Early Changes in Cortical Emotion Processing Circuits after Mild Traumatic Brain Injury from Motor Vehicle Collision.

Mild traumatic brain injury (mTBI) patients frequently experience emotion dysregulation symptoms, including post-traumatic stress. Although mTBI likely affects cortical activation and structure, resulting in cognitive symptoms after mTBI, early effects of mTBI on cortical emotion processing circuits have rarely been examined. To assess early mTBI effects on cortical functional and structural components of emotion processing, we assessed cortical activation to fearful faces within the first 2 weeks after motor vehicle collision (MVC) in survivors who did and did not experience mTBI. We also examined the thicknesses of cortical regions with altered activation. MVC survivors with mTBI (n = 21) had significantly less activation in left superior parietal gyrus (SPG) (-5.9, -81.8, 33.8; p = 10-3.623), left medial orbitofrontal gyrus (mOFG) (-4.7, 36.1, -19.3; p = 10-3.231), and left and right lateral orbitofrontal gyri (lOFG) (left: -16.0, 41.4, -16.6; p = 10-2.573; right: 18.7, 22.7, -17.7; p = 10-2.764) than MVC survivors without mTBI (n = 23). SPG activation in mTBI survivors within 2 weeks after MVC was negatively correlated with subsequent post-traumatic stress symptom severity at 3 months (r = -0.68, p = 0.03). Finally, the SPG region was thinner in the mTBI survivors than in the non-mTBI survivors (F = 11.07, p = 0.002). These results suggest that early differences in activation and structure in cortical emotion processing circuits in trauma survivors who sustain mTBI may contribute to the development of emotion-related symptoms.

EGY2, a chloroplast membrane metalloprotease, plays a role in hypocotyl elongation in Arabidopsis.

Intramembrane proteases control many important processes in a wide variety of organisms through regulated intramembrane proteolysis (RIP). However, very few intramembrane proteases have been characterized in plants. Intriguingly, EGY2 in Arabidopsis belongs to the Site-2 protease (S2P) family that performs RIP. It contains the conserved catalytic motifs, HExxH and NPDG on its multiple transmembrane helices. Four egy2 knockout mutants have significantly shorter hypocotyls and accumulate lower levels of fatty acids in seedlings. Accumulation of fatty acid biosynthesis enzymes in seedlings are also decreased in egy2 knockout mutants. EGY2 protein resides in the chloroplast and EGY2 transcripts are found throughout the plant except root. Recombinant EGY2 protein cleaves ß-casein in an ATP-independent manner. These results together suggest that EGY2 metalloprotease plays a role in hypocotyl elongation likely through a RIP dependent process to regulate the coordinated expression of nuclear- and plastid-encoded genes.

A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry.

PURPOSE: Approximately 5% of lung adenocarcinomas harbor an EML4-ALK gene fusion and define a unique tumor group that may be responsive to targeted therapy. However ALK-rearranged lung adenocarcinomas are difficult to detect by either standard fluorescence in situ hybridization or immunohistochemistry (IHC) assays. In the present study, we used novel antibodies to compare ALK protein expression in genetically defined lung cancers and anaplastic large cell lymphomas. EXPERIMENTAL DESIGN: We analyzed 174 tumors with one standard and two novel monoclonal antibodies recognizing the ALK protein. Immunostained tissue sections were assessed for the level of tumor-specific ALK expression by objective quantitative image analysis and independently by three pathologists. RESULTS: ALK protein is invariably and exclusively expressed in ALK-rearranged lung adenocarcinomas but at much lower levels than in the prototypic ALK-rearranged tumor, anaplastic large cell lymphoma, and as a result, is often not detected by conventional IHC. We further validate a novel IHC that shows excellent sensitivity and specificity (100% and 99%, respectively) for the detection of ALK-rearranged lung adenocarcinomas in biopsy specimens, with excellent interobserver agreement between pathologists (kappa statistic, 0.94). CONCLUSIONS: Low levels of ALK protein expression is a characteristic feature of ALK-rearranged lung adenocarcinomas. However, a novel, highly sensitive IHC assay reliably detects lung adenocarcinomas with ALK rearrangements and obviates the need for fluorescence in situ hybridization analysis for the majority of cases, and therefore could be routinely applicable in clinical practice to detect lung cancers that may be responsive to ALK inhibitors.

Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population.

PURPOSE: The anaplastic large cell kinase gene (ALK) is rearranged in approximately 5% of lung adenocarcinomas within the Asian population. We evaluated the incidence and the characteristics of ALK-rearranged lung adenocarcinomas within the western population and the optimal diagnostic modality to detect ALK rearrangements in routine clinical practice. EXPERIMENTAL DESIGN: We tested 358 lung adenocarcinomas from three institutions for ALK rearrangements by fluorescent in situ hybridization (FISH) and immunohistochemistry with and without tyramide amplification. The clinicopathologic characteristics of tumors with and without ALK rearrangements were compared. RESULTS: We identified 20 (5.6%) lung adenocarcinomas with ALK rearrangements within our cohort of western patients. ALK rearrangement was associated with younger age (P = 0.0002), never smoking (P < 0.0001), advanced clinical stage (P = 0.0001), and a solid histology with signet-ring cells (P < 0.0001). ALK rearrangement was identified by FISH in 95% of cases and immunohistochemistry with and without tyramide amplification in 80% and 40% of cases, respectively, but neither FISH nor immunohistochemistry alone detected all cases with ALK rearrangement on initial screening. None of the ALK-rearranged tumors harbored coexisting EGFR mutations. CONCLUSIONS: Lung adenocarcinomas with ALK rearrangements are uncommon in the western population and represent a distinct entity of carcinomas with unique characteristics. For suspected cases, dual diagnostic testing, with FISH and immunohistochemistry, should be considered to accurately identify lung adenocarcinomas with ALK rearrangement.