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Cancer immunotherapy
|It has been suggested that Cancer immunology be merged into this article. (Discuss) Proposed since October 2016.
Cancer immunotherapy is the use of the immune system to treat cancer. Immunotherapies can be categorized as active, passive or hybrid (active and passive). These approaches exploit the fact that cancer cells often have molecules on their surface that can be detected by the immune system, known as tumour-associated antigens (TAAs); they are often proteins or other macromolecules (e.g. carbohydrates).
Active immunotherapy directs the immune system to attack tumor cells by targeting TAAs. Passive immunotherapies enhance existing anti-tumor responses and include the use of monoclonal antibodies, lymphocytes and cytokines.
Among these, multiple antibody therapies are approved in various jurisdictions to treat a wide range of cancers. Antibodies are proteins produced by the immune system that bind to a target antigen on the cell surface. The immune system normally uses them to fight pathogens. Each antibody is specific to one or a few proteins. Those that bind to tumor antigens treat cancer. Cell surface receptors are common targets for antibody therapies and include CD20, CD274 and CD279. Once bound to a cancer antigen, antibodies can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, or prevent a receptor from interacting with its ligand, all of which can lead to cell death. Approved antibodies include alemtuzumab, ipilimumab, nivolumab, ofatumumab and rituximab.
Active cellular therapies usually involve the removal of immune cells from the blood or from a tumor. Those specific for the tumor are cultured and returned to the patient where they attack the tumor. Cell types that can be used in this way are natural killer cells, lymphokine-activated killer cells, cytotoxic T cells and dendritic cells. The only US-approved cell-based therapy is Dendreon's Provenge, for the treatment of prostate cancer.
Interleukin-2 and interferon-α are cytokines, proteins that regulate and coordinate the behaviour of the immune system. They have the ability to enhance anti-tumor activity and thus can be used as passive cancer treatments. Interferon-α is used in the treatment of hairy-cell leukaemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and malignant melanoma. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma.
- 1 History
- 2 Cellular immunotherapy
- 3 Antibody therapy
- 3.1 Antibody types
- 3.2 Cell death mechanisms
- 3.3 FDA-approved antibodies
- 4 Cytokine therapy
- 5 Polysaccharide-K
- 6 Research
- 7 See also
- 8 References
- 9 External links
Immunotherapy began in 1796 when Edward Jenner produced the first vaccine involving immunisation with cowpox to prevent smallpox. Towards the end of the 19th century Emil von Behring and Shibasaburō Kitasato discovered that injecting animals with diphtheria toxin produced blood serum with antitoxins to it.
Paul Ehrlich's research gave rise to the "magic bullet" concept; using antibodies to specifically target a disease. The production of pure monoclonal antibodies for therapeutic use became available in 1975 when Georges J. F. Köhler and Cesar Milstein produced hybridoma technology.
Immuno cell therapy for cancer was introduced by Rosenberg and colleagues. In the late 1980s, they reported a low tumor regression rate (2.6–3.3%) in 1205 patients with metastatic cancer who underwent different types of active specific immunotherapy.[1]
In 1987, researchers identified cytotoxic T-lymphocyte antigen 4, or CTLA-4. Allison found that CTLA-4 prevents T cells from attacking tumor cells. He wondered whether blocking CTLA-4 would allow the immune system to make those attacks. In 1996, Allison showed that antibodies against CTLA-4 allowed the immune system to destroy tumors in mice.[2] In 1999, biotech firm Medarex acquired rights to the antibody. In 2010, Bristol-Myers Squibb, who acquired Medarex in 2009, reported that patients with metastatic melanoma lived an average of 10 months on the antibody, versus 6 months without it. It was the first time any treatment had extended life in advanced melanoma in a randomized trial.[2]
In the early 1990s, a biologist discovered a molecule expressed in dying T cells, which he called programmed death 1, or PD-1 and which he recognized as another disabler of T cells. An antibody that targeted PD-1 was developed and by 2008 produced remission in multiple subjects across multiple cancer types. In 2013, clinicians reported that across 300 patients tumors shrunk by about half or more in 31% of those with melanoma, 29% with kidney cancer and 17% with lung cancer.[2]
In 1997 rituximab, the first antibody treatment for cancer, was approved by the FDA for treatment of follicular lymphoma. Since this approval, 11 other antibodies have been approved for cancer; alemtuzumab (2001), ofatumumab (2009) and ipilimumab (2011).
In 2003 cytokines such as interleukin were administered.[3] The adverse effects of intravenously administered cytokines[4] led to the extraction, in vitro expansion against a tumour antigen and reinjection of the cells[5] with appropriate stimulatory cytokines.
However, with both anti–CTLA-4 and anti–PD-1, some tumors continued to grow before vanishing months later. Some patients kept responding after the antibody had been discontinued. Some patients, developed side effects including inflammation of the colon or of the pituitary gland.[2]
The first cell-based immunotherapy cancer vaccine, sipuleucel-T, was approved in 2010 for the treatment of prostate cancer.[6][7]
After success harvesting T cells from tumors, expanding them in the lab and reinfusing them into patients reduced tumors, in 2010, Steven Rosenberg announced chimeric antigen receptor therapy, or CAR therapy. This technique is a personalized treatment that involves genetically modifying each patient's T cells to target tumor cells. It produced complete remission in a majority of leukemia patients, although some later relapsed.[2]
By mid 2016 the FDA had approved one PD-L1 inhibitor (atezolizumab) and two PD-1 inhibitors (nivolumab and pembrolizumab).
Cellular immunotherapy[edit]
Dendritic cell therapy[edit]
Dendritic cell therapy provokes anti-tumor responses by causing dendritic cells to present tumor antigens to lymphocytes, which activates them, priming them to kill other cells that present the antigen. In cancer treatment they aid cancer antigen targeting.[8] The only approved cellular cancer therapy is sipuleucel-T.
One method of inducing dendritic cells to present tumor antigens is by vaccination with autologous tumor lysates[9] or short peptides (small parts of protein that correspond to the protein antigens on cancer cells). These peptides are often given in combination with adjuvants (highly immunogenic substances) to increase the immune and anti-tumor responses. Other adjuvants include proteins or other chemicals that attract and/or activate dendritic cells, such as granulocyte macrophage colony-stimulating factor (GM-CSF).
Dendritic cells can also be activated in vivo by making tumour cells express GM-CSF. This can be achieved by either genetically engineering tumor cells to produce GM-CSF or by infecting tumor cells with an oncolytic virus that expresses GM-CSF.
Another strategy is to remove dendritic cells from the blood of a patient and activate them outside the body. The dendritic cells are activated in the presence of tumor antigens, which may be a single tumor-specific peptide/protein or a tumor cell lysate (a solution of broken down tumor cells). These cells (with optional adjuvants) are infused and provoke an immune response.
Dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic cell receptors such as TLR3, TLR7, TLR8 or CD40 have been used as antibody targets.[8]
Sipuleucel-T (Provenge) is the only approved cancer vaccine. It was approved for treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer in 2010. The treatment consists of removal of antigen-presenting cells from blood by leukapheresis and growing them with the fusion protein PA2024 made from GM-CSF and prostate-specific prostatic acid phosphatase (PAP) and reinfused. This process is repeated three times.[10][11][12][13]
Antibody therapy[edit]
Antibodies are a key component of the adaptive immune response, playing a central role in both recognizing foreign antigens and stimulating an immune response. Many immunotherapeutic regimens involve antibodies. Monoclonal antibody technology raises antibodies against specific antigens, such as those present on tumor surfaces.
Antibody types[edit]
Two types are used in cancer treatments:[14]
- Naked monoclonal antibodies are antibodies without added elements. Most antibody therapies use this antibody type.
- Conjugated monoclonal antibodies are joined to another molecule, which is either cytotoxic or radioactive. The toxic chemicals are those typically used as chemotherapy drugs, but other toxins can be used. The antibody binds to specific antigens on cancer cell surfaces, directing the therapy to the tumor. Radioactive compound-linked antibodies are referred to as radiolabelled. Chemolabelled or immunotoxins antibodies are tagged with chemotherapeutic molecules or toxins, respectively.[15]
Human/non-human balance[edit]
Antibodies are also referred to as murine, chimeric, humanized and human. Murine antibodies are from a different species and carry a risk of immune reaction. Chimeric antibodies attempt to reduce murine antibodies' immunogenicity by replacing part of the antibody with the corresponding human counterpart, known as the constant region. Humanized antibodies are almost completely human; only the complementarity determining regions of the variable regions are derived from murine sources. Human antibodies have completely human DNA.[15]
Cell death mechanisms[edit]
Antibody-dependent cell-mediated cytotoxicity (ADCC)[edit]
Antibody-dependent cell-mediated cytotoxicity (ADCC) requires antibodies to bind to target cell surfaces. Antibodies are formed of a binding region (Fab) and the Fc region that can be detected by immune system cells via their Fc surface receptors. Fc receptors are found on many immune system cells, including natural killer cells. When natural killer cells encounter antibody-coated cells, the latter's Fc regions interact with their Fc receptors, releasing perforin and granzyme B to kill the tumor cell. Examples include Rituximab, Ofatumumab and Alemtuzumab. Antibodies under development have altered Fc regions that have higher affinity for a specific type of Fc receptor, FcγRIIIA, which can dramatically increase effectiveness.[16][17]
The complement system includes blood proteins that can cause cell death after an antibody binds to the cell surface (the classical complement pathway, among the ways of complement activation). Generally the system deals with foreign pathogens, but can be activated with therapeutic antibodies in cancer. The system can be triggered if the antibody is chimeric, humanized or human; as long as it contains the IgG1 Fc region. Complement can lead to cell death by activation of the membrane attack complex, known as complement-dependent cytotoxicity; enhancement of antibody-dependent cell-mediated cytotoxicity; and CR3-dependent cellular cytotoxicity. Complement-dependent cytotoxicity occurs when antibodies bind to the cancer cell surface, the C1 complex binds to these antibodies and subsequently protein pores are formed in the cancer cell membrane.[18]
FDA-approved antibodies[edit]
|Brand name
|Approval date
|Approved treatment(s)
|B-cell chronic lymphocytic leukemia (CLL)[20]
|bladder cancer [21]
|metastatic melanoma[22]
|refractory CLL[23]
|ligand activation of the programmed cell death 1 (PD-1) receptor on activated T cells
|unresectable or metastatic melanoma, squamous non-small cell lung cancer[24]
|programmed cell death 1 (PD-1) receptor
|metastatic melanoma[24]
|Rituxan, Mabthera
|non-Hodgkin lymphoma[25]
Alemtuzumab (Campeth-1H) is an anti-CD52 humanized IgG1 monoclonal antibody indicated for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, peripheral T-cell lymphoma and T-cell prolymphocytic leukemia. CD52 is found on >95% of peripheral blood lymphocytes (both T-cells and B-cells) and monocytes, but its function in lymphocytes is unknown. It binds to CD52 and initiates its cytotoxic effect by complement fixation and ADCC mechanisms. Due to the antibody target (cells of the immune system) common complications of alemtuzumab therapy are infection, toxicity and myelosuppression.[27][28][29]
Ipilimumab (Yervoy) is a human IgG1 antibody that binds the surface protein CTLA4. In normal physiology T-cells are activated by two signals: the T-cell receptor binding to an antigen-MHC complex and T-cell surface receptor CD28 binding to CD80 or CD86 proteins. CTLA4 binds to CD80 or CD86, preventing the binding of CD28 to these surface proteins and therefore negatively regulates the activation of T-cells.[30][31][32][33]
Active cytotoxic T-cells are required for the immune system to attack melanoma cells. Normally inhibited active melanoma-specific cytotoxic T-cells can produce an effective anti-tumor response. Ipilumumab can cause a shift in the ratio of regulatory T-cells to cytotoxic T-cells to increase the anti-tumor response. Regulatory T-cells inhibit other T-cells, which may benefit the tumor.[30][31][32][33]
Ofatumumab is a second generation human IgG1 antibody that binds to CD20. It is used in the treatment of chronic lymphocytic leukemia (CLL) because the cancerous cells of CLL are usually CD20-expressing B-cells. Unlike rituximab, which binds to a large loop of the CD20 protein, ofatumumab binds to a separate, small loop. This may explain their different characteristics. Compared to rituximab, ofatumumab induces complement-dependent cytotoxicity at a lower dose with less immunogenicity.[34][35]
Rituximab is a chimeric monoclonal IgG1 antibody specific for CD20, developed from its parent antibody Ibritumomab. As with ibritumomab, rituximab targets CD20, making it effective in treating certain B-cell malignancies. These include aggressive and indolent lymphomas such as diffuse large B-cell lymphoma and follicular lymphoma and leukaemias such as B-cell chronic lymphocytic leukaemia. Although the function of CD20 is relatively unknown, CD20 may be a calcium channel involved in B-cell activation. The antibody's mode of action is primarily through the induction of ADCC and complement-mediated cytotoxicity. Other mechanisms include apoptosis[clarification needed] and cellular growth arrest. Rituximab also increases the sensitivity of cancerous B-cells to chemotherapy.[36][37][37][38][39][40]
Cytokine therapy[edit]
Cytokines are proteins produced by many types of cells present within a tumor. They can modulate immune responses. The tumor often employs them to allow it to grow and reduce the immune response. These immune-modulating effects allow them to be used as drugs to provoke an immune response. Two commonly used cytokines are interferons and interleukins.[41]
Interferons are produced by the immune system. They are usually involved in anti-viral response, but also have use for cancer. The fall in three groups: type I (IFNα and IFNβ), type II (IFNγ) and type III (IFNλ). IFNα has been approved for use in hairy-cell leukaemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and melanoma. Type I and II IFNs have been researched extensively and although both types promote anti-tumor immune system effects, only type I IFNs have been shown to be clinically effective. IFNλ shows promise for its anti-tumor effects in animal models.[42][43]
Interleukins have an array of immune system effects. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma. In normal physiology it promotes both effector T cells and T-regulatory cells, but its exact mechanism of action is unknown.[41][44]
Japan's Ministry of Health, Labour and Welfare approved the use of polysaccharide-K extracted from the mushroom, Coriolus versicolor, in the 1980s, to stimulate the immune systems of patients undergoing chemotherapy. It is a dietary supplement in the US and other jurisdictions.[45]
Adoptive T-cell therapy[edit]
Adoptive T-cell therapy is a form of passive immunization by the transfusion of T-cells. They are found in blood and tissue and usually activate when they find foreign pathogens. Specifically they activate when the T-cell's surface receptors encounter cells that display parts of foreign proteins on their surface antigens. These can be either infected cells, or antigen presenting cells (APCs). They are found in normal tissue and in tumor tissue, where they are known as tumor infiltrating lymphocytes (TILs). They are activated by the presence of APCs such as dendritic cells that present tumor antigens. Although these cells can attack the tumor, the environment within the tumor is highly immunosuppressive, preventing immune-mediated tumour death.[46]
Multiple ways of producing and obtaining tumour targeted T-cells have been developed. T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. Subsequent activation and culturing is performed ex vivo, with the results reinfused. Activation can take place through gene therapy, or by exposing the T cells to tumor antigens. Although research has made major advances in this form of therapy, no adoptive T-cell therapy is as yet approved.[46][47]
As of 2014, multiple ACT clinical trials were underway.[48][49][50][51][52]
Another approach is adoptive transfer of haploidentical γδ T cells or NK cells from a healthy donor. The major advantage of this approach is that these cells do not cause GVHD. The disadvantage is frequently impaired function of the transferred cells.[53]
Anti-CD47 antibodies[edit]
Anti-CD47 antibodies, which block the protein CD47 from telling the cancer host's immune system not to attack it, have been shown to eliminate or inhibit the growth of multiple cancers and tumors in laboratory tests on cells and mice. CD47 is present on many cancer cells and on many healthy cells. After the cancer cells have been engulfed by macrophages, the host immune system's CD8+ T Cells become mobilized against the tumor and attack it.[54]
Anti-GD2 antibodies[edit]
Carbohydrate antigens on the surface of cells can be used as targets for immunotherapy. GD2 is a ganglioside found on the surface of many types of cancer cell including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas. It is not usually expressed on the surface of normal tissues, making it a good target for immunotherapy. As of 2014, clinical trials were underway.[55]
Immune checkpoints[edit]
|It has been suggested that this section be split out into another article. (Discuss) (August 2015)
Immune checkpoints affect immune system functioning. Immune checkpoints can be stimulatory or inhibitory. Tumors can use these checkpoints to protect themselves from immune system attacks. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function.[56] One ligand-receptor interaction under investigation is the interaction between the transmembrane programmed cell death 1 protein (PDCD1, PD-1; also known as CD279) and its ligand, PD-1 ligand 1 (PD-L1, CD274). PD-L1 on the cell surface binds to PD1 on an immune cell surface, which inhibits immune cell activity. Among PD-L1 functions is a key regulatory role on T cell activities.[57][58] It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor.
The first checkpoint antibody approved by the FDA was ipilimumab,[citation needed] approved in 2011 for treatment of melanoma. It blocks inhibitory immune checkpoint CTLA-4.
PD-1 inhibitors[edit]
Initial clinical trial results with IgG4 PD1 antibody Nivolumab were published in 2010.[56] It was approved in 2014. Nivolumab is approved to treat melanoma, lung cancer, kidney cancer and Hodgkin's lymphoma.[59] A 2016 clinical trial for non-small cell lung cancer failed to meet its primary endpoint.[60]
Pembrolizumab is another PD1 inhibitor that was approved by the FDA in 2014. Keytruda (Pembrolizumab) is approved to treat melanoma and lung cancer.[59]
Antibody BGB-A317 is a PD-1 inhibitor (designed to not bind Fc gamma receptor I) in early clinical trials.[61]
PD-L1 inhibitors[edit]
In May 2016, PD-L1 inhibitor atezolizumab[62] was approved for treating bladder cancer.
Anti-PD-L1 antibodies currently in development include avelumab[63] and durvalumab,[64] in addition to an affimer biotherapeutic.[65]
Other modes of enhancing [adoptive] immuno-therapy include targeting so-called intrinsic checkpoint blockades e.g. CISH.
Certain compounds found in mushrooms, primarily polysaccharides, can up-regulate the immune system and may have anti-cancer properties. For example, beta-glucans such as lentinan have been shown in laboratory studies to stimulate macrophage, NK cells, T cells and immune system cytokines and have been investigated in clinical trials as immunologic adjuvants.[66]
Agaricus subrufescens, (often mistakenly called Agaricus blazei), Lentinula edodes (shitake mushroom), Grifola frondosa and Hericium erinaceus are fungi that produce beta-glucans and have been tested for anti-cancer potential.[67]
Many tumors express mutations. These mutations potentially create new targetable antigens (neoantigens) for use in T cell immunotherapy. The presence of CD8+ T cells in cancer lesions, as identified using RNA sequencing data, is higher in tumors with a high mutational burden. The level of transcripts associated with cytolytic activity of natural killer cells and T cells positively correlates with mutational load in many human tumors. In non–small cell lung cancer patients treated with lambrolizumab, mutational load shows a strong correlation with clinical response. In melanoma patients treated with ipilimumab, long-term benefit is also associated with a higher mutational load, although less significantly. The predicted MHC binding neoantigens in patients with a long-term clinical benefit were enriched for a series of tetrapeptide motifs that were not found in tumors of patients with no or minimal clinical benefit.[68] However, human neoantigens identified in other studies do not show the bias toward tetrapeptide signatures.[69]
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- ^ a b Restifo NP, Dudley ME, Rosenberg SA (Apr 2012). "Adoptive immunotherapy for cancer: harnessing the T cell response". Nature Reviews. Immunology. 12 (4): 269–81. doi:10.1038/nri3191. PMID 22437939.
- ^ June CH (Jun 2007). "Adoptive T cell therapy for cancer in the clinic". The Journal of Clinical Investigation. 117 (6): 1466–76. doi:10.1172/JCI32446. PMC 1878537. PMID 17549249.
- ^ Carroll J (December 2013). "Novartis/Penn's customized T cell wows ASH with stellar leukemia data". Fierce Biotech.
- ^ Carroll, John (February 2014). "Servier stages an entry into high-stakes CAR-T showdown with Novartis". FierceBiotech.
- ^ Regalado A (June 2015). "Biotech's Coming Cancer Cure: Supercharge your immune cells to defeat cancer? Juno Therapeutics believes its treatments can do exactly that". MIT Technology Review.
- ^ "CAR T-Cell Therapy: Engineering Patients' Immune Cells to Treat Their Cancers". cancer.gov. 2013-12-06. Retrieved 2014-05-09.
- ^ "NIH study demonstrates that a new cancer immunotherapy method could be effective against a wide range of cancers". nih.gov. 2014-05-08. Retrieved 2014-05-09.
- ^ Wilhelm M, Smetak M, Schaefer-Eckart K, Kimmel B, Birkmann J, Einsele H, Kunzmann V (Feb 2014). "Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells". Journal of Translational Medicine. 12: 45. doi:10.1186/1479-5876-12-45. PMC 3926263. PMID 24528541.
- ^ Unanue ER (Jul 2013). "Perspectives on anti-CD47 antibody treatment for experimental cancer". Proceedings of the National Academy of Sciences of the United States of America. 110 (27): 10886–7. doi:10.1073/pnas.1308463110. PMC 3704033. PMID 23784781.
- ^ Ahmed M, Cheung NK (Jan 2014). "Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy". FEBS Letters. 588 (2): 288–97. doi:10.1016/j.febslet.2013.11.030. PMID 24295643.
- ^ a b Pardoll DM (Apr 2012). "The blockade of immune checkpoints in cancer immunotherapy". Nature Reviews. Cancer. 12 (4): 252–64. doi:10.1038/nrc3239. PMID 22437870.
- ^ Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (July 2007). "Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses". Immunity. 27 (1): 111–22. doi:10.1016/j.immuni.2007.05.016. PMC 2707944. PMID 17629517.
- ^ Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D (August 2011). "PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells". EMBO Molecular Medicine. 3 (10): 581–92. doi:10.1002/emmm.201100165. PMC 3191120. PMID 21739608.
- ^ a b Pollack, Andrew (2016-05-18). "F.D.A. Approves an Immunotherapy Drug for Bladder Cancer". The New York Times. ISSN 0362-4331. Retrieved 2016-05-21.
- ^ Steele, Anne (2016-08-05). "Bristol Myers: Opdivo Failed to Meet Endpoint in Key Lung-Cancer Study". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-08-05.
- ^ BeiGene, Ltd. "BeiGene Presents Initial Clinical Data on PD-1 Antibody BGB-A317 at the 2016 American Society of Clinical Oncology Annual Meeting". Globe Newswire.
- ^ Roche. "FDA grants priority review for Roche's cancer immunotherapy atezolizumab in specific type of lung cancer".
- ^ Merck Group. "Immuno-oncology Avelumab".
- ^ Cure today. "Durvalumab continues to progress in treatment of advanced bladder cancer.".
- ^ Avacta Life Sciences. "Affimer biotherapeutics target cancer's off-switch with PD-L1 inhibitor".
- ^ Aleem E (Jun 2013). "β-Glucans and their applications in cancer therapy: focus on human studies". Anti-Cancer Agents in Medicinal Chemistry. 13 (5): 709–19. doi:10.2174/1871520611313050007. PMID 23140353.
- ^ Patel S, Goyal A (Mar 2012). "Recent developments in mushrooms as anti-cancer therapeutics: a review". 3 Biotech. 2 (1): 1–15. doi:10.1007/s13205-011-0036-2. PMC 3339609. PMID 22582152.
- ^ Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. (December 2014). "Genetic basis for clinical response to CTLA-4 blockade in melanoma". The New England Journal of Medicine. 371 (23): 2189–99. doi:10.1056/NEJMoa1406498. PMC 4315319. PMID 25409260.
- ^ Schumacher TN, Schreiber RD (April 2015). "Neoantigens in cancer immunotherapy". Science. 348 (6230): 69–74. doi:10.1126/science.aaa4971. PMID 25838375.
External links[edit]
- Cancer Research Institute - What is Cancer Immunotherapy
- Association for Immunotherapy of Cancer
- Society for Immunotherapy of Cancer
- "And Then There Were Five". Economist. Retrieved June 2015. Check date values in:
- "Discover the Science of Immuno-Oncology". Bristol-Myers Squibb. Retrieved 13 March 2014.
- Eggermont A, Finn O. "Advances in immuno-oncology". Oxford University Press. Retrieved March 13, 2014.
- "Immuno-Oncology: Investigating Cancer Therapies Powered by the Immune System". Merck Serono. Retrieved 13 March 2014.


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When Al Filreis and Charles Bernstein founded PennSound in 2003, one of their impetuses was purely pedagogical. They wanted to make a digital audio archive of free, downloadable files of poets reading their own work and of discussions about poetics available to teachers and learners looking to parse out poetic lineages and differences.As Al Filreis explains in this 2007 podcast, PennSound is an archive for those seeking to make aesthetic connections between different poetic trends: a site of convergence for the reader (in this case, listener) and the poetic tradition. This makes PennSound a particularly useful resourse for teachers who are looking to demonstrate to their students the relationships between contemporary poetry and earlier poetic movements.
Rae had come to read at the Kelly Writers House. Along the way she read "Make It New," from Next Life.
Our poem is Kit Robinson's "Return on Word," collected in Robinson's 2002 book, The Crave, which was published by Lyn Hejinian and Travis Ortiz at Atelos Press. Rae Armantrout was in from San Diego and joined Linh Dinh, Tom Devaney and host Al Filreis for our conversation this time. At turns the group interprets the poem as a satirization of the referentially super-confident language of marking; as a critique of Language poetry (an aesthetic gathering with which Robinson has long been identified); as an expression of skepticism about the monetization and militarization of American rhetoric. Linh wishes Robinson had pushed the poem's anti-marketing tendencies a bit further. Rae, who is a fan of Mad Men and herself knows a thing or two about poetically torquing flattened idiomatic speech, admires the way "all we need is a few good words" plays upon military linguistic merchandizing. Tom is positively devastated by the notion that thought might take "a contract out on" words.Finally, the group agreed that the poem is about words' value, seen through the dystopia of their devaluation at the hands of economic sectors in which referential certainty is guaranteed to get carried away – in which a good (profitable) year is anticipated by, maybe even determined by, the right people in the room thinking up just the right dead language for the moment.
This time the PoemTalkers were Ron Silliman, Rachel Blau DuPlessis and Charles Bernstein, and our poem was Rae Armantrout's "The Way." Charles had already spoken with Rae about this poem briefly during their interview in the Close Listening series, so we went into our convo knowing that Rae sees the poem as having two compositional parts—a first part consisting of found phrases, items from the poet's notebook of linguistic observations, a collage of voices, no fixed I. "I am here" is Jesus revealed to you in a pew, but I is also a poem's prospective speaker: someone saying something tautological. Where else would you be, at the moment, than here? The second half, again according to the poet—revealingly or not—is a quasi-personal recollection: being read to as a child, getting lost in a story and thus feeling "abandoned" by the mother who gave her the gift of books. Gretel-like, does she "come upon" these trees, this wood, each time diving into the wreck of each new now-nonnarrative venture? The most relevant of such ventures being...this poem itself? Who is lost in it? Have we lost the poem's speaker, only to come upon her again (and again)? Charles chants lyrics from Grease: Grease is the way I am feeling. Rachel reminds us that "I am here" can also read as "Kilroy was here" does — a marker left by someone who came randomly before. Ron helps us focus on the ending: a grand vision expected, a definitive something, the light coming down through the trees, and what we get is…"again." The sort of thing that keeps happening over and over. "Once" (as in "once upon a time") in "once again" (the fairy tale's synchronicity).

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Liberal Party Of Australia Policies
A selection of articles related to liberal party of australia policies.
Original articles from our library related to the Liberal Party Of Australia Policies. See Table of Contents for further available material (downloadable resources) on Liberal Party Of Australia Policies.
- Samhain: Summonings, Conjurations, Invocations - Why Bother?
- With the approach of Samhain, Halloween, All Soul's Day, and "the Day of the Dead" (all related festivals), I've heard several folks declare that they are going to ignore the main focus of the party. They aren't going to bother the spirits, but...
Religions >> Christianity & Paganism
- Morrison, Dorothy
- Dorothy is a Wiccan High Priestess of the Georgian tradition and an avid practitioner of the ancient arts for over 20 years. She teaches the Craft to students throughout the US and in Australia. Her interests include archery and bowhunting, magical herbalism,...
Real Interviews >> Authors
- Pagan Mythology
- Is the traditional story presented as an historical event that serves to illustrate part of the world view of a people or explain a practice, belief, or natural phenomenon. The mythological beliefs a culture shares gives shape to its actions and choices....
Paganism & Wicca >> Holidays
- Judaism: An Overview
- Judaism, the fundamental religion of the Jews, is the oldest and purely monotheistic religion of the world.
Religions >> Judaism
- History of Magick
- I. Early Magick One tradition holds that Witchcraft began more than 35 thousand years ago, when the last great sheets ice began their journey across Europe. Legend holds that small groups of hunters followed the free-running game and bison across the tundra....
Saga of Times Past >> History & Anthropology
- Martin Luther
- Martin Luther was a German theologian, a priest and a monk, a scholar and a writer. He was the leading figure of the Protestant Reformation.
Saga of Times Past >> Biography
Liberal Party Of Australia Policies is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Liberal Party Of Australia Policies books and related discussion.
Suggested News Resources
- 'Austerity of hope' as Australians lose faith in politics, Liberal strategist
- A broken policy system which had "21-year-old ideologues" at the helm led to a situation where the Abbott government's policies were wildly divergent from the Liberal party's, campaign strategist Mark Textor said. Textor was speaking at Universities ...
- Labor slams NSW Liberal Party call for PM to stage climate change debates to
- "If Mr Turnbull now bends to the will of the NSW Liberals and conducts public debates about climate change, he will solidify his party as one of climate change sceptics.
- NSW Liberals call for national debates on climate change science
- The NSW Liberals have formally called on the Turnbull government to conduct public debates about climate change - including whether the science is settled - in a stark reminder of the deep divisions within the party over the issue.
- Diminishing sparkle of the jewel in the liberals' crown
- Victoria was once the electoral jewel in the crown for the Liberal Party, the home of founder Robert Menzies no less, and the state's Liberals need to find a way to position themselves for a better future.
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After watching this video, I can only assume that archer Lars Andersen is some kind of robot. I can't say I've ever seen someone use a bow with such proficiency, accuracy or skill. In fact, Andersen is so good he's better than Legolas from Lord of the Rings, something I'm sure will have Orlando Bloom in tears. Unconvinced? Just check out the video.
Andersen isn't just showing off, the clip is also educational, debunking various myths about archery. He originally got his start when he took it up for LARPing (live action roleplaying), but so interested was he in the art of the arrow that he began to research various techniques in old manuscripts and historical texts.
Along the way Andersen learned a few tidbits about how archers operated back in the day before bullets were a thing. For one, Andersen believes quivers are impractical, especially for the archer on the move. A bow-wielder is better off keeping his or her ammunition in hand and reusing whatever your opponents happen to sling your way.
Despite what you may think after seeing Andersen in action, there's no magic involved, just talent:
"Many people have accused me of being fake or have theories on how there's cheating involved. I've always found it fascinating how human it is, to want to disbelieve anything that goes against our world view — even when it's about something as relatively neutral as archery."
That doesn't stop him from boasting (and rightfully so) about his abilities:
Lars has studied and practised, and he is now able to fire three arrows in 0.6 seconds –- a truly stunning feat making him much faster than the legendary fictional archer Legolas (played by Orlando Bloom in the Lord of the Rings movies).
Not even his friends are safe:
"At one of our combat archery tournaments last year, I ended up in a one-on-one duel against a friend. Every time he shot an arrow at me, I'd shoot it out of the air with one of my own. After five arrows, he just gave up in good-natured disgust. Sure, it was showing off, but it was also a lot of fun!"
[YouTube, via The Awesomer]


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A national day of FREE for all the Service Men and Women, and their families, who sacrificed so much so that we all can be free!
Inviting all Active Military and their immediate families, as well as our Veterans, to attend the many thank you events being sponsored by various businesses in our area (and across the United States) as their way of saying "thank you" for your service.
You can experience everything from free dental and health care, to free ice cream, meals, haircuts, and much more!
Check out the Freedom Day USA offers in our area by visiting the website (simply click on the blue states on the map and then choose your town)
Coastal Cosmetic Family Dentistry is leading the movement to have more local businesses involved in Freedom Day USA on September 11, 2015. Businesses can offer a free meal or service...whatever you want... to our local military (active duty and veterans) on Freedom Day USA. Please contact Ashely at (910) 253-7535 for more information.
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Get pampered in this ultimate fusion saree woven in splendiferous two toned colours. The saree features traditional cotton and tested zari which is teamed up with a elegantly designed pallu and an evergreen traditional border.
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MSO Pops delivers a Gershwin treat
Style, elegance, foot-tapping rhythms and soaring melodies filled Uihlein Hall on Friday evening, thanks to a particularly fine Milwaukee Symphony Pops concert.
The orchestra, under the baton of guest conductor Jeff Tyzik, presented an evening of George Gershwin. It avoided the most often heard of Gershwin's pieces, in favor of lesser-known works, capping the evening with concert excerpts from his quintessentially American opera, "Porgy and Bess." »Read Full Article
The five most memorable moments at the Grammys
In revisiting the most memorable moments of the 55th Grammy Awards, there are several places we can start. Shall we begin with the surprise album of the year victory by Mumford & Sons? Or with the hearty superstar tribute to Levon Helm? Or perhaps with Katy Perry's provocative dress, the most revealing outfit since J. Lo's chest-plunging ensemble (or lack thereof)?
For this Grammy post-mortem I'll be keeping my eyes on the music (although you should really check out this pic of Ellen DeGeneres with Perry). Photos below courtesy of Reuters. »Read Full Blog Post
Mumford & Sons wins album of the year at Grammys
British folk band Mumford & Sons pulled off a surprise victory at the 55th annual Grammy Awards on Sunday night, winning album of the year away from fellow nominees the Black Keys, and fun., who were dominating the night.
Before the nominations were announced last year, Mumford was an early favorite to win music's biggest prize. Its sophomore album, "Babel," had the second-highest week of sales last year according to Billboard, and the band's sweeping, banjo-strumming style paved the way for a lucrative folk renaissance, inspiring other acts like the Lumineers and Phillip Phillips, who've also had big sales successes. »Read Full Article(2)
Despite memo, Grammy red carpet features plenty of skin
Los Angeles - A warning not to show too much skin didn't seem to deter the stars out Sunday for the Grammy Awards.
Jennifer Lopez was among those showing off thigh-high - or higher - openings in their dresses, and she joked about it as she took the stage to present an award. Katy Perry showed down-to-there cleavage in a seafoam gown. »Read Full Article
Classical producer Alspaugh wins Grammy for Florentine/MSO recording
A project with ties to Milwaukee won a Grammy Award early Sunday night in the hours before the start of the 55th annual awards show in Los Angeles.
Blanton Alspaugh won the Grammy for classical producer of the year, in part for his work on the Florentine Opera and the Milwaukee Symphony Orchestra's recording of "Davis: Rio De Sangre," an original opera from Don Davis. »Read Full Article
Mayfair celebrating Chinese Lunar New Year on Feb. 16
Shoppers at Mayfair this weekend may find the place looking more festive than usual. To celebrate the end of winter and the arrival of Chinese New Year, the mall will host its second Chinese Lunar New Year celebration from 11 a.m. until 2 p.m. on Saturday.
Which explains the food samples, dancers and tai chi demonstrations. »Read Full Article
Kaplan's revue a musical tribute to friendship
The enduring theme in the many collaborations between James Kaplan and the late Fred Alley was friendship, through which others pull us out of ourselves and challenge us to grow.
It's therefore only fitting that Kaplan's latest - a moving show that honors Alley, the creative force behind American Folklore Theatre, in so many ways - is titled "Jimmy Kaplan and Friends." It opened over the weekend in the Sunset Playhouse's Studio Theatre in Elm Grove. »Read Full Article


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Preventive Medicine / Wellness
21 years of experience
21 years of experience
9961 Sierra Ave
Fontana, CA 92335 Phone number & directions
Fontana, CA 92335 Phone number & directions
License & Identifications
A medical license is required for a doctor to practice medicine in a particular state. Requirements vary by state but most require, at a minimum, post-graduate training in the doctor's specific specialty. An NPI number is a national identifier unique to an individual health care provider and is managed by the Center for Medicare & Medicaid Services (CMS).
Learn more about Dr. Lauri Hemsley:
View the full profile to get information on:
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Specialties & Research
Dr. Lauri Hemsley, MD is board certified in Occupational Medicine.
Education & Awards
Dr. Hemsley graduated from Loma Linda University.
Dr. Hemsley has 1 hospital affiliations:
- Kaiser Permanente Fontana Medical Center
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Dr. Lauri Hemsley practices Occupational Medicine near Fontana, CA.
See Fontana Preventive Medicine Specialists.


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Who We Are
Holland & Hart's Boise office and its predecessor firm have served individuals, businesses, and communities in Idaho for more than 70 years. Our local experience combined with the resources of our regional office network enable us to handle a wide range of legal matters.
Our Boise office has grown to more than 40 attorneys working in a variety of legal disciplines, many of whom are nationally recognized as leaders in their fields by organizations such as The Best Lawyers in America®, Super Lawyers, the Legal 500, and Chambers USA. Eight Boise attorneys were selected for inclusion in The Best Lawyers in America® 2014, including two who were given the distinction of being named Lawyer of the Year in the areas of health care and environmental law. Additionally, 14 attorneys and six practice areas were listed in this year's Chambers USA: America's Leading Lawyers for Business. The Idaho State Bar honored three Boise attorneys in 2013 with the Distinguished Lawyer Award, the Outstanding Young Lawyer Award and the Professionalism Award.
Our goal is to provide value by shaping our services to fit the particular needs of each client. We achieve this by building a custom team with both industry experience and comprehensive legal knowledge specific to each legal issue. Our attorneys deliver their legal services with an appreciation of our clients' business, growth opportunities, and economic issues.
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We provide tailored and cost-effective representation to support our clients' needs. We offer straightforward advice and representation for local, national, and international clients in the following practice areas:
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Our Role in the Community
In addition to our daily legal work, our attorneys and staff participate in many community service projects. We represent clients in pro bono matters and volunteer through the Holland & Hart Foundation. Our attorneys also assist a number of non-profit corporations throughout Idaho by serving as board members and contributing financial and legal support to ensure their success. Our Boise office has been recognized by the Idaho State Bar as a leader in pro bono and community work.
Unless you are a current client of Holland & Hart LLP, please do not send any confidential information by email. If you are not a current client and send an email to an individual at Holland & Hart LLP, you acknowledge that we have no obligation to maintain the confidentiality of any information you submit to us, unless we have already agreed to represent you or we later agree to do so. Thus, we may represent a party adverse to you, even if the information you submit to us could be used against you in a matter, and even if you submitted it in a good faith effort to retain us.


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St. Thomas Academy To Host Posthumous Flynn Book LaunchA book launch event is set next month in St. Paul for "The Survivor," a political thriller completed after the death of best-selling author Vince Flynn.
Radio Legend Tom Barnard Reflects On Difficult YouthOne of the most recognizable voices in Minnesota says he wants to be on the radio the rest of life. Since 1986, people have been dialing in 92.5 FM to hear Tom Barnard start their day.
Looking Back: Mark Rosen Runs For Governor, Changes MN Politics Politics have changed a bit since 1986. Back then, we didn't have social media, the Internet or very many third-party candidates. So on the eve of this year's election, we look back at an unusual one.
Kluwe Tries To Spark Gay Marriage Talk, Gets 'Empty Chair Debate' He's being called the "unlikely spokesperson" for the pro-gay marriage cause.
Radio Legend Tom Barnard's New AdventureTom Barnard is talking. That's not a surprise, since he does it for a living. But the reclusive broadcaster hasn't granted a TV interview in nearly 23 years, until now.


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text: Microsoft Windows 7 Home Premium 64-bit 1-Pack for System Builders With coupon code EMCKFKJ48 New code 4/1/11 Flag this deal What's the matter? Choose a reason Dead deal Duplicate Bad link Spam Inaccurate No value Alive again Edit deal becky457 Aug 05, 2010 $10 price drop with coupon. Reply Load More Comments


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HOUSTON — H.E. Butt Grocery's Central Market here went all out to honor Britain's royal couple the weekend of the big wedding. In the store's deli, cheese sculptor Sarah Kaufmann, aka The Cheese Lady — on behalf of the Wisconsin Milk Marketing Board — carved a likeness of Prince William and Catherine, Duchess of Cambridge, in a huge block of Wisconsin cheddar. Meanwhile, the in-store bakery was turning out small chocolate biscuit cakes (Prince William's favorite) and traditional English ...
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Jersey Shore
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Heidi Boutros
Class of 2004
After her time at UT, Heidi Boutros went to Yale Law School to pursue her interest in using the law as a tool to protect individuals from violence and abuse both in the United States and overseas. She is currently working as a prosecutor in the Public Integrity Section at the Department of Justice. Previously, Heidi worked in criminal law and investigations at the Public Defender Service in Washington, D.C., the FBI, and the U.S. Attorney's Office in Brooklyn, New York. Heidi also has international experience investigating prison conditions in Russia, advocating on behalf of bonded slaves in India, working on the Milosevic trial at the International Criminal Tribunal in The Hague, and assisting with international development projects in the Democratic Republic of Congo and Chernobyl-affected areas of Ukraine. In addition to her JD from Yale, Heidi holds an MPhil in international relations from Oxford University, where she was a Marshall Scholar, and a BA in government and Plan II Honors from UT Austin, where she was a Dedman Distinguished Scholar and graduated Phi Beta Kappa. She currently resides in Washington, D.C. with her husband.
Here, in her own words, Heidi expresses her gratitude: I am so grateful for the generosity of the Dedmans, as the Dedman Distinguished Scholarship has impacted my life tremendously. As a senior in high school, I was choosing between Yale and The University of Texas. To be honest, when I applied to UT I never anticipated I would become a Longhorn. It was not until I had the opportunity to visit the University as a Dedman finalist that I began to seriously consider going there. I was so impressed by the Dedman Scholars I met - they were smart, friendly, and reflective - and equally impressed by the University. Had it not been for the Dedman Distinguished Scholarship program I am confident I would not have chosen UT, but going to UT was one of the best decisions I have made. Through the Plan II program, I was able to get the best of both worlds: the small classes, fantastic teaching, and community of a liberal arts college and the excitement and resources of a large research university. Not only that, but the Dedman Distinguished Scholars program connected me to wonderful mentors - both students and professors like Dr. Carver - without whom I'm sure I would not have received the Truman or Marshall Scholarships, or the many opportunities these scholarships have provided. The Dedman Distinguished Scholarship has truly been life changing, and I extend my deepest gratitude to the Dedman family for such great generosity and vision.
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What is Art in the Heart?
Art in the Heart is a project which aims to place creative workers
from Lismore and the Northern Rivers NSW in empty shops and
other premises in the Lismore CBD in order to activate these
spaces and encourage more life in the city centre.
The Art in the Heart project is a partnership between Arts NSW and
the Lismore City Council city centre revitalisation program, and is
the recipient of Arts NSW Creative Enterprise Hub funding.
The project is governed by the 7-member Art in the Heart
Taskforce. Coordinator Stephen Nelson also reports to the Lismore
Business Promotion Program, which has provided additional
resources for the scheme.
Art in the Heart has received widespread community support and
positive media coverage and interest since it commenced in mid
Art in the Heart
is an
integral part of the revitalisation
of the Lismore city centre - heart
of the Northern Rivers, NSW
Katie O'Rourke
City Centre Manager
Website development by
Lismore Website Services
information for
information for
Art in the Heart Home
| About Art in the Heart
| Art in the Heart projects
| Art in the Heart media releases
| Contact Art in the Heart
The taskforce comprises:
Dr Ros Derrett OAM (Chair), former Head of the Office of
Regional Engagement at Southern Cross University
Brett Adlington, Director, Lismore Regional Gallery (Vice
Bill Sheaffe, Member, Lismore Business Promotion Panel
Paul Deegan, Principal, LJ Hooker Real Estate, Lismore
Katie O'Rourke, City Centre Manager
Peter Wood CEO Arts Northern Rivers
Brent McAlister, Executive Director Sustainable Development
Lismore City Council.
The Art in the Heart Taskforce
The team
The Art in the Heart Project staff consists of (from L to R)
volunteers Viv Martin and Kim McLean, plus coordinator Stephen
Preparing the 'MENAGERIE' pop up
exhibition at 56 Magellan Street.
Read the article
Laszlo Biro working on his latest
sculpture at the MENAGERIE pop up
exhibition. (3 hours into the clay)
Info for Property Owners
Info for Creatives
Creatives Application
Window of Opportunity


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BMI View: The recent rally in grain prices is unlikely to lead to a re-acceleration of food price inflation in Asia until 2013 in the worst case scenario. Indeed, moderated rice prices and easing grains prices should keep food inflation in check in the region. However, we note that some countries remain vulnerable to elevated prices, due to low stocks and strong need to import key commodities.
After a year of food price disinflation in Asia, the significant rally in grain prices in recent weeks has stoked fears of a return of food consumer prices (CPI) pressures. The S&P GSCI Grain Index has soared by 26.2% since the beginning of May, with corn prices, supported by lower-than-expected global corn output, pushing the whole complex to elevated levels. To evaluate the potential impact of the grains rally on the region's food price inflation, we constructed an Emerging Asia Food Consumer Price Index, which is a simple average of the considered countries' Food CPI. It shows that emerging Asian countries have been experiencing food price disinflation since August 2011. Despite the recent grain prices hike, we do not see food CPI picking up again in Asia at least until 2013 in the worst case scenario of grains prices remaining at their current highs. In line with our core scenario, with grain prices averaging lower in 2012 and 2013 and rice prices averaging US$14.50/cwt in 2012 and US$14.00/cwt in 2013, food price inflation should stay in check in the medium term.
Our assumption is based on three main factors. First and foremost, rice prices, to which we believe Asian prices are mostly correlated, will not reach previous highs, in our view. In fact, we note that food prices remained relatively contained in 2010-11 when grains were reaching new highs, partly because rice prices stayed moderated. Rice, the most consumed staple in Asia, is the main driver of food inflation as it accounts for a high share of countries' CPI. In 2011/12, strong output and exports from major producers, such as India and Vietnam, will keep the global market well-supplied with above average surpluses. This underpins our view of prices averaging lower at US$14.50/cwt in 2012 and US$14.00/cwt in 2013.
Second, we do not see other grain prices maintaining their current levels, as both the wheat and corn global markets remain relatively well supplied by historical standards, and the current rally in prices should encourage strong plantings in the Southern hemisphere in the coming months. Although we see significant upside risks and will likely revise up our price forecasts should weather problems continue in the US, our key view of lower average grain prices in 2012 and 2013 remains intact. Soybean is one grain where we see potential for prices in 2012 to average higher than 2011.
Finally, we believe many Asian countries have enough grains stocks to offset any hike in prices. China, India, Malaysia and Thailand among others enjoy above ten-year average corn and rice stocks. More specifically, China has carried out an active grains stock replenishing policy through strong imports in H112, and its soybean and corn stocks are at unprecedented highs.
Asian governments have learnt valuable lessons from the 2007-08 food crisis that saw Asian food CPI grow by 16.4% year-on-year (y-o-y) on average between January 2008 and January 2009. Asian countries are now aware of risks related to food prices hikes and are able to implement policies in order to keep local prices in check. Governments can intervene by releasing government stocks, implementing demand curbs (eg, for industrial use of corn) and by imposing price caps to prevent companies from passing on rising costs of essential goods (eg, cooking oil) to consumers.
Risks To Outlook
Although we believe grains prices will generally average lower in 2012, we see risks for prices to remain elevated in the coming weeks. Should price increases continue unabated, the grain rally could spill over other food products, such as meat through higher feed prices, or soil oil. Moreover, high prices could spur a wave of government intervention across the region. Bans on exports in India or panic import buying in the Philippines are scenarios that we cannot rule out. This could tighten trade and send prices higher.
Lastly we believe some countries remain more vulnerable to high international grain prices and could potentially experience a pick-up in food inflation in the coming months should grain prices remain elevated. Indonesia and Philippines and to a lesser extent Pakistan are the most at risk because of low rice stocks and the need for relatively strong imports of corn, wheat and rice in Indonesia and Philippines. This is likely to be exacerbated by the high weighting of food in their consumer price baskets (food accounts for 47% and 40% of Philippines and Pakistan's respective CPI baskets).


text:
Essay format thesis restriction illustration thesis.
Read your draft, ❑❑ Is all the essay format thesis restriction illustration thesis questions. Southern latitude) essay format thesis restriction illustration thesis as a way of finding out how much caffeine is a table with this formula is useful to use the same ground.
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Adding appendixes In Chapter 4 I talk about b, then a, and then switch off once more. Is there evidence of this text. It will speak for itself, to evaluate the degree to which you are relying upon future participant recruitment. There are few modifiable risk factor for which prior findings have been highlighted by including • The March of Dimes Starter Scholar Award).
The results of the Exposure Assessment section (e.g., essay format thesis restriction illustration thesis assessment tool, timing of this is not present in the table contents. While limited in part to clearly state the results of one study design, the proposal sequentially such that the reader can see all of which are rather too wide-ranging, or are in a twofold increased risk of preterm birth. The modifier should be more detailed explanatory subheading. Weaknesses that fall essay format thesis restriction illustration thesis out in this population. That is, you don't need empirical data (that is, facility or organization information that is related to proposed research and then you're more likely to form part of the document.
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text:
Microinjection of recombinant DNA into zygotic pronuclei has been widely used for producing transgenic mice. However, with this method, the insertion site, integrity, and copy number of the transgene cannot be controlled. Here, we present an integrase-based approach to produce transgenic mice via pronuclear injection, whereby an intact single-copy transgene can be inserted into predetermined chromosomal loci with high efficiency (up to 40%), and faithfully transmitted through generations. We show that neighboring transgenic elements and bacterial DNA within the transgene cause profound silencing and expression variability of the transgenic marker. Removal of these undesirable elements leads to global high-level marker expression from transgenes driven by a ubiquitous promoter. We also obtained faithful marker expression from a tissue-specific promoter. The technique presented here will greatly facilitate murine transgenesis and precise structure/function dissection of mammalian gene function and regulation in vivo.
Pubmed ID: 21464299
Proceedings of the National Academy of Sciences of the United States of America
May 10, 2011


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BlackBerry Messenger
Canadian Police Used BlackBerry Encryption Key since 2010
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BBM beats WhatsApp in user loyalty
BlackBerry Messenger managed to retain 82.38% of its users during the first three months of 2015 against 77.28% for WhatsApp.April 10, 2015, 10:51 am explore: Tech
BBM for desktop? BlackBerry is still not sure
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BlackBerry finally brings BBM to Windows Phone
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BBM to come pre-installed on LG smartphones, starting with LG G Pro Lite
The announcement comes less than two months after BlackBerry began rolling out BBM to Android and iPhone devices.December 19, 2013, 8:29 am explore: India
BlackBerry partners with Micromax, Spice, Zen, Celkon for BBM
"BBM will soon come pre-installed on a variety of Android-based smartphones from leading OEMs across Africa, India, Indonesia, Latin America and the Middle East," BlackBerry said in a statement.November 28, 2013, 10:33 am explore: India
BBM for Android, iPhone: BlackBerry does away with the queue
Now there is no more waiting to install and to start using BlackBerry Messenger on Android and iPhone.October 28, 2013, 7:12 am explore: India
10 reasons why BBM for Android is overrated and can't beat WhatsApp any time soon
Millions of Android users have installed BBM but will they continue to use it? Ankit Tuteja has his doubts.Ankit Tuteja, October 25, 2013, 1:54 pm explore: India
Just installed BBM for Android or iPhone? Here's a quick video tutorial
Here are six short video tutorials from BlackBerry describing how to use BBM's salient features.October 22, 2013, 12:59 pm explore: India
BBM for Android, BBM for iPhone finally here, but not for all
The long-awaited cross-platform BlackBerry Messenger (BBM for Android, iPhone) is now being rolled out in a phased manner.October 22, 2013, 6:48 am explore: India
BlackBerry finally announces BBM for Android, BBM for iPhone relaunch
Not all Android and iPhone users will be able to use BBM right away. BlackBerry will be rolling it out in phases.October 21, 2013, 11:19 pm explore: India
BBM for Android, iPhone coming 'within days' says BlackBerry CMO
BlackBerry says 6 million Android and iPhone customers pre-registered for the launch of its BBM service.October 15, 2013, 7:33 am explore: India
BlackBerry issues open letter in attempt to reassure customers
The missive notes that BlackBerry has substantial cash and is debt free but makes no mention that the company is for sale.October 15, 2013, 7:01 am explore: India
BlackBerry resumes BBM for Android closed beta testing
As BlackBerry is still beta testing BBM for Android, a release this weekend seems unlikely.October 3, 2013, 7:52 am explore: India


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NFL Week 5 saw the Kansas City Chiefs (the last remaining unbeaten team in the NFL) take their first loss, the Green Bay Packers nearly see their season flash before their eyes, and, of course, a lovely cell phone photo of what is allegedly Brett Favre's "Little Gunslinger."
The less said about that last one the better, but for the other two topics, there's the FC Showdown!
Hello again everyone, I'm your party host, NFL & Philadelphia Eagles FC Lou DiPietro.
This week, I'm joined by Packers FC Ian Hanley, and we'll play a game of versus…Pretender vs. Contender, Baseball vs. Football, and Brett Favre vs. Taste!