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Archive for the ‘Inflammasome’ Category


Natural Killer Cell Response: Treatment of Cancer

Curator: Larry H. Bernstein, MD, FCAP

 

Molecular mechanisms of natural killer cell activation in response to cellular stress

C J Chan1,2,3, M J Smyth1,2,3,4,5 and L Martinet1,2,4,5        Edited by M Piacentini

Cell Death and Differentiation (2014) 21, 5–14;    http://www.nature.com/cdd/journal/v21/n1/full/cdd201326a.htm

Protection against cellular stress from various sources, such as nutritional, physical, pathogenic, or oncogenic, results in the induction of both intrinsic and extrinsic cellular protection mechanisms that collectively limit the damage these insults inflict on the host. The major extrinsic protection mechanism against cellular stress is the immune system. Indeed, it has been well described that cells that are stressed due to association with viral infection or early malignant transformation can be directly sensed by the immune system, particularly natural killer (NK) cells. Although the ability of NK cells to directly recognize and respond to stressed cells is well appreciated, the mechanisms and the breadth of cell-intrinsic responses that are intimately linked with their activation are only beginning to be uncovered. This review will provide a brief introduction to NK cells and the relevant receptors and ligands involved in direct responses to cellular stress. This will be followed by an in-depth discussion surrounding the various intrinsic responses to stress that can naturally engage NK cells, and how therapeutic agents may induce specific activation of NK cells and other innate immune cells by activating cellular responses to stress.

 

  • Stress induces specific intrinsic and extrinsic physiological mechanisms within cells that lead to their identification as functionally abnormal
  • Sources of cellular stress can be nutritional, physical, pathogenic, or oncogenic
  • Intrinsic responses to cellular stress include activation of the DNA-damage response, tumor-suppressor genes, and senescence
  • The extrinsic response to cellular stress is activation of the immune system, such as natural killer cells
  • Intrinsic responses to cellular stress can directly upregulate factors that can activate the immune system, and the immune system been shown to be indispensable for the efficacy of some chemotherapy

Further critical determinants of intrinsic responses to stress and cell death that can activate the immune system must be identified

  • Identification of the different cellular pathways and molecular determinants controlling the immunogenicity of different cancer therapies is required
  • How can we harness the ability of therapeutic agents to activate both the intrinsic and extrinsic responses to cellular stress to achieve more specific and safer approaches to cancer treatment?

Any insult to a cell that leads to its abnormal behavior or premature death can be defined as a source of stress. As the turnover and maintenance of cells in all multi-cellular organisms is tightly regulated, it is essential that stressed cells be rapidly identified to avoid widespread tissue damage and to maintain tissue homeostasis. Various intrinsic cellular mechanisms exist within cells that become activated when they are exposed to stress. These include activation of DNA-damage response proteins, senescence programs, and tumor-suppressor genes.1 Extrinsic mechanisms also exist that combat cellular stress, through the upregulation of mediators that can activate different components of the immune system.2 Although frequently discussed separately, much recent evidence has indicated that intrinsic and extrinsic responses to cellular stress are intimately linked.3

As the link between cell intrinsic and extrinsic responses to stress have been uncovered, these observations are now being harnessed therapeutically, particularly in the context of cancer.4 Indeed, various chemotherapeutic agents and radiotherapy are critically dependent on the immune system to elicit their full therapeutic benefit.5, 6 The mechanisms by which this occurs may be twofold: (i) the induction of intrinsic cellular stress mechanisms activates innate immunity and (ii) the release and presentation of tumor-specific antigens engages an inflammatory adaptive immune response.

NK cells are the major effector lymphocyte of innate immunity found in all the primary and secondary immune compartments as well as various mucosal tissues.7 Through their ability to induce direct cytotoxicity of target cells and produce pro-inflammatory cytokines such as interferon-gamma, NK cells are critically involved in the immune surveillance of tumors8, 9, 10 and microbial infections.11, 12 The major mechanism that regulates NK cell contact-dependent functions (such as cytotoxicity and recognition of targets) is the relative contribution of inhibitory and activating receptors that bind to cognate ligands.

Under normal physiological conditions, NK cell activity is inhibited through the interaction of their inhibitory receptors with major histocompatibility complex (MHC) class I.13, 14 However, upon instances of cellular stress that are frequently associated with viral infection and malignant transformation, ligands for activating receptors are often upregulated and MHC class I expression may be downregulated. The upregulation of these activating ligands and downregulation of MHC class I thus provides a signal for NK cells to become activated and display effector functions. Activating receptors are able to provide NK cells with a strong stimulus in the absence of co-stimulation due to the presence of adaptor molecules such as DAP10, DAP12, FcRγ, and CD3ζ that contain immunoreceptor tyrosine-based activating motifs (ITAMs).15, 16,17 By contrast, inhibitory receptors contain inhibitory motifs (ITIMs) within their cytoplasmic tails that can activate downstream targets such as SHP-1 and SHP-2 and directly antagonize those signaling pathways activated through ITAMs.18, 19, 20 The specific details of individual classes of inhibitory and activating receptors and their ligands are summarized in Figure 1 and have been extensively reviewed elsewhere.14, 21 Instead, this review will more focus on the relevant activating receptors that are primarily involved in the direct regulation of NK cell-mediated recognition of cellular stress: natural killer group 2D (NKG2D) and DNAX accessory molecule-1 (DNAM-1).

Figure 1.

Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the authorNK cell receptors and their cognate ligands. Major inhibitory and activating receptors on NK cells and their cognate ligands on targets are depicted. BAT3, human leukocyte antigen (HLA)-B-associated transcript 3; CRTAM, class I-restricted T-cell-associated molecule; HA, hemagglutinin; HLA-E, HLA class I histocompatibility antigen, alpha chain E; IgG, immunoglobulin G; LFA-1, leukocyte function-associated antigen-1; LLT1, lectin-like transcript 1; TIGIT, T cell immunoglobulin and ITIM domain

Full figure and legend (185K)

NK Cell-Mediated Recognition of Cellular Stress by NKG2D and DNAM-1

NKG2D is a lectin-like type 2 transmembrane receptor expressed as a homodimer in both mice and humans by virtually all NK cells.22, 23 Upon interaction with its ligands, NKG2D can trigger NK cell-mediated cytotoxicity against their targets. The ligands for NKG2D are self proteins related to MHC class I molecules.24 In humans, these ligands consist of the MHC class I chain-related protein (MIC) family (e.g., MICA and MICB) and the UL16-binding protein (ULBP1-6) family.25, 26 In mice, ligands for NKG2D include the retinoic acid early inducible (Rae) gene family, the H60 family, and mouse ULBP-like transcript-1 (MULT-1).27, 28, 29 NKG2D ligands are generally absent on the cell surface of healthy cells but are frequently upregulated upon cellular stress associated with viral infection and malignant transformation.3, 30 Indeed, NKG2D ligand expression has been found on many transformed cell lines, and NKG2D-dependent elimination of tumor cells expressing NKG2D ligands has been well documented in vitro and in tumor transplant experiments.25, 30, 31, 32, 33 In humans, NKG2D ligands have been described on different primary tumors34, 35 and specific NKG2D gene polymorphisms are associated with susceptibility to cancer.36 Finally, blocking NKG2D through gene inactivation or monoclonal antibodies leads to an increased susceptibility to tumor development in mouse models,37, 38demonstrating the key role played by NKG2D in immune surveillance of tumors. NKG2D can also contribute to shape tumor immunogenicity, a process called immunoediting, as demonstrated by the frequent ability of tumor cells to avoid NKG2D-mediated recognition through NKG2D ligand shedding, as discussed later in this review.38, 39, 40

DNAM-1 is a transmembrane adhesion molecule constitutively expressed on T cells, NK cells, macrophages, and a small subset of B cells in mice and humans.41, 42, 43 DNAM-1 contains an extracellular region with two IgV-like domains, a transmembrane region and a cytoplasmic region containing tyrosine- and serine-phosphorylated sites that is able to initiate downstream activation cascades.41, 44 There is accumulating evidence showing that DNAM-1 not only promotes adhesion of NK cells and CTLs but also greatly enhances their cytotoxicity toward ligand-expressing targets.41, 45, 46, 47, 48, 49, 50 The ligands for DNAM-1 are the nectin/nectin-like family members CD155 (PVR, necl-5) and CD112 (PVRL2, nectin-2).45, 46 Like NKG2D ligands, DNAM-1 ligands are frequently expressed on virus-infected and transformed cells.51, 52DNAM-1 ligands, especially CD155, are overexpressed by many types of solid and hematological malignancies and blocking DNAM-1 interactions with its ligands reduces the ability of NK cells to kill tumor cells in vitro.41, 49, 53, 54, 55, 56, 57 Further evidence of the role of DNAM-1 in tumor immune surveillance is provided by studies using experimental and spontaneous models of cancer in vivo showing enhanced tumor spread in the absence of DNAM-1.47, 48, 49, 50, 58

As NKG2D and DNAM-1 ligands are frequently expressed on stressed cells, many studies have sought to determine the mechanisms that underpin these observations. The guiding hypothesis for these studies is that cell-intrinsic responses to stress are directly linked to cell-extrinsic responses that can trigger rapid NK cell surveillance and elimination of stressed cells. Indeed, major cell-intrinsic responses to cellular stress can directly lead to NK cell-activating ligand upregulation and are outlined in the following sections.

The DNA-Damage Response

Cellular stress caused by the activation of the DNA-damage response leads to downstream apoptosis or cell-cycle arrest. The activation of DNA-damage checkpoints occurs when there are excessive DNA strand breaks and replication errors, thereby representing an important tumorigenesis barrier that can slow or inhibit the progression of malignant transformation.59, 60 Two major transducers of the DNA-damage response are the PI3-kinase-related protein kinases ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related). ATM and ATR can modulate numerous signaling pathways such as checkpoint kinases (Chk1 and Chk2, which inhibit cell-cycle progression and promote DNA repair) and p53 (which mediates cell-cycle arrest and apoptosis).61

In addition to the induction of cell-cycle arrest and apoptosis, activation of the DNA-damage response has been shown to promote the expression of several activating ligands that are specific for NK cell receptors, primarily those of the NKG2D receptor. These findings have shown a critical direct link between cellular transformation, apoptosis, and surveillance by the immune system.62 The first evidence of this link between DNA damage and immune cell activation was provided by Raulet and colleagues who showed that NKG2D ligands were upregulated by genotoxic stress and stalled DNA replication conditions known to activate either ATM or ATR.63 These observations have now been extended by several other studies that have defined further DNA-damaging conditions (e.g., genotoxic drugs/chemotherapy, deregulated proliferation, or oxidative stress) that can promote NKG2D ligand upregulation.64, 65, 66, 67

The role of the DNA-damage response in controlling NKG2D ligand expression and subsequent NK cell activation has also been demonstrated in the context of anti-viral immunity, specifically in Abelson murine leukemia virus infection.68 This pathogen was shown to induce activation-induced cytidine deaminase (AID) expression outside the germinal center, resulting in generalized hypermutation, DNA-damage checkpoint activation, and Chk1 phosphorylation. The genotoxic activity of virally induced AID not only restricted the proliferation of infected cells but also induced the expression of NKG2D ligands. More recently, another member of APOBEC-AID family of cytidine deaminases, A3G, has been shown to promote the recognition of HIV-infected cells by NK cells after DNA-damage response activation.69 In this study, viral protein Vpr-mediated repair processes, which generate nicks, gaps, and breaks of DNA, activate an ATM/ATR DNA-damage response that leads to NKG2D ligand expression.

The DNA-damage sensors ATM and ATR have also been shown to regulate other key NK cell-activating ligands such as the DNAM-1 ligand, CD155.58, 65, 70 For example, in the Eμ-myc spontaneous B-cell lymphoma model, activation of the DNA-damage response leads to the upregulation of CD155 in the early-stage transformed B cells, subsequently activating spontaneous tumor regression in an NK cell- and T-cell-dependent manner.58 The DNA-damage response can also regulate the expression of the death receptor DR5.71 The engagement of DR5 by the effector molecule TRAIL, which is expressed by NK cells and T cells, can induce apoptosis of target cells and has been shown to have a key role in immune surveillance against tumors.72 Collectively, these results suggest that the detection of DNA damage, primarily through ATM and ATR, may represent a conserved protection mechanism governing the immunogenicity of infected or transformed cells, leading to direct recognition by NK cells (Figure 2).

Figure 2.

Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the authorOverview of the molecular pathways leading to NK cell recognition of intrinsic cellular stress. Oncogenic transformation and viral infection can activate intrinsic cellular responses to stress. These responses include activation of the DNA-damage response, senescence, tumor suppressors, and the presentation and/or release of HSPs that, in turn, can activate NK cells through various receptor–ligand interactions. Senescent cells can also release pro-inflammatory cytokines that can recruit NK cells and other innate immunity, such as macrophages. CCL2, C-C motif chemokine ligand 2; CXCL11, C-X-C motif chemokine ligand 11; DR, death receptor 5; IFN, interferon; IL, interleukin; LFA-1, leukocyte function-associated antigen-1; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand

Full figure and legend (146K)

As a result of these studies, many therapeutic agents known to induce DNA damage have been evaluated for their ability to increase the immunogenicity of cancer cells for a more targeted therapeutic approach using NK cells.64, 65 For example, treatment of multiple myeloma cells with doxorubicin, melphalan, or bortezomib can lead to DNAM-1 and NKG2D ligand upregulation.65Indeed, many chemotherapeutic agents commonly used, especially in hematological malignancies, can trigger the DNA-damage pathway. Therefore, it is reasonable to speculate that there is a general role of ATM and ATR in the induction of NK cell activation as a therapeutic effect of these agents.

Senescence

Cellular senescence is generally defined as a growth-arrest program in mammalian cells that limits their lifespan.73 The major type of cellular senescence is replicative senescence that occurs due to telomere shortening. However, it is now generally accepted that premature senescence can also occur due to oncogene activation (oncogene-induced senescence) and/or the loss/gain of tumor-suppressor gene function, in the absence of telomere shortening.74 Thus, premature senescence is an important barrier against malignant transformation.59 Upon engagement of the senescence program, although cells are in growth arrest, they remain metabolically active and can produce many pro-inflammatory cytokines, as well as upregulate adhesion molecules and activating ligands to alert the immune system.75, 76, 77Activation of the immune system, in particular innate immunity, has a critical role in the clearance of senescent cells.78, 79, 80, 81More specifically, in a model of hepatocellular carcinoma, it has been shown that reactivation of p53 can induce a senescence program, resulting in tumor regression through the activation of NK cells, macrophages, and neutrophils. Of note, intercellular adhesion molecule (ICAM)-1, which can trigger both adhesion and cytotoxicity of NK cells,82 and interleukin-15, a cytokine that can promote NK cell effector function,83 were both upregulated in senescent tumors. More recently, the potential contribution of NK cells was also shown in the clearance of senescent hepatic stellate cells, a mechanism important in limiting liver fibrosis in response to a fibrogenic agent.80 ICAM-1, NKG2D ligands (MICA and ULPB2), and DNAM-1 ligands (CD155) were all upregulated on senescent hepatic stellate cells.

The specific mechanisms linking the senescence program to immune activation are not yet fully understood. However, the intracellular molecular mechanisms that govern induction of senescence may provide possible indications. Both replicative senescence and premature senescence (e.g., oncogene-induced senescence) have been shown to have common molecular determinants, such as the activation of the DNA-damage response pathway (e.g., ATM and ATR) and downstream activation of p53 and p16INK4A.1, 59, 84, 85, 86 Activation of the DNA-damage response would presumably initiate the upregulation of NK cell-activating ligands as previously discussed. However, how senescence may be linked to the induction of pro-inflammatory cytokine release is a more compelling question and requires further investigation (Figure 2). Nevertheless, induction of pro-inflammatory cytokines is an important protective mechanism in order to recruit immune cells that can rapidly recognize and remove senescent cells. Interestingly, activation of NK cells by senescent cells has been observed in a clinical context when multiple myeloma cells were treated with chemotherapy and genotoxic agents.65 In this setting, NKG2D and DNAM-1 ligands were both upregulated through a mechanism that required activation of the DNA-damage pathway initiated by ATM and ATR.65

Tumor Suppressors: p53

p53 is a potent tumor suppressor and central regulator of apoptosis, DNA repair, and cell proliferation, that is activated in response to DNA damage, oncogene activation, and other cellular stress.87 The number of identified cellular functions that p53 regulates has greatly increased over the past few years, and there is now a vast array of evidence that shows that p53 can be induced by viral infection88 to limit pathogen spread by inducing apoptosis.89, 90 Furthermore, p53 not only acts as an intrinsic barrier against tumorigenesis or pathogenic spread but can also lead to increased cellular immunogenicity. For example, p53 reactivation in a hepatocellular carcinoma can promote tumor regression mediated by innate immunity.78 A direct link between p53 expression and immune cell recognition was recently provided by Textor et al.91 where expression of p53 in lung cancer cell lines strongly upregulated the NKG2D ligands ULBP1 and 2, resulting in NK cell activation. Subsequently, p53-responsive elements were found to directly regulate ULBP1 and 2 expression, the deletion of which abolished the capacity of p53 to mediate ULBP1 and 2 upregulation. Another recent report that used a pharmacological activator of p53 confirmed the ability of p53 to directly induce ULBP2 expression that was independent of ATM/ATR.92 However, it has also been shown that miR34a and miR34C microRNAs (miRNAs) induced by p53 can target ULBP2 mRNA and reduce its cell-surface expression, suggesting that p53 may have a dual role in regulating ULBP2 expression.93 Finally, early work showed that NKG2D ligands can be upregulated by ATR/ATM in the total absence of p53 in tumor cell lines,62, 63 suggesting the existence of ATM/ATR-dependent and p53-independent pathways that regulate NKG2D ligand expression in response to cellular stress.

In addition to regulating NK cell ligand expression, genetic reactivation of p53 in tumors can also induce a wide array of pro-inflammatory mediators ranging from adhesion receptor (ICAM-1) expression to the production of various chemokines (CXCL11 and monocyte chemoattractant protein-1) and cytokines (interleukin-15).78 Furthermore, recent studies in anti-viral immunity indicate that several interferon-inducible genes and Toll-like receptor-3 expression are direct transcriptional targets of p53 and that p53 contributes to production of type I interferon by virally infected cells.94, 95, 96 All together, these studies suggest that p53 accumulation could represent a key determinant of the immunogenicity of stressed cells that are infected or undergoing malignant transformation through its ability to regulate innate immune activation.

Oncogenes

Malignant transformation is a complex process that frequently involves the activation of one or more oncogenes in addition to the inactivation or mutation of tumor-suppressor genes (e.g., p53). Oncogene activation is a powerful inducer of cellular stress that is able to activate intrinsic cellular programs that lead to cell apoptosis or senescence (e.g., activation of the DNA-damage response and p53).1 In addition, many recent reports have also shown that major oncogenes can activate extrinsic responses to cellular stress through inducing the upregulation of NK cell-activating ligands.63, 97, 98 This suggests that oncogene activation can represent a key cellular event in alerting the immune system to ongoing cellular transformation (Figure 3).

Figure 3.

Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the authorMolecular mechanisms that regulate the cell surface expression of NKG2D ligands. The major group of NK cell-activating ligands that are upregulated by intrinsic cellular responses to stress are those that bind the NKG2D receptor. Activation of the DNA-damage response, senescence, oncogenes, tumor suppressors, or sensing of deregulated proliferation can induce NKG2D ligand gene transcription and increase mRNA translation, leading to extracellular protein expression. MMP, matrix metalloproteases

Full figure and legend (183K)

The enhanced expression of the proto-oncogene Myc has been described as a critical event leading to cellular transformation and is a frequently found genetic alteration in cancer.99 In a recent study, again using the Eμ-myc model, Medzhitov and colleagues demonstrated the ability of c-Myc to alert NK cells to early oncogenic transformation through the upregulation of Rae-1.97 In this study, the induction of Rae-1 was dependent on the direct regulation of Rae-1 transcription by Myc through its interaction with the Raet1 epsilon gene. Collectively, these results provide a possible direct molecular mechanism to explain the increased susceptibility of NKG2D gene-targeted mice to lymphoma development in the Eμ-myc model.38

Recent evidence suggests that several oncogenic mutations of Ras (H-Ras, N-Ras, and K-Ras) can also regulate NKG2D ligand expression in both mice and humans.98 Interestingly, in this case, NKG2D ligands were regulated through MAPK/MEK and PI3K pathways downstream of oncogenic H-RasV12. The activation of PI3K pathways, and more particularly the p110α subunits by virus-encoded proteins, has also been shown to induce the Rae-1 family of ligands.100 As many viruses can manipulate the PI3K pathway101 and tumors often bear Ras and p110α oncogene mutations,102 collectively, this data suggests that there is the existence of a common molecular mechanism by which NK cells sense cellular stress mediated by PI3K-dependent regulation of NKG2D ligands.

Interestingly, whereas Myc was involved in the transcriptional regulation of NKG2D ligands, PI3K can increase NKG2D ligand expression by increasing the translation of Rae-1 mRNA.98 This involved the induction of eIF4E, a protein that enhances the translation of mRNA.103 As number of tumors and viruses can upregulate host translation initiation machinery through the overexpression of eIF4E,104, 105 this may represent an important means by which NK cells can discriminate tumor- and virus-infected cells from normal cells.

Heat-Shock Proteins (HSPs)

HSPs are highly conserved intracellular chaperone molecules that are present in most prokaryotic and eukaryotic cells that mediate protection against cellular damage under conditions of stress. HSPs are distributed in most intracellular compartments of cells where they support the correct folding of nascent polypeptides, prevent protein aggregation, and assist in protein transport across membranes.106 Many tumors display overexpression of HSPs as a response to cellular stress induced by oncogenic transformation.107, 108 HSPs can also be mobilized to the plasma membrane, or even released from cells, under conditions of stress.109

Although intracellular HSPs can promote cell survival by interfering with different apoptosis components, many studies have reported that membrane-bound or soluble HSPs can directly stimulate innate immunity.110 A major immunostimulatory function of HSPs is to promote the presentation of tumor-specific antigens by MHC class I to CD8 T cells.111, 112, 113 Soluble and membrane-bound HSPs can also induce antigen-presenting cell maturation and the resultant secretion of pro-inflammatory cytokines.114, 115, 116Finally, HSPs may directly activate NK cells as HSP70, when overexpressed on tumor cells, can induce a selective dose-dependent increase in NK cell-mediated cytotoxicity in vitro.117 NK cells may directly recognize HSP70 through a 14-amino-acid oligomer (TKD) that is localized in the C-terminal domain of the protein through CD94.118, 119 Tumor-specific HSP70 that is either presented at the cell surface or secreted on exosomes can also enhance NK cell activity against diverse types of cancer in vivo.120, 121 Most importantly, hepatocellular carcinoma cells that are treated with various chemotherapeutic agents can become more susceptible to NK cell-mediated cytotoxicity through their release of HSP-containing exosomes, giving the aforementioned findings a therapeutic context.122 Collectively, these results suggest that HSP translocation to the plasma membrane or secretion during cellular stress may represent a potent danger signal that can stimulate NK cell activity, particularly in the context of cancer.

 

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Protein profiling in cancer and metabolic diseases

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Deep Protein Profiling Key

Company has encouraged by two recent reports that emphasise the importance of protein profiling to improve outcomes in cancer treatment.

http://www.technologynetworks.com/Proteomics/news.aspx?ID=190145

Proteome Sciences plc has strongly encouraged by two recent reports that emphasise the importance of protein profiling to improve outcomes in cancer treatment. These highlight the growing need for more detailed, personal assessment of protein profiles to improve the management of cancer treatment.

In the first study two groups from University College London and Cancer Research UK demonstrated that genetic mutations in cancer can lead to changes in the proteins on the cell surface1. These are new sequences which are seen as foreign by the body’s immune system and, with appropriate immunotherapy, the level of response in lung cancer was greatly enhanced.

However many of the patients with these types of mutations unfortunately still did not respond which highlighted the need for deeper analysis of the protein expression in tumours in order to better appreciate the mechanisms that contribute to treatment failure.

The second study, led by Professor Nigel Bundred of Manchester University, reported that use of two drugs that act on the same breast cancer target, an over-expressing protein called Her-2, were able to eradicate detectable tumours in around 10% of those treated in just 11 days, with 87% of those treated having a proteomic change indicating cells had stopped growing and/or cell death had increased2.

Whilst these results appear very promising it is worth noting that the over-expressing Her-2 target is only present in about 20% of breast tumours meaning this combination therapy was successful in clearing tumours in just 2% of the total breast cancer population.

Dr. Ian Pike, Chief Operating Officer of Proteome Sciences commented, “Both these recent studies should rightly be recognised as important steps forward towards better cancer treatment. However, in order to overcome the limitations of current drug therapy programs, a much deeper and more comprehensive analysis of the complex protein networks that regulate tumour growth and survival is required and will be essential to achieve a major advance in the battle to treat cancer.

“Our SysQuant® workflows provide that solution. As an example, in pancreatic cancer3 we have successfully mapped the complex network of regulatory processes and demonstrate the ability to devise personalised treatment combinations on an individual basis for each patient. A retrospective study with SysQuant® to predict response to the targeted drug Sorafenib in liver cancer is in process and we are planning further prospective trials to guide personalised treatment selection in liver cancer.

“We are already delivering systems-wide biology solutions through SysQuant® and TMTcalibrator™ programs to our clients that are generating novel biological data and results using more sensitive profiling that are helping them to better understand their drug development programs and to provide new biomarkers for tracking patient response in clinical trials.

“We are strongly positioned to deliver more comprehensive analysis of proteins and cellular pathways across other areas of disease and in particular to extend the use of SysQuant® with other leading cancer research groups in liver and other cancers.”

Proteome Sciences has also expanded its offering in personalised medicine through the use of its TMTcalibrator™ technology to uniquely identify protein biomarkers that reveal active cancer and other disease processes in body fluid samples. The importance of these ‘mechanistic’ biomarkers is that they are essential to monitor that drugs are being effective and that they can be used as early biomarkers of disease recurrence.

Using SysQuant® and TMTcalibrator™, Proteome Sciences can deliver more comprehensive analysis and provide unparalleled levels of sensitivity and breadth of coverage of the proteome, enabling faster, more efficient drug development and more accurate disease diagnosis.

 

Discovering ‘Outlier’ Enzymes

Researchers at TSRI and Salk Institute have discovered ‘Outlier’ enzymes that could offer new targets to treat type 2 diabetes and inflammatory disorders.

A team led by scientists at The Scripps Research Institute (TSRI) and the Salk Institute for Biological Studies have discovered two enzymes that appear to play a role in metabolism and inflammation—and might someday be targeted with drugs to treat type 2 diabetes and inflammatory disorders. The discovery is unusual because the enzymes do not bear a resemblance—in their structures or amino-acid sequences—to any known class of enzymes.

The team of scientists nevertheless identified them as “outlier” members of the serine/threonine hydrolase class, using newer techniques that detect biochemical activity. “A huge fraction of the human ‘proteome’ remains uncharacterized, and this paper shows how chemical approaches can be used to uncover proteins of a given functionality that have eluded classification based on sequence or predicted structure,” said co-senior author Benjamin F. Cravatt, chair of TSRI’s Department of Chemical Physiology.

“In this study, we found two genes that control levels of lipids with anti-diabetic and anti-inflammatory activity, suggesting exciting targets for diabetes and inflammatory diseases,” said co-senior author Alan Saghatelian, who holds the Dr. Frederik Paulsen Chair at the Salk Institute. The study, which appeared as a Nature Chemical Biology Advance Online Publication on March 28, 2016, began as an effort in the Cravatt laboratory to discover and characterize new serine/threonine hydrolases using fluorophosphonate (FP) probes—molecules that selectively bind and, in effect, label the active sites of these enzymes.

Pulling FP-binding proteins out of the entire proteome of test cells and identifying them using mass spectrometry techniques, the team matched nearly all to known hydrolases. The major outlier was a protein called androgen-induced gene 1 protein (AIG1). The only other one was a distant cousin in terms of sequence, a protein called ADTRP. “Neither of these proteins had been characterized as an enzyme; in fact, there had been little functional characterization of them at all,” said William H. Parsons, a research associate in the Cravatt laboratory who was co-first author of the study.

Experiments on AIG1 and ADTRP revealed that they do their enzymatic work in a unique way. “It looks like they have an active site that is novel—it had never been described in the literature,” said Parsons. Initial tests with panels of different enzyme inhibitors showed that AIG1 and ADTRP are moderately inhibited by inhibitors of lipases—enzymes that break down fats and other lipids. But on what specific lipids do these newly discovered outlier enzymes normally work?

At the Salk Institute, the Saghatelian laboratory was investigating a class of lipids it had discovered in 2014. Known as fatty acid esters of hydroxy fatty acids (FAHFAs), these molecules showed strong therapeutic potential. Saghatelian and his colleagues had found that boosting the levels of one key FAHFA lipid normalizes glucose levels in diabetic mice and also reduces inflammation.

“[Ben Cravatt’s] lab was screening panels of lipids to find the ones that their new enzymes work on,” said Saghatelian, who is a former research associate in the Cravatt laboratory. “We suggested they throw FAHFAs in there—and these turned out to be very good substrates.” The Cravatt laboratory soon developed powerful inhibitors of the newly discovered enzymes, and the two labs began working together, using the inhibitors and genetic techniques to explore the enzymes’ functions in vitro and in cultured cells.

Co-first author Matthew J. Kolar, an MD-PhD student, performed most of the experiments in the Saghatelian lab. The team concluded that AIG1 and ADTRP, at least in the cell types tested, appear to work mainly to break down FAHFAs and not any other major class of lipid. In principle, inhibitors of AIG1 and ADTRP could be developed into FAHFA-boosting therapies.

“Our prediction,” said Saghatelian, “is that if FAHFAs do what we think they’re doing, then using an enzyme inhibitor to block their degradation would make FAHFA levels go up and should thus reduce inflammation as well as improve glucose levels and insulin sensitivity.” The two labs are now collaborating on further studies of the new enzymes—and the potential benefits of inhibiting them—in mouse models of diabetes, inflammation and autoimmune disease.

“One of the neat things this study shows,” said Cravatt, “is that even for enzyme classes as well studied as the hydrolases, there may still be hidden members that, presumably by convergent evolution, arrived at that basic enzyme mechanism despite sharing no sequence or structural homology.”

Other co-authors of the study, “AIG1 and ADTRP are atypical integral membrane hydrolases that degrade bioactive FAHFAs,” were Siddhesh S. Kamat, Armand B. Cognetta III, Jonathan J. Hulce and Enrique Saez, of TSRI; and co-senior author Barbara B. Kahn of Beth Israel Deaconess Medical Center and Harvard Medical School

 

New Weapon Against Breast Cancer

Molecular marker in healthy tissue can predict a woman’s risk of getting the disease, research says.

Harvard Stem Cell Institute (HSCI) researchers at Dana-Farber Cancer Institute (DFCI) and collaborators at Brigham and Women’s Hospital (BWH) have identified a molecular marker in normal breast tissue that can predict a woman’s risk for developing breast cancer, the leading cause of death in women with cancer worldwide.

The work, led by HSCI principal faculty member Kornelia Polyak and Rulla Tamimi of BWH, was published in an early online release and in the April 1 issue of Cancer Research.

The study builds on Polyak’s earlier research finding that women already identified as having a high risk of developing cancer — namely those with a mutation called BRCA1 or BRCA2 — or women who did not give birth before their 30s had a higher number of mammary gland progenitor cells.

In the latest study, Polyak, Tamimi, and their colleagues examined biopsies, some taken as many as four decades ago, from 302 participants in the Nurses’ Health Study and the Nurses’ Health Study II who had been diagnosed with benign breast disease. The researchers compared tissue from the 69 women who later developed cancer to the tissue from the 233 women who did not. They found that women were five times as likely to develop cancer if they had a higher percentage of Ki67, a molecular marker that identifies proliferating cells, in the cells that line the mammary ducts and milk-producing lobules. These cells, called the mammary epithelium, undergo drastic changes throughout a woman’s life, and the majority of breast cancers originate in these tissues.

Doctors already test breast tumors for Ki67 levels, which can inform decisions about treatment, but this is the first time scientists have been able to link Ki67 to precancerous tissue and use it as a predictive tool.

“Instead of only telling women that they don’t have cancer, we could test the biopsies and tell women if they were at high risk or low risk for developing breast cancer in the future,” said Polyak, a breast cancer researcher at Dana-Farber and co-senior author of the paper.

“Currently, we are not able to do a very good job at distinguishing women at high and low risk of breast cancer,” added co-senior author Tamimi, an associate professor at the Harvard T.H. Chan School of Public Health and Harvard Medical School. “By identifying women at high risk of breast cancer, we can better develop individualized screening and also target risk reducing strategies.”

To date, mammograms are the best tool for the early detection, but there are risks associated with screening. False positive and negative results and over-diagnosis could cause psychological distress, delay treatment, or lead to overtreatment, according to the National Cancer Institute (NCI).

Mammography machines also use low doses of radiation. While a single mammogram is unlikely to cause harm, repeated screening can potentially cause cancer, though the NCI writes that the benefits “nearly always outweigh the risks.”

“If we can minimize unnecessary radiation for women at low risk, that would be good,” said Tamimi.

Screening for Ki67 levels would “be easy to apply in the current setting,” said Polyak, though the researchers first want to reproduce the results in an independent cohort of women.

 

AIG1 and ADTRP are atypical integral membrane hydrolases that degrade bioactive FAHFAs

William H ParsonsMatthew J Kolar, …., Barbara B KahnAlan Saghatelian & Benjamin F Cravatt

Nature Chemical Biology 28 March 2016                    http://dx.doi.org:/10.1038/nchembio.2051

Enzyme classes may contain outlier members that share mechanistic, but not sequence or structural, relatedness with more common representatives. The functional annotation of such exceptional proteins can be challenging. Here, we use activity-based profiling to discover that the poorly characterized multipass transmembrane proteins AIG1 and ADTRP are atypical hydrolytic enzymes that depend on conserved threonine and histidine residues for catalysis. Both AIG1 and ADTRP hydrolyze bioactive fatty acid esters of hydroxy fatty acids (FAHFAs) but not other major classes of lipids. We identify multiple cell-active, covalent inhibitors of AIG1 and show that these agents block FAHFA hydrolysis in mammalian cells. These results indicate that AIG1 and ADTRP are founding members of an evolutionarily conserved class of transmembrane threonine hydrolases involved in bioactive lipid metabolism. More generally, our findings demonstrate how chemical proteomics can excavate potential cases of convergent or parallel protein evolution that defy conventional sequence- and structure-based predictions.

Figure 1: Discovery and characterization of AIG1 and ADTRP as FP-reactive proteins in the human proteome.

 

http://www.nature.com/nchembio/journal/vaop/ncurrent/carousel/nchembio.2051-F1.jpg

(a) Competitive ABPP-SILAC analysis to identify FP-alkyne-inhibited proteins, in which protein enrichment and inhibition were measured in proteomic lysates from SKOV3 cells treated with FP-alkyne (20 μM, 1 h) or DMSO using the FP-biotin…

 

  1. Willems, L.I., Overkleeft, H.S. & van Kasteren, S.I. Current developments in activity-based protein profiling. Bioconjug. Chem. 25, 11811191 (2014).
  2. Niphakis, M.J. & Cravatt, B.F. Enzyme inhibitor discovery by activity-based protein profiling.Annu. Rev. Biochem. 83, 341377 (2014).
  3. Berger, A.B., Vitorino, P.M. & Bogyo, M. Activity-based protein profiling: applications to biomarker discovery, in vivo imaging and drug discovery. Am. J. Pharmacogenomics 4,371381 (2004).
  4. Liu, Y., Patricelli, M.P. & Cravatt, B.F. Activity-based protein profiling: the serine hydrolases.Proc. Natl. Acad. Sci. USA 96, 1469414699 (1999).
  5. Simon, G.M. & Cravatt, B.F. Activity-based proteomics of enzyme superfamilies: serine hydrolases as a case study. J. Biol. Chem. 285, 1105111055 (2010).
  6. Bachovchin, D.A. et al. Superfamily-wide portrait of serine hydrolase inhibition achieved by library-versus-library screening. Proc. Natl. Acad. Sci. USA 107, 2094120946 (2010).
  7. Jessani, N. et al. A streamlined platform for high-content functional proteomics of primary human specimens. Nat. Methods 2, 691697 (2005).
  8. Higa, H.H., Diaz, S. & Varki, A. Biochemical and genetic evidence for distinct membrane-bound and cytosolic sialic acid O-acetyl-esterases: serine-active-site enzymes. Biochem. Biophys. Res. Commun. 144, 10991108 (1987).

Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesteras-1 inhibitors

Proc Natl Acad Sci U S A. 2011 Apr 26; 108(17): 6811–6816.    doi:  10.1073/pnas.1015248108
National Institutes of Health (NIH)-sponsored screening centers provide academic researchers with a special opportunity to pursue small-molecule probes for protein targets that are outside the current interest of, or beyond the standard technologies employed by, the pharmaceutical industry. Here, we describe the outcome of an inhibitor screen for one such target, the enzyme protein phosphatase methylesterase-1 (PME-1), which regulates the methylesterification state of protein phosphatase 2A (PP2A) and is implicated in cancer and neurodegeneration. Inhibitors of PME-1 have not yet been described, which we attribute, at least in part, to a dearth of substrate assays compatible with high-throughput screening. We show that PME-1 is assayable by fluorescence polarization-activity-based protein profiling (fluopol-ABPP) and use this platform to screen the 300,000+ member NIH small-molecule library. This screen identified an unusual class of compounds, the aza-β-lactams (ABLs), as potent (IC50 values of approximately 10 nM), covalent PME-1 inhibitors. Interestingly, ABLs did not derive from a commercial vendor but rather an academic contribution to the public library. We show using competitive-ABPP that ABLs are exquisitely selective for PME-1 in living cells and mice, where enzyme inactivation leads to substantial reductions in demethylated PP2A. In summary, we have combined advanced synthetic and chemoproteomic methods to discover a class of ABL inhibitors that can be used to selectively perturb PME-1 activity in diverse biological systems. More generally, these results illustrate how public screening centers can serve as hubs to create spontaneous collaborative opportunities between synthetic chemistry and chemical biology labs interested in creating first-in-class pharmacological probes for challenging protein targets.

Protein phosphorylation is a pervasive and dynamic posttranslational protein modification in eukaryotic cells. In mammals, more than 500 protein kinases catalyze the phosphorylation of serine, threonine, and tyrosine residues on proteins (1). A much more limited number of phosphatases are responsible for reversing these phosphorylation events (2). For instance, protein phosphatase 2A (PP2A) and PP1 are thought to be responsible together for > 90% of the total serine/threonine phosphatase activity in mammalian cells (3). Specificity is imparted on PP2A activity by multiple mechanisms, including dynamic interactions between the catalytic subunit (C) and different protein-binding partners (B subunits), as well as a variety of posttranslational chemical modifications (2, 4). Within the latter category is an unusual methylesterification event found at the C terminus of the catalytic subunit of PP2A that is introduced and removed by a specific methyltransferase (leucine carbxoylmethyltransferase-1 or LCMT1) (5, 6) and methylesterase (protein phosphatase methylesterase-1 or PME-1) (7), respectively (Fig. 1A). PP2A carboxymethylation (hereafter referred to as “methylation”) has been proposed to regulate PP2A activity, at least in part, by modulating the binding interaction of the C subunit with various regulatory B subunits (810). A predicted outcome of these shifts in subunit association is the targeting of PP2A to different protein substrates in cells. PME-1 has also been hypothesized to stabilize inactive forms of nuclear PP2A (11), and recent structural studies have shed light on the physical interactions between PME-1 and the PP2A holoenzyme (12).

There were several keys to the success of our probe development effort. First, screening for inhibitors of PME-1 benefited from the fluopol-ABPP technology, which circumvented the limited throughput of previously described substrate assays for this enzyme. Second, we were fortunate that the NIH compound library contained several members of the ABL class of small molecules. These chiral compounds, which represent an academic contribution to the NIH library, occupy an unusual portion of structural space that is poorly accessed by commercial compound collections. Although at the time of their original synthesis (23) it may not have been possible to predict whether these ABLs would show specific biological activity, their incorporation into the NIH library provided a forum for screening against many proteins and cellular targets, culminating in their identification as PME-1 inhibitors. We then used advanced chemoproteomic assays to confirm the remarkable selectivity displayed by ABLs for PME-1 across (and beyond) the serine hydrolase superfamily. That the mechanism for PME-1 inhibition involves acylation of the enzyme’s conserved serine nucleophile (Fig. 3) suggests that exploration of a more structurally diverse set of ABLs might uncover inhibitors for other serine hydrolases. In this way, the chemical information gained from a single high-throughput screen may be leveraged to initiate probe development programs for additional enzyme targets.

Projecting forward, this research provides an example of how public small-molecule screening centers can serve as a portal for spawning academic collaborations between chemical biology and synthetic chemistry labs. By continuing to develop versatile high-throughput screens and combining them with a small-molecule library of expanding structural diversity conferred by advanced synthetic methodologies, academic biologists and chemists are well-positioned to collaboratively deliver pharmacological probes for a wide range of proteins and pathways in cell biology.

 

New weapon against breast cancer

Molecular marker in healthy tissue can predict a woman’s risk of getting the disease, research says

April 6, 2016 | Popular
BRC_Cancer605

 

New Group of Aging-Related Proteins Discovered

http://www.genengnews.com/gen-news-highlights/new-group-of-aging-related-proteins-discovered/81252599/

Scientists have discovered a group of six proteins that may help to divulge secrets of how we age, potentially unlocking new insights into diabetes, Alzheimer’s, cancer, and other aging-related diseases.

The proteins appear to play several roles in our bodies’ cells, from decreasing the amount of damaging free radicals and controlling the rate at which cells die to boosting metabolism and helping tissues throughout the body respond better to insulin. The naturally occurring amounts of each protein decrease with age, leading investigators to believe that they play an important role in the aging process and the onset of diseases linked to older age.

The research team led by Pinchas Cohen, M.D., dean and professor of the University of Southern California Leonard Davis School of Gerontology, identified the proteins and observed their origin from mitochondria and their game-changing roles in metabolism and cell survival. This latest finding builds upon prior research by Dr. Cohen and his team that uncovered two significant proteins, humanin and MOTS-c, hormones that appear to have significant roles in metabolism and diseases of aging.

Unlike most other proteins, humanin and MOTS-c are encoded in mitochondria. Dr. Cohen’s team used computer analysis to see if the part of the mitochondrial genome that provides the code for humanin was coding for other proteins as well. The analysis uncovered the genes for six new proteins, which were dubbed small humanin-like peptides, or SHLPs, 1 through 6 (pronounced “schlep”).

After identifying the six SHLPs and successfully developing antibodies to test for several of them, the team examined both mouse tissues and human cells to determine their abundance in different organs as well as their functions. The proteins were distributed quite differently among organs, which suggests that the proteins have varying functions based on where they are in the body. Of particular interest is SHLP 2, according to Dr. Cohen.  The protein appears to have insulin-sensitizing, antidiabetic effects as well as neuroprotective activity that may emerge as a strategy to combat Alzheimer’s disease. He added that SHLP 6 is also intriguing, with a unique ability to promote cancer cell death and thus potentially target malignant diseases.

Proteins That May Protect Against Age Related Illnesses Discovered

 

The cell proliferation antigen Ki-67 organises heterochromatin

 Michal Sobecki, 

Antigen Ki-67 is a nuclear protein expressed in proliferating mammalian cells. It is widely used in cancer histopathology but its functions remain unclear. Here, we show that Ki-67 controls heterochromatin organisation. Altering Ki-67 expression levels did not significantly affect cell proliferation in vivo. Ki-67 mutant mice developed normally and cells lacking Ki-67 proliferated efficiently. Conversely, upregulation of Ki-67 expression in differentiated tissues did not prevent cell cycle arrest. Ki-67 interactors included proteins involved in nucleolar processes and chromatin regulators. Ki-67 depletion disrupted nucleologenesis but did not inhibit pre-rRNA processing. In contrast, it altered gene expression. Ki-67 silencing also had wide-ranging effects on chromatin organisation, disrupting heterochromatin compaction and long-range genomic interactions. Trimethylation of histone H3K9 and H4K20 was relocalised within the nucleus. Finally, overexpression of human or Xenopus Ki-67 induced ectopic heterochromatin formation. Altogether, our results suggest that Ki-67 expression in proliferating cells spatially organises heterochromatin, thereby controlling gene expression.

 

A protein called Ki-67 is only produced in actively dividing cells, where it is located in the nucleus – the structure that contains most of the cell’s DNA. Researchers often use Ki-67 as a marker to identify which cells are actively dividing in tissue samples from cancer patients, and previous studies indicated that Ki-67 is needed for cells to divide. However, the exact role of this protein was not clear. Before cells can divide they need to make large amounts of new proteins using molecular machines called ribosomes and it has been suggested that Ki-67 helps to produce ribosomes.

Now, Sobecki et al. used genetic techniques to study the role of Ki-67 in mice. The experiments show that Ki-67 is not required for cells to divide in the laboratory or to make ribosomes. Instead, Ki-67 alters the way that DNA is packaged in the nucleus. Loss of Ki-67 from mice cells resulted in DNA becoming less compact, which in turn altered the activity of genes in those cells.

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Microbe meets cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Microbes Meet Cancer

Understanding cancer’s relationship with the human microbiome could transform immune-modulating therapies.

By Kate Yandell | April 1, 2016  http://www.the-scientist.com/?articles.view/articleNo/45616/title/Microbes-Meet-Cancer

 © ISTOCK.COM/KATEJA_FN; © ISTOCK.COM/FRANK RAMSPOTT  http://www.the-scientist.com/images/April2016/feature1.jpg

In 2013, two independent teams of scientists, one in Maryland and one in France, made a surprising observation: both germ-free mice and mice treated with a heavy dose of antibiotics responded poorly to a variety of cancer therapies typically effective in rodents. The Maryland team, led by Romina Goldszmidand Giorgio Trinchieri of the National Cancer Institute, showed that both an investigational immunotherapy and an approved platinum chemotherapy shrank a variety of implanted tumor types and improved survival to a far greater extent in mice with intact microbiomes.1 The French group, led by INSERM’s Laurence Zitvogel, got similar results when testing the long-standing chemotherapeutic agent cyclophosphamide in cancer-implanted mice, as well as in mice genetically engineered to develop tumors of the lung.2

The findings incited a flurry of research and speculation about how gut microbes contribute to cancer cell death, even in tumors far from the gastrointestinal tract. The most logical link between the microbiome and cancer is the immune system. Resident microbes can either dial up inflammation or tamp it down, and can modulate immune cells’ vigilance for invaders. Not only does the immune system appear to be at the root of how the microbiome interacts with cancer therapies, it also appears to mediate how our bacteria, fungi, and viruses influence cancer development in the first place.

“We clearly see shifts in the [microbial] community that precede development of tumors,” says microbiologist and immunologist Patrick Schloss, who studies the influence of the microbiome on colon cancer at the University of Michigan.

But the relationship between the microbiome and cancer is complex: while some microbes promote cell proliferation, others appear to protect us against cancerous growth. And in some cases, the conditions that spur one cancer may have the opposite effect in another. “It’s become pretty obvious that the commensal microbiota affect inflammation and, through that or through other mechanisms, affect carcinogenesis,” says Trinchieri. “What we really need is to have a much better understanding of which species, which type of bug, is doing what and try to change the balance.”

Gut feeling

In the late 1970s, pathologist J. Robin Warren of Royal Perth Hospital in Western Australia began to notice that curved bacteria often appeared in stomach tissue biopsies taken from patients with chronic gastritis, an inflammation of the stomach lining that often precedes the development of stomach cancer. He and Barry J. Marshall, a trainee in internal medicine at the hospital, speculated that the bacterium, now called Helicobacter pylori, was somehow causing the gastritis.3 So committed was Marshall to demonstrating the microbe’s causal relationship to the inflammatory condition that he had his own stomach biopsied to show that it contained no H. pylori, then infected himself with the bacterium and documented his subsequent experience of gastritis.4 Scientists now accept that H. pylori, a common gut microbe that is present in about 50 percent of the world’s population, is responsible for many cases of gastritis and most stomach ulcers, and is a strong risk factor for stomach cancer.5 Marshall and Warren earned the 2005 Nobel Prize in Physiology or Medicine for their work.

H. pylori may be the most clear-cut example of a gut bacterium that influences cancer development, but it is likely not the only one. Researchers who study cancer in mice have long had anecdotal evidence that shifts in the microbiome influence the development of diverse tumor types. “You have a mouse model of carcinogenesis. It works beautifully,” says Trinchieri. “You move to another institution. It works completely differently,” likely because the animals’ microbiomes vary with environment.

IMMUNE INFLUENCE: In recent years, research has demonstrated that microbes living in and on the mammalian body can affect cancer risk, as well as responses to cancer treatment. Although the details of this microbe-cancer link remain unclear, investigators suspect that the microbiome’s ability to modulate inflammation and train immune cells to react to tumors is to blame.
See full infographic: WEB | PDF
© AL GRANBERG

Around the turn of the 21st century, cancer researchers began to systematically experiment with the rodent microbiome, and soon had several lines of evidence linking certain gut microbes with a mouse’s risk of colon cancer. In 2001, for example, Shoichi Kado of the Yakult Central Institute for Microbiological Research in Japan and colleagues found that a strain of immunocompromised mice rapidly developed colon tumors, but that germ-free versions of these mice did not.6 That same year, an MIT-based group led by the late David Schauer demonstrated that infecting mice with the bacterium Citrobacter rodentium spurred colon tumor development.7 And in 2003, MIT’s Susan Erdman and her colleagues found that they could induce colon cancer in immunocompromised mice by infecting them with Helicobacter hepaticus, a relative of? H. pylori that commonly exists within the murine gut microbiome.8

More recent work has documented a similar link between colon cancer and the gut microbiome in humans. In 2014, a team led by Schloss sequenced 16S rRNA genes isolated from the stool of 90 people, some with colon cancer, some with precancerous adenomas, and still others with no disease.9 The researchers found that the feces of people with cancer tended to have an altered composition of bacteria, with an excess of the common mouth microbes Fusobacterium or Porphyromonas. A few months later, Peer Bork of the European Molecular Biology Laboratory performed metagenomic sequencing of stool samples from 156 people with or without colorectal cancer. Bork and his colleagues found they could predict the presence or absence of cancer using the relative abundance of 22 bacterial species, including Porphyromonas andFusobacterium.10 They could also use the method to predict colorectal cancer with about the same accuracy as a blood test, correctly identifying about 50 percent of cancers while yielding false positives less than 10 percent of the time. When the two tests were combined, they caught more than 70 percent of cancers.

Whether changes in the microbiota in colon cancer patients are harbingers of the disease or a consequence of tumor development remained unclear. “What comes first, the change in the microbiome or tumor development?” asks Schloss. To investigate this question, he and his colleagues treated mice with microbiome-altering antibiotics before administering a carcinogen and an inflammatory agent, then compared the outcomes in those animals and in mice that had received only the carcinogenic and inflammatory treatments, no antibiotics. The antibiotic-treated animals had significantly fewer and smaller colon tumors than the animals with an undisturbed microbiome, suggesting that resident bacteria were in some way promoting cancer development. And when the researchers transferred microbiota from healthy mice to antibiotic-treated or germ-free mice, the animals developed more tumors following carcinogen exposure. Sterile mice that received microbiota from mice already bearing malignancies developed the most tumors of all.11

Most recently, Schloss and his colleagues showed that treating mice with seven unique combinations of antibiotics prior to exposing them to carcinogens yielded variable but predictable levels of tumor formation. The researchers determined that the number of tumors corresponded to the unique ways that each antibiotic cocktail modulated the microbiome.12

“We’ve kind of proven to ourselves, at least, that the microbiome is involved in colon cancer,” says Schloss, who hypothesizes that gut bacteria–driven inflammation is to blame for creating an environment that is hospitable to tumor development and growth. Gain or loss of certain components of the resident bacterial community could lead to the release of reactive oxygen species, damaging cells and their genetic material. Inflammation also involves increased release of growth factors and blood vessel proliferation, potentially supporting the growth of tumors. (See illustration above.)

Recent research has also yielded evidence that the gut microbiota impact the development of cancer in sites far removed from the intestinal tract, likely through similar immune-modulating mechanisms.

Systemic effects

In the mid-2000s, MIT’s Erdman began infecting a strain of mice predisposed to intestinal tumors withH. hepaticus and observing the subsequent development of colon cancer in some of the animals. To her surprise, one of the mice developed a mammary tumor. Then, more of the mice went on to develop mammary tumors. “This told us that something really interesting was going on,” Erdman recalls. Sure enough, she and her colleagues found that mice infected with H. hepaticus were more likely to develop mammary tumors than mice not exposed to the bacterium.13The researchers showed that systemic immune activation and inflammation could contribute to mammary tumors in other, less cancer-prone mouse models, as well as to the development of prostate cancer.

MICROBIAL STOWAWAYS: Bacteria of the human gut microbiome are intimately involved in cancer development and progression, thanks to their interactions with the immune system. Some microbes, such as Helicobacter pylori, increase the risk of cancer in their immediate vicinity (stomach), while others, such as some Bacteroides species, help protect against tumors by boosting T-cell infiltration.© EYE OF SCIENCE/SCIENCE SOURCE
http://www.the-scientist.com/images/April2016/immune_2.jpg

 

 

© DR. GARY GAUGLER/SCIENCE SOURCE  http://www.the-scientist.com/images/April2016/immune3.jpg

At the University of Chicago, Thomas Gajewski and his colleagues have taken a slightly different approach to studying the role of the microbiome in cancer development. By comparing Black 6 mice coming from different vendors—Taconic Biosciences (formerly Taconic Farms) and the Jackson Laboratory—Gajewski takes advantage of the fact that the animals’ different origins result in different gut microbiomes. “We deliberately stayed away from antibiotics, because we had a desire to model how intersubject heterogeneity [in cancer development] might be impacted by the commensals they happen to be colonized with,” says Gajewski in an email to The Scientist.

Last year, the researchers published the results of a study comparing the progression of melanoma tumors implanted under the mice’s skin, finding that tumors in the Taconic mice grew more aggressively than those in the Jackson mice. When the researchers housed the different types of mice together before their tumors were implanted, however, these differences disappeared. And transferring fecal material from the Jackson mice into the Taconic mice altered the latter’s tumor progression.14

Instead of promoting cancer, in these experiments the gut microbiome appeared to slow tumor growth. Specifically, the reduced tumor growth in the Jackson mice correlated with the presence of Bifidobacterium, which led to the greater buildup of T?cells in the Jackson mice’s tumors. Bifidobacteriaactivate dendritic cells, which present antigens from bacteria or cancer cells to T?cells, training them to hunt down and kill these invaders. Feeding Taconic mice bifidobacteria improved their response to the implanted melanoma cells.

“One hypothesis going into the experiments was that we might identify immune-suppressive bacteria, or commensals that shift the immune response towards a character that was unfavorable for tumor control,” says Gajewski.  “But in fact, we found that even a single type of bacteria could boost the antitumor immune response.”

http://www.the-scientist.com/images/April2016/immune4.jpg

 

Drug interactions

Ideally, the immune system should recognize cancer as invasive and nip tumor growth in the bud. But cancer cells display “self” molecules that can inhibit immune attack. A new type of immunotherapy, dubbed checkpoint inhibition or blockade, spurs the immune system to attack cancer by blocking either the tumor cells’ surface molecules or the receptors on T?cells that bind to them.

CANCER THERAPY AND THE MICROBIOME

In addition to influencing the development and progression of cancer by regulating inflammation and other immune pathways, resident gut bacteria appear to influence the effectiveness of many cancer therapies that are intended to work in concert with host immunity to eliminate tumors.

  • Some cancer drugs, such as oxaliplatin chemotherapy and CpG-oligonucleotide immunotherapy, work by boosting inflammation. If the microbiome is altered in such a way that inflammation is reduced, these therapeutic agents are less effective.
  • Cancer-cell surface proteins bind to receptors on T cells to prevent them from killing cancer cells. Checkpoint inhibitors that block this binding of activated T cells to cancer cells are influenced by members of the microbiota that mediate these same cell interactions.
  • Cyclophosphamide chemotherapy disrupts the gut epithelial barrier, causing the gut to leak certain bacteria. Bacteria gather in lymphoid tissue just outside the gut and spur generation of T helper 1 and T helper 17 cells that migrate to the tumor and kill it.

As part of their comparison of Jackson and Taconic mice, Gajewski and his colleagues decided to test a type of investigational checkpoint inhibitor that targets PD-L1, a ligand found in high quantities on the surface of multiple types of cancer cells. Monoclonal antibodies that bind to PD-L1 block the PD-1 receptors on T?cells from doing so, allowing an immune response to proceed against the tumor cells. While treating Taconic mice with PD-L1–targeting antibodies did improve their tumor responses, they did even better when that treatment was combined with fecal transfers from Jackson mice, indicating that the microbiome and the immunotherapy can work together to take down cancer. And when the researchers combined the anti-PD-L1 therapy with a bifidobacteria-enriched diet, the mice’s tumors virtually disappeared.14

Gajewski’s group is now surveying the gut microbiota in humans undergoing therapy with checkpoint inhibitors to better understand which bacterial species are linked to positive outcomes. The researchers are also devising a clinical trial in which they will give Bifidobacterium supplements to cancer patients being treated with the approved anti-PD-1 therapy pembrolizumab (Keytruda), which targets the immune receptor PD-1 on T?cells, instead of the cancer-cell ligand PD-L1.

Meanwhile, Zitvogel’s group at INSERM is investigating interactions between the microbiome and another class of checkpoint inhibitors called CTLA-4 inhibitors, which includes the breakthrough melanoma treatment ipilimumab (Yervoy). The researchers found that tumors in antibiotic-treated and germ-free mice had poorer responses to a CTLA-4–targeting antibody compared with mice harboring unaltered microbiomes.15 Particular Bacteroides species were associated with T-cell infiltration of tumors, and feedingBacteroides fragilis to antibiotic-treated or germ-free mice improved the animals’ responses to the immunotherapy. As an added bonus, treatment with these “immunogenic” Bacteroides species decreased signs of colitis, an intestinal inflammatory condition that is a dangerous side effect in patients using checkpoint inhibitors. Moreover, Zitvogel and her colleagues showed that human metastatic melanoma patients treated with ipilimumab tended to have elevated levels of B. fragilis in their microbiomes. Mice transplanted with feces from patients who showed particularly strong B. fragilis gains did better on anti-CTLA-4 treatment than did mice transplanted with feces from patients with normal levels of B. fragilis.

“There are bugs that allow the therapy to work, and at the same time, they protect against colitis,” says Trinchieri. “That is very exciting, because not only [can] we do something to improve the therapy, but we can also, at the same time, try to reduce the side effect.”

And these checkpoint inhibitors aren’t the only cancer therapies whose effects are modulated by the microbiome. Trinchieri has also found that an immunotherapy that combines antibodies against interleukin-10 receptors with CpG oligonucleotides is more effective in mice with unaltered microbiomes.1He and his NCI colleague Goldszmid further found that the platinum chemotherapy oxaliplatin (Eloxatin) was more effective in mice with intact microbiomes, and Zitvogel’s group has shown that the chemotherapeutic agent cyclophosphamide is dependent on the microbiota for its proper function.

Although the mechanisms by which the microbiome influences the effectiveness of such therapies remains incompletely understood, researchers once again speculate that the immune system is the key link. Cyclophosphamide, for example, spurs the body to generate two types of T?helper cells, T?helper 1 cells and a subtype of T?helper 17 cells referred to as “pathogenic,” both of which destroy tumor cells. Zitvogel and her colleagues found that, in mice with unaltered microbiomes, treatment with cyclophosphamide works by disrupting the intestinal mucosa, allowing bacteria to escape into the lymphoid tissues just outside the gut. There, the bacteria spur the body to generate T?helper 1 and T?helper 17 cells, which translocate to the tumor. When the researchers transferred the “pathogenic” T?helper 17 cells into antibiotic-treated mice, the mice’s response to chemotherapy was partly restored.

Microbiome modification

As the link between the microbiome and cancer becomes clearer, researchers are thinking about how they can manipulate a patient’s resident microbial communities to improve their prognosis and treatment outcomes. “Once you figure out exactly what is happening at the molecular level, if there is something promising there, I would be shocked if people don’t then go in and try to modulate the microbiome, either by using pharmaceuticals or using probiotics,” says Michael Burns, a postdoc in the lab of University of Minnesota genomicist Ran Blekhman.

Even if researchers succeed in identifying specific, beneficial alterations to the microbiome, however, molding the microbiome is not simple. “It’s a messy, complicated system that we don’t understand,” says Schloss.

So far, studies of the gut microbiome and colon cancer have turned up few consistent differences between cancer patients and healthy controls. And the few bacterial groups that have repeatedly shown up are not present in every cancer patient. “We should move away from saying, ‘This is a causal species of bacteria,’” says Blekhman. “It’s more the function of a community instead of just a single bacterium.”

But the study of the microbiome in cancer is young. If simply adding one type of microbe into a person’s gut is not enough, researchers may learn how to dose people with patient-specific combinations of microbes or antibiotics. In February 2016, a team based in Finland and China showed that a probiotic mixture dubbed Prohep could reduce liver tumor size by 40 percent in mice, likely by promoting an anti-inflammatory environment in the gut.16

“If it is true that, in humans, we can alter the course of the disease by modulating the composition of the microbiota,” says José Conejo-Garcia of the Wistar Institute in Philadelphia, “that’s going to be very impactful.”

Kate Yandell has been a freelance writer living Philadelphia, Pennsylvania. In February she became an associate editor at Cancer Today.

GENETIC CONNECTION

The microbiome doesn’t act in isolation; a patient’s genetic background can also greatly influence response to therapy. Last year, for example, the Wistar Institute’s José Garcia-Conejo and Melanie Rutkowski, now an assistant professor at the University of Virginia, showed that a dominant polymorphism of the gene for the innate immune protein toll-like receptor 5 (TLR5) influences clinical outcomes in cancer patients by changing how the patients’ immune cells interact with their gut microbes (Cancer Cell, 27:27-40, 2015).

More than 7 percent of people carry a specific mutation in TLR5 that prevents them from mounting a full immune response when exposed to bacterial flagellin. Analyzing both genetic and survival data from the Cancer Genome Atlas, Conejo-Garcia, Rutkowski, and their colleagues found that estrogen receptor–positive breast cancer patients who carry the TLR5 mutation, called the R392X polymorphism, have worse outcomes than patients without the mutation. Among patients with ovarian cancer, on the other hand, those with the TLR5 mutation were more likely to live at least six years after diagnosis than patients who don’t carry the mutation.

Investigating the mutation’s contradictory effects, the researchers found that mice with normal TLR5produce higher levels of the cytokine interleukin 6 (IL-6) than those carrying the mutant version, which have higher levels of a different cytokine called interleukin 17 (IL-17). But when the researchers knocked out the animals’ microbiomes, these differences in cytokine production disappeared, as did the differences in cancer progression between mutant and wild-type animals.

“The effectiveness of depleting specific populations or modulating the composition of the microbiome is going to affect very differently people who are TLR5-positive or TLR5-negative,” says Conejo-Garcia. And Rutkowski speculates that many more polymorphisms linked to cancer prognosis may act via microbiome–immune system interactions. “I think that our paper is just the tip of the iceberg.”

References

  1. N. Iida et al., “Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment,” Science, 342:967-70, 2013.
  2. S. Viaud et al., “The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide,” Science, 342:971-76, 2013.
  3. J.R. Warren, B. Marshall, “Unidentified curved bacilli on gastric epithelium in active chronic gastritis,”Lancet, 321:1273-75, 1983.
  4. B.J. Marshall et al., “Attempt to fulfil Koch’s postulates for pyloric Campylobacter,” Med J Aust, 142:436-39, 1985.
  5. J. Parsonnet et al., “Helicobacter pylori infection and the risk of gastric carcinoma,” N Engl J Med, 325:1127-31, 1991.
  6. S. Kado et al., “Intestinal microflora are necessary for development of spontaneous adenocarcinoma of the large intestine in T-cell receptor β chain and p53 double-knockout mice,” Cancer Res, 61:2395-98, 2001.
  7. J.V. Newman et al., “Bacterial infection promotes colon tumorigenesis in ApcMin/+ mice,” J Infect Dis, 184:227-30, 2001.
  8. S.E. Erdman et al., “CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice,” Am J Pathol, 162:691-702, 2003.
  9. J.P. Zackular et al., “The human gut microbiome as a screening tool for colorectal cancer,” Cancer Prev Res, 7:1112-21, 2014.
  10. G. Zeller et al., “Potential of fecal microbiota for early-stage detection of colorectal cancer,” Mol Syst Biol, 10:766, 2014.
  11. J.P. Zackular et al., “The gut microbiome modulates colon tumorigenesis,” mBio, 4:e00692-13, 2013.
  12. J.P. Zackular et al., “Manipulation of the gut microbiota reveals role in colon tumorigenesis,”mSphere, doi:10.1128/mSphere.00001-15, 2015.
  13. V.P. Rao et al., “Innate immune inflammatory response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice,” Cancer Res, 66:7395, 2006.
  14. A. Sivan et al., “Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy,” Science, 350:1084-89, 2015.
  15. M. Vétizou et al., “Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota,”Science, 350:1079-84, 2015.

……..

 

Microbially Driven TLR5-Dependent Signaling Governs Distal Malignant Progression through Tumor-Promoting Inflammation

Melanie R. Rutkowski, Tom L. Stephen, Nikolaos Svoronos, …., Julia Tchou,  Gabriel A. Rabinovich, Jose R. Conejo-Garcia
Cancer cell    12 Jan 2015; Volume 27, Issue 1, p27–40  http://dx.doi.org/10.1016/j.ccell.2014.11.009
Figure thumbnail fx1
  • TLR5-dependent IL-6 mobilizes MDSCs that drive galectin-1 production by γδ T cells
  • IL-17 drives malignant progression in IL-6-unresponsive tumors
  • TLR5-dependent differences in tumor growth are abrogated upon microbiota depletion
  • A common dominant TLR5 polymorphism influences the outcome of human cancers

The dominant TLR5R392X polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal locations by increasing systemic IL-6, which drives mobilization of myeloid-derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated in TLR5-unresponsive tumor-bearing mice but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism.

see also… Immune Influence

In recent years, research has demonstrated that microbes living in and on the mammalian body can affect cancer risk, as well as responses to cancer treatment.

By Kate Yandell | April 1, 2016

http://www.the-scientist.com/?articles.view/articleNo/45644/title/Immune-Influence

Although the details of this microbe-cancer link remain unclear, investigators suspect that the microbiome’s ability to modulate inflammation and train immune cells to react to tumors is to blame. Here are some of the hypotheses that have come out of recent research in rodents for how gut bacteria shape immunity and influence cancer.

HOW THE MICROBIOME PROMOTES CANCER

Gut bacteria can dial up inflammation locally in the colon, as well as in other parts of the body, leading to the release of reactive oxygen species, which damage cells and DNA, and of growth factors that spur tumor growth and blood vessel formation.

http://www.the-scientist.com/images/April2016/ImmuneInfluence1_640px.jpg

http://www.the-scientist.com/images/April2016/ImmuneInfluence2_310px1.jpg

Helicobacter pylori can cause inflammation and high cell turnover in the stomach wall, which may lead to cancerous growth.

HOW THE MICROBIOME STEMS CANCER

Gut bacteria can also produce factors that lower inflammation and slow tumor growth. Some gut bacteria (e.g., Bifidobacterium)
appear to activate dendritic cells,
which present cancer-cell antigens to T cells that in turn kill the cancer cells.

http://www.the-scientist.com/images/April2016/ImmuneInfluence3_310px1.jpg

http://www.the-scientist.com/images/April2016/ImmuneInfluence4_310px1.jpg

Read the full story.

 

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Selye’s Riddle solved

Larry H. Bernstein, mD, FCAP, Curator

LPBI

 

Mathematicians Solve 78-year-old Mystery

Mathematicians developed a solution to Selye's riddle which has puzzled scientists for almost 80 years.
Mathematicians developed a solution to Selye’s riddle which has puzzled scientists for almost 80 years.

In previous research, it was suggested that adaptation of an animal to different factors looks like spending of one resource, and that the animal dies when this resource is exhausted. In 1938, Hans Selye introduced “adaptation energy” and found strong experimental arguments in favor of this hypothesis. However, this term has caused much debate because, as it cannot be measured as a physical quantity, adaptation energy is not strictly energy.

 

Evolution of adaptation mechanisms: Adaptation energy, stress, and oscillating death

Alexander N. Gorbana, , Tatiana A. Tyukinaa, Elena V. Smirnovab, Lyudmila I. Pokidyshevab,

Highlights

•   We formalize Selye׳s ideas about adaptation energy and dynamics of adaptation.
•   A hierarchy of dynamic models of adaptation is developed.
•   Adaptation energy is considered as an internal coordinate on the ‘dominant path’ in the model of adaptation.
•   The optimal distribution of resources for neutralization of harmful factors is studied.
•   The phenomena of ‘oscillating death’ and ‘oscillating remission’ are predicted.       

In previous research, it was suggested that adaptation of an animal to different factors looks like spending of one resource, and that the animal dies when this resource is exhausted.

In 1938, Selye proposed the notion of adaptation energy and published ‘Experimental evidence supporting the conception of adaptation energy.’ Adaptation of an animal to different factors appears as the spending of one resource. Adaptation energy is a hypothetical extensive quantity spent for adaptation. This term causes much debate when one takes it literally, as a physical quantity, i.e. a sort of energy. The controversial points of view impede the systematic use of the notion of adaptation energy despite experimental evidence. Nevertheless, the response to many harmful factors often has general non-specific form and we suggest that the mechanisms of physiological adaptation admit a very general and nonspecific description.

We aim to demonstrate that Selye׳s adaptation energy is the cornerstone of the top-down approach to modelling of non-specific adaptation processes. We analyze Selye׳s axioms of adaptation energy together with Goldstone׳s modifications and propose a series of models for interpretation of these axioms. Adaptation energy is considered as an internal coordinate on the ‘dominant path’ in the model of adaptation. The phenomena of ‘oscillating death’ and ‘oscillating remission’ are predicted on the base of the dynamical models of adaptation. Natural selection plays a key role in the evolution of mechanisms of physiological adaptation. We use the fitness optimization approach to study of the distribution of resources for neutralization of harmful factors, during adaptation to a multifactor environment, and analyze the optimal strategies for different systems of factors.

In this work, an international team of researchers, led by Professor Alexander N. Gorban from the University of Leicester, have developed a solution to Selye’s riddle, which has puzzled scientists for almost 80 years.

Alexander N. Gorban, Professor of Applied Mathematics in the Department of Mathematics at the University of Leicester, said: “Nobody can measure adaptation energy directly, indeed, but it can be understood by its place already in simple models. In this work, we develop a hierarchy of top-down models following Selye’s findings and further developments. We trust Selye’s intuition and experiments and use the notion of adaptation energy as a cornerstone in a system of models. We provide a ‘thermodynamic-like’ theory of organism resilience that, just like classical thermodynamics, allows for economics metaphors, such as cost and bankruptcy and, more importantly, is largely independent of a detailed mechanistic explanation of what is ‘going on underneath’.”

Adaptation energy is considered as an internal coordinate on the “dominant path” in the model of adaptation. The phenomena of “oscillating death” and “oscillating remission,” which have been observed in clinic for a long time, are predicted on the basis of the dynamical models of adaptation. The models, based on Selye’s idea of adaptation energy, demonstrate that the oscillating remission and oscillating death do not need exogenous reasons. The developed theory of adaptation to various factors gives the instrument for the early anticipation of crises.

Professor Alessandro Giuliani from Istituto Superiore di Sanità in Rome commented on the work, saying: “Gorban and his colleagues dare to make science adopting the thermodynamics style: they look for powerful principles endowed with predictive ability in the real world before knowing the microscopic details. This is, in my opinion, the only possible way out from the actual repeatability crisis of mainstream biology, where a fantastic knowledge of the details totally fails to predict anything outside the test tube.1

Citation: Alexander N. Gorban, Tatiana A. Tyukina, Elena V. Smirnova, Lyudmila I. Pokidysheva. Evolution of adaptation mechanisms: Adaptation energy, stress, and oscillating death. Journal of Theoretical Biology, 2016; DOI:10.1016/j.jtbi.2015.12.017. Voosen P. (2015) Amid a Sea of False Findings NIH tries Reform, The Chronicle of Higher Education.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Cardiomyocytes from mesenchmal stem cells?

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Introduction: A just published article from the Gladstone Institute establishes that cardiac muscle can be generated from inducible explandable  cardiovascular progenitor cells.  However, while the study has validity, it leaves much to be explained, especially in light of the references to many previous studies to generate cardiomycytes for heart failure.

Skin Cells Opening the Door to the Possibility of Personalized Medicine for Heart Attack Patients

iceC-Figure6

https://beyondthedish.files.wordpress.com/2016/03/iecpcs-give-rise-to-cms-ecs-and-smcs-in-vivo-and-improve-cardiac-function-after-mi.jpg?w=652

 

ieCPCs Give Rise to CMs, ECs, and SMCs In Vivo and Improve Cardiac Function after MI

(A–E) Immunofluorescence analyses of RFP and CM (A), EC (B and C), and SMC (D and E) markers in tissue sections collected 2 weeks after transplanting RFP-labeled ieCPCs at passage 10 into infarcted hearts of immunodeficient mice. Scale bars represent 100 μm.

(F and G) Ejection fraction and fractional shortening of the left ventricle (LV) quantified by echocardiography. Results from two independent experiments were shown. D, days; W, weeks.

(H–J) Cardiac fibrosis was evaluated at eight levels (L1–L8) by Masson’s trichrome staining 12 weeks after coronary ligation. The ligation site is marked as X. Sections of representative hearts are shown in (I) with quantification in (J). Scar tissue (%) = (the sum of fibrotic area or length at L1–L8/the sum of LV area or circumference at L1–L8) × 100. Scale bars represent 500 μm.

(K) Quantification of LV circumference of mouse hearts 12 weeks after transplantation of 2nd MEFs or ieCPCs. Data were summarized from 48 sections for each group. Data are mean ± SE. p < 0.05.

“Cardiac progenitor cells could be ideal for heart regeneration,” said senior author Sheng Ding, PhD, a senior investigator at Gladstone. “They are the closest precursor to functional heart cells, and, in a single step, they can rapidly and efficiently become heart cells, both in a dish and in a live heart. With our new technology, we can quickly create billions of these cells in a dish and then transplant them into damaged hearts to treat heart failure.”

 

Discussion:  The study raises some important questions.

  1. How are the cultured cells different than those used in previous studies?
  2. Cardiomyocytes and fibroblasts are both of mesodermal origin.  What determines which way the stem cell line will differentiate?
  3. What is the difference, if any, between the cell culture environment and the in vivo environment into which they are placed?
  4. There is a difference between chronic hypoxemia with congestive heart failure and acute coronary syndrome.  The experiment performed would be more apt to apply to post-ACS than to chronic heart failure.

 

Functional heart muscle regenerated in decellularized human hearts

March 11, 2016    http://snip.ly/txc6j#http://medicalxpress.com/news/2016-03-functional-heart-muscle-regenerated-decellularized.html

A partially recellularized human whole-heart cardiac scaffold, reseeded with human cardiomyocytes derived from induced pluripotent stem cells, being cultured in a bioreactor that delivers a nutrient solution and replicates some of the environmental conditions around a living heart. Credit: Bernhard Jank, MD, Ott Lab, Center for Regenerative Medicine, Massachusetts General Hospital

 

Massachusetts General Hospital (MGH) researchers have taken some initial steps toward the creation of bioengineered human hearts using donor hearts stripped of components that would generate an immune response and cardiac muscle cells generated from induced pluripotent stem cells (iPSCs), which could come from a potential recipient. The investigators described their accomplishments – which include developing an automated bioreactor system capable of supporting a whole human heart during the recellularization process—earlier this year in Circulation Research.

“Generating functional cardiac tissue involves meeting several challenges,” says Jacques Guyette, PhD, of the MGH Center for Regenerative Medicine (CRM), lead author of the report. “These include providing a structural scaffold that is able to support cardiac function, a supply of specialized cardiac , and a supportive environment in which cells can repopulate the scaffold to form mature tissue capable of handling complex cardiac functions.”

The research team is led by Harald Ott, MD, of the MGH CRM and the Department of Surgery, senior author of the paper. In 2008, Ott developed a procedure for stripping the living cells from a donor organ with a detergent solution and then repopulating the remaining extracellular matrix scaffold with organ-appropriate types of cells. Since then his team has used the approach to generate functional rat kidneys and lungs and has decellularized large-animal hearts, lungs and kidneys. This report is the first to conduct a detailed analysis of the matrix scaffold remaining after decellularization of whole human hearts, along with recellularization of the cardiac matrix in three-dimensional and whole-heart formats.

The study included 73 human hearts that had been donated through the New England Organ Bank, determined to be unsuitable for transplantation and recovered under research consent. Using a scaled-up version of the process originally developed in rat hearts, the team decellularized hearts from both brain-dead donors and from those who had undergone . Detailed characterization of the remaining cardiac scaffolds confirmed a high retention of matrix proteins and structure free of cardiac cells, the preservation of coronary vascular and microvascular structures, as well as freedom from human leukocyte antigens that could induce rejection. There was little difference between the reactions of organs from the two donor groups to the complex decellularization process.

Instead of using genetic manipulation to generate iPSCs from , the team used a newer method to reprogram skin cells with messenger RNA factors, which should be both more efficient and less likely to run into regulatory hurdles. They then induced the  to differentiate into or cardiomyocytes, documenting patterns of gene expression that reflected developmental milestones and generating cells in sufficient quantity for possible clinical application. Cardiomyocytes were then reseeded into three-dimensional matrix tissue, first into thin matrix slices and then into 15 mm fibers, which developed into spontaneously contracting tissue after several days in culture.

The last step reflected the first regeneration of human heart muscle from within a cell-free, human whole-heart matrix. The team delivered about 500 million iPSC-derived cardiomyocytes into the left ventricular wall of decellularized hearts. The organs were mounted for 14 days in an automated bioreactor system developed by the MGH team that both perfused the organ with nutrient solution and applied environmental stressors such as ventricular pressure to reproduce conditions within a living heart. Analysis of the regenerated tissue found dense regions of iPSC-derived cells that had the appearance of immature cardiac muscle tissue and demonstrated functional contraction in response to electrical stimulation.

“Regenerating a whole heart is most certainly a long-term goal that is several years away, so we are currently working on engineering a functional myocardial patch that could replace cardiac tissue damaged due a heart attack or heart failure,” says Guyette. “Among the next steps that we are pursuing are improving methods to generate even more – recellularizing a whole heart would take tens of billions—optimizing bioreactor-based culture techniques to improve the maturation and function of engineered cardiac tissue, and electronically integrating regenerated tissue to function within the recipient’s heart.”

Team leader Ott, an assistant professor of Surgery at Harvard Medical School, adds, “Generating personalized functional myocardium from patient-derived cells is an important step towards novel device-engineering strategies and will potentially enable patient-specific disease modeling and therapeutic discovery. Our team is excited to further develop both of these strategies in future projects.”

Explore further: A tool for isolating progenitor cells from human heart tissue could lead to heart repair

More information: Jacques P. Guyette et al. Bioengineering Human Myocardium on Native Extracellular MatrixNovelty and Significance, Circulation Research (2016). DOI: 10.1161/CIRCRESAHA.115.306874

 

Stem cell study in mice offers hope for treating heart attack patients

February 15, 2012  http://medicalxpress.com/news/2012-02-stem-cell-mice-heart-patients.html

 

Stem cell study in mice offers hope for treating heart attack patients

Cardiac stem cells, pictured here, give hope to patients who have suffered a heart attack. Credit: UCSF

A UCSF stem cell study conducted in mice suggests a novel strategy for treating damaged cardiac tissue in patients following a heart attack. The approach potentially could improve cardiac function, minimize scar size, lead to the development of new blood vessels – and avoid the risk of tissue rejection.

In the investigation, reported online in the journal PLoS ONE, the researchers isolated and characterized a novel type of cardiac stem cell from the tissue of middle-aged mice following a .

Then, in one experiment, they placed the in the culture dish and showed they had the ability to differentiate into cardiomyocytes, or “beating heart cells,” as well as endothelial cells and smooth muscle cells, all of which make up the heart.

In another, they made copies, or “clones,” of the cells and engrafted them in the tissue of other of the same genetic background who also had experienced heart attacks. The cells induced angiogenesis, or blood vessel growth, or differentiated, or specialized, into endothelial and smooth muscle cells, improving .

“These findings are very exciting,” said first author Jianqin Ye, PhD, MD, senior scientist at UCSF’s Translational Cardiac Stem Cell Program. First, “we showed that we can isolate these cells from the heart of middle-aged animals, even after a heart attack.” Second, he said, “we determined that we can return these cells to the animals to induce repair.”

Importantly, the stem cells were identified and isolated in all four chambers of the heart, potentially making it possible to isolate them from patients’ hearts by doing right ventricular biopsies, said Ye. This procedure is “the safest way of obtaining cells from the heart of live patients, and is relatively easy to perform,” he said.

“The finding extends the current knowledge in the field of native cardiac progenitor cell therapy,” said senior author Yerem Yeghiazarians, MD, director of UCSF’s Translational Cardiac Stem Cell Program and an associate professor at the UCSF Division of Cardiology. “Most of the previous research has focused on a different subset of cardiac progenitor cells. These novel cardiac precursor cells appear to have great therapeutic potential.”

The hope, he said, is that patients who have severe heart failure after a heart attack or have cardiomyopathy would be able to be treated with their own cardiac stem cells to improve the overall health and function of the heart. Because the cells would have come from the patients, themselves, there would be no concern of cell rejection after therapy.

The cells, known as Sca-1+ stem enriched in Islet (Isl-1) expressing cardiac precursors, play a major role in cardiac development. Until now, most of the research has focused on a different subset of cardiac progenitor, or early stage, cells known as, c-kit cells.

The Sca-1+ cells, like the c-kit cells, are located within a larger clump of cells called cardiospheres.

The UCSF researchers used special culture techniques and isolated Sca-1+ cells enriched in the Isl-1expressing cells, which are believed to be instrumental in the heart’s development. Since Isl-1 is expressed in the cell nucleus, it has been difficult to isolate them but the new technique enriches for this cell population.

The findings suggest a potential treatment strategy, said Yeghiazarians. “Heart disease, including heart attack and heart failure, is the number one killer in advanced countries. It would be a huge advance if we could decrease repeat hospitalizations, improve the quality of life and increase survival.” More studies are being planned to address these issues in the future.

An estimated 785,000 Americans will have a new heart attack this year, and 470,000 who will have a recurrent attack. Heart disease remains the number one killer in the United States, accounting for one out of every three deaths, according to the American Heart Association.

Medical costs of cardiovascular disease are projected to triple from $272.5 billion to $818.1 billion between now and 2030, according to a report published in the journal Circulation.

 

Sca-1+ Cardiosphere-Derived Cells Are Enriched for Isl1-Expressing Cardiac Precursors and Improve Cardiac Function after Myocardial Injury

Jianqin Ye , Andrew Boyle , Henry Shih , Richard E. Sievers , Yan Zhang , William Grossman , Harold S. Bernstein , Yerem Yeghiazarians
http://dx.doi.org:/10.1371/journal.pone.0030329

Background

Endogenous cardiac progenitor cells are a promising option for cell-therapy for myocardial infarction (MI). However, obtaining adequate numbers of cardiac progenitors after MI remains a challenge. Cardiospheres (CSs) have been proposed to have cardiac regenerative properties; however, their cellular composition and how they may be influenced by the tissue milieu remains unclear.

Methodology/Principal Finding

Using “middle aged” mice as CSs donors, we found that acute MI induced a dramatic increase in the number of CSs in a mouse model of MI, and this increase was attenuated back to baseline over time. We also observed that CSs from post-MI hearts engrafted in ischemic myocardium induced angiogenesis and restored cardiac function. To determine the role of Sca-1+CD45 cells within CSs, we cloned these from single cell isolates. Expression of Islet-1 (Isl1) in Sca-1+CD45 cells from CSs was 3-fold higher than in whole CSs. Cloned Sca-1+CD45 cells had the ability to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro. We also observed that cloned cells engrafted in ischemic myocardium induced angiogenesis, differentiated into endothelial and smooth muscle cells and improved cardiac function in post-MI hearts.

Conclusions/Significance  

These studies demonstrate that cloned Sca-1+CD45 cells derived from CSs from infarcted “middle aged” hearts are enriched for second heart field (i.e., Isl-1+) precursors that give rise to both myocardial and vascular tissues, and may be an appropriate source of progenitor cells for autologous cell-therapy post-MI.

 

Incorporation of Mg particles into PDLLA regulates mesenchymal stem cell and macrophage responses

Sandra C. Cifuentes1, Fátima Bensiamar2,3, Amparo M. Gallardo-Moreno3,4, Tim A. Osswald5, José L. González-Carrasco1,3, et al.
J Biomed Materials Res Part A  104(4), pages 866–878, April 2016                    http://dx.doi.org:/10.1002/jbm.a.35625

In this work, we investigated a new approach to incorporate Mg particles within a PDLLA matrix using a solvent-free commercially available process. PDLLA/Mg composites were manufactured by injection moulding and the effects of Mg incorporated into PDLLA on MSC and macrophage responses were evaluated. Small amounts of Mg particles (≤1 wt %) do not cause thermal degradation of PDLLA, which retains its mechanical properties. PDLLA/Mg composites release hydrogen, alkaline products and Mg2+ ions without changing pH of culture media. Mg-containing materials provide a noncytotoxic environment that enhances MSC viability. Concentration of Mg2+ ions in extracts of MSCs increases with the increment of Mg content in the composites. Incorporation of Mg particles into PDLLA stimulates FN production, ALP activity, and VEGF secretion in MSCs, an effect mediated by degradation products dissolved from the composites. Degradation products of PDLLA induce an increase in MCP-1, RANTES, and MIP-1α secretion in macrophages while products of composites have minimal effect on these chemokines. Regulation of MSC behavior at the biomaterial’s interface and macrophage-mediated inflammatory response to the degradation products is related to the incorporation of Mg in the composites. These findings suggest that including small amounts of Mg particles into polymeric devices can be a valuable strategy to promote osseointegration and reduce host inflammatory response. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 866–878, 2016.

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Success in Psoriasis Treatment

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Anti-IL17A Tx Clears Most Cases of Psoriasis

Durable long-term responses with ixekizumab, secukinumab

http://www.medpagetoday.com/MeetingCoverage/AAD/56597?xid=nl_mpt_guptaguide_2016-03-07

  • Note that these studies were published as abstracts and presented at a conference.
  • These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • More than half of patients with moderate-to-severe plaque psoriasis remained clear of lesions after a year of treatment with the interleukin-17A inhibitor ixekizumab.
  • Note that in another study, comparing two monoclonal antibodies for secukinumab (Cosentyx) or ustekinumab (Stelara) in patients with moderate to severe plaque psoriasis. showed sustained superiority for secukinumab (Cosentyx) over ustekinumab (Stelara).

More than half of patients with moderate-to-severe plaque psoriasis remained clear of lesions after a year of treatment with the interleukin-17A inhibitor ixekzumab, according to data reported here.

The 60-week follow-up data showed that 54% of patients treated with either of two doses of ixekizumab had 100% improvement in the Psoriasis Area and Severity Index (PASI 100). More than 70% achieved PASI 90, and more than 80% met criteria for PASI 75 response.

In general, the monoclonal antibody demonstrated good tolerability, associated with a discontinuation rate of about 5%, Andrew Blauvelt, MD, of Oregon Medical Research Center in Portland, reported at the American Academy of Dermatology meeting.

“Izekizumab treatment led to high clinical response rates and sustained efficacy in a majority of patients,” Blauvelt said. “More than half of ixekizumab-treated patients achieved complete resolution of psoriatic plaques at week 60. The safety profile for ixekizumab was similar to what was observed during the 12-week induction period.”

Ixekizumab is a specific inhibitor of the IL-17A receptor. The antibody was compared against placebo and etanercept (Enbrel) in two phase III trials that evaluated two ixekizumab dosing schedules (administration every 2 or 4 weeks). More than 1,200 patients were randomized 1:2:2:2 to placebo, etanercept (Enbrel) or one of the ixekizumab schedules.

As previously reported, the antibody demonstrated superior efficacy after a 12-week induction period. PASI 75 response rates were 7.3% with placebo, 53.4% with etanercept, and 84.2% and 87.3% with the two ixekizumab regimens. PASI 90 rates were 3.1%, 25.7%, 65.3%, and 68.1%. PASI 100 responses were attained by 0%, 73%, 35%, and 37.7%.

Upon completion of the induction phase, all patients transitioned to open-label ixekizumab, administered every 4 weeks. Blauvelt reported findings for patients who received only ixekizumab for the entire 60-week follow-up period.

The data showed that response rates attained at 12 weeks with ixekizumab held up through the 60-week follow-up period. The intention-to-treat analysis (n=771) showed response rates of 82%, 72%, and 54% for PASI 75, PASI 90, and PASI 100. A per-protocol analysis (n=722) showed a PASI 75 response rate of 87%, PASI 90 response rate of 77%, and PASI 100 response rate of 57%.

Cosentyx Versus Stelara

In another study reported here, long-term follow-up from a randomized trial comparing two other biologic drugs showed sustained superiority for secukinumab (Cosentyx) over ustekinumab (Stelara) in patients with moderate to severe plaque psoriasis.

The randomized comparison of secukinumab (Cosentyx) and ustekinumab involved almost 700 patients who had a baseline mean PASI score ≥12, an investigator global assessment score ≥3, and body surface area involvement ≥10%. They were randomized to the monclonal antibodies, and the primary endpoint was PASO 90 response at 16 weeks. As reported last year, secukinumab resulted in a PASI 90 rate of 80.1% versus 59.0% for ustekinumab (P<0.0001). PASI 100 rates were 45% and 29.2% (P<0.0001).

Follow-up in both groups continued to week 52, during which time patients treated with secukinumab continued to have better psoriasis clearance rates compared with those treated with ustekinumab, said Diamant Thaci, MD, of the University of Lubeck in Germany. The secukinumab group had a PASI 90 rate of 76.2% compared with 60.6% for the ustekinumab group (P<0.0001). PASI 100 rates (a secondary endpoint) were 45.9% and 35.8% with secukinumab and ustekinumab, respectively (P<0.05).

Investigators in the trial collected quality of life data by means of the Dermatology Qualty of Life Index (DLQI). A secondary endpoint was the proportion of patients with a DLQI score of 0 or 1 at week 52 (responder). Response rates were 71.6% with secukinumab and 59.2% with ustekinumab (P=0.0008). A significant between-group difference emerged at 4 weeks and persisted throughout the 52-week follow-up period, Thaci said.

Secukinumab and ustekinumab had similar and favorable safety profiles. No new or unexpected adverse events or toxicities occurred in either group. No patient developed tuberculosis, Crohn’s disease, or ulcerative colitis. The only notable difference was a higher incidence of candida infection with secukinumab (6.4% versus 1.6%). Thaci said none of the infections were serious.

 

The ixekizumab trial was supported by Eli Lilly.

Blauvelt disclosed relevant relationships with AbbVie, Amgen, Boehringer Ingelheim, Celgene, Dermira, Genentech, Janssen Ortho Biotech, Eli Lilly, Merck, Novartis, Pfizer, Regeneron, and Sandoz.

The secukinumab trial was supported by Novartis.

Thaci disclosed relevant relationships with AbbVie, Almiral, Amgen, Astellas, Biogen-Idec, Boehringer Ingelheim, Celgene, Dignity, Eli Lilly, Forward Pharma, GlaxoSmithKline, LEO Pharma, Janssen-Cilag, Maruho, Merck Sharp & Dohme, Mitsubishi Pharema, Novartis, Pfizer, Roche, Sandoz, Galapagos, Xenoport, Roche, and Mundipharma.

 

 

Lancet. 2015 Aug 8;386(9993):541-51. http://dx.doi.org:/10.1016/S0140-6736(15)60125-8. Epub 2015 Jun 10.
Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials.

BACKGROUND:

Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis.

METHODS:

In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov, numbers NCT01597245 and NCT01646177.

FINDINGS:

Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; [effect size 87·4% (97·5% CI 82·9-91·8) vs placebo; 48·1% (41·2-55·0) vs etanercept]) and 336 (87·3%; [80·0% (74·4-85·7) vs placebo; 33·9% (27·0-40·7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; [75·1% (69·5-80·8) vs placebo; 35·9% (28·2-43·6) vs etanercept]) and 325 (84·2%; [76·9% (71·0-82·8) vs placebo; 30·8% (23·7-37·9) vs etanercept]) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p<0·0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; [effect size 80·8% (97·5% CI 75·6-86·0) vs placebo; 47·2% (39·9-54·4) vs etanercept]) and 310 (80·5%; [73·8% (67·7-79·9) vs placebo; 38·9% (31·7-46·1) vs etanercept]) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; [70·5% (64·6-76·5) vs placebo; 36·9% (29·1-44·7) vs etanercept]) and 291 (75·4%; [68·7% (62·3-75·0) vs placebo; 33·8% (26·3-41·3) vs etanercept]) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p<0·0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted.

INTERPRETATION:

Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option.

FUNDING:

Eli Lilly and Co.

Copyright © 2015 Elsevier Ltd. All rights reserved.

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Inflammatory Disorders: Articles published @ pharmaceuticalintelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

This is a compilation of articles on Inflammatory Disorders that were published 

@ pharmaceuticalintelligence.com, since 4/2012 to date

There are published works that have not been included.  However, there is a substantial amount of material in the following categories:

  1. The systemic inflammatory response
    https://pharmaceuticalintelligence.com/2014/11/08/introduction-to-impairments-in-pathological-states-endocrine-disorders-stress-hypermetabolism-cancer/
    https://pharmaceuticalintelligence.com/2014/11/09/summary-and-perspectives-impairments-in-pathological-states-endocrine-disorders-stress-hypermetabolism-cancer/
    https://pharmaceuticalintelligence.com/2015/12/19/neutrophil-serine-proteases-in-disease-and-therapeutic-considerations/
    https://pharmaceuticalintelligence.com/2014/03/21/what-is-the-key-method-to-harness-inflammation-to-close-the-doors-for-many-complex-diseases/
    https://pharmaceuticalintelligence.com/2012/08/20/therapeutic-targets-for-diabetes-and-related-metabolic-disorders/
    https://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/
    https://pharmaceuticalintelligence.com/2012/07/08/zebrafish-provide-insights-into-causes-and-treatment-of-human-diseases/
    https://pharmaceuticalintelligence.com/2016/01/25/ibd-immunomodulatory-effect-of-retinoic-acid-il-23il-17a-axis-correlates-with-the-nitric-oxide-pathway/
    https://pharmaceuticalintelligence.com/2015/11/29/role-of-inflammation-in-disease/
    https://pharmaceuticalintelligence.com/2013/03/06/can-resolvins-suppress-acute-lung-injury/
    https://pharmaceuticalintelligence.com/2015/02/26/acute-lung-injury/
  2. sepsis
    https://pharmaceuticalintelligence.com/2012/10/20/nitric-oxide-and-sepsis-hemodynamic-collapse-and-the-search-for-therapeutic-options/
  3. vasculitis
    https://pharmaceuticalintelligence.com/2015/02/26/acute-lung-injury/
    https://pharmaceuticalintelligence.com/2012/11/26/the-molecular-biology-of-renal-disorders/
    https://pharmaceuticalintelligence.com/2012/11/20/the-potential-for-nitric-oxide-donors-in-renal-function-disorders/
  4. neurodegenerative disease
    https://pharmaceuticalintelligence.com/2013/02/27/ustekinumab-new-drug-therapy-for-cognitive-decline-resulting-from-neuroinflammatory-cytokine-signaling-and-alzheimers-disease/
    https://pharmaceuticalintelligence.com/2016/01/26/amyloid-and-alzheimers-disease/
    https://pharmaceuticalintelligence.com/2016/02/15/alzheimers-disease-tau-art-thou-or-amyloid/
    https://pharmaceuticalintelligence.com/2016/01/26/beyond-tau-and-amyloid/
    https://pharmaceuticalintelligence.com/2015/12/10/remyelination-of-axon-requires-gli1-inhibition/
    https://pharmaceuticalintelligence.com/2015/11/28/neurovascular-pathways-to-neurodegeneration/
    https://pharmaceuticalintelligence.com/2015/11/13/new-alzheimers-protein-aicd-2/
    https://pharmaceuticalintelligence.com/2015/10/31/impairment-of-cognitive-function-and-neurogenesis/
    https://pharmaceuticalintelligence.com/2014/05/06/bwh-researchers-genetic-variations-can-influence-immune-cell-function-risk-factors-for-alzheimers-diseasedm-and-ms-later-in-life/
  5. cancer immunology
    https://pharmaceuticalintelligence.com/2013/04/12/innovations-in-tumor-immunology/
    https://pharmaceuticalintelligence.com/2016/01/09/signaling-of-immune-response-in-colon-cancer/
    https://pharmaceuticalintelligence.com/2015/05/12/vaccines-small-peptides-aptamers-and-immunotherapy-9/
    https://pharmaceuticalintelligence.com/2015/01/30/viruses-vaccines-and-immunotherapy/
    https://pharmaceuticalintelligence.com/2015/10/20/gene-expression-and-adaptive-immune-resistance-mechanisms-in-lymphoma/
    https://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and-immunology/
  6. autoimmune diseases: rheumatoid arthritis, colitis, ileitis, …
    https://pharmaceuticalintelligence.com/2016/02/11/intestinal-inflammatory-pharmaceutics/
    https://pharmaceuticalintelligence.com/2016/01/07/two-new-drugs-for-inflammatory-bowel-syndrome-are-giving-patients-hope/
    https://pharmaceuticalintelligence.com/2015/12/16/contribution-to-inflammatory-bowel-disease-ibd-of-bacterial-overgrowth-in-gut-on-a-chip/
    https://pharmaceuticalintelligence.com/2016/02/13/cytokines-in-ibd/
    https://pharmaceuticalintelligence.com/2016/01/23/autoimmune-inflammtory-bowl-diseases-crohns-disease-ulcerative-colitis-potential-roles-for-modulation-of-interleukins-17-and-23-signaling-for-therapeutics/
    https://pharmaceuticalintelligence.com/2014/10/14/autoimmune-disease-single-gene-eliminates-the-immune-protein-isg15-resulting-in-inability-to-resolve-inflammation-and-fight-infections-discovery-rockefeller-university/
    https://pharmaceuticalintelligence.com/2015/03/01/diarrheas-bacterial-and-nonbacterial/
    https://pharmaceuticalintelligence.com/2016/02/11/intestinal-inflammatory-pharmaceutics/
    https://pharmaceuticalintelligence.com/2014/01/28/biologics-for-autoimmune-diseases-cambridge-healthtech-institutes-inaugural-may-5-6-2014-seaport-world-trade-center-boston-ma/
    https://pharmaceuticalintelligence.com/2015/11/19/rheumatoid-arthritis-update/
    https://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and-immunology/
    https://pharmaceuticalintelligence.com/2013/07/31/confined-indolamine-2-3-dehydrogenase-controls-the-hemostasis-of-immune-responses-for-good-and-bad/
    https://pharmaceuticalintelligence.com/2012/09/13/tofacitinib-an-oral-janus-kinase-inhibitor-in-active-ulcerative-colitis/
    https://pharmaceuticalintelligence.com/2013/03/05/approach-to-controlling-pathogenic-inflammation-in-arthritis/
    https://pharmaceuticalintelligence.com/2013/03/05/rheumatoid-arthritis-risk/
    https://pharmaceuticalintelligence.com/2012/07/08/the-mechanism-of-action-of-the-drug-acthar-for-systemic-lupus-erythematosus-sle/
  7. T cells in immunity
    https://pharmaceuticalintelligence.com/2015/09/07/t-cell-mediated-immune-responses-signaling-pathways-activated-by-tlrs/
    https://pharmaceuticalintelligence.com/2015/05/14/allogeneic-stem-cell-transplantation-9-2/
    https://pharmaceuticalintelligence.com/2015/02/19/graft-versus-host-disease/
    https://pharmaceuticalintelligence.com/2014/10/14/autoimmune-disease-single-gene-eliminates-the-immune-protein-isg15-resulting-in-inability-to-resolve-inflammation-and-fight-infections-discovery-rockefeller-university/
    https://pharmaceuticalintelligence.com/2014/05/27/immunity-and-host-defense-a-bibliography-of-research-technion/
    https://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and-immunology/
    https://pharmaceuticalintelligence.com/2013/07/31/confined-indolamine-2-3-dehydrogenase-controls-the-hemostasis-of-immune-responses-for-good-and-bad/
    https://pharmaceuticalintelligence.com/2013/04/14/immune-regulation-news/

Proteomics, metabolomics and diabetes

https://pharmaceuticalintelligence.com/2015/11/16/reducing-obesity-related-inflammation/

https://pharmaceuticalintelligence.com/2015/10/25/the-relationship-of-stress-hypermetabolism-to-essential-protein-needs/

https://pharmaceuticalintelligence.com/2015/10/24/the-relationship-of-s-amino-acids-to-marasmic-and-kwashiorkor-pem/

https://pharmaceuticalintelligence.com/2015/10/24/the-significant-burden-of-childhood-malnutrition-and-stunting/

https://pharmaceuticalintelligence.com/2015/04/14/protein-binding-protein-protein-interactions-therapeutic-implications-7-3/

https://pharmaceuticalintelligence.com/2015/03/07/transthyretin-and-the-stressful-condition/

https://pharmaceuticalintelligence.com/2015/02/13/neural-activity-regulating-endocrine-response/

https://pharmaceuticalintelligence.com/2015/01/31/proteomics/

https://pharmaceuticalintelligence.com/2015/01/17/proteins-an-evolutionary-record-of-diversity-and-adaptation/

https://pharmaceuticalintelligence.com/2014/11/01/summary-of-signaling-and-signaling-pathways/

https://pharmaceuticalintelligence.com/2014/10/31/complex-models-of-signaling-therapeutic-implications/

https://pharmaceuticalintelligence.com/2014/10/24/diabetes-mellitus/

https://pharmaceuticalintelligence.com/2014/10/16/metabolomics-summary-and-perspective/

https://pharmaceuticalintelligence.com/2014/10/14/metabolic-reactions-need-just-enough/

https://pharmaceuticalintelligence.com/2014/11/03/introduction-to-protein-synthesis-and-degradation/

https://pharmaceuticalintelligence.com/2015/09/25/proceedings-of-the-nyas/

https://pharmaceuticalintelligence.com/2014/10/31/complex-models-of-signaling-therapeutic-implications/

https://pharmaceuticalintelligence.com/2014/03/21/what-is-the-key-method-to-harness-inflammation-to-close-the-doors-for-many-complex-diseases/

https://pharmaceuticalintelligence.com/2013/03/05/irf-1-deficiency-skews-the-differentiation-of-dendritic-cells/

https://pharmaceuticalintelligence.com/2012/11/26/new-insights-on-no-donors/

https://pharmaceuticalintelligence.com/2012/11/20/the-potential-for-nitric-oxide-donors-in-renal-function-disorders/

 

 

 

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