Faculty Bibliography

Background and aims/UNASSIGNED:Recently, smooth muscle hypertrophy has been suggested to be a contributor in small bowel lesions secondary to Crohn's disease (CD), in addition to inflammation and fibrosis. Here, we assess the value of magnetic resonance imaging (MRI) for the characterization of histopathologic tissue composition of small bowel CD, including inflammation, fibrosis and smooth muscle hypertrophy. Methods/UNASSIGNED:35 consecutive patients (M/F 17/18, mean age 33y) with ileal CD who underwent small bowel resection (for stricture in 27 patients) and a preoperative contrast-enhanced MRI exam within one month before surgery were retrospectively included. Image assessment included qualitative (pattern/degree of enhancement, presence of ulcerations/fistulas/abscesses) and quantitative parameters [wall thickness on T2/T1-weighted images (WI), enhancement ratios, apparent diffusion coefficient (ADC), Clermont and MaRIA scores]. MRI parameters were compared with histopathologic findings including active inflammation, collagen deposition and muscle hypertrophy using Chi-2/Fisher or Mann-Whitney tests, and univariate/multivariate logistic/linear regression analyses. Results/UNASSIGNED:Forty ileal segments were analyzed in 35 patients. Layered pattern at early-post-contrast phase was more prevalent (OR=8/p=0.015), ADC was significantly lower (OR=0.005/p=0.028) and MaRIA score was significantly higher (OR=1.125/p=0.013) in inflammation grades 2-3 compared to grade 1. Wall thickness on T2WI was significantly increased (OR=1.688/p=0.043), and fistulas (OR=14.5/p=0.017) were more prevalent in segments with disproportionately increased muscle hypertrophy vs. those with disproportionately increased fibrosis. MaRIA/Clermont scores, wall thickness on T1WI and T2WI and ADC were all significantly correlated with degree of muscular hypertrophy. Conclusion/UNASSIGNED:MRI predicts the degree of inflammation, and can distinguish prominent muscle hypertrophy from prominent fibrosis in ileal CD with reasonable accuracy (AUROC>0.7).

Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c ^+/-(Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death. Accordingly, Mef2c-het mice exhibit decreased neurogenesis, enhanced neuronal apoptosis, and an increased ratio of excitatory to inhibitory (E/I) neurotransmission. Importantly, neurobehavioral deficits, E/I imbalance, and histological damage are all ameliorated by treatment with NitroSynapsin, a new dual-action compound related to the FDA-approved drug memantine, representing an uncompetitive/fast off-rate antagonist of NMDA-type glutamate receptors. These results suggest that MEF2C haploinsufficiency leads to abnormal brain development, E/I imbalance, and neurobehavioral dysfunction, which may be mitigated by pharmacological intervention.

BACKGROUND:The purpose of this study was to determine the impact of revised ASCO/CAP 2013 HER2 guidelines on the clinical practice of pathologists and oncologists. MATERIALS AND METHODS:Retrospective analysis of 1739 patients with invasive breast carcinoma who underwent reflex HER2 (fluorescence in situ hybridization [FISH]) testing, using both 2007 and 2013 guidelines (2007-2014). RESULTS:by 2013 guidelines. Sixty-two of these 69 cases shifted from HER2 equivocal to positive due to change in FISH ratio cutoff from 2.2 to 2.0. Six cases had FISH ratio < 2.0 but immunohistochemistry (IHC) score 3+ in 10% to 30% of tumor cells. One case had FISH ratio of 2.0 and IHC score 3+ in 10% to 30% of tumor cells. FISH and IHC test results were discordant in 5% (95% CI, 4%-6%) of cases using 2013 guidelines. No increase in HER2 FISH equivocal cases was observed. Reflex FISH testing of all IHC 1+ cases at our institution additionally detected 58 patients (5%; 95% CI, 4%-6%) with HER2 amplification. CONCLUSIONS:cases, without introducing significant difference in discordance rate of the IHC and FISH assays. Inclusion of HER2 copy number criterion does not increase the number of FISH equivocal cases in our cohort. We recommend IHC 1+ cases should be offered reflex FISH testing because failure to test them will miss a small number (5%) of potentially treatable cases.

Hepatic artery aneurysm (HAA), although rare, represents a serious diagnostic and therapeutic challenge due to high rupture rate and associated mortality. Early detection and accurate diagnosis are essential for successful management. Here, we present an extremely rare case of multi-focal intrahepatic HAA with confined intrahepatic rupture and hypermetabolic activity at PET imaging, simulating metastasis of melanoma. A retrospective review found only two other HAA at our institution between 2000 and 2015, both of which involved the extrahepatic artery. This report highlights the importance of clinical, radiological, and pathological correlation in the management of this rare condition.

The clinical significance of IMLN metastases in breast cancer is controversial. Although IMLN status is an integral part of current AJCC staging of breast cancer, the elective sampling of IMLN is not part of routine surgery for breast cancer. The purpose of this study was to determine the incidence of IMLN metastases, associated risk factors if any, and its impact on further management and outcome. We retrospectively studied 470 cases that underwent autologous reconstruction surgery between 2002 and 2014. Of 470 cases, 157 breast cancer cases had histology-confirmed IMLN removal during the reconstruction. Only 9 patients (6 %) showed IMLN metastases as compared to 45 (34 %) that showed axillary nodal metastases (p < 0.01). Interestingly, 4 patients had metastases limited to IMLN without any metastases to axillary nodes. IMLN metastasis was significantly associated with age <40 years, lymphovascular invasion, and negative PR status. IMLN metastasis resulted in upstaging of 2 patients from stage I to III, and 1 from stage II to III. Five patients received additional chest wall radiation to target the positive IMLNs. Nine of 157 (6 %) patients with IMLN removal during reconstruction had loco-regional recurrence/metastasis as compared to 20 of 293 (7 %) patients without IMLN removal (p > 0.05) (follow-up, 1-134 months). The overall rate of IMLN metastases (6 %) is much lower than the rate of axillary node metastases. Selective biopsy of IMLNs in patients with breast cancer, especially if younger than 40 years, and with lymphovascular invasion and negative PR status, may guide adjuvant treatment.

Parkinson's disease (PD) is characterized by loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). An association has been reported between PD and exposure to mitochondrial toxins, including environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived stem cell model of PD allowing comparison of A53T α-synuclein (α-syn) mutant cells and isogenic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations in A53T α-syn A9 DA neurons (hNs). We report a pathway whereby basal and toxin-induced nitrosative/oxidative stress results in S-nitrosylation of transcription factor MEF2C in A53T hNs compared to corrected controls. This redox reaction inhibits the MEF2C-PGC1α transcriptional network, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small-molecule high-throughput screening, we identify the MEF2C-PGC1α pathway as a therapeutic target to combat PD.

The synaptic toxicity of soluble amyloid-β (Aβ) oligomers plays a critical role in the pathophysiology of Alzheimer's disease (AD). Here we report that overexpressed α1-takusan, which we previously identified as a protein that enhances synaptic activity via interaction with PSD-95, mitigates oligomeric Aβ-induced synaptic loss. In contrast, takusan knockdown results in enhanced synaptic damage. α1-Takusan interacts with tau either directly or indirectly, and prevents Aβ-induced tau hyperphosphorylation and mitochondrial fragmentation. Deletion analysis identified the second domain (D2) within the takusan protein that is required for PSD-95 clustering and synaptic protection from Aβ. A 51 aa sequence linking D2 to the PDZ-binding C terminus was found to be as effective as full-length takusan in protecting synapses from Aβ-induced damage. Moreover, a sequence containing the D2 from the human protein discs large homolog 5, when linked to a C-terminal PDZ-binding motif, can also increase the clustering of PSD-95 in cortical dendrites. In summary, α1-takusan protects synapses from Aβ-induced insult via interaction with PSD-95 and tau. Thus, takusan-based protein sequences from either mouse or human may be of potential therapeutic benefit in AD.

Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer's disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here, using FRET-based glutamate sensor imaging, we show that amyloid-β peptide (Aβ) engages α7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons. In hippocampal autapses, this eNMDAR activity is followed by reduction in evoked and miniature excitatory postsynaptic currents (mEPSCs). Decreased mEPSC frequency may reflect early synaptic injury because of concurrent eNMDAR-mediated NO production, tau phosphorylation, and caspase-3 activation, each of which is implicated in spine loss. In hippocampal slices, oligomeric Aβ induces eNMDAR-mediated synaptic depression. In AD-transgenic mice compared with wild type, whole-cell recordings revealed excessive tonic eNMDAR activity accompanied by eNMDAR-sensitive loss of mEPSCs. Importantly, the improved NMDAR antagonist NitroMemantine, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from Aβ-induced damage both in vitro and in vivo.