CSM Flashcards

Question

What is HPV?

Answer 1

human papilloma virus 99% of all cervical cancers causes vulval and vaginal warts/pre-cancerous lesions HPV vaccine introduced in 2006

Answer 2

normal cells -> HPV infection -> low grade SIL -> de-regulation of E6/7 -> high grade SIL -> invasive cancer at each stage advances in telomerase activation, inhibition of apoptosis, genetic changes and immune response occur

Answer 3

A cell with a beneficial mutation or epigenetic change may continue to divide until a collection of identical cells or clone is formed. Cells from this clone may acquire new genetic and epigenetic changes which further enhance their growth and survival. Cell with mutation → hyperplasia → dysplasia → in situ cancer → invasive cancer.

Answer 4

In situ cancer is not able to invade the basomembrane stroma muscle or blood vessels. Invasive cancer has invaded the basomembrane.

Answer 5

it is the presence of multiple subclones, each with differing properties

Answer 6

In vitro: abnormal morphology/shape and can multiply wihtout attachement to a substrate In vivo: transformed cells can form tumours in immune com, promised hosts - genetic modification: abnormal chromosomes numbers and gene amplification - dont require growth factors - dont senescence - invasive behaviour

Answer 7

Tumour size Nodal status Tumour grade

Answer 8

Dukes A-D A - 5 yr survival > 90% B - 5 yr survival 55%-85% C- 5 yr survival 20-55% D - 5 yr survival < 5%

Answer 9

It is the process where environmental agents that damage DNA such as chemicals, radiation, and viruses lead to DNA damage in normal cells. This leads to mutation in somatic cells which can lead to activation of growth-promoting oncogenes, impaired apoptosis, and inactivation of tumour suppressor genes. These all lead to altered gene products such as abnormal structural and regulatory proteins that lead to a malignant tumour.

Answer 10

system of classifying cancer based on the degree of similarity to tissue of origin and other factors. Grade 1 is well-differentiated, Grade 2 is moderately differentiated, Grade 3 is poorly differentiated, and Grade 4 is anaplastic.

Answer 11

Grade - how bad do the cells look? The degree of similarity to tissue of origin grade 1-3 Stage - how far has the cancer spread? TNM staging = Tumour, Nodes, Metastases

Answer 12

It is the measurement associated with response to a given therapy.

Answer 13

A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease or the chance of the disease recurring (coming back).

Answer 14

Cytology cells such as in a pap smear Benign vs malignant histology (tissue) Prediction versus prognosis

Answer 15

Infectious agents are associated with 16% of cancers, and 12% of those are caused by viruses, which is equivalent to 2,230,000 new cases per year.

Answer 16

Epstein-Barr virus (EBV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Kaposi's sarcoma herpes virus (KSHV), Human T-cell lymphotropic virus T1, and Merkel cell polyomavirus.

Answer 17

HIV is not a cancer-causing virus. It suppresses the immune system, but it does not directly lead to cancer.

Answer 18

In developing nations, the cancers associated with infectious agents are breast, lung, bladder, non-Hodgkin's lymphoma, cervix uteri, liver, prostate, colorectal, esophagus, stomach, and oral cancer. In low-income countries, 26% of cancers are caused by viruses, while in high-income countries, only 8% are caused by viruses. This is due to differences in monitoring systems, access to vaccination, amount of HIV suppressing the immune system, exposure to pathogens, and access to treatment.

Answer 19

long latency period between primary infection and tumor development, only a small percentage of virus-infected individuals develop the tumor, and there are no animal models of human virus-associated cancers.

Answer 20

The Epstein Barr virus (EBV) is a herpesvirus with enveloped dsDNA, 172 kb. It is associated with nasopharyngeal carcinoma, Burkitt's lymphoma, and Hodgkin's lymphoma, among others. long latency period btw primary infection and tumour development only a small % of virus infected individuals go on to develop cancer NO animal models for virus associated cancer

Answer 21

virus infection always precedes cancer development, the virus is present in the malignant cells and not the surrounding non-malignant cells, and by using techniques like representational difference analysis to identify the virus.

Answer 22

the virus must be present along with other factors e.g. immunosuppression/chronic inflammation/UV exposure/genetic changes/other infections e.g. EBV + malaria + cMyc translocations - endemic Burkitt lymphoma Kaposi sarcoma + HIV HPV + UV + mutations HBV + hepatocellular carcinoma

Answer 23

EBV, malaria, and cMyc translocation leading to endemic Burkitt lymphoma; Kaposi's sarcoma in immunosuppressed patients; skin cancer in epidermodysplasia verciformus patients with HPV-5/8 and UV light exposure; and HBV causing hepatocellular carcinoma.

Answer 24

encode viral oncogenes that directly contribute to cancer cell transformation, inhibit a tumor suppressor gene, or directly activate a cellular oncogene.

Answer 25

introduce a viral oncogene into the host cell which directly contribute to cancer cell transformation e.g. HPV E6/7 or EBV LMP1 or MCP Large T directly activates a cellular oncogene directly inhibits a cellular TSG viral genes that control cell proliferation/survival, immune regulations = important in cancer development clonal integration of the viral DNA into the host

Answer 26

- encode proteins necessary and sufficient to replicate themselves - Do not need a host cell DNA replication machinery - establish latency in slow-replicating or non replicating cells

Answer 27

- Do not encode proteins to replication themselves - require host cell DNA replicaition machinery to replicate DNA - must deregulate the growth control of the infected cells - consequences for the host can be serious

Answer 28

genome divided into - early (non-structural)/late (structural)/non-coding regions RNA splicing to generate multiple RNAa - dependent upon host cell for replication and transcription

Answer 29

reliant on the induction of host cell replication factors and cell cycle regulators Early proteins E6/7 stimulate growth HPV encodes E7 which drives differentiating cells into S phase - E7 binds to RB - releases the E2F1 TF - causes the transcription of S phase genes inducing cyclin E and P53 P53 - removes virus infected cells via cell cycle arrest/apoptosis HPV encodes E6 which recruits cellular E6AP (cellular ubiquitin ligase) to degrade P53 - causes an accumulation of chromosomal mutations - including oncogenic mutations drives cervicale cancer

Answer 30

RB is a transcription factor that binds to E2F1 transcription factor for the S phase genes. Growth factor binds to the surface of the cell to cause activation of cyclin D which phosphorylates RB that releases E2F1 transcription factor to activate S phase genes.

Answer 31

cause Merkel cell carcinoma - skin cancer of Merkel cells higher incidence in immunosuppressed/elderly tumours appear on head and neck

Answer 32

Sensory-mechanoreceptor located in the stratum basale. It is a light touch receptor found in the skin and is abundant in fingertips. It makes synaptic contacts with somatosensory afferent nerve fibers.

Answer 33

Large T antigen plays a large role in Merkel cell polyomavirus replication by binding to the origin of replication of the viral DNA, acting as a helicase to unwind DNA, recruiting host DNA polymerase complex to this site, and initiating DNA replication. To replicate DNA, they use host DNA synthesis machinery. These proteins are produced in the S phase of the cell cycle, and polyomavirus manipulates resting cells to enter the cell cycle.

Answer 34

vaccination screening

Answer 35

tobacco use, diet, obesity, alcohol consumption, occupation, radiation exposure (both UV and ionizing), and infections.

Answer 36

PM sulphur dioxide ozone carbon monoxide nitrogen dioxide polycyclic aromatic hydrocarbons (PAHs)

Answer 37

chimney smoke, vinyl chloride, benzene, radium, arsenic, and other harmful chemicals.

Answer 38

contains over 60 carcinogens that can cause various types of cancer, including lung, oral, nasal, and esophageal cancer. The carcinogenic process is central to the DNA adducts induced by tobacco products.

Answer 39

aturally occurring fibrous silicate material. Prolonged inhalation of asbestos fibers can lead to fatal illnesses, such as pleural mesothelioma, which is caused almost exclusively by exposure to asbestos.

Answer 40

aturally occurring fibrous silicate material. Prolonged inhalation of asbestos fibers can lead to fatal illnesses, such as pleural mesothelioma, which is caused almost exclusively by exposure to asbestos.

Answer 41

altered adipokine productions subclinical chronic inflammation altered steroid metabolism insulin resistance altered metabolic microenvironment altered microbiomeExcess weight can increase the risk of developing certain types of cancer, such as endometrial and renal cancer, due to factors such as insulin resistance, increased estrogen levels, pro-inflammatory cytokines, and changes in the microenvironment of the stomach.

Answer 42

education vaccination control of occupational hazards reduction to sunlight exposure

Answer 43

chronic ethanol consumption leads to production of acetaldehyde and induction of oxidative stress and conversion of pro carcinogens to carcinogens

Answer 44

Non-nutritive substances found in vegetables that appear to have a positive effect on health, possess anti-carcinogen and anti-mutagenic properties

Answer 45

set of linked biochemical events that connect a specific biological stimulus with a specific cellular response.

Answer 46

cyclic AMP - PKA Ca2+ - CaM-kinase/PKC Ras MAP-kinase PIP3 - PKB

Answer 47

biochemical changes - changes in protein shape/charge/size functional changes - localisation/enzyme activity/complex formation/stability

Answer 48

tyrosine kinase receptors (TKR) and G-protein coupled receptors (GPCR).

Answer 49

7 transmembrane domain activates downstream signalling through the activation of G proteins energy source = GTP e.g. beta-adrenergic Rs/prostaglandin E2 Rs/rhodopsin

Answer 50

EGFR1-4, which form homodimers and heterodimers with other family members. EGFR1 is activated by a number of ligands including EGF and TGFa, while HER2 (EGFR2) is an orphan receptor and is activated by heterodimerisation with other family members. Overexpression/amplification/mutation of EGFR family members are implicated in about 30% of cancers.

Answer 51

Phosphatases can remove phosphate groups from proteins, allowing for switchable mechanisms to take proteins from one functional state to another by regulating the activity of kinases and phosphatases in cells. This is a form of post-translational modification.

Answer 52

Controlling cell growth and proliferation, and abnormalities in these pathways can lead to cancer predisposition. Understanding these pathways is important for developing therapy approaches and understanding therapy resistance mechanisms

Answer 53

Through intracellular signalling pathways, which connect a specific biological stimulus with a specific cellular response. Signalling molecules bind to specific receptors on the cell surface or inside the cell to elicit a response, such as migration, gene expression, or metabolism.

Answer 54

binding of a signalling molecule initiates receptor dimerisation kinase domains can now initiate autophosphorylation on multiple tyrosine residues which creats high affinity binding sites for proteins e.g. Grb-2 (MAP kinase pathway) and PI 3 kinase

Answer 55

Signalling pathway that regulates cell growth and differentiation. It involves the activation of RAS, which is an oncogene, leading to the activation of RAF, MEK, and ERK, which promotes cell cycle progression and gene transcription needed for cell survival and proliferation

Answer 56

cascade of phosphorylations leading to gene expression regulation: RAS acts as a switch in the MAP kinase pathway GEF e.g. SOS stimulates exchange of GDP for GTP RAS is a GTPase - catalyses the hydrolysis of GTP to GDP the intrinsic activity of RAS is poor need a GAP e.g. RASA1-3, NF1 - stimulates the intrinsic activity and hydrolysis of GTP RAS binds to RAF and promotes dimerisation and activation RAF activation leads to rapid signalling through phosphorylating events MEK phosphorylation occurs on an activation segment/loop in the kinase domain which leads to remodelling of the active site into an open conformation - for ATP and substrate binding phospho-ERK translocates into the nucleus and activates TF e.g. c-FOS and c-JUN by phosphorylation leading to changes in expression profiles

Answer 57

Signalling pathway that regulates cell growth, survival, and metabolism. Ras--> PI 3-kinase is activated by binding to phosphorylated Try residues on RTKs PI 3-kinase catalyses the phosphorylation of P1P2 to PIP3 PIP3 acts as a docking site for PDK1 and AKT upon binding PDK1 phosphorylates AKT active AKT is released into the cytosol for downstream signalling

Answer 58

removal of extracellular signals the inactivation of activated receptor tyrosine kinases by protein tyrosine phosphatases, the dephosphorylation of target proteins by serine/threonine phosphatases, removal of the PI(3,4,5)P3 signal by PTEN.

Answer 59

PTEN is a tumour suppressor gene that encodes for an enzyme called inositol lipid phosphatase, which removes phosphate from PI(3,4,5)P3 so that it no longer acts as a docking site for PDK1 and AKT. It is commonly lost in cancer, and inactivating mutations in PTEN can promote uncontrolled cell growth and survival.

Answer 60

grouping patients according to genetic lesions within individuals and targeting those lesions or the signalling pathway to which they contribute. This approach helps to improve treatment efficacy and reduce unnecessary side effects.

Answer 61

antibodies that have been modified to decrease their potential for immunogenicity by replacing parts of the antibody with human sequences. The advantages of humanized antibodies include increased potential for recruiting immune effector mechanisms and decreased potential for immunogenicity.

Answer 62

blockade of ligand binding to receptor, inhibition of receptor dimerization, receptor internalisation/degradation, and antibody-dependent cellular cytotoxicity (ADCC).

Answer 63

Loss or downregulation of HER2 receptors: Trastuzumab, a monoclonal antibody, primarily targets the HER2 receptor, which is overexpressed in certain cancers. Resistance can occur when cancer cells undergo a loss or downregulation of HER2 receptors, making them less susceptible to trastuzumab's effects. Cancer cells may activate alternative signaling pathways that bypass the HER2 receptor, allowing them to continue proliferating and surviving despite trastuzumab treatment. This can involve the activation of other receptor tyrosine kinases, such as EGFR or MET, which can drive tumor growth independently of HER2. PIK3CA mutations, can lead to resistance to trastuzumab. These alterations can activate downstream signaling events, rendering the tumor cells insensitive to the inhibitory effects of trastuzumab. PTEN loss or inactivation: Loss or inactivation of PTEN can lead to constitutive activation of the PI3K/AKT pathway, promoting cell survival and resistance to trastuzumab.

Answer 64

A normal cellular gene that controls processes such as proliferation, survival, and invasion.

Answer 65

A mutated form of a proto-oncogene that expresses gene products with aberrant activity or overexpresses normal gene products, contributing to the hallmarks of cancer.

Answer 66

Even if a cell has a normal allele, the presence of a mutated allele leads to altered protein expression due to dominant expression of the mutant gene.

Answer 67

1. Sustaining proliferative signaling 2. Evading growth suppressors 3. Activating invasion and metastasis 4. Enabling replicative immortality 5. Inducing angiogenesis 6. Resisting cell death

Answer 68

chronic proliferation mitogenic signals mehcanisms: - autocrine singalling - elevating number of receptors(hyperresponsive) - constitutive activation of components of sig pathways - defects on negative feedback mechanisms such as PTEN

Answer 69

loss of function mutations in TSGs usually need to deactivate both copies e.g RB

Answer 70

cancer cells dont obey the hayflick limit as they express telomerase no dont senescence

Answer 71

some oncogenes (Myc, Ras) can upregulate expression of angiogenic factors

Answer 72

crosstalk between cancer cells and cell of the neoplastic stroma - mesenchymal stem cells in tumour stroma secrete CCL5, stimulates invasion - Macrophages: Metalloproteeinases, EGF - inflammatory cells: extracellular matrix-degrating enzymes

Answer 73

1) reprogramming energy metabolism, cancder cells limit energy metabolism to glycolysis- aerobic. it allows diversion of glycolytic intermediates into biosynthesis pathways 2) evading immune system, cancer cells may paralse infiltrating CTLs and NK cells, such as TGF-b

Answer 74

point mutation -> protein with altered characteristics e.g. EGFR/RAS amplification of a genomic DNA region that induces the proto-oncogene -> overexpression of the gene and increased amounts of protein e.g. MYCN/EGFR chromosome translocations that bring a proto-oncogene into close proximity to a different promoter -> inappropriate gene and protein expression e.g. c-Myc/BCR-2 chromosome translocations resulting in the fusion of 2 genes together -> creates a chimeric fusion protein/gene with novel characteristics e.g. PML/RARA

Answer 75

1st generation TKIs - competitive ATP-mimics, reversible binding, freq. drug resistance 2nd generation TKIs - irreversible binding in the ATP pocket 3rd generation TKIs - bind more avidly to EGFR T790M mutants than wild-type EGFR

Answer 76

STI571/Gleevec/Imatinib = specific inhibitor of the BCR-ABL TK competitive inhibition of ATP binding to active site, inhibiting TK activity

Answer 77

EGF takes a signal to EGFR that passes it down to RAS, RAF, MEK, ERK, and transcription of genes.

Answer 78

Proteins such as EGFR that exist as inactive monomers in the membrane and, when they bind to EGF, dimerize and activate the receptor. The receptor then has activated phosphorylated tyrosine that binds to other cellular proteins and kickstarts other signaling pathways.

Answer 79

In frame deletion aa 747-752, which changes protein conformation and prolongs active dimer configuration missense mutation L858R (leu>arg), which increases kinase activity 50-fold of EGFR protein.

Answer 80

molecular switch involved in signal transduction

Answer 81

variably involve missense mutations affecting one of three codons (G12/13 and Q61) that block the hydrolysis of GTP to GDP, permanently turning on the molecular switch.

Answer 82

clustered in specific regions of the gene that encode important functional domains in the protein. Most mutations are missense mutations resulting in altered protein activity, and receptor tyrosine kinases (RTKs) are frequently mutated in cancer.

Answer 83

clustered in specific regions of the gene that encode important functional domains in the protein. Most mutations are missense mutations resulting in altered protein activity, and receptor tyrosine kinases (RTKs) are frequently mutated in cancer.

Answer 84

Too much production of mRNA and protein. This protein has normal activity, but overexpression leads to too much activity.

Answer 85

TF - oncogeneic activations are related to upregulation - required for cell rpoliferationand normally transiently expressed at low levels in the cell cycle - can activate or repress genes to be active forms a dimer with max

Answer 86

MYCN amplification is a genetic alteration in which the MYCN oncogene is amplified or duplicated in the genome of cancer cells. MYCN is a member of the MYC family of oncogenes and plays a critical role in regulating cell growth and division during development. However, when MYCN is amplified in cancer cells, it can lead to uncontrolled cell growth and contribute to the development and progression of several types of cancer.

Answer 87

Burkitt lymphoma is a highly aggressive B cell lymphoma derived from germinal centre B cells. All BL tumour cells carry a chromosomal translocation involving the c-MYC gene on chromosome 8 and one of the three immunoglobulin gene loci. The T(8:14) translocation places the IgH enhancer adjacent to c-MYC, leading to overexpression of c-MYC protein.

Answer 88

BCR-ABL fusion protein is a novel protein resulting from a translocation between chromosome 22 and 9, known as the Philadelphia chromosome. It is significant in chronic myeloid leukemia as it encodes a novel BCR-ABL fusion protein with tyrosine kinase activities, which leads to uncontrolled myeloblast growth and the accumulation of granulocytes in the blood.

Answer 89

It provides a better understanding of the function of aberrant oncogenes, detailed information about the mutational landscape of cancers, enables improved cancer diagnostic tests, and can be linked to prognostic information. It is also necessary for designing new targeted cancer treatments.

Answer 90

type of treatment that therapeutically targets key oncogenes in a patient's cancer, such as BCR-ABL in chronic myeloid leukemia, EGFR in lung cancer, and ALK in lung cancer.

Answer 91

uncontrolled clonal proliferation of myeloid cells, leading to accumulation of granulocytes in the blood

Answer 92

e.g. P53 induce apoptosis or senescence accelerate ageing may be selected to prevent cancer before the reproductive age but then reduce affect there after gene that protects against cancer development inhibitory functions acting as a break on cell proliferation, repairing DNA or inducing apoptosis

Answer 93

characterised by loss of function mutations. Inactivation of TSG leads to tumour development by eliminating a negative regulatory protein. Mutations in TSGs are usually recessive so both alleles must be mutated to have an effect.

Answer 94

retinoblastoma gene (RB).

Answer 95

Retinoblastoma is cancer of the eye. Most cases of retinoblastoma are sporadic and affect only one eye (unilateral). Familial occurrence is seen in rare cases. Inherited retinoblastoma often affects both eyes (bilateral).

Answer 96

Cancer is caused by two mutational events. Non-hereditary retinoblastoma requires two hits to develop, while hereditary retinoblastoma is much more likely to develop disease and also to occur in both eyes over time. The two hits for retinoblastoma are the first hit (nonsense, frameshift, splice site, missense mutation) and the second hit (loss of heterozygosity through nondisjunction or mitotic recombination).

Answer 97

RB LOF mutations (1st/2nd hit) - confined to hotspots 1st hit = nonsense/frameshift/missense mutations loss of heterozygosity (LOH) or 2nd hit LOH = chromosome loss/non-disjunction/deletion/recombination LOH more likely then 2nd hit

Answer 98

Cancer only develops when the cell becomes homozygous for the mutant RB. The first hit is typically a nonsense, frameshift, splice site, or missense mutation. The second hit is loss of heterozygosity (LOH) which is the loss of the second allele through nondisjunction or mitotic recombination. These mechanisms are more likely than point mutations of the second allele.

Answer 99

RB1 controls the G1-S checkpoint in the cell cycle. Loss of RB1 would mean that TF E2F would be uncontrolled and the expression of S phase genes would increase, resulting in uncontrolled proliferation.

Answer 100

pathway controls developmental processes and tissue homeostasis involves the binding Wnt ligands to Frizzled (FZD) Rs leads to activation of beta-catenin (TF) frequently mutated in cancer negatively regulating canonical WNT signaling, APC counteracts proliferation, promotes differentiation, facilitates apoptosis and suppresses invasion and tumor progression. APC further antagonizes canonical WNT signaling by interacting with and counteracting β-catenin in the nucleus.

Answer 101

Wnt OFF - proteasome able to degrade beta-catenin and prevent cell cycle progression Wnt ON - proteasome binds to FZD preventing beta-catenin degradation and allowing gene transcription

Answer 102

leads to loss of destruction complex, stabilisation of beta-catenin, and expression of Wnt target genes linked to cell proliferation. Loss of APC tumour suppressor gene is common in cancer, for example, 70% of colorectal cancer.

Answer 103

The second category of tumour suppressor genes functions to preserve the integrity of the genome. Bi-allelic loss of function has no immediate impact, but in the long term, it increases the genomic mutation rate, accelerates the accumulation of mutations in oncogenes and other TSGs, dysregulates cell growth, and accelerates cancer progression. Examples of genes in this category include p53, ATM, and BRCA1.

Answer 104

DNA damage/loss of genomic integrity -> cell cycle arrest + DNA repair or apoptosis - elimination of damaged DNA -> both maintain genomic integrity frequently mutated in cancer, mostly missense mutations - associated with advanced disease stage, metastasis and poor survival - that affect the DNA binding function of p53 TF function dominant negative effect of p53 mutations - only 1/4 in the tetramer must be affected to cause impaired DNA binding

Answer 105

P53 mutations predominantly affect DNA binding function, occur at hotspots, and are mainly missense mutations. P53 tetramers with even just one defective subunit are likely to have impaired DNA binding activity, resulting in a dominant negative effect.

Answer 106

autosomal dominant disease caused by an inherited mutation of p53 increased lifetime risk of cancer - early onset susceptible to multiple tumours

Answer 107

Cellular senescence is the process in which primary cells have a finite replicative capacity, undergoing growth arrest after around 50 cell divisions.

Answer 108

progressive loss of telomeres [erosion] induces a DNA damage response and this triggers senescence potent tumour suppressor

Answer 109

Stress or Abberant Signalling Induced Senescence NOT dependent on telomere shortening increased expression of Cdk inhibitors at senescence e.g. p16/p21 these block cyclin/Cdk activities and cell cycle progression telomere shortening and oncogene activation induce cellular senescence

Answer 110

- cells stopped in G1 but can be stimulated to restart division (reversible) - it occurs halfway through G1 phase - less durable form of cell cycle arrest - stimulated by depreciation of extracellular growth factors, contact inhibition, anti-proliferative cytokines

Answer 111

- telomere shortening - oncogene- induced senescence : chronic activation of tumour supressors (RB,P53) - ROS and other DNA damaging agents

Answer 112

cells have limited proliferative potential in culture: growth arrest after approx. 50 cell divisions

Answer 113

replicating- replicative don't respond to growth signals normal fibroblast morphology senescent- post-replicative don't respond to growth signals flattened morphology metabolically active altered gene expression change in tissue homeostasis

Answer 114

inherited form - 1 germline mutation, 2nd somatic mutation non-hereditary - both mutations are somatic nomenclature = gene: RB1, protein (gene product): pRB inactivated in many somatic human cancers

Answer 115

1. transcriptional repression (G0, G1) 2. phosphorylation of pRB (early G1) - by Cdk4/6 + Cyc D causes unlinking of HDAC 3. phosphorylation of pRB (late G1) - by Cdk2 + Cyc E causes unlinking of E2F/DP allowing for transcription of S phase genes

Answer 116

pRB in normal cells - E2F/DP TFs regulated by pRB resulting in regulated S-phase entry mutated pRB - E2F/DP TFs constitutively active, bypass the restriction point causing uncontrolled entry into S-phase

Answer 117

pRB and p53 are tumor suppressor gene products that play a critical role in cellular senescence by negatively regulating cell growth and maintaining cell cycle checkpoints to ensure genomic integrity.

Answer 118

induces expression of genes related to DNA replication such as cyclin E and S phase Cdks. constitutively bound to DNA E2F bound to RB results in E2F inhibition. when Rb is phosphorylated it releases E2F.

Answer 119

nucleoproteins structures 10-15kb (humans) in size that protect the chromosome ends [TTAGGG]n

Answer 120

maintains the telomeres reverse transcriptase [hTERT] and RNA Template-TERC telomerase activity in normal cells is absent or low, it is induced in most cancers (>90% dependent upon the tissue)

Answer 121

prevents the critical shortening of the telomeres extended life-span induce telomerase (hTERT)

Answer 122

D loop T loop strand invasion of the G-strand overhang restricts the access of telomerase into the telomere

Answer 123

Shelterin protein complexes, such as TRF1/2, play a critical role in telomere regulation by binding to telomeric duplex DNA, protecting telomeres from DNA damage surveillance, and maintaining telomeric chromatin structure

Answer 124

loss of TSGs and maintenance of telomeres by telomerase or ALT leads to cellular immortalisation

Answer 125

1. strand invasion of the template molecule and the formation of the HR intermediate structure 2. copying 3. dissolution of the HR intermediate 4. possible filling in of the complementary strand

Answer 126

it is activated in most cancers, contributing to cellular immortalization. Inhibiting telomerase can prevent cancer cell growth and potentially induce cell death.

Answer 127

pRB and p53 function can be inactivated through loss of tumor suppressor gene function, leading to loss of growth suppressive properties and/or loss of cell cycle checkpoint control, which results in enhanced proliferative potential.

Answer 128

cyclins are expressed during the cell cycle and they interact with Cdks. Cdks are kinases always expressed and induce mitosis. when they bind to cyclins there is a conformational change and they become active. cyclins determine Cdks substrate specificity

Answer 129

p53 regulates the G1-S checkpoint control by inhibiting cyclin D-CDK4/6 and cyclin E-Cdk2, preventing the G1 to S-phase transition in response to cellular stress and DNA damage.

Answer 130

Cells that bypass M1 senescence continue to erode telomeres, leading to unprotected chromosomes, chromosome abnormalities, genetic instability, and accumulation of mutations. This occurs in cells with inactive p53 and RB, where there is no check on proliferation.

Answer 131

damage signalling pathways 1+ "too short" telomeres induces a DNA damage signalling pathway - put a permanent holt on cell cycle progression

Answer 132

p53 activates p21 which induces senescence p16 inhibits the Cdk4/6, Cyc D complex inhibiting the phosphorylation of pRB therefore causing senescence loss of p53 and pRB causes a bypass of cellular senescence -> telomere shortening/dysfunction -> genomic instability -> mutations in critical genes -> early tumourigenesis

Answer 133

2nd proliferative barrier telomeres continue to erode the telomeres become too short and can't protect the chromosomes which triggers apoptosis failure to protect the chromosomes leads to chromosome abnormalities - chromosome end to end fusions or changes in copy number in cells with inactive pRB and p53 there is no check on proliferation - genetic instability and accumulation of mutations

Answer 134

cause accelerated telomere loss mutation/deletion of components of the TRF2 complex result in accelerated telomere loss A-T/Werner syndrome/bloom syndrome characterised by defects in DNA response/repair pathways

Answer 135

1. oligonucleotides complementary to the TERC template - Imetelstat 2. telomerase targeted immunotherapy - hTERT vaccines 3. targeting telomerase expressing cells with a suicide gene/oncolytic viruses

Answer 136

P53 responds to stress and recruits protein complexes activates ATM kinase that activates p43 It can phosphorylate p53 directly or check 2 kinase which then phosphorylated p53, can also inhibit MDM2 which is a neg regulator of p53. p53 is then a transcription factor that inhibits cyclin D-CDK4

Answer 137

leads to uncontrolled entry into S-pased though cyclin D-CDK4/6 and cyclin E-Cdk2

Answer 138

Driver mutations are those that initiate or progress cancer, while passenger mutations occur as cancer progresses but are not necessary for its progression.

Answer 139

The use of vemurafenib in malignant melanoma, which inhibits the bRAF kinase to switch off melanoma.

Answer 140

The adenoma-carcinoma sequence is a series of mutations that initiate and progress bowel cancer. It postulates that colorectal cancer starts with a mutation in the APC gene, followed by other mutations that progress the cancer.

Answer 141

Different cancers tend to have different driver mutations, depending on the initial tissue type and the context in which the cancer arises

Answer 142

mutational changes may have different effects in different tissues. Methods of distinguishing include molecular (cell biology) and bioinformatics approaches.

Answer 143

Tissue organoids are primary cells from normal tissue maintained in culture by manipulating signaling pathways. They are useful as in vitro model systems for studying the effects of mutations on the tissue in question.

Answer 144

Mouse models, such as the APC-/- min mouse in colorectal cancer, help confirm the role of driver mutations by demonstrating the effects of specific gene knockouts on cancer development.

Answer 145

datasets contain high read depth exome or whole genome sequencing of tumor-normal pairs across multiple tumor types, allowing mutational patterns to emerge that help distinguish driver and passenger mutations.

Answer 146

- identifying genes mutated more frequently than the background mutation rate, - identifying genes with a functional impact, and identifying mutations that cluster together in regions of high impact.

Answer 147

necrosis - spontaneous cell death apoptosis - programmed cell death autophagy - recycling of cellular components

Answer 148

apoptosis, an active process that follows a specific pattern and is as important for life as mitosis.

Answer 149

Apoptosis is an active, programmed cell death process, necrosis is "accidental" cell death, and autophagy is the recycling of cellular components.

Answer 150

Important apoptosis genes in C. elegans include ced-3 and ced-4, which are required for cell death, and ced-9, which antagonizes ced-3 and ced-4.

Answer 151

1) DNA fragmentation, 2) cell shrinkage and chromatin condensation, 3) membrane blebbing and fragmentation, 4) formation of apoptotic bodies, and 5) phagocytosis.

Answer 152

Caspases are a family of cysteine proteases that are the executors of apoptosis. They are inactive in cells as proenzymes, and their activation involves cleavage of their N-terminal polypeptide sequence.

Answer 153

The three pathways of apoptosis are the extrinsic pathway, the granzyme pathway, and the intrinsic pathway. All three converge at the activation of Caspase-3 and execution of apoptosis.

Answer 154

The extrinsic pathway of apoptosis involves ligands binding to and activating their death receptors (FAS), activation of the adapter protein (e.g. FADD), and activation of executioner caspases and the proteolytic cascade.

Answer 155

DNA fragmentation by endonucleases/DNAses enzymes are able to access the sites between the nucleosomes protein degradation (nuclear and cytoskeletal) by protease enzymes

Answer 156

cytoplasm begins to shrink following the cleavage of lamins and actin filaments organelles become more tightly packed the chromatin condenses following the breakdown of chromatin and nuclear structural proteins nuclei take a "horse-shoe" appearance

Answer 157

apoptotic cells undergo plasma membrane changes e.g. the transfer of the phospholipid phosphatidylserine from the inner leaflet of the cell to the outer surface promotes phagocytosis by macrophages

Answer 158

separation of fragments into apoptotic bodies apoptotic bodies will contain organelles, cytoplasm and/or DNA fragments enclosed by an intact plasma membrane

Answer 159

apoptotic bodies allow for easy clearance by macrophages macrophages recognise the phosphatidylserine on the cell membrane of the apoptotic bodies once engulfed the apoptotic bodies are degraded within phagolysosomes there is no inflammatory response because the the apoptotic cell contents is not released into the tissue

Answer 160

DNA damage signalling causes activation of the transcription factor p53 p53 promotes apoptosis if DNA damage is not repaired p53 activates pro-apoptotic genes: PUMA/BAX (intrinsic pathway) and FAS (extrinsic pathway) many chemotherapy agents aim to cause DNA damage by inducing apoptosis by p53 activity active p53 promotes apoptosis by repressing Bcl-2 expression MDM2 prevents apoptosis by exporting p53 form the nucleus and thus blocking its activity

Answer 161

The intrinsic pathway is activated by intracellular stress stimuli, such as the absence of growth factors or radiation. - increase expression of BAX/PUMA (pro-apoptotic) - lead to formation of pores in mitochondrial memebrane to increase permeability - released of cytochrone C - lead to formation of apoptosomes - then activation of casp-9 and then activation of executioner caspases Bcl-2 anti-apoptotic so increased expression can lead to over survival of cells that carry damage

Answer 162

The granzyme pathway is activated by cytotoxic T cells, which release granules containing perforin and granzyme. Perforin creates pores in the target cell membrane, allowing granzyme (A or B) to enter the target cell and degrade proteins or activate caspases.

Answer 163

- increase expression IAPS - increase expression Bcl-2 - mutations on P53

Answer 164

Apoptosis is an energy-dependent process triggered by internal or external signals, affecting single cells and causing cell shrinkage without an inflammatory reaction. Necrosis is not energy-dependent, caused by ischemia, toxins, or radiation, affecting groups of cells, leading to cell swelling, content release, and a marked inflammatory reaction.

Answer 165

Autophagy is a process of recycling and degrading cellular components in times of stress or starvation, providing energy to the cell. It can be both pro-survival and pro-death, depending on the context, and is involved in survival during short-term starvation, clearance of aggregate-prone proteins, and programmed cell death.

Answer 166

Faulty apoptosis can lead to autoimmune disease, neurodegenerative disease, and cancer, with over-proliferation of cells or decreased removal of cells causing the accumulation of cancer-causing mutations in DNA. Faulty autophagy can contribute to neurodegenerative disease, liver disease, cancer, and skeletal and cardiac muscle degeneration, impacting cell survival, longevity, and resistance to chemotherapy.

Answer 167

mTORC1 connects the environmental conditions with metabolic processes - nutrient rich conditions mTORC1 phosphorylates ATG13 inhibiting autophagy and promotes cell growth through the synthesis of proteins/lipids/nucleotides - starvation conditions mTORC1 is inhibited and Atg proteins are activated to initiate autophagy Atg proteins work to assemble the phagophore cellular components are trapped within the phagophore to create the autophagosome a double membrane bound vesicle autophagosome fuses with a lysosome making the autolysosome lysosomal hydrolase enzymes degrade trapped cellular components and the inner membrane macromolecules are released free nutrient levels reach a threshold which activates mTORC1 to switch off autophagy

Answer 168

activating the transcription factor p53, which can promote apoptosis if DNA damage cannot be repaired. However, the absence of functioning p53 may result in failure or necrosis, leading to inflammation and unpleasant side effects.

Answer 169

the metabolism of cancer cells has to change due to the alterations in physiology compared to the tissue from which they derive - increased cell proliferation - mutations in signalling pathways - detoxification of anti-cancer therapies - survival in inhospitable environments

Answer 170

refers to high lactate production in the presence of oxygen, also known as aerobic glycolysis, which is observed in cancer cells.

Answer 171

produces an acidic microenvironment used for diagnosis FDG-PET imaging - [18F] 2-fluoro-deoxy-D-glucose (FDG) is taken up by cells using glucose transporters, phosphorylated and then trapped in the cell

Answer 172

1) Mitochondrial energy generation is irreversibly damaged, 2) Changes in enzyme expression due to different signaling, and 3) Changes in the requirements for macromolecule synthesis.

Answer 173

no TCA cycle mutations in TCA cycle enzymes - familial cancer syndromes - pheochromocytoma and paraganglioma defects in SDH - leiomyoma defects in FH

Answer 174

c-Myc, p53, HIF1, and PTEN.

Answer 175

use glycolysis as a source for many important molecules like nucleotides, lipids, and amino acids. In some cases, cancer cells cannot meet these needs entirely and send signals to the body to provide additional resources

Answer 176

The plasma levels are depleted, leading to the body going into a starvation-like mode, in which it catabolizes the amino acids that form the muscle mass.

Answer 177

5-FU disrupts nucleotide synthesis by blocking thymidylate synthase, which is part of the metabolic pathway to synthesize dTTP. It may also elicit a DNA damage response by being incorporated into DNA and RNA.

Answer 178

Tumors are often poorly vascularized or have dysfunctional vasculature, leading to low oxygen levels in large areas of tumors. hypoxic phenotype: - slower proliferation - inc. cell migration - inc. in survival factors - silencing areas of chromatin - changes in cellular metabolism - reduced differentiation profile

Answer 179

Pros: Starving the tumor of nutrients should help fight the cancer. Easy access to endothelial cells Cons:Chemotherapeutic drugs may not be able to reach the core of the tumor, which can stabilize the tumor and help its progression.. bleeding, clots cant reduce tumour just slow growth

Answer 180

Hypoxia slows down cell division, increases cell migration, increases survival factors, silences chromatin areas, induces changes in cellular metabolism, and reduces differentiation profile.

Answer 181

Targeting enzymes involved in tumor acidification, such as carbonic anhydrase, Cariporide, or monocarboxylate transporters, can have severe side effects and impact other tissues, like the kidneys.

Answer 182

The difference between killing the tumor and killing the person is difficult to achieve when targeting glycolysis, as it is a metabolic pathway used by every cell in the body.

Answer 183

Glutamine, asparagine, and arginine.

Answer 184

injection with arginine deiminase, which degrades plasma arginine, reduced tumor growth by 50% in mouse models.

Answer 185

IDH1 (located in the cytosol), IDH2 (located in the mitochondria, not involved in TCA cycle), and IDH3 (involved in TCA cycle, never mutated in cancer).

Answer 186

IDH1 mutations lead to changes in epigenetic mechanisms, redox alterations, and activation of HIF1, which promotes cell survival.

Answer 187

IDH1 mutations are present in 75% of secondary gliomas, 13% of acute myeloid leukemia (AML), and more than 50% of chondrosarcomas. IDH1 mutations are also sporadically found in other tumors such as melanoma and pancreatic adenocarcinoma.

Answer 188

Mitomycin C, Cisplatin, Psoralens.

Answer 189

FA is a rare genetic disorder characterized by microcephaly, mental retardation, developmental delay, aplastic anaemia, predisposition to tumor development, and bone marrow failure. It is also associated with cellular/chromosome hypersensitivity to DNA inter-strand cross-linking agents.

Answer 190

FA is an autosomal recessive disease with genetically heterogeneous causes. 22 different genes (FANCA-FANCW) have been identified as the underlying cause of FA. 85% of cases involve mutations in FANCA, FANCC, or FANCG, while about 10% of cases involve mutations in FANCD1, FANCD2, FANCE, FANCF, and FANCL. The remaining 5% are caused by mutations in the other 8 genes.

Answer 191

phenotype - microcephaly - mental retardation - developmental delay - asplastic anaemia - predisposition to tumour development - bone marrow failure cellular/chromosomal hypersensitivity to DNA cross-linking agents = diagnostic test for FA - formation of chromosomal gaps/breaks, tri-/quadra-radial chromosomes, complex chromosomal rearrangement

Answer 192

many FA patients develop Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukaemia (AML) older FA patients are at higher risk of developing head/neck, gynaecological and or GI tumours carriers of the FANCD1/FANCN/FANCS mutations have a higher predisposition to the development of breast/ovarian cancer biallelic mutations in FNACD1 predispose for development of AML/T-ALL/Wilms' tumour/medulloblastoma/GBM

Answer 193

1) Crosslink recognition during S phase, recruitment of FA core complex. 2) Replication fork convergence at ICL, activation of FANC1 and FANCD2 through ubiquitination. 3) Recruitment of other proteins like nucleases, deubiquitination of FANC1 and FANCD2. 4) Rotation of crosslink out of helix and gap synthesis. 5) Repair of the other strand through homologous recombination involving BRCA1 and BRCA2.

Answer 194

Loss of ICL repair leads to under-replicated DNA, which separates during mitosis and forms micronuclei. This results in loss of genetic information and mitotic catastrophe.

Answer 195

Under replicated DNA and anaphase bridge formation contribute to chromosomal breakage at common fragile sites (CFS). DNA breaks caused by ICLs in FA cells are mis-repaired by NHEJ, leading to mitotic catastrophe.

Answer 196

likely caused by naturally occurring acetaldehyde (alcohol metabolism) or formaldehyde (histone demethylation, amino acid synthesis, tobacco smoke), which can induce DNA interstrand and protein-DNA crosslinks.

Answer 197

Acetaldehyde, a by-product of alcohol metabolism and intermediate of carbohydrate metabolism, and formaldehyde, an intermediate from histone demethylation and dealkylation of methylated DNA.

Answer 198

Reactive intermediates can induce DNA interstrand and protein-DNA crosslinks.

Answer 199

Endogenously-induced ICLs play a critical role in the development of FA. Without functional FA proteins, endogenously-induced ICLs cannot be repaired efficiently, leading to accumulation of DNA damage and ultimately to cell death. This is particularly problematic in rapidly dividing cells, such as those in the bone marrow, where the failure to repair ICLs leads to bone marrow failure and anemia. Moreover, the accumulation of DNA damage also increases the risk of cancer development.

Answer 200

The resulting mice had increased embryonic lethality, severe developmental defects, and severe cell attrition in the bone marrow and bone marrow failure when exposed to alcohol during pregnancy.

Answer 201

The Fanconi Anaemia pathway functions to maintain genomic integrity by promoting the repair of DNA inter-strand cross-links or DNA-protein cross-links.

Answer 202

a highly regulated process 1. formation of the pre-metastatic niche by primary tumour cells 2. primary cells escape from the pirmary tumour due to alterations in cell-cell adhesion/ECM reoranistion 3. enter the vasculature through the process of internalisation 4. travel along a gradient of chemokines to the target organ 6. interaction with the endothelial cells at the target organ through selectins/integrins 6. leave the vasculature via activation of integrins and MMP production 7. enter the new tumour environment where they either stay dormant or start proliferating

Answer 203

Smoking and drinking alcohol during pregnancy can cause developmental abnormalities in the fetus, most likely due to failed repair of ICLs and DPCs.

Answer 204

The premetastatic niche is formed when tumor cells at the primary tissue secrete soluble factors and extracellular components, modifying the target organs and changing the behaviors of cells. This recruits bone marrow-derived mesenchymal cells, which further modify the target organ by producing specific chemokines and attracting chemo cells.

Answer 205

facilitating active communication between tumor cells and surrounding cells, such as fibroblasts and adipocytes. This communication leads to the formation of cancer-associated cells.

Answer 206

Macrophages are actively recruited to epithelial cancer sites due to the production of CSF. They modify the behavior of tumor cells by producing EGF, making tumor cells more proliferative and invasive, which facilitates the metastatic cascade.

Answer 207

tumor cells invade the vasculature and some return to the primary tumor, where they act as changed entities and modify primary tumor cells.

Answer 208

Metastasis requires altered mechanisms of cell adhesion, proteolysis, migration, lymph-/angiogenesis, and homing to target organs

Answer 209

The transition to the invasive phenotype requires modification of cell-cell adhesion, such as the loss of intracellular adhesion, re-organization of the extracellular matrix, and modulation of cell-ECM adhesion

Answer 210

E-cadherin loss is seen in most invasive lobular carcinomas and around 50% of ductal carcinomas. Reduced E-cadherin expression is associated with shortened disease-free survival.

Answer 211

In malignant cells, cellular adhesion changes as cells lose cell-cell adhesion, leading to scattering and a more spindle-shaped morphology.

Answer 212

meshwork of macromolecules 2 main classes 1. polysaccaride chains: glycosoaminoglycans 2. fibrous proteins: collagens/laminis/fibronectin/elastin

Answer 213

focal adhesions - acitn hemidesmosomes - keratin

Answer 214

calcium dependent - E-cadherin - beta/alpha-catenin links to actin calcium independent - nectin - afadin links to acitn

Answer 215

cytoskeleton (actin/keratin filaments) linker proteins (catenins/desmoplakin) adhesion receptors

Answer 216

intergrins - 24 heterodimers 18alpha/8beta subunits - inside-out/outside-in signalling - binding to talin = essential for integrin activation surface proteoglycans DDR proteins

Answer 217

The interactions of tumor cells with the extracellular matrix are controlled by integrins, surface proteoglycans, and DDR proteins.

Answer 218

1. basement membrane - a complex of interacting proteins separating epithelial and endothelial cells from connective tissues 2. stromal environment (connective tissue matrix) - collagen fibrils and extracellular proteoglycans

Answer 219

parenchyma - tissues that confer function - can be either epithelial or connective tissue stroma - everything else - no organ can function without the mechanical and nutrient support of the stroma in tumours - parenchyma = malignant cells - stroma = non-malignant supporting cells, it is essential for tumour growth

Answer 220

The mechanism of homing in metastasis involves selective growth, selective adhesion to sites on endothelial cells at the site of organ homing, and selective chemotaxis of circulating tumor cells to the organ producing soluble attraction factors.

Answer 221

Parenchyma comprises the tissues that confer function, while stroma is everything else and consists of non-malignant supporting cells.

Answer 222

Kidney: epithelial tissue; spleen: connective tissue; heart: muscle tissue (cardiac muscle cells); brain: nervous tissue (nerve cell, glia).

Answer 223

Stroma provides mechanical and nutrient support for parenchyma, which is composed of malignant cells in the context of tumors.

Answer 224

Proposes that metastasis is the result of favorable interactions between tumor cells ('seed') and the organ microenvironment ('soil').

Answer 225

1. Hemostasis 2.Humoral inflammation (vascular permeabilization) 3.Cellular inflammation (immune cell infiltration) 4.Angiogenesis (formation of new blood vessels) 5.Generation of mature connective stroma

Answer 226

Hypoxia (low O2), acidosis, high interstitial fluid pressure (IFP), and extracellular matrix (ECM) remodeling.

Answer 227

Hypoxia (low O2), acidosis, high interstitial fluid pressure (IFP), and extracellular matrix (ECM) remodeling.

Answer 228

Increased - expanding tumour mass - abnormal ECM - fibroblasts contracting in matric - lack lymphatic vessels - leaky blood vessels - increase IFP poor prognosis - prevents fluid transport and drug delivery

Answer 229

1. cancer stem cells 2. endothelial cells can have tumour associated vasculature and lymphatic vessels present on peripheries of tumours 3. pericytes are specialised mesenchymal cell type, stability for vascular integrity and function 4. immune inflammatory cells e.g macrophages , lymphocytes, neutrophils, releases signal moleucles and can be pro and anti tumour 5. cancer associated fibroblasts such as myofibroblast usually present on site of chronic inflammtion and wound healing. in tumours: proliferation, angiogenesis and invasion

Answer 230

CAFs are an important constituent of the stroma that can directly and indirectly promote cancer progression and metastasis through angiogenesis and attracting pro-inflammatory cells. recruited by PDGF secrete growth factors (VEGF,TGF-b) exm protines and proteases

Answer 231

monocytes can differentiate into 2 types of macrophages depending on growth factor stimulation: M1: classical activation phagocytotic cells M2: alternative activation tissue remodelling during wound healing tumouirs secrete Il-4 that activated macrophaes and lead to production of matrix degrading enzymes.

Answer 232

Proteases such as matrix metalloproteinases (MMPs) break down the ECM, allowing remodeling, which in turn enables tumor growth and cell dissemination.

Answer 233

complex mix of cells that changes as the tumour develops invades and metastasises to new sites cancer associated fibroblasts (CAFs) = important constituent of the stroma - directly produce factors that promote angiogenesis - indirectly attract pro-inflammatory cells such as macrophages which stimulate cancer invasion

Answer 234

1. tumour vasculature VEGF and VEGR antagonists such as bevacuzumab RTK inhibitors such as brivinab EGFR neutralising ab 2. cancer associaetd inflammation: inhibiting TAM, target chemokines that lead to M2 recruitment

Answer 235

complex mix of cells that changes as the tumour develops invades and metastasises to new sites cancer associated fibroblasts (CAFs) = important constituent of the stroma - directly produce factors that promote angiogenesis - indirectly attract pro-inflammatory cells such as macrophages which stimulate cancer invasion

Answer 236

infiltrated-excluded, infiltrated-inflamed, and infiltrated-Tertiary Lymphoid Structures (TLS).

Answer 237

The two main categories of immune cells are innate immune cells and adaptive immune cells.

Answer 238

derived from circulating monocyte cells that enter tissues and develop into macrophages macrophages are versatile and plastic - they modify their phenotype to suit their surrounding environment divided into 2 subgroups M1 and M2 tumour associated macrophages (TAMs) are M2 likeomote angiogenesis, suppress other immune cells, and release factors that promote metastasis.

Answer 239

M1 induces by LPS and IFN gamma - pro-inflammatory/bactericidal - promote CD4 T cell differentiation into Th1/17 cells that support cellular immunity M2 induced by IL4/10/13 - are immunosuppressive - promote CD4 T cells to become Th2 and T-regs - unhelpful TAMs - poor prognosis in most studies - promote angiogenesis - infiltrate at an early stage - trigger the angiogenic switch - suppress other immune cell function - release factors that promote metastasis

Answer 240

MDSCs are induced by inflammation (IL1beta, IL6, and PGE2). They interfere with innate and adaptive immunity by inhibiting NK and DC function, inducing T reg cells, producing arginase, and causing depletion of arginine in the tumor.

Answer 241

tumour cells frequently downregulate MHC expression - should make them a target for NK cells intratumoural NK cells are often anergic - unable to release cytokines/kill targets suppression of NK function caused by TGF-beta released from tumour cells

Answer 242

Low arginine levels lead to decreased T-cell receptor signaling in T-cells by decreasing CD3zeta chain expression.

Answer 243

cytotoxic effector cells cytotoxic granules containing perforin and granzymes that trigger apoptosis in target cells produce cytokines INF-gamma and TNF-alpha

Answer 244

Th1, Th2, Th17, T-reg, T-fh, and Th9.

Answer 245

CD4 Th1 cells support cytotoxic CD8 T cells, activate macrophages, and can kill tumor cells in some cases.

Answer 246

increased numbers of T-reg cells correlate with poorer prognosis, although some studies in other cancers suggest increased numbers are beneficial.

Answer 247

T-reg cells suppress other immune cells by producing TGF-B and IL10, expressing high levels of CD25 (IL2 receptor) to starve effector T-cells of IL2, and producing adenosine.

Answer 248

Angiogenesis is the formation of blood vessels from pre-existing vessels. It plays a crucial role in physiological processes like wound healing, the menstrual cycle, and adaptation to increased muscle activity. In pathological processes, angiogenesis contributes to cancer, inflammatory diseases, and diabetic retinopathy.

Answer 249

Angiogenesis supports tumor growth by providing nutrients and oxygen, and it facilitates metastasis by providing a route for cancer cells to spread to other parts of the body. Hypoxia in growing tumors drives VEGF production, which promotes angiogenesis and creates a pro-angiogenic environment.

Answer 250

vasculogenesis: the formation of blood vessels from mesodermal derived angioblasts endothelial progenitors (angioblasts) differentiate from mesodermal cells angioblasts coalesce to form first embryonic vessels - dorsal aorta and cardinal vein angioblasts form blood islands which fuse together and remodel to form a primitive capillary plexus angiogenesis : angiogenic remodelling of the dorsal aorta, cardinal vein and vascular plexi give rise to the arteries, veins and capillaries angiogenic sprouting of new vessels pericytes are recruited to stabilise capillaries lymphatic endothelial cells sprout from veins and from the lymphatic system via lymphangiogenesis

Answer 251

Modes of angiogenesis in cancer include sprouting, intussusception, vasculogenesis, vessel co-option, vascular mimicry, and endothelial differentiation. Sprouting angiogenesis involves loosening of endothelial junctions, remodeling of the basement membrane, tip cell selection and sprout extension, lumen formation, and sprout fusion.

Answer 252

a transcription factor and master regulator of angiogenesis HIF-1 is made of 2 subunits HIF-1a and HIF-1b HIF-1a is degradation is regulated in response to O2 levels

Answer 253

high levels of O2 a proline hydroxylase enzyme hydroxylates proline residues on HIF-1a a ubiquitin ligase recognises this and binds which catalyses the poly-ubiquitination of HIF-1a poly-ubiquitinated HIF-1a is degraded by the proteosome

Answer 254

low O2 levels there is not enough O2 to drive the proline hydroxylation of HIF-1a HIF-1a is free to bind to HIF-1b and induce transcription of genes required for the adaption to hypoxic conditions key target = VEGF

Answer 255

VEGF is most potent stimulator of angiogenesis, secreted by many tumours in response to hypoxia and oncogene signalling. HIF-a is a TF. In normal conditions, its regulated by hydroxylation of proline residue. when hydroxylated, it can bind to pVHL. This stimulates Ubiquitination and degredation of HIF-a. Under hypoxia, pVHL becomes S-nitrosylated and cant bind to HIF-a. THen HIF-a is free to interact with HIF-b in the nucleus, leading to epxression of hypoxia related genes (VEGF)

Answer 256

endothelial specific factor VEGF-A = most potent angiogenic driver VEGFR signals via activation of VEGFR-2 a receptor tyrosine kinase dimerisation of VEGFR-2 activates signalling pathways which affect: proliferation/migration/survival/vascular permeability - via modulation of junctional proteins

Answer 257

prevent VEGF receptor binding so no downstream singalling. e.g Avastin (Bevacizumab) monoclonal ab against VEGF, used w chemo against metastatic crc, renal and nsclc. stops abberant angiogenesis, normalises tumour vasculature, promotes therapeutic delivery of chemotherapeutics- but can increase blood flow to tumour

Answer 258

Angiostatin primary tumours produce angiogenic factors that prevent secondary tumours from being vascularised, small tumours dont produce big

Answer 259

VEGF-A, the most potent VEGF family growth factor for driving angiogenesis, signals through VEGFR-2, a receptor tyrosine kinase. This activation leads to endothelial cell proliferation, survival, migration, and increased vascular permeability, which promotes tumor vessel formation.

Answer 260

number of pro- and anti-angiogenic factors angiogenesis occurs when the effects of the angiogenic activators are greater than those of the inhibitors- leads to new vessels

Answer 261

angiogenesis vasculogenesis intersusception vessel co-option vascular mimicry endothelial differentiation

Answer 262

involves the formation of a pillar which elongates splitting the vessel in 2 - rapid inc. in capillarity - requires minimal endothelial proliferation

Answer 263

formation of a lumen in the newly developing sprout newly formed stalk attracts pericytes to stabilise the newly formed vessel signalling btw tip and stalk cells maintain their different specification, expression of Delta-like 4 (DDL4) by tip cell signals to notch expressed by stalk cells tip cells navigate in response to guidance signals and adhere to the ECM (mediated by integrins) to migrate stalk cells behind the tip cell proliferate and extend the sprout VEGFR-2 is downregulated in stalk cells the sprouts from adjacent vessels grow towards each other

Answer 264

signalling btw endothelial cells and pericytes maintain quiescence of the newly formed vessel, angiopoeitin 1 (Ang 1) formation of tight junctions and barrier function basement membrane deposition pericyte maturation (PDGF, Ang1)

Answer 265

inhibiting the production of angiogenic factors, using neutralizing antibodies, soluble receptors, or receptor tyrosine kinase inhibitors. Bevacizumab (Avastin) is a monoclonal antibody that targets VEGF, and other drugs like sorafenib, sunitinib, and pazopanib also target VEGF signaling.

Answer 266

Tumor vessels are abnormal, leaky (increase interstitial pressure), and poorly perfused (increased VEGF), leading to persistent hypoxia.

Answer 267

Vasculogenesis is the formation of blood vessels from mesodermal-derived angioblasts. Endothelial progenitors (angioblasts) differentiate from mesodermal cells, coalesce to form the first embryonic vessels, and create blood islands that fuse and remodel to form a primitive capillary plexus.

Answer 268

HIF-1α degradation helps maintain oxygen homeostasis by responding to oxygen levels. In high oxygen conditions, HIF-1α is hydroxylated, poly-ubiquitinated, and degraded by the proteasome. In low oxygen conditions, HIF-1α stabilization promotes the expression of genes required for adaptation to hypoxic conditions, such as VEGF.

Answer 269

Breast cancer is the most common cancer among women, but lung cancer has a higher mortality rate.

Answer 270

People die from breast cancer due to metastatic spread to other organs such as liver, bones, and brain epithelial proliferation -> lobular/ductal -> high/low grade

Answer 271

1. Histological 2. In-situ carcinoma (still within the breast, e.g., 3. DCIS and lobular with no metastasis) 3. Ductal 4. Invasive carcinomas

Answer 272

Non-modifiable: age (peak 50-70), previous breast disease (benign), family history and BRCA, hormone-related factors. Modifiable: high socio-economic group (obesity, alcohol, high-fat diet, fewer pregnancies, and less likely to breastfeed), male gender (only 1% of cases).

Answer 273

Early menarche before 12, late menopause, no child or first child after 30, breastfeeding reduces risk, and increased BMI post-menopause.

Answer 274

Oestrogen receptor positivity is tested in biopsies/surgically removed primary tumors and sites of metastasis spread by immunohistochemistry. A tumor is deemed positive if at least 1% of cells express ER.

Answer 275

ER and PgR positive, HER2 negative low proliferation (Ki67 low) recurrence risk low few copy number changes few mutated genes (>5%) responsive to endocrine therapy less to chemotherapy

Answer 276

ER positive either HER2 positive OR high Ki-67 and PR-ve often aneuploid muttions in cyclin D1/EGFR1/PIK3CA/PTEN/TP53 responsive to endocrine therapy (less than luminal A) more sensitive to chemotherapy

Answer 277

BRCA1/2 mutations - high penetrance (high risk of developing cancer) - role in DNA repair - autosomal dominant other genes low penetrance - TP53 - switches on DNA repair pathways - ATM - recognised DNA damage - CHEK2: checkpoint kinase 2 (cell cycle control) - PALB2 -recruits RAD51 and BRCA2 to damage - rad51 - binds at site of DNA damage

Answer 278

Tamoxifen works by competitively binding to the oestrogen receptor, stopping the oestrogen receptor from dimerizing and recruiting coactivators. This alters TAF1 and TAF2 regions' activity, keeping cells in the G1 phase of the cell cycle, preventing proliferation.

Answer 279

Menopausal symptoms (hot flushes), fatigue, painful joints, nausea, rare occurrences of deep vein thrombosis, and endometrial cancer.

Answer 280

Luminal B is ER positive, either HER2 positive or has high Ki-67 and PR-negative, often aneuploid, less responsive to endocrine therapy than Luminal A, more sensitive to endocrine therapy, HER2 negative and is low grade with good prognosis

Answer 281

used to determine the most appropriate treatment for early-stage ER+ breast cancer patients. It tests a panel of 21 genes, and the results help decide whether to give chemotherapy or hormone therapy based on the number of mutations present.

Answer 282

HER2 overexpressing: ER and PR absent, responsive to Herceptin. Basal-like: generally triple-negative, high metastasi

Answer 283

Screening is the investigation of asymptomatic people to classify them as likely or unlikely to have a disease. People who appear likely to have the disease are investigated further and treated if necessary

Answer 284

Important public health problem, accepted treatment, available facilities, recognized presymptomatic or latent phase, suitable test or examination, test acceptability, understood natural history, agreed policy on treatment, economically balanced cost, and continuous case-funding.

Answer 285

Relatively common, severe consequences, detectable presymptomatic phase, early treatment advantage, and evidence of net benefit.

Answer 286

Lead time bias occurs when screening detects a disease in its presymptomatic phase, making the period between detection and death longer, but not necessarily increasing survival time.

Answer 287

diseases that may be identified via screening are more likely to be indolent and less aggressive conditions more aggressive disease is less likely to be detected by screening because it is likely to develop fully btw successive routine screening points survival following screen detected disease may be lengthened by the relatively less aggressive nature of the disease process length bias may be identified comparing the aggressiveness of disease detected clinically btw screens with that detected by screening

Answer 288

Sensitivity: proportion with condition who test positive. Specificity: proportion without condition who test negative. Positive predictive value: proportion with positive test who have the condition. Negative predictive value: proportion with negative test who do not have the condition.

Answer 289

1) Digital Rectal Examination (DRE) Transrectal Ultrasound (TRUS) Prostate Specific Antigen (PSA)

Answer 290

SCID is a genetic disorder that weakens the immune system, making patients highly susceptible to severe recurrent infections. Treatment involves a hematopoietic stem cell transplant.

Answer 291

The first lines of defense include skin, saliva, stomach acid, mucous, tears, sweat, and the lymphatic system.

Answer 292

types of blood immune cells that are made in the bone marrow. B cells develop in the bone marrow and make antibodies, while T cells travel to the thymus and develop before circulating in the body.

Answer 293

B cells recognize antigens through a B cell receptor made up of a heavy and a light chain with a Fab antigen-binding site. When a B cell recognizes an antigen and binds, it matures into a plasma cell that releases antibodies. T cells recognize peptides on antigen-presenting cells through a T cell receptor where heavy and light chains are anchored into the cell.

Answer 294

The MHC1 pathway involves the presentation of antigens expressed inside cells, which are degraded through proteosome into small peptide fragments that are translocated to the endoplasmic reticulum and bound onto MHC1, then translocated to the surface of the cell for presentation to CD8+ T cells. The MHC2 pathway involves the presentation of peptides from extracellular proteins that are taken up into the endosome pathway, where they are degraded by proteases into small peptide fragments that are bound to MHC2 and translocated onto the surface for CD4+ T cell recognition.

Answer 295

The MHC1 pathway involves the presentation of antigens expressed inside cells, which are degraded through proteosome into small peptide fragments that are translocated to the endoplasmic reticulum and bound onto MHC1, then translocated to the surface of the cell for presentation to CD8+ T cells. The MHC2 pathway involves the presentation of peptides from extracellular proteins that are taken up into the endosome pathway, where they are degraded by proteases into small peptide fragments that are bound to MHC2 and translocated onto the surface for CD4+ T cell recognition.

Answer 296

There are about 10^18 possible combinations of T cell receptors, which gives the immune system the ability to recognize almost anything throughout life. Thymic tolerance is a process by which T cells that recognize self are deleted during development, which reduces the number of possible combinations to about 10^14.

Answer 297

Cancer cells look similar to normal cells in terms of immunorecognition, and T cells that recognize self are deleted during development. However, the immune system can recognize viral proteins associated with cancer, overexpressed self proteins, lineage-specific antigens, and mutated self proteins such as CDK4. Cancer cells also have mechanisms to avoid immune recognition, such as downregulation of MHC, loss of components of the antigen processing pathway, and exploiting T cell checkpoints.

Answer 298

Immunological cancer interventions include the HPV vaccine to prevent cervical cancer, checkpoint blockade to reawaken T cells by interfering with cancer ligand PDL-1 binding, and CAR T cells, which are genetically engineered T cells that can recognize cancer.

Answer 299

The three types of chemotherapy are chemotherapy for advanced disease, adjuvant chemotherapy for systemic treatment following local radiotherapy or surgery, and primary or neo-adjuvant chemotherapy for initially treating locally advanced cancer to make it more amenable to subsequent surgery and control micro metastases.

Answer 300

Chemotherapy impacts the cell cycle, and there are cell cycle-specific drugs and cell cycle non-specific drugs. Cell cycle-specific drugs act on cells in specific phases of the cell cycle and are more effective against tumors with a higher percentage of replicating cells, while cell cycle non-specific drugs act on both resting and cycling cells and are useful against tumors with low or high percentages of replicating cells. The log-kill kinetics model states that theoretically, if enough chemotherapy cycles are given, a patient can be cured.

Answer 301

alkylating agents platinum agents antimetabolites topoisomerase inhibitors antimicrotubular agents other agents molecular targeted agents

Answer 302

covalently transfer alkyl groups to DNA bases 1. base alkylation - monofunctional DNA adducts, subsequent processing/repair of these lesions leads to SSBs in the DNA/mispairing of nucleotides 2. 2 bases are linked together by an alkylating agent forming cross-bridges cross-linking prevents DNA from being separated for DNA synthesis/transcription limited cell cycle specificity - binds directly to DNA

Answer 303

discovered electric current delivered to bacterial culture via platinum electrodes led to inhibition of bacterial growth active compound found to be cisplatin bind covalently to purine DNA bases (N7 position) bifuncitonal intra-strand crosslinks prevents DNA double strand from separating not S phase specific nephrotoxicity nad resistance

Answer 304

acts at a level of DNA synthesis interfere with incorporation of nucleic acid bases class 1 purine/pyrimidine analogues - inhibits formation of normal nucleotides - often inhibit enzymes essential for DNA and RNA synthesis class 2 prevent formation of reduced folate - essential for transfer of methyl groups in DNA synthesis usually S phase specific acts on cancer and normal cells that are dividing rapidly - can cause significant bone marrow and GI toxicity no late carcinogenesis

Answer 305

DNA topoisomerases - ubiquitous nuclear enzymes relax supercoiled dsDNA to allow DNA replication and RN transcription topoisomerase I = ss nicks - bind to and stabilise DNA topoisomerase I adducts - inhibits re-ligation of DNA strands - SSB in DNA - e.g. camptothecin/irinotecan/topotecan topoisomerase II = ds nicks - forms a complex with topoisomerase II after cleavage of DNA - inhibits re-ligation of DNA strands - SSB/DSB in DNA - e.g. etoposide/anthracyclines swivelling of supercoiled DNA occurs at nicks followed by re-ligation to relieve torsional strain

Answer 306

prevent spindle formation - essential for sorting and moving of chromosomes following replication at end of mitosis vinca alkaloids - vincristine/vinblastine/vinorelbine - binds to tubulin, preventing polymerisation of microtubules - inhibits progression through the cell cycle taxanes (paclitaxel/docetaxel) binds to tubulin (different site to vinca alkaloids) - prevents microtubular disassembly - disrupts normal microtubule dynamics that is required for cell division

Answer 307

myelosuppression mucositis diarrhoes alopecia germinal epithelium skin

Answer 308

nausea, vomiting neuropathy cardiac renal pulmonary allergy

Answer 309

The criteria for assessing response to chemotherapy are RECIST for stable response, which is defined as <30% decrease or <20% increase in the sum of defined measurable disease (unidimensional), and disease progression, which is defined as >20% increase in the sum of all measurable lesions or new lesions. Complete response is a prerequisite for cure and improved survival, while partial response has palliative value only, offset by drug toxicity effects and a more modest impact on survival. Stable response has any impact on survival limited to continuous, and the quality of response is defined by performance status and quality of life measurements.

Answer 310

provide maximum cell kill within the range of toxicity that can be tolerated for each drug, provide a broader range of coverage of resistant cells in a heterogeneous tumor population, and prevent or slow the development of drug-resistant cells. Targets are selected for the development of novel cancer drugs based on mutant oncogene products found in tumors and not normal tissue, tumor-induced alterations of the microenvironment needed for cancer progression, and genetics.

Answer 311

complete response (CR) - prerequisite (but not sufficient) for cure - implications for improved survival partial response (PR) - palliative value only, offset by drug toxicity effects - more modest impact on survival stable response - any impact on survival limited to continous (non-toxic) therapy quality of response may be defined by - performance status - quality of life measurements - relapse - free survival, from time all treatment discontinued

Answer 312

mutant oncogene products commonly found in tumours but not in normal tissues tumour induced alterations of the micro environment necessary for cancer progression e.g. angiogenesis must have a causal role in cancer development genetics and biology must be well established suitable for in vitro based assays suitable for pharmacological intervention

Answer 313

targeted drugs - target abnormalities typical of cancer cells - act selectively agains cancer cells - limited toxicity - often orally available - chronic treatment may control cancer for a long time chemotherapy - targets common ell growth mechanisms - equally affects normal and cancer cells - often very toxic - usually given IV - given only for a limited number of cycles (6-10)

Answer 314

Conventional 'small molecule' drugs Biopharmaceuticals Gene therapy Cell therapies

Answer 315

drug discovery.

Answer 316

The Lipinski rule of 5 evaluates whether a compound is likely to be orally active. A good drug candidate will have: Oral availability > 50% Activity such that dose ideally < 100mg per day T1/2 clearance in blood > 3hrs Good therapeutic index (high selectivity for target, minimal off target effects)

Answer 317

Exaggerated effect of drugs Side effects Toxic effects unrelated to drug pharmacology Idiosyncratic

Answer 318

Drug repurposing is using existing drugs for a new purpose, such as thalidomide for leprosy and myeloma and Viagra for high blood pressure and now for erectile dysfunction.

Answer 319

A screening program that uses a suitable assay to screen a large chemical compound library to find those with activity against the target.

Answer 320

Proteins overexpressed in tumors, tissue-specific proteins such as PSA, oncofetal antigens, and carbohydrate antigens are traditional tumor markers found in body fluids.

Answer 321

sensitivity = & of disease cancers correctly predicted specificity = % of non-cancers (controls) correctly predicted receiver operator characteristic (ROC) curve shows how sensitivity and specificity vary with the threshold used to define a positive test result

Answer 322

positive predicted value (PPV) = % positive tests correct negative predicted value (NPV) = % negative tests correct.

Answer 323

sensitivity and specificity disease prevalence (NPV/PPV) consequences of a false negative test consequences of a false positive test benefit to the patient - ability to detect cancer at an early stage/less invasively cost benefit (testing costs versus costs of more expensive investigations) circulating protein biomarkers are typically useful for monitoring disease but not screening, definitive diagnosis or treatment selection

Answer 324

Targeted measurements such as ELISA and immunohistochemistry are used to validate biomarkers. Appropriate clinical specimens are required for validation. Prospective randomized clinical trials, thorough clinical validation, thousands of patients, properly certified assays, patients investigated long term, and definitive benefits to the NHS are also needed to validate biomarkers.

Answer 325

ELISA (quanititative) lateral flow device (point of care, fast but often qualitative)

Answer 326

by OMIC tools/targeted measurements found in tissue/bio-fluid in only a few samples

Answer 327

A liquid biopsy is a non-invasive method of detecting cancer that involves analyzing blood plasma for signals from tumors. Circulating tumor cells and DNA are present in blood plasma, and their levels can be used to monitor tumor evolution and treatment response. Circulating tumor-free DNA can also be used to detect tumor-specific information such as mutations.

Answer 328

challenges - fragmented DNA - low quality DNA - low percentage of cell free DNA is actually ctDNA - careful sample collection and processing to minimise genomic DNA solutions - next generation sequencing (NGS) of thousands of tumours identified lots of potential ctDNA biomarkers technological advances = detection of cancer specific biomarkers in ctDNA possible

Answer 329

tumours shed cells into circulation (CTCs) very low numbers enriched using antibodies to cell surface proteins (EPCAM) or physical properties cells stained and counted (cytokeratin +ve, CD45 -ve) high numbers are indicative of poor outcome and need for more aggressive treatemtn falling numbers indicate therapy is working are prognostic in G3T1 bladder cancer - likely recurrence if present before surgery CTCs could be analysed for protein and RNA biomarkers plus the full-range of genomic changes and epigenetic changes - inform of tumour biology and treatment - select therapies based of the sensitivity of CTCs to drugs in vitro a very low no. of CTCs currently excludes a role in early diagnosis

Answer 330

Predictive biomarkers are used to decide which treatments are suitable for which cancer patients, while prognostic biomarkers indicate the likely course of the disease in untreated individuals. Prognostic markers can be DNA, RNA, or protein-based, and they are used to determine how aggressive the cancer is and how aggressive the treatment should be to avoid under/over treatment. Oncotype DX is an example of a breast cancer prognostic test.

Answer 331

Biomarkers such as FOBT for bowel cancer, PSA for prostate cancer, and CA-125 for ovarian cancer are used for screening pre-malignant conditions. These biomarkers detect blood or protein levels that are indicative of the presence of cancer in the body.

Answer 332

Biomarkers such as CEA for colorectal cancer and PSA for prostate cancer are used to assess after treatment. These biomarkers are used to measure the recurrence of cancer after treatment and to monitor treatment response.

Answer 333

Benign: - non-invasive - well defined border - well differentiated - regular nuclei - rare mitosis Malignant: - invasive/metastatic - poorly differentiated - irregular, larger nuclei - frequent mitosis

Answer 334

Benign: local multiplication of cells within tissue, growth confimed to specific site and no evidence of invading adjacent tissues Malignant: growth that is locally invasive; tumour cells spread locally wihtin a tissue and are disorganised Metastatic: tumour cells invade other tissues/ organs, a metastasis is a malignant growth formed by cells divided from a malignant primery tumour.

Answer 335

Hyperplasia: increased cell number they appear normal Dysplasia: changes in cell number and appearance, causing effecta on overall tissue archetecture. premalignant tissue Neoplasia: bening or malignant tumour composed of cells iwth abnormal appearance and proliferation

Answer 336

Cancer treatments aim to kill or remove all of the cancer cells, kill most cancer cells to prolong survival, or kill some cancer cells to palliate symptoms.

Answer 337

"Remission" means that most of the cancer cells have been killed through treatment.

Answer 338

measured by tumour response, which can be assessed using the Response Evaluation Criteria in Solid Tumours (RECIST).

Answer 339

complete response (CR)- dissappearance of all target lesions partial response (PR)- at least 30% decrease in sum of diameters progression disease (PD)- at least 20% increase in sum of diameters and stable disease (SD)- neithe sufficient shrinkage or growth

Answer 340

Tumour response does not necessarily lead to prolonged survival.

Answer 341

Overall survival time is the time from the start of treatment to the patient's death.

Answer 342

Disease-free survival time is the time prior to tumour relapse after radical treatment.

Answer 343

Progression-free survival time is the survival time prior to tumour progression.

Answer 344

A large group of patients is needed in a clinical trial to ensure that the treatment works effectively in a variety of patients from different centres.

Answer 345

A clinical trial is a planned experiment that involves patients and is designed to determine the most appropriate method of treating a medical condition in future patients.

Answer 346

randomized controlled trial (RCT), which directly compares the new treatment against the current standard of care, measuring clinically relevant outcomes.

Answer 347

phase I, which looks at safety profile and finds the maximum dosage; phase II, which looks at the efficacy of the dosage given; and phase III, which compares the new treatment against the standard of care to determine its true benefits.

Answer 348

measures the relative difference in survival between the new and standard treatments.

Answer 349

A waterfall plot in cancer treatment shows the amount of tumour shrinkage in each patient, with each bar representing a patient.

Answer 350

Biomarkers are molecules that indicate a particular biological state or condition, and can be used to predict the efficacy of treatment in cancer patients.

Answer 351

Hazard ratio= risk of death on NEW/ risk of death on STANDARD

Answer 352

Hazard Ratio of 0.5 means that the risk of death on the new treatment is half of that on the standard treatment.

Answer 353

The interpretation of the Hazard Ratio depends on the order of the comparison (new vs standard or standard vs new). For example, an HR of 0.5 is equivalent to an HR of 2, depending on the order of the comparison.

Answer 354

An HR below 1 means that the risk of death is reduced with the new treatment compared to the standard treatment.

Answer 355

development of chemotherapy alkylating agents identified through toxic effect of mustard gas folate antagonists developed from anaemia treatment folic acid as a treatment for anaemia, given to individuals with leukaemia cause an acceleration of symptoms folic acid antagonists developed as a chemotherapy

Answer 356

normal cells -> HPV infection -> low grade SIL -> de-regulation of E6/7 -> high grade SIL -> invasive cancer at each stage advances in telomerase activation, inhibition of apoptosis, genetic changes and immune response occur

Answer 357

PM sulphur dioxide ozone carbon monoxide nitrogen dioxide polycyclic aromatic hydrocarbons (PAHs)

Answer 358

progressive loss of telomeres [erosion] induces a DNA damage response and this triggers senescence potent tumour suppressor

Answer 359

2nd proliferative barrier telomeres continue to erode the telomeres become too short and can't protect the chromosomes which triggers apoptosis failure to protect the chromosomes leads to chromosome abnormalities - chromosome end to end fusions or changes in copy number in cells with inactive pRB and p53 there is no check on proliferation - genetic instability and accumulation of mutations

Answer 360

MMPs serine proteases adamalysin-related membrane proteases BMP1 type metalloprotinases heparanases cysteine proteases - cathepsins

Answer 361

complex mix of cells that changes as the tumour develops invades and metastasises to new sites cancer associated fibroblasts (CAFs) = important constituent of the stroma - directly produce factors that promote angiogenesis - indirectly attract pro-inflammatory cells such as macrophages which stimulate cancer invasion

Answer 362

angiogenic remodelling of the dorsal aorta, cardinal vein and vascular plexi give rise to the arteries, veins and capillaries angiogenic sprouting of new vessels pericytes are recruited to stabilise capillaries lymphatic endothelial cells sprout from veins and from the lymphatic system via lymphangiogenesis

Answer 363

angiogenic remodelling of the dorsal aorta, cardinal vein and vascular plexi give rise to the arteries, veins and capillaries angiogenic sprouting of new vessels pericytes are recruited to stabilise capillaries lymphatic endothelial cells sprout from veins and from the lymphatic system via lymphangiogenesis

Answer 364

low O2 levels there is not enough O2 to drive the proline hydroxylation of HIF-1a HIF-1a is free to bind to HIF-1b and induce transcription of genes required for the adaption to hypoxic conditions key target = VEGF

Answer 365

autosomal dominant cancer syndrome with mutation in the pVHL gene pVHL forms the recognition components of the E3 ubiquitin ligase for HIF-1a - pVHL provides the specificity for this E3 ubiquitin ligase - pVHL recognises hydroxylated prolines

Answer 366

DNA topoisomerases - ubiquitous nuclear enzymes relax supercoiled dsDNA to allow DNA replication and RN transcription topoisomerase I = ss nicks - bind to and stabilise DNA topoisomerase I adducts - inhibits re-ligation of DNA strands - SSB in DNA - e.g. camptothecin/irinotecan/topotecan topoisomerase II = ds nicks - forms a complex with topoisomerase II after cleavage of DNA - inhibits re-ligation of DNA strands - SSB/DSB in DNA - e.g. etoposide/anthracyclines swivelling of supercoiled DNA occurs at nicks followed by re-ligation to relieve torsional strain

Answer 367

complete response (CR) - prerequisite (but not sufficient) for cure - implications for improved survival partial response (PR) - palliative value only, offset by drug toxicity effects - more modest impact on survival stable response - any impact on survival limited to continous (non-toxic) therapy quality of response may be defined by - performance status - quality of life measurements - relapse - free survival, from time all treatment discontinued

Answer 368

tumours shed cells into circulation (CTCs) very low numbers enriched using antibodies to cell surface proteins (EPCAM) or physical properties cells stained and counted (cytokeratin +ve, CD45 -ve) high numbers are indicative of poor outcome and need for more aggressive treatemtn falling numbers indicate therapy is working are prognostic in G3T1 bladder cancer - likely recurrence if present before surgery CTCs could be analysed for protein and RNA biomarkers plus the full-range of genomic changes and epigenetic changes - inform of tumour biology and treatment - select therapies based of the sensitivity of CTCs to drugs in vitro a very low no. of CTCs currently excludes a role in early diagnosis

Answer 369

challenges - fragmented DNA - low quality DNA - low percentage of cell free DNA is actually ctDNA - careful sample collection and processing to minimise genomic DNA solutions - next generation sequencing (NGS) of thousands of tumours identified lots of potential ctDNA biomarkers technological advances = detection of cancer specific biomarkers in ctDNA possible

Answer 370

germline mutations - shared with relatives - present in every cell of the body - neutral or not somatic mutations - unique to patient - present in tumour cells - driver or passenger

Answer 371

chromosome number from 46 to 23, from 2N to N

Answer 372

duplication of the 23 chromosomes: 46 or 4N then cell division to form 2 cells with 23 chromosomes or 2N

Answer 373

mutation in a cancer susceptibility gene on chromosome 17 protein has a role in genomic stability autosomal dominant transmission 500 different mutations reported: nonsense/frameshift/missense/splice-site

Answer 374

mutation in a cancer susceptibility gene on chromosome 13 protein has a role in genomic stability autosomal dominant transmission 300 different mutations reported: nonsense/frameshift/missense

Answer 375

knudson's 2 hit hypothesis - inheriting 1 germline mutation was not sufficient enough to cause cancer, need a second somatic hit - more likely to get a somatic mutation if there is a germline mutation then if there was not germline mutation if the 1st hit is a germline mutation the 2nd somatic mutation is more likely to enable cancer

Answer 376

acquired mutations are passed on to the progeny during cell growth and division cells with cancer linked mutations proliferate more than normal cells causing the accumulation of mutations a cell with acquire enough mutations to become a cancer cell - subsequent cancer cells we be derived from this one cell

Answer 377

early somatic events are present in a high proportion of the cancer cells than later somatic events - present in a subset of cells

Answer 378

clinical applications different from research - faster/cheaper/more reliable different problem between research/clinical portable generation of machines WGS500 designs look at - de novo/recessive/familial/independent cohorts/cancer pairs/metastasis/progression

Answer 379

doesn't always fulfill the diploidy hypothesis 0 copy - no genotype 1 copy - A/B 2 copies - normal or homozygotes - AA/AB/BB or AA/BB 3 copies - allow up to 4 genotypes - AAA/AAB/ABB/BBB 4 copies - allow up to 5 genotypes - AAAA/AAAB/AABB/ABBB/BBBB always appears as AA, AB or BB (orNA)

Answer 380

abnormality of chromosome 22 - part of chromosome 9 is transferred to it bone marrow cells containing this are found in CML - piece of chromosome 9/chromosome 22 break off and switch places - BCR-ABL gene is formed on chromosome 22 where the piece of chromosome 9 attaches

Answer 381

most conventional NGS platforms use sequencing by synthesis ion torrent uses H+ release during sequence synthesis to determine changes in sequence illumina uses fluorophore during sequence synthesis to determine change in sequence both methods held back by short read lengths/relatively expensive

Answer 382

uses nonopores - protein pores attached to a semiconductor membrane allows voltage detection as DNA passes through voltage change determines base - allows detection of sequence also theoretically allows epigenetic modifications to be studied

Answer 383

1. patient diagnosed with cancer 2. cancer undergoes 'liquid biopsy' and sequencing to identify mutational drivers of cancer 3. surgery and/or targeted therapy 4. recurrence of cancer (back to 2) OR patient cured

Answer 384

tumours shed both cells and DNA into the circulation amounts are proportional to size/stage of tumour can be detected as part of a liquid biopsy CTCs harvested by physical/immunochemical capture

Answer 385

CRISPR = clustered regularly-interspaced short palindromic repeats CAS9 = CRISPR associated protein 9 CAS9 unwinds dsDNA and checks for matches between a guide RNA and the strand of interest if it finds a match it induces a DSB new sequence introduced as part of CRISPR-Cas9 complex NHEJ/HR repairs break and inserts new DNA

Answer 386

Angiostatin primary tumours produce angiogenic factors that prevent secondary tumours from being vascularised, small tumours dont produce big

Answer 387

some oncogenes (Myc, Ras) can upregulate expression of angiogenic factors

Answer 388

crosstalk between cancer cells and cell of the neoplastic stroma - mesenchymal stem cells in tumour stroma secrete CCL5, stimulates invasion - Macrophages: Metalloproteeinases, EGF - inflammatory cells: extracellular matrix-degrating enzymes

Answer 389

1) reprogramming energy metabolism, cancder cells limit energy metabolism to glycolysis- aerobic. it allows diversion of glycolytic intermediates into biosynthesis pathways 2) evading immune system, cancer cells may paralse infiltrating CTLs and NK cells, such as TGF-b

Answer 390

1. cancer stem cells 2. endothelial cells can have tumour associated vasculature and lymphatic vessels present on peripheries of tumours 3. pericytes are specialised mesenchymal cell type, stability for vascular integrity and function 4. immune inflammatory cells e.g macrophages , lymphocytes, neutrophils, releases signal moleucles and can be pro and anti tumour 5. cancer associated fibroblasts such as myofibroblast usually present on site of chronic inflammtion and wound healing. in tumours: proliferation, angiogenesis and invasion

Answer 391

1. cancer stem cells 2. endothelial cells can have tumour associated vasculature and lymphatic vessels present on peripheries of tumours 3. pericytes are specialised mesenchymal cell type, stability for vascular integrity and function 4. immune inflammatory cells e.g macrophages , lymphocytes, neutrophils, releases signal moleucles and can be pro and anti tumour 5. cancer associated fibroblasts such as myofibroblast usually present on site of chronic inflammtion and wound healing. in tumours: proliferation, angiogenesis and invasion