Background and purpose Cerebral aneurysm (CA) affects 3% of the population and is associated with hemodynamic stress and inflammation. Myeloperoxidase (MPO), a major oxidative enzyme associated with inflammation, is increased in CA patients, but whether MPO contributes to CA is not known. We tested the hypotheses that MPO is increased within human CA and is critical for formation and rupture of CA in mice. Methods Blood was drawn from the lumen of CAs and femoral arteries of 25 patients who underwent endovascular coiling of CA, and plasma MPO concentrations were measured with ELISA. Effects of endogenous MPO on CA formation and rupture were studied in MPO knockout (KO) mice and wild-type (WT) mice using an angiotensin II-elastase induction model of CA. In addition, effects of MPO on inflammatory gene expression in endothelial cells were analyzed. Results Plasma concentrations of MPO were 2.7-fold higher within CA than in femoral arterial blood in CA patients. MPO-positive cells were increased in aneurysm tissue compared with superficial temporal artery of CA patients. Incidence of aneurysms and subarachnoid hemorrhage was significantly lower in MPO KO than in WT mice. In cerebral arteries, proinflammatory molecules including TNFα, COX2, CXCL1, MMP8, CD68 and MMP13, and leukocytes were increased, and α-smooth muscle actin was decreased, in WT but not in MPO KO mice after induction of CA. MPO per se increased expression of VCAM1 and ICAM1 in endothelial cells. Conclusions These findings suggest that MPO may contribute importantly to formation and rupture of CA.

Macrophages play a central role in the inflammatory response leading to aneurysm formation, progression, and rupture. The purpose of this study was to determine whether granulocyte-monocyte colony-stimulating factor (GM-CSF) plays a role in the progression of human intracranial aneurysms. Specifically, we investigated whether there was a correlation between the aneurysm size and the concentration of GM-CSF in the lumen of intracranial aneurysms. The concentrations of GM-CSF in blood samples drawn from the lumen of 15 human unruptured saccular intracranial aneurysms of 14 consecutive patients were compared. The aneurysm size was 10.3 -9 mm on average. The mean plasma concentration of GM-CSF was 27.9 -3.1 pg/mL in the lumen of intracranial aneurysms. The mean plasma concentration of GM-CSF was significantly higher in aneurysms larger than 7 mm (30.1 -2.8 pg/mL) compared with aneurysms smaller than 7 mm (26.4 -2.4 pg/mL; p = 0.02). There was a significant positive correlation between the aneurysm size and the plasma concentration of GM-CSF (Spearman's rho = 0.55; p = 0.04). There is a significant positive correlation between the aneurysm size and the plasma concentration of GM-CSF in aneurysm lumens. This suggests that GM-CSF, through its stimulatory function on macrophages, may promote aneurysm progression and may be a possible therapeutic target.

Intracranial aneurysms are a life-threatening cerebrovascular pathology with a probability of spontaneous rupture. Current intervention techniques carry inherent risk. Recent investigation has reinforced inflammation's role in the pathophysiological process of cerebral aneurysms. These data suggest alternative diagnostic and noninvasive therapeutic strategies. Furthermore, novel characteristics of the underlying disease have been elucidated through distinct bioinformatic and gene expression profile analyses. This article will emphasize the most recent investigation, highlighting findings of clinical significance and etiological relevance.

IntroductionThymic carcinoma is a rare malignancy often presenting at an advanced stage. Radiation therapy and chemotherapy are often the only treatment options available to physicians.MethodsA 70-year-old man presented with an unresectable stage III thymic tumor and was treated with 45 Gy in 25 fractions followed by a boost of 21.6 Gy in 12 fractions. He was also treated with bortezomib for multiple myeloma unrelated to his primary malignancy.ResultsThe patient made a full recovery following the radiation regimen and remained disease free 4 years after the treatment.ConclusionExclusive treatment with intensity-modulated radiation therapy provides a viable treatment option for patients presenting with advanced stage thymic carcinoma.

Background: Colorectal cancer (CRC) is currently the third most common cancer worldwide and the second most deadly cancer. CRC is characterized by the loss of cellular architecture and altered polarity; features which can be controlled by cell-trafficking. In the intestine key cell trafficking pathways are controlled by Myosin 5b (MYO5B). Loss of functional MYO5B leads to profound changes in gastrointestinal epithelial cells including increased proliferation, alterations in tight junction proteins, and decreased differentiation. For MYO5B to be functional, it must be folded into the correct structure. This folding is accomplished by the chaperone UNC45A. Recent work indicates that MYO5B is decreased in gastric cancer and during colorectal tumor progression. However, the mechanism resulting in altered MYO5B expression in colorectal cancer is currently unknown. Hypothesis: We hypothesize that microRNAs regulate the expression of UNC45A which in turn can impact MYO5B function to promote colorectal cancer. Methods & Results: Analysis of high-throughput RNA-sequencing data in the Cancer Genome Atlas revealed that the MYO5B gene was hyper-methylated in CRC tumors (n=286) compared to controls (n=41). In gastric cancer, hyper-methylation leads to silencing of MYO5B gene expression. Consistent with findings in gastric cancer, we found that MYO5B gene expression was significantly reduced in CRC tumors. Immunostaining of CRC tumor arrays and analysis of the Clinical Proteomic Tumor Analysis Consortium demonstrated that MYO5B was also reduced at the protein level. For comparison, we examined MYO5B levels in normal human colonic organoid monolayers, immortalized human colon NCM-460 cells, and colon cancer cell lines T84 and HT29-MTX cells. By qPCR, we found that MYO5B gene expression was significantly reduced in the cancer cells compared to the human colonic organoids, confirming our database analysis. We reasoned that even if MYO5B was generated in CRC, it might not be functional if UNC45A was not present. Using the same databases, we found that UNC45A levels were unchanged at the level of gene expression, but significantly reduced at the level of protein. Analysis of miRMap data revealed that multiple microRNAs can target UNC45A. The top 10 UN45A-targeting microRNAs were all found to be increased in CRC compared to normal control tissue; suggesting that UNC45A protein may be diminished due to microRNA mediated cleavage. The functional significance of decreased MYO5B in CRC was highlighted by the fact that patients with lower levels of MYO5B had decreased survival compared to those with higher levels of MYO5B. Additionally, loss of MYO5B correlated with increased ribosome biogenesis; a key driver of tumor proliferation. Conclusions: These data indicate the MYO5B is likely decreased in CRC due to gene methylation and improper protein folding by UNC45A. Loss of MYO5B is significant since it is associated with a worse prognosis and c This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Intestinal enterocytes have an elaborate apical membrane of actin rich protrusions known as microvilli. The organization of microvilli is orchestrated by the intermicrovillar adhesion complex (IMAC) which connects the distal tips of adjacent microvilli. The IMAC is comprised of CDHR2 and CDHR5 as well as the scaffolding proteins USH1C, ANKS4B and Myosin 7b. To create an IMAC, cells must transport the proteins to the apical membrane. Myosin 5b (MYO5B) is a molecular motor that traffics ion transporters to the apical membrane of enterocytes, and we hypothesized that MYO5B may also be responsible for the localization of IMAC proteins. Methods & Results: To address this question, we used 2 different mouse models: (1) neonatal germline MYO5B knockout (MYO5B KO) mice and (2) adult intestinal specific tamoxifen inducible VillinCreERT2;MYO5Bflox/flox mice. In control mice, immunostaining revealed that CDHR2, CDHR5, USH1C, and MYO7B were highly enriched at the tips of the microvilli. In contrast, neonatal germline and adult MYO5B deficient mice showed loss of apical CDHR2, CDHR5, and MYO7B in the brush border and accumulation in a subapical compartment. Co-localization analysis revealed decreased Mander's coefficients in adult inducible MYO5B deficient mice compared to control mice for CDHR2, CDHR5, USH1C and MYO7B. Scanning electron microscopy images further demonstrated aberrant microvilli packing in adult inducible MYO5B deficient mouse small intestine. Conclusions: These data indicate that MYO5B is responsible for the delivery of IMAC components to the apical membrane.

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