C5a-C5AR1 axis as a potential trigger of the rupture of intracranial aneurysms.

Recent studies have indicated the involvement of neutrophil-mediated inflammatory responses in the process leading to intracranial aneurysm (IA) rupture. Receptors mediating neutrophil recruitment could thus be therapeutic targets of unruptured IAs. In this study, complement C5a receptor 1 (C5AR1) was picked up as a candidate that may cause neutrophil-dependent inflammation in IA lesions from comprehensive gene expression profile data acquired from rat and human samples. The induction of C5AR1 in IA lesions was confirmed by immunohistochemistry; the up-regulations of C5AR1/C5ar1 stemmed from infiltrated neutrophils, which physiologically express C5AR1/C5ar1, and adventitial fibroblasts that induce C5AR1/C5ar1 in human/rat IA lesions. In in vitro experiments using NIH/3T3, a mouse fibroblast-like cell line, induction of C5ar1 was demonstrated by starvation or pharmacological inhibition of mTOR signaling by Torin1. Immunohistochemistry and an experiment in a cell-free system using recombinant C5 protein and recombinant Plasmin indicated that the ligand of C5AR1, C5a, could be produced through the enzymatic digestion by Plasmin in IA lesions. In conclusion, we have identified a potential contribution of the C5a-C5AR1 axis to neutrophil infiltration as well as inflammatory responses in inflammatory cells and fibroblasts of IA lesions. This cascade may become a therapeutic target to prevent the rupture of IAs.

[Inflammatory Responses in Hemorrhagic Stroke].

Inflammation is triggered by various intrinsic and extrinsic stimuli as a protective machinery to maintain homeostasis in the human body. Usually, it is magnified in intensity initially and regresses rapidly afterwards; this phenomenon is called acute inflammation. However, it occasionally lasts a long time; this phenomenon is called chronic inflammation. Induction of some specific machineries, i.e., formation of a positive feedback loop, inflammatory cell infiltration, and changes in tissue architecture, is required for the transition to chronic inflammation; this differentiates chronic and acute inflammation in nature. Chronic inflammation is a common pathogenesis of various diseases, including cancer, vascular disease, and stroke. Recent experimental studies have clarified the crucial role of inflammatory responses in the development and progression of hemorrhagic stroke mediated by tissue destruction or some other aspects of diseases. In this review, we summarize the research findings of the role of inflammation in hemorrhagic stroke.

Symptomatic atherosclerotic plaque accompanied by carotid web.

Here, we describe a case of a 67-year-old man who was transferred to our hospital with complaints of sudden upper right limb weakness and ataxia. Scattered acute cerebral infarction was found in the watershed zone between the left anterior cerebral artery and the middle cerebral artery territories. A shelf-like structure at the origin of the left carotid artery and a vulnerable plaque distal to the lesion was found. Symptomatic atherosclerotic plaque with concomitant carotid web was diagnosed. Carotid endarterectomy resulted in good revascularization. Hemodynamic changes associated with vascular stenosis are involved in atherosclerosis. The current case is valuable and shows that carotid web can cause not only embolic infarction but also cerebral thrombosis due to atheroma formation in the carotid artery.

Intramural Hematoma in Vertebrobasilar Dolichoectasia-Related Stroke: A Retrospective Analysis of Six Consecutive Patients.

BACKGROUND: The pathophysiology underlying vertebrobasilar dolichoectasia (VBD) is largely unknown. However, a few reports have demonstrated that acute intramural hematoma (IMH) in VBD is associated with stroke. We aimed to investigate the clinical and radiological features of IMH in VBD and the role of IMH in predicting rupture and patient outcomes. METHODS: We retrospectively reviewed the medical records of patients treated in 2 stroke centers between January 2012 and December 2021. Patients presenting with VBD and stroke were eligible for study inclusion. We excluded patients with stroke caused by arterial dissection or artery-to-artery embolism. IMH was defined as a crescent-shaped area of high signal density in the vessel wall on axial computed tomography in the absence of an intimal flap, double lumen, and pearl-and-string sign. RESULTS: Six patients were analyzed. All presented with symptoms of brainstem/cerebellar infarction without headache. Interobserver agreement for the presence or absence of IMH was excellent (100%). IMH was detected in 5 patients. The positive predictive value of IMH for rupture was 80% (95% confidence interval, 28%-99.5%). The median time from symptom onset to rupture was 2.5 days (range, 1.5-4). Median computed tomography values were significantly higher within the IMH than those in the lumen of the basilar artery (70 vs. 44.5 Hounsfield units; P = 0.008). The modified Rankin scale score on day 30 after onset was 5 in 1 patient and 6 in the remaining 5. CONCLUSIONS: IMH in patients with VBD presenting with brainstem/cerebellar infarction should be regarded as a sign associated with a high risk of rupture.

3D Turbo Spin-echo MRI-based Mechanical Thrombectomy at Middle Cerebral Artery Bifurcations.

We describe three cases with acute middle cerebral artery (MCA) occlusion. From the pre-operative MRI, including three-dimensional turbo spin-echo sequences using T1WI and T2WI, we assessed both thrombus configuration and arterial anatomy at the MCA bifurcations. For efficient endovascular thrombectomy, we identified the applied MCA segment 2 (M2) branch, in which the main thrombus was buried. Sufficient recanalization after a single pass was achieved and the patients made a marked recovery. Although mechanical thrombectomy for M2 occlusion has not been of proven benefit, the endovascular procedure based on three-dimensional turbo spin-echo imaging is useful for more complete thrombus removal at MCA bifurcations.

True superficial temporal artery aneurysm: A case after extracranial-intracranial bypass surgery and a systematic review.

Background: Nontraumatic true superficial temporal artery aneurysm (STAA) is rare, and its characteristics and pathogenesis are unclear. Methods: We report a case of STAA and performed a systematic review of PubMed, Scopus, and Web of Science using the keyword "superficial temporal artery aneurysm" to include studies on STAA reported through July 2022. We excluded studies on STAA associated with trauma, arterial dissection, infection, or vasculitis. Results: A 63-year-old woman who underwent left superficial temporal artery (STA)-middle cerebral artery bypass surgery 8 years previously was diagnosed with an aneurysm located at the left STA. The blood flow volume estimated by ultrasonography was higher in the left STA than in the contralateral counterpart (114 mL/min vs. 32 mL/min). She underwent clipping surgery to prevent aneurysmal rupture without sequela. The lesion was diagnosed as a true aneurysm by histology. The systematic review identified 63 cases (including the present case) of nontraumatic true STAA. The median age of the patients was 57 (interquartile range [IQR]: 41-70) years. Most (90.5%) cases were detected as a palpable mass. Aneurysmal rupture occurred in only 1 (1.6%) case, despite the large size of aneurysms (median size: 13 [IQR: 8-20] mm) and the high frequency (33.3%) of aneurysmal growth during observation. Most (93.7%) patients underwent surgical resection of STAA without sequela. Conclusion: Our findings suggest that the pathogenesis of true STAA is promoted by hemodynamic stress. The systematic review clarified patients' and aneurysmal characteristics and treatment outcomes, providing further insight into the pathogenesis of nontraumatic true STAA.

A convexity meningioma presenting with an acute subdural hematoma.

BACKGROUND: Meningiomas presenting with acute subdural hematomas are extremely rare. To the best of our knowledge, only 45 cases have been reported to date. We report on a case of a meningioma mimicking an acute subdural hematoma as well as a thorough literature review. CASE DESCRIPTION: A 67-year-old man with no history of trauma was referred to our hospital with sudden onset of decreased level of consciousness and left hemiplegia. Computed tomography revealed an acute convexity subdural hematoma. Emergency surgery to remove the hematoma was performed. The hematoma was found to exist in the extra-axial space and the attached dura mater and pia mater remained intact. Pathological examination revealed a transitional meningioma, the World Health Organization Grade 1. Detailed medical history taken postoperatively revealed that a convexity meningioma had been diagnosed incidentally at another facility 1 year earlier. CONCLUSION: Acute subdural hematomas due to meningiomas are rare, and establishing the cause is challenging. Prompt and precise diagnosis of such entities may afford patients a better prognosis.

Cisplatin and ultra-violet-C synergistically down-regulate receptor tyrosine kinases in human colorectal cancer cells.

BACKGROUND: Platinum-containing anti-cancer drugs such as cisplatin are widely used for patients with various types of cancers, however, resistance to cisplatin is observed in some cases. Whereas we have recently reported that high dose UV-C (200 J/m²) induces colorectal cancer cell proliferation by desensitization of EGFR, which leads oncogenic signaling in these cells, in this study we investigated the combination effect of low dose cisplatin (10 µM) and low dose UV-C (10 J/m²) on cell growth and apoptosis in several human colorectal cancer cells, SW480, DLD-1, HT29 and HCT116. RESULTS: The combination inhibited cell cycle and colony formation, while either cisplatin or UV-C alone had little effect. The combination also induced apoptosis in these cells. In addition, the combination caused the downregulation of EGFR and HER2. Moreover, UV-C alone caused the transient internalization of the EGFR, but with time EGFR recycled back to the cell surface, while cisplatin did not affect its localization. Surprisingly, the combination caused persistent internalization of the EGFR, which results in the lasting downregulation of the EGFR. CONCLUSIONS: The combination of low dose cisplatin and low dose UV-C synergistically exerted anti-cancer effect by down-regulating RTK, such as EGFR and HER2. These findings may provide a novel strategy for the treatment of patients with colorectal cancer.

UVC irradiation suppresses platelet-derived growth factor-BB-induced migration in human pancreatic cancer cells.

We have recently reported that short wavelength ultraviolet-C (UVC) irradiation inhibits cell growth and induces apoptosis in human pancreatic cancer cells. In this study, we investigated the effect of UVC on platelet-derived growth factor (PDGF)-BB-induced migration in pancreatic cancer cells, AsPC1 and BxPC3. In cell migration assays using a Boyden chamber Transwell, PDGF-BB exerted a maximum effect on migration of these cells at a dose of 70 ng/ml after 36 h of treatment. PDGF-BB also caused phosphorylation of p44/p42 mitogen-activated protein kinase (MAPK), stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK) and Akt, but not of p38 MAPK in these cells. Pretreatment of these cells with UVC at a dose over 10 J markedly suppressed PDGF-BB-induced migration. Since UVC significantly inhibited PDGF-BB-induced phosphorylation of Akt, and subsequent glycogen synthase kinase (GSK) 3ß, but not p44/p42 MAPK and SAPK/JNK, it is likely that UVC inhibits PDGF-BB-induced migration by suppressing the Akt-GSK3ß pathway in pancreatic cancer cells. Taken together with our previous findings, UVC could be a useful tool for the treatment of patients with pancreatic cancer.

Phosphorylation status of heat shock protein 27 plays a key role in gemcitabine-induced apoptosis of pancreatic cancer cells.

Gemcitabine, an antitumor drug, is currently considered to be the standard of care for the treatment of advanced pancreatic cancer, but the clinical outcome is still not satisfactory. Although heat shock protein (HSP) 27 is implicated in the resistance to chemotherapy in several types of cancers, the precise role of phosphorylated HSP27 in cancer cells remains to be clarified. In this study, we investigated the relationship between the effect of gemcitabine and the phosphorylation status of HSP27 in pancreatic cancer cells, Panc1 and KP3. Gemcitabine suppressed pancreatic cancer cell growth and induced apoptosis. Gemcitabine caused activation of p38 mitogen-activated protein kinase (MAPK), MAPK-activated protein kinase 2 (MAPKAPK-2) and subsequently phosphorylation of HSP27 at Ser15, 78 and 82 without affecting total HSP27 levels. The inhibitions of p38 MAPK and MAPKAPK-2 reduced the phosphorylation of HSP27 and apoptosis in gemcitabine-treated cells. To further investigate the role of phosphorylated HSP27, we established Panc1 cell lines which were stably transfected with empty vector (empty cells), wild-type HSP27-encoding vector (WT cells) and 2 mutant HSP27-encoding vectors that mimic non-phosphorylated (3A), and phosphorylated (3D), respectively. In comparison of empty cells with WT cells, there was no difference in cell growth rate and the sensitivity to gemcitabine. Interestingly, cell growth of 3D cells was retarded as compared to that of 3A cells. Taken together, our results strongly suggest that phosphorylation status of HSP27 plays a key role in gemcitabine-induced growth suppression of pancreatic cancer.

Ultraviolet enhances the sensitivity of pancreatic cancer cells to gemcitabine by activation of 5' AMP-activated protein kinase.

Although gemcitabine is recognized as the standard drug for the treatment of advanced pancreatic cancer, the clinical outcome is not satisfactory. We recently reported that relatively high dose ultraviolet-C (UV-C; 200J) inhibits cell growth by desensitization of epidermal growth factor receptor (EGFR) in human pancreatic cancer cells. In the present study, we investigated the combination effects of low dose UV-C (10J) and gemcitabine on apoptosis and cell growth in these cells. UV-C enhanced gemcitabine-induced suppression of cell viability. In addition, the combination use clearly induced apoptosis, while neither UV-C nor gemcitabine alone did. Concurrently, combination use caused the decrease in the EGFR protein level and reduced EGF-induced activation of Akt pathway, subsequently resulting in accumulation of ß-catenin. The order of the treatment with UV-C and gemcitabine did not affect their synergistic effects on apoptosis and cell growth. Interestingly, combination use synergistically induced phosphorylation of 5' AMP-activated protein kinase (AMPK) alpha at Thr172 and acetyl-CoA carboxylase at Ser79 as a downstream molecular target of AMPK. AMPK activator, 5-aminoimidazole-4-carboxamide-1-ß-riboside, induced apoptosis and suppressed cell growth in these cells, thus suggesting that combination effects of UV-C and gemcitabine is due to the activation of AMPK. Together, our findings could provide a new aspect of pancreatic cancer therapy.

Ultraviolet irradiation can induce evasion of colon cancer cells from stimulation of epidermal growth factor.

Receptor down-regulation is the most prominent regulatory system of EGF receptor (EGFR) signal attenuation and a critical target for therapy against colon cancer, which is highly dependent on the function of the EGFR. In this study, we investigated the effect of ultraviolet-C (UV-C) on down-regulation of EGFR in human colon cancer cells (SW480, HT29, and DLD-1). UV-C caused inhibition of cell survival and proliferation, concurrently inducing the decrease in cell surface EGFR and subsequently its degradation. UV-C, as well as EGFR kinase inhibitors, decreased the expression level of cyclin D1 and the phosphorylated level of retinoblastoma, indicating that EGFR down-regulation is correlated to cell cycle arrest. Although UV-C caused a marked phosphorylation of EGFR at Ser-1046/1047, UV-C also induced activation of p38 MAPK, a stress-inducible kinase believed to negatively regulate tumorigenesis, and the inhibition of p38 MAPK canceled EGFR phosphorylation at Ser-1046/1047, as well as subsequent internalization and degradation, suggesting that p38 MAPK mediates EGFR down-regulation by UV-C. In addition, phosphorylation of p38 MAPK induced by UV-C was mediated through transforming growth factor-ß-activated kinase-1. Moreover, pretreatment of the cells with UV-C suppressed EGF-induced phosphorylation of EGFR at tyrosine residues in addition to cell survival signal, Akt. Together, these results suggest that UV-C irradiation induces the removal of EGFRs from the cell surface that can protect colon cancer cells from oncogenic stimulation of EGF, resulting in cell cycle arrest. Hence, UV-C might be applied for clinical strategy against human colon cancers.