Characterizing the functional phenotype of infiltrating macrophages in meningiomas

Meningiomas are the most common primary brain tumors, yet few successful non-invasive treatment options are available for patients. Immunotherapy has provided new insights into treatments for solid tumors. The immune infiltrate of meningiomas has been broadly characterized, showing a significant monocytic cell content, but little is known about the phenotype and function of these myeloid cells within the tumor environment. As circulating monocytes differentiate into macrophages with highly plastic character within tissue, it remains to be seen how the macrophages in meningiomas are influencing the tumor. As many studies have described the presence of monocytic subpopulations within other solid tumors, we hypothesize that meningiomas contain two populations of myeloid cells: a pro-inflammatory macrophage-like population, and an immunosuppressive myeloid-derived suppressor cell (MDSC)-like population. We collected fresh tumor samples and processed them into a single-cell suspension. The cells were then stained with fluorescently labeled surface marker antibodies commonly found on macrophages and MDSCs. We used flow cytometry to quantify the myeloid populations, sorted the populations with a FACSAria™, and analyzed their gene expression profiles with NanoString® and TaqMan®. Two distinct myeloid populations were found in all analyzed tumor samples, varying in macrophage-like to MDSC-like ratios from tumor to tumor. Gene expression analysis of these populations confirmed the sorting strategy and provided new clues into the identity and function of the myeloid cell populations infiltrating meningiomas. NanoString® results confirmed a high HLA-DR gene expression in the HLA-DR+ sorted populations. The tumor HLA-DR+ population was found to have higher gene expression relative to the HLA-DR- population for chemoattractants such as IL8, CCL3, and CCL4. Compared to a healthy blood monocyte control, tumor myeloid cells expressed higher levels of the genes C3AR1, ROCK2, IL10, NOS2, IL18, and CSF2. Finally, qPCR analysis and NanoString® results showed high expression of the gene IL6 in the non-immune cell tumor cells (CD45-). The IL6 cytokine has been shown to induce MDSCs. These findings may have significant implications in identifying new targets in immunotherapy to stop tumor growth and increase survival outcomes.2016-11-03T00:00:00

Energy source, protein metabolism, and hunter-gatherer subsistence strategies

During late winter and spring, hunter-gatherers in temperate, subarctic, and arctic environments often relied on diets that provided marginal or inadequate caloric intakes. During such periods, particularly when stored food supplies dwindled or were used up entirely, lean meat became the principal source of energy. Nutritional problems associated with high-protein, low-energy diets are discussed. These problems include elevated metabolic rates, with correspondingly higher caloric requirements, and deficiencies in essential fatty acids. The relative benefits of adding fat or carbohydrate to a diet of lean meat are evaluated in light of the protein-sparing capacities of these two nutrients. Experimental data indicate that although both enhance high-protein, low-energy diets, carbohydrate is a more effective supplement than fat. Given the nutritional inadequacies of a lean-meat diet, the paper concludes with a discussion of alternative subsistence strategies that increase the availability of carbohydrate or fat at the critical time of year.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25268/1/0000711.pd

The Perils of Single-Site Genetic Testing for Hereditary Cancer Syndromes in the Era of Next-Generation Sequencing.

Abstract A challenge in counseling patients with a family history suggesting a hereditary cancer syndrome is deciding which genetic tests or panels to order. In this article, we discuss the identification of multiple familial mutations through genetic counseling and panel testing. For patients meeting National Comprehensive Cancer Network criteria for clinical genetic testing, providers should consider expanded panels to provide a more complete assessment of one's genetic risk. The continued use of expanded panel testing in the clinical setting will help inform optimal management of cancer patients, as well as the management of their unaffected family members. The mutation discovered in this case was in the ATM gene. The clinical significance of the mutation, potential therapeutic targets, and proper clinical management are discussed. Key Points With single-site genetic testing, there is the potential to miss hereditary genetic syndromes that can be managed clinically. Between 4% and 6% of hereditary breast and ovarian cancer syndromes are caused by genes other than BRCA1 and BRCA2. ATM is a DNA mismatch repair gene associated with double-stranded DNA break repair and cell cycle checkpoint arrest. The risk of developing female breast cancer by age 50 and by age 80 in ATM heterozygotes is 9% and 17%–52%, respectively. </jats:sec

Technical note: standardized and semiautomated Harris lines detection

Arrest in long bone growth and the subsequent resumption of growth may be visible as radiopaque transverse lines in radiographs (Harris lines, HL; Harris, HA. 1933. Bone growth in health and disease. London: Oxford University Press). The assessment of individual age at occurrence of such lines, as part of paleopathological skeletal studies, is time-consuming and shows large intra- and interobserver variability. Thus, a standardized, automated detection algorithm would help to increase the validity of such paleopathological research. We present an image analysis application facilitating automatic detection of HL. On the basis of established age calculation methods, the individual age-at-formation can be automatically assessed with the tool presented. Additional user input to confirm the automatic result is possible via an intuitive graphical user interface. Automated detection of HL from digital radiographs of a sample of late Medieval Swiss tibiae was compared to the consensus of manual assessment by two blinded expert observers. The intra- and interobserver variability was high. The quality of the observer result improved when standardized detection criteria were defined and applied. The newly developed algorithm detected two-thirds of the HL that were identified as consensus lines between the observers. It was, however, necessary to validate the last one-third by manual editing. The lack of a large test series must be noted. The application is freely available for further testing by any interested researcher