How Much Radiation Can You Take?

Radiation therapy is becoming more and more common and as with many things that we have discussed here, the person to person variation in response to radiation exposure can be large. So what drives this difference in response to radiation dose. An answer is emerging from a series of studies that were undertaken using cells from xeroderma pigmentosum patients. You can read more about xeroderma pigmentosum here, but briefly these patients suffer from a dysfunction in the molecular system that repairs DNA double strand breaks.

In a 2010 Journal of Medical Genetics paper by Abbaszadeh et al. The authors piece together the role that a specific protein, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays double strand break repair induced by ionizing radiation. Ultimately specific alleles of the DNA-PK protein are identified that predispose these individuals to an extreme radiation sensitivity.

The authors leave us with an interesting statement:

“Finally, these data show how seemingly ‘mild’ or undiagnosed defects in DNA repair factors, while consistent with viability, can have catastrophic consequences should such an individual require cytotoxic anticancer RT. Simple pretreatment screening protocols such as measuring the induction of repair of nuclear gamma-H2AX foci in patient cells, to identify individuals at risk, would increase the safety of RT for such patients.”

I am asking the Tox1401 students to look into exactly what “pretreatment screening protocols such as measuring the induction of repair of nuclear gamma-H2AX foci in patient cells” is, so if you would like to know more, head on over to the comments section where they will provide a brief description of the procedure.

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66 thoughts on “How Much Radiation Can You Take?

  1. Radiation Therapy also known as Radiotherapy is used in cancer treatment. This helps treat the tumor at hand. Many cancer patients and physician find this treatment reliable. However, most people are affected with Xeroderma pigmentosum (XP), this means they are sensitive to sun or radiation.
    This disease is not something that can be easily diagnosed by a normal physical at the doctor’s office and even people with it might not know that they have it. It is a gene related disease and a family history will be needed, to determine the presence of it. In these particular people, their cells cannot make out and fix radiation damage to the DNA molecule that encodes for that gene, which is known as the DNA double-strand break repair.
    Because of this, precautions have to be taken when administrating Radiotherapy to all cancer treatment. This is why Abbaszadeh et al mentions pretreatment protocols. He gives a specific one, which is “measuring the induction of repair of nuclear gamma-H2AX foci in patient cells”. This simply is a test done to see if patients have the DNA double-strand break repair ability to be able to identify and fix radiation damage to their DNA before doctors go on to administer Radiotherapy.
    This pretreatment will mark out patients at risk and make Radiotherapy save and beneficial.

    • Another way you could test to see if the individual has XP is to sit them in the sun and observe how their skin reacts. Most indviduals with XP will react very severely to the sun. They’re skin will burn easily and they will have blottchy freckles all over they’re body. Unfortunately, this also affects the individual’s eyes as well. They’re skin is as sensitive as an albino person, but they look exactly like anybody else.

    • I also agree that radiation therapy is used in cancer treatment and it is used very often as well. It’s very true that many cancer patients and physician finds this treatment reliable. But I think patients with xeroderma pigmentosum (XP) are highly sensitive to sun or radiation so it will not be a very good choice for them. I totally agree that this disease is not something that can be easily diagnosed by a normal physical at the doctor’s office and even people with it might not know that they have it. This will put these patients in a dangerous situation since they are highly sensitive to light

    • the way you describe to prevent XP from harming the patient when doing the radiotherapy is very clear and the background information why XP is dangerous to cancer patient is wel described.

  2. Like every other disease, the need for information on a patient’s health is paramount when trying to diagnose and treat a disease. Various diseases can often cause intense problems for treatment of a second or conflicting disease. Treatments used for one disease may create problems for the second or third disease etc. One way to look at it is when a patient is described more than one drug. Doctors have to see if the drugs combined can create more serious complications or cancel each other out. This is the same case with disease treatments especially those involving a form of radiation. One example of a disease that has many difficulties treating and can cause conflicts with other disease is Xeroderma Pigmentosum. This particular disease has the property of being extremely sensitive to radiotherapy (Ultra Violet light), a treatment used for cancer patients in order to stop the growth of the tumors. However, if a patient with this disease is ever exposed to radiotherapy at various levels, possible double stranded breaks can occur as well as mutations in the DNA repair system ultimately leading to death. A less serious result would be chromosomal rearrangement such as deletion of genes, relocation, or even genes turning off or on that shouldn’t.
    Because of these situations and complications, pre-screening protocols must be followed by clinicians. These protocols are meant to prevent disasters that could be avoidable. Patients may have diseases that are dormant or at low levels and never know. If the disease could become dominant, increase in seriousness etc due to a treatment for another illness, the treatment should be avoided and alternatives should be sought. These protocols are meant to protect the patient and clinician.

    • This looks more like a summation of the paper than an explanation of measuring the induction of repair of nuclear gamma-H2AX foci in patient cells.

  3. A Double Strand Breaks is when a DNA strand is completely torn apart. These types of breaks are very dangerous. Double strand break repair is an important mechanism for repairing a break. Gamma-H2AX is a histone complex that facilitates repair of the break either via Non-homologous end joining (NHEJ) or Homologous directed repair (HR). NHEJ involves the looping together of a series of proteins to the ends of DNA and stabilizing them by attaching phosphate groups in hopes of recombining broken DNA ends. HR involves the trimming of back the break creating more options for recombination to occur. If there are ends that hang unevenly, HR will occur; trimming back DNA to even out the break. If the ends cleave evenly more than likely NHEJ will occur. If HR doesn’t work it causes death of the embryo. If the cell cannot fix a DNA break, the cell will die. For this reason, double strand breaks are extremely dangerous.
    DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is another protein that help phosphorylate and put together Double Strand Breaks. People with Xeroderma pigmentosum (XP) lack this mechanism to protect themselves from Ultraviolent light. They are extremely sensitive to light and are susceptible to skin cancer. These people are also sensitive to ionizing radiation. Searching for a pretreatment screening protocol means developing an alternative method of treatment for these individuals; knowing that they are sensitive to any sort of radiation and/or UV light. If a patient with XP were to develop cancer, radiation therapy would probably kill them. It is important to measure the induction of repair of nuclear gamma-H2AX foci can help identify individuals at risk and increase safety of radiation treatment for these patients. A pre-analysis of the individual can include sequencing the person’s genome and checking for a deletion of exon 31, which is associated with Infrared Sensitivity.

    • I thought your explanation was very good. It was very interesting as well and I loved the way you said “Double strand break repair is an important mechanism for repairing a break.” This sentence was very short and simple and also gets your point across as well. It’s very true that people with Xeroderma pigmentosum (XP) lack mechanisms to protect themselves from Ultraviolent light. I totally agree that they are extremely sensitive to light and are susceptible to skin cancer. They should not be given radiation therapy and an alternative treatment needs to be developed for these patients.

    • Your post is very informative and detailed such as your explanation of the DNA break repairs: the Non-homologous end joining (NHEJ) or Homologous directed repair (HR).

    • Your blog post was easy to understand and it was very organized. there was a thesis and you provided an example and defined what it was clearly. I also agree that it is important to measure the induction because it may be very risky!

  4. Today, radiation therapy is used commonly to treat many different forms of cancers. It induces DNA double strand breaks (DSBs) and defects in DNA DSB repair pathways lead to hypersensitivity to ionizing radiation, immunodeficiency, and increased cancer incidence. A patient with xeroderma pigmentosum, a rare autosomal recessive disease characterized by sensitivity to sunlight and susceptibility to skin cancers, exhibits dramatic clinical radiosensitivity following radiation therapy, which results in death. If patients with xeroderma pigmentosum exposed to radiation therapy in any condition, then a possible double stranded breaks can occur as well as mutations in the DNA repair system. As a result these patients will ultimately die because they were sensitive to radiation. This shows that defects in DNA repair systems can have catastrophic consequences.

    A simple pretreatment screening protocol such as measuring the induction of repair of nuclear gamma-H2AX foci in patient cells can increase the safety of patients with xeroderma pigmentosum. For pretreatment screening a clonogenic survival assays can be conducted to measure radiation sensitivity. This pretreatment screening protocol can be used in developing an alternative method of treatment for these individuals since they are highly sensitive to any sort of radiation therapy. The situation becomes very complicated when it comes to treating patients with xeroderma pigmentosum and pretreatment screening protocol can be used in these situations to measure the sensitivity of radiation. In such situations pretreatment screening protocol can come in very handy to diagnose the sensitivity of radiation in these patients. This will increase the safety of patients with xeroderma pigmentosum.

  5. Xeroderma Pigmentosum is a condition where a patient has a strong sensitivity to sun and radiation, which is also known as ‘dermipegmentosa’. Many patients dont even know that they have the disease since it is gene related, although it can be seen in children as young as a year old. When someone with xeroderma pigmentosum gets cancer, doctors must be espeically carefully when going about how to treat them with radiation therapy. This is because these patients have double stranded DNA breaks, preventing them from being able to use radiation to repair this damage. To test if patients have these breaks, a measurement of the induction repair of nuclear gamma H2-AX foci is a patient’s cells is taken. From this test, docotors can determine if whether or not the patient has these double stranded breaks, and therefore can select a radiation therapy treatment method that will be best for the patient.

    • your way of describing the the xp and the pretreatment is similar to most and clear and most.

  6. Xeroderma pigmentosum is a very rare skin disorder, where a person is highly sensitive to sunlight. Xeroderma pigmentosum is caused by a defect in one of the genes and is an autosomally recessive inherited disease. In order to inherit xeroderma pigmentosum, the person has to inherit one recessive xeroderma pigmentosum gene from each parent. People with xeroderma pigmentosum have a defect in the gene that is responsible for repairing cell damage caused by UV light. This defect leads to cancerous cells or cell death. Unfortunately, there is no cure for xeroderma pigmentosum. The main goal of treatment is to protect the patient from UV exposure and thus prevent the damaging effects it can have on the skin. With all this conditional problems when it comes to treatments doctors must take extreme precautions due to DNA double-strand breaks and single-strand breaks are not formed as a consequence of the direct absorption of UV radiation by DNA. Rather, they are formed as the consequence of the attempted repair of UV radiation-induced base damage in DNA. That is why when it comes to these patients the people who are giving these treatments must pretreatment screening protocols in order to make sure the treatment doesn’t become the cause of death.

    • good summary on Xeroderma pigmentosum. what should be done to monitor the amount out radiation?

      • good summary on Xeroderma pigmentosum. What should be done to monitor the amount of radiation? How should people be screened?

    • good explanation of the disease and what happens to people who have it, however you didn’t really touch a lot on what the pretreatment screenings should do or be, it would have been nice for you to expand more on that aspect.

    • What types of “pretreatment screening protocols such as measuring the induction of repair of nuclear gamma-H2AX foci in patient cells” could the patient with XP undergo?

  7. The Radiation Therapy is a method that is used in the cancer treatment. Cancer is a disease that causes cells to grow abnormally and out of control. In radiation therapy, high-energy X-rays are directed at a person’s body to kill cancer cells and keep them from growing and multiplying. While it’s killing the cancer, radiation therapy also can damage normal cells. The good news is that normal cells are more likely to recover from the effects of radiation. However, people with the condition of Xeroderma pigmentosum (XP) are extremely sensitive to the UV light and radiation. Therefore, those people with XP condition can not undergo the radiation therapy since this type of therapy will cause those people result in death due to the double stranded DNA breaks which are caused by XP. The measurement of the induction repair of nuclear gamma H2-AX foci can be used to examine if the people have this type of condition in order to give the appropriate treatment methods to them.

    • You gave a brief but useful explanation of the genetic condition. I wish there was a more clear explanation of H2-AX, however.

  8. People with the condition Xeroderma pigmentosum, are sensitive to Ultraviolet light so they are sensitive to the sun and radiation. This is because they lace a mechanism that would protect themselves from radiation damage thus causeing DNA double-strand breaks. If this person was exposed to radiotherapy too much or too long, it might cause DNA mutations which could cause chromosomal rearrangement, deletion of genes or abnormal gene functions. This would eventually lead to death.

    Gamma-H2AX is a histone complex that facilitates repair of the break either Non-homologous end joining (NHEJ) or Homologous directed repair (HR). NHEJ loops together of a group of proteins to the ends of DNA and stabilizing them by attaching phosphate groups which can recombine broken DNA ends. HR involves the trimming of back the break creating more options for recombination to occur.

    If the patients NER and NHEJ pathway are defective, undiagnosed defects in DNA repair pathway can leave the patients at risk of toxic amounts of radiation. Since anti cancer radiotherapy protocols exert cytotoxicity by causing DNA damage by making DNA double-strand breaks, people who are unable to repair are at higher risk of catastrophic consequences. A pretreatment protocol is would identify who is at risk so that modifications can be made to their treatment. By measuring the induction of repair of nuclear g-H2AX foci in patient cells and identifying the individuals at risk, it would increase the safety of radiation therapy for such patients.

    • Great analysis and explanation, you clearly explained the concept behind the condition and the method of treatment/diagnosis.

    • I agree with you that measuring the induction of repair of nuclear g-H2AX foci in patient cells , it would make the radiation therapy for such patients more safely.

  9. Anticancer radiotherapy treatments are constantly used in conjunction with pretreatment screening protocols to take care of any given cancer. The process simply cuts off that area of cells that potentially have a cancerous tumor before it takes root. However the high levels of radiation that a patient is exposed to despite the fact that is for a small period of time, does bring some concern to the field. A good example of this concern would be some patients that are suffering from Xeroderma Pigmentosum or (XP) which is a rare autosomal resessive disease characterized by high sensitivity to sunlight and other forms of UV radiation. XP can lead to breaking of the double strand (DSB) which is like a trimming of the double strand. It destroys DNA from the ends and if not stopped, works its way inward erasing the traces of the DNA strand. The one gene designed to fight against this breaking down is called gamma-H2aX or (g-H2AX). This protein works in two pathways: the Non-homologous end joining (NHEJ) or Homologous direct repair (HR). In NHEJ, there are a bunch of proteins that aim for the ends. Once they pair up with the ends with the complementary strands the DNA sequence is slightly altered, but fixed. In HR, the DNA tries to repair conservatively. It does this by forcing some end parts of the DNA to overhang and what overhangs gets deleted. It’s an attempt to even out the strands for re-annealing after DSB. The pathway that seems most likely is the NHEJ simply because it has a catalyst–the DNA-Dependant protein kinase catalytic subunit (DNA-PKcs) which is another protein that speeds up this process of the phosphorylation that allows for the combing of the DNA from the DSB.
    XP patients are kept under the clinical protocol so that the condition can be monitored, prolonged and eventually halted from becoming anything potentially worse. If these people are also suffering from cancer, there has to be another alternative despite it not being the most efficient of ways to solve the problem. However, it will keep the XP from getting worse from the exposure of radiation.

    • great explanation about radiation therapy. I epically like how you broke down the function of gamma-H2aX and explained the mechanism of how it prevents the breakdown of the double stranded DNA.

    • I really liked the way you explained y our example because it was so well written due to the way you organized it. I also agree that there has to be an alternative because there should be other ways to solve the problem.

  10. Still no explanation. What is the clinical protocol for measuring the induction of repair of nuclear gamma-H2AX foci in patient cells? Hint: Check the reference that follows this statement in the Abbaszadeh et al paper!

  11. Radiation therapy or radiotherapy is a technology that employs the use of ionization radiation to halt the progression/division of malignant cells. Radiation therapy focuses on cells locally and not systemically. The radiation therapy has different forms and sources. Some individuals are exposed to the radiation via an external machine that provides the necessary levels of radiation to inactivate cancerous cells. Also, some patients may have a small radioactive device inserted at the site of the tumor releasing radiation. Possible side effects of radiation therapy include the development of skin rashes, permanent pigmentation, and scarring.
    Xeroderma Pigmentation is a rare hereditary condition where an individual’s skin and tissue in certain areas become highly sensitive to UV light. Ultraviolet light damages DNA which is usually repaired by natural processes, however, individuals with xeroderma pigmentosa has lost this repair mechanism and succumb to significant skin damage. This condition is caused by double stranded DNA breaks. To analyze these DNA breaks in humans, an analysis of the patients the induction repair of nuclear gamma H2-AX foci. Physicians can analyze this information to discover potential double stranded DNA breaks and can design a suitable radiation treatment.

    • really informative explanation of the radiation therapy and the damage it can cause to a person with XP, however it would have been nice to go into more details of the disease. But otherwise it was a very informative and to the point response.

  12. The goal of pretreatment screening is to determine whether a diagnostic evaluation and office-based treatment are the best course of action for a particular patient. Simple pretreatment screening measures by the physician and patient can help offset fatal diseases and even death. Patients who have xeroderma pigmentosum are unable to repair DNA double strand breaks due to a dysfunction in their molecular system. When these patients and other patients receive radiation therapy they respond differently to it. Therefore it is important to perform a simple pretreatment screening protocol on patients to identify if they are at risk during radiation therapy. A simple pretreatment protocol that is used to diagnose defects in DNA repair pathways is the measuring of repair of nuclear gamma-H2AX in patient cells. Measures such as these can help detect defects in DNA repair pathways which if left undetected can cause life-threatenining toxicity to patients during radiation therapy. An immunofluorescence assay can be used to detect gamma-H2AX foci. H2AX foci, as untreated cells typically exhibit 0e2 foci per cell when they are expressed as the percentage of famma-h2AX positive cells containing 4 or more gamma h2AX foci. Monoclonal antibody nuclear g-H2AX foci were detected after 2 Gy irradiation. With the use of a fluorescence microscope, an analysis can be performs by counting the number of foci in a minimum of 100 nuclei of each cell line per time point. Simple pretreatment screening protocols such as this immunofluorescence assay can help combat cancer caused by radiation therapy.

  13. Radiation therapy has been a very effective treatment for cancer, however, it has negative effects on xeroderma pigmentosum (XP) patients. XP patients have disfunctionnal DNA-dependent protein kinase catalytic subunit (DNA-PKcs) that repair DNA double strand breaks. The alleles of DNA-PK protein in an individual can result in an extreme level of radiation sensitivity. Individuals who have defect in repairing DNA double stranded breaks (DNA DSB) are sensitive to ionizing radiation. Ionization radiation is a type of radiation that has a large amount of energy that causes atoms to become ionized. Often times, the process of H2AX phosphorylating into gamma-H2AX on serine 139 occurs at the site of DNA double strand breaks and it generates nuclear foci.
    The authors from the 2010 Journal of Medical Genetics paper by Abbaszadeh et al mentioned about some pretreatment protocols such as “…measuring the induction of repair of nuclear gamma-H2AX foci in patient cells…”. Often times, the process of H2AX phosphorylating into gamma-H2AX on serine 139 occurs at the site of DNA double strand breaks and it generates nuclear foci. To measure the radiation sensitivity, clonogenic survival assays can be conducted to cells that were exposed to radiation. After the exposure, the unrepaired foci and repaired foci can be marked based on the location of gamma-H2AX to identify the locations of DNA SAB.
    PMID: 12897845
    Biomedcentral: 1471-2407-10-4

    • I like how you explained the DNA-dependent kinases and how they affect XP patients. I feel that if you explained what clonogenic survival assays were, the end of your response would be more clear. I got confused especially at the last sentence when you mentioned DNA SAB.

  14. Xeroderma pigmentosum, also known as XP, is an autosomal recessive genetic disorder. It affects the DNA repair mechanisms within our body which, when working properly, repair the damages that are caused by ultraviolet, UV, light. Therefore, when a person is known to have XP exposure to sunlight, and artificial UV light is forbidden because the body will not know how to repair itself from the exposure. Patients with XP are much more prone and susceptible to all types of skin cancers. If a patient with this illness requires radiation therapy a physician needs to administer a test to measure the induction of repair of nuclear gamma-H2AX foci in the patients cells. This test is done to see if patients are infected with a double strand DNA break (which is the cause of XP). This break will impair the bodies ability to repair radiation damage to their DNA, so it is crucial a doctor administers it before passing out the radiation therapy. If a patient with XP is given radiation therapy the damage can be so significant that it can result in death. A pre screening evaluation of the persons family background and genome could be a very intelligent use of time for a doctor before administering the radiation therapy. When sequencing the genome one should evaluate any problems or concerns with exon 31, which is the exon associated with infrared sensitivity. Radiation therapy is not a technique that should be given without proper testing before hand. This therapy has many side effects for those who are not diagnosed with a disease such as XP, so if a seemingly healthy person can have problems with this treatment it is crucial we make sure we are not causing more harm than help to people with UV sensitivities that need cancer treatments.

    • I think you have a great handle on the articles because it shows you really understand the material. I like how you expanded on the tests done to patients with this condition, like the induction of repair of nuclear gamma-H2AX foci, because you did a great job explaining what it entails.

  15. Xeroderma pigmentosum is a genetic disease characterized by sensitivity to sunlight that results to the development of skin cancer at young age. People with xeroderma pigmentosum (XP) can only go outside safely after sun goes down. XP is caused by defective repair of damage done to DNA (the genetic material), damage caused by ultraviolet (UV) light. Where normal persons can repair UV-induced damage by inserting new bases into the DNA, XP patients do not have normal ability to repair the DNA damage inflicted by UV light. People with this disease have problems with repairing cell that was damaged by UV light because of this problem person get cancerous cells or cell death. There is no cure for xeroderma pigmentosum. The main purpose of treatment for people with this disease is to protect the patient from UV light and sunlight because this can result to the negative cause on the skin. As the people with XP have defects with double stranded DNA breaks doctors can’t use UV radiation on them because it can cause more damage. So to test the patients if he/she has DNA breaks, they use measurement of the induction repair of nuclear gamma H2-AX foci is a patient’s cells are taken. After this test, the treatment can be determined for the patient because the doctor will know if the person has defects on DNA double stranded breaks.

    • I like your summary of the paper however I wish you would give more description the H2-AX foci. It would have been better if you suggested the prescreening measures that can be used to detect if a person has XP. Your response was very logical and is a good start to explain what the prescreening methods are.

  16. Xeroderma pigmentosum is an autosomal recessive disease where patients are unable to protect themselves from UV radiation. Cells are often damaged by the cell and the inability to repair these cells can lead to skin cancers. It has been found that the histone γ-H2AX plays an important role in cell repair. Without the functioning histone, the cells are unable to be repaired and the chance of getting skin cancer increases. “Simple pretreatment screening protocols such as measuring the induction of repair of nuclear γ- H2AX… would increase the safety of RT for such patients” (Abbaszadeh).
    H2AX becomes phosphorylated when there are double stranded breaks in the DNA caused by UV radiation. A recent study showed that “γ-H2AX appears rapidly after exposure of cell cultures to ionizing radiation” (Rogakou). After exposure to radiation, about 1% of the H2AX histone becomes γ-phosphorylated. This means that in one in every 2,000,000 base pairs, there is a double strand break. The experiment was done on mice where they were exposed to lethal amounts of ionizing radiation. It was found that after ionizing radiation, there was a dramatic increase of γ-H2AX formation. A maximal amount of the γ-H2AX is seen after 10 minutes of radiation.
    To help detect this in humans, one can expose a person to UV radiation and then run a flow cytometry test. A cytometry test examines microscopic particles in an electric field while in a liquid. In this case, we would be looking for the γ-H2AX histone. We would fluorescently detect the presence of γ-H2AX to help determine if a patient has this disease.

    References:
    A novel splice variant of the DNA-PKcs gene is associated with clinical and cellular radiosensitivity in a patient with xeroderma pigmentosum.
    Abbaszadeh F, Clingen PH, Arlett CF, Plowman PN, Bourton EC, Themis M, Makarov EM, Newbold RF, Green MH, Parris CN.
    http://www.ncbi.nlm.nih.gov/pubmed?term=19797196

    DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139
    Emmy P. Rogakou, Duane R. Pilch, Ann H. Orr, Vessela S. Ivanova and William M. Bonner
    http://www.jbc.org/content/273/10/5858.long

    Olive PL, Banath JP. Phosphorylation of histone H2AX as a measure of radiosensitivity. Int. J. Radiat. Oncol. Biol. Phys 2004;58:331e5.
    http://www.ncbi.nlm.nih.gov/pubmed/14751500

  17. Xeroderma Pigmentosum, often-abbreviated XB, is an autosomal recessive disease that is expressed by many different genes(multigenic). Only homozygotes are affected when someone has this disease. Some of the detrimental affects to the carrier, include extreme sensitivity to sunlight, which slowly deteriorates regions of the skin and eyes. This disease is most commonly diagnosed at birth because they are extremely sensitive to the sun and develop large freckles as well as bad sunburns. At a young age those affected also have a greatly increased risk of developing skin cancer or cancer on the eyes. The diseases hinders those affected ability to repair UV-light damaged cells.

    After a DNA strand break (DSB), Human replication protein A (RPA) combines/works together in cell with gamma-H2AX to identify and fix DNA strand breaks, the H2AX helping to form histones as well as the structure of DNA. Any lack of association between the RPA and gamma-H2AX could lead to hindered DNA-damage recognition as well as repair. If it is found that there are problems in association of the two, that patient would have a poor ability to repair any breaks in their DNA, making radiation therapy an extremely risky form of cancer treatment they may have.

  18. Radiotherapy-induced DNA double-strand breaks, also known as DSBs, are critical cytotoxic lesions in DNA strands. Accurate repair of the disease is essential for the success of maintenance and propagation of genetic information. Inherited defects in DNA DSB repair pathways lead to hypersensitivity to ionizing radiation, immunodeficiency and increased cancer incidence. Two major pathways that have evolved in the repair of DSBs are HR (homologous recombination) and NHEJ (non-homologous end-joining). Depending on the type of break encountered, HR and NHEJ may either compete or co-operate to fix DSBs in the DNA of eukaryotic cells. Defects that may occur in either pathway are strongly associated with human disease such as immunodeficiency and cancer predisposition.
    Xeroderma pigmentosum (XP) is a disease that is characterized by sun sensitivity, ocular involvement, and greater risk of cutaneous and ocular neoplasm. Most individuals with XP develop dry skin and constellation of hyper- and hypopigmentation, atrophy, and telangiectasia. A patient with xeroderma pigmentosum complementation group C exhibited dramatic clinical radiosensitivity following radiotherapy which resulting in their death. Researchers transferred copies of human chromosomes containing genes involved in DNA DSB repair to XP14BRneo17 cells in an attempt to correct the radiation hypersensitivity. Repair of radiation induced DNA DSBs in XP14BR cells was significantly reduced compared with normal fibroblast cell lines. This provides evidence of a novel splice variant of the DNA-PKcs gene associated with radiosensitivity in a patient with xeroderma pigmentosum and report the first double mutant in distinct DNA repair pathways being consistent with viability.

    Sources:

    http://www.ncbi.nlm.nih.gov/pubmed?term=19797196

    http://www.ncbi.nlm.nih.gov/books/NBK1397/

    http://jmg.bmj.com/content/47/3/176.full.html

  19. Radiotherapy-induced DNA double-strand breaks, also known as DSBs, are critical cytotoxic lesions in DNA strands. Accurate repair of the disease is essential for the success of maintenance and propagation of genetic information. Inherited defects in DNA DSB repair pathways lead to hypersensitivity to ionizing radiation, immunodeficiency and increased cancer incidence. Two major pathways that have evolved in the repair of DSBs are HR (homologous recombination) and NHEJ (non-homologous end-joining). Depending on the type of break encountered, HR and NHEJ may either compete or co-operate to fix DSBs in the DNA of eukaryotic cells. Defects that may occur in either pathway are strongly associated with human disease such as immunodeficiency and cancer predisposition.
    Xeroderma pigmentosum (XP) is a disease that is characterized by sun sensitivity, ocular involvement, and greater risk of cutaneous and ocular neoplasm. Most individuals with XP develop dry skin and constellation of hyper- and hypopigmentation, atrophy, and telangiectasia. A patient with xeroderma pigmentosum complementation group C exhibited dramatic clinical radiosensitivity following radiotherapy which resulting in their death. Researchers transferred copies of human chromosomes containing genes involved in DNA DSB repair to XP14BRneo17 cells in an attempt to correct the radiation hypersensitivity. Repair of radiation induced DNA DSBs in XP14BR cells was significantly reduced compared with normal fibroblast cell lines. This provides evidence of a novel splice variant of the DNA-PKcs gene associated with radiosensitivity in a patient with xeroderma pigmentosum and report the first double mutant in distinct DNA repair pathways being consistent with viability.

  20. Xeroderma pigmentosum is a condition where the affected patient experiences sensitivity to the sunlight, ocular involvement and an extremely high risk of ocular and cutaneous neoplasms. Exposure to the sun can result in a severe burn with blistering of the skin. Patients affected can loose their eyelids in extreme cases and can even be impaired neurologically. The diagnosis of this disorder is dependent on the skin, eye and neurological effects experienced by a patient. This condition is primarily due to a mutation of the XPA and XPC genes, which links to the mechanism that could protect an individual from radiation and the DNA double-stranded breaks which would result from it.
    People with this condition are affected in a way where double strand breaks of DNA cannot repair itself. Because they are sensitive to radiation, alternate means of treatment must be explored. Cancer is one possible result of Xeroderma pigmentosum, and a patient with the condition would not be able to receive normal chemotherapy without severe consequences. It would be suggested to determine the level of severity which a patient would be affected by radiation. This precaution is known as a pretreatment protocol, and measuring the induction repair of nuclear Gamma H2-AX foci would help to determine whether an individual is at risk. It is important to take such precaution in order to protect a patient and determine the correct treatment.

    http://www.ncbi.nlm.nih.gov/pubmed?term=19797196
    http://www.jbc.org/content/273/10/5858.long

    • Melissa, your post was very informative and easy to understand. I also liked how you included the sites you used so that others can access them-it also shows that your post was well researched.

    • This was a really good paper. You gave specifics of what the scientists and doctors are looking for in the genome. Although we still don’t understand the protocol in depth, this gave us an basic understanding of how sensitivity of radiation can be applied to medication and cures.

  21. Xeroderma pigmentosum is a automsomal recessive disease. It is known as the skin being very sensitive to the sun which emits UV light. Some patients doesn’t even know that they have this disease until they go out in the sun and start and feel the effects of this illness. When a patient has a serious disease or worse, cancer, physicians strive to use radiation to destroy the tumor or cancerous tissue. However, due to the patients existing condition of xeroderma pigmentosum, the radiation may give the patient even more pain. This radiaton can cause a part of DNA to be torn apart which is known as a double strand break. There is a important function within the DNA that fixes this problem and it is called a double strand break repair. Gamma-H2AX is a protein that works in repairing these breaks. It can occur in one of two forms. One is NHEJ and the other is HR. NJEH stands for Non-homologous end joining and HR stands for Homologous directed Repair. NHEJ tries to add phosphate group in the DNA so maybe it can recombine the DNA ends. HR cuts the break ends in into even and compatible shapes so it can stick back to each other. Patients with xeroderma pigmentosum doesn’t perform these repair functions in their DNA when double strand breaks occur. For this reason, instead of using radiation to cure the patient, physicians must first confirm if the patient have xeroderma pigmentosum because during treatment, the radiation could cause more and new problems to the patient in addition to the one that’s trying to be fixed at hand such as a cancerous tumor. This leads to a need to do pretreatment screening procedures so if the patient has xeroderma pigmentosum, other alternatives must be sought in order to cure the patient.

  22. Radiation Therapy (Radiotherapy) is used often for cancer treatment. Unfortunately, however, Xeroderma pigmentosum (being sensitive to radion from the sun) can affect someone who has gotten radiation therapy. This is a gene related disease. Therefore, if someone has Xeroderma pigmentosum, it will be had for a person to get UV treatment through radio therapy due to being overexposure. If a person is overexposed to radioactivity, it may ultimately lead to the death of that person. Because these can be very complicated due to differences in the individual and differences in the amount of exposure an individual can take, pre-screening protocols must be taken in order to benefit the patient and avoid any problems that may occur.

    • Brief and informative summary, very easy to understand. Are there alternative ways to treat people with XP, other than radiation therapy?

  23. A very common way to help treat cancerous tumors is radiation therapy. As a result radiation therapy has helped many cancer patients. Like many treatments sometimes there can be serve side effects. Patients with a disease called Xeroderma pigmentosum, or commonly known as XP, are very sensitive to sunlight and Ultra Violet light. A person can be severely affected by XP or they can have a mild case to the point where it is not detected right away. Because of this sensitivity, depending on the levels of radiation they may cause the patient to undergo double stranded breaks in the DNA. Double stranded breaks cause the DNA to be torn apart completely. This can potentially be very dangerous because the breaks can form mutations in the cell that are beyond repair. Also these mutations can ultimately cause death if serious enough. Another possible outcome of a patient with XP is that there could be gene deletion, chromosomal rearrangement, gene relocation or the turning on and off of cells that should not be turned on or off.
    Radiation therapy can be very risky for people who have Xeroderma pigmentosum. Things can get even worse because sometime XP cannot be always detected in people who have very mild forms of the disease. In order to prevent patients with XP from having these serve side effects a simple pretreatment screening can be done. Using the induction repair of nuclear gamma H2-AX foci a patient’s cells can be tested to see if Double stranded breaks occur. This is a safe way to test if a patient can take radiation therapy and can show how many levels of radiation can be taken.

  24. DNA double strand break are especially hazardous to our well being and corresponds mainly to immuniodefiency and a variety of cancers. Double strand breaks occur during homologous recombination and non homologous end joining. It can even occur during DNA replication in which the template strand has been damaged. It can even occur due X-RAY radiation, gamma rays, UV light exposure, topoisomerase poisons and other damage to DNA which can be potentially harmful. This can lead to chromosome rearrangements and even lethality. AT (anti- cancer radiotherapy) induce DNA damage and is a better alternative to this problem. People who suffer from the disease XP ( Xeroderma pigmentosum) are extremely sensitive to sunlight and if exposed to sunlight their skin will begin to form blisters and in severe cases can be life threatening. This disease is cause d by nucleotide excision repair malfunction. This is common to albino individuals. Radio therapy although has induced double strand breaks it has caused patients to be more prone to cancer and has resulted in deaths with patients who suffer from Xeroderma pigmentosum. Patients exhibited sensitivity to radiation therapy. There have been many ways to help patients who have been diagnosed with cancer due to radiation therapy. The methods such as western blotting, detection of the H2AX foci using immunoflorensce assay

  25. Xeroderma pigmentosum (XP) is a disease characterized by an increased sensitivity to sun. Symptoms include blistering sunburn, erythema, and freckling upon minimal sun exposure. Individuals affected with XP have a defective DNA repair mechanism and makes them vulnerable to DNA strand breaks.XP is diagnosed by the examination of manifestations of the skin and eyes. Since it is an autosomal recessive trait, a family history can aid in diagnosis.
    People affected with XP will consequently be hypersensitive to radiation therapy. Due to this condition, doctors have to be particularly careful of the dose of radiation treatment given. In the Abbaszadeh et al paper, they were able to measure radiation sensitivity and repair of DNA double strand breaks, and were bale to sequence defective DNA repair genes. “DNA sequencing of the DNA-PKcs coding region revealed a 249-bp deletion (between base pairs 3656 and 3904) encompassing exon 31 of the gene.” By identifying this gene, scientists are now able to look for this gene and determine how sensitive one is to radiation before administering treatment.

    • This was a very simple explanation of the protocol and i think that is why it really made sense to me. You gave me a really good backbone of the protocol so now when i go to read complex papers, i will have a better understanding of what i am reading. I wish more papers explained things the way you did because it would make understanding and applying the information much more better.

    • I liked how to the point you were. There was enough information to not overwhelm the reader while also giving enough information to understand your conclusion.

  26. Over the past couple of years, radiation therapy has been revolutionized with new advancements in technology. Before radiation therapy was even more dangerous than it still is today because before, the patient was exposed to more radiation than was needed. Today, scientists have found new techniques to focus the radiation into the area of interest, particularly a group of cancerous cells. It is here that high-energy beams can be used to stop the diseased cells from growing and dividing. However, even though radiotherapy can be useful and potentially life-saving, some hazardous side effects can occur. On occasion, radiation therapy has been observed to cause double stranded breaks in DNA (DSBs). This can be not only specifically harmful to the patients, but can only be hazardous to future sons or daughters of that patient. In fact, even more dire consequences may result for the patient’s potential family because it may increase the chances of them being light sensitive to ionizing light, such as UV light and X-rays, having a weak immune system, or even probable cancer occurrence. It was found that a patient who suffered from xeroderma pigmentosum, that was treated with radiation therapy, passed away due to both the sensitivity towards ionizing light and unable to repair the DSBs that were present in the cells. As soon as this occurred, clinical protocols were made to determine the genetic defect that causes cellular radiation sensitivity.
    Xeroderma pigmentosum (XP) is a rare skin condition where a person is extremely sensitive to sun or UV light, has premature skin aging, and more prone to obtaining skin cancers. This disease is an autosomal recessive disease that is usually inherited and can affect both males and females. This means that in order to contract this disease, a person would have to have inherited two recessive xeroderma pigmentosum genes. Furthermore, the parents themselves would not show any signs or symptoms of the disease because they would be carriers. Parents who already have a child with xeroderma pigmentosum have 25% chance of having another child with the same condition. Some of the symptoms of this disease is reddening and scaling of the skin under sun exposure, eye sensitivity to the sun and can become irritated and bloodshot.
    DNA-PKcs is a vital genetic element in the repair of ionizing radiation-induced DNA DSBs. With this in mind, clinical protocols were devised to determine if there was any connection between radiation sensitivity and DNA-PKcs. Some of these protocols included the microcell mediated chromosome transfer, cDNA transfection, detection of the gamma H2AX foci through an immunofluorescence assay, and western blot analysis. However, in order to perform these protocols, a non-affected sample from the XP patient had to be gathered. Once obtained and examined, it was found that the sample was sensitive to ionizing radiation and damaged in DNA DSB repair. In an attempt to fix this, scientists performed the protocols named before. They transferred chromosome 8, which contained the DNA PKcs gene, and transported an expression construct containing the DNA-PKcs cDNA. This procedure managed to restore normal ionizing radiation sensitivity and repair of DNA double stranded breaks. It is also through western blot analysis that scientists were able to perceive a splicing defect in the production of the DNA-PKcs protein.

    Works Cited
    Derm Net. “Xeroderma pigmentosum”. 13 July 2010.
    http://www.dermnet.org.nz/systemic/xeroderma-pigmentosum.html
    Journal of Medical Genetics. “A novel splice variant of the DNA-PKcs gene is associated with
    clinical and cellular radiosensitivity in a patient with xeroderma pigmentosum”. 24 September 2009.
    http://jmg.bmj.com/content/47/3/176.full.html#ref-list-1

  27. Radiation therapy or radio therapy is used mostly for treating cancer to control malignant cells. The Totabl body irradiation is a type of radiotherapy technique used to prepare the body to receive a bone marrow transplant. By combining radiotherapy with surgery or other therapy (such as chemotherapy, hormone therapy) most common types of cancer can be treated. However there are those few people in the world with xeroderma pigmentosum (XP), which causes problem for them to be treated with radiotherapy. The XP is an autosomal recessive genetic disorder of the DNA repair in which the ability to repair damage caused by UV, the effect of radiotherapy. When this disease reaches a extreme point, contact with sunlight must be forbidden due to the sun emitting the wave off earth. Because the disease is gene related the diagnosis for this is not easily spotted. It is commonly mistaken with other diseases so before radiotherapy is performed there should be a pretreatment protocol. Measuring the induction of repair of nuclear gamma-H2AX foci in patient cells is one way to solve this problem.

  28. Now in days, the use of radiation therapy is necessary in treating various types of cancer. But this type of treatment is known to interfere with DNA double strand breaks ultimately causing immunodeficiency and an increase in one’s chance of developing cancer. It is important for an accurate double strand break to properly repair in order for propagation of genetic information and for maintenance purposes. The two pathways associated with DNA DSBs are the homologous recombination and the non-homologous end joining. Studies have shown that gamma-H2AX facilitates repair of the break by either homologous recombination or non-homologous end joining. Therefore a patient with xeroderma pigmentosum might have problems using the radiation therapy treatment. “Xeroderma pigmentosum is a rare autosomal recessive disease characterized by sensitivity to sunlight and susceptibility to skin cancers.” Depending on the radiation levels administered to the patient with XP, it can lead to adverse effects. But with the use of pretreatment screening protocols such as measuring the induction of repair of nuclear gamma-H2AX foci in patient cells, to identify individuals at risk, would increase the safety of radiation therapy for xeroderma pigmentosum.

    • I liked the idea of identifying individual risks. Though an obvious one such as exposure to sunlight is a major risk, it might not be the only one.

  29. Radiation therapy is a prominent method used in cancer treatment, but not everyone who undergoes this treatment will benefit from it. For example people who are diagnosed with Xeroderma pigmentosun (XP) are sensitive to radiation and to the sun. XP is not easily diagnosed by most physicians and can be an underlying disease for a long time, starting from childhood.
    Patients who have this disease have something called double stranded DNA breaks, this prevents radio therapy to go in and repair any of the damaged cells. Doctors have to be very careful when they are dealing with these types of patients, and the way they can determine if a patient does have XP is by measuring the induction repair of nuclear gamma H2-AX foci in the cells of the patient. This test will notify the doctor if there are any double stranded DNA breaks, and if not the doctor can begin with radiation therapy.

    • You should have gone into patient screening and how the test is conducted and if there is any harm to the patient. Otherwise short, simple and to the point.

  30. People who are diagnosed with Xeroderma Pigmentosun (XP) are characterized by sun sensitivity, ocular involvement, and greater than 1000-fold increased risk of cutaneous and ocular neoplasms. Xeroderma Pigmentosun (XP) is an an autosomal recessive disease and in order to contract this disease, a person would have to have inherited two recessive xeroderma pigmentosum genes from either parent. This disease is know to affect both males and females, it does not affect a person based on gender. Parents who have this disease have a one in four chance of spreading that disease to their offsprings. In order to treat them mall premalignant skin lesions one can treat it with either topical 5-fluorouracil or freeze with liquid nitrogen. Neoplasms, or anabnormal mass of tissue as a result of neoplasia, should be removed through electrodesiccation and curettage, surgical excision, or chemosurgery. In ordeer to prevent new neoplasms you have to use high-dose oral isotretinoin. Prevention after removing neoplasms is essential to prevent the growth of new skin lesions. Avoid sun and UV exposure with UV-blocking protective clothing, high sun-protective factor sunscreens and UV-absorbing glasses with side shields. It is important to go to the doctor for skin examination to see if you have grown any new lesions every 3-6 months. When x-radiation therapy is indicated, an initial small dose may be used to test for clinical hypersensitivity, although most persons with XP have a normal response to therapeutic x-radiation.

  31. Radiation Therapy, also known as Radiotherapy, is one of the most common forms of cancer treatment today. Many patients find this treatment reliable and effective. Unfortunately there is a dysfunction that causes some people to be unable to repair the double stranded breaks caused by the radiation therapy. This autosomal recessive disease is called Xeroderma pigmentosum. Exposure to UV light causes the patient’s DNA to practically tear apart. Normal people have a protein called Gamma-H2AX which cuts the DNA into 2 even strands and can reattach them with a phosphate group if they are not too badly damaged. Patients with this disease do not have that protein and cannot repair the damage caused by the radiation. Advanced prescreening is required to find the people that have this disease and then find an alternate course of treatment from the radiotherapy.
    Should everyone be tested for this problem even if the percentage of people that actually have this problem is minimal? The prescreening is a great idea and should be done to prevent any further damage and pain to the patient already suffering from cancer, but it comes at a cost. Also I would like to bring up that if people had issues with UV light you think they would know from getting other X-rays and what not in previous medical procedures or they would notice if they got sick every time they went out in the sun for just a little too long.

  32. Phosphorylation of histone H2AX occurs rapidly when it is in the presence of DNA DSB’s which is thought to believe that this process recruits repair enzymes to the site of the DSB. To have a better visual in detecting a single break within a nucleus, the visible foci, which contain a larger number of molecules of H2AX, are present at each double stranded break. It is said that image anaylsis of H2Ax foci is a more sensative approach in detecting individual double strand breaks but a more accurate procedure is said to be Flow Cytometry, which is said to provide an accurate way of measuring the rate of formation and loss of H2Ax in heterogenous population of cells.This technique provides valuable information regarding tumor and normal cell response to ionizing radiation.

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