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Posts Tagged ‘inflammation’


Lipoxin A4 Regulates Natural Killer Cell in Asthma

Reporter: Larry H Bernstein, MD, FCAP

Lipoxin A4 Regulates Natural Killer Cell and Type 2 Innate Lymphoid Cell Activation in Asthma
 C Barnig, M Cernadas, S Dutile,…BR Levy.
Sci Transl Med  27 Feb 2013. ; 5(174): p. 174ra26  SciTranslMed.             http://dx.doi.org/10.1126/scitranslmed.3004812
Asthma is a prevalent disease of chronic inflammation in which
  • endogenous counterregulatory signaling pathways are dysregulated.
Recent evidence suggests that innate lymphoid cells (ILCs), including
  • natural killer (NK) cells and
  • type 2 ILCs (ILC2s),
    • can participate in the regulation of allergic airway responses,
    • in particular airway mucosal inflammation.
Sci Transl Med 27 February 2013:  5(174) 174ra26        http://dx.doi.org/10.1126/scitranslmed.3004812
Both NK cells and ILC2s expressed
  • the pro-resolving ALX/FPR2 receptors.
Lipoxin A4, a natural pro-resolving ligand for ALX/FPR2 receptors, significantly
  • increased NK cell–mediated eosinophil apoptosis and
  • decreased IL-13 release by ILC2s.
Together, these findings indicate that ILCs are targets for lipoxin A4
  • to decrease airway inflammation and mediate the catabasis of eosinophilic inflammation

Molecular biology for formyl peptide receptors in human diseases
Yongsheng Li , 

Leukocytes accumulate at sites of inflammation and immunological reaction in response to locally existing chemotactic mediators. The first chemotactic factors structurally defined were N-formyl peptides. Subsequently, numerous ligands were identified

FPRs interact with this menagerie of structurally diverse pro- and anti-inflammatory ligands to possess important regulatory effects in multiple diseases, including

  1. inflammation,
  2. amyloidosis,
  3. Alzheimer’s disease,
  4. prion disease,
  5. acquired immunodeficiency syndrome,
  6. obesity,
  7. diabetes, and
  8. cancer.

How these receptors recognize diverse ligands and how they contribute to disease pathogenesis and host defense are basic questions currently under investigation that

    • would open up new avenues for the future management of inflammation-related diseases.

FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis 
PMaderna, DC Cottell, T Toivonen, N Dufton, J Dalli, M Perretti and C Godson
The FASEB Journal Nov 2010; 24 (11): 4240-4249      Published online June 22, 2010, http://dx.doi.org/10.1096/fj.10-159913

Lipoxins (LXs) are endogenously produced eicosanoids with well-described anti-inflammatory and proresolution activities,

  • stimulating nonphlogistic phagocytosis of apoptotic cells by macrophages.

LXA4 and the glucocorticoid-derived annexin A1 peptide (Ac2–26) bind to a common G-protein-coupled receptor, termed FPR2/ALX. However, direct evidence of the involvement of FPR2/ALX in the anti-inflammatory and proresolution activity of LXA4 is still to be investigated. Here we describe FPR2/ALX trafficking in response to LXA4 and Ac2–26 stimulation. We have transfected cells with HA-tagged FPR2/ALX and studied receptor trafficking in unstimulated, LXA4 (1–10 nM)- and Ac2–26 (30 μM)-treated cells using multiple approaches that include immunofluorescent confocal microscopy, immunogold labeling of cryosections, and ELISA and investigated receptor trafficking in agonist-stimulated phagocytosis. We conclude that PKC-dependent internalization of FPR2/ALX is required for phagocytosis. Using bone marrow-derived macrophages (BMDMs) from mice in which the FPR2/ALX ortholog Fpr2 had been deleted, we observed

  • the nonredundant function for this receptor in LXA4 and Ac2–26 stimulated phagocytosis of apoptotic neutrophils.
  1. LXA4 stimulated phagocytosis 1.7-fold above basal (P<0.001) by BMDMs from wild-type mice, whereas no effect was found on BMDMs from Fpr2−/− mice.
  2. Ac2–26 stimulates phagocytosis by BMDMs from wild-type mice 1.5-fold above basal (P<0.05), but  Ac2–26 failed to stimulate phagocytosis by BMDMs isolated from Fpr2−/− mice.

These data reveal novel and complex mechanisms of the FPR2/ALX receptor trafficking and functionality in the resolution of inflammation.—
Maderna, P., Cottell, D. C., Toivonen, T., Dufton, N., Dalli, J., Perretti, M., Godson, C.
http://www.FASEB.j.org/FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis.
We have transfected cells with HA-tagged FPR2/ALX and studied receptor trafficking in unstimulated, LXA4 (1–10 nM)- and Ac2–26 (30 μM)-treated cells using multiple approaches and conclude that PKC-dependent internalization of FPR2/ALX is required for phagocytosis. Using bone marrow-derived macrophages (BMDMs) from mice in which the FPR2/ALX ortholog Fpr2 had been deleted,

  • we observed the nonredundant function for this receptor in LXA4 and Ac2–26 stimulated phagocytosis of apoptotic neutrophils.

LXA4 stimulated phagocytosis 1.7-fold above basal (P<0.001) by BMDMs from wild-type mice,

  • whereas no effect was found on BMDMs from Fpr2−/− mice.

Ac2–26 stimulates phagocytosis by BMDMs from wild-type mice 1.5-fold above basal (P<0.05)

  •  Ac2–26 failed to stimulate phagocytosis by BMDMs isolated from Fpr2−/− mice relative to vehicle.

These data reveal novel and complex mechanisms of the FPR2/ALX receptor trafficking and functionality in the resolution of inflammation.
The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo.
Chiang, N., Serhan, CN, Dahlen, SE, Drazen, JM, Hay, DW, Rovati, GE, et al.
Pharmacol. Rev. 2006; 58, 463–487.      http://www.PharmacolRev.com/The_lipoxin_receptor_ALX:_potent_ligand_specific_and_stereoselective_actions_in_vivo/

Asthma Obstruction of the lumen of the bronchi...

Asthma Obstruction of the lumen of the bronchiole by mucoid exudate, goblet cell metaplasia, epithelial basement membrane thickening and severe inflammation of bronchiole. (Photo credit: Wikipedia)

Schematic diagram indicating the complementary...

Schematic diagram indicating the complementary activities of cytotoxic T-cells and NK cells. (Photo credit: Wikipedia)

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Author and Curator: Ritu Saxena, Ph.D.

 

Introduction

Nitric oxide (NO) is a lipophilic, highly diffusible and short-lived molecule that acts as a physiological messenger and has been known to regulate a variety of important physiological responses including vasodilation, respiration, cell migration, immune response and apoptosis. Jordi Muntané et al

NO is synthesized by the Nitric Oxide synthase (NOS) enzyme and the enzyme is encoded in three different forms in mammals: neuronal NOS (nNOS or NOS-1), inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3). The three isoforms, although similar in structure and catalytic function, differ in the way their activity and synthesis in controlled inside a cell. NOS-2, for example is induced in response to inflammatory stimuli, while NOS-1 and NOS-3 are constitutively expressed.

Regulation by Nitric oxide

NO is a versatile signaling molecule and the net effect of NO on gene regulation is variable and ranges from activation to inhibition of transcription.

The intracellular localization is relevant for the activity of NOS. Infact, NOSs are subject to specific targeting to subcellular compartments (plasma membrane, Golgi, cytosol, nucleus and mitochondria) and that this trafficking is crucial for NO production and specific post-translational modifications of target proteins.

Role of Nitric oxide in Cancer

One in four cases of cancer worldwide are a result of chronic inflammation. An inflammatory response causes high levels of activated macrophages. Macrophage activation, in turn, leads to the induction of iNOS gene that results in the generation of large amount of NO. The expression of iNOS induced by inflammatory stimuli coupled with the constitutive expression of nNOS and eNOS may contribute to increased cancer risk. NO can have varied roles in the tumor environment influencing DNA repair, cell cycle, and apoptosis. It can result in antagonistic actions including DNA damage and protection from cytotoxicity, inhibiting and stimulation cell proliferation, and being both anti-apoptotic and pro-apoptotic. Genotoxicity due to high levels of NO could be through direct modification of DNA (nitrosative deamination of nucleic acid bases, transition and/or transversion of nucleic acids, alkylation and DNA strand breakage) and inhibition of DNA repair enzymes (such as alkyltransferase and DNA ligase) through direct or indirect mechanisms. The Multiple actions of NO are probably the result of its chemical (post-translational modifications) and biological heterogeneity (cellular production, consumption and responses). Post-translational modifications of proteins by nitration, nitrosation, phosphorylation, acetylation or polyADP-ribosylation could lead to an increase in the cancer risk. This process can drive carcinogenesis by altering targets and pathways that are crucial for cancer progression much faster than would otherwise occur in healthy tissue.

NO can have several effects even within the tumor microenvironment where it could originate from several cell types including cancer cells, host cells, tumor endothelial cells. Tumor-derived NO could have several functional roles. It can affect cancer progression by augmenting cancer cell proliferation and invasiveness. Infact, it has been proposed that NO promotes tumor growth by regulating blood flow and maintaining the vasodilated tumor microenvironment. NO can stimulate angiogenesis and can also promote metastasis by increasing vascular permeability and upregulating matrix metalloproteinases (MMPs). MMPs have been associated with several functions including cell proliferation, migration, adhesion, differentiation, angiogenesis and so on. Recently, it was reported that metastatic tumor-released NO might impair the immune system, which enables them to escape the immunosurveillance mechanism of cells. Molecular regulation of tumour angiogenesis by nitric oxide.

S-nitrosylation and Cancer

The most prominent and recognized NO reaction with thiols groups of cysteine residues is called S-nitrosylation or S-nitrosation, which leads to the formation of more stable nitrosothiols. High concentrations of intracellular NO can result in high concentrations of S-nitrosylated proteins and dysregulated S-nitrosylation has been implicated in cancer. Oxidative and nitrosative stress is sensed and closely associated with transcriptional regulation of multiple target genes.

Following are a few proteins that are modified via NO and modification of these proteins, in turn, has been known to play direct or indirect roles in cancer.

NO mediated aberrant proteins in Cancer

Bcl2

Bcl-2 is an important anti-apoptotic protein. It works by inhibiting mitochondrial Cytochrome C that is released in response to apoptotic stimuli. In a variety of tumors, Bcl-2 has been shown to be upregulated, and it has additionally been implicated with cancer chemo-resistance through dysregulation of apoptosis. NO exposure causes S-nitrosylation at the two cysteine residues – Cys158 and Cys229 that prevents ubiquitin-proteasomal pathway mediated degradation of the protein. Once prevented from degradation, the protein attenuates its anti-apoptotic effects in cancer progression. The S-nitrosylation based modification of Bcl-2 has been observed to be relevant in drug treatment studies (for eg. Cisplatin). Thus, the impairment of S-nitrosylated Bcl-2 proteins might serve as an effective therapeutic target to decrease cancer-drug resistance.

p53

p53 has been well documented as a tumor suppressor protein and acts as a major player in response to DNA damage and other genomic alterations within the cell. The activation of p53 can lead to cell cycle arrest and DNA repair, however, in case of irrepairable DNA damage, p53 can lead to apoptosis. Nuclear p53 accumulation has been related to NO-mediated anti-tumoral properties. High concentration of NO has been found to cause conformational changes in p53 resulting in biological dysfunction.. In RAW264.7, a murine macrophage cell line, NO donors induce p53 accumulation and apoptosis through JNK-1/2.

HIF-1a

Hypoxia-inducible factor 1 (HIF1) is a heterodimeric transcription factor that is predominantly active under hypoxic conditions because the HIF-1a subunit is rapidly degraded in normoxic conditions by proteasomal degradation. It regulates the transciption of several genes including those involved in angiogenesis, cell cycle, cell metabolism, and apoptosis. Hypoxic conditions within the tumor can lead to overexpression of HIF-1a. Similar to hypoxia-mediated stress, nitrosative stress can stabilize HIF-1a. NO derivatives have also been shown to participate in hypoxia signaling. Resistance to radiotherapy has been traced back to NO-mediated HIF-1a in solid tumors in some cases.

PTEN

Phosphatase and tensin homolog deleted on chromosome ten (PTEN), is again a tumor suppressor protein. It is a phosphatase and has been implicated in many human cancers. PTEN is a crucial negative regulator of PI3K/Akt signaling pathway. Over-activation of PI3K/Akt mediated signaling pathway is known to play a major role in tumorigenesis and angiogenesis. S-nitrosylation of PTEN, that could be a result of NO stress, inhibits PTEN. Inhibition of PTEN phosphatase activity, in turn, leads to promotion of angiogenesis.

C-Src

C-src belongs to the Src family of protein tyrosine kinases and has been implicated in the promotion of cancer cell invasion and metastasis. It was demonstrated that S-nitrosylation of c-Src at cysteine 498 enhanced its kinase activity, thus, resulting in the enhancement of cancer cell invasion and metastasis.

Reference:

Muntané J and la Mata MD. Nitric oxide and cancer. World J Hepatol. 2010 Sep 27;2(9):337-44. http://www.ncbi.nlm.nih.gov/pubmed/21161018

Wang Z. Protein S-nitrosylation and cancer. Cancer Lett. 2012 Jul 28;320(2):123-9. http://www.ncbi.nlm.nih.gov/pubmed/22425962

Ziche M and Morbidelli L. Molecular regulation of tumour angiogenesis by nitric oxide. Eur Cytokine Netw. 2009 Dec;20(4):164-70.http://www.ncbi.nlm.nih.gov/pubmed/20167555

Jaiswal M, et al. Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol. 2001 Sep;281(3):G626-34. http://www.ncbi.nlm.nih.gov/pubmed/11518674

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Ulcerative colitis

Ulcerative colitis (Photo credit: Wikipedia)

Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis

Reporter: Larry Bernstein, MD

This is an overview of a recently published article about a new treatment for ulcerative colitis. It also reviews the use of a class of drug in inflammatory conditions, and introduces the problem of sepsis.

Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis.
WJ Sandborn, S Ghosh, J Panes, I Vranic, C Su, for the Study A3921063 Investigators
N Engl J Med 2012; 367:616-624 August 16, 2012
http://www.nejm.org/doi/full/10.1056/NEJMoa1112168?query=TOC

 

Ulcerative colitis  is a chronic inflammatory disease of the colon that belongs to a group of diseases lumped together as Inflammatory Bowel Disease (IBD). There is a distinction to be made between Crohn’s disease, which may be limited to the small intestine (regional enteritis), the terminal ileum, or a portion of the transverse colon, and ulcerative colitis.

In ulcerative colitis the inflammation is limited to the mucosa and submucosa, but in Crohn’s disease there is a deep penetration of the intestinal wall (fistula) that may extend to the peritoneum causing abscess, scarring, peritonitis and possibly volvulus, obstruction and gangrenous bowel, which necessitate surgical resection. IBD tends to occur in children and young adults, repeats in families, and requires dietary management (fluid intake, Metamucil, restriction of fiber) . It is characterized by abdominal pain, diarrhea, bleeding, weight loss, and episodic fever, but also may be associated with joint pain.
Conservative medical treatment focuses on suppressing the immune response using 5-ASA, azathioprine, 6-mercaptopurine. If severe, biologic therapy is used to treat patients with severe Crohn’s disease that does not respond to any other types of medication, such as a TNF (tumor necrosis factor) inhibitor which can have secondary effects, and they are not universally effective. The importance of immunity can’t be understated, it involves a large portion of immune system and primitive Toll-like receptors (TLRs) that trigger signaling pathways. TLRs represent an important mechanism by which the host detects a variety of microorganisms that colonize in the gut. Endothelial and epithelial cells, and resident macrophages are potent producers of inflammatory cytokines, interleukins, IL-1, IL-6, and TNF-α, which are distinguished from another set that is treated in this study. In addition, there is a balance that has to be achieved between suppression and upregulation in treatment, which is referred to as immunomodulation.
The opposite of immunosuppression is upregulation It is cental to recent advances in chemotherapy of melanolma, small cell carcinoma and NSCCL of lung, and treatment resistant prostate cancer. An example is ipilimumab, whic upregulates cytotoxic T-cells to destroy cancer cells, but it has runaway destructive effects on the GI tract.

This study investigates the use of tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain–containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation.

The mechanism of drug action

Jak 1 and 3 inhibitor, which is targeted at blocking signaling involving gamma chain–containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. The result would be to block signaling involving (gamma chains)–suppressing “lymphokines” 2, 4, 7, 9, 15, and 21. The lymphocyte pool is regional, being the antibody mediated immune system of the Bursa of Fabricius (B-lymphocytes, as opposed to the thymic derived T-cells) that form the largest immune organ extending the length of the intestines and the stomach.  The family transmission suggests an epigenetic event.

  • Gastrointestinal Tract
  • Oropharynx – Tonsils
  • Distal small intestine (ilieum) – Peyer’s Patches
  • Appendix, cecum

However, this classification of the lymphocytes has much greater complexity than I indicate.  The so called B-cells have receptors that recognize foreign antigen, but the T-cells have similar receptors and are tied to both the innate and the adaptive immune response.  Lymphocytes are the predominant cells of the immune system, but macrophages and plasma cells are present also.  Lymphocytes circulate, alternating between the circulatory blood stream and the lymphatic channels.  The end result of the immune reaction is the production of specific antibodies and antigen-reactive cells. These cells are called lymphocytes and are found in the blood and in the lymphoid system.

See Appendix

Trial features: double-blind, placebo-controlled, phase 2 trial; Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks.
Study goal: evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis.

Primary outcome: a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1.
Results and conclusion: The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.39), 3 mg (P=0.55), 10 mg (P=0.10), and 15 mg (P<0.001), respectively, as compared with 42% of patients receiving placebo.
Clinical remission (defined as a Mayo score ≤2, with no subscore >1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.76), 3 mg (P=0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500.
Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202.)
Commentary: The study is only phase 2, and it is also limited to disease of the descending colon. The next phase will be necessary to determine the effect on a larger population at the selected dose, and will be necessary to determine both the size of the effect and identify unexpected adverse effects. We also have to keep in mind that the success of the study would limit the treatment to a subset of patients with IBD.

Efficacy of Proposed Treatment:

  • it is effective at about 40% remission for 8 weeks compared to 10% for placebo, or an adjusted actual 30% for 8 weeks.
  • A much larger study needs to be done to see how well the dose holds up, as well as the dosing interval. There are two factors that will affect the t1/2 of the drug so that 1/2 dose could be replaced at the end of t1/2.
  • The dose of 15 mg was no better for clinical response.
  • I would think that the next trial might give a loading dose of 15 mg, and then 7 mg (better that 3 mg) would be replaced every t1/2.  But this is more complicated than usual.

I identified two steps, not one direct effect.

  • The inhibitor has to balance the production rate versus the removal rate of the T-cell population. The drug itself is not measured, only the effect. I know that albumin, the liver produced protein, has a half-life of removal of 21 days. Platelets are short shelf-life as well as rapid turnaround in plasma.
  •  I don’t know what is the local production and removal rate of lymphocytes in the gut. That would be the key determinant for dosing.

The following may shed some light on what has been discussed:

Common characteristics of the lymphoid system.

  • The lymphoid system involves organs and tissues where lymphocytic cells originate as lymphocyte precursors that mature and differentiate, and either lodge in the lymphoid organs or move throughout the body.
  • Precursor cells originate in the yolk sac, liver, spleen, or bursa of Fabricius (or its mammalian equivalent, the bone marrow) in an embryo or fetus.
  • Stem cells from bone marrow or embryonic tissues are deposited and mature into lymphocytes in the central or primary lymphoid organs, which include the thymus and the bursa or bone marrow. Upon maturation, the lymphocytes undergo further maturation toward immunocompetence and production of immunoglobulins or sensitized lymphocytes.

Adaptive immunity has 2 main classes:

  • Antibody-mediated – B Lymphocyte
  • Cell-mediated – T Lymphocyte

Lymph follicles are our point of reference:

  • Organized concentrations of Lymphocytes
  • No capsule, covered by epithelia
  • Nodules are unit structure seen in a node
  • Oval concentrations in meshwork of reticular cells

If pathogens initially evade constitutive defenses, they may yet be attacked by more specific inducible defenses. The inducible defenses are so-called because they are induced upon primary exposure to a pathogen or one of its products. The inducible defenses must be triggered in a host, take time to develop, and are a function of the immune response. The type of resistance thus developed in the host is called acquired immunity.

Three important features of the immunological system relevant to host defense and/or “immunity are:

1. Specificity. An antibody or reactive T cell will react specifically with the antigen that induced its formation; it will not react with other antigens. Generally, this specificity is of the same order as that of enzyme-substrate specificity or receptor-ligand specificity.

  • The specificity of the immune response is explained on the basis of the clonal selection hypothesis: during the primary immune response, a specific antigen selects a pre-existing clone of specific lymphocytes and stimulates exclusively its activation, proliferation and differentiation.

2.  Memory. The immunological system has a “memory”.

  • Once the immunological response has reacted to produce a specific type of antibody or reactive T cell, it is capable of producing more of the antibody or activated T cell more rapidly and in larger amounts.

3. Tolerance. An animal generally does not undergo an immunological response to its own (potentially-antigenic) components.

  • The animal is said to be tolerant, or unable to react to its own potentially-antigenic components.

Gene expression – CD28 signal transduction , λδ T repertoire and antigen reactivity

Efficient lymphokine gene expression appears to require both T-cell antigen receptor (TCR) signal transduction and an uncharacterized second or costimulatory signal. CD28 is a T-cell differentiation antigen that can generate intracellular signals that synergize with those of the TCR to increase T-cell activation and interleukin-2 (IL-2) gene expression.

  • These investigators examined the effect of CD28 signal transduction on granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3), and gamma interferon (IFN-gamma) promoter activity.
  • Stimulation of CD28 in the presence of TCR-like signals increases the activity of the GM-CSF, IL-3, and IFN-gamma promoters by three- to sixfold.
  • As previously demonstrated for the IL-2 promoter, the IL-3 and GM-CSF promoters contain distinct elements of similar sequence which specifically bind a CD28-induced nuclear complex.
  • Mutation of the CD28 response elements in the IL-3 and GM-CSF promoters abrogates the CD28-induced activity without affecting phorbol ester- and calcium ionophore-induced activity.
  • These studies indicate that the TCR and CD28-regulated signal transduction pathways, coordinately regulate the transcription of several lymphokines, and the influence of CD28 signals on transcription is mediated by a common complex.

Fraser JD, Weiss A.  Regulation of T-cell lymphokine gene transcription by the accessory molecule CD28. Mol Cell Biol. 1992 Oct;12(10):4357-63.

These investigators looked at the relevance λδ T repertoire and the antigen reactivity of clones isolated from CSF in multiple sclerosis (MS).

  • they found an increased percentage of V delta 1+ cells as compared to peripheral blood of the same donors.
  • Phenotypic analysis of cells from MS CSF with V gamma- and V delta-specific monoclonal antibodies (mAb) showed that the V delta 1 chain is most frequently associated with gamma chains belonging to the V gamma 1 family.
  • Sequence analysis of TCR genes revealed heterogeneity of junctional regions in both delta and gamma genes indicating polyclonal expansion. gamma delta clones were established and some recognized glioblastoma, astrocytoma or monocytic cell lines.
  • Stimulation with these targets induced serine esterase release and lymphokine expression characteristic of the TH0-like phenotype.
  • Remarkably, these tumor-reactive gamma delta cells were not detected in the peripheral blood using PCR oligotyping, but were found in other CSF lines independently established from the same MS patient.
  • in the CSF there is a skewed TCR gamma delta repertoire and suggest that gamma delta cells reacting against brain-derived antigens might have been locally expanded.

Nick S, Pileri P, Tongiani S, Uematsu Y, Kappos L, De Libero G. T cell receptor gamma delta repertoire is skewed in cerebrospinal fluid of multiple sclerosis patients: molecular and functional analyses of antigen-reactive gamma delta clones. Eur J Immunol. 1995 Feb;25(2):355-63. PMID: 1328852 [PubMed – indexed for MEDLINE] PMCID: PMC360359 Free PMC Article

B Cells and T Cells:  Addendum

users.rcn.com/jkimball.ma.ultranet/…/B/B_and_Tcells.htmlShareAIDS; Building the T-cell Repertoire; Gamma/Delta T Cells … T cells specific for this structure (i.e., with complementary TCRs) bind the B cell and; secrete lymphokines that: … Each chain has a variable (V) region and a constant (C) region.

Although mature lymphocytes all look pretty much alike, they are extraordinarily diverse in their functions. The most abundant lymphocytes are:

  • B lymphocytes (often simply called B cells) and
  • T lymphocytes (likewise called T cells).
  • B cells are produced in the bone marrow.
  •  The precursors of T cells are also produced in the bone marrow but leave the bone marrow and mature in the thymus (which accounts for their designation).
  • Each B cell and T cell is specific for a particular antigen. What this means is that each is able to bind to a particular molecular structure.

The specificity of binding resides in a receptor for antigen:

  • the B cell receptor (BCR) for antigen and
  • the T cell receptor (TCR) respectively.

Both BCRs and TCRs share these properties:

  • They are integral membrane proteins.
  • They are present in thousands of identical copies exposed at the cell surface.
  • They are made before the cell ever encounters an antigen.
  • They are encoded by genes assembled by the recombination of segments of DNA.

How antigen receptor diversity is generated.

  • They have a unique binding site.
  • This site binds to a portion of the antigen called an antigenic determinant or epitope.
    The binding, like that between an enzyme and its substrate depends on complementarity of the surface of the receptor and the surface of the epitope.
  • The binding occurs by non-covalent forces (again, like an enzyme binding to its substrate).

Successful binding of the antigen receptor to the epitope, if accompanied by additional signals, results in:

  • stimulation of the cell to leave G0 and enter the cell cycle.
  • Repeated mitosis leads to the development of a clone of cells bearing the same antigen receptor; that is, a clone of cells of the identical specificity.

BCRs and TCRs differ in:

  • their structure;
  • the genes that encode them;
  • the type of epitope to which they bind.

heavy (H) plus kappa (κ) or lambda (λ) chains for BCRs;

alpha (α) and beta (β) or gamma (γ) and delta (δ) chains for TCRs)

……is encoded by several different gene segments.

The genome contains a pool of gene segments for each type of chain. Random assortment of these segments makes the largest contribution to receptor diversity.

There are two types of T cells that differ in their TCR:

alpha/beta (αβ) T cells. Their TCR is a heterodimer of an alpha chain with a beta chain. Each chain has a variable (V) region and a constant (C) region. The V regions each contain 3 hypervariable regions that make up the antigen-binding site. [Link]

gamma/delta (γδ) T cells. Their TCR is also a heterodimer of a gamma chain paired with a delta chain.

The discussion that follows now concerns alpha/beta T cells. Gamma/delta T cells, which are less well understood, are discussed at the end [Link].

The TCR (of alpha/beta T cells) binds a bimolecular complex displayed at the surface of some other cell called an antigen-presenting cell (APC).

Most of the T cells in the body belong to one of two subsets. These are distinguished by the presence on their surface of one or the other of two glycoproteins designated:

  • CD8+ T cells bind epitopes that are part of class I histocompatibility molecules. Almost all the cells of the body express class I molecules.
  • CD4+ T cells bind epitopes that are part of class II histocompatibility molecules. Only specialized antigen-presenting cells express class II molecules.

These include:

  • dendritic cells
  • phagocytic cells like macrophages and
  • B cells!

Building the T-cell Repertoire

T cells have receptors (TCRs) that bind to antigen fragments nestled in MHC molecules. But,

  • all cells express class I MHC molecules containing fragments derived from self proteins;
  • many cells express class II MHC molecules that also contain self peptides.

This presents a risk of the T cells recognizing these self-peptide/self-MHC complexes and mounting an autoimmune attack against them. Fortunately, this is usually avoided by a process of selection that goes on in the thymus (where all T cells develop).

Appendix

FDA approves Abbott Humira as Ulcerative Colitis therapy
PBR Staff Writer Published 01 October 2012
The USFDA has approved Abbott’s Humira (adalimumab) for the treatment of adult patients with moderate to severe Ulcerative Colitis (UC) when certain other medicines have not worked well enough.
Humira, which works by inhibiting tumour necrosis factor-alpha (TNF-alpha), was previously approved for the treatment of moderate to severe Crohn’s disease.

Abbott Global Pharmaceutical Research and Development senior vice president John Leonard said, “Since the first FDA approval of HUMIRA in late 2002, Abbott has continued to investigate the medication in multiple conditions with the goal of bringing this treatment option to more patients who may benefit from it.”

The approval was based on the data from two phase 3 studies, ULTRA 1 and ULTRA 2, both of which enrolled adult patients who had moderately to severely active UC despite concurrent or prior treatment with immunosuppressants.  This should have special significance in view of the past history, which may be explainable, but also keep in mind the serious risks of complications.

It is worthy of comment that anti-TNF treatment was previously rejected in trials for use in sepsis leading to Multiple Organ Dysfunction Syndrome and cardiovascular collapse (shock).  More recently an anti-Factor Xa drug, Xygris,  to prevent hypercoagulability only in severe sepsis was withdrawn.

Anti TNF for sepsis

1.   In a group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively.

Panacek EAMarshall JCAlbertson TEJohnson DH, at al.  Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab’)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levelsCrit Care Med. 2004 Nov;32(11):2173-82.

2. No survival benefit was found for the total study population, but patients with increased circulating TNF concentrations at study entry appeared to benefit by the high dose anti-TNF antibody treatment. Increased interleukin (IL)-6 levels predicted a fatal outcome (p =.003), but TNF levels were not found to be a prognostic indicator. TNFlevels were higher (206.7 +/- 60.7 vs. 85.9 +/- 26.1 pg/mL; p <.001) and outcome was poor (41% vs. 71% survival; p =.007) in patients who were in shock at study entry when compared with septic patients not in shock.

Fisher CJ JrOpal SMDhainaut JFStephens S, et al. Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group.  Critical Care Medicine [1993, 21(3):318-327] (PMID:8440099)

3.  Large clinical trials involving anti-TNF-alpha MAb have proven to be less conclusive and less successful than clinicians had hoped. The International Sepsis Trial (INTERSEPT), reported by Cohen and Carlet,[14] was designed to assess the safety and efficacy of Bay x 1351, a murine MAb to recombinant human TNF-alpha in patients with sepsis. The INTERSEPT trial was an international, multicenter trial involving 564 patients, 420 of whom were in septic shock. The main study end point — 28-day survival — showed no significant benefit for the treatment group vs controls. Prospectively, the researchers identified 2 secondary variables: shock reversal and frequency of organ failure. Post-28-day survival, treatment groups showed a more rapid reversal of shock compared with placebo, as well as a significant delay in time to first organ failure. The researchers concluded that the anti-TNF-alpha antibody may have a role as adjunctive therapy, but that such a putative role requires more in the way of clinical trial confirmation.

In the TNF-alpha MAb Sepsis Study Group trial, also called the North American Sepsis Trial I (NORASEPT I), Abraham and associates[15] evaluated the efficacy and safety of an anti-TNF-alpha MAb in the treatment of patients with sepsis syndrome. A total of 994 patients in 31 hospitals were enrolled in a randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. Patients were stratified into shock/nonshock subgroups, then randomized to receive a single infusion of 15 mg/kg of anti-TNF-alpha MAb, 7.5 mg/kg of anti-TNF-alpha MAb, or placebo. The researchers found that among all infused patients, there was no difference in mortality among those receiving therapy and those on placebo. In septic shock patients (n = 478), however, there was a trend toward a reduction in all-cause mortality, which was most evident 3 days after infusion. At day 3, 25 of 162 patients treated with the 15 mg/kg dose died; 22 of 156 treated with 7.5 mg/kg died, but 44 of 160 placebo-treated patients died (15 mg/kg: 44% mortality reduction vs placebo, P = .01; 7.5 mg/kg: 48% reduction vs placebo, P = .004). However, at day 28, the reduction in mortality of shock patients was not significant for either dose of the anti-TNF-alpha MAb relative to placebo.

All studies of MAb against TNF in septic patients and found an absolute risk reduction of 3.5%. The most recently published clinical trial found an absolute reduction in mortality of 3.7%.

Of note, therapy with MAb against TNF has been proven efficacious for treatment of rheumatoid arthritis and is approved by the US Food and Drug Administration for this purpose.

New directions in research on severe sepsis. Human trials with TNF alpha.  Medscape.

4. Why the poor results with sepsis?

This would be sufficient for another discussion.  That can be left for another day.

Sepsis

Sepsis syndrome, or sepsis, is an adverse systemic response to infection that includes fever, rapid heartbeat and respiration, low blood pressure and organ dysfunction associated with compromised circulation.

LPS is a major constituent of Gram-negative bacterial cell walls (see section 3-0) and is essential for membrane integrity. The portion of LPS that causes shock is the innermost and most highly conserved phosphoglycolipid, lipid A. Lipid A is a phosphoglycolipid consisting of a core hexosamine disaccharide with ester- and amide-linked acylated fatty acid tails arranged in either asymmetric or symmetric arrays that anchor the structure in the membrane. It acts by potently inducing inflammatory responses that are life-threatening when systemic, and is known as bacterial endotoxin.  Mice deficient in any of the LPS receptor components are more
susceptible to Gram-negative bacterial infection but, at the same time, are less susceptible to the sepsis syndrome.

TLRs have a lethal function in the septic shock syndrome. The physiological function of signaling through phagocyte TLRs is to induce the release of the cytokines TNF, IL-1, IL-6, IL-8 and IL-12 and trigger the inflammatory response, which is critical to containing bacterial infection in the tissues. However, if infection disseminates in the blood, the widespread activation of phagocytes in the bloodstream is catastrophic. Increase in the numbers of circulating neutrophils, or neutrophilia, is driven by effects of colony stimulating factors, such as G-CSF.

Time course of sepsis. The clinical manifestations of sepsis are manifested by successive waves of the serum cytokine cascade. In humans injected with purified LPS, TNF rises almost immediately and peaks at 1.5 h; the sharp decline of TNF may be due to modulation by its soluble receptor sTNFR. A second wave of cytokines that peaks at 3 h activates the acute-phase response
in the liver, the systemic pituitary response (via IL-6 and IL-1), and the activation and chemotaxis of neutrophils (via IL-6, IL-8 and  G-CSF). Neutrophil activation results in the release of lactoferrin from neutrophil secondary granules; the activation of endothelial procoagulants with the rise of tissue plasminogen activator (t-PA). Pituitary-derived adrenocorticotropic hormone (ACTH)  and migration inhibition factor (MIF) peak at 5 h and coincide with peak levels of the regulatory cytokines IL-Ra and IL-10 that counteract the release or activity of inflammatory cytokines. Diffuse endothelial activation is shown by the appearance of soluble E-selectin that peaks at about 8 h and remains elevated for several days.

Susceptibility to LPS Toxicity in Gene Knockout Mice

Defect:
High LPS; Low LPS/D-Gal

Proteins

 

LPS recognition
CD14
LBP
TLR4
MD-2
MyD88
SR-A

phagocyte function
Hck/Fgr
CAM-1
L-selectin
GM-CSF
TNFR1

inflammation
TNFR2
IL-1Ra
IL-1β
IFN-γR
caspase 1
The proteins encoded by the deleted genes are listed. SR-A is scavenger receptor A; Hck and Fgr are Src-family kinases with an essential role in integrin-mediated migration of neutrophils out of the bloodstream.

The Immune Response to Bacterial InfectionSepsis Syndrome: Bacterial Endotoxin
Chapter 9-3.  2007. p 232-233. New Science Press Ltd

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Curated by: Dr. Venkat S. Karra, Ph.D.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease resulting in chronic activation of self-reactive lymphocytes and pro-inflammatory myeloid cells. SLE may also be caused by certain drugs called drug-induced lupus erythematosus.  People with SLE have abnormal deposits in the kidney cells. This leads to a condition called lupus nephritis. Patients with this condition may eventually develop kidney failure and need dialysis or a kidney transplant. The underlying cause of autoimmune diseases is not fully known and so far there is no cure for SLE.

SLE effects multiple end organs including the kidneys, brain, joints and skin and causes damage to many different parts of the body, including:

1. Blood clots in the legs (deep vein thrombosis) or lungs (pulmonary embolism)

2. Destruction of red blood cells (hemolytic anemia) or anemia of chronic disease

3. Fluid around the heart, pericarditis, endocarditis or inflammation of the heart (myocarditis)

4. Fluid around the lungs (pleural effusions) and damage to lung tissue

5. Pregnancy complications, including miscarriage

6. Stroke

7. Severely low blood platelets (thrombocytopenia)

8. Inflammation of the blood vessels

The molecular basis for the various manifestations of this autoimmune disease and the impact of the systemic autoimmune process on basic metabolic processes in the body are currently obscure.

However, recently a metabolomic study was executed first to understand the metabolic disturbances that underlie systemic lupus erythematosus (SLE). The study compared the sera of 20 SLE patients against that of healthy controls, using LC/MS and GC/MS platforms. Validation of key differences was performed using an independent cohort of 38 SLE patients and orthogonal assays.

The SLE metabolome exhibited profound lipid peroxidation, reflective of oxidative damage. Deficiencies were noted in the cellular anti-oxidant, glutathione, and all methyl group donors, including cysteine, methionine, and choline, as well as phosphocholines.

SLE sera showed evidence of profoundly dampened glycolysis, Krebs cycle, fatty acid β oxidation and amino acid metabolism, alluding to reduced energy biogenesis from all sources.

Whereas long-chain fatty acids, including the n3 and n6 essential fatty acids, were significantly reduced, medium chain fatty acids  and serum free fatty acids were elevated.

The best discriminators of SLE included elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5-HETE.

Comprehensive profiling of the SLE metabolome reveals evidence of heightened oxidative stress, inflammation, reduced energy generation, altered lipid profiles and a pro-thrombotic state.

From this study it is evident that first supplementing the diet with essential fatty acids, vitamins and methyl group donors offers novel opportunities for disease modulation in this disabling systemic autoimmune ailment.

Second quickly identifying selected molecules/ therapies is another opportunity to resetting the SLE metabolome. One such opportunity is to use adrenocorticotropic hormone (ACTH) analogue.

With Prednisone, up to 90% of adults with minimal change disease (MCD) will respond to initial therapy and may require further immunosuppression. But with diseases such as idiopathic membranous nephropathy (iMN) and focal segmental glomerulosclerosis (FSGS), for which first-line therapies produce substantially lower response rates than for MCD and physicians are often compelled to use second-, third-, and even fourth-line therapies to achieve remission.

ACTH usage is not new, it was widely used way back in 1950s for the treatment of childhood nephrotic syndrome. Now there is a renewed interest in using ACTH as treatment for nephrotic syndrome as a second, third or even fourth line treatment, particularly in patients who are resistant to conventional therapies.

Subsequent clinical studies demonstrated that ACTH has prominent antiproteinuric and renoprotective effects that are not entirely explained by steroidogenic actions.

Adrenocorticotropic hormone (ACTH), also known as corticotropin, is a polypeptide tropic hormone produced and secreted by the anterior pituitry gland. It is an important component of the hypothalamic-pituitary-adrenal axis (HPA) and is often produced in response to biological stress. Its principal effects are increased production and release of corticosteriods. HPA is a complex set of direct influences and feedbackk interactions among the hypothalamus, the pituitary gland  and the adrenal glands.

A deficiency of ACTH is a cause of secondary adrenal insufficiency and an excess of it is a cause of Cushing’s syndrome.

Steroid hormones ( steriod that acts as a hormone) can be grouped into five groups by the receptors to which they bind: glycocorticoids, mineralcarticoids, androgens, estrogens, and progestrogens.

Steroid hormones help control metabolism, inflammation, immune functions, salt and water balance, development of sexual characteristics, and the ability to withstand illness and injury.

As a potent physiological agonist of melanocortin system that could directly target renal parenchymal cells, such as podocytes, ACTH might serve as a promising therapy for nephrotic glomerulopathies (a disease affecting the renal glomeruli – inflammatory or non-inflammatory).

Mineralocorticoids are hormones that were involved in the retention of sodium. The primary endogenous mineralocorticoid is aldosterone. Aldosterone acts on the kidneys to provide active reabsorption of sodium and an associated passive reabsorption of water, as well as the active secretion of potassium in the principal cells of the cortical collecting tubule and active secretion of protons via proton ATPases in the lumenal membrane of the intercalated cells of the collecting tubule. This in turn results in an increase of blood pressure and blood volume.

Aldosterone is produced in the cortex of the adrenal gland and its secretion is mediated principally by angiotensin II but also by adrenocorticotropic hormone (ACTH) and local potassium levels.

Aldosterone and cortisol (a glucosteroid) have similar affinity for the mineralocorticoid receptor; however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. Glucocorticoid concentrations are a balance between production under the negative feedback control and diurnal rhythm of the HPA axis, and peripheral metabolism, for example by the enzyme 11beta-hydroxysteroid dehydrogenase type1 (11B-HSD1), which catalyses the reduction of inactive cortisone (11-DHC in mice) to cortisol (corticosterone in mice). Reductase activity is conferred upon 11B-HSD1 by hexose-6-phosphate dehydrogenase (H6PDH). 11B-HSD1 is implicated in the development of obesity.

Knock out of H6PDH resulted in a substantial increase in urinary DHC metabolites in males (65%) and females (61%). Knock out of 11B-HSD1 alone or in combination with H6PDH led to a significant increase (36% and 42% respectively) in urinary DHC metabolites in females only. Intermediate 11B-HSD1/H6PDH heterozygotes maintained a normal HPA axis.

Urinary steroid metabolite profile by GC/MS as a biomarker assay may be beneficial in assaying HPA axis status clinically in cases of congenital and acquired 11B-HSD1/H6PDH deficiency

ACTH acts through the stimulation of cell surface ACTH receptors, which are located primarily on adrenocortical cells of the adrenal cortex. This results in the synthesis and secretion of gluco- and mineralo-corticosteriods and androgenic steroids.

An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids. This enzyme, 11-beta hydroxysteriod dehydrogenase type II (protein: HSD11B2), catalyzes the deactivation of glucocorticoids to 11-dehydro metabolites.

ACTH acts at several key steps to influence the steroidogenic pathway in the adrenal cortex:

ACTH stimulates lipoprotein uptake into cortical cells. This increases the bio-availability of cholestrol in the cells of the adrenal cortex.

ACTH increases the transport of cholesterol into the mitochondria and activates its hydrolysis.

ACTH Stimulates cholesterol side-chain cleavage enzyme, which makes the rate-limiting step in steroidogenesis. This results in the production of pregnenolone.

Receptor-binding studies have revealed that mineralcorticoids show a strong affinity for ACTH thereby establishing the potential for this hormone to activate mineralocorticoid receptors (MCRs). There are five MCRs and all of them show affinity for ACTH.

MCRs are expressed in kidney cells and that indicates that kidney is a target organ for the affects of ACTH.

Functions include:

1. Steroidogenic and adrenotropic activity

2. A multifaceted extra adrenal action that is mediated by the different MCRs present in the peripheral tissues and CNS

3. Has a lipostatic effect and stimulates lipolysis – (thus ACTH deficiency leads to obesity)

4. Its administration lowers levels of plasma lipids including Triglycerides, Total cholestrol, LDL-cholestrol and phospholipids

5. Its administration (complete ACTH molecule) rapidly increases the plasma insulin

Other activities include:

1. regulation of skin and hair pigmentation,

2. modulation of sebacious gland function and

3. anti-inflammatory and immunomodulatory functions

The total adrenocorticotropic hormone (ACTH) analogue is available as H.P. Acthar Gel (repository corticotropin injection) and is used for:

1. Monotherapy treatment of infantile spasms (IS) in infants and children under 2 years of age.

2. The treatment of exacerbations of multiple sclerosis in adults.

3. For inducing a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus.

4. Also:: rheumatic disorders; collagen diseases; dermatologic diseases; allergic states; ophthalmic diseases and respiratory diseases.

FDA approved indications for the above prodcut are available at the following URL:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697107/table/t1-ptj34_5p250/

Disclaimer: This is for information purpose only, not a medical advise.

For a full list of warnings, precautions, and adverse events related to Acthar, please refer to the full Prescribing Information including the Medication Guide for the treatment of Infantile Spasms and discuss this information with your healthcare provider.

Literature:

The renaissance of corticotropin therapy in proteinuric nephropathies

Metabolic Disturbances Associated with Systemic Lupus Erythematosus

H.P. Acthar Gel and Cosyntropin Review

Childhood nephrotic syndrome—current and future therapies

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Curator: Venkat Karra, Ph.D.

Cancer is a broad group of various diseases involving unregulated cell growth. It is medically known as a malignant neoplasm. In cancer, cells divide and grow uncontrollably and invade nearby parts of the body. The cancer may also spread to more distant parts of the body through the lymphatic system or bloodstream, it is called metastasis. However, not all tumors are cancerous. Some tumors do not grow uncontrollably, do not invade neighboring tissues, and do not spread throughout the body which are called Benign tumors.

There are more than 100 types of Cancers. Follow the link to know more:

http://www.cancer.gov/cancertopics/types/alphalist

Classification of Cancers:

There are five broad groups that are used to classify cancer.

  1. Carcinomas: These are characterized by cells that cover internal and external parts of the body such as lung, breast, and colon cancer.
  2. Sarcomas:These are characterized by cells that are located in bone, cartilage, fat, connective tissue, muscle, and other supportive tissues.
  3. Lymphomas:These are cancers that begin in the lymph nodes and immune system tissues.
  4. Leukemias:These are cancers that begin in the bone marrow and often accumulate in the bloodstream.
  5. Adenomas:These are cancers that arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular tissues.

Causes

  • Hereditary (about 5-10%)
  • Environmental (90-95% of cases) factors e.g.,
  • Tobacco (25-30%) – about 70% of the lung cancers are due to tobacco habit
  • Infections (15-20%)
  • Radiation (both ionizing and non-ionizing, up to 10%)
  • Obesity (30-35%) and
  • Pollutants,Sedentary life, poor diet etc. are likely to cause cancer.

These can directly damage genes or combine with existing genetic faults within cells to cause the disease.

Detection

Presence of certain signs and symptoms, screening tests including medical imaging etc. can be used.

Diagnosis

Cancer can be diagnosed by microscopic examination of a tissue sample called biopsy.

Visit Link for details: http://cancer.stanford.edu/information/cancerDiagnosis/

Treatment

Cancer is usually treated with chemotherapy, radiation therapy and surgery.

Survival

Survival depends greatly by the type and location of the cancer and the extent of disease at the start of treatment. The risk of developing cancer generally increases with age.

Young People with Cancer, visit the following link for details:

http://www.cancer.gov/cancertopics/coping/youngpeople/page6

For Types of Childhood Cancer, visit the following link:

http://www.cancer.gov/cancertopics/coping/youngpeople/page13

For common medical procedures, visit the following link:
http://www.cancer.gov/cancertopics/coping/youngpeople/page6

Signs and Symptoms

Initially there will be no signs and symptoms but only appearing as the mass that continues to grow or ulcerates. The findings that result depends on the type and location of the cancer. For example,

Mass effects from Lung Cancer – can cause blockage of the bronchus resulting in cough (coughing up blood if there is ulceration) or pneumonia.

Oesophageal Cancer – can cause narrowing of the esophagus making it difficult or painful to swallow.

Colorectal Cancer – may lead to changes in bowel habits and bleeding leading to anemia.

General symptoms may include:

  • Unintentional weight loss,
  • Fever,
  • Being excessively tired,
  • Changes to the skin,
  • Hodgkin disease,
  • Leukemias, and
  • Persistent fever due to Cancers of the liver or kidney.

Symptoms of metastasis include:

  • Enlarged lynph nodes which can be felt or sometimes seen under the skin and are typically hard),
  • Enlarged liver or spleen which can be felt in the abdomen,
  • Pain or fracture of affected bones, and
  • Neurological symptoms.

It is nearly impossible to prove what caused a cancer in any individual, because most cancers have multiple possible causes. For example, lung cancer could be due to tobacco habbit or could be a result of air pollution or radiation.

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