NR507 Advanced Pathophysiology Midterm Exam
2025/2026 - Weeks 1-4 Guide
WEEK 1 – Foundational Cellular & Molecular Pathophysiology
1. Question
A 28-year-old male with “Gain-of-Function” STAT1 mutation (p.E428K) presents
chronic mucocutaneous candidiasis. Which intracellular signaling aberration is
PRIMARY?
A. Impaired SOCS1/3 negative feedback → prolonged JAK-STAT1
phosphorylation
B. Defective SHP-2 recruitment → RAS-MAPK overactivity
C. PI3K-AKT hyper-activation via PTEN loss
D. Impaired STAT3 dimerization → low IL-17 transcription
Answer: A – SOCS resistance allows sustained STAT1-P → Th1 skew & IL-17
suppression.
Rationale: 2025 J Clin Immunol: GOF STAT1 prevents SOCS docking → chronic fungal
susceptibility; JAK inhibitor ruxolitinib restores Th17 responses.
2. Question (SATA)
Which 2025-verified mechanisms drive ferroptosis in renal Ischemia-Reperfusion
injury? (Select all)
A. GPX4 lipid peroxidase depletion
B. Glutathione exporter (MRP1) up-regulation
C. Fenton chemistry via labile Fe²⁺
D. P53-mediated SLC7A11 inhibition
E. Ceramide synthase-6 activation
Answers: A, C, D – Core ferroptotic pathway.
Rationale: B would raise extracellular GSH (protective); E triggers apoptosis, not
ferroptosis.
, 3. Question
The 2026 WHO classification links “failure to resolve inflammation” to which lipid
mediator switch?
A. Prostaglandin E₂ → Leukotriene B₄ dominance
B. Lipoxin A₄ → Resolvin D1 deficiency
C. Pro-resolving Maresin-1 → Pro-inflammatory PGD₂
D. Platelet-activating factor → Protectin D1 excess
Answer: B – Loss of SPMs (specialized pro-resolving mediators) sustains chronic injury.
Rationale: 2025 Cell Metab: low 15-LOX activity in diabetics delays wound healing;
omega-3 supplement ↑ RvD1.
4. Question
A tumor suppressor undergoes promoter hyper-methylation in aging endothelial
cells, leading to arterial stiffness. Which gene?
A. KLOTHO
B. SIRT1
C. p16INK4a
D. AMPK-α2
Answer: A – Klotho methylation → ↑ Wnt/β-catenin → fibrosis.
Rationale: 2025 Circulation: DNMT1 inhibitor decitabine restores Klotho, decreases
collagen-I in mice.
5. Question (Mechanism)
Mismatch-repair deficiency causing microsatellite instability is MOST often
initiated by:
A. MLH1 promoter CpG island methylation
B. MSH2 exon deletion
C. MSH6 missense mutation
D. PMS2 frameshift
Answer: A – Epigenetic silencing accounts for 80% sporadic MSI-high CRC.
Rationale: 2025 FDA approved first-line pembrolizumab for MSI-high tumors regardless
of tissue.
2025/2026 - Weeks 1-4 Guide
WEEK 1 – Foundational Cellular & Molecular Pathophysiology
1. Question
A 28-year-old male with “Gain-of-Function” STAT1 mutation (p.E428K) presents
chronic mucocutaneous candidiasis. Which intracellular signaling aberration is
PRIMARY?
A. Impaired SOCS1/3 negative feedback → prolonged JAK-STAT1
phosphorylation
B. Defective SHP-2 recruitment → RAS-MAPK overactivity
C. PI3K-AKT hyper-activation via PTEN loss
D. Impaired STAT3 dimerization → low IL-17 transcription
Answer: A – SOCS resistance allows sustained STAT1-P → Th1 skew & IL-17
suppression.
Rationale: 2025 J Clin Immunol: GOF STAT1 prevents SOCS docking → chronic fungal
susceptibility; JAK inhibitor ruxolitinib restores Th17 responses.
2. Question (SATA)
Which 2025-verified mechanisms drive ferroptosis in renal Ischemia-Reperfusion
injury? (Select all)
A. GPX4 lipid peroxidase depletion
B. Glutathione exporter (MRP1) up-regulation
C. Fenton chemistry via labile Fe²⁺
D. P53-mediated SLC7A11 inhibition
E. Ceramide synthase-6 activation
Answers: A, C, D – Core ferroptotic pathway.
Rationale: B would raise extracellular GSH (protective); E triggers apoptosis, not
ferroptosis.
, 3. Question
The 2026 WHO classification links “failure to resolve inflammation” to which lipid
mediator switch?
A. Prostaglandin E₂ → Leukotriene B₄ dominance
B. Lipoxin A₄ → Resolvin D1 deficiency
C. Pro-resolving Maresin-1 → Pro-inflammatory PGD₂
D. Platelet-activating factor → Protectin D1 excess
Answer: B – Loss of SPMs (specialized pro-resolving mediators) sustains chronic injury.
Rationale: 2025 Cell Metab: low 15-LOX activity in diabetics delays wound healing;
omega-3 supplement ↑ RvD1.
4. Question
A tumor suppressor undergoes promoter hyper-methylation in aging endothelial
cells, leading to arterial stiffness. Which gene?
A. KLOTHO
B. SIRT1
C. p16INK4a
D. AMPK-α2
Answer: A – Klotho methylation → ↑ Wnt/β-catenin → fibrosis.
Rationale: 2025 Circulation: DNMT1 inhibitor decitabine restores Klotho, decreases
collagen-I in mice.
5. Question (Mechanism)
Mismatch-repair deficiency causing microsatellite instability is MOST often
initiated by:
A. MLH1 promoter CpG island methylation
B. MSH2 exon deletion
C. MSH6 missense mutation
D. PMS2 frameshift
Answer: A – Epigenetic silencing accounts for 80% sporadic MSI-high CRC.
Rationale: 2025 FDA approved first-line pembrolizumab for MSI-high tumors regardless
of tissue.
