Near-infrared imaging via upconversion in Er3+:CaF2 crystal with dual wavelength excitation.

We propose a system for imaging 1510 nm near-infrared (NIR) wavelength via upconversion (UC) luminescence in an Er3+-doped CaF2 crystal. Er3+ ions are excited from the ground to the excited state levels by an 800-nm pre-excitation wavelength, followed by the promotion of these ions to a higher energy level by the NIR excitation wavelength. Relaxation of these excited ions gives rise to 540 nm UC luminescence in the visible region, enabling the detection of the 1510 nm NIR wavelength. Using this UC scheme, 1510 nm was successfully imaged. Our system enables imaging of NIR wavelengths using low-cost optics and readily available Si-based detectors that are sensitive only to visible wavelengths, opening new possibilities for detection and imaging of NIR wavelengths.

Bilateral ballism as limb-shaking transient ischemic attacks treated with unilateral carotid artery stent placement.

Bilateral limb-shaking transient ischemic attack (LS-TIA) is a rare disease involving carotid artery stenosis, characterized by ballism-like involuntary movements of the arms and legs. We describe the case report of a male patient in his 80s presented with continuous bilateral ballism in the arms and legs and tongue dyskinesia. Magnetic resonance imaging showed no ischemic lesions, while cerebral angiography revealed right internal carotid artery (ICA) occlusion and 80% stenosis of the left ICA. 99mTc-ethyl cysteinate dimer single-photon emission computed tomography demonstrated hypoperfusion in the right cerebral cortex but hyperperfusion in both basal ganglia. Left ICA stenting was performed, and involuntary limb shaking disappeared. This case report highlights the importance of accurate diagnosis and treatment of bilateral ballism as LS-TIA.

Mid-infrared imaging through up-conversion luminescence in trivalent lanthanide ion-doped self-organizing optical fiber array crystal.

We propose a scheme for imaging mid-infrared (MIR) wavelengths via pre-excitation-assisted up-conversion luminescence in lanthanide ion (Ln3+)-doped Self-organizing Optical FIber Array (SOFIA) crystal. First, near-infrared pre-excitation wavelength excites an electron from the ground state to an excited state of Ln3+. Next, the MIR wavelength to be imaged promotes this excited electron to a higher-lying energy state. Finally, relaxation of the electron from the higher-lying energy state to the ground state emits the up-conversion luminescence in the visible region, completing the MIR-to-visible wavelength conversion. An analysis of the 4f to 4f intra-configurational energy level transitions in Ln3+, together with an appropriate selection of the pre-excitation wavelength and the visible luminescence constrained within the 500-700 nm wavelength range, reveals that trivalent erbium (Er3+), thulium (Tm3+), holmium (Ho3+), and neodymium (Nd3+) can be used to image MIR wavelengths. Our proposed scheme, called MIR imAging through up-Conversion LuminEscence in a SOFIA crystal, will enable the imaging of MIR wavelengths using low-cost optics and readily available silicon-based detectors in the visible spectral region and will open up new possibilities for MIR wavelength detection and imaging.

Tunable vacuum ultraviolet cross-luminescence from KMgF under high pressure as potential fast-response scintillator.

We report on the potential of the potassium magnesium fluoride (KMgF) crystal as a fast-response scintillator with tunable cross-luminescence (CL) emission wavelength through high-pressure applications. By performing first-principles density functional theory calculations using the Perdew-Burke-Ernzerhof (PBE) hybrid functional including exact exchange (PBE0) and Green's function and screened Coulomb interaction approximation as implemented in the Vienna Ab initio Simulation Package using plane-wave basis sets within the projector-augmented wave method, we identify the specific valence-to-core band transition that results in the experimentally observed CL emission at 148 nm (8.38 eV) and 170 nm (7.29 eV) wavelengths with intrinsically fast decay times of 290 ps and 210 ps, respectively. Uniform volume compression through hydrostatic high-pressure applications could decrease the energy gap between the valence and core bands, potentially shifting the CL emission wavelength to the ultraviolet (UV) region from 200 nm (6.2 eV) to 300 nm (4.1 eV). The ability to tune and shift the CL emission to UV wavelengths allows for the detection of the CL emission using UV-sensitive photodetectors in ambient atmosphere instead of highly specialized vacuum UV detectors operating in vacuum while maintaining the intrinsically fast CL decay times, thereby opening up new possibilities for KMgF as a fast-response scintillator.

Disability, quality of life, productivity impairment and employer costs of migraine in the workplace.

BACKGROUND: Migraine is the leading cause of days lost due to disability in the world among people less than 50 years of age. There is a paucity of evidence on the impact of migraine and other headache disorders and the cost and productivity losses in the workplace. METHODS: Employee population survey assessed prevalence, characteristics, and disability of headache disorders at a Japanese information technology company. This study was supported by the World Health Organization Western Pacific Region Office and International Headache Society. RESULTS: 2458 (1963men, 495 women) out of 2494 responded to the survey that utilized ICHD-3 beta criteria. Among these, 13% (205 male/123 female) had migraine (M), 53% (1093 male/207 female) had tension-type headache (TTH) and 4% (61 male/27 female) had migraine and TTH (M/TTH). The number of days when productivity at work was reduced by half or more because of headache was significantly higher in migraine compared to TTH. The norm-based scoring of SF-12v2 was significantly lower in M/TTH and M than TTH. The economic loss due to absenteeism for migraine was calculated to be $ 238.3US$/year/person for day-off and 90.2US$/year/person for half-day off using migraine disability assessment score (MIDAS). The economic loss due to presenteeism for migraine was calculated to be $ 375.4US$/year/person using MIDAS and 2217US$/year/person using work productivity and activity impairment questionnaire (WPAI). Furthermore, estimated cost of productivity loss associated with presenteeism using WPAI was calculated at 21.3 billion US$/year in Japan as a whole. CONCLUSIONS: This study revealed a high prevalence and disease burden among employees with migraine that is associated with substantial losses in productivity and employer cost. These results support the development and implementation of workplace programs to improve migraine management in the workplace and reduce the burden and costs associated with lost workplace productivity.

Resilience to capsaicin-induced mitochondrial damage in trigeminal ganglion neurons.

Capsaicin is an agonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). Strong TRPV1 stimulation with capsaicin causes mitochondrial damage in primary sensory neurons. However, the effect of repetitive and moderate exposure to capsaicin on the integrity of neuronal mitochondria remains largely unknown. Our electron microscopic analysis revealed that repetitive stimulation of the facial skin of mice with 10 mM capsaicin induced short-term damage to the mitochondria in small-sized trigeminal ganglion neurons. Further, capsaicin-treated mice exhibited decreased sensitivity to noxious heat stimulation, indicating TRPV1 dysfunction, in parallel with the mitochondrial damage in the trigeminal ganglion neurons. To analyze the capsaicin-induced mitochondrial damage and its relevant cellular events in detail, we performed cell-based assays using TRPV1-expressing PC12 cells. Dose-dependent capsaicin-mediated mitochondrial toxicity was observed. High doses of capsaicin caused rapid destruction of mitochondrial internal structure, while low doses induced mitochondrial swelling. Further, capsaicin induced a dose-dependent loss of mitochondria and autophagy-mediated degradation of mitochondria (mitophagy). Concomitantly, transcriptional upregulation of mitochondrial proteins, cytochrome c oxidase subunit IV, Mic60/Mitofilin, and voltage-dependent anion channel 1 was observed, which implied induction of mitochondrial biogenesis to compensate for the loss of mitochondria. Collectively, although trigeminal ganglion neurons transiently exhibit mitochondrial damage and TRPV1 dysfunction following moderate capsaicin exposure, they appear to be resilient to such a challenge. Our in vitro data show a dose-response relationship in capsaicin-mediated mitochondrial toxicity. We postulate that induction of mitophagy and mitochondrial biogenesis in response to capsaicin stimulation play important roles in repairing the damaged mitochondrial system.

Functional interactions between transient receptor potential M8 and transient receptor potential V1 in the trigeminal system: Relevance to migraine pathophysiology.

Background Recent genome-wide association studies have identified transient receptor potential M8 ( TRPM8) as a migraine susceptibility gene. TRPM8 is a nonselective cation channel that mediates cool perception. However, its precise role in migraine pathophysiology is elusive. Transient receptor potential V1 (TRPV1) is a nonselective cation channel activated by noxious heat. Both TRPM8 and TRPV1 are expressed in trigeminal ganglion (TG) neurons. Methods We investigated the functional roles of TRPM8 and TRPV1 in a meningeal inflammation-based migraine model by measuring the effects of facial TRPM8 activation on thermal allodynia and assessing receptor coexpression changes in TG neurons. We performed retrograde tracer labeling to identify TG neurons innervating the face and dura. Results We found that pharmacological TRPM8 activation reversed the meningeal inflammation-induced lowering of the facial heat pain threshold, an effect abolished by genetic ablation of TRPM8. No significant changes in the heat pain threshold were seen in sham-operated animals. Meningeal inflammation caused dynamic alterations in TRPM8/TRPV1 coexpression patterns in TG neurons, and colocalization was most pronounced when the ameliorating effect of TRPM8 activation on thermal allodynia was maximal. Our tracer assay disclosed the presence of dura-innervating TG neurons sending collaterals to the face. Approximately half of them were TRPV1-positive. We also demonstrated functional inhibition of TRPV1 by TRPM8 in a cell-based assay using c-Jun N-terminal kinase phosphorylation as a surrogate marker. Conclusions Our findings provide a plausible mechanism to explain how facial TRPM8 activation can relieve migraine by suppressing TRPV1 activity. Facial TRPM8 appears to be a promising therapeutic target for migraine.

A theoretical study on the size-dependence of ground-state proton transfer in phenol-ammonia clusters.

Geometries and infrared (IR) spectra in the mid-IR region of phenol-(ammonia)n (PhOH-(NH3)n) (n = 0-10) clusters have been studied using density functional theory (DFT) to investigate the critical number of solvent molecules necessary to promote ground-state proton transfer (GSPT). For n ≤ 8 clusters, the most stable isomer is a non-proton-transferred (non-PT) structure, and all isomers found within 1.5 kcal mol-1 from it are also non-PT structures. For n = 9, the most stable isomer is also a non-PT structure; however, the second stable isomer is a PT structure, whose relative energy is within the experimental criterion of population (0.7 kcal mol-1). For n = 10, the PT structure is the most stable one. We can therefore estimate that the critical size of GSPT is n = 9. This is confirmed by the fact that these calculated IR spectra are in good accordance with our previous experimental results of mid-IR spectra. It is demonstrated that characteristic changes of the ν9a and ν12 bands in the skeletal vibrational region provide clear information that the GSPT reaction has occurred. It was also found that the shortest distance between the π-ring and the solvent moiety is a good indicator of the PT reaction.

Temporal profiles of high-mobility group box 1 expression levels after cortical spreading depression in mice.

INTRODUCTION: Cortical spreading depression (CSD) has recently been shown to induce the release of the nuclear protein termed high-mobility group box 1 from neurons, causing activation of the trigeminovascular system. Here, we explored the effects of single and multiple cortical spreading depression inductions on high-mobility group box 1 (HMGB1) transcriptional activity relative to high-mobility group box 1 protein expression levels and intracellular localization in cortical neurons and astrocytes. METHODS: Single or multiple cortical spreading depression inductions were achieved by KCl application to the mouse cerebral cortex. The animals were sacrificed at 30 minutes, 3 hours and 24 hours after cortical spreading depression induction. High-mobility group box 1 expression levels were explored with in situ hybridization, Western blotting and immunostaining. RESULTS: Cortical spreading depression up-regulated high-mobility group box 1 transcriptional activity in neurons at 3 hours in a manner that was dependent on the number of cortical spreading depression inductions. At 24 hours, the high-mobility group box 1 transcriptional activity had returned to basal levels. Cortical spreading depression induced a reduction in high-mobility group box 1 protein expression at 3 hours, which was also dependent on the number of cortical spreading depression inductions. Following cortical spreading depression, the release of high-mobility group box 1 from the nucleus was observed in a small proportion of neurons, but not in astrocytes. CONCLUSION: Cortical spreading depression induced translocation of high-mobility group box 1 from neuronal nuclei, driving transcriptional up-regulation of high-mobility group box 1 to maintain protein levels.

Theoretical Study on the Size Dependence of Ground-State Proton Transfer in 1-Naphthol-Ammonia Clusters.

The geometries of 1-naphthol-(ammonia)n (1-NpOH-(NH3)n) (n = 6-9) clusters have been calculated by using the density functional theory (DFT) to investigate ground-state proton transfer (GSPT). For n ≤ 7 clusters, the most stable isomer is a non-proton-transferred (non-PT) structure, and isomers within 1.4 kcal/mol unstable from it were also non-PT structures. For n = 8 and 9, the most stable isomer is also a non-PT structure; however, the second stable isomer is the PT structure, of which the relative energy is within 0.5 kcal/mol. We therefore concluded that the threshold size of GSPT is n = 8 under the conventional experimental condition. It is also found that the minimal distance between the π-ring and the solvent moiety is a good indicator of the PT reaction. This suggests that the solvation of the π-ring is important to trigger the PT reaction.

The mechanism of excited-state proton transfer in 1-naphthol-piperidine clusters.

The geometries of 1-naphthol-(piperidine)n (1-NpOH-(Pip)n) (n = 0-3) clusters have been calculated by using density functional theory (DFT) and time-dependent density functional theory (TD-DFT) methods to investigate excited-state proton transfer (ESPT) in the low-lying singlet excited states, La and Lb. For the n = 1 cluster, no PT structure was found in Lb and La as well as the ground state, S0. For n = 2, optically accessible Lb from S0 shows the PT structure. We therefore concluded that the threshold size of ESPT is n = 2, which is consistent with previous experimental results. ESPT in 1-NpOH-(Pip)n is simply triggered by optical excitation to Lb. It is essentially different from the 1-NpOH-(NH3)n cluster in which an internal conversion process is required to promote ESPT. From the calculated structures, the importance of the solvation of the π-ring is strongly suggested rather than the proton affinity in ESPT.

[A Patient with Advanced Gastric Cancer who Underwent Emergency Stenting for Carotid Artery Stenosis].

We report the case of a patient with advanced gastric cancer who underwent emergency stenting for carotid artery stenosis that was causing fluctuating symptoms of cerebral ischemic stroke. A 66-year-old man presented with transient dysarthria and right hemifacial palsy. Examination revealed left internal carotid artery stenosis, as well as anemia caused by advanced gastric cancer. The man was treated on an outpatient basis using antiplatelet medication and anti-cancer therapy. Two months later, he developed recurrent ischemic stroke;because of this progression, a stent was placed in the carotid artery. After surgery, the cerebral ischemia resolved and did not recur before his death 6 months later. In conclusion, surgical intervention is a viable treatment option for internal carotid artery stenosis in cancer patients whose general health status is good.

[Headache in consideration of gender].

Among headaches sufferers in Japan, especially the number of migraine sufferers in Japan is estimated about 8,400 thousands, and the ratio of men and women is said to be about 1 to 4. The pathophysiology of migraines has been commonly explained by the trigeminovascular theory, and recent studies have suggested that the cause of migraines stems from cortical hypersensitivity. As to prophylactic treatment of migraine, anti-epileptic drugs such as valproic acid for cephalic hypersensitivity symptoms may be effective for reducing intensity and frequency of attacks and first line abortive medicine are triptans, which are widely prescribed. Considering from migraine treatment methods from childhood to elder women, to decreasing hypersensitivity of the brain in each life stage will lead falling into medication over used headache and also suppressing development of dizziness, tinnitus, or cephalic ringing in future, and shows that anti-epileptics are effective for treating this condition.

[Migraine During Pregnancy].

Migraine without aura reportedly improves during pregnancy, and this phenomenon is attributed to the sustained elevation and lack of fluctuations in the endogenous estrogen levels. In contrast, the occurrence of aura (such as visual symptoms) has been reported in patients having migraine with aura. Furthermore, the risk of gestational hypertension and preeclampsia is demonstrably significantly higher in patients with migraine than in healthy individuals. Hence, recognizing that pregnant women with migraine are at high risk of developing cardiovascular diseases is crucial.

Reduction of TRPV1 expression in the trigeminal system by botulinum neurotoxin type-A.

Botulinum neurotoxin type-A (BoNT-A) is clinically used for patients with pain disorders and dystonia. The precise mechanism whereby BoNT-A controls pain remains elusive. Here, we studied how BoNT-A affects the expression of the transient receptor potential vanilloid subfamily member 1 (TRPV1), a cation channel critically implicated in nociception, in the trigeminal system. Histological studies revealed that subcutaneous BoNT-A injection (0.25, 0.5, or 5 ng/kg) into the face targeted the ophthalmic division of trigeminal ganglion (TG) neurons and decreased TRPV1-immunoreactive neurons in the TG and TRPV1-immunoreactive fibers in rat trigeminal terminals. Of note, TG neurons that received projections from the dura mater, a principal site of headache generation, had reduced TRPV1 expression. BoNT-A-induced cleavage of SNAP25 (synaptosomal-associated protein of 25-kDa) in the TG became obvious 2 days after BoNT-A administration and persisted for at least 14 days. Quantitative real-time RT-PCR (reverse transcription-polymerase chain reaction) data indicated that the TRPV1-decreasing effects of BoNT-A were not mediated by transcriptional downregulation. By employing a surface protein biotin-labeling assay, we demonstrated that BoNT-A inhibited TRPV1 trafficking to the plasma membrane in primary TG neurons. Moreover, Y200F-mutated TRPV1, which is incapable of trafficking to the plasma membrane, was expressed in PC12 cells by transfection, and pharmacological studies revealed that TRPV1 in the cytoplasm was more predisposed to proteasome-mediated proteolysis than plasma membrane-located TRPV1. We conclude that the mechanism by which BoNT-A reduces TRPV1 expression involves the inhibition of TRPV1 plasma membrane trafficking and proteasome-mediated degradation in the cytoplasm. This paradigm seems to explain how BoNT-A alleviates TRPV1-mediated pain. Our data reveal a likely molecular mechanism whereby BoNT-A treatment reduces TRPV1 expression in the trigeminal system and provide important clues to novel therapeutic measures for ameliorating craniofacial pain.

Interactions between migraine and tension-type headache and alcohol drinking, alcohol flushing, and hangover in Japanese.

The aim of the study was to investigate associations between headache types and alcohol drinking, alcohol flushing, and hangover. Alcohol consumption is inhibited by the presence of inactive aldehyde dehydrogenase-2 (ALDH2) whose carriers are susceptible to alcohol flushing and hangovers. We conducted a cross-sectional study of the 2,577 subjects (men/women: 1,018/1,559) who reported having ever experienced headaches unrelated to common colds and alcohol hangovers among 5,408 (2,778/2,630) Tokyo health checkup examinees. We used a questionnaire inquiring about current and past facial flushing after drinking a glass of beer which identifies the presence of inactive ALDH2 with a sensitivity and specificity of approximately 90%. Based on ICHD-II criteria migraine was diagnosed in 419 (75/344) subjects, and tension-type headache (TTH) in 613 (249/364). We classified the headaches of the remaining 1,545 (694/851) of headaches sufferers into the category "other headaches (OH)". The migraineurs drank alcohol less frequently than the subjects with TTH among current/past alcohol flushers and than the subjects with OH regardless of flushing category. No such difference in drinking frequency was observed between TTH and OH. Current/past flushers drank alcohol less frequently than never flushers, and the likelihood that male migraineurs would avoid alcohol drinking than men with TTH or OH was stronger among current/past flushers than among never flushers. Flushers and women were more susceptible to hangover than never flushers and men, respectively, regardless of headache type. Among never flushers, women with migraine were more susceptible to hangover than women with OH. The difference in alcohol sensitivity may partly explain less alcohol consumption by migraineurs.

[Cephalic hypersensitivity syndrome].

The number of patients suffering from chronic headache accompanied by dizziness and cephalic ringing is gradually increasing. Pathophysiology of migraine has been commonly explained by trigeminovascular theory, although recent studies have suggested that the cause of the migraine stems from cortical hyperexcitability. We measured EEG in 1,000 patients suffering from daily headache accompanied by dizziness and cephalic ringing. Here we defined a new syndrome,"cephalic hypersensitivity syndrome" as a subliminal cortical hyperexcitability which itself is invisible but apparently seen as some symptoms such as dizziness and cephalic ringing. The cephalic hypersensitivity syndrome should be treated to attenuate the excitability by an appropriate triptan medication during attacks so as to exhibit its recurrence.

Implications of immune cells in oncolytic herpes simplex virotherapy for glioma.

Despite current progress in treatment, glioblastoma (GBM) remains a lethal primary malignant tumor of the central nervous system. Although immunotherapy has recently achieved remarkable survival effectiveness in multiple malignancies, none of the immune checkpoint inhibitors (ICIs) for GBM have shown anti-tumor efficacy in clinical trials. GBM has a characteristic immunosuppressive tumor microenvironment (TME) that results in the failure of ICIs. Oncolytic herpes simplex virotherapy (oHSV) is the most advanced United States Food and Drug Administration-approved virotherapy for advanced metastatic melanoma patients. Recently, another oHSV, Delytact®, was granted conditional approval in Japan against GBM, highlighting it as a promising treatment. Since oncolytic virotherapy can recruit abundant immune cells and modify the immune TME, oncolytic virotherapy for immunologically cold GBM will be an attractive therapeutic option for GBM. However, as these immune cells have roles in both anti-tumor and anti-viral immunity, fine-tuning of the TME using oncolytic virotherapy will be important to maximize the therapeutic efficacy. In this review, we discuss the current knowledge of oHSV, with a focus on the role of immune cells as friend or foe in oncolytic virotherapy.

Targeting protein arginine methyltransferase 5 sensitizes glioblastoma to trametinib.

Background: The prognosis of glioblastoma (GBM) remains dismal because therapeutic approaches have limited effectiveness. A new targeted treatment using MEK inhibitors, including trametinib, has been proposed to improve GBM therapy. Trametinib had a promising preclinical effect against several cancers, but its adaptive treatment resistance precluded its clinical translation in GBM. Previously, we have demonstrated that protein arginine methyltransferase 5 (PRMT5) is upregulated in GBM and its inhibition promotes apoptosis and senescence in differentiated and stem-like tumor cells, respectively. We tested whether inhibition of PRMT5 can enhance the efficacy of trametinib against GBM. Methods: Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, ELISA, and western blot were analyzed. In vivo, NSG mice were intracranially implanted with PRMT5-intact and -depleted GBMNS, treated with trametinib by daily oral gavage, and observed for tumor progression and mice survival rate. Results: PRMT5 depletion enhanced trametinib-induced cytotoxicity in GBMNS. PRMT5 knockdown significantly decreased trametinib-induced AKT and ERBB3 escape pathways. However, ERBB3 inhibition alone failed to block trametinib-induced AKT activity suggesting that the enhanced antitumor effect imparted by PRMT5 knockdown in trametinib-treated GBMNS resulted from AKT inhibition and not ERBB3 inhibition. In orthotopic murine xenograft models, PRMT5-depletion extended the survival of tumor-bearing mice, and combination with trametinib further increased survival. Conclusion: Combined PRMT5/MEK inhibition synergistically inhibited GBM in animal models and is a promising strategy for GBM therapy.

NOTCH-Induced MDSC Recruitment after oHSV Virotherapy in CNS Cancer Models Modulates Antitumor Immunotherapy.

PURPOSE: Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH, however the consequences of NOTCH on oHSV-induced immunotherapy is largely unknown. Here we evaluated the impact of NOTCH blockade on virus-induced immunotherapy. EXPERIMENTAL DESIGN: RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis of patients with recurrent glioblastoma (GBM) treated with oHSV was used to evaluate the effect of NOTCH signaling on virus-induced immunotherapy. RESULTS: TCGA data analysis of patients with grade IV glioma and oHSV treatment of experimental brain tumors in mice showed that NOTCH signaling significantly correlated with a higher myeloid cell infiltration. Immunofluorescence staining and RNA-seq uncovered a significant induction of Jag1 (NOTCH ligand) expression in infiltrating myeloid cells upon oHSV infection. Jag1-expressing macrophages further spread NOTCH activation in the tumor microenvironment (TME). NOTCH-activated macrophages increased the secretion of CCL2, which further amplified myeloid-derived suppressor cells. CCL2 and IL10 induction was also observed in serum of patients with recurrent GBM treated with oHSV (rQnestin34.5; NCT03152318). Pharmacologic blockade of NOTCH signaling rescued the oHSV-induced immunosuppressive TME and activated a CD8-dependent antitumor memory response, resulting in a therapeutic benefit. CONCLUSIONS: NOTCH-induced immunosuppressive myeloid cell recruitment limited antitumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy.