PBL Topic 4 Case 4 Flashcards
1
Q
What is the function of the ileocecal valve?
A
- Prevents backflow of faecal contents from the cecum into the ileum
- By closing when excessive pressure building up in cecum
2
Q
What is the function of the ileocecal sphincter?
A
- Remains constricted
- To slow emptying of ileal contents into cecum
3
Q
Identify factors that affect the degree of contraction of the ileocecal valve and intensity of peristalsis in the terminal ileum
A
- Distension of the cecum
- Irritation in the cecum
- Via the myenteric reflex in the gut wall and extrinsic autonomic nerves
4
Q
Identify the functional anatomy of the colon
A
- Proximal half is concerned with absorption of water and electrolytes
- Distal half is concerned with storage of faecal matter
5
Q
Outline the role of of serotonin on peristalsis in the colon
A
- Released from neuroendocrine cells
- In response to luminal distension
- Which activates HT4 receptors
- Which results in activation of sensory neurons (calcitonin gene-related peptide)
6
Q
Outline the process of mixing movements in the colon
A
- Combined contraction of circular muscles and longitudinal muscle
- Causes unstimulated portion to bulge outward (haustration)
- Disappears and reappears in a nearby area
- Provides mixing and propulsion
7
Q
What are mass movements?
A
- Propulsive movements
- Which takes over propulsive role of haustrations
8
Q
How frequently do mass movements occur?
A
- One to three times per day
- For about 15 minutes at a time
9
Q
Outline the process of mass movement
A
- Constrictive ring occurs in response to distended or irritated point in transverse colon
- Portion distal to ring loses its haustration and contracts as a single unit
- Which propels faecal contents down the colon
- Relaxes after 2-3 minutes and another mass movement occurs more distally
10
Q
Identify two reflexes involved in the facilitation of mass movements
A
- Gastrocolic reflex and duodenocolic reflex
- Which arise from distension or irritation of stomach/duodenum
- And are transmitted by way of autonomic nervous system
11
Q
Why is the rectum typically empty of faeces?
A
- Sphincter
- Sharp angulation
12
Q
Outline the process of defecation
A
- Mass movement forces faeces into rectum
- Contraction of rectum
- Relaxation of anal sphincters
13
Q
Identify the two anal sphincters
A
- Internal sphincter, composed of circular smooth muscle
- External anal sphincter, composed of striated voluntary muscle that surrounds the internal sphincter
14
Q
Identify the innervation of the external anal sphincter
A
- Pudendal nerve
15
Q
What is the intrinsic reflex?
A
- Distension of rectal wall
- Initiates afferent signals through the myenteric plexus
- To initiate peristaltic waves in the descending colon. sigmoid and rectum
- And relaxation of the internal sphincter
16
Q
What is the parasympathetic defecation reflex?
A
- Stimulation of nerve endings in rectum
- Which are transmitted into spinal cord
- And then reflexly back to descending colon, sigmoid and rectum by way of pelvic splanchnic nerves
- Which greatly intensify the peristaltic waves and relax the sphincters
17
Q
Identify three factors that increase the intra-abdominal pressure and force faecal contents into rectum
A
- Deep breath which moves the diaphragm downward
- Closure of glottis
- Contraction of abdominal wall muscles
18
Q
What is the peritoneointestinal reflex?
A
- Results from irritation of the peritoneum
- Strongly inhibits the excitatory enteric nerves
- To cause intestinal paralysis (especially in patients with peritonitis)
19
Q
What are the renointestinal and vesicointestinal reflexes
A
- Inhibition of intestinal activity
- As a result of kidney or bladder irritation
20
Q
How do the crypts of Lieberkuhn in the large intestine differ to those in the small intestine?
A
- No villi
21
Q
How do the epithelial cells in the large intestine differ to those in the small intestine?
A
- No enzymes
- Consist mainly of mucus secreting cells
22
Q
Identify three causes of mucus secretion in the large intestine
A
- Direct, tactile stimulation of the epithelial cells
- Local nervous reflexes
- Stimulation of the pelvic splanchnic nerves
23
Q
Identify three protective functions of mucus in the large intestine
A
- Excoriation by chyme
- Bacterial activity
- Faecal acids
24
Q
Identify the mechanism of diarrhoea
A
- Irritation of large intestine
- Causes secretion of extra large quantities of water and electrolytes and viscid alkaline mucus
- Which dilutes irritating factors
25
Identify one advantage and one disadvantage of diarrhoea
- Causes rapid movement of irritating factor towards anus to be expelled
- Loss of large quantities of water and electrolytes causing dehydration
26
How many mL of chyme pass through the ileocecal valve into the large intestine each day? How many mL of this remains in faeces?
- 1500 ml
| - 100 ml
27
How is the large intestine adapted to absorb sodium ions more completely?
- No back-diffusion of ions
- Due to tighter gap junctions
- Allows for a steeper concentration gradient
28
What is the role of bicarbonate ion secretion in the large intestine?
- Helps to neutralise the acidic end products of bacterial action
- Provides an exchange transport process for chloride ions
- Which helps to create an osmotic gradient for absorption of water
29
identify substances formed as a result of bacterial activity in the large intesitne
- Vitamin K
- Vitamin B12
- Vitamin B1 (thiamine)
- Vitamin B2 (riboflavin)
- Flatus gases
30
Identify three gases that make up flatus
- Carbon dioxide
- Methane
- Hydrogen gas
31
Identify the components of faeces
- 3/4 water 1/4 solid
- 30% dead bacteria
- 40% undigested roughage
- Dried constituents of digestive juices
- Bile pigments
- Inorganic matter
- Protein
32
Why is faeces brown?
- Stercobilin
- Urobilin
- Derivatives of bilirubin
33
Outline the four stages of the cell cycle
- G1: Preparation for DNA synthesis
- S phase: DNA synthesis
- G2 phase: Preparation for division
- M Phase: Mitosis
34
Which stages of the cell cycle constitute interphase?
- G1
- S
- G2
35
Where are the two checkpoints located in the cell cycle? What is the importance of them?
- Before S phase and M phase
- Halts the cell cycle in response to DNA damage
- To maintain genetic stability
36
What is G0?
- Quiescent phase
| - Where cells are not rapidly divide
37
What are positive and negative regulators?
- Positive regulators control the changes necessary for cell division
- Negative regulators control positive regulators
38
Identify two families of proteins that control the progress through the cell cycle, and the way in which they control this
- Cyclins and cyclin dependent kinases
- Cyclin activates CDK
- Which allows CDK to phosphorylate the proteins necessary for a particular step in the cycle
39
How is cyclin degraded?
- Ubiquitin / protease system
- Enzymes add small molecules of ubiquitin to cyclin
- Which directs the cyclin to a proteasome where it is degraded
40
Identify the main cyclins involved in the cell cycle and their associated CDK
- Cyclin A: CDK1 + CDK2
- Cyclin B: CDK1
- Cyclin D: CDK4 + CDK6
- Cyclin E: CDK2
41
Outline the role of Cyclin D in cell cycle control
- Binds with CDK4 + CDK6
- To phosphorylate retinoblastoma protein
- Which allows passage of cells from G0 to G1
42
Which phases of the cell cycle are controlled by each cyclin?
- G1-S: Cyclin E
- S-G2: Cyclin E and Cyclin A
- G2-M: Cyclin A and Cyclin B
43
Outline the process of mitosis
- Prophase: Condensation of chromosomes, disintegration of nuclear membrane
- Metaphase: Chromosomes align on equator of cell
- Anaphase: Mitotic apparatus captures and draws chromosomes to opposite poles of cell
- Telophase: Formation of nuclear membranes, cytokinesis
44
Identify two negative regulator of the cell cycle
- Hypophosphorylated Rb
| - CDK Inhibitors
45
Identify the two families of CDK inhibitors
- CIP family: p21, p27, p57
| - Ink family p16, p19, p15
46
How does the p53 gene induce DNA repair?
- Codes for p53 protein
- Which accumulates in cells
- Activates transcription factors such as p21
- Which inactivates cyclin / CDK complexes
- Thus preventing Rb phosphorylation
- Arresting cell at checkpoint 1
47
Which cyclin is thought to be involved in arresting the cell cycle at checkpoint 2?
- Cyclin B
48
Outline the extrinsic pathway of apoptosis
- Binding of TNF to the death domain of a Fas receptor (e.g. CD95)
- Causing Fas receptors to trimerise
- And activate an initiator caspase (caspase 8)
49
Outline the intrinsic pathway of apoptosis
- p53 activates BCL-2 proteins e.g. Bax, Bak
- Which promote release of cytochrome C from mitochondria
- Which complexes with Apaf-1
- This complex combines with procaspase 9 to activate it
- Which orchestrates the effector caspase pathway
50
What is the apoptosome?
- Complex of cytochrome C, Apaf-1 and procaspase 9
51
Outline the execution phase of apoptosis
- Executioner caspases cleave DNA repair enzymes, protein kinase C and cytoskeleton components
- DNAase cuts DNA between nucleosomes
- Nucleus shrinks (pyknosis) and fragments (karyorrhexis)
52
What is the role of apoptotic initiating factor (AIF)?
- Enters cell nucleus and triggers cell suicide
53
What is a polyp?
- Protuberant growth
- Divided into epithelial and mesenchymal polyps
- Which are subdivided into benign and malignant categories
54
Identify four types of benign epithelial polyps
- Adenomas
- Hamartomatous
- Hyperplastic
- Inflammatory
55
What is the incidence of adenomas?
- 20% of population
56
Identify the types of adenomas
- Tubular: 75%
- Villous: 10%
- Tubulovillous: 15%
57
Identify three structural features of a tubular adenoma
- Pedunculated
- Smaller (<10 mm in diameter)
- Crypts lined by mucus secreting epithelium
58
Describe the structure of a villous adenoma
- Sessile
- Larger (20 mm in diameter)
- Villi lined by columnar epithelium showing dysplasia
59
Describe the structure of hyperplastic polyps
- Sessile
- Elongated crypts with serrated appearance
- No dysplasia
60
Which gene is defective in most instances of hyperplastic polyps?
- BRAF
61
When do inflammatory polyps typically occur?
- In IBD
62
Name a condition that results in widespread hamartomatous polyps. Which gene is defective in this condition?
- Peutz-Jeghers syndrome
| - STK11
63
Outline a clinical feature of Peutz-Jeghers syndrome?
- Melanin pigmentation in lips, mouth and digits
64
Identify four types of benign mesenchymal polyps
- Lipomas
- Fibromas
- Haemangiomas
- Lymphangiomas
65
Which gene is affected in familial adenomatous polyposis?
- APC gene
- A tumour suppressor gene
- On 5q21
66
What is the colorectal cancer risk in FAP?
- 100%
67
How is FAP inherited?
- Autosomal dominant
68
Which gene is affected in hereditary non polyposis colorectal cancer (Lynch 1 or 2)?
- MSH2 and MLH1
| - Which are mismatch repair genes
69
What is the colorectal cancer risk in HNPCC?
- 70-80%
70
How is HNPCC inherited?
- Autosomal dominant
71
What is the mean age of adenoma development in FAP?
- 16
72
What are the treatment options for FAP?
- Prophylactic colectomy
- With ileorectal anastomosis
- Often before the age of 20
73
Describe the activation of oncogenes in the development of colorectal cancer
- KRAS: increased proliferation and reduced apoptosis through MAPK pathway
- c-MYC: increased DNA synthesis through encoding of a phosphoprotein
74
Identify the loss of function mutations of tumour suppressor genes in the development of colorectal cancer
- Point mutation of APC with subsequent loss of healthy allele
- MCC mutation whose gene product is involved in cell cycle control
- DCC involved in control of apoptosis
- T43 involved in DNA repair
- NME1 involved in metastasis
75
Describe the defects in DNA repair in the development of colorectal cancer
- Defects in DNA repair genes manifest as microsatellite instability
- Including hMLH1 and hMSH2 (in HNPCC)
76
Identify the role of the more recently discovered beta-catenin oncogene in the development of colorectal cancer
- Typically phosphorylated by GSK3 which causes its degradation
- Mutation allows WNT to bind to frizzled protein
- Which inhibits phosphorylation of beta catenin
- Which can now enter nucleus where it interacts with transcription factors
- Changing gene expression and increasing cellular proliferation
77
Outline the epidemiology of colorectal cancer
- Third most common worldwide
- More common in Western countries
- Second most common cancer in UK
- Incidence increases with age (average at diagnosis = 60-65)
78
Identify six factors that increase the risk of colorectal cancer
- Increasing age
- Saturated fats and red meat
- Colorectal polyps
- Obesity
- Smoking
- Acromegaly
79
Identify three factors that decrease the risk of colorectal cancer
- Vegetables, garlic, milk and calcium
- Exercise
- Aspirin and other NSAIDs
80
Identify a condition implicated in the development of colorectal cancer
- Ulcerative colitis
81
What percentage of cancers occur in the rectum?
- 50%
82
What percentage of cancers occur in the sigmoid colon?
- 30%
83
What type of cancers are most commonly found in the rectum? What symptoms is this associated with?
- Ulcerating type
- Rectal bleeding
- Mucus discharge
- Feeling of incomplete emptying
84
What type of cancers are most commonly found in the descending and sigmoid colon? What symptoms is this associated with?
- Stenosing type
| - Producing obstruction
85
What type of cancers are most commonly found in the right colon? What symptoms is this associated with?
- Polypoid / Fungating
- Occult bleeding
- Patient develops iron deficiency anaemia
86
Why are cancers in the cecum and ascending colon more likely to be advanced at the time of presentation?
- Distensibility of cecum and fluid bowel contents
87
What is the gold standard investigation for colorectal cancer? Identify two advantages of this method
- Colonoscopy
- Allows for biopsy and removal of polyps
- Higher sensitivity and specificity
88
Identify a non-invasive investigation for colorectal cancer that has replaced double contrast barium enema
- CT colnography
89
Identify two investigations useful for detecting hepatic metastasis
- Intraoperative ultrasound
| - CT
90
Name an antigen that can be raised in colorectal cancer
- Serum carcinoembryonic antigen (CEA)
91
Identify a surgical intervention for rectal cancer
- Total mesorectal excision with a low rectal anastomosis
92
Identify a surgical intervention for colonic cancer
- Segmentation resection with restorative anastomosis
| - Removal of lymph nodes as far as the root of the mesentery
93
Identify a treatment that has increased the proportion of advanced colorectal tumours that can be resected?
- Cisplatin and 5-fluorouracil
| - With radiotherapy
94
Why are Dukes C and Duke B rectal cancers given postoperative radiotherapy? Why is this not helpful for colic cancers proximal to the descending colon?
- To reduce the risk of local recurrence if operate resection margins are involved
- Difficulties delivering a sufficient dose without toxicity to adjacent structures
95
Identify two follow-up investigations following surgical removal of colorectal cancesr
- Colonoscopy
| - CEA measurements
96
Outline the staging and survival for colorectal cancer
- Stage 1 / Duke's A: T1/T2 90% 5 year survival rate
- Stage 2 / Duke's B: T3/T4 65% 5 year survival rate
- Stage 3 / Duke's C: N1/N2 35% 5 year survival rate
- Stage 4 / Duke's D: M1 7% 5 year survival rate
97
In the pathological sequence of the development of colorectal cancer:
Identify the changes that cause the formation of a small polypoid adenoma from normal epithelium
- APC mutation
- MCC mutation
- 5q mutation
- c-MYC activation
- 'Susceptibility gene' 8q24
98
In the pathological sequence of the development of colorectal cancer:
Identify the changes that cause the formation of a large polypoid adenoma from a small polypoid adenoma
- KRAS mutation
99
In the pathological sequence of the development of colorectal cancer:
Identify the changes that cause the formation of an invasive carcinoma from a large polypoid adenoma
- p53 mutation
| - 18q deletion
100
In the pathological sequence of the development of colorectal cancer:
Identify the changes that cause the metastasis in invasive adenocarcinoma
- NME1 deletion
101
What percentage of cancers are familial and what percentage are sporadic?
- Familial: 1%
| - Sporadic: 99%
102
What is the difference between chromosomal and microsatellite instability?
- Chromosome instability causes chromosome breaks due to numerical and structural abnormalities
- Microsatellite instability due to defective DNA mismatch repair
103
What is a gatekeeper gene?
- Inhibits proliferation of, or promote death of, cells with damaged DNA
104
What is a caretaker gene?
- Maintain the integrity of the genome by repairing DNA damage
105
Identify a gatekeeper gene that is a transcription factor that responds to DNA damage
- P53
106
Identify a gatekeeper that controls the cell cycle at the G1/S checkpoint
- RB1
107
Identify a gatekeeper that regulates the beta catenin function in the WNT pathway
- APC
108
Identify a caretaker that is involved in DNA repair and is susceptible to mutation in pancreatic cancer?
- BRCA2
109
Identify a caretaker gene involved in DNA mismatch repair that is susceptible to mutation in Lynch syndrome
- MSH2
| - MLH1
110
Identify four methods of oncogene activation
- Translocation of oncogene to an actively transcribed site
- Point mutation causing it to be hyperactive
- Amplification by insertion of multiple copies of an oncogene
- Insertion of promotor sequences of a retrovirus
111
Identify an oncogene that is a platelet derived growth factor
- Sis
112
Identify an oncogene that is a a receptor for epidermal growth factor
- erb-B
113
Identify two oncogenes involved in intracellular signalling (protein-tyrosine kinase)
- src
| - abl
114
Identify an oncogene that is a transcription factor for driving proliferation and regulating apoptosis
- myc
115
Identify an oncogene that is involved in intracellular signalling (GTP-binding, binary switch)
- ras
116
How are chemotherapy drugs combined together?
- Based on differing mechanisms and non-overlapping toxicities
- To avoid resistance and minimise adverse effects
117
How are chemotherapy drugs administered (timings)?
- Given over a period of days
| - Followed by a rest of a few weeks
118
Identify 4 alkylating agents
- Cyclophosphamide
- Cisplatin
- Busulfan
- Oxaliplatin
119
Outline the mechanism of action of alkylating agents
- Formation of a carbonic ion with only six electrons in outer shell
- React with nucleophiles in DNA (e.g. N7 of guanine)
- Causing intra-chain cross linking or interchain cross linking (if bifunctional)
- Resulting in transcription interference and chain breakage
120
Identify four adverse effects of alkylating agents
- Bone marrow depression
- GI disturbances
- Sterility
- Increased risk of leukaemia
121
Identify two examples of antimetabolites
- Methotrexate
| - Fluorouracil
122
Outline the mechanism of action of methotrexate
- Higher affinity for DHFR than DHF
- Reducing intracellular THF
- Which is required for carrying methyl groups for conversion of DUMP to DTMP by thymidylate synthase
- Which is essential for DNA synthesis
123
Outline the mechanism of action of fluorouracil
- Converted into a fraudulent nucleotide, FDUMP
- Which interacts with thymidylate synthase
- But is not converted into DTMP
- Which is essential for DNA synthesis
124
Identify phase specific agents that act in S phase
- Methotrexate
| - Fluorouracil
125
Outline the mechanism of action of doxorubicin
- Inhibits DNA and RNA synthesis
| - Through interference with topoisomerase II
126
Outline the mechanism of action of bleomycin
- Causes fragmentation of DNA chains
127
Identify two types of resistance to anticancer drugs
- Primary resistance: present when drug is first given
| - Acquired: developed during treatment with drug
128
Outline the role of P-glycoprotein (P-gp/MDR1) in resistance to anticancer drugs
- Decreases accumulation of drugs in cells
| - By picking up foreign chemicals (e.g. drugs) and expelling them
129
Identify five main side effects of chemotherapy and how they are managed
- Vomiting (metoclopramide)
- Hair loss (scalp cooling)
- Tiredness (nutrition and hydration)
- Myelosuppression (give molgramostim)
- Mucositis (antiseptic mouthwash)
130
Outline the mechanism of action of cinnarizine
- H1 receptor antagonist
| - Vestibular nuclei
131
Outline the mechanism of action of metoclopramide / domperidone
- D2 receptor antagonist
| - Chemoreceptor trigger zone
132
Outline the mechanism of action of ondansetron
- 5-Ht3 receptor antagonist
| - Chemoreceptor trigger zone
133
Identify an antispasmodic drug
- Hyoscine butyl-bromide
134
Identify 8 psychological factors in the initiation and promotion of cancer
- Behavioural factors
- Stress
- Life events
- Control
- Coping styles
- Depression
- Personality
- Hardiness
135
Describe a type C personality
- Helpless
- Passive
- Appeasing
136
Describe the components of hardiness
- Control
- Commitment
- Challenge
137
Identify psychologicla consequences of cancer
- Depression
- Anxiety
- Anger
- Fighting spirit
138
Identify the components of a fighting spirit
- Searching for meaning (cause of their cancer)
- Gaining a sense of mastery (medication and positive thinking)
- Self-enhancement through social downward comparison
139
Identify how psychology can be used to alleviate symptoms of cancer
- Pain management through biofeedback and hypnosis
- Treating nausea and vomiting through relaxation and desensitisation
- Social support interventions to reduce denial and promote hope
- Body image counselling
- Cognitive adaptation strategies to increase well-being and decrease distress
140
Describe a whole person approach in the psychological alleviation of cancer symptoms
- Relaxation
- Mental imagery
- Exercise
141
Identify the three basic mechanisms needed to transform a normal cell into a neoplastic cell
- Immortalisation by telomerase expression
- Removal of growth inhibition by Inactivation of both copies of a tumour suppressor gene
- Autocrine growth stimulation by mutation of proto-oncogenes to produce oncogenes
142
Identify four nuclear changes in neoplastic cells
- Enlargement of nucleus
- Dark staining (hyperchromasia)
- Variability in shape and size
- Chromatin clumping (pleomorphism)
143
What is molgramostim? What is its mechanism of action and what is it used to treated?
- Recombinant GM-CSF
- Which functions as an immune stimulator
- Used to manage myelosuppression with chemotherapy
144
What is the role of ALT?
- Aminotransferase
- Transfer of amino group of alanine to alpha-ketoglutarate
- To produce pyruvate and glutamate
145
What is the role of AST?
- Aminotransferase
- Transfer of amino group of aspartate to alpha-ketoglutarate
- To produce oxaloacetate and glutamate
146
What are ABC transporters?
- (A)TP (B)inding (C)assette Transporter Pumps
- Which are depending on hydrolysis of ATP to transport molecules
- Examples include BSEP2 and MRP2 which secrete bile salts from hepatocytes into bile canaliculi
