199 Questions
In Systemic Lupus Erythematosus (SLE), which component of the innate immune system is activated?
All components of the innate immune system
What is the consequence of decreased clearance of apoptotic cells in SLE?
Prolonged exposure to potential auto-antigens
What is the outcome of using Rituximab for treating SLE?
Not very effective for SLE
Which treatment induces plasma cell apoptosis?
Bortezomib
What is the function of Atacicept in treating SLE?
Binds both BAFF and APRIL
What is the outcome of using CD19-targeting CAR- T cells for refractory SLE?
High efficacy in 5 out of 5 patients
What is unknown about CD19-targeting CAR- T cells for treating SLE?
Long-term remission
Which of the following treatments has a safety issue?
Atacicept
What is the target of CD19-targeting CAR- T cells?
CD19
What percentage of skin cancer deaths are due to melanoma?
80%
What is the estimated lifetime risk of developing skin cancer for an average Australian?
1 in 2
What is the approximate percentage of skin cancers that are non-melanoma?
95%
What is the approximate incidence rate of skin cancer in Australia compared to the U.S.A, Canada, and U.K?
2-3 times higher
What is the primary UV radiation range responsible for skin damage?
UVB (280-320nm)
What is the predominant type of skin cancer in Australia?
Basal Cell Carcinoma
What is the approximate percentage of skin cancers that are Basal Cell Carcinomas?
80%
What is the organizational structure of the skin that is affected in skin cancer?
Basal lamina
What is the primary environmental risk factor associated with melanoma?
Exposure to ultraviolet (UV) light
What is the percentage of skin cancers attributed to melanoma?
5%
What is the increased risk associated with COX-2 inhibitors?
5 x increase in risk of heart attack and high blood pressure
What is the percentage of deaths from skin cancer attributed to melanoma?
80%
What is the association between childhood sunburn and melanoma?
Strong association
What is the five-year survival rate for metastatic melanoma patients?
14%
What is the significance of a single amino acid change in a protein?
It can have a significant impact on protein function/expression/activity
Which process contributes to the prolongation of exposure to potential autoantigens in SLE?
Decreased clearance of apoptotic cells
What is the consequence of decreased anti-inflammatory heme oxygenase-1 (HO-1) in SLE?
Increased proinflammatory cytokine production
What is the role of innate immune system activation in SLE?
Promoting tissue damage
What is the consequence of immune complex deposition in kidneys glomeruli in SLE?
Lupus nephritis
What is the outcome of decreased interleukin-2 (IL-2) on ILC2 cells in SLE?
Increased proinflammatory cytokine production
What is the consequence of decreased IFNα in SLE?
Increased proinflammatory cytokine production
What is the role of infiltrating tissue lesions in SLE?
Promoting tissue damage
What is the consequence of reduced number of ILC2 cells in SLE?
Increased proinflammatory cytokine production
What is the primary function of melanocytes in the skin?
To produce melanin
Why is fair skin a risk factor for the development of skin cancer?
Because it has less melanin to protect the skin from UV radiation
What is the primary characteristic of stage 0 melanoma?
Melanoma in situ, confined to the epidermis
During which stage of melanoma tumorigenesis is VEGF expression likely to be increased?
Stage 4, when the melanoma has metastasized to distant organs
What is the primary characteristic of the initiation stage of carcinogenesis?
Genetic alterations that lead to the dysregulation of signaling pathways
What is the primary function of tumor suppressor genes, such as p53?
To regulate cell cycle and induce apoptosis
During which stage of carcinogenesis do epigenetic changes lead to the accumulation of preneoplastic cells?
Promotion
What is the primary characteristic of cancer cells compared to normal cells?
They exhibit phenotypic differences, such as loss of tumor suppressor genes expression
What is the primary advantage of using AAV vectors for gene delivery?
They lack the integration-promoting gene and rarely integrate into the human genome
What is the primary function of RPE65 in the visual cycle?
To reduce all-trans-retinal to all-trans-retinol
What is the primary cause of Leber congenital amaurosis?
Autosomal recessive mutations in the RPE65 gene
What is the primary advantage of using rAAV vectors for gene therapy?
They can transduce both dividing and non-dividing cells
What is the primary characteristic of AAV vectors?
They have very low immunogenicity and are non-pathogenic
What is the primary stage of the visual cycle where RPE65 is involved?
Reduction of all-trans-retinal to all-trans-retinol
What is the primary advantage of using gene therapy for Leber congenital amaurosis?
It can restore partial vision in patients
What is the primary significance of the RPE65 gene in the visual cycle?
It is required for the reduction of all-trans-retinal to all-trans-retinol
What is the primary role of the skin in the human body?
To perform many critical roles
What percentage of skin cancers are attributed to melanoma?
5%
What is the primary difference between melanoma and non-melanoma skin cancer?
Type of skin cells affected
What is the primary outcome of the multi-step process of carcinogenesis?
Formation of a malignant tumor
What is the primary risk factor associated with melanoma?
UV radiation
What is the primary function of basal cells in the skin?
To form the basal lamina
What is the primary outcome of epigenetic changes during the promotion stage of carcinogenesis?
Accumulation of preneoplastic cells
What is the primary characteristic of the expansion/progression stage of carcinogenesis?
Clonal expansion of malignant cells
Which of the following is a characteristic of the cytochrome P450 'super' family of enzymes?
Broad substrate specificity
What is the result of enzyme inhibition in drug metabolism?
Reduced activity of metabolising enzymes
Which of the following is an example of an enzyme inducer?
All of the above
What is the role of the liver in drug metabolism?
Primary site of drug metabolism
Which of the following is a consequence of saturable enzyme activity?
Decreased drug metabolism
What is the purpose of the NADPH-P450 reductase enzyme in drug metabolism?
To catalyse oxidative metabolism
Which of the following is a route of excretion for drugs?
Lungs
What is the consequence of enterohepatic recycling?
Decreased drug elimination
What is the primary environmental risk factor associated with melanoma?
Exposure to ultraviolet (UV) light
What is the percentage of skin cancer deaths attributed to melanoma?
80%
What is the significance of a single amino acid change in a protein?
It can have a significant impact on protein function/expression/activity
What is the association between childhood sunburn and melanoma?
Childhood sunburn increases the risk of melanoma later in life
What is the primary function of zinc finger proteins in the AAV gene therapy for Hunter Syndrome?
To bind to a specific part of the albumin gene to introduce a double stranded break
What is the significance of COX-2 inhibitors in cancer treatment?
They have unclear benefits
What is the mechanism by which the IDS gene is inserted into the target locus?
Homology direct repair (HDR)
What is the distribution of Squamous Cell Carcinoma (SCC)?
It is found in skin, lung, and colon
What is the primary function of melanocytes in the skin?
To regulate skin pigmentation
What is the role of the IDS gene AAV in the AAV gene therapy for Hunter Syndrome?
To deliver the IDS gene to the liver cell
What is the five-year survival rate for metastatic melanoma patients?
14%
What is the consequence of zinc finger protein binding to the albumin gene?
Introduction of a double stranded break in the albumin gene
What is the target of the AAV gene therapy for Hunter Syndrome?
Liver cell
How many AAVs are delivered to a liver cell in the AAV gene therapy for Hunter Syndrome?
3
What is the purpose of the zinc finger protein DNA instructions in the AAV gene therapy for Hunter Syndrome?
To bind to a specific part of the albumin gene to introduce a double stranded break
What is the consequence of the double stranded break introduced by the zinc finger proteins in the albumin gene?
Insertion of the IDS gene into the target locus
What is the primary function of Zinc Finger proteins 1 & 2 in AAV gene therapy for Hunter Syndrome?
To bind to a specific part of the albumin gene to introduce a double-stranded break
What is the purpose of delivering multiple AAVs to a liver cell in AAV gene therapy for Hunter Syndrome?
To deliver the IDS gene, Zinc Finger proteins 1 & 2, and HDR template to the liver cell
What is the mechanism of action of Zinc Finger proteins 1 & 2 in AAV gene therapy for Hunter Syndrome?
They bind to a specific part of the albumin gene to introduce a double-stranded break
What is the role of homology-directed repair (HDR) in AAV gene therapy for Hunter Syndrome?
To repair the double-stranded break in the albumin gene
What is the purpose of the IDS gene in AAV gene therapy for Hunter Syndrome?
To provide a functional copy of the IDS gene to the liver cell
What is the primary advantage of using AAV vectors for gene delivery in AAV gene therapy for Hunter Syndrome?
They are non-infectious and non-integrating
What is the mechanism by which AAV vectors deliver the IDS gene to the liver cell?
Through a process of receptor-mediated endocytosis
What is the primary function of the albumin gene in AAV gene therapy for Hunter Syndrome?
To provide a target site for Zinc Finger proteins 1 & 2
What is the primary advantage of using AAV vectors for gene delivery?
They are non-pathogenic and have low immunogenicity.
What is the consequence of autosomal recessive mutations in the RPE65 gene?
Blindness in children
What is the role of RPE65 in the visual cycle?
Converting all-trans-retinal to 11-cis-retinal
What is the primary characteristic of rAAV vectors?
They lack the integration-promoting gene
What is the primary advantage of using gene therapy for Leber congenital amaurosis?
It can restore vision in affected children.
What is the primary stage of the visual cycle where RPE65 is involved?
Conversion of all-trans-retinal to all-trans-retinol
What is the primary limitation of AAV vectors for gene delivery?
The size of the insertion is a limiting factor.
What is the significance of the 204 clinical trials using AAV vectors worldwide?
They have demonstrated the efficacy of AAV vectors for gene therapy.
What is the purpose of gene disruption in therapeutic gene editing?
To silence a pathogenic gene
What is the mechanism of action of zinc finger nucleases (ZFNs) in site-directed nucleases?
A series of protein modules that bind 3 nucleotides
What is the difference between HDR and NHEJ gene correction?
HDR corrects a deleterious insertion, while NHEJ deletes a pathogenic gene
What is the role of Fok1 nuclease in site-directed nucleases?
It becomes active when the dimer is formed
What is the advantage of using CRISPR/Cas9 in gene editing?
It uses an RNA molecule that binds nucleotides
What is the difference between TALENs and ZFNs?
TALENs bind individual nucleotides, while ZFNs bind 3 nucleotides
What is the purpose of HDR gene correction?
To correct a deleterious insertion
What is the role of the PAM protospacer in CRISPR/Cas9?
It targets the Cas9 nuclease to the site
What is the primary function of autoantibody-secreting plasma cells in autoimmune diseases?
To secrete effector molecules
What is the major challenge in targeting plasma cells for autoimmune disease treatment?
Distinguishing between pathogenic and non-pathogenic plasma cells
What is the goal of personalized medicine in the context of autoimmune diseases?
To consider each patient and disease independently, using high-level data machinery
What is the potential benefit of genome-wide screening for genes related to autoimmune diseases?
Stratifying diseases to allow for more targeted treatment
What is the primary advantage of using high-throughput analysis of integrated datasets in autoimmune disease diagnosis?
Combining genetic, biochemical, epigenetic, RNA, and proteomics data for more accurate diagnosis
What is the role of autoantibodies in autoimmune diseases?
To target the body's own tissues
What is the primary goal of depleting plasma cells in autoimmune disease treatment?
To redirect the immune response towards non-autoreactive targets
What is the primary challenge in developing effective diagnostics for autoimmune diseases?
Distinguishing between autoimmune diseases and other conditions
What is the likely effect of the T266K mutation on Sos activity and function?
Decreased GEF activity and Ras activation
What is the likely effect of the Sos T266K mutation on signalling components upstream of Sos?
Decreased activation of upstream signalling components
What is the likely mechanism of Vemurafenib-resistance in the patients with the BRAF(V600E) mutation?
Selection of clones with additional mutations
Where in the signalling pathway do you predict there may be a causative mutation in the five patients who did not respond to the initial Vemurafenib treatment, but did respond to the subsequent MEK inhibitor?
Between BRAF and MEK1/2
Which signalling component(s) would you investigate next for gene mutation(s) as a potential causative candidate(s) in the five patients who did not respond to the initial Vemurafenib treatment, but did respond to the subsequent MEK inhibitor?
All of the above
What is the likely effect of the T266K mutation on Ras activation?
Decreased Ras activation
What is the significance of the 100% development of resistance to Vemurafenib in the patients with the BRAF(V600E) mutation?
It suggests that the patients may have additional mutations
What is the likely effect of the Sos T266K mutation on downstream signalling components, specifically MEK1/2?
Decreased activation of MEK1/2
What is the major determinant of dosing frequency, time to eliminate the drug, and time required to reach steady state?
Plasma half-life (t½)
What is the relationship between plasma half-life (t½) and clearance (CL)?
t½ is inversely proportional to CL
What is the characteristic of zero-order elimination kinetics?
Rate of elimination is independent of plasma concentration
What is the formula to calculate the maintenance dose rate?
DR = CL x Cp
What is the significance of the steady state concentration?
It is the concentration achieved after repeated dosing
What is the relationship between clearance (CL) and dose rate (DR)?
CL is directly proportional to DR
What is the consequence of a relatively small change in dose for a drug with zero-order kinetics?
A disproportionate increase in plasma concentration
What is the relationship between plasma half-life (t½) and the time required to reach steady state?
The time required to reach steady state is 4-5 times t½
What is the primary function of Phase II drug metabolism?
To make the drug more water-soluble
What is the consequence of Phase II drug metabolism?
The metabolite becomes more water-soluble
Where does Phase I drug metabolism occur?
In the liver and other tissues, such as the intestine
A drug with a very high volume of distribution (Vd) is likely to have a high degree of
lipophilicity
What is the consequence of Phase I drug metabolism?
The metabolite becomes more pharmacologically active
What is the primary factor that determines the renal clearance of a drug?
Glomerular filtration rate (GFR)
What is the significance of Phase II drug metabolism?
It is not considered important for drug-drug interactions
What is the significance of Phase I drug metabolism?
It is important for prodrugs
A drug with a low volume of distribution (Vd) is likely to be restricted to which compartment?
Plasma volume
What is the result of Phase II drug metabolism on the metabolite?
It becomes more water-soluble
What is the formula to calculate the volume of distribution (Vd)?
Vd = dose / [plasma]
Which of the following processes is responsible for the excretion of inactive drug?
Metabolic degradation
What is the result of Phase I drug metabolism on the metabolite?
It becomes more pharmacologically active
A drug with a high volume of distribution (Vd) is likely to have a high degree of
lipophilicity
What is the primary factor that determines the rate of renal clearance of a drug?
Free drug concentration in plasma
Which of the following is a characteristic of a drug with a high volume of distribution (Vd)?
Distributed throughout total body water
What is the primary enzyme responsible for the metabolism of warfarin?
CYP2C9
What is the primary goal of pharmacogenomics?
To develop personalized treatment plans
What is the formula for calculating clearance?
CL = Dose Rate / Cp
What is the component of the vitamin K reductase complex that affects warfarin dosing?
VKORC1
What is the term for the volume of plasma cleared of drug per unit time?
Clearance
What is the minimum effective concentration of a drug?
MEC
What is the term for the steady-state concentration of a drug?
Css
What is the primary factor that affects the elimination of a drug?
All of the above
What is the primary factor that determines the reabsorption of a drug in the plasma?
Lipid solubility
What is the effect of Phase I reactions on a drug's polarity?
Increases polarity
What is the role of enzymatic metabolism in the excretion of lipid-soluble drugs?
Makes lipid-soluble drugs more water-soluble
What is the equation for calculating the total amount of a drug eliminated via the kidneys?
Amount filtered + amount secreted - amount reabsorbed
What is the primary difference between Phase I and Phase II reactions in drug metabolism?
Phase I reactions are catabolic, while Phase II reactions are anabolic
What is the effect of a high urine flow rate on the reabsorption of a drug?
Decreases reabsorption
What is the primary factor that determines the renal clearance of a highly ionised drug?
Ionisation state
What is the effect of enzymatic metabolism on the elimination of a lipid-soluble drug?
Increases the elimination of the drug
What is the significance of a single amino acid change in a protein?
It can have a significant impact on the function, expression, or activity of the protein.
What is the primary risk factor associated with melanoma development?
Exposure to ultraviolet (UV) light
What is the outcome of using COX-2 inhibitors for cancer treatment?
It is associated with a 5-fold increase in heart attack risk and high blood pressure.
What percentage of skin cancer deaths are attributed to melanoma?
80%
What is the significance of childhood blistering sunburns in melanoma development?
It is associated with a higher risk of melanoma development.
What is the primary characteristic of melanoma?
It is responsible for the majority of skin cancer deaths.
What is the significance of mole number (>20 moles) in melanoma development?
It is a risk factor for melanoma development.
What is the primary effect of immune deposits on the glomerular capillaries in SLE?
They cause the glomerular capillaries to appear thickened.
What is the significance of early organ damage in SLE patients?
It is associated with a higher mortality rate in SLE patients.
What is the target of autoantibodies in SLE?
Molecules in the nuclei.
What is the role of TLR7 and TLR9 in SLE?
They are 'danger sensors' on antigen-presenting cells and B cells.
What is the characteristic of disease exacerbation in SLE?
It is a cyclic process.
What is the significance of the survival probability graph in SLE patients?
It shows the effect of early organ damage on survival probability.
What is the primary feature of the glomerular capillaries in SLE patients with early organ damage?
They are thickened.
What is the association between disease duration and survival probability in SLE patients?
Longer disease duration is associated with lower survival probability.
Which cytokine-targeting therapy is under investigation for autoimmune diseases?
Mirikizumab
What is the target of B cell-targeting therapies, such as Ianalumab?
B cell survival factor (BAFF)
What is the structure of Evobrutinib, a kinase-targeting therapy?
Small molecule BTK inhibitor
Which autoimmune disease is being investigated for treatment with Tolebrutinib, a kinase-targeting therapy?
Multiple sclerosis
What is a disadvantage of using regulatory T (Treg) cells as a cell therapy for autoimmune diseases?
They can switch from immunosuppressive to effector function
What is a feature of CAR-T cell therapies, such as those targeting the surface antigen on B cells?
They target all cells expressing the surface target antigen
Which autoimmune disease is being investigated for treatment with Ianalumab, a B cell-targeting therapy?
Primary Sjögren syndrome
What is the structure of Mirikizumab, a cytokine-targeting therapy?
Anti-IL-23 mAb
What is the target of the drug Belimumab?
B cell survival factor BAFF
Which of the following B cell-targeting therapies is approved for Rheumatoid arthritis?
Rituximab
What is the function of BAFF in B cell development?
It promotes B cell survival throughout differentiation stages
Which of the following B cell-targeting therapies is approved for Multiple sclerosis?
Ocrelizumab
What is the mechanism of action of Belimumab?
It blocks BAFF-mediated signaling
Which of the following B cell-targeting therapies is approved for Neuromyelitis optica spectrum disorders?
Ineblizumab
What is the type of monoclonal antibody that Belimumab is?
Human IgG1 recombinant monoclonal antibody
In which year was Belimumab approved for Systemic Lupus Erythematosus (SLE)?
2011
What is the primary mechanism by which melanin protects against UV-induced DNA damage?
Absorption of UV light by melanosomes
What is the consequence of a loss of melanin in the skin?
Increased risk of skin cancer, including melanoma
What is the function of SOS in the MAPK pathway?
Guanine nucleotide exchange factor that activates Ras
What is the effect of the V600E mutation on B-Raf activity?
500x increase in B-Raf activity
What is the primary function of melanosomes?
Transporting melanin within cells
What is the percentage of melanomas that contain a BRAF mutation?
60%
What is the role of B-Raf in the MAPK pathway?
Phosphorylating MEK
What is the consequence of a lack of melanin in the skin, as seen in conditions such as albinism and vitiligo?
Increased risk of skin cancer, including melanoma
Study Notes
Systemic Lupus Erythematosus (SLE)
- Activation of the innate immune system is part of the inflammatory response in SLE
- Decreased clearance of apoptotic cells leads to prolonged exposure of potential autoantigens
- Decreased clearance of apoptotic cells also leads to decreased anti-inflammatory cytokines and increased pro-inflammatory cytokines
- Immune complexes deposit in kidneys, leading to lupus nephritis
- Current and potential treatments for SLE include Rituximab, Bortezomib, Atacicept, and CD19-targeting CAR-T cells
Skin Cancer
- Skin cancer is the most common cancer in Australia, with the highest incidence rate worldwide
- There are three main types of skin cancer: Basal Cell Carcinoma (BCC), Squamous Cell Carcinoma (SCC), and Malignant Melanoma (MM)
- Risk factors for skin cancer include UV radiation, fair skin, and family history
- Skin cancer can be divided into melanoma and non-melanoma skin cancer (BCC and SCC)
Melanoma
- Melanoma originates from melanocytes in the basal layer of the epidermis and in the eye
- Exposure to UV light is the only known environmental risk factor for melanoma
- Childhood blistering sunburn (>3 episodes) is strongly associated with the development of melanocytic neoplasia later in life
- Family history, fair skin, and mole number (>20 moles) are also important risk factors for melanoma
- Melanoma accounts for only 5% of all skin cancers but is responsible for 80% of deaths from skin cancer
Cancer Development
- Cancer development is a multi-step process involving initiation, promotion, and progression
- Initiation involves genetic alteration, which can be spontaneous or induced by a carcinogenic agent
- Promotion involves epigenetic changes that may be lengthy and can be altered by chemopreventive agents
- Progression involves further genetic changes associated with acquisition of invasive and metastatic potential
Gene Therapy
- AAV vectors are typically "gutted" to make room for gene delivery and for safety reasons.
- The size of the insertion is a limiting factor.
- AAV vectors lack the integration-promoting gene, resulting in rare and random integration into the human genome.
- rAAV can transduce both dividing and non-dividing cells, with stable transgene expression for years in postmitotic tissue.
- AAV vectors are not pathogenic and have very low immunogenicity.
- As of November 2017, there were 204 clinical trials worldwide that used AAV vectors.
Leber Congenital Amaurosis
- Leber congenital amaurosis is a common cause of blindness in children, affecting 2-3 per 100,000 newborns.
- It is caused by autosomal recessive mutations in about 13 different genes, including RPE65.
- RPE65 is produced in the retinal pigment epithelium (RPE) and is required in the visual cycle.
- The visual cycle involves the absorption of light, which causes isomerization of 11-cis-retinal to all-trans-retinal in photoreceptors for phototransduction.
AAV Gene Therapy for Hunter Syndrome
- AAV gene therapy for Hunter Syndrome involves delivering three different AAVs to a liver cell:
- 1 IDS gene AAV
- 1 Zinc Finger no. 1 DNA instructions
- 1 Zinc Finger no. 2 DNA instructions
- Zinc finger proteins 1 and 2 bind to a specific part of the albumin gene to introduce a double-stranded break.
Phase I Drug Metabolising Enzymes
- Phase I drug metabolising enzymes have broad substrate specificity.
- One enzyme may catalyse the metabolism of many different drugs.
- One drug may be metabolised by multiple enzymes or isoenzymes.
- Liver drug metabolising enzymes are usually embedded in the endoplasmic reticulum (microsomal).
- The cytochrome P450 "super" family is an important family of enzymes that catalyse oxidative metabolism of a range of xenobiotics.
Cytochrome P450s
- Cytochrome P450s differ in amino acid sequence, sensitivity to inhibitors and inducing agents, and substrate specificity.
- There are approximately 74 CYP450 gene families, with three major families involved in drug metabolism in the liver (CYP1, CYP2, CYP3).
- Enzyme reaction requires molecular oxygen, NADPH, and NADPH-P450 reductase (a flavoprotein).
Drug Interactions via Metabolising Enzymes
- Metabolising enzymes are potentially saturable, and their activity can be influenced by many factors, including genetics and other drugs.
- Enzyme inhibition occurs when drugs metabolised by the same enzyme are administered together, competing for the metabolising enzyme.
- Enzyme induction occurs when some drugs increase the activity or levels of the enzymes that metabolise them.
Biliary Clearance of Drugs
- Biliary clearance of drugs involves enterohepatic recycling.
- Other routes for excretion of drugs include the lungs, which can remove gases and volatile liquids.
Skin Cancer
- Skin cancer is the most common of all cancers in Australia, with an incidence rate 2-3 times that of the USA, Canada, and UK.
- Skin cancer represents approximately 80% of all cancer diagnoses in Australia.
- One in two Australians will get skin cancer in their lifetime.
- 80% of skin cancer deaths are due to melanoma.
Basal Cell Carcinoma, Squamous Cell Carcinoma, and Malignant Melanoma
- Basal cell carcinoma (BCC) accounts for approximately 80% of skin cancer cases.
- Squamous cell carcinoma (SCC) accounts for approximately 15% of skin cancer cases.
- Malignant melanoma (MM) accounts for approximately 5% of skin cancer cases.
Risk Factors for Skin Cancer
- Risk factors for skin cancer include UVB and UVA radiation.
- Skin cancer is divided into melanoma and non-melanoma skin cancer, which includes SCC and BCC.
Model for the Initiation, Promotion, and Progression of SCC
- SCC is present in other tissues, including lung and colon, where it poses a major health risk.
- COX-2 inhibitors have unclear benefits, with conflicting data on their effectiveness in shrinking tumours.
Melanoma
- Melanoma originates from melanocytes, found in the basal layer of the epidermis and also in the eye.
- The only known environmental risk factor is exposure to ultraviolet (UV) light.
- Strong association between childhood blistering sunburn (>3 episodes) and development of melanocytic neoplasia later in life.
- Family history, fair skin, and mole number (>20 moles) are also important risk factors.
- Melanoma accounts for only approximately 5% of all skin cancers but is responsible for 80% of deaths from skin cancer.
- Previously, approximately 14% of metastatic melanoma patients survived for five years.
AAV Gene Therapy
- AAV vectors are commonly used in biotech, where the genome is gutted to make space for gene delivery and for safety reasons.
- The size of the insertion is a limiting factor.
- AAV vectors lack the integration-promoting gene, resulting in rare and random integration into the human genome.
- rAAV can transduce both dividing and non-dividing cells, with stable transgene expression for years in postmitotic tissue.
- rAAV is not pathogenic and has very low immunogenicity.
- As of November 2017, 204 clinical trials worldwide have used AAV vectors.
RPE65 Gene Therapy
- RPE65 is a common cause of blindness in children, occurring in 2-3 per 100,000 newborns.
- Autosomal recessive mutations in about 13 different genes, including RPE65, can cause Leber congenital amaurosis.
- RPE65 is produced in the retinal pigment epithelium (RPE) and is required for the visual cycle.
- The visual cycle involves the absorption of light, isomerization of 11-cis-retinal to all-trans-retinal, and the decay of activated rhodopsin.
Therapeutic Gene Editing
- Gene disruption: silences a pathogenic gene.
- NHEJ gene correction: deletes a pathogenic insertion.
- HDR gene correction: corrects a deleterious insertion.
- HDR stands for homology-directed repair.
Targeting Specific Genes
- Zinc finger nucleases (ZFNs): use a series of protein modules that bind 3 nucleotides, bringing Fok1 nuclease to the site.
- Transcription activator-like effector nucleases (TALENs): use a series of protein modules that bind individual nucleotides, bringing Fok1 nuclease to the site.
- RNA-guided engineered nucleases (CRISPR/Cas9): use an RNA molecule that binds nucleotides and targets Cas9 nuclease to the site.
Enzyme Replacement Therapy
- AAV gene therapy for Hunter Syndrome involves delivering 3 different AAVs to a liver cell.
- The 3 AAVs are: 1 IDS gene AAV, 1 Zinc Finger no. 1 DNA instructions, and 1 Zinc Finger no. 2 DNA instructions.
- Homology direct repair (HDR) is used to introduce a double-stranded break.
Potential Target for Autoimmune Diseases
- Autoantibody-secreting plasma cells are a key target for autoimmune diseases.
- Depleting plasma cells while redirecting the immune response towards non-autoreactive cells is a possible strategy.
- Challenges include understanding key processes and important genes for plasma cell survival.
Future Perspectives for Treating Autoimmune Diseases
- New diagnostics: genome-wide screening for genes related to certain autoimmune diseases, and detailed disease stratifying.
- Personalized medicine: high-level data machinery harnessing information collected on a per-patient basis.
- Preventive medicine: identifying risk factors and groups, and longitudinal monitoring of the immune status of high-risk patients.
Plasma Half-Life (t½)
- Plasma half-life (t½) is the time taken for the amount of drug in the plasma to fall by half.
- t½ is a major determinant of: • dosing frequency • time to eliminate the drug (4-5 t½s) • time required to reach steady state with repeat dosing (4-5 t½s)
First-Order Elimination Kinetics
- Rate of elimination is driven by plasma concentration (Cp).
- Constant/repeated dosing will achieve a steady state Cp.
- Time to reach steady state is determined by t½.
- Time for "removal" is determined by t½.
Zero-Order Elimination Kinetics
- Rate of elimination is independent of Cp.
- t½ will vary with plasma concentration.
- Relatively small changes in dose can lead to a disproportionate increase in plasma concentration.
Volume of Distribution (Vd)
- Vd is a theoretical concept that represents the volume into which a drug appears to be distributed with a concentration equal to that of plasma.
- Vd relates the plasma concentration to the total amount of drug in the body.
- Vd can be estimated by comparing the amount in the body (dose) to the plasma concentration.
Renal Clearance
- Renal clearance involves glomerular filtration, tubular secretion, and reabsorption.
- Glomerular filtration depends on [free drug] in plasma and glomerular filtration rate (GFR).
- Tubular secretion involves specific transporters (e.g., OAT, OCT).
- Reabsorption depends on lipid solubility and urine flow rate.
Drug Metabolism
- Drug metabolism makes lipid-soluble drugs more water-soluble so that they can be excreted via the kidneys.
- Metabolism depends on various enzymes, mostly located intracellularly.
- Phase I reactions involve functionalization (oxidation, reduction, or hydrolysis), increasing polarity.
- Phase II reactions involve conjugation with endogenous molecules.
Pharmacogenomics
- Pharmacogenomics is the use of genetic information to guide drug therapy.
- Genetic differences can predict individual responses to drugs.
Drug Clearance
- Clearance (CL) is the volume of plasma cleared of drug per unit time.
- CL depends on [drug] in urine, urine flow rate, and [free drug] in plasma.
- CL can be divided into renal, liver, and other clearance components.
Elimination of Drug
- The time it takes to eliminate the drug depends on the plasma half-life (t½).
- The amount of drug eliminated via the kidneys is the sum of amount filtered, secreted, and reabsorbed.
Systemic Lupus Erythematosus (SLE)
- Mortality in SLE is linked to early organ damage, with a significant difference in survival probability between patients with and without early damage.
- Autoantibodies in SLE are against molecules in nuclei, including dsDNA, ribonucleoproteins, and other nuclear proteins complexed with nucleic acids.
- These autoantigens are ligands for 'danger sensors' on antigen-presenting cells and B cells, such as TLR7 and TLR9.
Cyclic Exacerbation of Disease
- Cyclic exacerbation of disease is a characteristic of SLE, as described by Liu & Davidson (2012) and Bluestone J.A. (2007).
Current Treatment for Autoimmune Diseases
- B cell-targeting therapies are used to treat autoimmune diseases, including:
- Anti-CD20 mAb (Rituximab) for rheumatoid arthritis
- Anti-CD20 mAb (Ocrelizumab) for multiple sclerosis
- Anti-CD19 mAb (Ineblizumab) for neuromyelitis optica spectrum disorders
- Anti-BAFF mAb (Belimumab) for SLE, which blocks BAFF-mediated signaling and has moderate efficacy
Treatment Under Investigation for Autoimmune Diseases
- Cytokine-targeting therapies, such as Mirikizumab, are being investigated for diseases like psoriasis, ulcerative colitis, and Crohn's disease.
- B cell-targeting therapies, such as Ianalumab, are being investigated for SLE and primary Sjögren syndrome.
- Kinase-targeting therapies, such as Evobrutinib, Tolebrutinib, Fenebrutinib, and Rilzabrutinib, are being investigated for diseases like multiple sclerosis, pemphigus vulgaris, and immune thrombocytopenia.
Potential Treatment for Autoimmune Diseases
- Cell therapies, such as regulatory T (Treg) cells, are being investigated, but have the disadvantage of potentially switching from immunosuppressive to effector function.
- CAR (chimeric antigenic receptor) T cells are being investigated, which target all cells expressing the surface target antigen.
Squamous Cell Carcinoma (SCC)
- SCC is present in other tissues, including lung and colon, where it poses a major health risk.
- COX-2 inhibitors have unclear benefits, with conflicting data and potential risks, such as a 5-fold increase in the risk of heart attack and high blood pressure.
Melanoma
- Melanoma originates from melanocytes, found in the basal layer of the epidermis and also in the eye.
- The only known environmental risk factor is exposure to ultraviolet (UV) light.
- Strong association between childhood blistering sunburn (>3 episodes) and development of melanocytic neoplasia later in life.
- Family history, fair skin, and mole number (>20 moles) are also important risk factors.
- Melanoma accounts for only ~5% of all skin cancers but is responsible for 80% of deaths from skin cancer.
The Role of Melanin in Skin Cancer
- Melanin plays a protective role against UV-induced DNA damage via absorption of UV light.
- Melanin is transported within cells via melanosomes/granules, which accumulate over the nucleus to form a "melanin cap".
- Loss of melanin significantly increases the risk of skin cancer, including melanoma.
B-Raf/MAPK Signaling in Melanoma
- MAPK pathway is a major pro-proliferative signaling pathway in melanocytes.
- B-Raf is a serine/threonine kinase that activates MEK.
- ~60% of melanomas contain a BRAF mutation, with 90% of these mutations being a single amino acid substitution (V600E) resulting in a 500x increase in BRAF activity and constitutive activation of MAPK signaling.
This quiz covers the relationship between the innate immune system and Systemic Lupus Erythematosus (SLE), including the activation of the innate immune system and its effects on the body. It also explores the decreased clearance of apoptotic cells and its consequences.
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