Hematology Oncology - UWorld Flashcards
HIV drugs from the outside in
Maraviroc: CCR5 receptor inhibitor
Enfuvirtide: fusion inhibition by blocking gp41
Efavirenz, nevirapine: NNRTI (do not require intracellular phosphorylation for activation)
Zidovudine, emtricitabine: NRTIs (must be converted to monophosphate form by cellular thymidine kinase before conversion to active triphosphate forms)
Raltegravir: integrase inhibition
Ritanovir, saquinavir: protease inhibition
How do WBCs get from the intravascular space to the site of infection?
Margination: vascular leakage causes leukocyte margination toward vascular walls
Rolling: loose binding of sialylated carbohydrate groups on the endothelium (Sialyl Lewis X & PSGL-1) to L-selectin (PMNs) or E/P-selectin (endothelial cells).
Activation: slow rolling allows PMNs to sample chemokines being secreted from inflamed tissue, resulting in a conformational change in their expressed integrins
Tight adhesion and crawling: PMNs firmly attach to ICAM-1 or CD18 beta-2 integrins (Mac-1 and LFA-1) on endothelial cells
- **LAD type 1 = absence of CD18 -> decreased synthesis of Mac-1 and LFA-1 skin infections without pus formation and delayed umbilical cord separation.
- **LAD type 2 = less severe
- **LAD type 3 = similar to type 1, but associated bleeding due to poor synthesis of beta-3 integrins on platelets
Transmigration: after crawling to the periphery of the endothelial cells, PMNs attach to PECAM-1 and squeeze out of the vasculature
Types of hemoglobin that make up the RBCs in a normal person
97% HbA = alpha2beta2
2.5% = HbA2 = alpha2delta2 *elevated in thalassemia
Region of the lymph node largely populated by T-cells and dendritic cells
Parafollicular cortex (poorly developed in DiGeorge syndrome)
What is the difference between the primary and secondary follicles in the lymph node.
Primary: dense packing of dormant B-cells
Secondary: proliferating B-cells and follicular dendritic cells
Lymph nodes changes in patients with X-linked (Bruton’s) agammaglobulinemia
Poorly formed primary follicles and germinal centers due to poor B-cell differentiation
What makes up the medulla of the lymph node?
Medullary cords: B cells, plasma cells and macrophages
Medullary sinuses: reticular cells and macrophages
Cell surface receptor that binds parvovirus and allows cellular entry
Erythrocyte P antigen
Origin of cells in carcinoid tumors
Enterochromaffin cells
Normal platelets and poor aggregation after addition of normal plasma and ristocetin vs. good aggregation after ristocetin and plasma.
Ristocetin increases expression of Gp1b on platelets. In vWF deficiency, there is little vWF to bind Gp1b and there is minimal improvement despite increased expression of Gp1b on platelets.
Bernard-Soulier syndrome is due to absence of Gp1b on platelets. Although platelets will not aggregate with ristocetin, addition of normal plasma will induce aggregation.
Glanzmann thrombasthenia is due to defective GpIIb-IIIa that prevents platelet-platelet adherence. Ristocetin test will be normal in these patients.
Aminocaproic acid vs. protamine sulfate
Aminocaproic acid - reverses tPA conversion of plasminogen to plasmin
Protamine sulfate - reverses heparin by binding to and inactivating heparin
Enzymes that take heme in the periphery to conjugated bilirubin in the bile
Heme oxygenase breaks down heme to biliverdin -> biliverdin reductase reduces biliverdin to bilirubin and it is transported to the liver bound to albumin -> glucuronyl transferase conjugates bilirubin to glucuronic acid, making soluble and excretable in bile
Sickle cell anemia mutation
AR point mutation in the 6th codon of the beta-globin gene causing Glu -> Val. This results in formation of HbS, which polymerizes with other Hgb at low O2 tension.
This can be diagnosed by Hgb electrophoresis, with the HbS moving more slowly than the other Hgb due to the mutation.
Brain centers that trigger vomiting
Area postrema in the 4th ventricle has M1, H1, D2, 5-HT3 and neurokinin-1 chemoreceptors
Nucleus tracts solitaires in the medulla receives neuronal input from GI tract (CN IX, X), area postrema, vestibular system (CN VIII) and CNS
Best drugs for treatment of chemotherapy-induced vomiting
5-HT3 antagonists: ondansetron, granisetron
D2 antagonists: metaclopramide, prochlorperazine
NK1 antagonists: aripepitant, fosaprepitant
A patient has a lymph node biopsy that shows packed follicles that obscure the normal lymph node architecture, with abundant centrocytes (small cleaved cells) and a t(14;18) translocation. What is causing his condition?
Overactivation of the anti-apoptotic gene Bcl-2 occurs as a result of this translocation and causes follicular lymphoma, which is consistent with his biopsy
t(9;22)
BCR-ABL translocation resulting in constitutively active tyrosine kinase activity and CML
A patient with a lymph node biopsy presents with diffuse medium sized lymphocytes with interspersed macrophages, a high proliferation index represented by a Ki-67 fraction around 95% and a t(8;14) translocation.
Over activation of the transcription regulator c-MYC resulting in Burkitt lymphoma
Causes of left and right shifts on the Hbg binding curve
Left
- Decreased H+
- Decreased 2,3-BPG
- Decreased temperature
Right
- Increased H+
- Increased 2,3-BPG
- Increased temperature
HbC
Result of Glu -> Lys substitution on Hgb. Cells do not sickle because Lys is negatively charged. This hgb moves even slower than HbS on Hgb electrophoresis
A patient presents with DIC. Peripheral blood smear shows immature myeloid cells with needle-shaped intracytoplasmic inclusions that stain positive for peroxidase. What caused this patients condition? Treatment?
Acute promyelocytic anemia (M3 AML) is due to t(15;17) that causes fusion of the retinoic acid receptor to the PML gene. Consequently, these patients are highly responsive to treatment with all trans retinoic acid.
Why is DRE a good test for prostatic adenocarcinoma
The neoplastic growth typically occurs in the peripheral zone of the prostate
Process leading to cellular apoptosis
Initiation
- Intrinsic damage from toxins, radiation, heat -> expression of phosphatidyl serine and/or thrombospondin on plasma membrane
- Extrinsic TNF and Fas ligand binding to TNF receptor 1 or Fas receptor (CD95), respectively
- Mitochondrial mediated pathway
Control
- Intrinsic: Bas, Bam and Bim replace anti-apoptotic molecules Bcl-2 and Bcl-x in the mitochondrial membrane, release of cytochrome c and caspase activation
- Extrinsic: binding death receptor brings caspases in close proximity
Destruction
-Cysteine on caspases cleave aspartic acid residues and digest cellular proteins
Pure red cell aplasia
Inhibition of red cell precursors by IgG antibodies or cytotoxic T-lymphocytes resulting in reduced erythropoietic products and normal granulopoiesis and thrombopoiesis. Causes include thymomas, lymphocytic leukemias and parvovirus B19 infection.
Most common childhood brain tumors and how to differentiate between them
1) Pilocytic astrocytoma: benign, cystic cerebellar or hemispherical mass with solid tumor protruding from cyst wall. Biopsy shows Rosenthal fibers.
2) Medulloblastoma: malignant, mass in cerebellar vermis, biopsy shows sheets of small round blue cells
3) Ependymomas: ventricular masses presenting with hydrocephalus, biopsy shows rosettes
Mutation seen in patients with polycythemia vera
Constitutive activation of cytoplasmic JAK-2 tyrosine kinase
Where is factor VIII produced
Endothelial cells
Lymph node drainage for all cutaneous areas beneath the umbilicus, exceptions?
Pretty much all cutaneous areas below the umbilicus drain to the superficial inguinal nodes. Exceptions include the testes (para-aortic LNs), glans and posterior calves (both drain to deep inguinal nodes).
Common cause of adult T-cell lymphoma
HTLV
Why does the spleen enlarge in patients with hereditary spherocytosis
The RBCs cannot pass through the cords of Billroth and are sequestered in the spleen
Why might you add allopurinol to a patient’s chemo regimen to improve efficacy?
It inhibits xanthine oxidase, which is necessary for the breakdown and inactivation of 6-MP. This shunts more 6-MP towards HGPRT, which converts it to its active metabolites that inhibit purine synthesis (6-TG). Note that 6-MP can also be inactivated by TPMT in the liver, which is not inhibited by allopurinol.
Mechanism of action of azathioprine
It is broken down to 6-MP after metabolism and similarly inhibits de novo purine synthesis
Neoplasms that can be treated with IL-2
Melanoma and renal cell carcinoma
Imatinib mesylate
BCR/ABL tyrosin kinase inhibitor, used to treat CML from t(9;22)
Abciximab, eptifibatide and tirofiban
Anti-GpIIb-IIIa anti-coagulant
Process of tumor transition from in situ to invasive
1) Downregulation of E-cadhedrins -> detachment of neoplastic cells from surrounding cells
2) Expression of laminin or other adhesion molecules and tumor adherence to the basement membrane
3) Production of cathespin D protease and metalloproteinases that help degrade the basement membrane and invade deeper tissue
Pathogenesis of paroxysmal nocturnal hemoglobinuria
PIGA mutation -> absence of GPI anchor -> defective complement inhibitor (CD55 and CD59) attachment to RBC membrane -> complement MAC formation -> hemolysis -> triad of anemia, hypercoaguability and pancytopenia
Treatment of HIT
Stop heparin and start a direct thrombin inhibitor (argatroban, hirudin, lepirudin) because these patients are at continued risk for thrombosis, but cannot be on heparin or LMWH.
A patient presents with abdominal pain, vomiting, peripheral neuropathy, neuropsychiatric derangement and reddish urine that darkens on exposure to light. How do you treat this patient?
She has acute intermittent porphyria due to PBG deaminase deficiency resulting in accumulation of PBG (urine that darkens with sunlight). To limit accumulation of PBG, you can give these patient glucose and heme in an acute attack (they inhibit ALA synthase). Patients should avoid P450 inducers (EtOH, tobacco, drugs) because this will up regulate ALA synthase and precipitate further attacks.
Topoisomerase I vs II
I) introduces single-stranded breaks into DNA to relieve negative supercoiling during transcription (inhibited by topotecan)
II) introduces double-stranded breaks into DNA to relieve positive and negative supercoiling (double strand break ligation inhibited by etoposide)
Malaria treatment
Chloroquine if confirmed chloroquine-sensitive region
Mefloquine if chloroquine resistant region
Atovoquine-proguanil and artemisinins are also useful
Add primaquine if P. vivax or P. ovale to treat dormant liver hypnozoites
TdT
Adds V, D and J regions to the antibody for diversity. Present in all immature lymphocytes (T and B cells) and indicative of ALL.
Mutation that causes beta-thalassemia
Around the AUG start codon on the beta-globin mRNA there is a Kozak sequence reading gccRccAUGG, where R can be guanine or adenine. This sequence acts as an initiator for translation. Beta-thalassemia occurs when the R is a cytosine and there is poor translation initiation.
What might you see on light microscopy of a female who is susceptible to X-linked recessive mutations?
Absence of hypermethylated, deacetylated compact heterochromatin at the periphery of the cells (Barr bodies, inactivated female X chromosome)
What keeps cells bound to basement membranes and the extracellular matrix
Fibronectin, collagen and laminin all bind cellular integrins
HbA, HbS and HbF in normal, sickle trait and sickle cell disease patients
Normal: HbA > HbF absent HbS
Trait: HbA > HbS > HbF
Sickle cell disease: HbS > HbF absent HbA
Mechanism of activation of most pro-carcinogens
Microsomal mono-oxygenase (P450 system)
What causes basophilic stippling
Abnormal degradation of rRNA due to Pb inhibition of nucleotidase
How does Pb cause microcytic anemia
It inhibits ALA-dehydratase, limiting the amount of heme that can be synthesized for RBC Hgb.
Why prescribe pyridoxine with INH
INH pyridoxine phosphokinase, an enzyme that converts B6 to its active metabolite pyridoxal 5’ phosphate
Characteristics of anaplastic tumors
Numerous mitoses and giant tumor cells
How are eukaryotes able to produce multiple protein products from a single mRNA transcript?
Alternative mRNA splicing
Stop codons
UAA, UAG and UGA
Consequence of incorporation of the MDR1 gene into neoplastic cells
Formation of P-glycoprotein, which pumps chemo drugs out of the neoplastic cells, rendering them ineffective
Factors that promote angiogenesis
FGF-2 is involved in endothelial cell proliferation, migration and differentiation.
VEGF increases endothelial cell proliferation and motility. IL-1 and IFN-gamma can cause increased VEGF release from macrophages.
mTOR pathway
Growth factor binds to the receptor -> tyrosine residue autophosophorylation -> PI3K activation -> PIP2 phosphorylation to PIP3 -> Akt (Protein Kinase B) activation -> Akt activates mTOR -> mTOR translocates to nucleus to activate genes involved in cell survival, anti-apoptosis and angiogenesis.
Note that this pathway is inhibited by PTEN because it removes a phosphate from PIP3
How to limit hemorrhagic cystitis secondary to cyclophosphamide use
Mesna, it binds the inactive metabolites (acrolein) that are cytotoxic to the uroepithelial cells
Medication you can give to limit doxorubicin (anthracycline) cardiotoxicity
Dexrazoxane, an iron chelator
