, Question 1
A tumor demonstrates loss of heterozygosity at the RB1 locus with retained
expression of a hyperphosphorylated RB protein. Which mechanism best
explains how this finding can still drive uncontrolled G1/S transition?
A. RB hyperphosphorylation by constitutively active CDK4/6-cyclin D
complexes inactivates RB, releasing E2F independently of allelic loss.
B. Loss of heterozygosity at RB1 always produces a nonfunctional RB
protein, so the phosphorylated band represents a different protein.
C. Hyperphosphorylated RB is the active tumor-suppressing form that
blocks E2F, so the tumor must have a separate CDKN2A deletion.
D. RB phosphorylation is irrelevant to cell cycle control; only p53
mutation determines G1/S progression.
Correct Answer: A - RB hyperphosphorylation by constitutively
active CDK4/6-cyclin D complexes inactivates RB, releasing E2F
independently of allelic loss.
RATIONALE
RB function is regulated by phosphorylation: CDK4/6-cyclin
D-mediated hyperphosphorylation inactivates RB, releasing E2F and
permitting S-phase entry even when one RB1 allele remains. LOH
alone would not explain continued proliferation if RB were
hypophosphorylated and active. The other options misstate RB
biology or overstate p53's exclusive role.
Question 2
In a patient with sepsis-induced acute kidney injury, which combination of
urinary indices most strongly supports prerenal azotemia rather than intrinsic
acute tubular necrosis?
A. Fractional excretion of sodium <1%, urine osmolality >500 mOsm/kg,
bland urinary sediment
B. Fractional excretion of sodium >2%, urine osmolality <350 mOsm/kg,
Page 2
, muddy brown casts
C. Fractional excretion of sodium <1%, urine osmolality <350 mOsm/kg,
white blood cell casts
D. Fractional excretion of sodium >2%, urine osmolality >500 mOsm/kg,
renal tubular epithelial cells
Correct Answer: A - Fractional excretion of sodium <1%, urine
osmolality >500 mOsm/kg, bland urinary sediment
RATIONALE
Prerenal azotemia reflects intact tubular sodium avidity and
concentrating ability, producing FENa <1%, high urine osmolality,
and bland sediment. Intrinsic ATN damages tubules, causing FENa
>2%, isosthenuria, and muddy brown casts. Options C and D mix
contradictory indices that do not fit either classic pattern.
Question 3
Which statement best explains why immune checkpoint inhibitors targeting
PD-1 can paradoxically accelerate tumor growth in a subset of patients with
glioblastoma?
A. PD-1 blockade removes inhibitory signaling on regulatory T cells,
enhancing immunosuppression within the tumor microenvironment.
B. PD-1 blockade eliminates all CD8+ cytotoxic T cells, leaving only
myeloid-derived suppressor cells.
C. Glioblastoma cells lack PD-L1, so the drug has no target and directly
stimulates tumor proliferation.
D. Checkpoint inhibitors induce antibody-dependent cellular cytotoxicity
against normal astrocytes, causing reactive gliosis that mimics
progression.
Correct Answer: A - PD-1 blockade removes inhibitory signaling
on regulatory T cells, enhancing immunosuppression within the
tumor microenvironment.
Page 3
, RATIONALE
In some tumors, PD-1/PD-L1 signaling restrains regulatory T cells;
blocking it can expand Treg-mediated immunosuppression and
promote hyperprogression. Glioblastoma often has a highly
immunosuppressive microenvironment where this paradox is
observed. The other options misstate PD-1 biology or invent
mechanisms not supported by evidence.
Question 4
A patient with chronic heart failure has elevated BNP but normal left
ventricular ejection fraction and evidence of impaired relaxation on
echocardiography. Which pathophysiologic mechanism most directly explains
the elevated filling pressures?
A. Increased myocardial stiffness from titin isoform switching and
interstitial fibrosis, impairing diastolic relaxation
B. Reduced sarcoplasmic reticulum calcium reuptake causing systolic
calcium overload and hypercontractility
C. Upregulation of beta-1 receptors producing excessive inotropy and
reduced end-diastolic volume
D. Primary mitochondrial uncoupling leading to ATP depletion and
systolic failure with preserved ejection fraction
Correct Answer: A - Increased myocardial stiffness from titin
isoform switching and interstitial fibrosis, impairing diastolic
relaxation
RATIONALE
Heart failure with preserved ejection fraction (HFpEF) is driven by
impaired diastolic relaxation, often from titin isoform shifts (more
N2B, stiffer) and fibrosis, raising filling pressures despite normal EF.
Systolic calcium overload and beta-receptor upregulation describe
hyperdynamic or systolic failure, not HFpEF. Mitochondrial
uncoupling would more likely impair systolic function.
Page 4
A tumor demonstrates loss of heterozygosity at the RB1 locus with retained
expression of a hyperphosphorylated RB protein. Which mechanism best
explains how this finding can still drive uncontrolled G1/S transition?
A. RB hyperphosphorylation by constitutively active CDK4/6-cyclin D
complexes inactivates RB, releasing E2F independently of allelic loss.
B. Loss of heterozygosity at RB1 always produces a nonfunctional RB
protein, so the phosphorylated band represents a different protein.
C. Hyperphosphorylated RB is the active tumor-suppressing form that
blocks E2F, so the tumor must have a separate CDKN2A deletion.
D. RB phosphorylation is irrelevant to cell cycle control; only p53
mutation determines G1/S progression.
Correct Answer: A - RB hyperphosphorylation by constitutively
active CDK4/6-cyclin D complexes inactivates RB, releasing E2F
independently of allelic loss.
RATIONALE
RB function is regulated by phosphorylation: CDK4/6-cyclin
D-mediated hyperphosphorylation inactivates RB, releasing E2F and
permitting S-phase entry even when one RB1 allele remains. LOH
alone would not explain continued proliferation if RB were
hypophosphorylated and active. The other options misstate RB
biology or overstate p53's exclusive role.
Question 2
In a patient with sepsis-induced acute kidney injury, which combination of
urinary indices most strongly supports prerenal azotemia rather than intrinsic
acute tubular necrosis?
A. Fractional excretion of sodium <1%, urine osmolality >500 mOsm/kg,
bland urinary sediment
B. Fractional excretion of sodium >2%, urine osmolality <350 mOsm/kg,
Page 2
, muddy brown casts
C. Fractional excretion of sodium <1%, urine osmolality <350 mOsm/kg,
white blood cell casts
D. Fractional excretion of sodium >2%, urine osmolality >500 mOsm/kg,
renal tubular epithelial cells
Correct Answer: A - Fractional excretion of sodium <1%, urine
osmolality >500 mOsm/kg, bland urinary sediment
RATIONALE
Prerenal azotemia reflects intact tubular sodium avidity and
concentrating ability, producing FENa <1%, high urine osmolality,
and bland sediment. Intrinsic ATN damages tubules, causing FENa
>2%, isosthenuria, and muddy brown casts. Options C and D mix
contradictory indices that do not fit either classic pattern.
Question 3
Which statement best explains why immune checkpoint inhibitors targeting
PD-1 can paradoxically accelerate tumor growth in a subset of patients with
glioblastoma?
A. PD-1 blockade removes inhibitory signaling on regulatory T cells,
enhancing immunosuppression within the tumor microenvironment.
B. PD-1 blockade eliminates all CD8+ cytotoxic T cells, leaving only
myeloid-derived suppressor cells.
C. Glioblastoma cells lack PD-L1, so the drug has no target and directly
stimulates tumor proliferation.
D. Checkpoint inhibitors induce antibody-dependent cellular cytotoxicity
against normal astrocytes, causing reactive gliosis that mimics
progression.
Correct Answer: A - PD-1 blockade removes inhibitory signaling
on regulatory T cells, enhancing immunosuppression within the
tumor microenvironment.
Page 3
, RATIONALE
In some tumors, PD-1/PD-L1 signaling restrains regulatory T cells;
blocking it can expand Treg-mediated immunosuppression and
promote hyperprogression. Glioblastoma often has a highly
immunosuppressive microenvironment where this paradox is
observed. The other options misstate PD-1 biology or invent
mechanisms not supported by evidence.
Question 4
A patient with chronic heart failure has elevated BNP but normal left
ventricular ejection fraction and evidence of impaired relaxation on
echocardiography. Which pathophysiologic mechanism most directly explains
the elevated filling pressures?
A. Increased myocardial stiffness from titin isoform switching and
interstitial fibrosis, impairing diastolic relaxation
B. Reduced sarcoplasmic reticulum calcium reuptake causing systolic
calcium overload and hypercontractility
C. Upregulation of beta-1 receptors producing excessive inotropy and
reduced end-diastolic volume
D. Primary mitochondrial uncoupling leading to ATP depletion and
systolic failure with preserved ejection fraction
Correct Answer: A - Increased myocardial stiffness from titin
isoform switching and interstitial fibrosis, impairing diastolic
relaxation
RATIONALE
Heart failure with preserved ejection fraction (HFpEF) is driven by
impaired diastolic relaxation, often from titin isoform shifts (more
N2B, stiffer) and fibrosis, raising filling pressures despite normal EF.
Systolic calcium overload and beta-receptor upregulation describe
hyperdynamic or systolic failure, not HFpEF. Mitochondrial
uncoupling would more likely impair systolic function.
Page 4
