EP4-induced mitochondrial localization and cell migration mediated by CALML6 in human oral squamous cell carcinoma.

Lymph node metastasis, primarily caused by the migration of oral squamous cell carcinoma (OSCC) cells, stands as a crucial prognostic marker. We have previously demonstrated that EP4, a subtype of the prostaglandin E2 (PGE2) receptor, orchestrates OSCC cell migration via Ca2+ signaling. The exact mechanisms by which EP4 influences cell migration through Ca2+ signaling, however, is unclear. Our study aims to clarify how EP4 controls OSCC cell migration through this pathway. We find that activating EP4 with an agonist (ONO-AE1-473) increased intracellular Ca2+ levels and the migration of human oral cancer cells (HSC-3), but not human gingival fibroblasts (HGnF). Further RNA sequencing linked EP4 to calmodulin-like protein 6 (CALML6), whose role remains undefined in OSCC. Through protein-protein interaction network analysis, a strong connection is identified between CALML6 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), with EP4 activation also boosting mitochondrial function. Overexpressing EP4 in HSC-3 cells increases experimental lung metastasis in mice, whereas inhibiting CaMKK2 with STO-609 markedly lowers these metastases. This positions CaMKK2 as a potential new target for treating OSCC metastasis. Our findings highlight CALML6 as a pivotal regulator in EP4-driven mitochondrial respiration, affecting cell migration and metastasis via the CaMKK2 pathway.

Store-operated calcium entry via ORAI1 regulates doxorubicin-induced apoptosis and prevents cardiotoxicity in cardiac fibroblasts.

Despite exhibiting cardiotoxicity, doxorubicin (DOX) is widely used for cancer treatments. Cardiac fibroblasts (CFs) are important in the pathogenesis of heart failure. This necessitates the study of the effect of DOX on CFs. The impairment of calcium (Ca2+) homeostasis is a common mechanism of heart failure. Store-operated Ca2+ entry (SOCE) is a receptor-regulated Ca2⁺ entry pathway that maintains calcium balance by sensing reduced calcium stores in the endoplasmic reticulum. ORAI1, a calcium channel protein and the most important component of SOCE, is highly expressed in human cardiac fibroblasts (HCFs). It is upregulated in CFs from failing ventricles. However, whether ORAI1 in HCFs is increased and/or plays a role in DOX-induced cardiotoxicity remains unknown. In this study, we aimed to elucidate the relationship between ORAI1/SOCE and DOX-induced heart failure. Induction of apoptosis by DOX was characterized in HCFs. Apoptosis and cell cycle analyses were performed by fluorescence-activated cell sorting (FACS). Reactive oxygen species (ROS) production was measured using fluorescence. YM-58483 was used as an ORAI1/SOCE inhibitor. ORAI1-knockdown cells were established by RNA interference. In vivo experiments were performed by intraperitoneally injecting YM-58483 and DOX into mice. We first demonstrated that DOX significantly increased the protein expression level of p53 in HCFs by western blotting. FACS analysis revealed that DOX increased early apoptosis and induced cell cycle arrest in the G2 phase in fibroblasts. DOX also increased ROS production. DOX significantly increased the expression level of ORAI1 in CFs. Both YM-58483 and ORAI1 gene knockdown attenuated DOX-induced apoptosis. Similarly, YM-58483 attenuated cell cycle arrest in the G2 phase, and ORAI1 knockdown attenuated DOX-induced ROS production in HCFs. In the animal experiment, YM-58483 attenuated DOX-induced apoptosis. In HCFs, ORAI1/SOCE regulates p53 expression and plays an important role in DOX-induced cardiotoxicity. ORAI1 may serve as a new target for preventing DOX-induced heart failure.

Reconstructive embolization for contralateral vertebral artery dissecting aneurysm that developed after internal trapping of ruptured vertebral artery dissection: A case report and literature review.

Background: It is not well-known that contralateral vertebral artery dissecting aneurysms (VADA) may be newly revealed after parental artery occlusion for unilateral VADA. However, the optimal treatment strategies and perioperative management have not been established. In this report, we present the case of a patient who required reconstructive embolization in the subacute stage for contralateral VADA developed after endovascular internal trapping of the ruptured VADA. Case Description: A 61-year-old man developed subsequent disturbance of consciousness. Head CT showed a diffuse and symmetrical SAH. 3DCT revealed a fusiform aneurysm of the left intracranial vertebral artery with bleb formation. We performed emergency endovascular parent artery occlusion of the left vertebral artery. A digital subtraction angiography on postoperative day 16 showed continued occlusion of the left VA, and a fusiform aneurysm was noted at the right VA. We performed reconstructive embolization and the patient eventually recovered with minimal persistent symptoms. Conclusion: Since the outcomes of contralateral VAD complicated by infarction or hemorrhage are poor, and most cases develop within 7-14 days after endovascular internal trapping for unilateral VAD, performing bilateral radiographic reinspection within this time frame is recommended for early detection and preventive treatment of possible contralateral VADs.

Double Meningioma: A Case of Two Fibrous Meningiomas Coexisting Isolatedly in Meningothelial Meningioma.

Meningiomas are the most common intracranial primary neoplasm in adults, and show various histological subtypes, indicating heterogeneous clinical and molecular genetic characteristics. Different subtypes of meningioma coexisting independently within the main tumor of another different subtype is a quite rare clinical situation. A 69-year-old woman presented with a several- year history of dizziness as a non-specific complaint. Magnetic resonance imaging (MRI) revealed an extra-axial mass lesion in the left parieto-occipital region including two well-demarcated, round mass components. Total resection was performed via left parieto-occipital craniotomy. Two white masses were identified within the main tumor, with neither showing dural attachments. Pathological findings showed the main mass represented meningothelial meningioma and the demarcated mass lesions were both fibrous meningiomas. No transitional features existed between these subtypes. No differences in genetic characteristics were evident between subtypes of meningioma. We have described, apparently for the first time, a case of two fibrous meningiomas coexisting in an isolated manner in meningothelial meningioma with the similar molecular genetic profile.

Spinal Cord Infarction after Mechanical Thrombectomy for Acute Basilar Artery Occlusion: A Case Report and Review of the Literature.

Objective: We report a case of spinal cord infarction following mechanical thrombectomy for acute basilar artery occlusion, and describe the pathophysiological mechanism of spinal cord infarction and its possible prevention. Case Presentation: A 70-year-old man developed dysarthria and left-sided sensory impairment and was then diagnosed with acute basilar artery occlusion. Mechanical thrombectomy was performed using a 6-Fr guiding sheath via the left vertebral artery (VA). Complete recanalization was achieved within 1.5 hours. However, toward the end of the procedure, the guiding sheath was wedged in the distal portion of the VA. Postoperatively, left-sided flaccid paralysis and right-sided sensory deficit were observed. Cervical magnetic resonance imaging (MRI) demonstrated an acute spinal cord infarction on the left side, at the level of C3. The cause of infarction was suspected to be the wedging of the guiding sheath during the procedure. Conclusion: Spinal cord infarction is a rare but serious complication of mechanical thrombectomy for acute basilar artery occlusion. The selection of appropriate procedure, device, and safe access route are essential for the success of a mechanical thrombectomy for acute basilar artery occlusion.

Incision Edge "Lifting Method" in Cerebral Bypass Surgery: A Novel Optional Technique for Narrow or Thin Recipient Arteries.

BACKGROUND: Cerebral bypass surgery, such as the superficial temporal artery-middle cerebral artery bypass, is one of the essential procedures for cerebral revascularization. However, very narrow or thin blood vessels will increase the risk of anastomotic problems, such as occurs in Moyamoya disease. For such vessels, we have devised a "lifting method" in the recipient arteriotomy. In the present study, we have introduced this novel optional technique and evaluated its effects. METHODS: The lifting method is a procedure of lifting the incision edge of a linear incision on the recipient vessel to widen the ostium. We attempted the lifting method in 23 consecutive patients (41 arteries) and, as a historical control, compared the results with those from the conventional method in 25 consecutive patients (37 arteries) for the previous 3 years. We compared patient age, years of surgical experience, recipient vessel diameter, anastomotic events, and final patency. As a subanalysis, the same evaluations were performed separately for patients with Moyamoya disease. Furthermore, the time required for the lifting procedure was measured retrospectively. RESULTS: The incidence of anastomotic events with the conventional method was 13.5% overall and 19% in those with Moyamoya disease. No adverse events occurred with the lifting method (P < 0.05). No statistically significant differences were found for the other factors, including final patency between the 2 groups. The time required for the lifting procedure averaged 1 minute, 15 seconds. CONCLUSIONS: Use of the lifting method widens and secures the ostium in a recipient vessel and greatly facilitates operability. We have found it to be a foolproof method enabling safe and reliable anastomosis even with narrow or thin vessels.

[Efficacy and Safety of Salvage ESHAP Chemotherapy for Recurrent/Refractory PCNSLs].

BACKGROUND: Primary central nervous system lymphoma(PCNSL)is a primary brain tumor, which appears commonly and occupies around 4.6% of all primary brain tumors. The standard therapy for this tumor is high-dose methotrexate chemotherapy(HD-MTX)and whole-brain irradiation. No salvage therapies for HD-MTX therapy-refractory or recurrent PCNSLs have been standardized. In our institution, ESHAP therapy(high-dose cytarabine:2,000mg, cisplatin:25mg/m2, etoposide:40mg/m2, methylprednisolone:500mg)was administered as a secondary chemotherapy, and the efficiency was examined. METHODS: We administered ESHAP therapy as secondary chemotherapy for patients with refractory/recurrent PCNSL after HD-MTX therapy. Patients with PCNSL who were diagnosed and treated at our institute since 1996 were retrospectively studied. Clinical evaluations were performed based on Karnofsky Performance Status and overall survival, and the effect of ESHAP therapy was evaluated using the Response Assessment in Neuro-Oncology criteria. RESULTS: The number of patients with refractory/recurrent PCNSLs were 18(28-77 years of age, median age of 58.5 years). The response rate(RR)after the first course of salvage ESHAP therapy was 77.8%(14 cases), and complete response(CR)was achieved in 6 cases. The RR after the final course of ESHAP therapy was as high as 61.1%(11 cases), and 4 patients retained CR status. In patients with refractory PCNSL who were treated with HD-MTX, the RR in the final course of salvage ESHAP therapy was as high as 77.8%(7 cases), and 3 patients retained CR status during the periods. The occurrence rate of Grade 3 or higher adverse events, according to the Common Terminology Criteria for Adverse Events version 4.0, was 66.7%(12 cases);all events that were associated with blood and lymphatic system disorders were quickly alleviated, and no fatal adverse events occurred. CONCLUSION: In this study, we retrospectively examined the efficacy of ESHAP therapy as a secondary chemotherapy for patients with refractory/recurrent PCNSL after receiving HD-MTX therapy. Based on our findings, we suggest that ESHAP therapy should be considered as an encouraging secondary chemotherapy for patients with refractory/recurrent PCNSL.