Blog Questions

The questions concerning your paper are below. My advice is for you to try to divide them up roughly evenly among your group members. You are even welcome to post the answers independently if you'd like; just be sure to reiterate the questions. Please come see me if you need help!

1. State each of Darwin’s four postulates. Fully explain how the generation of treatment-resistant pattern iii Neuroblastoma cells (sensu the first paragraph of the article, page 37) meets each of the four postulates for evolution by natural selection. 

1       1. Individual variation occurs. This was represented in the clinical variations of each neuroblastoma category and disease pattern presented in the study.  This specifically came down to the molecular profile of each tumor as variation should be assumed between any individuals whether they have Neuroblastoma or not.

·        2. Some of this variation is heritable. Neuroblastoma can be directly traced to precursor cells of the peripheral sympathetic nervous system that have been genetically passed on from the parental generation. This study has also shown that Neuroblastoma correlates with the arm of chromosome 1, a chromosome obviously passed on from parents to offspring.

·        3. There are more offspring produced than able to survive. Several children within a population will be born with the hereditable variation in these precursor cells that cause Neuroblastoma while some children will not. Thus, rendering those who do inherit the variation (that has been selected for Neuroblastoma) a possibility of an early death because unfortunately not every person survives this cancer.

·        4. Natural selection acts on a population. Neuroblastoma reduces the fitness of an individual. It changes an individuals ability to survive and reproduce in a population. Because fitness is reduced, the heritable cells that are precursors to Neuroblastoma should eventually be selected against.

 

2. Use the NCBI website to perform a nucleotide BLAST on the Accession number NM_005378.4 (http://blast.ncbi.nlm.nih.gov/Blast.cgi?PROGRAM=blastn&BLAST_PROGRAMS=megaBlast&PAGE_TYPE=BlastSearch&SHOW_DEFAULTS=on&LINK_LOC=blasthome0). Paste the accession number into the box, click “others” under Database, and then hit the BLAST button. Scroll down to the Descriptions, and name five different taxa that come up in your results. What does that tell you about this oncogene (MYCN)?

These are five different taxa related to our search:

         1. Pan troglodytes- Chimps    4763/4826

         2. Pongo abelii- Orangutans   4623/4826

         3. Macaca mulatta- Rhesus macaque    4538/4826

         4. Nomascus leucogenys- Northern white-cheeked gibbon    3025/4826

         5. Sus scrofa- Wild boar    2928/4826

The main idea that this BLAST shows about the MYCN oncogene is that it is NOT unique to Homo sapiens. In fact there are 99 percent identical nucleotides between humans, chimps and orangutans and 98 percent identical between humans and macaques. The numbers listed above are the exact numbers of identical nucleotides for that species in comparison to humans. For example, a chimp has 4763 identical nucleotides to a human's 4826 nucleotides (in reference to this oncogene that is). It is also evident that even outside of the primate family, there are still 90 percent identical nucleotides to humans as seen in the wild boar.

3. Think back to the QTL paper we discussed in class. What 4-5 general steps do quantitative geneticists take to find a candidate gene for a quantitative trait; and more specifically, what steps did these authors take to narrow down the pool of potential genes contributing to NB?

·      

         1.The authors first found candidates and then searched for several genetic events as possible indicators of neuroblastoma. There genetic events were as follows: 1. allelic losses at chromosomes 1p, 11q, 14q, 9p, 9q, 2q, and 18q, 2. gains at chromosomes 17q, 18q, 1q, and 5q, 3. amplification of the oncogene MCYN, and  4. altered DNA index.

        2. Next, they followed 16 microsatellite markers from chromosome 1and performed genetic analysis of 120 NB.

·       3. The third step included studying what genes were linked to the markers. They also added additional markers to study the more frequent gene losses past what the initial group had lost, and then did linkage mapping. 

-       4. In the fourth step they reviewed data of PCR products, compared allelic ratios between normal heterozygous and tumor heterozygous materials to determined loss of heterozygosity. They utilized Southern blot, quantitative PCR, or fluorescence in situ hybridization to determine copy number of MYCN and DNA index

·       5. Finally, the authors prepared statistical data for review to determine allelic loss or no loss.

4. The authors assert that genomic instability, whether chromosomal or molecular, leads to LOH. Define loss of heterozygosity and explain how it can cause tumorigenesis. Keep in mind the importance of heterozygosity to a population of organisms and apply that logic to the importance of heterozygosity in a population of cells.

Heterozygosity is a source of variation and is evolutionarily important to populations. The loss of heterozygosity is defined as the loss of function of one allele when the other allele is already inactivated. In Neuroblastoma,  a parental gene (tumor suppressors) that possess an inactivated allele are passed on to the offspring. When the corresponding allele is also inactivated by a mutation within the offspring, the tumor suppressor gene can no longer be produced and therefore tumors are not suppressed. In this particular study, precursor cells of Neuroblastoma are non-suppressed so proliferation of tumorigenesis is allowed.

Bonus: Considering your interview with Dr. Mozer and this paper, please briefly describe the influence Dr. LaQuaglia has had on your project.
-Dr. Walker

Dr. Mozer was a previous personal connection of Cynthia's. It was Dr. Mozer that gave us the personal account of Neuroblastoma and the initial connection to Dr. LaQuaglia's work. From there we found Dr. LaQuaglia's research had deepened our understanding of the science behind and potential for Neuroblastoma. Thinking back on our interview and Dr. Mozer’s comments in regard to Dr. LaQuaglia, we would say that LaQuaglia’s indirect influence on our project could be summed up in the word “promise”. This is because it moved our thoughts on Neuroblastoma into an “exciting corridor of discoveries” because this is an area where Dr. LaQuaglia is not afraid to step into. A place with several doors, if you will imagine, that he has or is willing to open and walk into all for Neuroblastoma research. With his extensive research he can then make the weighty decisions of whether to continue research in a direction or go towards a different "door". This provided us with a form of exhilaration that kept our project interesting because we knew we could look forward to new advancements. In connection to grid mapping, we believe the ability for all researchers to have access to various projects may save time and efforts. It can possible prevent the redundancies of research and give way to a new freedom of advancement in scientific research and this is exciting!    

Journal Article

Below is a link to a research study relating Neuroblastoma to loss of heterozygosity on a particular chromosome. Interesting relationship... check it out by clicking the link below!

Clinical Categories of Neuroblastoma are Associated with Different Patterns of Loss of Heterozygosity of Chromosome Arm 1p

Citation:

Mora, Jaume, V. Cheung Nai-Kong, et al. "Clinical Categories of Neuroblastoma are Associated with Different Patterns of Loss of Heterozygosity on Chromosome Arm 1p." Journal of Molecular Diagnostics. 2.1 (2000): 37-46. Web. 16 Apr. 2012. <http://www.journals.elsevierhealth.com/periodicals/jmdi/article/S1525-1578(10)60613-7/fulltext>. 

Interview Response

Megan's Interview Response

1.     Describe your feelings about or response to the interview?

       

       I felt as if our interviewee's (Dr. Mozer) very personal relationship with neuroblastoma enabled him to provide a lot of information for us. I feel as if most medical cases, especially dealing with cancer , are always unique to the individual. Therefore, after the interview I felt like I learned more about the disease from a unique personal stand point as well as received a first hand opinion of treatment options and research on the disease. It was also neat to hear about how he was still up to date on findings and an active advocate for the research on Neuroblastoma.

2.     What changes occurred for you as a result of you interview?

       I gained a different outlook on the role that a patient and/or his or her family should play in the medical process. Through Dr. Mozer's account of how he and his wife were the joining factor between all the different doctors and their son, I believe now that a patients participation in their own medical knowledge does and should play a large role in health care.

3.     Did anything about it disturb you?

       

       The only part of the interview that disturbed me was when we were talking about experiences with insurance companies and payment for medical services. Specifically, to hear that so many patients suffer because of insurance denial on claims and as a result do not receive potential life saving care was disturbing. It was interesting and saddening to hear a personal account of these dealings and the lengths gone to receive necessary and rightful payment of certain medical services.

4.     Describe the connections you found between the interview and your research/classwork?

       

       The main connection I found between the interview and my classwork was the foundations noted by Dr. Mozer that work to raise money specifically for Neuroblastoma research and our grid computing project. After having done research on grid computing and Neuroblastoma, it was neat to hear of other organizations working to raise money for research. This was especially important after reading in Dr. Mozer's Journal article "A Doctor's Worst Nightmare, My own Child has Cancer" that only about 0.3 percent of the National Cancer Institute's budget goes towards Neuroblastoma.


Cynthia's Interview Response

1.     Describe your feelings about or response to the interview?

      My initial response to the interview was one of admiration.  Just the fact that one day all seems well with your child and then in a matter of minutes a diagnosis like neuroblastoma is given to you; and, everything about your day and the days to come is lived in the present.  Actions, thoughts and moving forward all collide together with one common goal, curing your child.  Here a pediatrician was up against a life-altering diagnosis that was not to be given to a patient’s parents but, to him and his own wife about their child.  It was a heartfelt and an educational interview.  Probably more educational from a medical provider’s viewpoint, in that there is more to a diagnosis than an answer to symptoms and prognosis.  Medical personnel need to always be cognizant of the fact that they are treating a person, not a disease. 

2.      What changes occurred for you as a result of your interview?

      I think I am more aware of the financial hardships that are put on families with this type of diagnosis.  I know somehow I knew that financial strains were there, I guess I just thought more institutions and medical personnel were able to help out with that part of dealing with the disease.  With the tremendous amount of medical expenses these families encounter, it seems that there would be a system in place for helping out financially so that families did not need to lose all of their financial worth.  It is sad with the capabilities in medical care that we have available in the USA that people go without medical care because of the expense and/or dictation of what an insurance company will or will not pay.  

3.       Did anything about it disturb you?

Yes, to be truthful, the reflections on the insurance processes were depressing.  The actual ability of an insurance company to determine what treatment route a patient should follow is despicable.  Limiting drugs of choice, treatment protocols because of the trial phase it may be in, and where a patient can or cannot be treated is not a decision for insurance companies.  A doctor and informed team of medical personnel should be the ones to confer and decide on a treatment plan for these patients.

4.       Describe the connections you found between the interview and your research/class  work?

      Some connections I found between this interview and our research include the following:  1. Support for additional monoclonal antibody lines 2.  Support for more stem cell research 3.  The need for more trials to be funded and expand on the current research of those already in progress And 4.  The sharing of research among all researchers in an organized manner like grid-computing

Liz's Interview Response

1. Describe your feelings about or response to the interview.

      Dr. Mozer is a phenomenal source on the subject of neuroblastoma.  His personal account is moving and scientific knowledge is astounding.

      One thing that struck me was Dr. Mozer’s compassionate care.  Through the telling of his family’s story he attempts to remind other physicians (and pre-med students) that their scientific conclusions effect real people. 

2. What changes occurred for you as a result of your interview?

      I realized how important advocacy for those in need is.  Life changing diagnoses are just that and any support that you can provide to the patient and others close is extremely important.

3. Did anything about the interview disturb you?

      Yes! The large role that third parties (insurance companies) can play in healthcare is disturbing.  The amount of stress and set back they can induce to those in need is a lot larger than I realized. The limits they set require fighting for what’s right by both the health care provider and the family/patient.

4. Describe the connections you found between the interview and your research & classwork.

      Dr. Mozer and his recommended research articles focus a lot on immunology.  Jacob underwent mono colonial antibody therapy at the end of his treatments to help keep him in remission.  This relates to coursework in many of my biology courses.

 

A Physician’s Personal Account of Neuroblastoma

Dr. Mark Mozer, a local pediatrician, knows from his own personal experience the effects of a neuroblastoma diagnosis.  It was May 12, 1998 when Dr. Mozer and his wife learned that their 16-month-old son, Jacob, had a rare childhood cancer.  Jacob was diagnosed with stage IV neuroblastoma.  During our interview Dr. Mozer was candid when answering questions and straight forward about his concerns before and after the diagnosis.  At times he was reflective, revealing his feelings regarding his fears and hopes for Jacob and his family. 

Looking back 2-3 months before Jacob’s diagnosis, Dr. Mozer attributed his son’s fussiness for what seemed to be a normal symptom of teething.  He recalled Jacob running low-grade fevers and would vomit sometimes.  Mozer went on to say, “Then one night while Cheryl, his wife, was giving Jacob a bath (she) noticed his belly being big.”   He silently worried that Jacob might have hepatoblastoma.  In a slow soft tone, Mozer added, “That was a Monday night,” as he recalled the night before Jacob’s diagnosis. They took Jacob to one of his colleagues who happened to be working that evening.  Jacob was scheduled for an ultrasound the next day at Children’s Mercy Hospital (CMH) Kansas City, Missouri.

“Once the ultrasound was done, Jacob was taken in for a CT scan.  And that is when he got the diagnosis.”  Dr. Mozer went on to say, “It hits you like a ton of bricks and your life is immediately turned upside down.  At the time I knew very little about neuroblastoma.  I knew the survival rate was about 40%.”

Jacob was admitted the same day as his CT scan and started on the CCG (Children’s Cancer Group) chemotherapy protocol which included biopsies in the following day.  Two to three weeks subsequent to his first round of chemo, Jacob’s tumor continued to increase in size.  “It was obvious that he (Jacob) needed a much more aggressive treatment,” Mozer stated.  He was then changed to the Sloan-Kettering protocol for treatment of his tumor.  The tumor had wrapped itself around vital organs. It needed to be surgically removed.  Mozer and his wife researched medical literature to see who was publishing work on neuroblastoma, which led him to call the top 7 or 8 surgeons in the country.  A doctor in New York, Dr. Michael P. La Quaglia (at Memorial Sloan-Kettering Cancer Center) said he could get 100% of the tumor out in comparison to others who said they could only remove 70-80%.   “That made the decision real easy,” according to Mozer with a smile and then as if thinking out loud stated, “He (Dr. La Quaglia) has a history of taking out neuroblastomas that nobody else will touch.”

Jacob was taken to New York for surgery at Memorial Sloan-Kettering and came back Kansas City CMH to finish his chemo, bone marrow transplant and radiation therapies.  Jacob’s tumor did not respond to the antibodies used locally (CH13.18); however, did respond to monoclonal antibodies (3F8) developed by Dr. Nai-Kong V. Cheung and his medical team at Sloan-Kettering in the mid 1980s.  Once again, Jacob was taken back to Sloan-Kettering for monoclonal antibody treatment.  The antibodies were and still are in Phase II clinical trials.

Between hospitals, treatments and juggling the normal routine with the new routine, life was stressful on several levels.  “There were times when you wondered (about hope), but if you don’t have hope, you don’t have anything.  When they say your kid has a 10% survival rate, it is still a 10% chance to survive and as a parent you are going to do whatever you need to do to give him the best opportunity”

Jacob’s older brother, Nick, was only four years at the time of his brother’s diagnosis.  He is now 17 years old.  When asked how this has changed Nick, Dr. Mozer responded saying, “Nick was four at the time, and that’s the time when you are developing all of your psychological personality.  My comment has always been that Jacob was too young.  I say that Jacob bears all the physical scares and Nick bears all the emotional scares.”  He hesitated briefly as if in thought and then continued, “I think it certainly affected him, my own personal opinion is, I think there were abandonment issues.  Nick would go to sleep, Jacob would spike a fever, we’d run down to CMH, Nick would wake up with us gone, (he) in the care of grandma and grandpa.  His whole life was turned upside down because of that.  On the flip side, he has taken the advocacy that I took to and has gone full steam, he has been a huge factor with Alex’s lemonade stands*, and we couldn’t have done that without him.  He is really into community service, so there have been some positives from it as well.”

Dr. Mozer continued working his full-time occupation as a pediatrician throughout Jacob’s illness.  Cheryl left her job to be with Jacob and try to keep some normalcy in the home.  Their schedules were hectic and upon remembering the constant shuffle Mozer said, “I remember going (to CMH), they have the parents’ rooms, I’d go down take a shower, put on fresh clothing and exchange places with Cheryl.”  The next day they would do the same. According to Mozer, the key was to stay positive and hopeful; they didn’t have time to think otherwise.  They never gave up hope.  This way of thinking and approaching the illness helped keep their family unit closer together.  Unfortunately not all marriages survive an illness like this.  Mozer stated, “When kids get cancer, a lot of families end up in huge financial trouble and most of them end up on Medicaid, and because of that the divorce rate is over 50%.  That’s just because of the stress.”

When asked, if you had a patient today with a similar diagnosis, what would you tell the parents is the key to fighting this illness.  Dr. Mozer replied, “You have to be your child’s advocate, even if you have the best doctor in the world you have to advocate for your child.  Nobody knows your child better than you do, especially when he is given the chemo regimen, you know how he responds to this medicine and that medicine, doctors are only human and your child can’t always speak for themselves so as the parent you need to be there for them.”

Jacob’s response to the treatment was positive.  He was officially in remission one year after his initial diagnosis.  He is doing well at the age of 14.  Dr. Mozer has written an article A doctor’s worst nightmare: My own child has cancer, published in Medical Economics (June 5, 2000)**.   His reason, “I wrote it mainly for doctors to kind of see what it’s like to be on the other side.”

*Alex’s Lemonade Stand Foundation was founded by Alexandra Scott, who was diagnosed with neuroblastoma shortly before she was one year old.  The organization raises money to help fight childhood cancer.  Please go to the website and read the story. http://www.alexslemonade.org/?gclid=CIq0q4eupK4CFQReTAodIRTbPw

**http://medicaleconomics.modernmedicine.com/memag/article/articleDetail.jsp?id=122334

http://www.mskcc.org/cancer-care/doctor/michael-la-quaglia

http://www.mskcc.org/cancer-care/doctor/nai-kong-cheung

Introduction

Introduction and Background: Neuroblastoma

Grid Computing

Grid computing is an ever-evolving group of computer systems used cohesively to correlate information about particular subjects. Grid computing helps maintain, link, and make accessible the important knowledge among all those seeking a common goal. According to Search Data Center this type of research shows potential because of these three reasons: 1. Cost effective, 2. problem solving in areas that need vast amounts of computer power, and  3. the ability for an immense group of researchers to join together to work towards a common purpose. (1)

What is Neuroblastoma?

Neuroblastoma is the development of a malignant tumor in infants and children. The tumor is formed within the tissues of the sympathetic nervous system and can occur in many different areas of the body. In several cases the tumors begin within the adrenal gland, next to the spinal cord, or in the chest. From there the cancer often times spreads to the bones, bone marrow, liver, lymph nodes, skin, and around the eyes. Unfortunately, in majority of cases, by the time a diagnosis is made the cancer has already spread. (2)

Disease Statistics

The disease occurs in approximately 1 out if 100,000 Children.

It is slightly more common in boys.

Most commonly diagnosed before age five. (2)

Among the most frequent of solid tumors in children during the first two years of life.

Accounts for 50% of all tumors in children.

Accounts for 6-10% of all childhood cancers.

Accounts for 15% of cancer related deaths in children. (3)

Suggested Causes

The direct cause of neuroblastoma is still being researched but certain doctors are suggesting it is related to a cell growth occurring during the development of the adrenal glands and sympathetic ganglia. It has been suggested that three proteins, TrkB, ALK, and SCxx, are expressed at elevated levels or have undergone mutations in especially aggressive neuroblastomas. Scientists believe that if these proteins are blocked or disabled then chemotherapy could work at a more successful rate. In particular, the study of certain drugs with proper shapes and chemical make up are being explored as options to block these proteins. World Community Grid is involved in the simulation of experiments for testing the millions of potential drugs. The results will reveal the best drugs to block those proteins, which will then allow them to be implemented into laboratory testing for the drug’s efficiency against neuroblastoma. (3)

(1) http://searchdatacenter.techtarget.com/definition/grid-computing

(2) http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002381/

(3) http://www.worldcommunitygrid.org/research/hfcc/faq.do#397

Images

 http://surgery.med.umich.edu/pediatric/clinical/physician_content/n-z/neuroblastoma.shtml

Figure 2: A) Infant with a large, distended abdomen and a right-sided abdomen mass. B) Infant with stage 4-S neuroblastoma with multiple skin nodules, sometimes called the blueberry muffin syndrome. C) This skin tumor on the scalp is found in another infant with stage 4-S neuroblastoma. 

http://www.eapsa.org/AM/Template.cfm?Section=Resources&TEMPLATE=/CM/ContentDisplay.cfm&CONTENTID=1597