Genomics midterm

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what is SCID

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what is SCID

a defect in B and T lymphocytes

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what are the 3 types of SCID

mutation in interleukin 2 receptor gamma (IL2RG) gene, mutation of JAK3 (chromosome 19) which is an important signalling molecule activated by IL2RG, a lack of the enzyme adenosine deaminase (ADA) coded for by a gene on chromosome 20

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what is ADA (adenosine deaminase)

enzyme needed for converting adenosine to inosine

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how does ADA deficiency cause SCID

dATP builds up causing decrease in NT reductase which results in no dNTP sythesis which decreases lymphocyte proliferation. dATP build up also decreased S-adenosylhomocysteine hydrolase which results in no methylstion of proteins, NAs, etc. dATP and SAH are toxic to lymphocytes and affected children become susceptible to a wide range of infectious diseases

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what does Adagen treat

ADA deficiency

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what is Adagen made of

PEG enhanced version of ADA enzyme

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why are injections of unmodified ADA not effective for ada deficiency?

short circulating time of less than 30 mins and potential for immunogenic reactions (from bovine)

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how does Adagen work in treating ADA deficiency

attachment of PEG to ADA allows enzyme to achieve full therapeutic effect by increasing the circulating life and masking the bovine derived ADA to avoid immunogenic reactions

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what is mucopolysaccharidosis and what causes it

inherited metabolic diseases caused by absence or malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans (GAG)

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GAG good functions

help build bone, cartilage, tendons, corneas, skin and CT, are also found in the fluid at joints as lubricants

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what is missing/dysfunctional in mucopolysaccharidosis

absense or dysfunctioning of any of the 11 enzymes required to break down GAGs

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what happens when GAGs accumulate in mucopolysaccharidosis

permenant progressive cellular damage that affects the individual’s appearance, physical abilities, organ and system functioning, mental development

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what are the 3 subtypes of MPS I


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which MPS subtype is most severe


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which MPS subtype is least severe


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what do all MPS I subtypes result from

absence of or insufficient levels of the enzyme alpha-L-iduronidase (IDUA) which is needed to breakdown GAGs

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features of MPS-I H (hurlers syndrome) subtype

progressive deterioration, enlarged liver, spleen, heart, dwarfism, gargoyle like faces, progressive mental retardation

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what does laronidase (aldurazyme) treat

alpha-L-iduronidase deficiency (MPS I)

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what is laronidase-rch made of

naturally occuring enzyme alpha-L-iduronidase produced by recombinant DNA in a chinese hamster ovary (CHO) cell line

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what causes Gaucher disease

absence of beta-D-glucosyl-N-acylsphingosine glucohydrolase (beta glucocerebrosidase) which hydrolyzes glycolipid glucocerebroside to glucose and ceramide. this causes cells to fill up with undigested fat, glucocerebroside

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where does glucocerebroside accumulate with deficiency of beta-glucocerbrosidase

tissue macrophases in liver, spleen, bone marrow

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complications of gaucher disease

severe anemia, thrombocytopenia, progressive hepatosplenomegaly, bone pain, osteonecrosis, osteopenia, secondary pathological fractures

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what is cerezyme

a variant of human beta-glucocerebrosidase

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how is cerezyme produced

recombinant dna technology using CHO

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structure of cerezyme

4 N linked glycosylation sites,differs from placental glucocerebrodase by one AA (histadine to arginine) the oligosaccharide chains at glycosylation sites have been modified to terminate in mannose sugars which are specifically recognized by endocytic carbohydrate receptors on macrophages

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indications of cerezyme

for long term enzyme replacement therapy for patients with type 1 gaucher disease with one or more of the following conditions: anemia, thrombocytopenia, bone disease, hepatomegaly or splenomegaly

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what does lysosomal acid lipase (LAL) do

hydrolyzes lipids to cholesterol esters and triglycerides

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LAL deficiency complications

enlarged liver, fibrosis, cirrhosis, liver failure, low HDL, high LDL, heart attack and stroke, enlarged spleen, low platelet count leading to bleeding problems, pain, bleeding, diarrhea, poor absorption of nutrients leading to malnutrition and poor growth

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LAL deficiency treatments

low fat diets, lipid lowering meds, stem cell transplant, liver transplant, IV infusion of sebelipase alpha (Kanuma)

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2 strategies for cancer therapies

cell division and cell communication based therapy

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what does L-asparaginase treat


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MOA of L-asparaginase for leukemia

L-asparaginase hydrolyzes asparagine to aspartic acid and ammonia. by depleting blood asparagine the fast dividing leukemia cells are starved (asparagine in diet is essential for leukemia cell growth)

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why does using L-asparaginase for leukemia not starve other cells causing toxicities?

most cells make their own asparagine using asparagine synthetase

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asparagine synthetase components

two identical subunits

NH2 from glutamine and aspartic acid=asparagine

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L-asaparaginase components

four identical subunits. a threonine protease. the active sites (threonine) cleave asparaginine to make aspartate. can also cleave glutamine to glutamate but at a slower rate

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what is the benefit of PEG-L-asparaginase

the pegylation increase half life and decreases immunogenecity

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indications of PEG-L asparaginase

acute lymphoblastic leukemia, non hodgkins lymphoma and other leukemias

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how often should PEG-L-asparaginase administered

no more frequently than every 14 days

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what does urate oxidase do

break down uric acid (final product of purine metabolic pathway) to 5-hydroxyisourate and allantoin

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what species’ is urate oxidase absent in

humans and primates

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what does excessive concentrations of uric acid in bloodstream cause

gout and uric kidney stones

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chemotherapy effects in uric acid

causes excessive accumulation of uric acid as cancer cells die causing hyperuricemia, a type of tumor lysis syndrome leading to acute renal failure

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what is ELITEK and how is it produced

recombinant urate oxidase produced by genetically modified Saccharomyces cerevisae strain

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components of ELITEK

tetrameric protein with identical subunits of a MM of 34kDa. monomor made up of a single 301 AA polypeptide chain with no intra/inter disulfide bridges and is N terminal acetylated

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ELITEK indications

management of plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumour malignancies who are receiving anti cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid. also used in chronic hyperuricemia in patients with treatment failure gout

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how is uric acid excreted in humans

into urine as insoluble crystals

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strategies to decrease uric acid

inhibiting xanthine oxidase and provision of urate oxidase

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what is cystic fibrosis

an inherited chronic disease that affects lungs and digestive system of children and adults. a defective gene causes the body to produce thick, sticky mucus that clogs lungs leading to life threatening infections, and obstructs the pancreas and stops natural enzymes from helping body break down DNA and absorb food

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CF symptoms

salty tasting skin, persistent coughing, frequent lung infections, wheezing/SOB, poor growth/weight gain, greasy/bulky stools

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what is the pathogenesis of pulmonary involvement in CF

formation of abnormal cystic fibrosis transmembrane conductance regulator (CFTR) which produces dehydrated airway secretions with abnormal clearance properties resulting in very thick mucous containing large quantities of DNAs

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how does tenacious mucous contribute to downward progression of CF lung disease

obstruction leads to infection which leads to inflammation. neutrophils help fight infection but they die leaving behind extracellular DNA which accumulates and thickens mucous further. neutrophils also produce elastases and oxidants which contribute to extensive epithelial damage and bronchiectasis

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what is pulmozyme

recombinant human deoxyribonuclease I

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how is pulmozyme administered


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how does pulmozyme work

breaks down excessive amounts of DNAs present in Cf patients which alleviates obstructive pulmonary difficulties and decreases infections and inflammation

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what does erythropoietin (EPO) do

stimulates RBC production

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what triggers production of EPO

bleeding and higher O2 demand

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what is EPO used to treat

anemia (associated w/chronic renal failure, caused by drugs/chemo), severe blood loss in certain patients who’s religion forbids blood transfusion

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where is EPO predominantly produced

liver in fetal and perinatal period, renal in adulthood

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what is EPOGEN (Epoetin alfa)

recombinant EPO

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what is EPOGEN used for

doping in sports

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what is Aranesp (darbepoetin alfa)

an erythropoiesis stimulated protein, closely related to EPO

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how is Aranesp (darbepoetin alfa) produced

Chinese hamster ovary (CHO) cells

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Aranesp (darbepoetin alfa) structural differences and their function from recombinant human EPO (EPOGEN)

5 chains instead of 3- 2 additional N-glycosylation sites, causing decreased receptor binding affinity compared to Epoietin alpha but efficacy was not comprimised due to longer circulation time

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structural modifications of methoxy polyethylene glycol-epoetin beta (Mircera)

methoxy polyethylene glycol (MPEG) is attached to the -NH2 of N terminus and all lysine side groups

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benefit of methoxy polyethylene glycol-epoetin beta

longer circulating half life than epoeitin alpha and beta and EPOGEN

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dosing of methoxy polyethylene glyvol-epoietin beta

once a month

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what is neupogen(filgrastim)

granulocyte colony stimulating factor (recombinant version of a human protein)

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what does neupogen (filgrastrim) do

selectively stimulates the production of infection fighting WBC (neutrophil)

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how is neupogen (filgrastrim) produced

human granulocyte colony stimulating factor gene is inserted into E coli bacteria (addition of methionine on N terminal is necessary for expression in e coli)

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is neupogen glycosylated


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neupogen clinical applications

used to decrease incidence of infection in certain cancer treatments

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differences between Neulasta (pegfilgrastim) and Neupogen(filgrastim)

longer circulating time of 15-80hr (due to PEG)

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what is Leukine(sargramostim)

recombinant granulocyte-macrophage colony stimulating factor (rhu GM-CSF)

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what is Leukine used for

following chemo therapy in elder pts to speed up recovery of neutrophils and to reduce the incidence of severe and life threatening infections, also used in stem cell transplantation settings

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what does PROLEUKIN IL-2 do

increase production of T lymphocytes and NK cells, and may improve the function of other cells like lymphokine-activated killer cells and tumor infiltrating lymphocytes

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what is PROLEUKIN IL-2

synthetic form of IL-2 (via recombinant DNA technology)

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what is PROLEUKIN IL-2 used for

metastatic cancers (renal cell, melanoma)

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what is Neumega IL-11

a thrombopoietic growth factor

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what does Neumega do

directly stimulates the proliferation of HSC and megakaryocytic progenitor cells, induces megakaryotic maturation resulting in increased platelet production

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how is Neumega produced

in E coli by recombinant DNA technology

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structure difference between IL-11 and Neumega

neumega lacks one amino acid terminal proline residue

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Neumega indications

prevention of severe thrombocytopenia, reduction of need for platelet transfusions

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interferon functions

antiviral and antitumour properties, macrophage and NK lymphocyte activation, enhancement of MHC I,II,III therefore presentation of foreign antigens to T cells

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type 1 alpha/beta interferon characteristics

secreted by many cell types (T/B lymphocytes, NK cells, macrophages (fibroblasts, endothelial cells, osteoblasts) stimulate macrophages and Nk cells to elicit anti viral response, also active against tumours

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type II interferon characteristics

produced in activated T cells and NK cells, possess weak anti viral and anti tumour effects, potentiate effects of type I interferons (recruits lymphocytes to site of infection increasing inflammation, stimulates macrophages to kill engulfed bacteria)

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what is interferon alfa-2a (Roferon-a) used for

used for cancer treatment and antiviral treatment (hairy cell leukemia, AIDS related Kaposi’s sarcoma, chronic myelogenous leukemia, hep c)

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what is Pegsys (pegylated IFN alpha 2-a)

pegylated interferons with increased half life of once weekly vs 3 times weekly (used for chronic hep b/c)

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what is Intron A (interferon alfa-2b)

recombinant, used for anticancer/antiviral (hairy cell leukemia, genital warts, AIDS related Kaposis sarcoma, chronic hep b/c, malignant melanoma, etc)

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what is Alferon-N (interferon alfa-n3) used for

treatment of genital/perianal warts caused by HPV

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what is Actimunne (interferon gamma-1b) used for

chronic granulomatous disease, malignant osteopetrosis

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IFN side effects

flu like symptoms, convulsions, hair thinning, erythema, pain, hardness at injection site (more common with interferon beta 1-b and pegylated interferon alfa-2b)

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type I w interferon characteristics

released by leukocytes at site of viral infection and tumours

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what does Leukine (sargramostim) do

accelerates myeloid recovery, including increasing the number and activity of neutrophils, monocytes/macrophages, myeloid derived dendritic cells

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biotechnology definition

the use of tissue culture, living cells, or cellular enzymes to produce a defined product

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optical isomers of amino acids

all L form in mammalian cells except glycine

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stability and degradation

terms to define how much of the active drug is available for use

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what is chemical instability

covalent bond modifications of proteins via bond formation or cleavage

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examples of chemical instability

deamidation, hydrolysis, oxidation, racemization, beta-elimination

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which AA undergo deamidation

asparagine (asn), glutamine (gln)

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what happens during deamidation

amide converts to acid and ammonia (NH3)

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