Post transcriptional modification of hnRNA in eukaryotes includes three event. Splicing is removal of introns from the primary transcript and ligation of exons to form a continuous sequence specifying a functional polypeptide. Capping of eukaryotic mRNAs refers to addition of 7-Methylguanosine to the 5’ end of almost all eukaryotic mRNAs in an unusual 5’,5’- triphosphate linkage. Tailing refers to cleavage of 3’ end and addition of 80 to 250 A residues to create a poly(A) tail.

The practice of commercial exploitation of biochemicals or genetic materials which occur naturally is known as biopiracy. Typically, indigenous people have traditional cognition primarily consisting of biological features and genetic diversity of the natural environment from one generation to another. Few of the traditional knowledge relevant to global survival has the elements listed below:

1. Farming or Agriculture.
2. Medicinal Plants.
3. Varieties of Food crops.

The essential components for the survival of rural and indigenous people include conservation of habitat, species, and biodiversity.

- Replication of DNA begins at ori, to form a replication fork. 

- DNA dependant DNA polymerase forms a new strand in 5' ---> 3' direction. 

- Role of DNA ligase is to join discontinuously synthesised fragments.

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Recombination can occur between any two genes on a chromosome, the amount of crossing over is a function of how close the genes are to each other on the chromosome. If two genes are far apart, for example at opposite ends of the chromosome, crossover and non-crossover events will occur in equal frequency.  Crossing-over occurs when two homologous chromosomes exchange genetic material during meiosis I. The closer together two genes are on a chromosome, the less likely their alleles will be separated by crossing-over.

tRNA is called an adapter molecule because it attaches itself via initiation and elongation factors to the ribosome- mRNA complex which facilitates the incorporation of the correct amino acid to the growing polypeptide chain by its specific anticodon to the mRNA codon.

Francis Crick suggested that each amino acid has specific "adapter", a molecule which recognizes specific piece of DNA. Assembly of amino acids is determined by a recognition between the adaptor and DNA molecule which serves as the informational template.

Restriction enzymes cut DNA bonds between 3′ OH of one nucleotide and 5′ phosphate of the next one at the specific restriction site. Adding methyl groups to certain bases at the recognition sites on the bacterial DNA blocks the restriction enzyme to bind and protects the bacterial DNA from being cut by themselves.  Each restriction enzyme cuts DNA at a different restriction site. Some restriction enzymes make staggered cuts through a DNA molecule, producing. Restriction enzymes cut through both nucleotide strands, breaking the DNA into fragments, but they don't always do this in the same way.  This overhanging nucleotide strand is called a sticky end because it can easily bond with complementary DNA fragments.

Blunt and sticky ends areresult of restriction endonuclease action on double stranded DNA.

Sticky Ends – are staggered ends on a DNA molecule with short, single-stranded overhangs. 

Blunt Ends  are a straight cut, down through the DNA that results in a flat pair of bases on the ends of the DNA.

Biocontrol refers to the use of biological methods for controlling plant diseases and pests.

Chemicals, insecticides and pesticides are extremely harmful to human beings and also these pollute our environment.

The use of biocontrol measures will greatly reduce our dependence on toxic chemicals and pesticides.

Biocontrol agents are which are useful in controlling plant diseases and pests are-

• The ladybird, a beetle with red and black markings and dragon flies are useful to get rid of aphids and mosquitoes respectively.

• Bacteria Bacillus thuringiensis (Bt) is used to get rid of butterfly caterpillars where dried spores of Bacillus thuringiensis are mixed with water and sprayed onto vulnerable plants such as brassicas and fruit trees and these are eaten by the insect larvae and in the gut of the larvae, the toxin is released and the larvae get killed.
• Trichoderma species are free-living fungi found in the root ecosystem these are effective as biocontrol agents of several plant pathogens.
• Baculoviruses are pathogens that attack insects and other arthropods and the majority of baculoviruses used as biological control agents are in the genus Nucleopolyhedrovirus.

Principles of cancer immunotherapy
Clinical oncology for students > Principles of cancer immunotherapy
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Information on authorship and revision

Last modified:
29 November 2016 09:57:06

Author(s):

    Dr Craig Gedye — Author
    Cancer Council Australia Oncology Education Committee — Co-author

      Cite this page

Contents

    1 Introduction
    2 The immune system
    3 Controlling the immune system: immune checkpoints
    4 Cancer immunosurveillance and immunoevasion
    5 Spectrum of cancer immunotherapy
    6 Active non-specific cancer immunotherapy
    7 Active specific cancer immunotherapy
    8 Passive non-specific cancer immunotherapy
    9 Passive specific cancer immunotherapy
    10 Immune checkpoint inhibitors
    11 Mechanism of action of immune checkpoint inhibitors
    12 Current examples of immune checkpoint inhibitors
    13 Side effects of checkpoint immunotherapy antibodies
    14 Managing side-effects of immune checkpoint cancer immunotherapy
    15 Managing expectations of immune checkpoint cancer immunotherapy

Introduction

Cancer immunotherapy has a long history, but has rapidly developed since 2010. The goals of cancer immunotherapy are to kill or control cancer cells by activating, or reactivating the immune system.

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The immune system

Our immune systems have evolved to a complex system involving innate and adaptive immune systems. Innate immunity starts with physical barriers (skin, mucus), and involves non-specific defences from immune cells such as neutrophils and natural killer cells. The adaptive immune system has evolved from innate immune cells, which include B-cells that produce antibodies, and is governed by lymphocytes, primarily alpha/beta, which include CD4+ helper, CD8+ killer and FOXP3+ regulatory T-cells.

The adaptive immune system is most relevant in managing the immune system, addressing viral infections, and has evolved to be the most important part of the immune system in terms of controlling and eliminating cancer.

Adaptive immune cells recognise other cells via antigen presentation. A small peptide fragment of a native, viral or cancer protein (the antigen or epitope) is “presented” on a cell surface complex made of proteins called the major histocompatibility complex (MHC). These epitopes are then recognised by proteins (e.g. the T-cell receptor, TCR) on the surface of individual T- or B-cell lymphocytes (Figure A). The repertoire of human T-cells and B-cells can recognise up to 109 individual patterns. The outcome of antigen presentation and recognition is determined by the balance of interactions between pairs of immune checkpoint costimulatory molecules (e.g. CTLA4-CD80, OX40-OX30L, CD154-CD40, PD1-PDL1; Figure B below).

Figures A and B

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Controlling the immune system: immune checkpoints

Uncontrolled immune activation leads to autoimmune diseases like ulcerative colitis, dermatitis and interstitial pneumonitis. The activity of the immune system is modulated and carefully controlled by costimulatory molecules called immune checkpoints. When antigen recognition occurs, a committee of other molecules interact on the surface of the immune cell and the target cell to determine the balance of the interaction. If the signals are largely positive, the immune cell activates and is primed to attack the antigen presented by the target cell. However if the balance of signals is negative, then the immune cell can become inactivated, sometimes permanently, and the antigen is accepted as a normal/self antigen (Figure B). Immune checkpoints of relevance to cancer include CTLA4, PD1 and PDL1 (see above).

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Cancer immunosurveillance and immunoevasion

Every cancer that becomes clinically detectable and relevant has survived elimination by the immune system. As soon as tiny cancers form, the aberrant proteins they express from mutated genes generate so-called “neoantigens” that can be recognised by the immune system by antigen presentation, targeting the aberrant cell for destruction.

Cancers are edited by this process, and may be eliminated at this point; so called immunosurveillance. Some cancers can enter a state of equilibrium with the immune system, and though present, remain clinically undetectable and irrelevant. If this balance is then later disturbed, for example by immunosuppression caused by age, illness or iatrogenic causes, the cancer can escape and evade immune control.

Cancer immunotherapies attempt to redress these escape mechanisms at many points, but a key mechanism for cancer cells to evade the immune system seems to be via negative immune checkpoint signalling (Figure C).

Figure C

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Spectrum of cancer immunotherapy

Cancer immunotherapies can be categorised by whether:

    they actively stimulate the immune system, or passively alter immune system signalling or cell populations, and,
    the treatment is targeted at a specific, known antigenic target, or is non-specifically stimulating the immune system.

Spectrum of cancer immunotherapy
(adapted from Davis et al., 2000)

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Active non-specific cancer immunotherapy

    Bacillus Calmette-Guerin (BCG) is one of the most commonly used and earliest discovered cancer immune therapies. This live attenuated strain of Mycobacterium tuberculosis is instilled intravesically to reduce recurrence of debulked non-muscle invasive bladder cancer. The mechanism of action is a non-specific inflammatory reaction; side effects can include dysuria and other lower urinary tract symptoms.
    Immunostimulatory cytokines such as interferon-alpha and interleukin-2 were previously mainstay treatments of metastatic renal-cell carcinoma and melanoma. Interferon-alpha was used as adjuvant therapy in resected high-risk melanoma, though the survival advantage was debatable. Interleukin-2 is still used in some countries in a limited highly restricted patient population. Treatment requires ICU admission due to severe systemic inflammatory responses and hypotension. A proportion of patients who took IL2 have experienced long-term remission of their cancer.
    Oncolytic viruses such as T-VEC (talimogene laherparepvec) and CAVATAK® (Coxsackievirus A21) are attenuated or modified viruses that can be injected directly into tumour masses or administered intravenously. Infection of tumour cells is associated with activation of an immune response, that in some patients can even spread to other, uninjected tumour sites (the “abscopal” effect). Many viruses are being explored, but none are yet in routine clinical practice.

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Active specific cancer immunotherapy

    Cancer vaccines have been trialled in many different formats, but all attempt to direct the immune system to recognise particular antigens that are then hoped to cause recognition and elimination of the cancer. Cancer vaccines can target a single peptide, a protein, or autologous or allogenic cancer cells. Unfortunately most of these vaccines have failed to improve patient outcomes. Sipeleucel-T is an allogeneic vaccine using prostate cancer cell lines that has a modest effect in prostate cancer, but is not available in Australia.
    Oncogenic virus vaccines are the most common and important form of cancer immunotherapy. Vaccines that prevent infection by the hepatitis B virus (causing hepatocellular carcinoma) or the human papillomavirus (causing cervical, ****, penile and some head and neck cancers) are internationally and numerically the most effective and most cost-effective cancer immunotherapies available.
    CAR-T-cells are autologous patient derived T-cells, that have been genetically modified to display cancer cell recognition molecules on their cell surface. In isolated cases these have generated extraordinary responses (e.g. CD19+ paediatric B-ALL) but with considerable toxicity.

Reproductive health in a society helps to prevent the spread of various sexually transmitted diseases and impart the ability to produce offspring carrying better survival rates. *** education helps in maintaining the population size and to avoid unwanted pregnancies.

In a DNA molecule, the number of cytosine molecules is equal to guanine molecules and the number of adenine molecules is equal to thymine molecules. Thus, if a double-stranded DNA has 20% cytosine, it has 20% guanine. Thus, C + G makes 40% of the total bases. The remaining 60% includes both adenine and thymine which are in equal amounts. So, the percentage of adenine is 30%.

More than 70 percent of species recorded on the Earth are animals and only 22 percent species are plants. There is quiet a large difference in their percentage. This is because animals have adapted themselves to ensure their survival in changing environments in comparison to plants. For example, insects and other animals have developed a complex nervous system to control and coordinate their body structure. Also, repeated body segments with paired appendages and external cuticles have made insects versatile and have given them the ability to survive in various habitats as compared to other life forms.

Chromosomal abnormalities are the type of genetic disorders caused due to the change in one or many chromosomes or the abnormal arrangement of the chromosomes. There are different types of chromosomal abnormalities as follows:

• Aneuploidy – It is a condition in which there is a loss or gain of chromosomes due to abnormal segregation of genes during cell division.
• Polyploidy – It is a condition in which the count of the entire set of chromosomes increases due to the failure of cytokinesis in cell division. It is mostly observed in plants.

In trisomy, there is an extra copy of ONE chromosome in an egg or sperm cell.  As a result, after fertilisation the foetus has 47 chromosomes instead of the usual 46.  An example of this is Downs Syndrome, in which there is an extra chromosome 21. 

In triploidy, the foetus has an entire extra set of chromosomes -- so it has 69 chromosomes instead of the usual 46.  A triploid foetus almost always results in miscarriage or stillbirth.  There is too much genetic material for the baby to survive.  If it is born, it dies in infancy. 

The cell structure comprises individual components with specific functions essential to carry out life’s processes. These components include- cell wall, cell membrane, cytoplasm, nucleus, and cell organelles. Read on to explore more insights on cell structure and function.

Cell Membrane

• The cell membrane supports and protects the cell. It controls the movement of substances in and out of the cells. It separates the cell from the external environment. The cell membrane is present in all the cells.
• The cell membrane is the outer covering of a cell within which all other organelles, such as the cytoplasm and nucleus, are enclosed. It is also referred to as the plasma membrane.
• By structure, it is a porous membrane (with pores) which permit the movement of selective substances in and out of the cell.  Besides this, the cell membrane also protects the cellular component from damage and leakage.
• It forms the wall-like structure between two cells as well as between the cell and its surroundings.
• Plants are immobile, so their cell structures are well-adapted to protect them from external factors. The cell wall helps to reinforce this function.

Cell Wall

• The cell wall is the most prominent part of the plant’s cell structure. It is made up of cellulose, hemicellulose and pectin.
• The cell wall is present exclusively in plant cells. It protects the plasma membrane and other cellular components. The cell wall is also the outermost layer of plant cells.
• It is a rigid and stiff structure surrounding the cell membrane.
• It provides shape and support to the cells and protects them from mechanical shocks and injuries.

Cytoplasm

• The cytoplasm is a thick, clear, jelly-like substance present inside the cell membrane.
• Most of the chemical reactions within a cell take place in this cytoplasm.
• The cell organelles such as endoplasmic reticulum, vacuoles, mitochondria, ribosomes, are suspended in this cytoplasm.

Nucleus

• The nucleus contains the hereditary material of the cell, the DNA.
• It sends signals to the cells to grow, mature, divide and die.
• The nucleus is surrounded by the nuclear envelope that separates the DNA from the rest of the cell.
• The nucleus protects the DNA  and is an integral component of a plant’s cell structure.