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Bacteria and tumours: causative agents or opportunistic inhabitants?
Joanne Cummins1 &
Mark Tangney1
Infectious Agents and Cancer volume 8, Article number: 11 (2013) Cite this article
Associations between different bacteria and various tumours have been reported in patients for decades. Studies involving characterisation of bacteria within tumour tissues have traditionally been in the context of tumourigenesis as a result of bacterial presence within healthy tissues, and in general, dogma holds that such bacteria are causative agents of malignancy (directly or indirectly). While evidence suggests that this may be the case for certain tumour types and bacterial species, it is plausible that in many cases, clinical observations of bacteria within tumours arise from spontaneous infection of established tumours. Indeed, growth of bacteria specifically within tumours following deliberate systemic administration has been demonstrated for numerous bacterial species at preclinical and clinical levels. We present the available data on links between bacteria and tumours, and propose that besides the few instances in which pathogens are playing a pathogenic role in cancer, in many instances, the prevalent relationship between solid tumours and bacteria is opportunistic rather than causative, and discuss opportunities for exploiting tumour-specific bacterial growth for cancer treatment.
The development of cancer is associated with several genetic and environmental factors. Furthermore there has been an association between the development of cancer and bacterial and viral infections for decades. Several viruses can integrate into the human genome and directly initiate tumourigenesis, such as human papillomavirus (HPV) in cervical cancer and herpesvirus in Kaposi's sarcoma [1, 2]. In other cases, the development of cancer is indirect, such as with Helicobacter pylori, which contributes to both gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma due to chronic inflammation caused by the bacteria [3, 4]. This notwithstanding, observations made in the course of numerous studies have reported different indigenous bacterial species being isolated from infected lesions in patients (Table 1) [5, 6]. As early as 1868 Bush reported 2 patients with sarcoma that had been infected with Streptococcus and Coley also detected the presence of S. pyogenes in a patient suffering from neck cancer [7, 8]. In 1907 Fibiger discovered that the parasitic nematode (Spiroptera neoplastica) was associated with cancer development in rats, while it was later found that the development of cancer was associated with a vitamin A deficiency he paved the way for future discoveries in cancer causing bacteria and viruses [9]. In 1911 Francis Peyton Rous was the first to discover that cancer could be transmitted by a virus (later known as Rous sarcoma virus), but it wasn't until years later that his results were accepted by the scientific community [10, 11]. In 1926 Glover stated that certain bacteria were consistently isolated from neoplastic tissue [12]. Furthermore between the years of 1936–1955 several different publications all reported the presence of microbes in cancer tissue [13–15]. More recently, it has been shown that bacteria are naturally capable of homing to tumours when systemically administered, resulting in high levels of replication locally [16]. This was originally established following IV administration of species of Clostridium, and in more recent years with numerous bacterial species, including, Salmonella, Bifidobacterium, Escherichia coli, Vibrio cholerae and Listeria monocytogenes. Furthermore, various clinical trials have shown the ability of different bacterial strains to home to and replicate specifically within tumours [17–19].
Table 1 Overview of bacteria identified in different tumour types
The presence of bacteria within tumours could be due to infection via the vasculature and their ability to survive and grow due to the presence of nutrients within the hypoxic region of the tumour at a later stage in tumour growth (see below for proposed mechanism). For example, sampling from humans has indicated that bacterial translocation of Gastro-Intestinal Tract (GIT)-associated bacteria may be a phenomenon that occurs in healthy individuals representing a normal physiological event without deleterious consequences [40]. It may be that bacteria egress from the GIT at very low numbers, and are normally quickly eliminated by the immune system. However, the phenomenon of bacterial replication within tumours results in dramatic increases in bacterial numbers within a confined region.
This review will focus on bacteria that have been identified within patient tumours and how they might be used to aid in early detection (in the context of causative agents) or treatment (subsequent infection) of cancers.
Bacteria as causative agents of cancer
There are several bacteria that have been associated or defined as being causative agents of cancer (Table 1). The most widely known of these bacteria would be H. pylori which is the strongest known risk factor for gastric cancer [41]. However only a small minority of those infected develop gastric cancer or precancerous gastric lesions. The reason for this is thought to be due to several factors; strain biodiversity, geographical distribution and environmental factors. H. pylori is also associated with an increased risk of pancreatic cancer, thought to occur through pathophysiological actions of the bacterium [41, 42]. Recent data also support the hypothesis that H. pylori is also associated with a slightly increased risk of colorectal cancer [39].
Furthermore recent data promotes the paradigm that gut bacteria can influence cancer risk in extra-intestinal organs [43, 44]. The means by which this occurs is not fully elucidated, but is thought to involve both immunity and metabolism as key factors in tumour promotion by intestinal bacteria [45]. H. hepaticus is a murine enterohepatic bacterium that causes hepatitis and hepatocellular carcinoma (HCC) in some strains of mice [46]. A recent study by Rogers demonstrated increased liver tumours in mice colonized with H. hepaticus in the lower bowels but without any requirements for hepatic translocation or hepatitis induction [45]. This lead to the conclusion, that H. hepaticus promotes liver cancer from its endogenous niche in the lower bowels. Another study using Apcmin/+Rag2−/− mice demonstrated an increased risk of mammary cancer when infected with H. hepaticus, further suggesting that gut microbes can promote extra-intestinal cancer [44].
One of the bacterial agents that have been found to be regularly associated with colorectal carcinoma (CRC) is Streptococcus bovis/gallolyticus. S. bovis/gallolyticus is a transient normal flora in the gut thought to be present in 2.5-15% of individuals [47–49]. One theory for the association between S. bovis/gallolyticus and CRC is due the increased load of S. bovis/gallolyticus in the colon, which has been shown to be associated with inflammatory bowel disease or malignant/premalignant lesions of the tumour. From the research preformed to date it is believed that S. bovis/gallolyticus association with CRC seems to be of etiological nature and the proposed carcinogenic potential of S. bovis/gallolyticus is most likely a propagation factor for premalignant tissues. The early detection of CRC via identification of S. bovis/gallolyticus DNA or antibodies may be a potential screening method for at high-risk groups [50].
C. pneumoniae is a Gram-negative bacillus and an obligate intracellular parasite that causes respiratory infections in over 50% of adults. The relationship between C. pneumoniae and lung cancer has been studied for over 10 years by clinical and laboratory research methods but the results have been inconsistent. Recently a meta-analysis approach was used to analyse previously published data [51]. They concluded a dose–response effect in which increasing lung cancer risk was associated with increasing IgA (serological criteria for chronic infection) antibody titre, also suggested that higher titre may be a better predictor of lung cancer risk than lower antibody titres [51]. All these studies also indicated that C. pneumoniae infection was associated with increased risk of lung cancer in certain sub-groups such as young individuals, men, former smokers and for squamous cell carcinomas or small cell carcinomas [22, 51–55].
The other side of the coin: opportunistic infections of established tumours
While bacterial presence in certain tumours is associated with the development of that cancer, in many cases, bacteria present in tumours may reflect local infections of existing malignant tissue [56]. Observations made in the course of numerous studies have reported different indigenous bacterial species being isolated from infected lesions in patients (Table 1). After Bush's report of Streptococcus in sarcomas in 1868 [7], William Coley, the "father of immunotherapy", identified the presence of S. pyogenes in soft tissue sarcoma, and was one of the first to characterise concomitant infection of tumours and how this could lead to remission of incurable neoplastic malignancy [57, 58]. In recent years there have been a number of studies that show a correlation between bacterial infection and tumour regression. Ruckdeschel et al. found that patients who developed empyema after lung cancer had a significantly improved survival rate after 5 years compared with uninfected patients (50% v's 18%) [59]. Furthermore, two patients with malignant CNS tumours unexpectedly regressed after infection. Of these patients, one of the infections was viral in nature while the second was found to feature Corynebacterium hemolyticum and Staphylococcus epidermidis. The patient survived for 9 years after his tumour was originally discovered [60]. A recent study to determine the survival rate after infection in glioblastoma multiforme patients demonstrated no survival advantage in patients with post-operative infection but they did find that the deep infection subgroup showed a trend towards increased survival [61]. Bohman and colleagues literature search revealed 9 patients with malignant intracranial tumours who experienced prolonged survival due to infection with a mean survival of 7.5-8 years and no evidence of central nervous system recurrence upon death. The majority of patients had infections with either S. aureus or Enterobacter aerogens[61].
Mechanisms of bacterial replication within tumours
There are several proposed factors involved in how bacteria replicate and survive within tumours. Traditionally, the main mechanism is thought to be due to the hypoxic nature of many solid tumours, which results in low oxygen levels compared with normal tissues, providing a unique growth environment for anaerobic and facultative anaerobic bacteria [62]. Other factors contributing to bacterial replication in the tumour include the presence of bacterial nutrients within the necrotic region such as purines [63]. Furthermore, the involvement of bacterial chemotaxis towards chemo-attractant compounds present in necrotic regions (e.g. aspartate, serine, citrate, ribose or galactose) produced by quiescent cancer cells has also been suggested as a contributing factor [63].
As knowledge in the field grows, elements believed to be key for tumour-specific bacterial replication include aberrant neovasculature and local immune suppression [63]. As tumours develop, they promote the construction of new blood vessels (neo-angiogenesis). However, these newly formed vessels are highly disorganized with incomplete endothelial linings and blind ends, resulting in 'leaky' blood vessels and slow blood flow. This leaky tumour vasculature may allow circulating bacteria to enter tumour tissue, and embed locally (Figure 1) [63]. Furthermore, a variety of mechanisms are employed by cancerous cells to avoid recognition by the immune system resulting in insufficient immune activity within tumours, potentially providing a refuge for bacteria to evade immune clearance, not present elsewhere in the body [64, 65].
Proposed mechanism of bacterial entry to and proliferation within tumours. Tumour (pink/purple) development leads to recruitment of new blood supply, involving disorganized and leaky vasculature, permitting circulating bacteria (black) to enter the tumour. Bacteria replicate primarily within hypoxic (pink) tumour regions, which feature immune suppression, abundant nutrients and low oxygen.
Systemic microbes: routes of infection
While blood is taken to be free of bacteria in healthy individuals, it is plausible that establishment of a tumour infection might occur even with extremely low numbers of viable bacteria, given the phenomenon of tumour-specific bacterial growth. This hypothesis suggests the tumour providing a localized 'amplified read-out' for bacterial infection, which is otherwise unapparent. Presence of bacteria in the blood stream may be due to wound infection (e.g. post surgery), or bacterial translocation (BT) from the gastrointestinal tract (GIT).
GIT translocation
BT is the invasion of indigenous intestinal bacteria through the gut mucosa into normal sterile tissue [66]. The means by which bacteria translocate is thought to be by two distinct pathways of gastrointestinal permeability: (1) transcellular through the enterocytes and (2) paracellular using tight junctions [67]. There are also thought to be two major methods by which bacterial compounds gain access to systemic circulation; (1) through the enteric venous system to the portal vein and (2) following lymphatic drainage. After much analysis it is thought that the lymphatic route is the primary pathway of translocation [67]. Experimental and clinical studies have detected both indigenous and non-indigenous bacteria within the mesenteric lymph node (MLN). Some studies have demonstrated that BT from the gut to the MLN is quiet common, with it occurring in 4-59% of patients [67]. Furthermore patients needing surgery for abdominal infection fared much worse if the MLN was infected with non-indigenous bacteria [67]. In normal healthy individuals, the normal immune response will destroy bacteria associated with BT by phagocytosis. However, immunocompromised individuals have a higher risk of being affected by BT. Cannon et al., found that one of the main underlying conditions increasing patients susceptibility to BT associated bacteraemia was cancer [68]. Penn and colleagues demonstrated an increased translocation from the GIT of S-180 tumour-bearing mice, leading them to postulate that the immune deficiencies associated with tumour growth may be adequate to allow the viable bacteria to translocate from the GIT to the developing tumour [69]. Our group has shown that oral administration of non-pathogenic bacteria to mice results in trafficking from the GIT with subsequent homing to and replication specifically in tumours [70].
The ability of microorganisms to translocate, survive, and proliferate in extra-intestinal tissues involves complex interactions between the host defence mechanisms and the bacterium's ability to invade host tissues. Although the importance of host immune function and the bacterium's intestinal population size have been implicated as significant contributory factors, the precise mechanisms involved remains unknown [5, 66, 69, 71].
The oral microbiome
As described earlier, members of the oral microbiota have been associated with pancreatic cancer [72, 73]. Farrell and colleagues carried out microbial profiling using the Human Oral Microbe Identification Microarray (HOMIM) to compare the salivary microbiota between 10 pancreatic cancer patients and 10 normal matched healthy controls [72]. In their study they found that the levels of Neisseria elongata and Streptococcus mitis were decreased in the cancer patients relative to healthy controls and the level of Granulicaetella adiacens was increased in the cancer patients. These results validate a link between N. elongata and G. adiacens with periodontal disease, which has been linked to an increased risk of pancreatic cancer [72]. Farrell et al., postulated that as G. adiacens, an opportunistic pathogen, may be associated with systemic inflammation and an elevation in this bacteria could be related to the decreased levels of S. mitis[72]. Furthermore S. mitis plays a protective role against the adhesion of carcinogenic bacteria and the loss of S. mitis may contribute to aggressive periodontitis. Whether the variation in oral bacteria in pancreatic cancer is causative rather than reactive would have to be investigated further to determine how local oral bacteria without entering the blood stream could potentially cause systemic diseases, chronic inflammation and neoplasia [72]. In the case of periodontal bacteria, such as Porphyromonas gingivalis it is believed that lymph vessel openings trap bacteria en route from the mouth to the blood stream and then carry them to the vein of the venous angle near the supraclavicular area [74]. A previous study by Sakamoto and colleagues analysed the regional lymph nodes of 30 patients with oral cancer [75]. A total of 153 lymph nodes were harvested for microbiological examination. It was found that viable bacteria were found in 45% of the lymph nodes from 83% of patients. The cervical lymph nodes are in contact with the lymphatic flow before returning to the thoracic duct. The presence of viable bacteria, mainly oral streptococcus, in these lymph nodes supports the hypothesis of the association between oral mucosal damage and bacterial invasion into general circulation [75]. Furthermore the anaerobic bacteria detected (Peptostreptococcus) in the lymph nodes have been detected in gastrointestinal tumour tissue suggesting that the oral mucosal defect could promote translocation of anaerobes into the regional nodes [75, 76].
Farrell and colleagues then evaluated the specificity of the microbial biomarkers against another HOMIM microbial study that had been performed on lung cancer. They observed that none of the bacterial biomarkers validated in their study was significantly altered in the microflora profile of lung cancer [72]. This validates that the microbial biomarkers present in the saliva are specific for pancreatic cancer.
Fusobacterium
A bacterium that of late has been linked with CRC is Fusobacterium nucleatum[35, 36]. F. nucleatum is an invasive, adherent and pro-inflammatory anaerobe that is commonly found in dental plaque and is well known to be associated with periodontitis [77–79]. However, Fusobacterium is also known to be a gut commensal with probiotic features [79]. Castellarin and colleagues analysed the RNA sequence of 11 matched pairs of colorectal carcinoma and adjacent normal tissue and found an over-representation of F. nucleatum[35]. They postulated that the presence of the bacterium within the tumour could just represent an prevalent infection at an immunocompromised site or may be involved in tumourigenesis [75].
Another study using a similar method identified the presence of several Fusobacterium species in CRC, in particular F. nucleatum, F. mortiferum and F. necrophrum[36]. They believe that Fusobacterium may be following the concept of the "alpha-bug" theory –where certain members of a microbial community are capable of remodelling the microbiome as a whole to drive proinflammatory immune responses and colonic epithelial cell transformation leading to cancer [36, 80]. In addition, Fusobacterium has been associated with inflammatory bowel disease (IBD), one of the three highest risk factors for developing CRC [81]. Kostic and colleagues postulate that Fusobacterium may contribute to tumourigenesis in a limited subset of patients mainly thorough an inflammatory mediated mechanism [36].
One interesting facet of F. nucleatum is that it is one of the most prevalent species found in infections of the amniotic fluid and the placenta leading to pre-term birth [82, 83]. There is also a correlation between pre-term birth and periodontal disease. During periodontal infection the quantities of periodontal pathogens increases dramatically leading to transient bacteraemia [84–86]. This can lead to selective colonization of undesired sites. The ability of F. nucleatum to proliferate in the placenta and eventually spread to the amniotic fluid and foetuses may in part be due to local immunosuppression in reproductive organs during pregnancy [87]. Furthermore the slow blood flow rate and low shear force in the venous sinuses of the placenta provides an opportunity for F. nucleatum to adhere and invade the endothelial cells [87]. As similar conditions occur within a tumour this may be a reason why F. nucleatum has been identified within CRC. Even if there is no etiological link between the bacterium and CRC the significant abundance of Fusobacterium in CRC may be used for screening purpose [35].
Exploitation of opportunistic infective agents
The ideal anti-cancer therapy would selectively eradicate tumours, whilst minimizing side effects to normal tissue. Use of bacteria to specify therapeutic agents to tumours presents an attractive strategy in this context, since we and others have shown in mice that bacteria naturally replicate specifically within tumours when systemically administered [88]. Various preclinical trials have shown the ability of different bacterial strains to traffic to tumour sites, locally produce therapeutic agents, and mediate highly effective and specific therapeutic responses. Bacterial cancer therapies to date have utilized 'laboratory' strains (e.g. Salmonella typhimurium or clostridia), and while results in murine models have been impressive, successes have failed to be replicated in patients, with the inherent pathogenicity and immunogenicity of the bacteria employed outweighing therapeutic responses in patients.
Various preclinical and clinical trials have shown the ability of different bacterial strains to selectively traffic to tumour sites, and mediate highly effective and specific therapeutic responses [63]. A wide range of gene therapy strategies exists, aiming at inducing malignant cell death, either directly (e.g. using 'suicide' genes) or indirectly, such as cancer immunotherapy approaches based on killing tumour cells through intervention of various effector cells of the immune system [89]. The specific nature of bacterial colonisation of tumours could be exploited to aid in cancer treatment. In the case of non-invasive bacteria, strains can be engineered to secrete therapeutic proteins locally within the tumour environment, external to tumour cells [90]. This cell therapy approach is suitable for indirectly acting therapeutic strategies such as anti-angiogenesis and immune therapy.
Angiogenesis is the formation of new capillary blood vessels from existing microvessels [63]. The anti-angiogenesis strategy seeks to prevent the formation of new vessels. Gene-based anti-angiogenic therapy has been used in conjunction with other approaches to decrease angiogenesis. Bifidobacterial expression of endostatin genes, an endogenous inhibitor of angiogenesis, have shown promise in pre-clinical trials [63]. In addition Salmonell a VPN2009 has been successful in mediating anti-angiogenic therapy [63]. The immune therapy approach focuses on killing the tumour cell through direct or indirect alteration of immune effector cells (i.e. CD8+, T cells or NK cells). S. Typhimurium has been used in several murine trials examining immunotherapies, with significant tumour reduction resulting from local bacterial expression or tumour cell expression of the immune-stimulating molecules IL-18, CCL21, LIGHT or Fas ligand [63]. Preclinical studies have also used bifidobacteria in combination therapy with cytokines such as granulocyte colony-stimulating factor (GCSF), resulting in superior anti-tumour effects [63].
However, bacterial studies have largely focused on delivery of genes for subsequent tumour cell expression of anti-cancer agents utilizing pathogenic invasive bacterial species. Invasive bacteria are capable of delivering genes intracellularly with the aim of targeting bactofection to tumours. Bactofection is bacterial-mediated transfer of plasmid DNA to mammalian cells and has shown potential as a method to express heterologous proteins in different mammalian cells types [91, 92]. In bactofection the bacteria contain a plasmid-based gene for transfer to the new host cells. Delivery of genetic material is achieved through entry of the entire bacterium into the target cells. Spontaneous or induced bacterial lysis leads to release of the plasmid for future eukaryotic cell expression. Various bacterial species including Salmonella spp., L. monocytogenes, and E. coli have been examined as bactofection vectors. Salmonella is the most widely studied genus for bactofection with numerous studies demonstrating therapeutic expression and anti-tumour efficacy [63]. Preclinical trials utilising various attenuated, replication incompetent strains of salmonellae delivered by direct intratumoural or systemic administration have achieved impressive anti-tumour responses using a range of therapeutic approaches. The mechanism of DNA transfer is at present poorly understood for many species, and may depend on properties inherent to the bacteria and the cell type involved [93]. Invasive strains are pathogenic in nature and therefore invade healthy tissue (liver, spleen, MLN etc.), and safety concerns need to be addressed before such an approach becomes applicable in humans [63].
Furthermore bacteria, which replicate within tumours, can be engineered to express imaging agents, allowing detection of the bacteria and the potential tumour site [63]. Given the vital aspect of early detection for cancer treatment the potential for tumour-specific bacteria in diagnostic applications is attractive. If there is a definitive link between cancer development and bacterial infection this can be used in developing new treatment strategies for cancer. Furthermore microbes can affect the metabolism of pharmaceutical agents including those used to treat cancer. Therefore better knowledge of microbe composition and metabolic activity could improve therapeutic options.
The examples provided here are not comprehensive, but are rather an indication of the alternative impacts bacteria may have on different types of cancers. Screening for bacteria present in cancer tissues of various histological types may open up new dimensions in our understanding of this relationship, and its importance, if any. As high throughput deep sequencing technologies become more available, mining for bacterial strains adapted to survive within the tumour microenvironment will permit dedicated studies on this phenomenon, perhaps even leading to the characterisation of a potential 'tumour microbiome', and may also advance the development of live bacterial vectors for tumour-specific delivery of therapeutic agents.
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Wei MQ: Facultative or obligate anaerobic bacteria have the potential for multimodality therapy of solid tumours. Eur J Cancer. 2007, 43 (3): 490-496. 10.1016/j.ejca.2006.10.005.
Baban CK: Bacteria as vectors for gene therapy of cancer. Bioeng Bugs. 2010, 1 (6): 385-394. 10.4161/bbug.1.6.13146.
Bermudes D, Low B, Pawelek J: Tumor-targeted Salmonella. Highly selective delivery vectors. Adv Exp Med Biol. 2000, 465: 57-63.
Sznol M: Use of preferentially replicating bacteria for the treatment of cancer. J Clin Invest. 2000, 105 (8): 1027-1030. 10.1172/JCI9818.
Berg RD, Garlington AW: Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect Immun. 1979, 23 (2): 403-411.
Balzan S: Bacterial translocation: overview of mechanisms and clinical impact. J Gastroenterol Hepatol. 2007, 22 (4): 464-471. 10.1111/j.1440-1746.2007.04933.x.
Cannon JP: Pathogenic relevance of Lactobacillus: a retrospective review of over 200 cases. Eur J Clin Microbiol Infect Dis. 2005, 24 (1): 31-40. 10.1007/s10096-004-1253-y.
Penn RL, Maca RD, Berg RD: Increased translocation of bacteria from the gastrointestinal tracts of tumor-bearing mice. Infect Immun. 1985, 47 (3): 793-798.
Cronin M: Orally administered bifidobacteria as vehicles for delivery of agents to systemic tumors. Mol Ther. 2010, 18 (7): 1397-1407. 10.1038/mt.2010.59.
Berg RD: Translocation of enteric bacteria in health and disease. Curr Stud Hematol Blood Transfus. 1992, 59: 44-65.
Farrell JJ: Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut. 2012, 61 (4): 582-588. 10.1136/gutjnl-2011-300784.
Goldenberg RL, Culhane JF: Preterm birth and periodontal disease. N Engl J Med. 2006, 355 (18): 1925-1927. 10.1056/NEJMe068210.
Iwai T: Periodontal bacteremia and various vascular diseases. J Periodontal Res. 2009, 44 (6): 689-694. 10.1111/j.1600-0765.2008.01165.x.
Sakamoto H: Isolation of bacteria from cervical lymph nodes in patients with oral cancer. Arch Oral Biol. 1999, 44 (10): 789-793. 10.1016/S0003-9969(99)00079-5.
Sjostedt S: Microbial colonization of tumors in relation to the upper gastrointestinal tract in patients with gastric carcinoma. Ann Surg. 1988, 207 (3): 341-346. 10.1097/00000658-198803000-00020.
Han YW: Interactions between periodontal bacteria and human oral epithelial cells: Fusobacterium nucleatum adheres to and invades epithelial cells. Infect Immun. 2000, 68 (6): 3140-3146. 10.1128/IAI.68.6.3140-3146.2000.
Signat B: Fusobacterium nucleatum in periodontal health and disease. Curr Issues Mol Biol. 2011, 13 (2): 25-36.
Swidsinski A: Acute appendicitis is characterised by local invasion with Fusobacterium nucleatum/necrophorum. Gut. 2011, 60 (1): 34-40. 10.1136/gut.2009.191320.
Sears CL, Pardoll DM: Perspective: alpha-bugs, their microbial partners, and the link to colon cancer. J Infect Dis. 2011, 203 (3): 306-311. 10.1093/jinfdis/jiq061.
Strauss J: Invasive potential of gut mucosa-derived Fusobacterium nucleatum positively correlates with IBD status of the host. Inflamm Bowel Dis. 2011, 17 (9): 1971-1978. 10.1002/ibd.21606.
Chaim W, Mazor M: Intraamniotic infection with fusobacteria. Arch Gynecol Obstet. 1992, 251 (1): 1-7. 10.1007/BF02718272.
Hill GB: Preterm birth: associations with genital and possibly oral microflora. Ann Periodontol. 1998, 3 (1): 222-232. 10.1902/annals.1998.3.1.222.
Carroll GC, Sebor RJ: Dental flossing and its relationship to transient bacteremia. J Periodontol. 1980, 51 (12): 691-692. 10.1902/jop.1980.51.12.691.
Daly C: Bacteraemia caused by periodontal probing. Aust Dent J. 1997, 42 (2): 77-80. 10.1111/j.1834-7819.1997.tb00100.x.
Daly CG: Bacteremia due to periodontal probing: a clinical and microbiological investigation. J Periodontol. 2001, 72 (2): 210-214. 10.1902/jop.2001.72.2.210.
Han YW: Fusobacterium nucleatum induces premature and term stillbirths in pregnant mice: implication of oral bacteria in preterm birth. Infect Immun. 2004, 72 (4): 2272-2279. 10.1128/IAI.72.4.2272-2279.2004.
Cronin M: High resolution in vivo bioluminescent imaging for the study of bacterial tumour targeting. PLoS One. 2012, 7 (1): e30940-10.1371/journal.pone.0030940.
Tangney M: Gene therapy for prostate cancer. Postgrad Med. 2010, 122 (3): 166-180. 10.3810/pgm.2010.05.2154.
Tangney M: Gene therapy for cancer: dairy bacteria as delivery vectors. Discov Med. 2010, 10 (52): 195-200.
van Pijkeren JP: A novel Listeria monocytogenes-based DNA delivery system for cancer gene therapy. Hum Gene Ther. 2010, 21 (4): 405-416. 10.1089/hum.2009.022.
Vassaux G: Bacterial gene therapy strategies. J Pathol. 2006, 208 (2): 290-298. 10.1002/path.1865.
Loessner H, Weiss S: Bacteria-mediated DNA transfer in gene therapy and vaccination. Expert Opin Biol Ther. 2004, 4 (2): 157-168. 10.1517/14712598.4.2.157.
The authors wish to acknowledge support relevant to this manuscript from the Health Research Board grants HRA_POR/2012/99 and HRA_POR/2010/138, and the European Commission Seventh Framework Program grant PIOF-GA-2009-255466.
Cork Cancer Research Centre, BioSciences Institute, University College Cork, Cork, Ireland
Joanne Cummins & Mark Tangney
Joanne Cummins
Mark Tangney
Correspondence to Mark Tangney.
Both authors were involved in writing and reviewing this article. Both authors read and approved the final manuscript.
Cummins, J., Tangney, M. Bacteria and tumours: causative agents or opportunistic inhabitants?. Infect Agents Cancer 8, 11 (2013). https://doi.org/10.1186/1750-9378-8-11
Accepted: 24 March 2013
Mesenteric Lymph Node
Bacterial Translocation
Lung Cancer Risk
Aggressive Periodontitis


text:
package io.elegie.luchess.app.lucene4x.index.analysis;

import java.io.IOException;
import java.io.Reader;
import java.util.ArrayList;
import java.util.Arrays;
import java.util.List;

import org.apache.lucene.analysis.Tokenizer;
import org.apache.lucene.analysis.tokenattributes.CharTermAttribute;
import org.apache.lucene.analysis.tokenattributes.PayloadAttribute;
import org.apache.lucene.analysis.tokenattributes.PositionIncrementAttribute;
import org.apache.lucene.util.BytesRef;

/**
 * This tokenizer will receive a sequence of moves, separated by a character
 * passed to the constructor, and will tokenize them, respecting the following
 * rules:
 *

 *
The whole sequence will be made into a single token, so as to allow
 * PrefixQueries.

 *
Opening moves sequences will be made into tokens as well, up to the
 * analysis depth, so as to allow for fast search, using TermQueries. For
 * instance, tokens such as "e4", "e4 e5", "e4 e5 Nf3" will be generated.

 *
All tokens for opening moves will have a payload containing the next
 * move, so that continuations may be calculated in an efficient way. The token
 * containing the whole sequence of moves will have no payload, because it
 * already has all the moves. In practice, this means that continuations will be
 * available only for sequences of moves of a length inferior to the analysis
 * depth.

 *

 */
public class MoveTextTokenizer extends Tokenizer {

    /**
     * This is the first token for all move texts, i.e. "move zero".
     */
    public static final char MOVE_ZERO = 'X';

    /**
     * Since we have an internal "move zero", we need to increase the actual
     * analysis depth by one.
     */
    private static final int MOVE_ZERO_ANALYSIS_OFFSET = 1;

    /**
     * The maximal PGN move length (e.g. Nf3xg1, exd8=Q), minus the check sign,
     * used to initialize capacities of our subsequent buffers.
     */
    private static final int MAX_MOVE_LENGTH = 6;

    private final int analysisDepth;
    private final char moveSeparator;
    private List<Byte> previousMove;
    private List<List<Byte>> allMoves;
    private boolean finished;

    private CharTermAttribute termAtt = addAttribute(CharTermAttribute.class);
    private PositionIncrementAttribute positionAtt = addAttribute(PositionIncrementAttribute.class);
    private PayloadAttribute payloadAtt = addAttribute(PayloadAttribute.class);

    protected MoveTextTokenizer(Reader input, int analysisDepth, char moveSeparator) {
        super(input);
        this.analysisDepth = analysisDepth + MOVE_ZERO_ANALYSIS_OFFSET;
        this.moveSeparator = moveSeparator;
    }

    @Override
    public final void reset() throws IOException {
        super.reset();
        previousMove = null;
        allMoves = new ArrayList<>();
        finished = false;
    }

    @Override
    public final boolean incrementToken() throws IOException {
        if (finished) {
            return false;
        }
        initialize();
        return process();
    }

    private void initialize() {
        clearAttributes();
        if (previousMove == null) {
            previousMove = Arrays.asList((byte) MOVE_ZERO);
        } else {
            positionAtt.setPositionIncrement(0);
        }
    }

    private boolean process() throws IOException {
        allMoves.add(previousMove);
        List<Byte> currentMove = readNextMove();
        if (allMoves.size() > analysisDepth) {
            while (!currentMove.isEmpty()) {
                allMoves.add(currentMove);
                currentMove = readNextMove();
            }
        }
        termAtt.append(new String(getAllMoves(), "UTF-8"));
        if (currentMove.isEmpty()) {
            finished = true;
        } else {
            payloadAtt.setPayload(new BytesRef(getBytes(currentMove)));
            previousMove = currentMove;
        }
        return true;
    }

    private List<Byte> readNextMove() throws IOException {
        List<Byte> result = new ArrayList<>(MAX_MOVE_LENGTH);
        int data = input.read();
        while (data != moveSeparator && data != -1) {
            if (accept(data)) {
                result.add((byte) data);
            }
            data = input.read();
        }
        return result;
    }

    private byte[] getAllMoves() {
        List<Byte> result = new ArrayList<>();
        int size = allMoves.size();
        for (int ii = 0; ii < size; ii++) {
            result.addAll(allMoves.get(ii));
            if (ii < size - 1) {
                result.add((byte) moveSeparator);
            }
        }
        return getBytes(result);
    }

    private byte[] getBytes(List<Byte> source) {
        byte[] target = new byte[source.size()];
        for (int j = 0; j < source.size(); j++) {
            target[j] = source.get(j);
        }
        return target;
    }

    // --- Filtering check marks out ------------------------------------------

    /**
     * The chars to be excluded from the produced tokens. These are the chess
     * check marks, and we remove them because they are optional, and could
     * therefore be omitted.
     */
    private static final List<Character> EXCLUDE_CHARS = Arrays.asList('+', '#');

    /**
     * @param value
     *            The char to be tested
     * @return True if the char should be accepted in the final indexed
     *         representation of the move.
     */
    private static boolean accept(int value) {
        return !EXCLUDE_CHARS.contains((char) value);
    }

    /**
     * @param value
     *            The raw text representation of the move.
     * @return The final representation, with optional parts excluded.
     */
    public static String filter(String value) {
        StringBuilder result = new StringBuilder();
        for (int ii = 0; ii < value.length(); ii++) {
            char part = value.charAt(ii);
            if (accept(part)) {
                result.append(part);
            }
        }
        return result.toString();
    }

}

redpajama_set_name: RedPajamaGithub


text:
Nicki Minaj and Beyoncé Just Dropped a Music Video on Tidal
By Daniel D'Addario
May 18, 2015 4:59 PM EDT
Streaming service Tidal, and the artists who've invested in it, have promised exclusive material to fans willing to pay. Today, that promise bore fruit for fans of Beyoncé and Nicki Minaj, as the artists released their video for "Feeling Myself" on the platform.
The video, for a collaboration on Minaj's 2014 album The Pinkprint, depicts the most fun weekend any two friends have ever had at Coachella, with water pistols, burgers and fries, and time spent relaxing in a kiddie pool. Given the two stars at the center of the video, though, no one should be surprised to know there's some fairly committed dancing, too.
The video is available for Tidal subscribers here.
Here's What Jaden Smith Wore to Prom
The 25 Defining Works of the Black Renaissance

redpajama_set_name: RedPajamaCommonCrawl


These non-binding good practices are intended to assist policymakers and practitioners as they develop, implement, and evaluate policies and programs to confront the homegrown terrorism phenomenon. This document is intended to be a complementary piece to The Hague-Marrakech Memorandum on Good Practices for a More Effective Response to the FTF Phenomenon (The Hague-Marrakech Memo) and the Addendum to The Hague-Marrakech Memorandum focusing on returning FTFs, in order to ensure a comprehensive response to the current terrorism landscape.
Returning and relocating families present complex policy challenges that require comprehensive action addressing the unique circumstances of each returnee. 2 Timely detection and identification of returning FTFs and their family members is complicated by the various travel routes they use, and measures they often take, to avoid detection, which can impede efforts to track and monitor travel. International cooperation and internal integration procedures that could provide early warning of returnees often could be improved.
The Abuja Recommendations are geared towards policy makers, law enforcement officials, and prosecutors with the aim of offering recommendations to investigators and prosecutors of terrorism cases to help build a solid case based on strong and admissible evidence.
These recommended good practices are intended to address violent extremism that is conducive to terrorism in all its forms and manifestations. They stress the importance of firmly embedding content- and communications based responses within a comprehensive online and offline approach to preventing and countering violent extremism and terrorism involving the active participation and collaboration of all States and international and regional organizations while respecting privacy and freedoms of expression, association, peaceful assembly, and religion or belief.
The Sahel region is noteworthy for its vast, sometimes ill-defined, and lightly patrolled land borders. Terrorists exploit this geographical feature by planning attacks in one State, committing them in another, and returning to the first State or traveling to a third State. Terrorist groups also take advantage of weak border controls to plan and execute the kidnappings for ransom that are now an established and significant source of funding for terrorist training and recruitment. Additionally, criminal actors whose activities may intersect with and enable those of terrorist groups—including weapons, drugs, and human smugglers—exploit weak border controls.
This is UNESCO's first Teacher's Guide on the Prevention of Violent Extremism through education. This document has been developed in direct response to the needs of UNESCO's Member States as expressed in the landmark 197/EX Decision 46 taken by UNESCO's Executive Board in October 2015, which calls on the Organization to enhance its capacity to provide assistance to countries as they work to strengthen their education sector responses to violent extremism, including through human-rights based Global Citizenship Education (GCED) programmes, keeping in mind national contexts.
Terrorism is a global phenomenon that presents a direct and multi-faceted threat to human security. States have a responsibility to protect populations from terrorism-related threats, which requires actions taken consistent with human rights and the rule of law. Legislatures bear a primary responsibility in the establishment of such a framework. An engaged and independent legislative body is a critical element in developing a legitimate and comprehensive counter terrorism (CT) strategy that ensures an effective response to terrorism including with necessary oversight measures to protect human rights.
Violent extremism is an affront to the purposes and principles of the United Nations. It undermines peace and security, human rights and sustainable development. No country or region is immune from its impacts.
Note: This document aims to provide additional guidance to Members States in their efforts to develop rehabilitation and reintegration programmes for violent extremist offenders and to address violent extremism in prison settings. It summarizes the conclusions/findings of an expert workshop convened by UNCCT, UNICRI and the Government of Turkey in Istanbul, on 19-20 May 2014.
Note: This document will be submitted to the GCTF and to the UN's Interregional Crime and Justice Research Institute to provide additional guidance to GCTF members and other countries who are attempting to incorporate the Rome Memorandum into their own programs. This document summarizes the conclusions/findings of the expert workshop convened by Hedayah and the International Centre for Counter-Terrorism – The Hague (ICCT) in Abu Dhabi, May 8-9, 2013. The list of participants in that session is below. The participants have not, however, endorsed this document.
A strong and independent judiciary that fairly and expeditiously adjudicates terrorism and other national security offenses is critical for public confidence in the legitimacy of judicial institutions, is an effective deterrent to terrorism, and minimizes the risk of violations of fundamental human rights.
This document offers guidance for national governments interested in developing or refining a national countering violent extremism (CVE) strategy, or CVE components as part of a wider counter-terrorism (CT) strategy or framework. It includes good practices that have emerged from experiences in this field over the past few years and draws on them to inform future efforts. Where a national strategy is not currently attainable, this document outlines initial steps that could be taken to lay the groundwork for future national CVE strategy development, e.g. initial dialogue between governments and communities targeted for radicalization and recruitment. In this context, CVE refers to the wide spectrum of largely preventive actions and interventions that involves identifying the local factors of radicalization and recruitment to violent extremism, and designing programming to prevent and counter these processes. This includes efforts that may be undertaken by governments, international organizations and civil society.
Note: This document will be submitted to the GCTF to provide additional guidance to GCTF Members States and other countries in their efforts to incorporate the Rome Memorandum into their own programmes to address violent extremism in prison settings. This document summarizes the conclusions/findings of the expert workshop convened by the Spanish Government and UNICRI in Madrid, on 29-30 October 2013.
The threat posed by "Foreign Terrorist Fighters" (FTFs) – individuals who travel abroad to a State other than their States of residence or nationality to engage in, undertake, plan, prepare, carry out or otherwise support terrorist activity or to provide or receive training to do so (often labeled as "terrorist training") – is a major issue for international and national security. Governments continue to grapple with how to address the complex set of challenges posed by this threat. Many countries are concerned that the rising number of people, especially youth, radicalized to violence and traveling to fight or train alongside terrorist groups in conflict and non-conflict areas will become further radicalized and pose a new terrorist threat to their home or third countries, including transit countries.
A guide for those who must develop and execute programs and policies regarding the specific circumstances surrounding children who are in the criminal justice system charged with committing acts of terrorism or violent extremism.
In its efforts to counter violent extremism, the GCTF has highlighted the importance of multi-sectoral approaches that involve government and non-government agencies, the private sector, religious leaders, and civil society. Specifically, the GCTF emphasized the importance of understanding and addressing community needs as a way to tackle violent extremism. A critical component of this community level engagement is community-oriented policing, which is collaboration between the police and the community that identifies and solves community problems.
The growing emphasis on prison-based rehabilitation programs in governments' efforts to counter violent extremism results from three factors: first, prisons may become 'safe havens' for terrorists carrying on their operations, including radicalizing new members; second, some imprisoned extremists will eventually be released and thus must be disengaged; third, prison settings can be a setting where positive change can occur, as violent extremists are cut off from their old networks and influences.
Action plan that enumerates an illustrative list of actionable, rule-of-law based measures and initiatives that States are currently employing that have indicators of being successful in the effort to identify and counter the activities of terrorist recruiters and facilitators.
A set of non-binding recommendations regarding the range of measures that might be employed at the national or local level as an alternative to pre-trial detention or postconviction incarceration for individuals charged with, or convicted of, terrorism-related offenses.
States to develop counterterrorism strategies that are consistent with the UN Global Counter-Terrorism Strategy and the criminal justice to develop effective institutions and other measures that allow governments to provide security, justice, liberty, and development opportunities for their citizens.
Declaration on Counterterrorism and the Rule of Law calls for members of the Global Counterterrorism Forum to "develop good practices for an effective and rule of law-based criminal justice sector response to terrorism."
Commitment to assist and support the victims of terrorism in all its forms and manifestations, according to our national laws and international principles.
This action plan includes the need to further strengthen efforts to support victims of terrorism in all of its manifestation as well as associations of victims of terrorism.
Successful in-prison rehabilitation does not have a one-size-fits-all approach. It begins with clearly defined objectives and metrics for success and failure.
A series of expert meetings, workshops, conferences and research hosted by the GCTF, Hedayah and various other partners convened educators, experts, practitioners and policymakers to share experiences and enhance understanding on education and countering violent extremism (CVE). These events also led to the drafting and development of the Abu Dhabi Memorandum for Good Practices on Education and Countering Violent Extremism, which was adopted at the September 2014 GCTF Fifth Ministerial Meeting in New York City. The topic of education and CVE was also a key component of the agenda at the White House Summit on Countering Violent Extremism in February 2015. A preliminary list of recommended action items was developed as part of the Follow-on Action Agenda coming out of the Summit. In addition, the European Union's Radicalisation Awareness Network (RAN), specifically the RAN PREVENT Working Group, has developed a Manifesto titled "Empowering Educators and Schools" aimed at outlining principles for ministries of education investing in CVE efforts within the European context which was endorsed in March 2015 by the Ministers of Education within the European Union. Drawing on these multilateral developments and existing body of knowledge on education and CVE, this non-binding action plan for education and CVE provides an illustrative list for how to advance and implement the good practices already outlined in the Abu Dhabi Memorandum.
Addendum relating to elements of Good Practice of the GCTF's The Hague-Marrakech Memorandum on Good Practices for a More Effective Response to the FTF Phenomenon and other relevant issues pertaining to RFTFs.


With CD included. Level very easy to easy with words and illustrations, divided into 2 parts: Piano 2 Hands and Piano 4 Hands.
CAMBIER / LE COZ MICHEL - D'où viens-tu bergère ?
Intended primarily for younger pianists or beginners, these traditional Christmas songs will delight the whole family, who will follow the lyrics on the collection or sing on the beautiful playback of the CD.
With versions specially written for the youngest, but also in 4 hands, this collection allows the choice to play the piano or to sing these great classics of Christmas, in any conviviality!
Beyond the pedagogical scope of its repertoire, this book, illustrated and in color, in a happy and family spirit, is a must at the end of the year!


Here are some helpful tips on using the Apple Music app.
The For you area of the Apple Music app gives you access to Apple Music editors' handpicked albums and playlists based on the music they like.
The New area lets you explore this week's freshest tracks, videos and playlists selected by Apple Music editors.
The Radio area lets you enjoy great music on stations curated by artists and music experts - or you can start your own.
You don't need an Apple Music membership to tune in to Beats 1 for free.
The Connect area lets you follow your favourite artists to get an inside look at their world and share it with friends.
The My Music area lets you add songs from the Apple Music library to your personal library - and browse, sort and search.
The Apple Music Playlists area lets you discover your perfect mix from playlists curated by industry tastemakers and Apple Music editors.
The My Playlist area of the Apple Music app allows you to create, name and even add cover art to your own personal playlists and share them.
Or you can call the Apple Care Team directly on 0800 107 6285.


text:
Q: Union control states I would like to make binary or on UIControlState. In obj-C I would use binary | operator, but in swift I have to use:
imageView.setBackgroundImage(blueBackground, forState: UIControlState.Highlighted.union(.Selected))

But code above (especially if I have more than two states to make union) hard to understand. Is there any simpler way to do that like:
imageView.setBackgroundImage(blueBackground, forState: UIControlState.Highlighted | UIControlState.Selected)

A: For OptionSetType, just put them into an array, like this:
 imageView.setBackgroundImage(blueBackground, forState: [.Highlighted, .Selected])

redpajama_set_name: RedPajamaStackExchange


text:
"""
Import/Export Contacts API
"""

import csv
from django.http import HttpResponse
import StringIO
import datetime

class ProcessTransactions():
    "Import/Export Contacts"

    def export_transactions(self, transactions):
        "Export transactions into CSV file"

        response = HttpResponse(mimetype='text/csv')
        response['Content-Disposition'] = 'attachment; filename=Transactions_%s.csv'% datetime.date.today().isoformat()

        writer = csv.writer(response)
        headers = ['name', 'source', 'target', 'liability', 'category', 'account', 'datetime', 'value', 'details']
        writer.writerow(headers)
        for transaction in transactions:
            row = []
            row.append(transaction)
            row.append(transaction.source)
            row.append(transaction.target)
            row.append(transaction.liability)
            row.append(transaction.category)
            row.append(transaction.account)
            row.append(transaction.datetime)
            row.append(transaction.get_relative_value())
            row.append(transaction.details)
            writer.writerow(row)
        return response

    def import_transactions(self, content):
        "Import transactions from CSV file"

        f = StringIO.StringIO(content)
        transactions = csv.DictReader(f, delimiter=',')

        self.parse_transactions(transactions)

    def parse_transactions(self, transactions):
        "Break down CSV file into transactions"


File photo of an exterior view of the National University Hospital in Singapore.
In a statement to CNA later on Wednesday, NUH said that "there was no negligence or mismanagement".
"The hospital is aware of the family's concerns. Mdm Goh suffered a complication following brain surgery, which was appropriately treated by the hospital's surgery team," it said.
"The hospital's review, with an independent specialist opinion, showed that appropriate care was rendered and there was no negligence or mismanagement. The hospital intends to defend the suit brought by the patient's family," it added.


text:
← Back to INVESTOR TIMES
Financial Markets News
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FREEDOM OUTPOST
Chelsea Clinton: Scalia's Out of the Way, so now we can gut the Second Amendment
The death of Supreme Court Justice Antonin Scalia in February left the nation in shock. It further made his death questionable that an autopsy was not performed. It also stirred up some controversy in the Senate as to whether or not they would even have hearings regarding an Obama appointment to replace Scalia, namely Merrick Garland. However, now we have Chelsea Clinton referencing Scalia's death as she campaigns for her criminal mother, Hillary, and she has declared the without Scalia around, they will be able to pass gun control.
Chelsea Clinton spoke at an event in Maryland on Thursday and claims that since Justice Antonin Scalia had died, now is now to pass gun control legislation, which she believes the Supreme Court will "make a definitive ruling" ruling on in favor of gutting the Second Amendment.
"It matters to me that my mom also recognizes the role the Supreme Court has when it comes to gun control. With Justice Scalia on the bench, one of the few areas where the Court actually had an inconsistent record relates to gun control," Clinton said. "Sometimes the Court upheld local and state gun control measures as being compliant with the Second Amendment and sometimes the Court struck them down."
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Now, some used to think that Chelsea was innocent and that it was only her parents who were the corrupt ones. That has long been left behind, especially in light of the fact that she is right in the middle of The Clinton Foundation scandal.
Clinton went on to cite ultra-leftist gun grabbing advocates to bolster her promotion of more gun control.
"If you listen to Moms Demand Action and the Brady Campaign and major efforts for smart sensible and enforceable gun control across our country, with disclosure having endorsed my mom, they say the next time the court rules, it will make a definitive ruling," she said. "So, it matters to me that my mom is the only person running for president, who not only constantly makes that connection, but also has a strong record on gun control and standing up to the NRA. This is one of those issues I didn't know I could care more about until I became a mother and I think every day about the Sandy Hook families' children don't come home from school, and I can't even imagine that living horror and tragedy."
Well, let's just be honest about a few things, shall we? First, Moms Demand Action engage in outright lying, rude behavior (for which they were removed from a Tulsa Chipotle) and even engage in indecent protests.
Second, the Brady Campaign is teamed up with America's enemies, including the Islamic Society of North America, to take guns from Americans.
Third, Hillary Clinton is a known criminal and her attacks on the Second Amendment, no matter what the Supreme Court rules, are criminal in themselves. Even now the FBI is saying she is a criminal due to her illegal email server which put Americans at far more risk than law-abiding gun owners. In fact, it could be said that because of Mrs. Clinton's actions and inactions that four Americans are now dead! I worry far more about a wicked witch like Hillary Clinton than I do about law-abiding gun owners.
Fourth, it's a stretch to think about Sandy Hook, since there are still many questions regarding what took place there and why? It certainly was brought front and center for Obama to push for more gun control, that's for sure. The good thing was that it was stopped dead in its tracks.
Fifth, and finally, if Chelsea understood motherhood, she would have herself at home taking care of her child (Titus 2:4-5) rather than doing all this pandering. If she truly understood what it is to protect her child, she would never send them to public schools, something the Clintons don't do anyway. She would also learn to use a weapon to defend herself and her child when presented with a threat. That's what real mothers do Chelsea! They certainly don't promote a woman who is advancing the same gun control agenda the Weimar Republic did and was later fulfilled under the Nazi regime in Germany under Adolph Hitler.
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US Tax Dollars & Lives Wasted: Islamic State of Iraq and Syria Forces Overrun US Trained Iraqis in Mosul
Acquitted Bundy Defendants File $60 Million Lawsuit Against Corrupt Prosecutors, FBI & BLM
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Taking Sides: The Christian's Responsibility in Civic Affairs II
EgyptAir MS804 Flight Attendant posted Picture on Facebook of Plane crashing a year before She Died
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Man Jailed After Claiming to be 'Transgender' to Assault Women in Shelter
Trump: Democrats Against North Korea Summit Just Like They Defend MS-13 & Attack Tax Cuts
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Benefits of Membership - Parksville & District Chamber of Commerce, Parksville, B.C. • Join the Chamber Today!
From hotel discounts to discounted fuel and banking services, members of the Parksville Chamber of Commerce gain exclusive access to these and other terrific incentives for becoming a member. Interested in building connections with China? How about preferred rates with VersaPay and First Data Merchant Services? The benefits of becoming a Parksville Chamber of Commerce member are simply incredible.
Contact the Parksville Chamber of Commerce to learn how to access these benefits.
The Chamber hosts nine General Membership Dinner Meetings annually, where members have the opportunity to share ideas and business information, to connect with others, listen to a guest speaker and promote their business.
Our monthly Business after Business (BaB) events are also a great way to meet other members. As the host of a BaB, you have the opportunity to showcase your business to a captive audience or simply a chance to hook up with someone to play golf with on Saturdays.
Referrals are a big part of what we do. On average, the Visitor Centre welcomes over 25,000 people each year and answers many telephone inquiries. Local residents, businesses and tourists are seeking information on: Accommodations, Shopping, Relocation, Attractions, Restaurants and Services. Members can display their business cards/brochures at the Centre to capture the attention of visitors.
Our Website and its Business Directory are the main source of information for the many daily inquiries by phone, email and in person about local businesses. Your membership includes a basic listing, a link to your site / email, a location map and the tools to load your own logos and pictures.
We have a Social Media presence through Facebook and Twitter (with over 1,500 followers), and like/follow our members and others so we can pass on relevant, member to member, information to our followers.
We work behind the scenes to promote your business 24/7. When potential clients stop by the Chamber office or come in to the Parksville Visitor Centre, we point new customers in your direction through word-of-mouth advertising. Put your promotional material on display and find potential clients when and where they're looking. Our Online Member Directory has the double impact of enabling people to find out about your business through the Official Chamber Site while simultaneously increasing the visibility of your own website on the search engines.
We are always looking for new ways to expose your business to our members. Our staff, both at the Visitor Centre and the Chamber office is open to suggestions which may work better for your type of business. You can leverage our advertising budget to increase your visibility. Call our staff to discuss how we can help you in promoting your business.
The Parksville and District Chamber of Commerce has teamed up with industry, business associations, and other Chambers of Commerce to work with municipal, provincial and federal government bodies to find solutions to issues that negatively affect business and/or our community.
A list of the Policy and Position papers in the works is right here.
We have partnered with First Data Canada, a leader in the payments industry, to help your business Sell More and Save More. All members are provided exclusive low rates on merchant services; low credit and debit card processing costs, ecommerce tools, mobile payment apps, and a user-friendly online reporting tool to support and grow your business.
Call the Chamber officer at 250-248-3613 to find out more.
This program is based on "Members Supporting Members". Participating members offer 10%, 20%, or 30% off of their regular prices to other members. The use of your member card identifies those who participate. This program encourages our members to shop locally; it's a win-win.
With the cost of fuel today, ANY discount can make a difference. We are pleased to participate in special programs and be able to pass these discounts to you. Our current partners are: PetroCanada, Shell Fleet Plan, Esso Imperial Oil. Contact us to learn more.
Parksville & District Chamber of Commerce Members can take advantage of exclusive discounts on UPS and Purolator Small Package shipments, Brokerage and Freight shipments. Whether you send one package a week or 50, you save right from the start. No minimums. No hassle.
There are several other affinity programs you may access, including Hotel and Travel Discounts, Small Business BC webinars, and more.
Don't forget the Hotel Discounts!
Exclusive Worldwide Discounts for Chamber Members.
Chamber members can now receive hotel discounts in Canada and around the world for unlimited business and leisure travel. The B.C. Chamber of Commerce member hotel discount program is provided for the exclusive access of our members and their employees.
Savings may be as much as 50%, and average 10-20% below market rates.
Take me to the hotel discounts!
Payworks is the most competitively priced program of on-line payroll services available. Will remit your Revenue Canada payments for free. Must be an active Chamber member for this special pricing.
"Go Green" and save 10% per payroll run and 10% off the per employee charge by printing your own reports and/or pay statements.
Stay informed about Chamber events and activities through the weekly "Chamber e-Connection". Members are encouraged to use this newsflash as a way to communicate with other members...a Value-Added benefit of your Chamber Membership! Send your e-flash submissions to the e-connection publisher, and we will include member info that is directly relevant, member to member, as well as newsworthy, to give you the business edge. If we keep each other up-to-date about our businesses, then it will make cross-referrals more effective.
Regular editorials in the Parksville Qualicum Beach News and Business Vancouver Island papers are submitted by Chamber staff, and, of course, the website is a source of information as well.
The Chamber also maintains a Facebook page and Twitter feed, for immediate updates and information bulletins that, we hope, will be of interest to our followers.
One of the goals of the Parksville & District Chamber of Commerce is to encourage our members to shop locally. Your member card is a reminder of the great value Chamber members offer to one another. These discounts will be offered year round, on REGULAR pricing, unless otherwise stated.


Making sure your brand stands out in a crowded market can be a challenge. It requires imagination, creativity and the desire to create something different – plus of course the right team to make it happen. It is where live art comes into its own – and we love it.
They are a myriad of ways to engage your customers (or customers to be) using art. Done right, brand engagement activities can create a real buzz around your brand – driving both awareness and likelihood to purchase.
We love the variety of these projects, and coming up with a proposal that encapsulates what your brand is about is a challenge we thrive on. From creating a huge graffiti mural for Wireless to capture the energy, spirit and vibe of this amazing urban music festival, to designing bespoke t-shirts onsite to promote the Discovery Adventures new product range at Debenhams, Oxford Street.
Other projects have involved using our skills to raise awareness of important issues – including taking over three iconic billboards at Old Street Junction, using our graffiti art skills to create a powerful message to highlight the fact that suicide is the biggest killer of young men in the UK. This particular project is also listed on Creative Bloq's 40 traffic-stopping examples of billboard advertising.
So, if you want your target market to engage with you, why not challenge us to come up with a solution that excites and inspires?


Any international shipping and import charges are paid in part to Pitney Bowes Inc. Why is this review inappropriate? Is there any available? If you'd like to get the additional items you've selected to qualify for this offer, close this window and add these items to your cart. Resume making your offer , if the page does not update immediately.
Please enter 5 or 9 numbers for the ZIP Code. It works fine with both laptops and desktops. Select a valid country.
Yahoo Messenger 7, Questions. Brand new in opened box.
Learn More – opens in a new window or tab International shipping and import charges paid to Pitney Bowes Inc. If you were to log on to the manufacturer's web site, I think you will be Not finding what you are looking for? See all komercos has no other items for sale.
This item will ship to United Statesbut the seller has not specified shipping options. Kensington K notebook dock. Alun Cox Level 3 Expert Answers.
Estimated on or before Wed. Get the item you ordered or get your money back. Watch list is full. Have one to sell?
Any international shipping and import charges are paid in part to Pitney Bowes Inc. Delivery time is estimated using our proprietary method which is based on the buyer's proximity to the item location, the shipping service selected, the seller's shipping history, and other factors. There are 1 items available. Learn more – opens in a new window or tab. The item may be missing the original packaging, or in the original packaging but not sealed.
Learn More – opens in a new window or tab Any international shipping is paid in part to Pitney Bowes Inc. Report item – opens in a new window or tab. Kensington Notebook Dock Model K Ratings and Reviews Write a review. Kenaington Notebook Dock K that I want to start using again.
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At VMworld 2017, VMware announced the availability of VMware Cloud on AWS and of the six initial VMware Cloud Services. VMware Cloud on AWS offers customers the long expected capability of deploying VMware's Cloud Foundation Suite of SDDC products (vSphere, NSX and vSAN) to AWS. VMware Cloud Services enable operators, developers, security experts and compliance staff to consistently deploy and operate application infrastructure across today's most popular clouds: AWS, Google, Azure and vSphere. Today, both offerings, VMware Cloud on AWS and VMware Cloud Services are available from AWS U.S. West (Oregon Region), but can be used worldwide. VMware and Amazon are planning to roll out both offerings worldwide during 2018.
"Oh, I'm not coming to VMworld this year, we are at Jenkins instead." This is a sentence I've heard quite a few times now from vendors that I'm used to seeing at VMworld and it makes me wonder what's going on.
VMware and OpenStack: A Marriage Made in Heaven?
As promised in my previous post on "Software Defined Storage – Why Customers Should Care", I want to follow-up with a brief overview of the competitive landscape.
As promised in my previous post on "Software Defined Storage - Why Customers Should Care", I want to follow-up with a brief overview of the competitive landscape.


I am happy to be on the road again for preaching the science of Krishna consciousness all over the world. The entire world is suffering due to a lack of Krishna consciousness and by the grace of my spiritual master, His Divine Grace A.C. Bhaktivedanta Swami, we have the medicine which will deliver the entire world from its precarious condition. Life is not meant for sense enjoyment. It is meant for engaging ourselves in the service of the Lord. And there is no greater service to the Lord than bringing his lost children back to Him.
Question: How to Know One's Occupational Duty?
When I was reading chapter three of the Bhagavad-gita I understood the importance of occupational duty and how lust is our enemy. But I failed to understand what is occupational duty and how one can identify his or her duty. In those days people followed the varnashrama system, but how is it applicable in today's life?
For perfect understanding of occupational duty one should fully surrender himself at the lotus feet of the bona fide spiritual master. The spiritual master will then engage him in doing his duty in such a way that it is pleasing to Krishna. And in this way by pleasing Krishna he will become free from lust. This is the real meaning of varnashrama.


Recently I won a Fly Marcos in a raffle, those have a front motor and slightly wobbly stub axles, so they are not the best runners. I needed an excuse to try a printed chassis and this was it. I ordered the Olifer chassis that is made for the Fly Marcos and it was delivered on the promised date. The chassis was just about perfect as received. The only changes that I made were to shave the bottom of the guide flag holder and to sand the sides of the chassis a little. The car turned out to be much lighter than our rules permit, I did add some weight to the motor pod for a start, but the car was still a bit light when I tested it last night. The car looks to be a good runner, but it wants to tip at the limit, enough lead low in the chassis to bring the car to the minimum weight limit should fix that.
Great work, it certainly looks as good as it should!
What interior did you use?
I was trying to lower the CG, but I had to use the dash and rear deck portions of the original interior to hold the glass in place. The rest of the interior is a Champion vacuum formed tray type.
I don't have my own 1/32nd track, so I am only able to try out cars on race night. I added a little weight to the Marcos to bring it up to the minimum and also moved the weight that was on the top of the motor pod to the bottom. The car really sticks now, it is a dream to drive. One of the other guys took the car for a spin and really liked it. I was surprised that most of the guys were not aware that printed chassis were available for a fair number of cars. Most of them have some cars that are not competitive, so they just sit on the shelf.


The 46.5m Antara yacht (ex: Tamsen) was built in 1991 by Perini Navi. She features an exterior design by Perini Navi and an interior by Perini Navi. She cruises at 11.0 kn and reaches a top speed of 14.0 kn. She can sleep up to 10 guests taken care of by a crew of 7.
Antara yacht owner, captain or broker, contact us directly to promote your yacht for sale or update the information.


Heat Arms (ヒートアームズ) is a boss fought at the end of Lava Reef Zone Act 1. It will first attack with two swaying antenna-like machines that fire a round of projectiles at you. The top circle part of each must be hit 4 times to destroy them; this is a harder task for Knuckles, who can only hit them when they come down. After shooting at you, they will sink down and a robotic hand that resembles the final boss' at the Death Egg Zone will attempt to crush you, leaving a moment for you to attack when it slams down. The boss -- the hand specifically -- takes six hits -- defeating the antennae is not necessary.
Unlike most times when the character is crushed, this will not kill them, but act like a normal attack; Super and Hyper Forms can damage the robot when it is crushed down on them. After it attacks once, the antennas will come back if not defeated and continue that cycle; otherwise, that hand will come out again. Overall, this boss should give you little trouble and only serve up as a warm up for the much harder boss later in the zone. It is possible to be crushed by it in Super/Hyper form but only if the player uses spin dash while under it for some reason. Tails, due to his smaller size, will be crushed even when not spindashing.


text:
Google Launches Street Art Project
By Jeanette D. Moses
Street Art NYC
The graffiti mecca known as 5 Pointz may have been white-washed last November, but now it's impressive artwork can live forever thanks to a new Google Cultural Institute project.
Google's Street Art Project, which launched Tuesday, features over 5,000 images documenting temporary public art installations from around the world.
Users can browse through public exhibitions in Mexico City, Lisbon or buildings that have since been painted over or completely demolished, like 5 Pointz or Tour Paris 13. The work can be explored by exhibit, artist or location and big names like Shepard Fairey, Banksy and INVADER all make appearances.
Although the database is maintained by Google, according to the New York Times the company avoided curating from Street View. Instead, Google is working with organizations like Street Art NYC, Global Street Art Foundation and MoSA to create collections.
What famous street art would you like to see added to this database?


We are joined by Mike Russell this week, where we discuss his recent experience teaching writing to a group of marketers. Joel and Mike dig deep into the process of writing, especially as it pertains to digital marketing and non-writers writing copy. Joel explains what "writing bravely" means, and how it pertains to not just your writing, but also to your person. We also go back and forth on how to best deal with clients messing with copy.


Fabulous St.Lawrence waterfront contemporary home. This property boasts an oversized (VERY PRIVATE) 5.4 acre landscaped lot with 328`riverfront. The property is located in the Ogd.City school district and has 3540sq.ft., 9-rooms,4 bedrooms and 3.5 baths. The bathrooms all come equipped w/heated towel racks,the master suite bathroom has both a garden bathtub & oversized shower stall. The master suite has Brazilian hardwood floors, a gas fireplace and glass doors to an outdoor patio. All the bedrooms have ceiling fans.The floors in both the exercise rm., & study are oak hardwood.The exercise room has a great river view! The house comes equipped w/three fireplaces 2-gas & one wood. The house is wired for sound,security & central vac. The formal Liv.Rm. has hardwood floors, a wet bar and a wood burning fireplace.The screened enclosed porch measures 11×23 is an ideal entertaining spot. ALL ROOMS AFFORD A GREAT ST.LAWRENCE RIVER VIEW! The 3-st. att.garage is completely finished,insulated & heated w/ a separate gas furnace. The property is located 45 minutes from Ottawa & 2 hrs.from Montreal Canada. Call today for your private viewing appointment.


text:
Contests and Contests
October activity schedule
Literary, Artistic and Scientific Athenaeum of Cádiz
THURSDAY, 3
Solemn opening of the 2019-2020 Course.
Simplified reading of the 2018/2019 Course Report by the Secretary General, Mr. Antonio Ares Camerino.
Opening Lesson by Dr. D. Esteban Pacha Vicente (Attaché of Transport and Infrastructure of the Embassy of Spain in London. Captain of the Merchant Marine. Doctor of Nautical Science and Engineering from the Polytechnic University of Catalonia. Atheneist) with the conference entitled, "Understanding the global scene as a basis for cultural, scientific, social and economic development. The 2030 Agenda or the impact of Brexit on that global scene. "
Presents: Mr. Ignacio Moreno Aparicio (Honorary President of the Athenaeum).
Chair: Mr. José Almenara Barrios (President of the Athenaeum).
The President of the Athenaeum closed the act
TUESDAY, 8
Literary gathering: "The summer of my life".
Coordinated by: Rafaela Becerra and Mr. Ramón Luque (Board Members)
WEDNESDAY, 9
Presentation of the book: "Dictionary of Cadiz philosophers", by D. Joaquin Carretero, by the professors: Ms. Juana Sánchez-Gey, Mr. Rafael Serrano, Mr. Antonio Bocanegra and Mr. Antonio Castillo.
Sports Talk: "Analysis of current affairs."
Coordinates: Mr. Manuel Lapi (Member of the Board of Directors)
Musical gathering: "Verdi: La Traviata"
Coordinates: Mr. Juan Pablo Otero (Member of the Board of Directors)
THURSDAY, 17
Cycle of conferences of the V Centenary of the First Circumnavigation of the World. Conference "Architecture and urban planning of Sanlúcar in the time of Magallanes and Elcano", by Mr. José María Esteban González (1st Vice President of the Ateneo de Cádiz)
Activity of the Ateneo-UCA Chair. Conference. "Santiago de Chile and Cádiz: heritage and landscape as new spatial expressions of tourism", by Professor Dª. Carolina Quilodrán Rubio of the Faculty of Architecture and Urbanism of the University of Chile.
Presents: Mr. Ángel Guisado Cuéllar (President of the O'Higginiano Institute in Cádiz, and Ateneísta).
Chair: Ms. Amelia Rodríguez Martín (Director of the Ateneo-UCA Chair).
International Politics Talk: "What is happening in Cuba?" It will have the participation of José Antonio Barroso, former Mayor of Puerto Real.
Coordinated by: Ms. Purificación González de la Blanca (Member of the Board of Directors) and Mr. Juanlu González (International Analyst) Members of the Ojos para la Paz International Collective.
Pharmacy gathering: "The Cosmetics of the women of Don Quixote".
Coordinates: Ms. Paloma Ruiz Vega (Member of the Board of Directors)
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Hi there, I was wondering if you could help me with a query.
You can apply for a L tourit visa from the Public Security Bureau (PSM) Exit and Entry Administration office for the municipalitywhere your are studing after your 3 months' study.
Please note that the travel agencies don't have the right to cancel your visa. The fact is that your original business visa will be automatically cancelled after you get the tourist visa.
Hi. Could you help me about the location of Shantao?


Home / Posts taggedForex stock"
2 handel "lingo" Einer der großen Vorteile der Handel mit Währungen ist, dass der Forex-Markt. The forex quote includes the currency abbreviations for the currencies in question. An item that can be forex position größenrechner for another.
Well then you can use price action to scalp 1, 5, and 15 minute charts with ease. I wont aktion forex though, scalp trading is so fast paced that it can become overwhelming. So you need to scalp the right way. Don't have time to read this article right now?


Join Professors Arnaldo Cruz-Malavé, Chris GoGwilt, and Cynthia Vich in a discussion with acclaimed author and cultural critic Jean Franco on her latest book Cruel Modernity (Duke UP, 2013). The discussion will take place on Wednesday, April 2, from 5:00-7:00pm in Rm. 430BC, Fordham Law School (140 West 62nd Street) in New York. A reception and book signing will follow.
This discussion is co-sponsored by the departments of Modern Languages and Literatures and English, the programs in Latin American and Latino Studies, Comparative Literature, Peace and Justice Studies, American Studies and Women's Studies, and the Institute of International Humanitarian Affairs, the Office of Multicultural Affairs, and the Fordham School of Law.
Prof. GoGwilt is author of The Passage of Literature: Genealogies of Modernism in Conrad, Rhys, and Pramoedya; Prof. Vich has written extensively on Peruvian indigenista movements and on violence in literature and film; and Prof. Cruz-Malavé writes on gender and sexuality in Caribbean and Latino literatures.


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