Predicting Chronic Subdural Hematoma Resolution and Time to Resolution Following Surgical Evacuation.

Background: Growing evidence suggests that chronic subdural hematoma (CSDH) may have long-term adverse effects even after surgical evacuation. Hematoma recurrence is commonly reported as a short-term, postoperative outcome measure for CSDH, but other measures such as hematoma resolution may provide better insight regarding mechanisms behind longer-term sequelae. This study aims to characterize postoperative resolution times and identify predictors for this relatively unexplored metric. Methods: Consecutive cases (N = 122) of burr hole evacuation for CSDH by a single neurosurgeon at Columbia University Irving Medical Center from 2000 to 2019 were retrospectively identified. Patient characteristics, presenting factors, and date of hematoma resolution were abstracted from the electronic health record. Outcome measures included CSDH resolution at 6 months, surgery-to-resolution time, and inpatient mortality. Univariate and multivariate analyses were performed to determine predictors of outcome measures. Results: Hematoma resolution at 6 months was observed in 58 patients (47.5%), and median surgery-to-resolution time was 161 days (IQR: 85-367). Heavy drinking was predictive of non-resolution at 6 months and longer surgery-to-resolution time, while increased age was predictive of non-resolution at 6 months. Antiplatelet agent resumption was associated with non-resolution at 6 months and longer surgery-to-resolution time on univariate analysis but was not significant on multivariate analysis. Conclusion: Postoperative resolution times for most CSDHs are on the order of several months to a year, and delayed resolution is linked to heavy drinking and advanced age. Subsequent prospective studies are needed to directly assess the utility of hematoma resolution as a potential metric for long-term functional and cognitive outcomes of CSDH.

Differential expression of microRNA and arachidonic acid metabolism in aspirin-treated human cardiac and peri-cardiac fat-derived mesenchymal stem cells.

Aspirin is a widely used drug with anti-coagulating and anti-inflammatory effects on atherosclerotic vascular disease. The goal of this study was to investigate expression of microRNA (miR) in association with changes in arachidonic acid (AA) metabolism in cardiac and surrounding fat mesenchymal stem cells (MSCs) treated with or without aspirin. Aspirin-targeted endogenous lipid metabolites that impact specific miRNA expression were examined by mass spectrometry. The pattern of miR expression was characterized using a microarray of 1100 miRs. There were a dozen miRs expressed differentially in MSCs from human myocardium and peri-myocardial fat tissue at baseline, including hsa-miR-1307-3p, 765, 4739, 3613-3p, 4281, 6816-5p, 2861, and 146b-5p. After exposure to aspirin, cardiac MSCs expressed an array of of miRs (eg, hsa-miR-4734, 10a-5p, 4267, 3197, and 3182), while generation of their endogenous AA metabolites was depressed. However, in the peri-cardiac adipose tissue-derived MSCs, treatment with the same doses of aspirin caused mild changes in the miR expression levels. In conclusion, MSCs from human myocardium and peri-myocardial fat tissue respond differentially to aspirin treatment by alterations in miR expression and AA metabolism. The study further raises an intriguing issue as to whether the copious amounts of aspirin taken worldwide by patients with cardiovascular disease may have direct impacts on their heart repair processes by regulation of stromal cell miR expression and AA metabolism.

Novel method to detect, isolate, and culture prostate culturing circulating tumor cells.

BACKGROUND: Effectively detecting and culturing circulating tumor cells (CTCs), is critical for diagnosis of early metastasis, monitoring anti-cancer therapeutic efficacy, and drug screening. However, most current FDA approved CTC detection methods are based on antibody binding, which has limitations due to the nature of variations in antibody preparation and antibody-CTC size mismatches. Thus, searching for alternative and advanced methods is urgent and necessary. METHODS: Prostate cancer tissue was digested by collagenase and cultured. Cancer stromal cells were identified and labelled with 4',6-diamidino-2-phenylindole (DAPI) before incubation with whole blood of cancer mice (bearing a later stage of prostate cancer). The attached blood CTCs on the DAPI-labeled cancer stromal cells were detected, isolated, cultured and produced into individual cancer cell lines. RESULTS: Five clones of prostate cancer cells isolated from cancer tissue were successfully cultured. One (Clone-1) of the five clones showed positive staining for all three cancer stromal cell markers (CD133, α2ß1 integrin and CD44). Clone-1 cells rich with epithelial cell adhesion molecule (EpCAM) on the cell surface were further identified. The Clone-1 stromal cells labeled as "bait" attracted and caught a trace number of CTCs from the whole blood of mice with advanced stage cancer. Efficient culturing of the caught CTCs from single cell to forming of individual cancer cell line(s) were established. CONCLUSIONS: We present a fundamental advancement of CTC detection and culturing using a different mechanism (cell-cell interaction) rather than the traditional antibody-based immune-binding, such as CellSearchTM system. This study has potential to be fully developed into a novel approach for early cancer metastasis detection, and chemotherapy efficacy monitoring. The efficiently cultured CTCs could be used for single-clone CTC analysis and anti-cancer drug screening to further advance the development of individualized medicine.

Prostaglandin E2 produced by inducible COX-2 and mPGES-1 promoting cancer cell proliferation in vitro and in vivo.

AIM: Many cancers originate and flourish in a prolonged inflammatory environment. Our aim is to understand the mechanisms of how the pathway of prostaglandin E2 (PGE2) biosynthesis and signaling can promote cancer growth in inflammatory environment at cellular and animal model levels. MAIN METHODS: In this study, a chronic inflammation pathway was mimicked with a stable cell line that over-expressed a novel human enzyme consisting of cyclooxygenase isoform-2 (COX-2) linked to microsomal (PGE2 synthase-1 (mPGES-1)) for the overproduction of pathogenic PGE2. This PGE2-producing cell line was co-cultured and co-implanted with three human cancer cell lines including prostate, lung, and colon cancers in vitro and in vivo, respectively. KEY FINDINGS: Increases in cell doubling rates for the three cancer cell types in the presence of the PGE2-producing cell line were clearly observed. In addition, one of the four human PGE2 subtype receptors, EP1, was used as a model to identify PGE2-signaling involved in promoting the cancer cell growth. This finding was further proven in vivo by co-implanting the PGE2-producing cells line and the EP1-positive cancer cells into the immune deficient mice, after that, it was observed that the PGE2-producing cells promoted all three types of cancer formation in the mice. SIGNIFICANCE: This study clearly demonstrated that the human COX-2 linked to mPGES-1 is a pathway that, when mediated by the EP, is linked to promoting cancer growth in a chronic inflammatory environment. The identified pathway could be used as a novel target for developing and advancing anti-inflammation and anti-cancer interventions.

Screening and identification of dietary oils and unsaturated fatty acids in inhibiting inflammatory prostaglandin E2 signaling in fat stromal cells.

BACKGROUND: The molecular mechanisms of dietary oils (such as fish oil) and unsaturated fatty acids, which are widely used by the public for anti-inflammation and vascular protection, have not been settled yet. In this study, prostaglandin E(2) (PGE(2))-mediated calcium signaling was used to screen dietary oils and eight unsaturated fatty acids for identification of their anti-inflammatory mechanisms. Isolated fat/stromal cells expressing endogenous PGE(2) receptors and an HEK293 cell line specifically expressing the recombinant human PGE(2) receptor subtype-1 (EP(1)) were cultured and used in live cell calcium signaling assays. The different dietary oils and unsaturated fatty acids were used to affect cell signaling under the specific stimulation of a pathological amount of inflammatory PGE(2). RESULTS: It was identified that fish oil best inhibited the PGE(2) signaling in the primary cultured stromal cells. Second, docosahexaenoic acid (DHA), found in abundance in fish oil, was identified as a key factor of inhibition of PGE(2) signaling. Eicosapentaenoic acid (EPA), another major fatty acid found in fish oil and tested in this study was found to have small effect on EP(1) signaling. The study suggested one of the four PGE(2) subtype receptors, EP(1) as the key target for the fish oil and DHA target. These findings were further confirmed by using the recombinant EP(1) expressed in HEK293 cells as a target. CONCLUSION: This study demonstrated the new mechanism behind the positive effects of dietary fish oils in inhibiting inflammation originates from the rich concentration of DHA, which can directly inhibit the inflammatory EP(1)-mediated PGE(2) receptor signaling, and that the inflammatory response stimulated by PGE(2) in the fat stromal cells, which directly related to metabolic diseases, could be down regulated by fish oil and DHA. These findings also provided direct evidence to support the use of dietary oils and unsaturated fatty acids for protection against heart disease, pain, and cancer resulted from inflammatory PGE(2).