Tip Detection-Antegrade Dissection and Re-Entry With New Puncture Wire in CTO Intervention: Revolution Through 3D-Wiring.

Background: The authors devised the tip detection (TD) method and developed AnteOwl WR intravascular ultrasound to standardize intravascular ultrasound-based 3-dimensional wiring for intraplaque tracking in chronic total occlusion (CTO)-percutaneous coronary intervention (PCI). The TD method also allowed antegrade dissection and re-entry (ADR). Combining TD-ADR with Conquest Pro 12 Sharpened Tip (CP12ST) wire, a new ADR wire with the strongest penetration force developed to date, enabled re-entry anywhere except calcification sites. Objectives: This study investigated the efficacy and feasibility of TD-ADR by comparison of procedural outcomes with Stingray-ADR in CTO-PCI. Methods: Twenty-seven consecutive CTO cases treated by TD-ADR with CP12ST wire between August 2021 and April 2023 and 27 consecutive CTO cases treated by Stingray-ADR with Conquest 8-20 (CP20) wire between March 2018 and July 2021 were retrospectively enrolled as the TD-ADR by CP12ST wire group and Stingray-ADR by CP20 wire group, respectively, from 4 facilities that could share technical information on these procedures. Results: The success rate of the ADR procedure was significantly improved (27 of 27 cases [100%] vs 18 of 27 cases [67%], respectively; P = 0.002) and total procedural time was significantly reduced (median procedural time: 145.0 [Q1-Q3: 118.0-240.0] minutes vs 185.0 [Q1-Q3: 159.5-248.0] minutes, respectively; P = 0.028) in the TD-ADR by CP12ST wire group compared to the Stingray-ADR by CP20 wire group. There were few in-hospital major adverse cardiac and cerebrovascular events or no complications in either group. Conclusions: TD-ADR by CP12ST wire can standardize highly accurate ADR in CTO-PCI.

Scalp Nerve Block Alleviates Headaches Associated With Sonication During Transcranial Magnetic Resonance-Guided Focused Ultrasound.

BACKGROUND AND OBJECTIVES: In magnetic resonance-guided focused ultrasound (MRgFUS) procedures, headache is a frequent symptom and cause of treatment discontinuation. Herein, we assessed the efficacy of scalp nerve block (SNB) for alleviating headache during MRgFUS procedures. METHODS: The effect of SNB on intraprocedural headache was examined by retrospectively comparing 2 patient cohorts at a single institution. During the study period from April 2020 to February 2022, an SNB protocol for all patients with a skull density ratio ≤0.55 was instituted on October 6, 2021. The number of patients with a skull density ratio ≤0.55 was 34 before the protocol and 36 afterward. Headache intensity was evaluated using a numerical rating scale (NRS) after each sonication. To evaluate the effect of SNB on headache intensity, multiple regression analysis was performed per patient and per sonication. In the per-patient analysis, the effect of SNB was evaluated using the maximum NRS, mean NRS, and NRS at the first ultrasound exposure that reached 52.5°C. In the per-sonication analysis, the effect of SNB was evaluated not only for the entire sonication but also for sonications classified into ≤9999 J, 10 000 to 29 999 J, and ≥30 000 J energy doses. RESULTS: With SNB, headache alleviation was observed in the NRS after the first sonication that reached 52.5°C in each patient (ß = -2.40, 95% CI -4.05 to -0.758, P = .00499), in the NRS when all sonications were evaluated (ß = -0.647, 95% CI -1.19 to -0.106, P = .0201), and in the NRS when all sonications were classified into 10 000 to 29 999 J (ß = -1.83, 95% CI -3.17 to -0.485, P = .00889). CONCLUSION: SNB significantly reduced headache intensity during MRgFUS, especially that caused by sonication with a moderate-energy dose. These findings suggest that scalp nerves play a role in headache mechanisms during MRgFUS.

KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels.

AIMS: As heart failure (HF) progresses, ATP levels in myocardial cells decrease, and myocardial contractility also decreases. Inotropic drugs improve myocardial contractility but increase ATP consumption, leading to poor prognosis. Kyoto University Substance 121 (KUS121) is known to selectively inhibit the ATPase activity of valosin-containing protein, maintain cellular ATP levels, and manifest cytoprotective effects in several pathological conditions. The aim of this study is to determine the therapeutic effect of KUS121 on HF models. METHODS AND RESULTS: Cultured cell, mouse, and canine models of HF were used to examine the therapeutic effects of KUS121. The mechanism of action of KUS121 was also examined. Administration of KUS121 to a transverse aortic constriction (TAC)-induced mouse model of HF rapidly improved the left ventricular ejection fraction and improved the creatine phosphate/ATP ratio. In a canine model of high frequency-paced HF, administration of KUS121 also improved left ventricular contractility and decreased left ventricular end-diastolic pressure without increasing the heart rate. Long-term administration of KUS121 to a TAC-induced mouse model of HF suppressed cardiac hypertrophy and fibrosis. In H9C2 cells, KUS121 reduced ER stress. Finally, in experiments using primary cultured cardiomyocytes, KUS121 improved contractility and diastolic capacity without changing peak Ca2+ levels or contraction time. These effects were not accompanied by an increase in cyclic adenosine monophosphate or phosphorylation of phospholamban and ryanodine receptors. CONCLUSIONS: KUS121 ameliorated HF by a mechanism totally different from that of conventional catecholamines. We propose that KUS121 is a promising new option for the treatment of HF.

Ten-year clinical outcomes from a randomized trial comparing new-generation everolimus-eluting stent versus first-generation Sirolimus-eluting stent: Results from the RESET extended study.

BACKGROUND: New-generation drug-eluting stents (DES) achieved technological innovations and reported clinical advantages as compared with first-generation DES in clinical trials with 3-5 years follow-up. However, detailed clinical outcome data in very long-term follow-up is still scarce. OBJECTIVES: To evaluate 10-year clinical outcomes after first- and new-generation DES implantation. METHODS: In this extende follow-up study of the RESET, which is a largest randomized trial comparing everolimus-eluting stent (EES) with Sirolimus-eluting stent (SES), the study population consisted of 2892 patients from 84 centers. The primary efficacy and safety endpoints were target lesion revascularization (TLR) and a composite of death or myocardial infarction (MI), respectively. Complete 10-year follow-up was achieved in 87.9% of patients. RESULTS: Cumulative 10-year incidences of TLR and non-TLR were not significantly different between EES and SES (13.9% vs. 15.7%, Log-rank p = 0.20, and 33.4% vs. 31.3%, Log-rank p = 0.30). The cumulative 10-year incidence of death/MI was also not significantly different between the groups (32.5% vs. 34.4%, Log-rank p = 0.18). Cumulative 10-year incidence of definite stent thrombosis was numerically lower in EES than in SES (1.0% vs. 1.7%, Log-rank p = 0.16). The lower risk of EES relative to SES was significant for a composite endpoint of target lesion failure (TLF: 19.6% vs. 24.9%, Log-rank p = 0.001) and target vessel failure (TVF: 26.7% vs. 31.4%, Log-rank p = 0.006). CONCLUSION: During 10-year of follow-up, the risks for primary efficacy and safety endpoints were not significantly different between new-generation EES and first-generation SES, although EES compared with SES was associated with a lower risk for composite endpoints such as TLF and TVF.

Inhibition of microRNA-33b in humanized mice ameliorates nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma in their advanced stages; however, there are currently no approved therapies. Here, we show that microRNA (miR)-33b in hepatocytes is critical for the development of NASH. miR-33b is located in the intron of sterol regulatory element-binding transcription factor 1 and is abundantly expressed in humans, but absent in rodents. miR-33b knock-in (KI) mice, which have a miR-33b sequence in the same intron of sterol regulatory element-binding transcription factor 1 as humans and express miR-33b similar to humans, exhibit NASH under high-fat diet feeding. This condition is ameliorated by hepatocyte-specific miR-33b deficiency but unaffected by macrophage-specific miR-33b deficiency. Anti-miR-33b oligonucleotide improves the phenotype of NASH in miR-33b KI mice fed a Gubra Amylin NASH diet, which induces miR-33b and worsens NASH more than a high-fat diet. Anti-miR-33b treatment reduces hepatic free cholesterol and triglyceride accumulation through up-regulation of the lipid metabolism-related target genes. Furthermore, it decreases the expression of fibrosis marker genes in cultured hepatic stellate cells. Thus, inhibition of miR-33b using nucleic acid medicine is a promising treatment for NASH.

Cerebral tumor embolism from thyroid cancer treated by mechanical thrombectomy: illustrative case.

BACKGROUND: Development in mechanical thrombectomy is progressing dramatically. Tumor embolism has been rarely reported on the basis of pathological study of the retrieved thrombus. Herein, the authors report a case of cerebral tumor embolism from advanced thyroid cancer, which was successfully treated with mechanical thrombectomy. OBSERVATIONS: A 57-year-old man was diagnosed with thyroid cancer with multiple lung metastases and chemotherapy was planned. He experienced left hemiparesis and was bought to the emergency section of the authors' hospital. Magnetic resonance angiography revealed right internal carotid artery occlusion and endovascular treatment was performed. Using a combination of aspiration catheter and stent retriever, white jelly-like embolus was retrieved. The pathological study demonstrated thyroid cancer embolism. Pulmonary vein invasion following lung metastasis of thyroid cancer was most presumably the cause of the tumor embolism. LESSONS: Lung metastasis invading the pulmonary vein may be a cause of tumor embolism. Mechanical thrombectomy using a combination of stent retriever and aspiration catheter is effective in removing the tumor embolus and the pathological examination of the embolus is essential.

Insights into the molecular interaction of cyclodextran with a guest molecule: A computational study.

Cyclodextran (CI) is a cyclic oligosaccharide in which d-glucose forms a ring structure by α-1,6 glycoside linkage and forms an inclusion complex with various guest molecules. In this study, we conducted quantum chemical calculations and molecular dynamics (MD) simulations to analyze the molecular interaction mechanism of CI with a guest molecule. Calculations of cyclodextrin (CD), in which d-glucose forms a ring structure by α-1,4 glycoside linkage, were also performed for comparison. Here, coenzyme Q10 (CoQ10), a promising molecule for industrial application with CI, was chosen as a guest molecule. Our MD simulation demonstrated that the molecular fluctuation was similarly large for both CI and CD when CoQ10 was absent. In the case that CoQ10 exists, the CD was found to form a rigid one-by-one inclusion structure, while CI does not. Additional simulations including multiple CI-8s indicated the possibility that an inclusion structure is maintained by the existence of other CI-8s.

Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth.

Herpes simplex virus thymidine kinase (HSVTK)/ganciclovir (GCV) suicide gene therapy has a long history of treating malignant gliomas. Recently, stem cells from human exfoliated deciduous teeth (SHED), which are collected from deciduous teeth and have excellent harvestability, ethical aspects, and self-renewal, have been attracting attention mainly in the field of gene therapy. In the present study, we assessed SHED as a novel cellular vehicle for suicide gene therapy in malignant gliomas, as we have previously demonstrated with various cell types. SHED was transduced with the HSVTK gene (SHEDTK). In vitro experiments showed a significant bystander effect between SHEDTK and glioma cell lines in coculture. Furthermore, apoptotic changes caused by caspase 3/7 activation were simultaneously observed in SHEDTK and glioma cells. Mice implanted with a mixture of U87 and SHEDTK and treated with intraperitoneal GCV survived for longer than 100 days. Additionally, tumors in treatment model mice were significantly reduced in size during the treatment period. SHEDTK implanted at the contralateral hemisphere migrated toward the tumor crossing the corpus callosum. These results suggested that SHEDTK-based suicide gene therapy has potent tumor tropism and a bystander-killing effect, potentially offering a new promising therapeutic modality for malignant gliomas.

Factors associated with the location of perivascular space enlargement in middle-aged individuals undergoing brain screening in Japan.

OBJECTIVE: In elderly populations, the enlargement of the perivascular space is related to small vessel disease and the glymphatic system. Enlarged perivascular spaces (EPVS) in the basal ganglia (EPVS-BG) and EPVS in the centrum semiovale (EPVS-CSO) are associated with different pathophysiological processes. However, the prevalence of EPVS and the factors associated with EPVS location in healthy middle-aged individuals are still unclear. We aimed to determine the prevalence of EPVS and the factors associated with EPVS location among healthy individuals in their 40 s METHODS: This study included 5000 consecutive healthy individuals who underwent screening for brain diseases in Japan from August to December 2018. Of them, the data of individuals in their 40 s were extracted and analyzed. The associations of age, sex, body mass index, smoking and drinking history, and medical history with EPVS location were investigated. Similar analyses were performed for the other age groups. A literature review on the factors associated with EPVS location was also performed. RESULTS: A total of 1720 individuals in their 40 s were finally included. The prevalence of EPVS-BG and EPVS-CSO was 7.7% and 9.2%, respectively. Age (years), smoking history, and hypertension were associated with EPVS-BG; none of the studied factors were found to be associated with EPVS-CSO. In the elderly, the factors previously reported to be associated with EPVS-BG included atherosclerosis change, while the factors associated with EPVS-CSO were cerebral amyloid angiopathy-related formation. CONCLUSION: Both EPVS-BG and EPVS-CSO occurred among healthy individuals in their 40 s, but they did so rarely, and less prevalently than in older age groups. EPVS-BG and EPVS-CSO may represent early imaging signs of the atherosclerotic and cerebral amyloid angiopathy processes, respectively. DATA AVAILABILITY: The anonymized data for this study will be shared upon any qualified investigator's request to the corresponding author. Primary data from this study will be made available upon reasonable request in accordance with the review board of the research institute.

Efficacy of HSV-TK/GCV system suicide gene therapy using SHED expressing modified HSV-TK against lung cancer brain metastases.

Lung cancer is one of the most common cancers, and the number of patients with intracranial metastases is increasing. Previously, we developed an enzyme prodrug suicide gene therapy based on the herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) system using various mesenchymal stem cells to induce apoptosis in malignant gliomas through bystander killing effects. Here, we describe stem cells from human exfoliated deciduous teeth (SHED) as gene vehicles of the TK/GCV system against a brain metastasis model of non-small cell lung cancer (NSCLC). We introduced the A168H mutant TK (TKA168H) into SHED to establish the therapeutic cells because of the latent toxicity of wild type. SHED expressing TKA168H (SHED-TK) exhibited chemotaxis to the conditioned medium of NSCLC and migrated toward implanted NSCLC in vivo. SHED-TK demonstrated a strong bystander effect in vitro and in vivo and completely eradicated H1299 NSCLC in the brain. SHED-TK cells implanted intratumorally followed by GCV administration significantly suppressed the growth of H1299 and improved survival time. These results indicate that the TKA168H variant is suitable for establishing therapeutic cells and that intratumoral injection of SHED-TK followed by GCV administration may be a useful strategy for therapeutic approaches.

Inhibition of microRNA-33b specifically ameliorates abdominal aortic aneurysm formation via suppression of inflammatory pathways.

Abdominal aortic aneurysm (AAA) is a lethal disease, but no beneficial therapeutic agents have been established to date. Previously, we found that AAA formation is suppressed in microRNA (miR)-33-deficient mice compared with wild-type mice. Mice have only one miR-33, but humans have two miR-33 s, miR-33a and miR-33b. The data so far strongly support that inhibiting miR-33a or miR-33b will be a new strategy to treat AAA. We produced two specific anti-microRNA oligonucleotides (AMOs) that may inhibit miR-33a and miR-33b, respectively. In vitro studies showed that the AMO against miR-33b was more effective; therefore, we examined the in vivo effects of this AMO in a calcium chloride (CaCl2)-induced AAA model in humanized miR-33b knock-in mice. In this model, AAA was clearly improved by application of anti-miR-33b. To further elucidate the mechanism, we evaluated AAA 1 week after CaCl2 administration to examine the effect of anti-miR-33b. Histological examination revealed that the number of MMP-9-positive macrophages and the level of MCP-1 in the aorta of mice treated with anti-miR-33b was significantly reduced, and the serum lipid profile was improved compared with mice treated with control oligonucleotides. These results support that inhibition of miR-33b is effective in the treatment for AAA.

Migration Capacity of Stem Cells from Human Exfoliated Deciduous Teeth Towards Glioma.

BACKGROUND: Stem cells from human exfoliated deciduous teeth (SHED) are a mesenchymal stem cell type and have recently attracted attention for their high proliferative rate, multipotency, and immunosuppressive properties. However, SHED have not yet been investigated for anticancer properties. We therefore investigated whether SHED can be used as a treatment modality, particularly for anti-glioma therapy. METHODS: In vitro, we examined the mobility of SHED and their ability to migrate towards glioma-conditioned medium and specific growth factors secreted by malignant gliomas. In vivo, we transplanted SHED into the left hemisphere of nude mice that had been previously implanted with human malignant glioma U87 cells into the right hemisphere. We assessed whether SHED had tumorigenic potential. RESULTS: SHED exhibited strong migration ability towards malignant glioma in both in vitro and in vivo assays. In vitro, SHED migrated towards glioma-conditioned medium and specific growth factors such as stem cell factor, platelet-derived growth factor BB, C-X-C motif chemokine ligand 12, and vascular endothelial growth factor. SHED were accumulated around tumor cells in the contralateral hemisphere 1 week after transplantation. Moreover, SHED remained in the brains of nude mice 150 days after transplantation. Finally, we verified that SHED had no malignant transformation or engraftment of SHED in the mouse brain. CONCLUSIONS: Our findings indicate that SHED can potentially be applied to track malignant glioma.

Aspiration After Sealing the Entrance by Stenting Is a Promising Method to Treat Subintimal Hematoma.

Creation of a distal re-entry site is widely performed to treat subintimal hematoma. However, this method has a risk of further vessel damage. The present aspiration technique after sealing the entry site by stenting is more promising because the hematoma can be reduced without additional vessel damage. (Level of Difficulty: Advanced.).

Prevalence and risk factors for brain white matter changes in young and middle-aged participants with Brain Dock (brain screening): a registry database study and literature review.

This study aimed to determine the prevalence and risk factors for brain white matter changes in normal young and middle-aged participants who underwent Brain Dock (brain screening). We analyzed 5,000 consecutive healthy participants from the Brain Dock registry between August to December 2018. Age, sex, body mass index (BMI), medical history, deep subcortical white matter high intensity (DSWMH), periventricular high intensity (PVH), and enlargement of perivascular space (EPVS) were investigated in relation to age. The prevalence of DSWMH, PVH, and EPVS were 35.3%, 14.0%, and 17.8%, respectively. Multivariate logistic regression analyses for brain white matter changes were conducted. The significant risk factors in participants aged < 50 years were: age (OR:1.09, 95% CI:1.07-1.12), the female sex (1.29, 1.03-1.60), BMI obesity (1.86, 1.12-3.08), and hypertension (1.67, 1.18-2.35) for DSWMH; age (1.08, 1.04-1.13) and the female sex (1.56, 1.03-2.36) for PVH; and age (1.07, 1.05-1.10) and the female sex (0.77, 0.60-1.00) for EPVS. In conclusion, age was consistently identified as a significant risk factor in young and middle-aged participants. Some risk factors for brain white matter changes were identified even in young and middle-aged participants in this study. Further longitudinal studies should be done in the future.

microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity.

Adaptive thermogenesis is essential for survival, and therefore is tightly regulated by a central neural circuit. Here, we show that microRNA (miR)-33 in the brain is indispensable for adaptive thermogenesis. Cold stress increases miR-33 levels in the hypothalamus and miR-33-/- mice are unable to maintain body temperature in cold environments due to reduced sympathetic nerve activity and impaired brown adipose tissue (BAT) thermogenesis. Analysis of miR-33f/f dopamine-ß-hydroxylase (DBH)-Cre mice indicates the importance of miR-33 in Dbh-positive cells. Mechanistically, miR-33 deficiency upregulates gamma-aminobutyric acid (GABA)A receptor subunit genes such as Gabrb2 and Gabra4. Knock-down of these genes in Dbh-positive neurons rescues the impaired cold-induced thermogenesis in miR-33f/f DBH-Cre mice. Conversely, increased gene dosage of miR-33 in mice enhances thermogenesis. Thus, miR-33 in the brain contributes to maintenance of BAT thermogenesis and whole-body metabolism via enhanced sympathetic nerve tone through suppressing GABAergic inhibitory neurotransmission. This miR-33-mediated neural mechanism may serve as a physiological adaptive defense mechanism for several stresses including cold stress.

IDH1 mutations induce organelle defects via dysregulated phospholipids.

Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring a mutation in isocitrate dehydrogenase 1 mutation (IDH1mut) acquire a different tumor biology and clinical manifestation from those that are IDH1WT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we uncover increased monounsaturated fatty acids (MUFA) and their phospholipids in endoplasmic reticulum (ER), generated by IDH1 mutation, that are responsible for Golgi and ER dilation. We demonstrate a direct link between the IDH1 mutation and this organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate-limiting enzyme in MUFA biosynthesis. Inhibition of IDH1 mutation or SCD silencing restores ER and Golgi morphology, while D-2HG and oleic acid induces morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produces IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing new insight into the link between lipid metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.

Takotsubo cardiomyopathy following mechanical thrombectomy for acute ischemic stroke: illustrative case.

BACKGROUND: Excess neurological stress by hemorrhagic stoke induces cardiomyopathy, namely takotsubo cardiomyopathy. Here, the authors report a case of takotsubo myopathy following mechanical thrombectomy for acute large vessel occlusion. OBSERVATIONS: A 73-year-old man was emergently brought to the authors' hospital because of left hemiparesis and consciousness disturbance. An ischemic lesion of the right cerebral hemisphere and the right internal carotid artery occlusion was revealed. Emergently, endovascular treatment was performed, and occlusion of the artery was reanalyzed. However, he suffered from hypotension with electrocardiogram abnormality. Subsequently, coronary angiography was performed, but the arteries were patent. The authors made a diagnosis of takotsubo cardiomyopathy. LESSONS: Endovascular recanalization for large cerebral artery occlusion is so effective that it is becoming widely used. Even in the successful recanalization, we need to care for the takotsubo cardiomyopathy.

Nicotine does not affect stem cell properties requisite for suicide gene therapy against glioma.

OBJECTIVE:: Glioblastoma is one of the most lethal tumors in adult central nervous system with a median survival of a year and half and effective therapeutic strategy is urgently needed. For that reason, stem cell-based suicide gene therapies have attracted much interest because of potent tumor tropism of stem cells and bystander effect. In this current clinical situation, stem cells are promising delivery tool of suicide genes for glioma therapy. Since habitual cigarette smoking still prevails worldwide, we investigated the effect of nicotine on stem cell tropism toward glioma and gap junctional intercellular communication (GJIC) function between glioma and stem cells, both of which are important for suicide gene therapies. Methods: Mouse induced pluripotent stem cell-derived neural stem cells (iPS-NSCs) and human dental pulp mesenchymal stem cells (DPSCs) were used. The effect of nicotine on tumor tropism to glioma-conditioned medium (CM) at a non-cytotoxic concentration was assessed with Matrigel invasion assay. Nicotine effect on GJIC was assessed with the scrape loading/dye transfer (SL/DT) assay for co-culture of glioma and stem cells and the parachute assay among glioma cells using high-content analysis. Results: Tumor tropism of iPS-NSCs toward GL261-CM and DPSCs toward U251-CM was not affected by nicotine (0.1 and 1 µM). Nicotine at the concentrations equivalent to habitual smoking (1 µM) did not affect GJIC of iPS-NSC/GL261 and DPSC/U251 and GJIC among each glioma cells. Conclusions: The study demonstrated that non-cytotoxic concentrations of nicotine did not significantly change the stem cell properties requisite for stem cell-based suicide gene therapy.

Homeobox A4 suppresses vascular remodeling by repressing YAP/TEAD transcriptional activity.

The Hippo signaling pathway is involved in the pathophysiology of various cardiovascular diseases. Yes-associated protein (YAP) and transcriptional enhancer activator domain (TEAD) transcriptional factors, the main transcriptional complex of the Hippo pathway, were recently identified as modulators of phenotypic switching of vascular smooth muscle cells (VSMCs). However, the intrinsic regulator of YAP/TEAD-mediated gene expressions involved in vascular pathophysiology remains to be elucidated. Here, we identified Homeobox A4 (HOXA4) as a potent repressor of YAP/TEAD transcriptional activity using lentiviral shRNA screen. Mechanistically, HOXA4 interacts with TEADs and attenuates YAP/TEAD-mediated transcription by competing with YAP for TEAD binding. We also clarified that the expression of HOXA4 is relatively abundant in the vasculature, especially in VSMCs. In vitro experiments in human VSMCs showed HOXA4 maintains the differentiation state of VSMCs via inhibition of YAP/TEAD-induced phenotypic switching. We generated Hoxa4-deficient mice and confirmed the downregulation of smooth muscle-specific contractile genes and the exacerbation of vascular remodeling after carotid artery ligation in vivo. Our results demonstrate that HOXA4 is a repressor of VSMC phenotypic switching by inhibiting YAP/TEAD-mediated transcription.

Acute and chronic hemorrhage from radiation-induced cavernous malformation associated with late-delayed radiation necrosis in long surviving glioma patients: A case report.

Although radiation therapy is a standard treatment strategy for patients with glioma, its delayed complications are not clearly understood. Radiation-induced cavernous malformation (RICM) is one of the complications in the delayed phase following radiation therapy, which usually occurs in children. Herein we present three cases of RICM with radiation necrosis in long surviving adult glioma patients, 2 with oligoastrocytoma and one with anaplastic ependymoma. Two of three patients had received an obvious overdose of radiation by additional stereotactic radiation therapy. Repeated episodes of either acute or chronic hemorrhages from RICM worsened the neurological symptoms in all cases. The interval between the last irradiation and the occurrence of symptoms was 45-173 months. The presence of hypointense rim on FLAIR or T2* on magnetic resonance imaging, which resembles the appearance of sporadic cavernous malformations, could be helpful in differentiating RICM from tumor recurrence. Surgical resection was effective in alleviating the symptoms. Microscopically, RICM is a vascular lesion with vulnerable vessels, which are observed in the center of the radiation necrosis. Repeated hemorrhages from these vessels cause either gradual or sudden worsening of neurological symptoms. Therefore, radiation overdose, which results in radiation injury, should be avoided in low grade glioma patients, who could potentially survive for a long period.