Recurrent seizures lead to accumulation of the activity-dependent transcription factor ∆FosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer’s disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ∆FosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ∆FosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection to dentate granule cells, indicating that ∆FosB may act over long timescales to coordinate neuroprotective pathways. To test this hypothesis, we used viral-mediated expression of ∆JunD to interfere with ∆FosB signaling over the course of several months in transgenic mice expressing mutant human amyloid precursor protein (APP), which exhibit spontaneous seizures and develop AD-related neuropathology and cognitive deficits. Our results demonstrate that persistent ∆FosB activity acts through discrete modes of hippocampal target gene regulation to modulate neuronal excitability, limit recurrent seizure activity, and provide neuroprotection to hippocampal dentate granule cells in APP mice.

Alzheimer disease (AD), the most prevalent neurodegenerative disorder, causes progressive cognitive decline and degeneration of synapses and neurons. Some neurological impairments in AD may reflect reversible network dysfunction rather than loss of neurons. Biochemical and genetic studies have identified several molecules that may play a causal role in AD pathogenesis. We will review how these molecules impair memory. Many molecules that are important for synaptic plasticity are altered in AD, including receptors, channels, kinases, and neuromodulators. We will discuss how these molecular alterations, as well as cellular and network level alterations, could contribute to deficits in synaptic plasticity and memory.

ARID2 (ARID2), CTNNB1 (β catenin), tumor protein 53 (p53), and PIK3CA (p110α) mutations are implicated in hepatocellular carcinoma (HCC); and previous work has contributed to thorough molecular characterization of these events. However, studies that assess the impact of these mutations on downstream protein expression, especially those that evaluate all 4 cancer markers simultaneously, are relatively lacking. Hence, the present study uses immunohistochemistry to assess protein expression patterns of ARID2, β-catenin, p53, and p110α in HCCs and adjacent nonneoplastic cirrhotic tissues from 58 explanted livers. Notably, this study is the first to our knowledge to investigate ARID2 protein expression in the liver. The frequency of ARID2 mutations detected using our immunohistochemistry method was similar to that reported in previous molecular studies. Furthermore, we found that loss of ARID2 protein expression may be associated with recurrence, although further studies must be done to validate these findings in a larger population. We found that expression patterns of the 4 cancer markers were independent of each other, suggesting separate pathways of hepatocarcinogenesis. We also did not observe an association between viral etiology and protein expression. Consistent with previous studies, overexpression of p53 correlated with poor differentiation. Lastly, 17.5% of HCCs paradoxically had diffuse loss of the oncoprotein p110α compared with strong expression in background cirrhotic liver. The exact mechanism is unclear, but enigmatic loss of oncoprotein function has been described in other carcinomas and could potentially have significant implications for the use of mechanistic target of rapamycin (mTOR) drug therapies.

The Child-Turcotte-Pugh (CTP) score is a widely used predictor of long-term survival in cirrhosis that has been incorporated into liver cancer staging systems such as the Barcelona Clinic Liver Cancer (BCLC) algorithm.CTP calculation requires 3 "objective" values: total bilirubin, serum albumin and International Normalized Ratio (INR), as well as 2 "subjective" variables: severity of ascites and hepatic encephalopathy.No system to quantify CTP score from administrative databases has been validated.The Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) study is a multicenter collaborative study to evaluate the outcomes and cost of hepatocellular carcinoma (HCC) in the U.S. Veterans Health Administration (VHA).In order to match cirrhotic patients with HCC to similar cirrhotic patients without HCC, we developed and validated an algorithm to extrapolate virtual CTP (vCTP) scores from data in the VHA Corporate Data Warehouse (CDW).Methods: The derivation cohort consisted of 150 subjects with ICD9 codes of 155.0 or 155.2 (HCC) randomly selected from all patients diagnosed with HCC from 2008-2010 at 7 validation sites (Boston, Bronx, Brooklyn, Philadelphia, Minneapolis, and West Haven VA Medical Centers).The validation cohort consisted of 150 subjects with ICD9 codes of 571.2, 571.5 or 571.6 (cirrhosis) in the first quarter of 2009 randomly selected from the same sites.Investigators at each site reviewed each chart and calculated actual CTP (aCTP) scores based on available data.We tested several strategies incorporating laboratory data, pharmacy data, ICD9 and CPT codes.The optimal algorithm incorporated laboratory data (albumin, bilirubin, INR) obtained proximate to the diagnosis date for the HCC cohort (and in a given quarter for the cirrhotic cohort); CPT codes for paracentesis and TIPSS; and pharmacy data for lactulose, rifaximin, furosemide, spironolactone and amiloride.Performance characteristics of each vCTP subscore and total score were evaluated.The vCTP score was tested as a predictor of survival on a cohort of 682 patients with HCC and correlated as expected in BCLC-A disease.Results: Spearman correlations among vCTP subscores and total score are shown in Table 1 for each cohort.In the derivation cohort, total vCTP matched aCTP in 54/79 (68%) cases and 76/79 (96%) were within 1 point (Spearman R=0.83, p<0.0001).In the validation cohort, total vCTP matched aCTP in 38/55 (69%) and 54/55 (98%) were within 1 point (Spearman R=0.85, p<0.0001).Conclusion: We developed and validated an algorithm to extrapolate the CTP score from data in a large administrative database with excellent correlation to actual CTP score on chart review.This algorithm may be applied to administrative healthcare databases for the purpose of stratifying cirrhotic patients by disease severity when studying any topic relevant to liver disease.Table 1.Correlations for vCTP subscores and total score