8. Cancer Human Viruses Flashcards
NOTE:
Cancer viruses are also called:
____ viruses and ____ viruses
These names are interchangeable.
oncogenic
tumorigenic
A general example of how viruses can cause cancer
Number 1/2/3 are saying that a virus can infect. On the top in number 4 its saying they can cause tumors. Make the separation into the two parts: tumor and infection. Some but not all can cause tumors.
1. Lytic infection
A. The virus goes in and ____ the cell.
2. Persistant infection
A. Some viruses go in and they reside there at ____ levels. They are held down by the immune system and don’t explode unless you become ____.
3. Latent infection
A. Like ____. Go into the genome and stays there. There are some other tricks too for latency.
- Tumor
A. ____ is the first step towards cancer. It doesn’t mean that you have cancer yet. It
just means that you took a cell that is now able to live forever.
B. In contrast, if you took any cell from your body and culture it they will only Iive for so many
cell cycles.
C. Immortalized cells are not necessarily ____ because if you put one into an organism
the immune system may detect and kill it. To become a tumor the ____ response must
be evaded.
D. Viruses don’t “want” to cause ____. A small subset of the ____
used for lytic infection can inadvertently be used to make a cell become ____ and
eventually become a tumor.
destroys
low
immunodeficient
HIV
immortialization
cancerous
immune
tumors
machinery
immortalized
Cancer viruses immortalize cells as a first step in tumorigenesis
Normal cells will grow and completely stop growing due to contact inhibition of adjacent cells –> virus –> cells become virally transformed are not ____ by adjacent cells. they continue to divide. they are immortalized.
Cancer viruses immortalizing cells is our first step in tumorigenesis.
• Take cells from human and put them on a tissue culture plate. There’s 4 normal cells with nuclei (left picture).
• If you take a virus and you infect the cells – you either kill all of the cells or depending on if you put in the cancer genes only for this virus – In some cases, you end up with ____ cells. This is basically all of these cells going crazy and forming a mass (right picture).
contact inihibited
immortalized
How do viruses disrupt the cell cycle and how does this lead to cancer? Part I
- human body has 10^13 - 10^14 cells.
- the vast majority of these cells are non-dividing and have an arrested cell cycle, i.e., they are ____
Reads slide. Quiescent doesn’t mean they are sleeping. It means they are not ____. They are working, metabolizing, etc. We do have some rapidly dividing cells like our ____, blood cells. NON fast dividing cells would be ____ and neuronal cells.
quiescent
dividing
skin
muscle cells
How do viruses disrupt the cell cycle and how does this lead to cancer? Part 2
NORMAL CELL CYCLE: The pRB Check Points
When the rb protein becomes dephosphorylated (Rb) it binds to ____, which prevents E2F from ____ the cell cycle
NOTE: normal ____ cells remain at this stage
When the Rb proteins becomes phophosrylated, it dissociates from E2F, which now enables E2F to ____ the cell cycle
He wants to make the cell cycle simple. Remember two things: the gas pedal and the brake.
• Every cell has a cycle by nature. A cell has to go through a phase of which it is going to grow… like G is growth phase.
• A stage called S where there is DNA synthesis occurring. You have your genome and you are making a duplicate of it.
• And then you have M, which is mitosis where the cell has two copies of DNA and is going to divide and give you two cells. There are points where it stops (go to the next slide).
E2F
activating
quiescent
activate
How do viruses disrupt the cell cycle and how does this lead to cancer? Part 3
- when a virus infects a quiescent cell, it must ‘activate’ it in order to utilize the host cell machinery.
a viral protein causes loss of control of ____ checkpoints. the cell is no longer regulated and keeps dividing.
the cancer virus onco-protein (i.e. HPV ____) blocks control of cell cycle by binding RB. this enables the free E2F to go unchecked and stimulate the cell cycle continuously.
- Point is that in the cell cycle E2F is the gas pedal. It is a cellular gene/protein. It says GO.
- Then there is another protein called Rb that says STOP.
- When a virus infects a quiescent cell it must activate it in order to utilize the host machinery. What happens with cancer is that you are taking away the break. The cell should want to stop and it doesn’t. A virus protein causes loss of control of pRb checkpoints.
- There’s two famous proteins in science that you will read about forever in your career. One is a RB–retinoblastoma protein. The other is p53, which is the guardian of the genome.
pRB
E7
How do viruses disrupt the cell cycle and how does this lead to cancer? part 4
rapidly dividing cells, with no cell cycle check points, will accumulate mutations in their DNA. normally, cellularl ____ protein (the guardian of the genome) senses these mutations and either blocks the cell cycle or forces the cell to self-destruct (apoptosis).
p53
how do viruses disrupt the cell cycle and how does this lead to cancer? part 5
in virus infected cells, a viral (i.e. ____ protein of HPV) binds p53 cellular and prevents it from blocking the cell cycle or undergoing apoptosis
the cell is now ____ by the virus!
E6
immortalized
how do viruses disrupt the cell cycle and how does this lead to cancer? part 6
a continuous cell cycle generates mutations that ____ the genome and brings about cellular changes i.e. the ability to escape an ____ response. this progresses to tumor formation and ____
de-stabilize
immune
metastasis
introduction summary: how cancer viruses disrupt the cell cycle and cause tumors.
viral onco-proteins can disrupt the cell cycle (____) so that the cells continue to divide. by analogy to a car, the ____ is pushed all the way down.
the cell senses danger (DNA damage) but ____ and ____ are blocked (p53). the brakes don’t work. mutations lead to genome ____ which progress to tumors.
pRB accelerator growth arrest apoptosis destabilization
• Hepatitis B/C are big in the wheel representing all of the viruses. Very important. ____ is the predominant one. B has a ____, but C has a new ____. They are easily transmitted by ____.
C
vaccine
drug
blood
• What causes hepatitis?
The liver is the chemical factory of the body. It is where you process everything, especially foreign stuff. Every time you take a medicine, the medicine always goes through your liver first in something called ____
metabolism.
• Then it goes through it again, which is ____ metabolism.
• Each time you get modifications of the drug that was put in until it is destroyed and goes to the ____ and is excreted.
• If you get abnormal metabolism, and something is going wrong with the liver, the liver can give you hepatitis. This means ____ of the liver. If you OD on
Tylenol its because the liver is overwhelmed.
• If any of these insults (hepatitis B/C viruses, abnormality in metabolism), then you get inflammation of the liver. You eventually get ____, which is scarring and loss of function. And then eventually you get ____.
first pass
second pass
kidney
inflammation
cirrhosis
liver cancer
• Theres a lot of “hepatitis” viruses but they have nothing really in common other than the fact that they infect the liver. B/C are totally different viruses! One is ____ the other is ____.
• There is a vaccine for ____ (and for B but he didn’t say that here). There’s B/C which
are important for us. Then there’s the others.
RNA
DNA
A
hepatitis is defined as “liver inflammation”
what is viral hepatitis?
hepatitis means ____ of the liver. it is often caused by a ____ and most common forms are A, B and C.
liver disease caused by viral hepatitis ____ can progress to cancer.
Hepatitis is inflammation of the liver. It can be caused by many things but we are
looking at the B/C viruses. These (A/B/C) are the common viruses of the liver. None of them mean you will get liver cancer, it just makes it more likely.
inflammation
virus
B and C
How do you get liver cancer: • Drink tons of \_\_\_\_ • Hep B/C viruses ◦ \_\_\_\_ is the big one • When you drink alcohol and have hepatitis C it adds to the odds and the wheel grows. Its an \_\_\_\_ effect.
alcohol
C
additive
hepatitis
A - found in ____ water or food. ____ is available that gives lifetime immunity.
B - is ____. transmitted by ____ contact with bodily fluids. can cause chronic hepatitis, lead to cirrhosis and liver cancer. also has a ____.
C - is the most common ____ illness in the US. there is no ____ and it is transmitted in the same way as hepatitis ____. it also leads to liver failure and cancer.
new drug for hepatitis C (____)
unsanitary
vaccine
everywhere
direct
vaccine
blood-born
vaccine
B
epclusa
• Don’t get lost in this
• Modes of transmission of B/C - any kind of activity that causes a breakage of ____ and a fluid to fluid (____) exchange is how it works.
• Dental treatment with ____ equipment is a great way to transfer the
viruses.
blood vessels
blood-to-blood
unsterilized
Pathology of viral hepatitis
note: although hepatitis type B is a ____ virus and hepatitis type C is an ____ virus, their pathologies are very similar.
• Its a ____ cancer. Its not like you have a normal liver and then the next day its cancerous. Thats what this is showing.
• These viruses can cause progression to liver damage and they undergo a pathology that is common.
◦ First thing you see if ____ of the liver.
◦ Then you see ____ tissue.
◦ Then then you see ____ where liver is destroyed. This can lead to death.
You can’t process and get rid of things like medicine and foreign things now.
• Can take years
DNA
RNA
progressive
fibrosis
cirrhotic
liver cancer
- “What I would look at is the liver cirrhosis and the scar tissue to give yourself a background feel about what this is about.”
- (Start with blue circle). Shows how you can have any of the viruses and alcohol or compounds to injure the liver. It becomes a chronic disease. You get cirrhosis which is ____ (in red). These show you the certain cellular events that are occurring (subsequent pathways). So you go from well differentiated cells to ones that are poorly differentiated (purple). They are no longer functioning liver cells anymore.
- stellate cells are ____ storing cells
- cirrhosis is the replacement of normal functional liver cells with ____ tissue
- ____ nodules result from an increase in the amount of tissue that results from cell proliferation
- dysplastic nodules are abnormal appearing ____ cells
- ____ are structures at the end of chromosomes that protect them from fusion and degradation
scar tissue fat scar hyperplastic precancerous telomeres
• The numbers are not important and should not be memorized and will not be on the exam. But what you want to know for yourself is the magnitude of some
things.
• Even if you don’t die from a liver disease your ____ of life would be greatly
impaired. Can get cancer of the liver and that could kill you.
quality
hep B virus symptoms
- ____
- loss of appetite
- ____
- vomiting
- ____ & eyes (jaundice)
- dark-colored urine
- ____ stool
it is estimated that ____% f all americans have been infected with HBV
lethargy
fever
yellow skin
light colored
hepatitis type B virus transmission rates
• Mom can pass it to infant \_\_\_\_ • Can also be \_\_\_\_ ◦ \_\_\_\_ drug use, sharing needles ◦ Don't share \_\_\_\_ there's bleeding ◦ \_\_\_\_ contact ◦ Easy to transmit which is why its rampant
easily host to host IV toothbrushes sexual
note: ____ intergrates into the genome. ____ does not integrate.
• HBV DNA has these proteins. You can have a normal liver become a chronic hepatitis and a carcinoma. These show you the events the occur though every one of these kinds of relationships.
• When you have these events occurring. When you have the integration of HBV into DNA you get expression of these viral proteins that lead to the ____
inflammation of the liver, ____, and genetic instability.
• Genetic alterations and mutations are occurring and thats the bad part which will lead to the carcinoma/cancer.
hep B
hep C
necrosis
oxidative stress
possible outcomes of HBV infection
• Don’t memorize the stats just be aware of them.
• There’s ____ hep B infection. This leads to ____ HBV infection. This leads to chronic hepatitis.
• This is good at showing the timeline.
◦ ____% of people 5 years later end up with chronic hepatitis after getting
infected. Then 5 years later ____% end up with liver failure which can lead to
death. This is why we have so many people who need liver transplants.
- In 5 years 6-15% of people get ____ carcinoma which leads to death.
- The point is that something that occurred years before ends up causing problems ____ later.
acute
chronic
12-25
20-23
hepatocellular
years
hepatitis B vaccination
recombinant DNA vaccine
- introduced in 1986 in USA
- has replaced ____ vaccine
- ____ effective
- available as ____ or combined vaccine
active substance:
- HBsAg derived from culture of ____ or ____ cells
adjuvant:
- ____ or thiomersal
storage:
- ____
- ____ avoided
• HBsAg = Hep B surface antigen
◦ Viral protein that was through recombent DNA made in cells, either yeast or mammalian cells. Can be easily cultured in lab. Just the ____ part not the
viral part.
• Then you put it into an adjuvant that helps it to be delivered.
• Then you can freeze it and take it out and use it.
• Produced in 1986
plasma derived
cost
monovalent
yeast
mammalian
alum
2 to 8
freezing
protein
HBsAg of hepatitis B virus is produced in yeast to make the subunit vaccine
◦ HBsAg (circles on the outside) can be ____ away – or make them through ____ rather – and you can make this in the absence of the whole ____ through genetic engineering and into yeast. The vaccine works well.
stripped
recombinant DNA
virus
hepatitis C
- transmission via ____ and ____ (____ too)
- hep C associated with liver ____ and ____
- most common ____infection in the US
- most common cause of ____ hepatitis
• Its a different virus altogether from B. But its transmitted by ____ and ____ which is the same and its also associated with liver cancer and cirrhosis.
blood sex perinatally cancer cirrhosis bloodborne chronic viral
sex
blood
Sources of infection for persons with hepatitis C
- ____ drug users are big. 60% of them will have hep C.
- 15% of ____ active people.
- ____ before screening for virus in the past.
- ____, perinatal (around birth) healthcare workers.
injecting
sexually
transfusions
hemodialysis
Progression of HCV to HCC over time
• Don’t remember the numbers but remember the progression.
• ____% get infected, 90% go from infection phase to ____, 15% go to
____, then 1% get ____.
• I want you to see it takes years for the progression to occur.
100
chronic hepatitis
cirrhosis
hepatocellular carcinoma
- ____ need to watch out.
- 3 million in the US are infected.
- Most of them baby boomers. ____ who are infected don’t know they have it.
baby boomers
3/4
• Screening procedure. You come in and do a blood test, you are negative and you go over here and you are okay. If you are ____ you undergo a couple different types of tests. You want to be very careful what you tell a patient and be sure you are right. Tests need to be ____ and ____.
positive
repeated
verified
A new effective hepatitis C treatment! epclusa is a combination of 2 ____. it blocks all 6 ____ of chronic hepatitis C virus.
- Theres a new hep C treatment called epclusa. Its a combo of two antivirals. In other words these are ____ structures. They are down down at the bottom and are very complex looking with multiple ____. They are drugs that are really terrific.
- They work at ____ – and we don’t need to go through the mechanism and the details – they block the hep C maturation and replication and its assembly.
- Whenever you make a cocktail of drugs you want to make sure that the drugs each hit a separate indistinct target, so that way if the first target fails the second target can hit it and you know it will work.
antivirals genotypes chemical rings blocking
EBV
- ____, herpes virus
- most people who become infected with EBV develop ____
- lt is ____ transmitted. in the US 90% of adults have been infected with EBV.
- when children become infected with EBV they have ____ or only mild symptoms.
- if the first infection occurs during adolescence, it can cause ____ 30-50% of the time. (sometimes called the ____ disease)
- EBV infects ____ cells and ____ cells
- after the first EBV infection, the virus perists latently in the ____ cells for life
- it causes ____ in AIDs patients
DNA immunity orally no infectious mononucleosis kissing B epithelial B hairy leukoplakia
EBV
is associated with human cancers that include:
1. ____
2. ____
african burkitt lymphoma
nasopharyngeal carcinoma
epidemiology of african burkitt lymphoma
burkitt lymphoma (BL) is common amongst ____ in africa.
BL accounts for 30-50% of all ____ cancer in equatorial Africa with an estimated incidence of 3 to 6 cases per 100,000 children per year.
the incidence of BL in africa is approximately ____-fold higher than that seen in the US.
children
childhood
50
EBV
african burkitt lymphoma was discovered by denis burkitt in 1958 who was working as a physician in Uganda.
this largey a tumor of the ____, where there is massive swelling. it is seen largely children in Africa.
jaw
ABL: a 100% ____ associated cancer
strong association with ____ and EBV in ABL
suggested that malaria (a mosquito carrying a parasite) weakens the ____ to allow EBV to become cancerous
chronic malaria may reduce ____ to EBV. the disease characteristically mainly involves the ____ and ____ bones.
• In the US > not same relationship bc we don't have malaria here ○ Combine parasite with viral infection; parasitic infection lowers your immunity and cannot fight off EBV
EBV
malaria
immune system
resistance
jaw
facial
EBV
ABL is:
- a cancer that initiates in ____
- ____-growing human tumor*
- responds to ____ enabling survival in more than 50% of patients.
B cells
fastest
chemotherapy
____ days post-treatment the patient recovers with chemotherapeutics
6
Epidemiology of EBV - Nasopharyngeal carcinoma
- endemic to south china, africa, arctic eskimos.
this is a malignant tumor of the ____ epithelium of the nasopharynx. - 100% of tumors contain ____ DNA
- rates are less than 1 per 100,000 in most world populations. in ____ (guangdong) the rates are 25 per 100,000
- nasopharyngeal carcinomas are found in association with ____ of latent EBV. the exact mechanism is unknown.
- There is a 25-fold increase of rate in southern China
- EBV > B cells > nasopharyngeal carcinoma
squamous
EBV
southern china
reactivation
EBV- nasopharyngeal carcinoma
- it is a ____ tumor of the nasopharynx
- signs and symptoms include:
- cervical ____, bloody discharge from the nose, nasal ____, hearing loss in ____ ear, frequent ____ infections, double vision, ____ and pain the face and neck
rare lymphadenopathy congestion one ear headache
NPC tissue stained for the presence of ____ antigens
EBV late
• Grows around the ____, around the cranial nerve, and then spreads into ____; the ____ is also affected
ear
cheekbone
hypopharynx
EBV - nasopharyngeal carcinoma treatment
- ____
- chemotherapy
- ____
surgery
radiotherapy
HPV causes ____ cancer (____% certain)
HPV may cause some ____ cancers
• Some - cancers can be caused by a variety of mechanisms; but the virus is something that can trigger cancer of the H+N, but there may be other causes (\_\_\_\_, or others) which result in cancer of H+N
cervical
100
H+N
environmental
HPV
cancer transformation
transforming activity of HPV16 is associated with mainly ____ and ____ proteins
E6 adn E7 are multifunctional proteins that can increase ____ and survival by interfering with ____ activity.
• E > early, L > late ○ Early (gets virus into cell and gets it to replicate) before DNA synthesis; late after DNA synthesis (coat proteins) • Need to know the important strains: \_\_\_\_ (6, 11, 18) • 16 > highly tumorigenic
E6
E7
cell proliferation
tumor suppressor
16
HPV immortalizes cells by using the viral E7 protein to bind ____ and the E6 protein to bind ____. this results in blocking the cell cycle and apoptosis.
• E7 > pRB (the \_\_\_\_); E6 > p53 (\_\_\_\_ of genome)*
pRb
p53
brake
guardian
HPV and cervical cancer
US statistics:
- in 2009, estimated 11,270 new cases of invasive cervical cancer with 4,070 deaths
- median age of diagnosis - ____ years
- prevalence of greatest in ____ (____ > AA > caucasians)
• Prevalence may be greatest because of \_\_\_\_
48
minority women
hispanics
screenings
Epidemiology of HPV infection
- 10% worldwide prevalence (highest in ____).
- 20 million in US currently infected with ____ strain
- 5.5 million/yr in YS acquire new genital HPVinfection
- 3/4 of infections occur in ____ year olds
- among women 14-59, overall HPV prevalence - 27%
- almost 40% of ____ active 14-19 year old girls and 50% of ____ active 20-24 year olds infected
- prospective study of female college students: 26% infected at baseline; of those who were negative, 43% acquired HPV ____ over 3 years
africa anogenital 15-24 sexually sexually
infection
human papillomavirus (HPV)
- ____ DNA virus infects human e____ cells
- there are >200 different strains of the virus
- considered the most common ____ transmitted infection in the US
double-stranded
epithelial
sexually
HPV- types in cervical cancer
- HPV present in virtually all ____ cancers
- infection is generally indicated by the detection of HPV ____
- HPV types ____ and ____ account for most cervical cancers
(16 = ____%, 18 = ____%)
cervical DNA 16 18 54 13
HPV - natural history
- over ____of sexually active women and men infected with HPV at some point in their lives
- most HPV infections are ____ and transient (~91% resolve without treatment in ____ years).
- r____ or re-infection possible.
- in some individuals, HPV infections result in ____ warts or Pap test abnormalities
- persistence of HPV infection (with high-risk subtypes) associated with a variety of ____ cancers.
half asymptomatic 2 reactivation genital anogenital
epidemiology of HPV and cervical cancer
- over 99% of cervical cancers have HPV ____ detected within the tumor
- 70% of cervical cancer is caused by one of two types of HPV, ____ or 18
- the ____ HPV vaccine protects against types ____, 11, ____ and 18
DNA
quadrivalent
6
16
HPV vaccine
gardasil (Merck)
- FDA approved 6/06
- ____ vaccine (HPV4)
- uses ____-lke particles, recombinat ____ proteins of indiviudal HPV types
- protects against HPV ____, 11, ____, 18
- indicated for girls and women ____ years of age (now ____ also)
* The GSK > only does 16/18 * Using recombinant DNA to make proteins in the lab; not using any virus at all * When first came out > \_\_\_\_ regarding administration (condoning sex)
quadrivalent virus L1 capsid 16 9-26 boys social backlash
HPV vaccine eifficacy - HPV4
clinical trials demonstated
- 98% efficacy in preventing ____ pre-cancers caused by targeted HPV types in women uninfected at baseline
- girls who have not already been infected with any of the 4 sub-types of HPV get the most ____ from vaccine (44% efficacy in all women irrespective of baseline HPV status)
- vaccine nearly 100% efficacious in preventing ____ pre-cancers and ____ casued by targeted HPV types
- may offer cross-protection against HPV type ____
cervical benefit vulvuar/vaginal genital warts 31
recommendations: national organizations
- vaccine most effective if given before 1st ____ contact
- females who have equivocal or ____ Pap tests, ____ HPV tests, or genital warts can receive HPV vaccine
- vaccine recipients should be advised that data do not indicate that the vaccine will have any ____ effect on existing HPV infection, cervical lesions, or genital warts
- vaccination can provide protection against infection with vaccine HPV types not already ____
sexual abnormal positive therapeutic acquired
if a woman is already infected with HPV:
- no ____ effect demonstated on already-present HPV infection or associated disease
- however, vaccine still ____ - can protect against other sub-types of virus, or re-infection
therapeutic
recommended
larynx and pharynx cancers
Oropharyngeal cancer (HPV-associated)
• \_\_\_\_, earaches, difficulty \_\_\_\_
hoarseness
swallowing
Oropharyngeal cancer
risk factors:
- traditional - ____ and alchol
- emerging - ____ infection
- alarming rise in oropharyngeal cancer in ____ (40-50) males w/o traditional risk factors
- 70% of oropharyngeal cancers in the US are HPV-related ____ cell carcinomas
- an epidemic of HPV-mediated malignancy projected to surpass the incidence rate of ____ cacner by 2020 in US
tobacco HPV middle aged squamous cervical
HPV infection
- has predilection for ____ in humans, > 100 subtypes
- most common ____ transmitted infection
- greater than 50% of sexually active will have ____ infection at some time during their lives
- a small percent will have ____ infection at any given time of which only 1% are ____ subtypes
mucocutaneous keratinocytes sexually genital oral oncogenic
the palatine and lingual tonsils are uniquely susceptible to HPV infection (immune-priveleged sites)
• The ____ and ____ tonsils are uniquely susceptible to HPV infection
• The tonsils are interestingly – they represent an immune system thats really a
lymphatic tissue in the oral cavity – the palatines and the linguinals. Those are
the tonsil types that you find in the oral cavity.
• Basically they see bacteria coming in the oral cavity and they are loaded with ____ cells and they make antibodies and they are protective like that. They are the ____ line of defense when something comes into the mouth.
• The primary tumors in the head and neck are often seen in the tonsils ____, in
other words if you took a section of a tonsil a crypt is like a cavity– a deep
narrow cavity and you can find that the tumors are really small and we won’t be able to see it. They go down below into the crypt and they develop there.
• There are no ____ and symptoms in the beginning.
palatine lingual B first crypts signs
oral HPV infection
natural history
- majority of virally-mediated OPC are casued by ____ (main subtype involved in cervical cancer)
- our knowledge about the natural history (incidence and clearance) of oral HPV infection is ____
- need prospective studies to examine temporal relationship between oral HPV detection and risk of ____
HPV16
limited
OPC
HPV vaccination
impact on OPC
- currently approved HPV vaccines protect against oncogenic HPV implicated in ____ and ____ cancer as well as strains casuing ____ warts
- although not evaluated in RCT, HPV vaccination may also prevent ____ HPV infection & HPV-induced ____ malignancy
- 2014 CDC study suggests currently available HPV vaccines could prevent most ____ cancers in the US
- costa rica vaccine trial (CVT) shows vaccine efficacy against HPV16 and HPV18 infections at the ____, anal, and oral regions among ____ women
cervical
anal
anogenital
oral
oropharyngeal
oropharyngeal
cervical
naive
