Macrophages, Neutrophils, and Cancer: A Double Edged Sword

The tumor microenvironment is a well-recognized framework, in which myeloid cells play important roles in cancer development from tumor initiation to metastasis. Immune cells present in the tumor microenvironment can promote or inhibit cancer formation and development. Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to distinct signals the cells of the monocyte-macrophage lineage have the ability to display a wide spectrum of activation states; classical Ml or alternative M2 macrophages represent extremes of a continuum of this activation. Tumor-associated macrophages generally acquire an M2-like phenotype that is relevant for their participation in tumor growth and progression. There is now evidence that also neutrophils can be driven towards distinct phenotypes in response to microenvironmental signals. In fact they can interact with distinct cell populations and produce a wide number of cytokines and effector molecules. Therefore, macrophages and neutrophils are both integrated in the regulation of the innate and adaptive immune responses in various inflammatory situations, including cancer. These findings have triggered efforts to target tumor-associated macrophages and neutrophils. In particular, "reeducation" to activate their antitumor potential or elimination of tumor promoting cells is a new strategy undergoing preclinical and clinical evaluation

Exploiting nutritional value of staple foods in world’s semi-arid areas: risks and benefits, challenges and opportunities of sorghum

Sorghum (Sorghum bicolor (L.) Moench) is a drought-resistant crop and an important food resource in terms of nutritional as well as social-economic values, especially in semi-arid environments. Cultivar selection and processing methods have been observed to impact on composition and functional and nutritional value of sorghum. Amino acid imbalance, cyanogenic glycosides, endogenous anti-nutrients, mycotoxins and toxic elements are among factors impairing its nutritional value. This paper reviews possible approaches (varieties selection, production practices, cooking processes) to improve the benefits-to-risks balance of sorghum meal, to mitigate the risk of deficiencies and/or imbalances and to improve effects on human nutrition. Opportunity for avoiding dietary diversification in high sorghum consumers is also discussed, e.g., tryptophan and niacin deficits potentially related to pellagra, or unavailability of proteins and divalent cations (e.g., Fe, Zn) due to the antinutrient activity of phytic acid and tannins. As potential candidate for production investments, the role of sorghum in preserving biological diversity is also considered.JRC.J.4-Agriculture and Life Sciences in the Econom

Role of Metalloproteases in the Release of the IL-1 type II Decoy Receptor

The IL-1 type II receptor (decoy RII) is a nonsignaling molecule the only established function of which is to capture IL-1 and prevent it from interacting with signaling receptor. The decoy RII is released in a regulated way from the cell surface. Here, we reported that hydroxamic acid inhibitors of matrix metalloproteases inhibit different pathways of decoy RII release, including the following: (a) the slow (18 h) gene expression-dependent release from monocytes and polymorphonuclear cells exposed to dexamethasone; (b) rapid release (minutes) from myelomonocytic cells exposed to tumor necrosis factor, chemoattractants, or phorbol myristate acetate; (c) phorbol myristate acetate-induced release from decoy RII-transfected fibroblasts and B cells. Inhibition of release was associated with increased surface expression of decoy RII. Inhibitors of other protease classes did not substantially affect release. However, serine protease inhibitors increased the molecular mass of the decoy RII released from polymorphonuclear cells from 45 to 60 kDa. Thus, irrespective of the pathway responsible for release and of the cellular context, matrix metalloproteases, rather than differential splicing, play a key role in production of soluble decoy RII

PTX3 Regulation of Inflammation, Hemostatic Response, Tissue Repair, and Resolution of Fibrosis Favors a Role in Limiting Idiopathic Pulmonary Fibrosis

PTX3 is a soluble pattern recognition molecule (PRM) belonging to the humoral innate immune system, rapidly produced at inflammatory sites by phagocytes and stromal cells in response to infection or tissue injury. PTX3 interacts with microbial moieties and selected pathogens, with molecules of the complement and hemostatic systems, and with extracellular matrix (ECM) components. In wound sites, PTX3 interacts with fibrin and plasminogen and favors a timely removal of fibrin-rich ECM for an efficient tissue repair. Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown origin, associated with excessive ECM deposition affecting tissue architecture, with irreversible loss of lung function and impact on the patient’s life quality. Maccarinelli et al. recently demonstrated a protective role of PTX3 using the bleomycin (BLM)-induced experimental model of lung fibrosis, in line with the reported role of PTX3 in tissue repair. However, the mechanisms and therapeutic potential of PTX3 in IPF remained to be investigated. Herein, we provide new insights on the possible role of PTX3 in the development of IPF and BLM-induced lung fibrosis. In mice, PTX3-deficiency was associated with worsening of the disease and with impaired fibrin removal and subsequently increased collagen deposition. In IPF patients, microarray data indicated a down-regulation of PTX3 expression, thus suggesting a potential rational underlying the development of disease. Therefore, we provide new insights for considering PTX3 as a possible target molecule underlying therapeutic intervention in IPF

Why research on endocrine disrupting chemicals is still worthwhile

Abstrac

Changes of particle size distribution and chemical composition of a hay-based ration offered once or twice daily to dairy cows

The objective of this experiment is to evaluate the changes of particle size distribution and chemical composition of the total mixed ration (TMR) based on hay as the main forage component ("dry" TMR) and distributed once (7.00 am) or twice (7.00 am and 1.00 pm) daily to 32 lactating cows. The trial was divided in two periods of 14 days each. Diet (DM=53.7%) was formulated in order to assure the nutritional requirements of cows producing 24 kg/d of milk (crude protein=14.4% DM; NDF=40.9% DM; milk FU=0.88/kg DM) and additional amounts of concentrates were distributed using automatic feeders. Four TMR samples were collected daily (7.00 am, 10.00 am, 1.00 pm, 4.00 pm) for six days during each experiment period for a total number of 48 feed samples. Each feed sample was subjected to the estimation of the particle size distribution using the separator of Pennsylvania State University composed of two sieves (diameters of 19 and 8 mm) and a collector on the bottom, and to the determination of the chemical composition. Changes of all three particle size fractions for TMRs were observed during the day with distributions of the TMR both once and twice daily. With the once daily distribution, the large particles fraction increased linearly (P<0.001) from 19.7 to 23.4, 32.2, and 35.1%, while the finest particle fraction decreased (from 60.1 to 58.3, 50.0, 47.8%). According to particle size changes, the chemical composition varied significantly at the different times of sampling when TMR was distributed once daily. Significant variations of DM were detected for TMR with a linear (P<0.001) increase (from 54.4 to 57.9, 60.7, 61.5%). Considering once TMR distribution, the values of NDF and starch showed an opposite trend with an increase of 6.5 and a decrease of 8.3 points from 7.00 am to 4.00 pm (i.e., 9 hrs after distribution). Correlations were estimated between chemical and physical characteristics of TMRs. NDF content was positively and significantly correlated to the fraction of particles retained by a 19 mm sieve (r=0.42; P<0.001) and negatively correlated with the smaller particles (r=-0.51; P<0.001). In conclusion, when the TMRs are prepared excluding corn/hay silages, twice daily distributions of diet can avoid the selection of large feed by the cows, thereby preserving both a uniform particle size distribution and a steady chemical composition of the diet during the day. However, the cost for the extra time needed for twice daily dis- tribution should be carefully considered

Expression and involvement of c-fos and c-jun protooncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines

Cell death induced by growth factor withdrawal is a programed event in which gene transcription and translation are required. Thus, it is likely that genes encoding for transcriptional factors can play an important role in this process. We have tested this hypothesis by analyzing c-fos and c-jun protooncogene expression and involvement in lymphoid cells deprived of growth factors. Interleukin (IL)-6- and IL-2-dependent mouse cell lines undergo programmed cell death after growth factor deprivation. Northern blot analysis shows that c-fos and c-jun protooncogenes are rapidly induced (within 60 min) after growth factor deprivation in IL-6- and IL-2-dependent mouse cells. Induction is transient, being undetectable at 120 min after deprivation. Induction of these protooncogenes is at the transcriptional level, as demonstrated by actinomycin D and nuclear run-off experiments. Antisense oligonucleotides directed against c-fos and c-jun mRNAs consistently reduced the expression of these genes in treated cells. This reduction was associated with increased survival of growth factor-deprived lymphoid cells, thus suggesting that the expression of c-fos and c-jun protooncogenes may represent an important early event in the activation of the genetic program of cell death

Analysis of Food Safety and Security Challenges in Emerging African Food Producing Areas through a One Health Lens: The Dairy Chains in Mali

Challenges posed by changes in livestock production in emerging food producing areas and demographic development and climate change require new approaches and responsibilities in the management of food chains. The increasingly recognized role of primary food producers requires the support of the scientific community to instruct effective approaches based on scientific data, tools, and expertise. Mali is an emerging food producing area, and this review covers (i) the dairy farming scenario and its environment, (ii) the role of dairy production in food security, including the greatly different animal rearing systems in the Sahel and tropical regions, (iii) risk management pillars as modern infrastructures, effective farmer organizations, and institutional systems to guarantee animal health and safety of products, and (iv) feasible interventions based on good practices and risk assessment at the farm level (e.g., sustainable use of fertilizers, feeds, veterinary drugs, and pesticides) to protect consumers from food safety hazards. Social innovation based on the empowerment of the primary food producers emerges as crucial for sustainable and safe food production. Sustainable policies should be supported by the mobilization of stakeholders of One Health, which is a science-based approach to linking human health and nutrition with the health and management of food producing animals and environmental safety. In the context of the complex, multifaceted scenario of Mali dairy production, this article presents how a cost-effective animal health and food safety scheme could be established in the dairy production chain. Because milk is a major commodity in this country, benefits could be derived in food security, public health, the resilience of the farming system, animal husbandry, and international trade

GALDIERO is CO-FIRST AUTHOR. Phagocytes as Corrupted Policemen in Cancer-Related Inflammation

Inflammation is a key component of the tumor microenvironment. Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) are prototypic inflammatory cells in cancer-related inflammation. Macrophages provide a first line of resistance against infectious agents but in the ecological niche of cancer behave as corrupted policemen. TAMs promote tumor growth and metastasis by direct interactions with cancer cells, including cancer stem cells, as well as by promoting angiogenesis and tissue remodeling and suppressing effective adaptive immunity. In addition, the efficacy of chemotherapy, radiotherapy, and checkpoint blockade inhibitors is profoundly affected by regulation of TAMs. In particular, TAMs can protect and rescue tumor cells from cytotoxic therapy by orchestrating a misguided tissue repair response. Following extensive preclinical studies, there is now proof of concept that targeting tumor-promoting macrophages by diverse strategies (e.g., Trabectedin, anti-colony-stimulating factor-1 receptor antibodies) can result in antitumor activity in human cancer and further studies are ongoing. Neutrophils have long been overlooked as a minor component of the tumor microenvironment, but there is evidence for an important role of TANs in tumor progression. Targeting phagocytes (TAMs and TANs) as corrupted policemen in cancer may pave the way to innovative therapeutic strategies complementing cytoreductive therapies and immunotherapy