General questions Flashcards
What is your favorite part of the thesis
I like (and dislike) my studies for different reasons I like study III because we have a well defined exposure and outcome, and data on lots of potential confounders and thus I think we were able to handle potential confounding by indication nicely. We had active comparators, although the main csDMARD comparator was not a new user design, we had a new user design in a sensitivity analysis. A new user design deals with depletion of susceptibles.
What is your least favorite part of the thesis?
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How does chronic inflammation cause cancer?
-Chronic inflammation is thought to be, at least theroretically involved in all stages of cancer. Most of the evidence come from experimental experimental models.
-It seems that most of the time it is local inflammation, caused by e.g. microbial agents or chemical agents, that cause the inflammation that leads to inflammation.
Inflammation can lead to mutations as well as epigenetic changes, and cellular stress.
-Chronic inflammation can also lead to loss of barrier function, which can bring stem cells in contact with inflammatory cells!
-Inflammation can also lead to changes in the microbiota, leading to an enrichment of bacterial species harboring genotoxic compounds, such as som strains of e.coli.
-Homeostasis is an important concept, where inflammtion and immunity is tightly regulated. The evoultionary pressure has always been strong in favor of fighting of pathogens, and this is thought to sometimes have come with a trade-off for developing cancers in middle- or old age, at least past the childbearing ages.
-In some cases inflammation is thought to increase the risk of cancer by inducing death of neighboring cells, needed for the tumor to grow. For example in UC, which is associated with significant tissue damage and ulceration, the risk of colorectal cancer is much higher than in Crohns, which is more assoicqated with transmural inflammation but not widespread epithelial damage.
-Local inflammation can lead to tumerogenensis, local inflammation at the target site,e.g. in the lung can facilitate metastasis
How does chronic inflammation cause cancer?
-Chronic inflammation is thought to be, at least theroretically involved in all stages of cancer. Most of the evidence come from experimental experimental models.
-It seems that most of the time it is local inflammation, caused by e.g. microbial agents or chemical agents, that cause the inflammation that leads to inflammation.
Inflammation can lead to mutations as well as epigenetic changes, and cellular stress.
-Chronic inflammation can also lead to loss of barrier function, which can bring stem cells in contact with inflammatory cells!
-Inflammation can also lead to changes in the microbiota, leading to an enrichment of bacterial species harboring genotoxic compounds, such as som strains of e.coli.
-Homeostasis is an important concept, where inflammtion and immunity is tightly regulated. The evoultionary pressure has always been strong in favor of fighting of pathogens, and this is thought to sometimes have come with a trade-off for developing cancers in middle- or old age, at least past the childbearing ages.
-In some cases inflammation is thought to increase the risk of cancer by inducing death of neighboring cells, needed for the tumor to grow. For example in UC, which is associated with significant tissue damage and ulceration, the risk of colorectal cancer is much higher than in Crohns, which is more assoicqated with transmural inflammation but not widespread epithelial damage.
-Local inflammation can lead to tumerogenensis, local inflammation at the target site,e.g. in the lung can facilitate metastasis
-Conversely, inflammation contributes to cellular stress and may induce DNA damage.
-Inflammation favors the initial genetic mutation or epigenetic mechanisms that drive cell transformation and cancer initiation
-It acts as a tumor promoter by establishing a tissue microenvironment that allows the tumor to progress and metastasize and by establishing immunosuppressive mechanisms that prevent an effective immune response against the tumor
TNF and cancer?
There is so much evidence of the relation between TNF and cancer but most of it comes from experimental animal models and cell lines.
-TNF knockout möss mindre cancer
What about systemic inflammation?
Well we know that BMI (kanske inflammation) increases the risk of esophageal adenocarcinoma, thyroid, colon, and renal cancers. Endometrie, gallbladder which might be due to systemic inflammation.
Levels of TNF and IL-6 are poor prognostic factors, induce fever, wasting, cachexia.
Has been used as cancer treatments with varied success
-COX2 överuttrycks i tidiga stadier av nästan alla tumörer
-COX2 hämmare visade lovande resultat men studier avbröts pga toxiciete
immunological aberrations
- activation of T cells, B cells anddendritic cells,
- impaired clearance of apop-totic material,
- overactive T–B cell interactions,
- molecular mimicry,
- chimerism and faulty selection.
RA criteria
- Ledinvolvering (mer än en stor ger poäng, små leder ger mer poäng)
- Duration mer än 6 veckor
- ACPA/RF
- Normal CRP/ESR
SLE kriterier
ANA antikroppar plus
- kliniska manifestationer (feber, hematologiska, neuropsykiatriska, mukokutanösa, pleura/pericard, njure)
- komplenet, antid-DS eller anti-smith antikroppar, eler Anticardiolipin/anti beta2gp1-ak/lupus antikoagulant
DAS28
number of tender/swollen joints, CRP or EST, and global health
TNFi, effekt, tid till effekt, biverkningar
anti tnf alpha
dagar-veckor
40% svarar mycket bra, 30 måttligt, 30 inte alls (i studier på pateitner där de flesta redan testat andra dmards)
få, allvarig infektion, TB,
Försiktighet vid t.ex. allvarlig hjärtsvikt, infektioner (hepatit C, TBC)
Methotrexat, effekt, tid till effekt, biverkningar
Folatantagonist (purnisynteshämmare)
4-8 veckor, maximal effekt kan ta lång tid
30% svarar bra, resten partiell eller ingen eller biverkan
ilamående håravfall, lever benmärg, metotrexatlunga
Rituximab, effekt, tid till effekt, biverkningar
CD-20 hämmare
1-3 månader
Hälften svarar bra (de flesta redan testat TNFI), effekt varar i 6-12 månader, god effekt av förnyad behandling
Risk för infektion likvärdig med TNFi (trots närmast total depletion av b-celler i blodet
Abatacept, effekt, tid till effekt, biverkningar
CTLA-4 agonist, förhindrar excessiv aktivering av t-cellet
3-6 månader
Likvärdig med TNFi
infektion, god säkerhet
Tocilizumab, effekt, tid till effekt, biverkningar
IL-6 hämmare
inom veckor
Likvärdig med TNFi
Leverpåverkan, neutropeni, tromocytopeni, förhöjt kolesterol och LDL
