The prairie farm rehabilitation administration and the community pasture program, 1937-1947

In 1935, following years of drought, economic depression, and massive relief expenditures, the federal government of Canada passed the Prairie Farm Rehabilitation Act (PFR Act) to arrest soil drifting, improve cultivation techniques, and conserve moisture on the Canadian prairies. Activities under the act were to last no more than five years and cost no more than five million dollars. By 1937, the act was amended to remove unsuitable land from cultivation permanently, and develop federally controlled community pastures. Settlers on unsuitable land were relocated to reduce relief expenditures, and farmers on quality land could balance their operations by grazing livestock on nearby pastures. The first ten years of the community pasture program (1937-1947) represented an important stage in the federal interpretation of the prairie region. For decades, Ottawa had administered the prairies with policies that reflected a sense of the region's uniformity and a faith in the power of dry farming techniques. The community pasture program acknowledged the ecological diversity of the prairies and the need for agricultural activities to suit the region's natural limitations. Efforts to develop community pastures were complicated however, by economic, political and social circumstances. By the five-year mark of the program, pasture development was at a virtual standstill. But as federal rehabilitation officials negotiated with prairie governments and private landowners for control of land in community pastures, the region was increasingly understood. In practice, the community pasture program reflected the understanding that broadly-based land use policy had to be flexible in order to accommodate the ecological and social diversity of the prairies

Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types

BACKGROUND: Inhibition of the PD-L1/PD-1 immune checkpoint axis represents one of the most promising approaches of immunotherapy for various cancer types. However, immune checkpoint inhibition is successful only in subpopulations of patients emphasizing the need for powerful biomarkers that adequately reflect the complex interaction between the tumor and the immune system. Recently, recurrent copy number gains (CNG) in chromosome 9p involving PD-L1 were detected in many cancer types including lung cancer, melanoma, bladder cancer, head and neck cancer, cervical cancer, soft tissue sarcoma, prostate cancer, gastric cancer, ovarian cancer, and triple-negative breast cancer. METHODS: Here, we applied functional genomics to analyze global mRNA expression changes associated with chromosome 9p gains. Using the TCGA data set, we identified a list of 75 genes that were strongly up-regulated in tumors with chromosome 9p gains across many cancer types. RESULTS: As expected, the gene set was enriched for chromosome 9p and in particular chromosome 9p24 (36 genes and 23 genes). Furthermore, we found enrichment of two expression programs derived from genes within and beyond 9p: one implicated in cell cycle regulation (22 genes) and the other implicated in modulation of the immune system (16 genes). Among these were specific cytokines and chemokines, e.g. CCL4, CCL8, CXCL10, CXCL11, other immunoregulatory genes such as IFN-G and IDO1 as well as highly expressed proliferation-related kinases and genes including PLK1, TTK, MELK and CDC20 that represent potential drug targets. CONCLUSIONS: Collectively, these data shed light on mechanisms of immune escape and stimulation of proliferation in cancer with PD-L1 CNG and highlight additional vulnerabilities that may be therapeutically exploitable

Cancer immunoediting by the innate immune system in the absence of adaptive immunity

Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2, and RAG2x γc mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2x γc mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting

Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity

Tumor-associated myeloid cells have been implicated in regulating many of the “hallmarks of cancer” and thus fostering solid tumor development and metastasis. However, the same innate leukocytes also participate in anti-tumor immunity and restraint of malignant disease. While many factors regulate the propensity of myeloid cells to promote or repress cancerous growths, polarized adaptive immune responses by B and T lymphocytes have been identified as regulators of many aspects of myeloid cell biology by specifically regulating their functional capabilities. Here, we detail the diversity of heterogeneous B and T lymphocyte populations and their impacts on solid tumor development through their abilities to regulate myeloid cell function in solid tumors

Cellular Phenotype-Dependent and -Independent Effects of Vitamin C on the Renewal and Gene Expression of Mouse Embryonic Fibroblasts

Vitamin C has been shown to delay the cellular senescence and was considered a candidate for chemoprevention and cancer therapy. To understand the reported contrasting roles of vitamin C: growth-promoting in the primary cells and growth-inhibiting in cancer cells, primary mouse embryonic fibroblasts (MEF) and their isogenic spontaneously immortalized fibroblasts with unlimited cell division potential were used as the model pair. We used microarray gene expression profiling to show that the immortalized MEF possess human cancer gene expression fingerprints including a pattern of up-regulation of inflammatory response-related genes. Using the MEF model, we found that a physiological treatment level of vitamin C (10−5 M), but not other unrelated antioxidants, enhanced cell growth. The growth-promoting effect was associated with a pattern of enhanced expression of cell cycle- and cell division-related genes in both primary and immortalized cells. In the immortalized MEF, physiological treatment levels of vitamin C also enhanced the expression of immortalization-associated genes including a down-regulation of genes in the extracellular matrix functional category. In contrast, confocal immunofluorescence imaging of the primary MEF suggested an increase in collagen IV protein upon vitamin C treatment. Similar to the cancer cells, the growth-inhibitory effect of the redox-active form of vitamin C was preferentially observed in immortalized MEF. All effects of vitamin C required its intracellular presence since the transporter-deficient SVCT2−/− MEF did not respond to vitamin C. SVCT2−/− MEF divided and became immortalized readily indicating little dependence on vitamin C for the cell division. Immortalized SVCT2−/− MEF required higher concentration of vitamin C for the growth inhibition compared to the immortalized wildtype MEF suggesting an intracellular vitamin C toxicity. The relevance of our observation in aging and human cancer prevention was discussed

Sequence of the hyperplastic genome of the naturally competent Thermus scotoductus SA-01

<p>Abstract</p> <p>Background</p> <p>Many strains of <it>Thermus </it>have been isolated from hot environments around the world. <it>Thermus scotoductus </it>SA-01 was isolated from fissure water collected 3.2 km below surface in a South African gold mine. The isolate is capable of dissimilatory iron reduction, growth with oxygen and nitrate as terminal electron acceptors and the ability to reduce a variety of metal ions, including gold, chromate and uranium, was demonstrated. The genomes from two different <it>Thermus thermophilus </it>strains have been completed. This paper represents the completed genome from a second <it>Thermus </it>species - <it>T. scotoductus</it>.</p> <p>Results</p> <p>The genome of <it>Thermus scotoductus </it>SA-01 consists of a chromosome of 2,346,803 bp and a small plasmid which, together are about 11% larger than the <it>Thermus thermophilus </it>genomes. The <it>T. thermophilus </it>megaplasmid genes are part of the <it>T. scotoductus </it>chromosome and extensive rearrangement, deletion of nonessential genes and acquisition of gene islands have occurred, leading to a loss of synteny between the chromosomes of <it>T. scotoductus and T. thermophilus</it>. At least nine large inserts of which seven were identified as alien, were found, the most remarkable being a denitrification cluster and two operons relating to the metabolism of phenolics which appear to have been acquired from <it>Meiothermus ruber</it>. The majority of acquired genes are from closely related species of the Deinococcus-Thermus group, and many of the remaining genes are from microorganisms with a thermophilic or hyperthermophilic lifestyle. The natural competence of <it>Thermus scotoductus </it>was confirmed experimentally as expected as most of the proteins of the natural transformation system of <it>Thermus thermophilus </it>are present. Analysis of the metabolic capabilities revealed an extensive energy metabolism with many aerobic and anaerobic respiratory options. An abundance of sensor histidine kinases, response regulators and transporters for a wide variety of compounds are indicative of an oligotrophic lifestyle.</p> <p>Conclusions</p> <p>The genome of <it>Thermus scotoductus </it>SA-01 shows remarkable plasticity with the loss, acquisition and rearrangement of large portions of its genome compared to <it>Thermus thermophilus</it>. Its ability to naturally take up foreign DNA has helped it adapt rapidly to a subsurface lifestyle in the presence of a dense and diverse population which acted as source of nutrients. The genome of <it>Thermus scotoductus </it>illustrates how rapid adaptation can be achieved by a highly dynamic and plastic genome.</p

Inflammation and breast cancer. Metalloproteinases as common effectors of inflammation and extracellular matrix breakdown in breast cancer

Two rapidly evolving fields are converging to impact breast cancer: one has identified novel substrates of metalloproteinases that alter immune cell function, and the other has revealed a role for inflammation in human cancers. Evidence now shows that the mechanisms underlying these two fields interact in the context of breast cancer, providing new opportunities to understand this disease and uncover novel therapeutic strategies. The metalloproteinase class of enzymes is well studied in mammary gland development and physiology, but mostly in the context of extracellular matrix modification. Aberrant metalloproteinase expression has also been implicated in breast cancer progression, where these genes act as tumor modifiers. Here, we review how the metalloproteinase axis impacts mammary physiology and tumorigenesis and is associated with inflammatory cell influx in human breast cancer, and evaluate its potential as a regulator of inflammation in the mammary gland

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy