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Tumor Escape and Progression under Immune PressureView this Special Issue
Review Article | Open Access
Amedeo Amedei, Chiara Della Bella, Elena Silvestri, Domenico Prisco, Mario M. D'Elios, "T Cells in Gastric Cancer: Friends or Foes", Journal of Immunology Research, vol. 2012, Article ID 690571, 10 pages, 2012. https://doi.org/10.1155/2012/690571
T Cells in Gastric Cancer: Friends or Foes
Gastric cancer is the second cause of cancer-related deaths worldwide. Helicobacter pylori is the major risk factor for gastric cancer. As for any type of cancer, T cells are crucial for recognition and elimination of gastric tumor cells. Unfortunately T cells, instead of protecting from the onset of cancer, can contribute to oncogenesis. Herein we review the different types, “friend or foe”, of T-cell response in gastric cancer.
Gastric cancer (GC) is the second cause of cancer worldwide for cancer-related deaths . The regional variations mainly reflect differences in the prevalence of Helicobacter pylori infection, which accounts for more than 60% of GC worldwide .
Helicobacter pylori infection is very common in human populations but only 1% of infected individuals develop gastric cancer in response to persistent infection [2–4]. Certainly Helicobacter pylori plays a crucial role [3–5], but also host factors are relevant for the outcome of the infection [6, 7]: actually, many studies showed that the subset of patients who progress to gastric cancer appear to have an increased incidence of some polymorphisms in proinflammatory cytokines and particularly IL-1.
The response of the body to a cancer is not a unique mechanism but has many similarities with inflammation and wound healing. The last century Virchow’s  observation of a close association between cancer and inflammation anticipated the current interest in the role of immunity in tumor pathogenesis.
Recent insights into the dynamics of the tumor microenvironment have begun to clarify the mechanisms underlying tumor-promoting inflammation, which bears striking similarities to wounds that fail to heal [9, 10]. Approximately 20% of cancer deaths worldwide are currently linked to unresolved infection or inflammation, with gastrointestinal malignancies representing a significant proportion of this disease burden: the most frequent associations are gastric carcinoma and Helicobacter pylori infection [3–10], colorectal carcinoma and inflammatory bowel disease , pancreatic carcinoma and chronic pancreatitis .
Unresolved inflammation generates a microenvironment that facilitates cellular transformation and the propagation of invasive disease. Chronic tissue damage triggers a repair response including the production of growth and survival factors, proangiogenesis cytokines, and immune regulatory networks [7, 8].
The release of inflammatory cell-derived reactive oxygen species coupled with stimulated epithelial cell proliferation creates an elevated risk of mutagenesis. In addition, cross-talk between neoplastic cells and immune elements throughout the smoldering inflammation perpetuates the transforming environment, which provides the evolving tumor cells with sufficient opportunity to acquire mutations and epigenetic alterations that are necessary for cell autonomy.
Inflammatory circuits can considerably differ in different tumors in terms of cellular and cytokine networks and molecular drivers. However, macrophages are a common and fundamental component of cancer promoting inflammation. The drivers of macrophage functional orientation include tumor cells, cancer-associated fibroblasts, B cells, and T cells.
It is not unfrequent that gastric cancer patients with the same TNM stage pursue different clinical courses. Histopathologic classifications, including WHO classification  and molecular classifications , have also been applied for the prediction of patient survival, but their prognostic accuracies are controversial . In addition, many attempts have been made to link molecular events in cancer cells with patient outcome, but none of these have been proved to be clinically meaningful. As a consequence, new prognostic determinants in conjunction with the TNM stage are required to more reliably and precisely predict patients’ clinical course.
As the cancer immunosurveillance hypothesis was first proposed, the concept that the immune system can recognise and eliminate tumor cells has been energetically debated. Many experimental studies in rodents have shown that the immune system indeed functions to protect murine hosts against development of both chemically induced and spontaneous tumors . Furthermore, in humans, epidemiologic investigations indicate that immunocompromised patients have a higher probability to develop cancers of both viral and nonviral origin, which supports the cancer immunosurveillance concept . In addition, current evidence indicates a positive correlation between the presence of lymphocytes in tumor tissue and increased patient survival.
Recent studies have highlighted that several types of tumor infiltrating lymphocytes (TIL) are associated with a better disease outcome for various human cancers [16–18], demonstrating that higher numbers of CD3+, CD8+, or CD45RO+ T cells in tumor tissue are significantly correlated with lower frequencies of lymph node metastasis, disease recurrence, or longer patient survival. Wang et al. advocated that the type, density, and location of immune cells in colorectal cancer have prognostic values that are superior to and independent of those of the TNM classification .
However, tumors have developed a number of different strategies to escape immune surveillance, such as the loss of tumor antigen expression, the expression of Fas ligand (Fas-L) or CD200 that can induce apoptosis in activated T cells, the secretion of immunosuppressive cytokines, such as IL-10 or TGF-, or the generation of regulatory T cells, and MHC downregulation or loss . An alteration in HLA class I expression occurs in many cancers, such as gastric cancer  and potentially plays a role in the clinical course of the disease by enabling tumor cells to escape T-cell-mediated immune responses . Recent observations suggest that the induction of T-cell apoptosis coexisting with a downregulation of TCR- molecules may be responsible for T-cell dysfunction in patients with gastric cancer .
Within TIL population, there are also T regulatory cells (Tregs), which are able to inhibit the immune response mediated by CD4+ and CD8+ T cells in preventing allograft rejection, graft versus host disease, and autoimmune disease [23, 24].
In cancer individuals, Tregs were found to downregulate the activity of effector function against tumors, resulting in T-cell dysfunction in cancer-bearing hosts [25, 26]. High numbers of Tregs were indeed reported in patients with different type of cancer [27–29] such as gastric and esophageal cancer . These observations led us to the hypothesis that tumor-bearing hosts with advanced cancers have an increased population of Tregs, which might inhibit the tumor-specific T-cell response.
The aim of this paper is to highlight the role of different T-cell populations involved in gastric cancer immune response and to evaluate their impact in blocking/promoting the development of gastric cancer.
2. Protective Role of Cytotoxic T Cells
A large body of evidence indicates that in gastrointestinal malignancies, endogenous responses may inhibit tumor growth and perhaps modulate the clinical course of the disease. Many reports have been obtained on colorectal carcinoma: the type, density, and intratumoral location of the lymphocyte infiltrate have been shown to be more informative biomarkers than the TNM or Duke’s classification . In this context, dense infiltrates composed of cytotoxic memory T cells are strongly associated with a reduced risk of recurrence after surgery and increased overall survival. In particular, patients with early-stage cancers but an absence of T-cell infiltrates display poor outcomes, whereas subjects with significant tumor burdens but robust T-cell infiltrates showed improved outcomes [23, 31].
The prognostic role of tumor-infiltrating immune cells in patients with gastric cancer is largely unknown. Only a few reports have been issued on the association between tumor infiltrating immune cells and the clinical outcome in GC: Ishigami et al.  reported that patients showing a high level of natural killer cell infiltration in tumor tissues have a better prognosis, and Maehara et al.  showed that a high density of dendritic cell infiltration is associated with the absence of lymph node metastasis. On the other hand, the group of Fukuda  found no significant difference in survival between patients with marked or slight TIL infiltration. However, they detected TILs by immunostaining in GC patients, classified cases into groups with marked or slight TIL infiltration, and did not determine TIL numbers.
T-cell-mediated adaptive immunity is considered to play a major role in antitumor immunity. In mouse models, it has been demonstrated that adaptive immunity prevents the development of tumors and inhibit tumor progression .
Accordingly, recent data  showed that in GC high densities of immune cells related to adaptive immunity (especially cytotoxic T cells and memory T cells) are associated with favorable survival and indicate that adaptive immunity plays a role in the prevention of tumor progression.
TIL density is also correlated with the presence of lymph node metastasis but not with the depth of tumor invasion. On the basis of this finding, the authors suspect that the prognostic role of TIL is mainly due to decreased metastatic potential and suggest the following possible mechanisms. First, the expansion of clones with metastatic potential usually containing larger amounts of aberrantly expressed proteins, including proteins that contribute to metastasis, which may act as tumor-associated antigens. As a result, these clones are more likely to be destroyed by in situ immune reactions. Second, a high density of TIL means a healthy immune system, and therefore, immune reaction occurring in lymph node may also exert a proper function against tumor cells that have drained into lymph nodes in patients with high TIL densities. Third, tumor burden of metastatic foci in lymph node is less bulky than those of primary foci, and thus, metastatic foci are more likely to be susceptible to complete destruction by immune reaction.
Many experimental and clinical observations suggest that metastatic growth in mice and humans is more difficult to control through vaccination and T-cell response, and new observations indicate that immunity against early and even preneoplastic lesions is stronger than against advanced tumors [37–39]. In some cases, enhanced anticancer T-cell activity may thus prevent metastasis rather than eliminating established metastatic nodules. Recently, Kim and coll.  evaluated the antitumor activity of ex vivo expanded T cells against human GC. For this purpose, human peripheral blood mononuclear cells were cultured with IL-2-containing medium in anti-CD3 antibody-coated flasks for 5 days, followed by incubation in IL-2-containing medium for 9 days. The resulting populations were mostly CD3+ T cells (97%): 11% CD4+ and 80% CD8+. This heterogeneous cell population was also called cytokine-induced killer (CIK) cells. CIK cells strongly produced IFN-, moderately TNF-, but not IL-2 and IL-4. At an effector-target cell ratio of 30 : 1, CIK cells destroyed 58% of MKN74 human GC cells. In addition, CIK cells at doses of 3 and 10 million cells per mouse inhibited 58% and 78% of MKN74 tumor growth in nude mouse xenograft assays, respectively. This study suggests that CIK cells may be used as an adoptive immunotherapy for gastric cancer patients.
The adoptive immunotherapy of GC with CIK cells has been also reported in preclinical and clinical studies . MHC-I-restricted CTLs from GC patients recognize tumor-associated antigen and react specifically against self-tumor cells [41–43]. One tumor-specific antigen, MG7-antigen, showed great potential for predicting early cancer as well as for inducing immune responses to GC [44, 45]. Using HLA-A-matched allogeneic GC cells to induce tumor-specific CTLs appears to be an alternative immunotherapy option for gastric cancer . Also, CIK cells in combination with chemotherapy showed benefits for patients who suffer from advanced gastric cancers [46, 47]. The serum levels of tumor markers were significantly decreased, the host immune function was increased and the short-term curative effect as well as the quality of life, were improved in patients treated by chemotherapy plus CIK cells compared to those in patients treated by chemotherapy alone .
Most studies analyzing T-cell response to tumor-associated antigens (TAAs) have emphasized CD8+ T cells thus far. However, CD4+ T cells may play a crucial role in both the induction and activation of TAA-specific memory CD8+ T cells toward cytotoxic effector T cells [49, 50].
Recently Amedei et al.  analyzed the functional properties of the T-cell response to different antigen peptides related to GC in patients with gastric adenocarcinoma. A T-cell response specific to different peptides of GC antigens tested was documented in 17 out of 20 patients. Most of the cancer peptide-specific TILs expressed a T helper 1 (Th1)/T cytotoxic 1 (Tc1) profile and cytotoxic activity against target cells. The effector functions of cancer peptide-specific T cells obtained from the peripheral blood of the same patients were also studied, and the majority of peripheral blood peptide-specific T cells also expressed the Th1/Tc1 functional profile.
In conclusion, in most patients with gastric adenocarcinoma, a specific type 1 T-cell response to GC antigens was detectable and would have the potential of hamper tumor cell growth.
3. T Regulatory Cells in Cancer
The physiological role of Tregs is the protection against the autoimmune diseases through the direct suppression of T effector cells reacting against “self,” although they can be also involved in the control of immune response against exogenous antigens . Since most antigens expressed by neoplastic cells are “self”-antigens , it is commonly considered that Tregs are also involved in the suppression of the immune response against tumors, favoring tumor escape from immune response . TILs consist of various antitumor effector and regulatory subsets. T-cell infiltration is associated with good tumor prognosis in many types of cancers. CD8+ and CD4+ T lymphocytes are effector cells thought to be associated with a favorable prognosis . While CD8+ T cells are the main effectors of antitumor immunity, CD4+ T cells induce and maintain CD8 response . On the other hand, regulatory lymphocytes, a subset of T cells which inhibit the antitumor immune reaction have been described to be associated with unfavorable prognosis [57–62]. Tregs cells are known to attenuate host antitumor immunity by suppressing T-cell proliferation, antigen presentation, and cytokine production . As the tumor progresses and becomes established in the host, the population of TILs is skewed to favor regulatory T cells over the helper CD4+ T cells .
Studies of regulatory T cells in GC are very few and have yielded conflicting results. Haas et al.  reported that stromal but not intraepithelial regulatory T cells are associated with a favorable prognosis. Mizukami et al.  reported that the localization pattern but not the absolute number of regulatory T cells was associated with the prognosis. In breast cancer, it has been demonstrated that pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating Foxp3+ regulatory T cells . It has been demonstrated that in some kidney tumors Treg frequency is significantly higher in patients with worse prognosis . Conversely, several recent reports highlighted a protective role of Treg in cancer . In renal cancer, Siddiqui et al. showed no correlation between tumor-infiltrating Treg frequency and disease progression . The significance of regulatory T cell in GC as a poor prognostic factor has also been investigated. Perrone et al.  and Shen et al.  reported unfavorable prognosis with increased intratumoral regulatory T cells.
Two different studies [69, 70] confirmed that GC cell can induce Tregs development via TGF-1 production; in particular the level of serum TGF-1 in GC patients ( ng/mL) was significantly higher than that of the gender- and age-matched healthy controls ( ng/mL). Furthermore, the higher TGF-1 level correlated with the increased population of CD4+Foxp3+ Tregs in advanced GC. A significant higher frequency of CD4+Foxp3+ Tregs was observed in PBMCs cultured with the supernatant of MGC than GES-1 (10.6% ± 0.6% versus 8.7% ± 0.7%). Moreover, using the purified CD4+CD25− T cells, the authors confirmed that the increased Tregs were mainly induced from the conversation of CD4+CD25− naive T cells, and induced Tregs were functional and able to suppress the proliferation of effector T cells. Finally, they demonstrated that GC cells induced the increase in CD4+Foxp3+ Tregs via TGF-1 production. Gastric cancer cells upregulated the production of TGF-1 and the blockade of TGF-1 partly abrogated Tregs phenotype.
The second study  investigated the frequency of Foxp3+ Tregs within CD4+ cells in TILs, regional lymph nodes, and PBL of GC patients. Furthermore, to elucidate the mechanisms behind Treg accumulation within tumors, authors evaluated the relationship between CCL17 or CCL22 expression and the frequency of Foxp3+ Tregs in GC. CD4+CD25+Foxp3+ Tregs were counted by flow cytometry and evaluated by immunohistochemistry. Moreover, an in vitro migration assay using Tregs derived from GC was performed in the presence of CCL17 or CCL22. As a result, the frequency of Foxp3+ Tregs in TILs was significantly higher than that in normal gastric mucosa (12.4% ± 7.5% versus 4.1% ± 5.3%). Importantly, the increase in Tregs in TILs occurred to the same extent in early and advanced disease. Furthermore, the frequency of CCL17+ or CCL22+ cells among CD14+ cells within tumors was significantly higher than that of normal gastric mucosa, and there was a significant correlation between the frequency of CCL171+ or CCL22+ cells and Foxp3+ Tregs in TILs. In addition, the in vitro migration assay indicated that Tregs were significantly induced to migrate by CCL17 or CCL22. In conclusion, CCL17 and CCL22 within the tumor are related to the increased population of Foxp3+ Tregs, with such an observation occurring in early GC.
Since the Tregs may restrain the antitumor activity of cytotoxic T cells, the balance of effector and suppressor cells may also prove to be a decisive factor in patient outcome, and a recent study  contains the first evidence related to the prevalence of Tregs in gastric and esophageal cancer. The authors shown increased populations of CD4+/CD25+cells in peripheral blood T cells from patients with gastric and esophageal cancers in comparison with healthy donors. Moreover, the population of CD4+/CD25+ cells in the TILs of GC was higher than that in normal gastric mucosa. Authors also confirmed that CD4+/CD25+ isolated from patient peripheral blood had a regulatory function by evaluating cytokine production and suppressive activity.
Moreover, the population of CD4+/CD25+ cells in the TILs of GC patients with advanced disease was significantly more extended than that in TILs of patients with early-stage disease or that in intraepithelial lymphocytes of normal gastric mucosa. As a functional consequence, CD4+/CD25+ cells did not produce IFN- but large amounts of IL-10. Also, the proliferation of CD4+/CD25− cells was inhibited in the presence of CD4+/CD25+ cells in a dose-dependent manner, so confirming that CD4+/CD25+ has an inhibitory activity corresponding to Tregs.
Similar results were obtained by Shen and coll. , who demonstrated that increased CD4(+)CD25(+)CD127(low/−) regulatory T cells were also present in the tumor microenvironment, such as those found in the ascites fluid, tumor tissue, or adjacent lymph nodes. In addition, they found that CD4(+)CD25(+)CD127(low/−) Tregs suppressed effector T-cell proliferation and also correlated to advanced stage of GC, suggesting that CD4(+)CD25(+)CD127(low/−) can be used as a selective biomarker to enrich human Treg cells and also to perform functional in vitro assays in GC.
4. Th17 in Cancer
A new subset of Th cells, named Th17 cells, producing IL-17 alone or in combination with IFN-, has been identified . Th17 cells may also secrete IL-6, IL-22, and TNF- and play a critical role in protection against microbial challenges, particularly extracellular bacteria and fungi . The role of Th17 cells in tumor immunology can be dichotomous: Th17 cells indeed seem to play a role both in tumorigenesis and eradication of an established tumor. Many laboratories have studied Th17 populations in blood and occasionally tissues of patients with various cancers. A potential protective effect of Th17 cells has been reported in cancer affecting mucosal tissues, such as gut, lung, and skin [74, 75]. An increase in Th17 cells has been detected in peripheral blood, tumor microenvironment and tumor-draining lymph nodes of several different human and mouse tumor types , such as ovarian cancer .
A recent study has shown that the number of Th17 cells increased in the TILs from melanoma, breast, and colon cancers ; Th17 cells were also suggested as a prognostic marker in hepatocellular carcinoma . In contrast to data on solid tumors, little is known about Th17 cells in hematological malignancies. Serum IL-17 levels were recently shown to be elevated in patients with multiple myeloma, especially in stages II and III of the disease. Thus, current data confirm a role for IL-17 in the promotion of angiogenesis and in the progression of multiple myeloma . Th17 cell frequencies and IL-17 concentrations were significantly higher in peripheral blood samples from untreated patients with acute myeloid leukemia than in those from healthy volunteers and were reduced in the former after chemotherapy .
On the other hand, some studies have found that the number of Th17 cells is decreased in several types of tumor. The levels of tumor-infiltrating Th17 cells and IL-17 in ascites were reduced in a group of ovarian cancer patients with more advanced disease and seemed to positively predict outcome . A low number of Th17 cell is present in the tumor microenvironment of non-Hodgkin’s lymphoma because malignant B cells may upregulate Treg cells and inhibit Th17 cells . Th17 cells are present in much lower numbers in HER2-positive breast cancer patients than in either healthy controls or HER2-negative patients .
One study in prostate cancer demonstrated that Th17 cells infiltrating the tumor correlated inversely with the Gleason score . This implied that Th17 cells mediate an antitumor effect in the development of prostate cancer. One group found that IL-17 promoted the tumorigenicity of human cervical tumors in nude mice but inhibited the growth of hematopoietic tumors, mastocytoma P815, and plasmocytoma in immunocompetent mice [86, 87].
It is clear that the Th17 cells have an ambiguous role in cancers: they can both encourage and inhibit cancer progression.
The mechanism of Th17 cells upregulation in tumor is not clear. Charles et al. found that TNF- enhanced tumor growth via the inflammatory cytokine IL-17 in a mouse model of ovarian cancer and in patients with advanced cancer . Su et al. demonstrated that tumor cells and tumor-derived fibroblasts secrete monocyte chemotactic protein 1(MCP-1) and RANTES that mediate the recruitment of Th17 cells .
More recently, Kuang et al. showed that tumor-activated monocytes promote expansion of Th17 cells by secreting a set of key proinflammatory cytokines in the peritumoral stroma of hepatocarcinoma tissues . It is clear that Treg cells efficiently suppressed the function of antitumor CD8+ T cells [92, 93]. A recent study reported that IL-2 regulates the balance between tumor Treg and Th17 cells by stimulating the differentiation of the former and inhibiting that of the latter in the tumor microenvironment .
The mechanism of Th17 cells’ antitumor activity remains largely unknown. One recent work has reported antitumor activity of IL-17 by means of a T-cell-dependent mechanism .
Two studies by Benatar et al. demonstrated that IL-17E, a cytokine with significant homology to IL-17, has antitumor activity in multiple tumor models, and that eosinophils and B cells are involved in the antitumor mechanism of action of IL-17E [94, 95].
Th17 cells may contribute to protective human tumor immunity by inducing Th1-type chemokines and stimulating CXCL9 and CXCL10 production to recruit effector cells to the tumor microenvironment. A recent study has also demonstrated that almost half of IL-17-producing CD4+ T cells isolated from hepatocarcinoma tissues simultaneously produced IFN- .
An interesting work of the Gaudernack group has demonstrated that IL-17-secreting T cell clones obtained from long-term survivors after immunotherapy also secreted IFN-, IL-4, IL-5, and IL-13 . More recently, it was shown that Th17 cells and IL-17 participate in antitumor immunity by facilitating dendritic cell recruitment into tumor tissues and promoting the activation of tumor-specific CD8+ T cells .
It was even most intriguing that the Th17 frequencies increased during treatment with trastuzumab in patients with breast cancer  or with metastatic melanoma treated with the anticytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibody tremelimumab .
Alvarez et al. demonstrated that dendritic and tumor cell fusions transduced with adenovirus encoding CD40L eradicate B-cell lymphoma and induce a Th17 type response in a murine lymphoma model . Moreover, Derhovanessian et al. has observed a highly significant correlation between a higher frequency of IL-17-producing T-cells prevaccination and a shorter time to metastatic progression after immunotherapy . These data imply the important involvement of Th17 cells in the response to cancer immunotherapy (Table 1).
Zhang et al.  preliminairly reported that compared with healthy volunteers, patients with GC had a higher proportion of Th17 cells in peripheral blood. The increased prevalence of Th17 cells was associated with clinical stage and in advanced disease increased populations of Th17 cells were present also in tumor-draining lymph nodes. Furthermore, the mRNA expression levels of Th17-related factors (IL-17 and IL-23p19) in tumor tissues and the serum concentrations of IL-17 and IL-23 cytokines were significantly increased in patients with advanced GC. The results indicate that Th17 cells may contribute to GC pathogenesis.
5. Concluding Remarks
This paper has highlighted the key roles that T-cell populations play in promotion and/or protection of gastric cancer.
In summary, high densities of cytotoxic T cells and memory T cells are usually associated with favorable survival, indicating the importance of adaptive immunity in the prevention of gastric cancer ; as a matter of fact the adoptive immunotherapy of GC with T cells has been also reported in different preclinical and clinical studies . MHC-I restricted CTLs from GC patients recognize tumor-associated antigen and react specifically against self-tumor cells [42, 43], such as MG7-antigen, which shows great potential for predicting early cancer as well as for inducing immune responses to GC [44, 45].
Different studies sometimes reported controversial results, for example, some study showed that Tregs are protective, while others that the Tregs, present in TILs or in peripheral blood of GC patients, are able to suppress the effector T cells, thus promoting the tumor progression [30, 68].
In addition, although not conclusively, recent data suggested that Th17 cells might somehow contribute to GC pathogenesis .
On the basis of clinical and experimental evidence, it is reasonable to conclude that the T immune response in GC has double faces as Janus, one friend and one foe, and that to obtain successful immunotherapy might involve a combined approach, which intensify the effector functions of cytotoxic T cells and probably reduce the suppressive T cells.
The authors thank the Ministry of University and Research and the Italian Ministry of Health for supporting our studies. They thank R. Plyne for English editing.
- M. Ezzati, S. J. Henley, A. D. Lopez, and M. J. Thun, “Role of smoking in global and regional cancer epidemiology: current patterns and data needs,” International Journal of Cancer, vol. 116, no. 6, pp. 963–971, 2005.
- D. M. Parkin, “The global health burden of infection-associated cancers in the year 2002,” International Journal of Cancer, vol. 118, no. 12, pp. 3030–3044, 2006.
- J. Parsonnet, G. D. Friedman, D. P. Vandersteen et al., “Helicobacter pylori infection and the risk of gastric carcinoma,” New England Journal of Medicine, vol. 325, no. 16, pp. 1127–1131, 1991.
- P. Correa, “Bacterial infections as a cause of cancer,” Journal of the National Cancer Institute, vol. 95, no. 7, p. E3, 2003.
- R. M. Peek Jr. and M. J. Blaser, “Helicobacter pylori and gastrointestinal tract adenocarcinomas,” Nature Reviews Cancer, vol. 2, no. 1, pp. 28–37, 2002.
- E. M. El-Omar, M. Carrington, W. H. Chow et al., “The role of interleukin-1 polymorphisms in the pathogenesis of gastric cancer,” Nature, vol. 412, no. 6842, p. 99, 2001.
- M. M. D'Elios, B. J. Appelmelk, A. Amedei, M. P. Bergman, and G. Del Prete, “Gastric autoimmunity: the role of Helicobacter pylori and molecular mimicry,” Trends in Molecular Medicine, vol. 10, no. 7, pp. 316–323, 2004.
- F. Balkwill and A. Mantovani, “Inflammation and cancer: back to Virchow?” The Lancet, vol. 357, no. 9255, pp. 539–545, 2001.
- H. F. Dvorak, “Tumors: wounds that do not heal: similarities between tumor stroma generation and wound healing,” New England Journal of Medicine, vol. 315, no. 26, pp. 1650–1659, 1986.
- M. M. D'Elios, A. Amedei, and G. Del Prete, “Helicobacter pylori antigen-specific T-cell responses at gastric level in chronic gastritis, peptic ulcer, gastric cancer and low-grade mucosa-associated lymphoid tissue (MALT) lymphoma,” Microbes and Infection, vol. 5, no. 8, pp. 723–730, 2003.
- A. Ekbom, “Risk of cancer in ulcerative colitis,” Journal of Gastrointestinal Surgery, vol. 2, no. 4, pp. 312–313, 1998.
- A. B. Lowenfels, P. Maisonneuve, G. Cavallini et al., “Pancreatitis and the risk of pancreatic cancer: International Pancreatitis Study Group,” The New England Journal of Medicine, vol. 328, no. 20, pp. 1433–1437, 1993.
- C. Fenoglio-Preiser, F. Carneiro, P. Correa et al., “Gastric carcinoma,” in World Health Organization Classification of Tumors; Pathology and Genetics of Tumors of the Digestive System, S. R. Hamilton and L. A. Aaltonen, Eds., pp. 37–52, IARC Press, Lyon, France, 2000.
- C. N. Chen, J. J. Lin, J. J. W. Chen et al., “Gene expression profile predicts patient survival of gastric cancer after surgical resection,” Journal of Clinical Oncology, vol. 23, no. 29, pp. 7286–7295, 2005.
- W. Zou, “Regulatory T cells, tumour immunity and immunotherapy,” Nature Reviews Immunology, vol. 6, no. 4, pp. 295–307, 2006.
- X. C. Wang, J. Q. Zhang, Y. Q. Shen, F. Q. Miao, and W. Xie, “Loss of heterozygosity at 6p21.3 underlying HLA class I downregulation in gastric cancer,” Journal of Experimental and Clinical Cancer Research, vol. 25, no. 1, pp. 115–119, 2006.
- C. C. Chang, M. Campoli, and S. Ferrone, “HLA class I defects in malignant lesions: what have we learned?” Keio Journal of Medicine, vol. 52, no. 4, pp. 220–229, 2003.
- A. Takahashi, K. Kono, H. Amemiya, H. Iizuka, H. Fujii, and Y. Matsumoto, “Elevated caspase-3 activity in peripheral blood T cells coexists with increased degree of T-cell apoptosis and down-regulation of TCR zeta molecules in patients with gastric cancer,” Clinical Cancer Research, vol. 7, no. 1, pp. 74–80, 2001.
- G. P. Dunn, L. J. Old, and R. D. Schreiber, “The three Es of cancer immunoediting,” Annual Review of Immunology, vol. 22, pp. 329–360, 2004.
- J. Galon, A. Costes, F. Sanchez-Cabo et al., “Type, density, and location of immune cells within human colorectal tumors predict clinical outcome,” Science, vol. 313, no. 5795, pp. 1960–1964, 2006.
- Q. Gao, S. J. Qiu, J. Fan et al., “Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection,” Journal of Clinical Oncology, vol. 25, no. 18, pp. 2586–2593, 2007.
- G. P. Dunn, L. J. Old, and R. D. Schreiber, “The immunobiology of cancer immunosurveillance and immunoediting,” Immunity, vol. 21, no. 2, pp. 137–148, 2004.
- M. Asano, M. Toda, N. Sakaguchi, and S. Sakaguchi, “Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation,” Journal of Experimental Medicine, vol. 184, no. 2, pp. 387–396, 1996.
- S. Sakaguchi, N. Sakaguchi, J. Shimizu et al., “Immunologic tolerance maintained by CD25+CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance,” Immunological Reviews, vol. 182, pp. 18–32, 2001.
- R. Somasundaram, L. Jacob, R. Swoboda et al., “Inhibition of cytolytic T lymphocyte proliferation by autologous CD4+/CD25+ regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor-β,” Cancer Research, vol. 62, no. 18, pp. 5267–5272, 2002.
- M. Awwad and R. J. North, “Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamide-resistant murine tumor: a consequence of eliminating precursor L3T4+ suppressor T-cells,” Cancer Research, vol. 49, no. 7, pp. 1649–1654, 1989.
- E. Y. Woo, C. S. Chu, T. J. Goletz et al., “Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer,” Cancer Research, vol. 61, no. 12, pp. 4766–4772, 2001.
- E. Y. Woo, H. Yeh, C. S. Chu et al., “Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation,” Journal of Immunology, vol. 168, no. 9, pp. 4272–4276, 2002.
- U. K. Liyanage, T. T. Moore, H. G. Joo et al., “Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma,” Journal of Immunology, vol. 169, no. 5, pp. 2756–2761, 2002.
- F. Ichihara, K. Kono, A. Takahashi, H. Kawaida, H. Sugai, and H. Fujii, “Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers,” Clinical Cancer Research, vol. 9, no. 12, pp. 4404–4408, 2003.
- F. Pagès, A. Berger, M. Camus et al., “Effector memory T cells, early metastasis, and survival in colorectal cancer,” New England Journal of Medicine, vol. 353, no. 25, pp. 2654–2666, 2005.
- S. Ishigami, S. Natsugoe, K. Tokuda et al., “Prognostic value of intratumoral natural killer cells in gastric carcinoma,” Cancer, vol. 88, no. 3, pp. 577–583, 2000.
- Y. Maehara, S. Tomisaki, S. Oda et al., “Lymph node metastasis and relation to tumor growth potential and local immune response in advanced gastric cancer,” International Journal of Cancer, vol. 74, no. 2, pp. 224–228, 1997.
- K. Fukuda, S. Tsujitani, Y. Maeta, K. Yamaguchi, M. Ikeguchi, and N. Kaibara, “The expression of RCAS1 and tumor infiltrating lymphocytes in patients with T3 gastric carcinoma,” Gastric Cancer, vol. 5, no. 4, pp. 220–227, 2002.
- G. P. Dunn, L. J. Old, and R. D. Schreiber, “The immunobiology of cancer immunosurveillance and immunoediting,” Immunity, vol. 21, no. 2, pp. 137–148, 2004.
- H. E. Lee, S. W. Chae, Y. J. Lee et al., “Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer,” British Journal of Cancer, vol. 99, no. 10, pp. 1704–1711, 2008.
- Y. A. Alpizar, B. Chain, M. K. Collins et al., “Ten years of progress in vaccination against cancer: the need to counteract cancer evasion by dual targeting in future therapies,” Cancer Immunology, Immunotherapy, vol. 60, no. 8, pp. 1127–1135, 2011.
- S. C. Gilbert, “T-cell-inducing vaccines—what's the future,” Immunology, vol. 135, no. 1, pp. 19–26, 2012.
- A. Jorritsma, T. N. M. Schumacher, and B. A. G. John Haanen, “Immunotherapeutic strategies: the melanoma example,” Immunotherapy, vol. 1, no. 4, pp. 679–690, 2009.
- Y. J. Kim, J. Lim, J. S. Kang et al., “Adoptive immunotherapy of human gastric cancer with ex vivo expanded T cells,” Archives of Pharmacal Research, vol. 33, no. 11, pp. 1789–1795, 2010.
- D. Sangiolo, “Cytokine induced killer cells as promising immunotherapy for solid tumors,” Journal of Cancer, vol. 2, pp. 363–368, 2011.
- T. Hoshino, N. Seki, M. Kikuchi et al., “HLA class-I-restricted and tumor-specific CTL in tumor-infiltrating lymphocytes of patients with gastric cancer,” International Journal of Cancer, vol. 70, no. 6, pp. 631–638, 1997.
- K. Kono, Y. Rongcun, J. Charo et al., “Identification of HER2/neu-derived peptide epitopes recognized by gastric cancer-specific cytotoxic T lymphocytes,” International Journal of Cancer, vol. 78, no. 2, pp. 202–208, 1998.
- D. L. Guo, M. Dong, L. Wang, L. P. Sun, and Y. Yuan, “Expression of gastric cancer-associated MG7 antigen in gastric cancer, precancerous lesions and H. pylori-associated gastric diseases,” World Journal of Gastroenterology, vol. 8, no. 6, pp. 1009–1013, 2002.
- K. Wu, Y. Nie, C. Guo, Y. Chen, J. Ding, and D. Fan, “Molecular basis of therapeutic approaches to gastric cancer,” Journal of Gastroenterology and Hepatology, vol. 24, no. 1, pp. 37–41, 2009.
- J. Jiang, N. Xu, C. Wu et al., “Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells,” Anticancer Research, vol. 26, no. 3, pp. 2237–2242, 2006.
- C. Wu, J. Jiang, L. Shi, and N. Xu, “Prospective study of chemotherapy in combination with cytokine-induced killer cells in patients suffering from advanced non-small cell lung cancer,” Anticancer Research, vol. 28, no. 6, pp. 3997–4002, 2008.
- S. Sun, X. M. Li, X. D. Li, and W. S. Yang, “Studies on inducing apoptosis effects and mechanism of CIK cells for MGC-803 gastric cancer cell lines,” Cancer Biotherapy and Radiopharmaceuticals, vol. 20, no. 2, pp. 173–180, 2005.
- F. G. Gao, V. Khammanivong, W. J. Liu, G. R. Leggatt, I. H. Frazer, and G. J. P. Fernando, “Antigen-specific CD4+ T-cell help is required to activate a memory CD8+ T cell to a fully functional tumor killer cell,” Cancer Research, vol. 62, no. 22, pp. 6438–6441, 2002.
- M. M. D'Elios and M. P. Bergman, “Cytotoxic T cells in H. pylori-related gastric autoimmunity and gastric lymphoma,” Journal of Biomedicine and Biotechnology, vol. 2010, Article ID 104918, 2010.
- A. Amedei, E. Niccolai, C. Della Bella et al., “Characterization of tumor antigen peptide-specific T cells isolated from the neoplastic tissue of patients with gastric adenocarcinoma,” Cancer Immunology, Immunotherapy, vol. 58, no. 11, pp. 1819–1830, 2009.
- L. Maggi, V. Santarlasci, F. Liotta et al., “Demonstration of circulating allergen-specific CD4+CD2Foxp3+ T-regulatory cells in both nonatopic and atopic individuals,” Journal of Allergy and Clinical Immunology, vol. 120, no. 2, pp. 429–436, 2007.
- H. Nishikawa, T. Kato, K. Tanida et al., “CD4+CD25+ T cells responding to serologically defined autoantigens suppress antitumor immune responses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 19, pp. 10902–10906, 2003.
- C. Baecher-Allan and D. E. Anderson, “Immune regulation in tumor-bearing hosts,” Current Opinion in Immunology, vol. 18, no. 2, pp. 214–219, 2006.
- Y. Cho, M. Miyamoto, K. Kato et al., “CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma,” Cancer Research, vol. 63, no. 7, pp. 1555–1559, 2003.
- P. Yu and Y. X. Fu, “Tumor-infiltrating T lymphocytes: friends or foes?” Laboratory Investigation, vol. 86, no. 3, pp. 231–245, 2006.
- F. A. Sinicrope, R. L. Rego, S. M. Ansell, K. L. Knutson, N. R. Foster, and D. J. Sargent, “Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma,” Gastroenterology, vol. 137, no. 4, pp. 1270–1279, 2009.
- R. P. Petersen, M. J. Campa, J. Sperlazza et al., “Tumor infiltrating FOXP3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients,” Cancer, vol. 107, no. 12, pp. 2866–2872, 2006.
- J. Fu, D. Xu, Z. Liu et al., “Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients,” Gastroenterology, vol. 132, no. 7, pp. 2328–2339, 2007.
- T. J. Curiel, G. Coukos, L. Zou et al., “Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival,” Nature Medicine, vol. 10, no. 9, pp. 942–949, 2004.
- G. J. Bates, S. B. Fox, C. Han et al., “Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse,” Journal of Clinical Oncology, vol. 24, no. 34, pp. 5373–5380, 2006.
- G. Perrone, P. A. Ruffini, V. Catalano et al., “Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer,” European Journal of Cancer, vol. 44, no. 13, pp. 1875–1882, 2008.
- M. Haas, A. Dimmler, W. Hohenberger, G. G. Grabenbauer, G. Niedobitek, and L. V. Distel, “Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia,” BMC gastroenterology, vol. 9, article 65, 2009.
- Y. Mizukami, K. Kono, Y. Kawaguchi et al., “Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer,” British Journal of Cancer, vol. 98, no. 1, pp. 148–153, 2008.
- S. Ladoire, L. Arnould, L. Apetoh et al., “Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating Foxp3+ regulatory T cells,” Clinical Cancer Research, vol. 14, no. 8, pp. 2413–2420, 2008.
- F. Liotta, M. Gacci, F. Frosali et al., “Frequency of regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma,” BJU International, vol. 107, no. 9, pp. 1500–1506, 2011.
- S. A. Siddiqui, X. Frigola, S. Bonne-Annee et al., “Tumor-infiltrating Foxp3−CD4+CD25+ T cells predict poor survival in renal cell carcinoma,” Clinical Cancer Research, vol. 13, no. 7, pp. 2075–2081, 2007.
- Z. Shen, S. Zhou, Y. Wang et al., “Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer,” Journal of Cancer Research and Clinical Oncology, vol. 136, no. 10, pp. 1585–1595, 2010.
- X. L. Yuan, L. Chen, T. T. Zhang et al., “Gastric cancer cells induce human CD4+Foxp3+ regulatory T cells through the production of TGF-β1,” World Journal of Gastroenterology, vol. 17, no. 15, pp. 2019–2027, 2011.
- Y. Mizukami, K. Kono, Y. Kawaguchi et al., “CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer,” International Journal of Cancer, vol. 122, no. 10, pp. 2286–2293, 2008.
- L. S. Shen, J. Wang, D. F. Shen et al., “CD4+CD25+CD12 regulatory T cells express Foxp3 and suppress effector T cell proliferation and contribute to gastric cancers progression,” Clinical Immunology, vol. 131, no. 1, pp. 109–118, 2009.
- C. T. Weaver, L. E. Harrington, P. R. Mangan, M. Gavrieli, and K. M. Murphy, “Th17: an effector CD4 T cell lineage with regulatory T cell ties,” Immunity, vol. 24, no. 6, pp. 677–688, 2006.
- E. Bettelli, M. Oukka, and V. K. Kuchroo, “TH-17 cells in the circle of immunity and autoimmunity,” Nature Immunology, vol. 8, no. 4, pp. 345–350, 2007.
- C. M. Wilke, K. Bishop, D. Fox, and W. Zou, “Deciphering the role of Th17 cells in human disease,” Trends Immunology, vol. 32, no. 12, pp. 603–611, 2011.
- B. F. Zamarron and W. Chen, “Dual roles of immune cells and their factors in cancer development and progression,” International Journal of Biological Sciences, vol. 7, no. 5, pp. 651–658, 2011.
- I. Kryczek, S. Wei, L. Zou et al., “Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment,” Journal of Immunology, vol. 178, no. 11, pp. 6730–6733, 2007.
- Y. Miyahara, K. Odunsi, W. Chen, G. Peng, J. Matsuzaki, and R. F. Wang, “Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 40, pp. 15505–15510, 2008.
- X. Su, J. Ye, E. C. Hsueh, Y. Zhang, D. F. Hoft, and G. Peng, “Tumor microenvironments direct the recruitment and expansion of human Th17 cells,” Journal of Immunology, vol. 184, no. 3, pp. 1630–1641, 2010.
- J. P. Zhang, J. Yan, J. Xu et al., “Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients,” Journal of Hepatology, vol. 50, no. 5, pp. 980–989, 2009.
- M. G. Alexandrakis, C. A. Pappa, S. Miyakis et al., “Serum interleukin-17 and its relationship to angiogenic factors in multiple myeloma,” European Journal of Internal Medicine, vol. 17, no. 6, pp. 412–416, 2006.
- C. Wu, S. Wang, F. Wang et al., “Increased frequencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia,” Clinical and Experimental Immunology, vol. 158, no. 2, pp. 199–204, 2009.
- I. Kryczek, M. Banerjee, P. Cheng et al., “Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments,” Blood, vol. 114, no. 6, pp. 1141–1149, 2009.
- Z. Z. Yang, A. J. Novak, S. C. Ziesmer, T. E. Witzig, and S. M. Ansell, “Malignant B cells skew the balance of regulatory T cells and T H17 cells in B-cell non-Hodgkin's lymphoma,” Cancer Research, vol. 69, no. 13, pp. 5522–5530, 2009.
- C. Horlock, B. Stott, P. J. Dyson et al., “The effects of trastuzumab on the CD4+CD25+FoxP3+ and CD4+IL17A+ T-cell axis in patients with breast cancer,” British Journal of Cancer, vol. 100, no. 7, pp. 1061–1067, 2009.
- K. S. Sfanos, T. C. Bruno, C. H. Maris et al., “Phenotypic analysis of prostate-infiltrating lymphocytes reveals T H17 and Treg skewing,” Clinical Cancer Research, vol. 14, no. 11, pp. 3254–3261, 2008.
- E. Tartour, F. Fossiez, I. Joyeux et al., “Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice,” Cancer Research, vol. 59, no. 15, pp. 3698–3704, 1999.
- F. Benchetrit, A. Ciree, V. Vives et al., “Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism,” Blood, vol. 99, no. 6, pp. 2114–2121, 2002.
- H. Takahashi, M. Numasaki, M. T. Lotze, and H. Sasaki, “Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells,” Immunology Letters, vol. 98, no. 2, pp. 189–193, 2005.
- M. Numasaki, J. I. Fukushi, M. Ono et al., “Interleukin-17 promotes angiogenesis and tumor growth,” Blood, vol. 101, no. 7, pp. 2620–2627, 2003.
- K. A. Charles, H. Kulbe, R. Soper et al., “The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humans,” Journal of Clinical Investigation, vol. 119, no. 10, pp. 3011–3023, 2009.
- D. M. Kuang, C. Peng, Q. Zhao, Y. Wu, M. S. Chen, and L. Zheng, “Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells,” Hepatology, vol. 51, no. 1, pp. 154–164, 2010.
- P. A. Antony, C. A. Piccirillo, A. Akpinarli et al., “CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells,” Journal of Immunology, vol. 174, no. 5, pp. 2591–2601, 2005.
- K. L. Knutson, M. L. Disis, and L. G. Salazar, “CD4 regulatory T cells in human cancer pathogenesis,” Cancer Immunology, Immunotherapy, vol. 56, no. 3, pp. 271–285, 2007.
- T. Benatar, M. Y. Cao, Y. Lee et al., “Virulizin induces production of IL-17E to enhance antitumor activity by recruitment of eosinophils into tumors,” Cancer Immunology, Immunotherapy, vol. 57, no. 12, pp. 1757–1769, 2008.
- T. Benatar, M. Y. Cao, Y. Lee et al., “IL-17E, a proinflammatory cytokine, has antitumor efficacy against several tumor types in vivo,” Cancer Immunology, Immunotherapy, vol. 59, no. 6, pp. 805–817, 2010.
- J. A. Kyte, S. Trachsel, B. Risberg, P. thor Straten, K. Lislerud, and G. Gaudernack, “Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination,” Cancer Immunology, Immunotherapy, vol. 58, no. 10, pp. 1609–1626, 2009.
- N. Martin-Orozco, P. Muranski, Y. Chung et al., “T helper 17 cells promote cytotoxic T cell activation in tumor immunity,” Immunity, vol. 31, no. 5, pp. 787–798, 2009.
- E. Alvarez, E. Moga, J. Barquinero, J. Sierra, and J. Briones, “Dendritic and tumor cell fusions transduced with adenovirus encoding CD40L eradicate B-cell lymphoma and induce a Th17-type response,” Gene Therapy, vol. 17, no. 4, pp. 469–477, 2010.
- E. Derhovanessian, V. Adams, K. Hähnel et al., “Pretreatment frequency of circulating IL-17+CD4+ T-cells, but not Tregs, correlates with clinical response to whole-cell vaccination in prostate cancer patients,” International Journal of Cancer, vol. 125, no. 6, pp. 1372–1379, 2009.
- B. Zhang, G. Rong, H. Wei et al., “The prevalence of Th17 cells in patients with gastric cancer,” Biochemical and Biophysical Research Communications, vol. 374, no. 3, pp. 533–537, 2008.
- J. L. Gnerlich, J. B. Mitchem, J. S. Weir et al., “Induction of Th17 cells in the tumor microenvironment improves survival in a murine model of pancreatic cancer,” The Journal of Immunology, vol. 185, no. 7, pp. 4063–4071, 2010.
- M. D. Sharma, D. Y. Hou, Y. Liu, and P. A. Koni, “Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes,” Blood, vol. 113, no. 24, pp. 6102–6111, 2009.
- P. Muranski, A. Boni, and P. A. Antony, “Tumor-specific Th17-polarized cells eradicate large established melanoma,” Blood, vol. 112, no. 23, pp. 362–673, 2008.
- Z. J. Ye, Q. Zhou, Y. Y. Gu et al., “Generation and differentiation of IL-17–producing CD4+ T cells in malignant pleural effusion,” The Journal of Immunology, vol. 185, no. 10, pp. 6348–6354, 2010.
Copyright © 2012 Amedeo Amedei et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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I launched 1mile2go photography with a vision to capture intentional and candid moments for all projects I take on board. I enjoy experimenting in different photography styles and enjoy all facets. Currently I have been predominantly working on Portraits and Events.
I enjoy the emotions that can be captured, especially for special portraits and events.
Feel free to browse through my work and get in touch via provided social media links. I hope you like what you see as much as I enjoyed creating it with my clients.

domain: artistic


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Zach Galifianakis & Wife Quinn Lundberg Welcome Baby Number Two!
The couple welcomed their son Rufus Emmanuel Lundberg on November 7th but have been keeping the big news under wraps.
Zach and Quinn are already parents to a three-year-old little boy, but kept his arrival a secret too!
The parents didn’t share the news for over a year until Zach revealed they had welcomed a baby boy during a 2014 appearance on the Tonight Show Starring Jimmy Fallon.
Congratulations Zach and Quinn!!

domain: celebrity


Mechanical Project Manager
Strong Group are currently working with a leading specialist in providing ductwork ventilation services and they are currently seeking a Mechanical Project Manager to join their team.
Within this role as Mechanical Project Manager, you will be responsible for managing multiple ductwork installation projects throughout North east region.
Mechanical Project Manager resposibilities and experience required:
* Ideally from a ductwork background, but a solid AC/Mechanical background will be considered
* Experience in leading sub - contractors
* Reporting into a Operations Manager
* Overseeing the budgets for site
* Responsible for site teams
* Project values up to £1m
For more details, please apply!


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domain: literature


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Each product has been independently selected by our editorial team. We may receive commissions from some links to products on this page. Promotions are subject to availability and retailer’s terms.
With Marvel Studios’ Black Panther: Wakanda Forever premiering on November 11, 2022, LEGO celebrates the legacy of Chadwick Boseman’s portrayal of King T’Challa in the original 2018 movie with a life-size bust of 76215 Black Panther. At 2,961 pieces, the giant bust is the first of its kind for a LEGO Marvel theme, and you’ll be able to display it in either a standard pose or the very appropriate “Wakanda Forever” cross-arm pose.
Life-size LEGO 76215 Black Panther Bust will be available to order Starting tonight Sep 30 / Oct 1 at 9 PM PT / 12 AM EDT Here in the LEGO Store Priced at $349.99. When complete, the statue will measure 18 inches tall x 20 inches wide x 11 inches deep. It will be launched alongside several other large LEGO sets, including the 7411 Super Mario The Mighty Bowser.
As noted, the bust of Black Panther appears as a tribute to the late Chadwick Boseman before Wakanda Forever, who has the difficult task of continuing the story without him. Shuri Laetitia Wright is in the driver’s seat this time, and I spoke to her recently diverse On how the movie honors Boseman:
“It’s an incredible honor for Chadwick Boseman,” she said. “It’s a jam full of exciting stuff. In November, he couldn’t have come sooner, so I’m excited to see you guys.”
Wright continued: “We honored him with our commitment to the story he started, the legacy he started with this franchise, and we committed every day to working hard no matter what the circumstances we faced. We faced a lot of circumstances. A. A lot of difficult situations, but we came together as a team. We put everything in this movie.”
In “Black Panther: Wakanda Forever”, “In Marvel Studios”, Queen Ramonda (Angela Bassett), Shuri (Letitia Wright), M’Baku (Winston Duke), Okoye (Danai Gurira), Dora Milaje (including Florence Kasumba), fought to protect their nation from the interference of world powers in the wake of King T’Challa’s death. As the Wakandans strive to embrace their next chapter, the heroes must band together with the help of War Dog Nakia (Lupita Nyong’o) and Everett Ross (Martin Freeman) and forge a new path for the kingdom of Wakanda. The film stars Tenoch Huerta as Namor, the king of a nation hidden under the sea, and also stars Dominic Thorne, Michaela Cowell, Mabel Cadena, and Alex Livanale.
Black Panther: Wakanda Forever is scheduled for release on November 11, 2022. Ryan Coogler returns to direct Part Two and is also developing a new Marvel TV series for Disney+ that also takes place in the Wakanda universe. The film stars Lupita Nyong’o, Danai Gurira, Winston Duke, Letitia Wright, Angela Bassett, Dominique Thorne, Michaela Cole, Florence Kasumba, Tenoch Huerta and Martin Freeman.

domain: entertainment


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- Dashcam video of Lowe's truck crash going viral (7/26/17)1
- Chaffee City Council fires officer facing criminal charge (7/23/17)1
- Wreck flips Lowe's truck in Cape (7/25/17)4
- Major Case Squad seeks woman in connection with homicide investigation (7/26/17)
- Cape theater acts to eliminate bedbugs, closes one of its auditoriums (7/27/17)1
- More details emerge in Perryville police-misconduct case (7/21/17)
- Former Sikeston DPS director denies knowing about allegations against detective (7/20/17)1
- Jackson Homecomers begins Tuesday; new features planned (7/25/17)
- Book focuses on history of Briarwood Manor in Cape (7/23/17)
- Cape school board welcomes five administrators (7/25/17)
Tommy Sowers Puts His Boots on the Ground Again
This July, Tommy Sowers will be continuing a project he began in January: Boots on the Ground.
Earlier this year, Tommy and his dog Chuck traveled around the twenty-eight counties of Missouri's Eighth District, spending a day and a night in each. Tommy also conducted "workdays", working side-by-side with residents of many of the counties: he was a teacher in one, a bartender in another and a chicken-fryer in another.
Sowers will be packing the truck and putting his boots on the ground again in July, spending a day in each of the twenty-eight counties of Missouri's Eighth. In addition to meetings with voters and more workdays, Sowers will be conducting Town Halls to discuss voter concerns and to answer their questions.
Said Sowers Campaign Manager Jonathan Feifs, "Boots on the Ground wasn't just a one-time event for Tommy, it's a guiding principle of his entire campaign. He's going to be out on the road in the as much as possible between now and Election Day. The call for new blood in Washington is resonating with the people of the district and our campaign is building a formidable organization to win in November."
Sowers, an 11-year Army Special Forces veteran, is running for Congress against incumbent Jo Ann Emerson, a former insurance lobbyist from Washington, DC. Tommy Sowers is the Democratic candidate for Missouri's 8th Congressional district and does not face opposition in the primary. Emerson will face a Republican primary challenger, cattle rancher Bob Parker, in August.
The county schedule for Sowers in the 8th District is as follows:
3 St Francois
12 New Madrid

domain: politics


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Thanks, Reno Tahoe!
Ready to seize the day… and the night? Kayak all day and crowd surf all night in the city of no last call. Find inspiration and lose inhibition as you explore our city’s legendary nightlife. With events, concerts and much more happening every weekend, you won’t want to miss a thing. From rooftop craft brews to downtown dining, here you’ll elevate your night. Staying in is the only thing that’s off the table.
Reno Tahoe isn’t your basic vacation destination. It’s a collision of contrasts. This is where majestic mountains converge on high desert. Where wildlife meets urban grit. You can crowd surf all night and paddleboard all day. Support a start-up and down a craft brew. It’s where you can see, do and be near anything, as long as you’re fueled by ambition. So, what’s first?
If you’re looking for an awesome event to attend today, this weekend or in the coming months, look no further. The Reno Tahoe Events & Festivals brochure is chock-full of hundreds of unique, exciting and memorable experiences. Click on the image to browse the brochure.

domain: travel


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CARDIFF Council spent tens of thousands of pounds for the Lord Mayor to be driven to official engagements over the last year.
A freedom of information (FOI) request revealed that the council spent £21,321 on costs relating to relief chauffeurs in 2022/23. The council spent £7,410 on the same thing in 2021/22.
The FOI also revealed that the council spent £17,252 on vehicle hire/leasing for the mayoral car from 2021 to 2023. This includes maintenance charges such as servicing, MOT and tyres.
Cardiff Council has defended the amount spent on transporting the Lord Mayor, currently Councillor Graham Hinchey, saying the figures being quoted in the FOI response represent a tiny fraction of the Council’s overall net annual budget.
A spokesperson for Cardiff Council, said: “In line with the local authority’s commitment to sustainable transport, and for Cardiff to become a net zero carbon city, the Lord Mayor’s car is now an electric vehicle, having made the switch in July, 2022.
“In 2021/22, the number of official engagements for the Lord Mayor, and therefore the use of the official car, dropped significantly to 96, due to the Covid-19 pandemic.
“The number of official engagements, and car usage, in 2022/23 increased back to the levels broadly seen prior to the pandemic.”
Other information from the FOI revealed that £1,300 was spent on fuel costs from 2021 to 2023 (£890 in2021/22 and £410 in 2022/23) for the mayoral car. A total of £720 was spent on car insurance from 2021 to 2023.
Cardiff Council last month voted through a council tax increase and school meals price hike as it faces a £24 million budget gap for 2023/24.
The council spokesperson added: “In 2022/23, The Lord Mayor attended over 230 official engagements which required use of the Mayoral car, many of which are at the invitation of community projects, charities, schools and care homes.
“Alternative modes of transport would not be practical, given the number, scope and timings of these engagements. The Lord Mayor attended many more appointments on top of these official engagements.
“The Lord Mayor’s Chauffeur, and the electric car, ensure that the First Citizen of Cardiff and Consort arrive at their engagements on schedule, dressed in the appropriate civic regalia, which is of both historical and cultural significance, in a manner befitting the status of the office of The Rt Hon, The Lord Mayor of the City and County of Cardiff.
“In their role as First Citizen, the Lord Mayor is strictly politically neutral, with the role being rotated between parties, usually on an annual basis.
“The role of Lord Mayor brings significant value to the city, both in terms of the stature of the office, and the charitable work undertaken.
“The figures being quoted represent a tiny fraction of the Council’s overall net annual budget, and the costs associated with the office of Lord Mayor have reduced significantly over the years.”
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domain: news


text:
Urban Flats Builder sets focus on mid-rise market
Urban Flats Builder, an experienced real estate development firm, brings both residential and commercial building design expertise to Houston's mid-rise market.
The company enters the thriving Houston market by announcing several mid-rise developments centrally located in the sought-after Museum District.
The Caroline campus is comprised of three buildings, all on spacious corner lots surrounded by sprawling 100-year-old oak trees.
The buildings are at 4820 Caroline (Oaks on Caroline), 4802 Caroline (Ridge on Caroline), and 4810 Caroline (Park on Caroline).
Breaking ground soon is Museum Flats, the latest project positioned at 5717 Almeda. The building exteriors reflect the charm of the Texas Hill Country, while the interiors reflect a refined European aesthetic with an abundance of natural light.
Each single-level apartment flat offers residents a balcony to enjoy the park and city views. The units are steps away from the running trails and bike paths of Hermann Park, Houston light rail and 22 museums.
"Our intent during the design process of our developments is to limit the amount of HOA fees. Our association dues are much lower and more affordable. We have streamlined everything, including maintenance, to fit our residents' lifestyles perfectly," said David Antoniono, president of Infinity Texas Development.
The Urban Flats team also consists of experienced engineers, who dedicate their talents to attention to detail.
Urban Flats Builder is focused on quality, and buildings are made to last with cast-in-place concrete, which absorbs sound and affords a structure longevity, stability and integrity, Antoniono said.
"Urban Flats Builder is pioneering the way the industry delivers mid-rise construction based on our extensive commercial industrial experience," Antoniono said.
For more information, call Peek Realty at 713-527-PEEK.

domain: geography


text:
Stryker Rejuvenate & ABG II Lawsuits Consolidated in Multidistrict Litigation
U.S. District Judge Donovan W. Frank will be overseeing all federal lawsuits against Stryker Orthopaedics alleging injuries and permanent disability from the recalled Rejuvenate and ABG II hip replacements. The Judicial Panel on Multidistrict Litigation (JPML) has agreed to transfer almost 50 cases to the U.S. District Court for the District of Minnesota for coordinated pretrial proceedings.
The newly established products liability multidistrict litigation (MDL) will assist in conserving judicial resources and time, by centralizing plaintiffs with common allegations and issues of fact under one court.
While MDL is a positive step for plaintiffs in that it promotes efficiency (discovery is coordinated; litigation strategies are organized), it may still be years before anyone sees resolution to their claims. Before bellwether trials are selected as representative cases, attorneys must gather evidence, depose witnesses and complete all discovery processes to present to the presiding judge. Even if a jury hands down a verdict in favor of the plaintiff, Stryker will likely appeal – delaying those much needed funds for that much longer.
In the meantime, plaintiffs may be dealing with rising medical bills and other financial strains associated with a defective hip replacement. Many have lost their jobs and required rehabilitative therapy following hip revision surgery.
Rather than settle prematurely for a lesser amount, plaintiffs may opt for a pre settlement cash advance to tide them over until their case is won or settled. With the assistance of Stryker hip lawsuit loans, plaintiffs can leave their financial worries behind and focus on their recovery and future litigation.
Stryker hip recall prompts wave of lawsuits
Stryker Rejuvenate and ABG II modular-neck stem hip systems were approved by the FDA in 2008 and 2009 for use in total hip arthroplasty. The company promoted the systems as a safer alternative to traditional metal-on-metal hip implants, which had been linked to severe complications and early failure rates. However, the two piece femoral neck and stem components were both comprised of metal, that when implanted, were prone to fretting metal ions as the parts rubbed together. Recipients of the devices began complaining of unexplained pain, swelling and difficulty walking or standing for long periods. The majority were forced to endure hip revision surgery to remove the implant and replace it with another prosthetic.
In July 2012, Stryker mandated a voluntary recall for both the ABG II and Rejuvenate hip implants, stating that design flaws made both prone to fretting and corrosion, leading to adverse tissue reactions among patients.
Common complications associated with the Stryker hip replacements include:
- Chronic pain
- Metallosis – a form of metal poisoning
- Pseudotumor formation
- Tissue damage
- Tissue death (necrosis)
- Bone loss
- Premature loosening
- Device failure requiring revision surgery
The Stryker hip recall ultimately prompted litigation against the manufacturer with plaintiffs demanding damages for:
- Past, present and future medical costs including those for hip revision surgery
- Lost income
- Diminished earning capacity
- Pain and suffering
- Punitive damages to punish and deter future similar conduct
Risk free cash advance for your pending lawsuit
With the recent establishment of Stryker hip multidistrict litigation, plaintiffs may see a light at the end of the tunnel. But, as with most cases alleging injuries from medical devices, litigation can be prolonged and expensive.
That’s where Stryker hip pre settlement funding can help: a cash advance that is granted based on your predicted pretrial settlement or court award. For those who need an immediate influx of cash to help with legal fees, court costs, hospital bills, rent, or car payments, LawStreet Capital has a risk-free solution.
Apply for Stryker hip lawsuit loans today
If you have a pending claim against Stryker Othopaedics but need financial assistance today, contact LawStreet Capital to learn how Stryker hip lawsuit loans can benefit you. With our risk-free legal funding services, you won’t have to rely on high interest bank loans or credit cards. We assume all risk, since your cash advance is non-recourse. That means you only pay back the balance if you secure compensation in your case. To apply, call 1.866.FUND.662

domain: law


text:
The Slavic peoples lived in close contact with the Byzantines. This constant interaction had a strong influence on the Slavs. By 1453 A.D., when the Byzantine Empire was conquered and destroyed, the Slavs shared many aspects of their culture, including their language, religion, government styles, and many of their traditions.
With the Byzantines now gone, the Slavs became the guardians of the Eastern Orthodox faith. These religious practices would be handed down from generation to generation until the present day.
A pessimist sees the difficulty in every opportunity; an optimist sees the opportunity in every difficulty.
Sir Winston Churchill
In A.D 1349 to upgrade the fighting skill of the peasantry, King Edward III of England banned all sports in his country save one--archery.

domain: history


text:
To complicate the issue further, many women are not comfortable disclosing information about their sex life. Just like men, women may be too proud or too ashamed to admit that they may be experiencing sexual dysfunction. Everyone should feel empowered to make their own choices when it comes to your sex life. Sexual dissatisfaction may even lead to relationship issues.
Dr. Sodhi will treat all causes of sexual dysfunction and may recommend hormone replacement therapy or sex therapy. ThermiVa is a non-hormonal, non-surgical treatment that can increase clitoral sensitivity if administered properly.

domain: medical


A Politico/Morning Consult poll released on Wednesday shows 52 percent of voters approve of President Donald Trump’s job performance, but that statistic is in the second-to-last paragraph of the Politico article about the poll.
The article states:
Public opinion of the new health care proposal is limited thus far, though the POLITICO/Morning Consult poll does show less fervent opposition to the bill than a SurveyMonkey poll of adult Americans released on Tuesday.
Similarly, the Politico/Morning Consult survey also shows more positive opinions of the job Trump is doing as president. In the new poll, 52 percent of voters approve of Trump’s job performance, more than the 43 percent who disapprove. But, on balance, most polls show more disapprove than approve of the job Trump is doing.
Politico chose instead for its article, entitled “Poll: Voters Wary of GOP Health Care Bill,” to lead with the divide among voters on approval of the GOP’s American Health Care Act:
Nearly half of voters support the new Republican health care bill but the elements they like best are holdovers from the Affordable Care Act, according to a new Politico/Morning Consult poll.
The new survey — conducted in the days following release of the bill by House GOP leaders — underscores the political thicket that President Donald Trump and congressional Republicans face in taking on the issue. While Americans are open to the GOP proposal, there is pessimism that rolling back Obamacare will improve quality, price and coverage.
Overall, 46 percent of voters approve of the GOP health care proposal, more than the 35 percent who disapprove. Nineteen percent of voters say they don’t have an opinion of the bill.
But any support is shallow: Only 4-in-10 voters say they either ‘strongly approve’ or ‘strongly disapprove’ of the bill, with strong disapproval (22 percent) slightly outpacing strong approval (18 percent).
“Given the wave of criticism from both parties following the rollout of the bill, this is a relatively strong starting point for GOP leaders and the White House,” Kyle Dropp, Morning Consult’s co-founder and chief research officer, is quoted as saying in the article. “However, it will be important to track how public opinion stands up as more information is released in the coming weeks.”
The article notes that the poll was conducted before the Congressional Budget Office released its score of the GOP bill, “but voters were already leaning toward doubt that the House GOP bill would increase the number of Americans on the rolls: Only a quarter thought more Americans would have insurance, fewer than the 38 percent who thought fewer Americans would be enrolled.”
The Politico/Morning Consult poll surveyed 1,983 registered voters and has a margin of error of plus or minus two percentage points.
“Morning Consult is a nonpartisan media and technology company that provides data-driven research and insights on politics, policy and business strategy,” the article’s tag states.


text: If humanity is to avoid the unmanageable and manage the unavoidable of climate change, we must pursue the best options available. FMNR certainly seems to be one of them, at least for the poorest members of the human family. "Let's look at what's already been achieved in Africa and build on that," urged Reij. "In the end, what happens in Africa will depend on what Africans do, so they must own the process. For our part, we must realize that farmers in Africa know a lot, so there are things we can learn from them as well."

domain: sociology


Moyo Drums are the finest quality handmade steel tongue drums available. Each drum is made by hand with no heat applied, which can alter the sound of these types of instruments. We seek for the best sound quality through our manufacturing process and our sound dampening yarn band. Most of these drums have pentatonic tuning so all the notes sound great together. We also make drums inspired Hang Drum Integral scales. All Moyo Drum scales are related to pentatonic scales in A-440 tuning that play beautifully with western instruments, especially Native American Style flutes.
New! Yami Drum, the Moyo Drum little sister. Only 9” diameter and only 5 lbs, very portable! Plays extremely easily by hand, but can be played with the rubber ball sticks, included with this style. No need for a table stand, rubber feet added to the bottom of the drum. Small size and our higher tones return! Available in F#, Gm and High Am.
For videos and more info Click Here
Dhavani Drums are steel tongue drums, hand made from the same high quality materials and care as the Moyo Drums but are designed with alternative tunings with specific spiritual and therapeutic qualities. These drums are best used for yoga, meditation, relaxation, Chakra healing or Music Therapy.


text:
Le Duc Veggie will be present with a new stand at the international fair Anuga in Cologne from 9 -13 October.
There we will receive our customers and introduce a new vegetarian finger food concept: Veggie Fries.
We look forward to welcome you in Hall 4.2 on D-060.
Ik ga akkoord met het privacy beleid *
* Verplicht veld
For years, Le Duc has been making veggie appetizers with what nature gives us. Why that’s the most important, we show in our new brand movie. Especially for foodservice buyers we immediately give inspiration which dishes you can create and present with it to your customers.

domain: food


text:
Glostrup a. This page was last edited on 7 Mayat Hidden categories: Alphabetocal also city ; urban planning. Filter by starting letters of Frederikshavn journal classifieds online city cities: See Article History.
Namespaces Article Talk. Folketal 1. The city was founded as a fortified Viking settlement in the 8th century. This page was last changed on 22 Aprilat Fredericia  . DKISO3:This article shows a list of cities in Denmark by population.
The population is measured by Statistics Denmark  for urban areas Danish: Smaller settlements are by Danmarks Statistik included in numbers for rural areas landdistrikter.
Media related to Populated places in Denmark at Wikimedia Commons. From Esbjer, the free encyclopedia. For conurbations as well as cities, see List of urban areas in Denmark by population.
Folketal 1. Siden 1.
The Five Biggest Cities In Denmark
List of cities in Europe. List of towns in Europe.
Part of the Kingdom of Denmark. Coat of arms Flag National civic anthem Royal anthem. Outline Index. Retrieved from " https: Cities and towns in Denmark Lists of populated places in Denmark Lists of cities in Scandinavia Lists of cities by country. Hidden categories: All articles with failed verification Articles with failed verification from October Commons category link is locally defined. Namespaces Article Talk.
Views Read Edit View history. In other projects Wikimedia Commons.
This page was last edited on 7 Mayat This article shows a list of cities in Denmark by population. The population is measured by 5, Esbjerg,,,, 0,37%. 6, Randers, For more details, find city below this text. Continent: Europe. Not full list!
Only 50 largest cities in alphabetical order: Aabenraa Esbjerg (South Denmark).,(See alphabetical odder Arctic Ocean, pelagic sediments, Erman Suite, Esbjerg City, Denmark, Etchegoin, Formation, ❶Randers  .
See Article History.
This article shows a list of cities in Denmark by population. Sankt Klemens.
Copenhagen Languages: Denmark on map. Siden 1.
List of cities in Denmark Esbjerg
Esbmerg end of May Aalborg Festival is one of the biggest festivals held in the Scandinavian region. Holstebro  . Info Print Print. Copenhagen . Not full list! Table Of Contents.|International ICC network. National ICC networks: Cities participating in Intercultural cities Index.
You are here: ICC Networks. Twitter Facebook. Contact us.]


text:
The Princess Bride 2007 Horror Movie Review
Horror movies Review
From celebrated director Rob Reiner (When Harry Met Sally) and OscarÂ(r)-winning* screenwriter William Goldman (Chaplin) comes “an enchanting fantasy” (Time) filled with adventure, romance and plenty of “good-hearted fun” (Roger Ebert)! Featuring a spectacular cast thatincludes Robin Wright (Forrest Gump), Cary Elwes (Liar, Liar), Mandy Patinkin (Dick Tracy) and Billy Crystal (City Slickers), this wonderful fairy tale about a Princess named Buttercup and her beloved is “a real dream of a movie” (People)! *1969: OriginalScreenplay, Butch Cassidy and the Sundance Kid 1976: Adapted Screenplay, All the President’s Men
About The Princess Bride (2007)
The Princess Bride
Cary Elwes, Mandy Patinkin, Chris Sarandon, Christopher Guest, Wallace Shawn,
Rating: 3 / 5 stars from 5 users.
PG (Parental Guidance Suggested)Runtime:
98 minutesDirector: Rob Reiner,
Cool Posts From Around the Web:
Related The Princess Bride News
Check out the synopsis and full details for Kill For Me starring hot girls Katie Cassidy and Tracy Spiridakos. We have the artwork, press release, synopsis and special features for this upcoming horror home video.
Ivan Zuccon, Italian filmmaker who also made Colour From the Dark and Nympha will now be starting pre production on Wrath of the Crows. Directing will be Ivan Zuccon and Roberta Marrelli and a screenplay from both Zuccon and Gerardo Di Filippo. Starring Debbie Rochon and Tiffany Shepis.
The Mortal Instruments: City of Bones hits Blu-ray/DVD on December 3, 2013. The special features look pretty good including an interactive way for the viewer to learn about the characters lineage, lots of documentary type features, deleted scenes and the music video for the film. I love it when the…
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Ivan Sivak - SOFTWARE
Check of messages on the POP3 server with ability to delete message from the server, without urgency to download it. It is possible to apply simple Spam filter. SSL is supported. Guards specified e-mail boxes and is announcing new incoming messages. E-Mail guard is a shareware developed by Ivan Sivak - SOFTWARE and listed in communications other e-mail tools software.
Version: 3.02 Released: 4/12/2009
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Download Link: Download
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text:
A panel that includes patients, clinicians, and methodologists create a new set of recommendations for treating gastrointestinal bleeding prophylaxis.
A new set of recommendations for treating critically ill patients with gastrointestinal bleeding prophylaxis call for the use of proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs), despite an increased risk of pneumonia.
Zhikang Ye, Department of Pharmacy, Beijing Chaoyang Hospital, Capital Medical University, led a panel that included patients, clinicians, and methodologists that developed recommendations using standards for trustworthy guidelines and the GRADE approach, a systematic technique to rating the certainty of evidence in systematic reviews and other evidence syntheses.
The new recommendations are based on a linked systematic and network meta-analysis. A weak recommendation means that both options are reasonable.
One of the recommendations in the new guideline is the suggestion on using acid suppression for people with higher risk of gastrointestinal bleeding—4% or higher.
The second new recommendation is for critically ill patients who are going to receive prophylaxis against gastrointestinal bleeding to use a PPI or H2RA. However, they do not suggest using sucralfate for this patient population.
“The panel identified risk categories based on evidence, with variable certainty regarding risk factors,” the authors wrote. “The panel suggests using a PPI rather than a H2RA (weak recommendation) and recommends against using sucralfate (strong recommendation).”
While gastric acid suppression with proton pump inhibitors or histamine-2 receptor antagonists are commonly done to prevent gastrointestinal bleeding in critically ill patients, existing guidelines vary in their recommendations to which population to treat and which agent to use.
“This guideline panel makes a weak recommendation for using gastrointestinal bleeding prophylaxis in critically ill patients at high risk (>4%) of clinically important gastrointestinal bleeding, and a weak recommendation for not using prophylaxis in patients at lower risk of clinically important bleeding (≤4%),” the authors wrote.
The new guidelines are a direct result of the publication of a new large, randomized controlled study involving 12,660 critically ill patients in 72 trials. The investigators found reviewing 12,660 critically ill patients in 72 trials that both treatments—PPIs and H2RAs—reduce the risk of clinically important bleeding.
They also found with moderate certainty that the effect is larger in patients at higher bleeding risk—those with a coagulopathy, chronic liver disease, or receiving mechanical ventilation but not enteral nutrition or two or more of mechanical ventilation with enteral nutrition, acute kidney injury, sepsis, and shock.
However, these medicines may also increase the risk of pneumonia (low certainty) and probably do not have an effect on mortality (moderate certainty), length of hospital stays, or other relevant outcomes. PPIs likely reduce the risk of bleeding more than H2RAs (moderate certainty).
“In most critically ill patients, the reduction in clinically important gastrointestinal bleeding from gastric acid suppressants is closely balanced with the possibility of pneumonia,” the authors wrote. “Clinicians should consider individual patient values, risk of bleeding, and other factors such as medication availability when deciding whether to use gastrointestinal bleeding prophylaxis.”
On average, 4% of critically ill patients develop gastrointestinal bleeding, with a leading causing being physiologic stress that cause stress ulcers in the esophagus, stomach or duodenum. Critical illness is also linked with other forms of upper gastrointestinal bleeding.
The study, “Gastrointestinal bleeding prophylaxis for critically ill patients: a clinical practice guideline,” was published online in The BMJ.

domain: health


text:
This series is meant to paint a realistic, well-sourced and objective portrait of American health care early in the 21st century as compared with that of our 29 partners in the Organization for Economic Cooperation and Development (OECD, all of us comprising the most developed democracies in the world), and to examine how workers’ compensation fits into that mix. We’ve done a lot of the former and some of the latter. Now it’s time to finish the job.
First, a bullet-point recap. In Parts One through Four we saw that:
- American per capita health care spending is two and a half times the average in the OECD and 25% higher than our closest competitor, Switzerland.
- American per capita health care spending on pharmaceuticals is double that of the average in the OECD.
- We perform more sophisticated testing and surgeries than any other country.
- Our physicians earn double the compensation of their OECD counterparts.
- Our hospital stays are 25% shorter and our doctor visits 42% fewer than other OECD citizens.
- Despite all the spending, we don’t live longer and are no healthier than the average among OECD countries.
- There has been explosive growth in the incidence of Type 2 Diabetes, much of it caused by an epidemic of obesity, and 27% of the per capita increase in our spending on health care since 1987 is attributable to obesity.
- At nearly 31%, the percentage of obese adults in the US is the highest in the OECD and 25% higher than Mexico, the country that wins obesity’s OECD silver medal, yet we been unable either to halt or reverse the growth of obesity in America.
- Thirty-one percent of our total health care expenditures go toward insurance administrative costs, far more than any other OECD country.
Meanwhile, over on the workers’ comp side of things…
It is indisputable that health care costs in America far exceed those for any other OECD country and have been sharply and steadily rising over the last 20 years. Bleak as that portrait is, the situation with health care costs in workers compensation is even more dire:
- Since 1996, worker’ compensation medical treatment costs, representing only 3% – 4% of total US spending on health care, have been rising at twice the rate of those sharply and steadily rising group health costs.
- We spend significantly more to treat worker injuries than similar injuries in group health, principally because of over-utilization of medical services.
- Pharmaceutical costs, representing 18% of total incurred losses at the fifth service year, are a large chunk of the ice beneath the water line, the costs that are often hidden and unknowable (When have you ever seen prescription drugs itemized on a loss run?). If you are an employer, ask yourself these questions: Do you have any idea of the prescription drugs your injured workers are taking? Do you have any idea of the extent to which your injured workers are being prescribed narcotics, such as OxyContin, Actiq, Fentora, Duragesic, even Vicodin? If not, you need to have an immediate talk with your insurer and your Pharmacy Benefit Manager. It’s that important.
None of us can do much about the ridiculous costs of health care in America today. To quote Hercule Poirot, the problem is “a many-headed Hydra.” But employers and insurers can do something about the ridiculous costs of health care in workers’ compensation. What, you say?
At the end of this five-part series, here is a conclusion and a modest proposal, which to many will seem trite, even pedestrian, but 24 years working with more than 4,000 clients guarantees it works:
Conclusion: medical costs grow as indemnity costs grow, because injured workers stay out of work longer than is medically necessary.
The modest proposal: A caring, aggressive, systemic, performance-oriented and measured program that focuses on a) preventing injuries from occurring in the first place and b) if injuries do occur despite your best efforts, bringing injured employees back to work in some medically approved capacity of temporary modified duty as quickly as possible. This early return to work will keep injured workers connected to the workplace and the ingrained routine of getting up, getting dressed and going to work every day. Absent that, the injured worker will stay at home where he or she will create a new routine of staying out of work and making up his or her own, stay-at-home modified duty program. If I were injured and could not go to work because my employer had nothing for me to do, that’s what I would do, and so would you. And that does not have to happen.
It’s a lot of work, but it’s as simple as that.
I’ve enjoyed writing this series. I hope it’s given you something to think about.