shared and distinct functionality in macrophages and that NRP2 isoform expression identifies unique TAM subsets in breast cancer.AcknowledgementsThis work was supported by awards from the Susan G. Komen Foundation (CCR15329745), U.S. Department of Defense (W81XWH1910650), and American Lung Association/Thoracic Surgery Foundation to ACS. RD was supported by funding from a Department of Veteran's Affairs Career Development Award (CX001771-01A2) and the University of Pittsburgh's Dean Faculty Advancement Award. ESY was supported by the NCI of the NIH under R03 CA245774. MTL was supported by the NCI of the NIH under awards R01CA181450 and R01CA206012 as well as ITTC/UPMCE. RD and ACS were further supported by funding from the Department of Cardiothoracic Surgery.ReferencesWilliams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. Npj Breast Cancer [Internet]. Breast Cancer Research Foundation/Macmillan Publishers Limited; 2016;2:15025. Available from: http://dx.doi.org/10.1038/npjbcancer.2015.252.Nasarre P, Gemmill RM, Potiron VA, Roche J, Lu X, Barón AE, et al. Neuropilin-2 is upregulated in lung cancer cells during TGF-β1–Induced epithelial–mesenchymal transition. Cancer Res [Internet] 2013;73:7111 LP–7121. Available from: http://cancerres.aacrjournals.org/content/73/23/7111.abstract3.Gemmill RM, Nasarre P, Nair-Menon J, Cappuzzo F, Landi L, D'Incecco A, et al. The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer. Sci Signal [Internet] 2017;10. Available from: http://stke.sciencemag.org/content/10/462/eaag0528.abstractEthics ApprovalThe study was approved by the University of Pittsburgh's Institutional Review Board approval number CR19120172-005.

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.

Respiratory disorders including chronic obstructive pulmonary disease, asthma, and increased susceptibility to lung infections are a prominent component of Gulf War Illness (GWI). Although the mechanisms of GWI are unknown, chronic immune dysfunction is a consistent factor of this multi-symptomatic disorder. Alveolar macrophages (AMs) represent the predominant mononuclear phagocytes of the pulmonary mucosa, orchestrating the host response to pathogens and environmental stimuli via balanced induction of inflammatory, anti-inflammatory, and pro-resolution mediators. Utilizing commercially available instrumentation, we evaluated the effect of aerosolized exposure to two putative GW toxins, the pesticide malathion and diesel exhaust particulate (DEP), on the immune composition and inflammatory response of the lung in FVB/N mice. Toxin exposure resulted in gross lung pathology with variable increases in protein, lactose dehydrogenase, and cytokines in bronchoalveolar lavage (BAL). Aerosolized toxin exposure reduced AMs in the lung and BAL, associated with a shift to wound-healing phenotypes and concomitant influx of monocyte-derived progenitors from the circulation. Exposure to DEP and malathion, either alone or in combination, induced varying levels of dysfunction in flow-sorted AMs ex vivo as determined by inhibited migration, cytokine production, and phagocytosis. Toxin-induced alterations were associated with unique transcriptional profiles following RNA sequencing analysis. Collectively, these findings suggest that respiratory toxin-induced macrophage dysfunction may establish a state of frustrated immune resolution underlying the chronic immunopathology of respiratory GWI.

Digital preservation is a challenging topic. The digital world evolves so quickly that it is hard to keep up with all the new developments, or understand the shelf life of various digital media because it has been changing exponentially fast.

Summary Obesity has become pandemic. In America, as obesity has increased, the amount of sleep Americans get per night has decreased, and studies are now showing an association. Epidemiological studies on short sleep duration (SSD) and obesity have been conducted in children and adults, and show an overall positive association. Leptin and ghrelin, two hormones that control appetite, have been studied as a mechanism for SSD causing obesity. Low leptin and high ghrelin levels have been seen in sleep deprivation, the effect of which is an increase in appetite that could be linked to obesity. Decreasing media use, namely television and computers, could be one way to increase nightly sleep and potentially help people lose weight. Paediatric studies have shown an association with bedroom media use and shorter sleep duration. Adult studies are lacking in this area. Limitations in the literature include self-report in a majority of sleep studies and only a suggested causal link between SSD and obesity among all of the epidemiological studies. In conclusion, obesity is a global problem with great complexity. Encouraging people to get more sleep could be one part of the solution to help them lose weight and gain health.

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.

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.

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.

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 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.