Role of Apolipoprotein E in the Hippocampus and Its Impact following Ionizing Radiation Exposure.

Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and brain injury repair. In the brain, ApoE is produced predominantly by astrocytes, but it is also abundantly expressed in most neurons of the CNS. In this study, we addressed the role of ApoE in the hippocampus in mice, focusing on its role in response to radiation injury. To this aim, 8-week-old, wild-type, and ApoE-deficient (ApoE-/-) female mice were acutely whole-body irradiated with 3 Gy of X-rays (0.89 Gy/min), then sacrificed 150 days post-irradiation. In addition, age-matching ApoE-/- females were chronically whole-body irradiated (20 mGy/d, cumulative dose of 3 Gy) for 150 days at the low dose-rate facility at the Institute of Environmental Sciences (IES), Rokkasho, Japan. To seek for ApoE-dependent modification during lineage progression from neural stem cells to neurons, we have evaluated the cellular composition of the dentate gyrus in unexposed and irradiated mice using stage-specific markers of adult neurogenesis. Our findings indicate that ApoE genetic inactivation markedly perturbs adult hippocampal neurogenesis in unexposed and irradiated mice. The effect of ApoE inactivation on the expression of a panel of miRNAs with an established role in hippocampal neurogenesis, as well as its transcriptional consequences in their target genes regulating neurogenic program, have also been analyzed. Our data show that the absence of ApoE-/- also influences synaptic functionality and integration by interfering with the regulation of mir-34a, mir-29b, and mir-128b, leading to the downregulation of synaptic markers PSD95 and synaptophysin mRNA. Finally, compared to acute irradiation, chronic exposure of ApoE null mice yields fewer consequences except for the increased microglia-mediated neuroinflammation. Exploring the function of ApoE in the hippocampus could have implications for developing therapeutic approaches to alleviate radiation-induced brain injury.

Second-degree atrioventricular block induced by electrical stimulation of transcranial motor-evoked potential: a case report.

BACKGROUND: Although several complications of transcranial motor-evoked potentials (Tc-MEPs) have been reported, reports of arrhythmias during Tc-MEP are very rare. CASE PRESENTATION: A 71-year-old woman underwent transforaminal lumbar interbody fusion under general anesthesia, with intraoperative Tc-MEP monitoring. Preoperative electrocardiography showed an incomplete right bundle branch block but no cardiovascular events in her life. After induction of anesthesia, Tc-MEP was recorded prior to the surgery. During the Tc-MEP monitoring, electrocardiography and arterial blood pressure showed a second-degree atrioventricular block, but it improved rapidly at the end of the stimulation, and the patient was hemodynamically stable. Tc-MEP was recorded seven times during surgery; the incidence of P waves without QRS complexes was significantly higher than before stimulation. The surgery was uneventful, and she was discharged eight days postoperatively without complications. CONCLUSIONS: Our case suggests that electrical stimulation for Tc-MEP can cause arrhythmia. Electrocardiography and blood pressure must be closely monitored during Tc-MEP monitoring.

Postoperative hyperammonemic encephalopathy due to unexpected constipation in a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: a case report.

BACKGROUND: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive urea cycle disorder associated with a high risk of exacerbation of hyperammonemia during the perioperative period. Here, we describe an adult patient with HHH syndrome who developed hyperammonemic encephalopathy secondary to postoperative constipation. CASE PRESENTATION: A 52-year-old patient with HHH syndrome underwent intrathecal baclofen pump insertion for lower limb spasticity under general anesthesia. The surgery was uneventful, without any increase in serum ammonia levels. However, after surgery, he was constipated, and on postoperative day (POD) 3, he fell into a coma with an exacerbation of hyperammonemia (894 µg/dL). After administering a glycerin enema, he defecated, leading to a rapid decrease in serum ammonia levels to 165 µg/dL. He regained consciousness, and serum ammonia levels remained stable as long as he defecated. CONCLUSIONS: We suggest strict management of defecation during the perioperative period to prevent hyperammonemia in patients with HHH syndrome.

An analysis of the effects of chronic low dose-rate radiation exposure on cancer focusing on the differences among cancer types.

PURPOSE: The effect of chronic low dose-rate radiation exposure on cancers was investigated by analyzing the data of mice experiments conducted at the Institute for Environmental Sciences (IES). This analysis focuses on the differences between malignant lymphomas and solid cancers. MATERIALS AND METHODS: The analysis is conducted based on the mathematical model introduced in our previous work. The model is expanded to analyze malignant lymphomas and solid cancers separately. Using the expanded model, the effect of chronic low dose-rate radiation on malignant lymphomas and solid cancers are discussed based on their occurrences, progressions, and mortalities. RESULTS: Non-irradiated control group and 20 mGy/day × 400 days irradiated groups are analyzed. The analysis showed that radiation exposure shortened mean life expectancy for both malignant lymphomas and solid cancers (shorter by 89.6 days for malignant lymphomas and 149.3 days for solid cancers). For malignant lymphomas, both the occurrence and the progression are affected by radiation exposure. The mean age at which malignant lymphoma developed in mice was shortened by 32.7 days and the mean progression period was shortened by 57.3 days. The occurrence of solid cancer is also affected by radiation exposure, wherein the mean age at which solid cancer develops was shortened by 147.9 days. However, no significant change in progression period of solid cancers was seen in the analysis. CONCLUSIONS: The analysis showed that the occurrence and mean lifespan are affected in both malignant lymphomas and solid cancers. The shortening of the progression period is only seen in malignant lymphoma, no significant change was observed in solid cancers.

Human-mouse comparison of the multistage nature of radiation carcinogenesis in a mathematical model.

Mouse models are vital for assessing risk from environmental carcinogens, including ionizing radiation, yet the interspecies difference in the dose response precludes direct application of experimental evidence to humans. Herein, we take a mathematical approach to delineate the mechanism underlying the human-mouse difference in radiation-related cancer risk. We used a multistage carcinogenesis model assuming a mutational action of radiation to analyze previous data on cancer mortality in the Japanese atomic bomb survivors and in lifespan mouse experiments. Theoretically, the model predicted that exposure will chronologically shift the age-related increase in cancer risk forward by a period corresponding to the time in which the spontaneous mutational process generates the same mutational burden as that the exposure generates. This model appropriately fitted both human and mouse data and suggested a linear dose response for the time shift. The effect per dose decreased with increasing age at exposure similarly between humans and mice on a per-lifespan basis (0.72- and 0.71-fold, respectively, for every tenth lifetime). The time shift per dose was larger by two orders of magnitude in humans (7.8 and 0.046 years per Gy for humans and mice, respectively, when exposed at ~35% of their lifetime). The difference was mostly explained by the two orders of magnitude difference in spontaneous somatic mutation rates between the species plus the species-independent radiation-induced mutation rate. Thus, the findings delineate the mechanism underlying the interspecies difference in radiation-associated cancer mortality and may lead to the use of experimental evidence for risk prediction in humans.

Nonmagnetic framboid and associated iron nanoparticles with a space-weathered feature from asteroid Ryugu.

Extraterrestrial minerals on the surface of airless Solar System bodies undergo gradual alteration processes known as space weathering over long periods of time. The signatures of space weathering help us understand the phenomena occurring in the Solar System. However, meteorites rarely retain the signatures, making it impossible to study the space weathering processes precisely. Here, we examine samples retrieved from the asteroid Ryugu by the Hayabusa2 spacecraft and discover the presence of nonmagnetic framboids through electron holography measurements that can visualize magnetic flux. Magnetite particles, which normally provide a record of the nebular magnetic field, have lost their magnetic properties by reduction via a high-velocity (>5 km s-1) impact of a micrometeoroid with a diameter ranging from 2 to 20 µm after destruction of the parent body of Ryugu. Around these particles, thousands of metallic-iron nanoparticles with a vortex magnetic domain structure, which could have recorded a magnetic field in the impact event, are found. Through measuring the remanent magnetization of the iron nanoparticles, future studies are expected to elucidate the nature of the nebular/interplanetary magnetic fields after the termination of aqueous alteration in an asteroid.

Effect of aromatherapy with peppermint essential oil on the gag reflex: a randomized, placebo-controlled, single-blind, crossover study.

BACKGROUND: Sensitive gag reflexes prevent dental patients from receiving appropriate treatment. Aromatherapy helps patients relax during dental procedures. However, the effect of aromatherapy on the gag reflex caused by the stimulation of the oral cavity is unknown. This study aimed to evaluate whether aromatherapy reduces gag reflexes during oral stimulation. METHODS: In this randomized, placebo-controlled, single-blind, crossover study, the gag reflexes of 24 healthy individuals (12 females and 12 males; mean age: 34.3 ± 9.5 years) were quantified. A standard saliva ejector was slowly guided down the participant's throat to determine the maximum tolerance of the gag reflex, and the insertion distance was measured to quantify the gag reflex. All individuals participated in an aromatherapy session with peppermint essential oil and a placebo session with distilled water. The gag reflex was quantified before (baseline) and after each session. Another measurement was performed using nitrous oxide/oxygen inhalation as a positive control. RESULTS: Gag reflex values significantly increased after aromatherapy with both peppermint essential oil and placebo compared to baseline values (paired t-test, P < 0.001 and P = 0.014, respectively). The gag reflex value also increased significantly during nitrous oxide/oxygen inhalation (paired t-test, P < 0.001). There was no significant difference in the increase rate of gag reflex values between the positive control and aromatherapy interventions, but it was significantly lower after the placebo intervention (repeated measures analysis of variance, P = 0.003; post-hoc test, P = 0.83 and P = 0.02). CONCLUSION: Aromatherapy with peppermint essential oil has the potential for reducing gag reflex during dental procedures. TRIAL REGISTRATION: The study was registered in the University hospital Medical Information Network Clinical Trials Registry under the code UMIN000050616 (approved 17/03/2023).

A mathematical model for radiation-induced life-shortening attributed to cancer.

PURPOSE: In this paper, we described our mathematical model for radiation-induced life shortening in detail and applied the model to the experimental data on mice to investigate the effect of radiation on cancer-related life-shortening. MATERIALS AND METHODS: Our mathematical model incorporates the following components: (i) occurrence of cancer, (ii) progression of cancer over time, and (iii) death from cancer. We evaluated the progression of cancer over time by analyzing the cancer incidence data and cumulative mortalities data obtained from mice experiments conducted at the Institute for Environmental Sciences (IES). RESULTS: We analyzed non-irradiated control and 20 mGy/day × 400 days irradiated groups. In the analysis, all malignant neoplasms were lumped together and referred to as 'cancer'. Our analysis showed that the reduction in lifespan (104 days in median) was the result of the early onset of cancer (68 days in median) and the shortening of the cancer progression period (48 days in median). CONCLUSIONS: We described in detail our mathematical model for radiation-induced life-shortening attributed to cancer. We analyzed the mice data obtained from the experiment conducted at the IES using our model. We decomposed radiation-induced life-shortening into the early onset of cancer and the shortening of the cancer progression period.

[Rectal cancer with multiple metastases complicated by Crohn's disease 5 years after surgery:a case report].

In recent years, with the rising incidence of patients having long-term Crohn's disease, there has been an increase in the number of reports of carcinogenesis from dysplasia with chronic inflammation as the primary pathogenic factor. We hereby report a case of multiple metastases that appeared 5 years after surgery, in a patient with rectal cancer who had Crohn's disease. A man in his 50s was diagnosed with Crohn's disease which affected his small and large intestines 21 years back. The patient was being treated with oral steroids, 5-aminosalicylic acid, and modified nutrition. Infliximab was added to the treatment after it was introduced 11 years ago. He also had a history of rectal cancer and had undergone surgery for the same 5 years back. He was diagnosed with stage II cancer, and had not received any adjuvant chemotherapy. However, 5 years after surgery, multiple metastases recurred, and chemotherapy with mFOLFOX6 was administered. Additionally, for treating his Crohn's disease, which was also active, infliximab was changed to vedolizumab;however, the patient died a year later. Colorectal cancer accompanied with Crohn's disease has a higher risk of developing metastasis and is associated with poorer prognosis as compared to the noncomplicated colorectal cancer. Regarding treatment modalities, while searching for multidisciplinary treatment methods centered on surgical treatment in collaboration with medical oncologists and radiologists, the safety of treatment for Crohn's disease in patients with cancer must be borne in mind. The rising prevalence of cases of colorectal cancer with Crohn's disease is expected to lead to the formulation of specialized diagnostic and treatment strategies for these patients.

White Cord Syndrome After Cervical Laminoplasty in an 81-Year-Old Man.

White cord syndrome (WCS) shows high intramedullary signaling in T2-weighted MRI with worsening motor nerve symptoms after cervical spinal decompression surgery. It has been reported in only 13 cases. An 81-year-old man had numbness, weakness, and impaired fine motor control in both upper limbs for the previous five years. C3, C4, C6, open-door laminoplasty, and C5 laminectomy were performed. Intraoperative transcranial motor evoked potential normalization by compound muscle action potential showed an 80% reduction in amplitude in the right abductor pollicis brevis and a 96% reduction in the right abductor hallucis. Tetraplegia occurred immediately after the operation. Magnetic resonance imaging (MRI) on the day after the operation showed intramedullary T2 high signals at the C4 and C5 levels. According to Brunnstrom's staging, the upper and lower right limbs and the lower left limb were at stage two, and the upper left limb was at stage three, six months after the operation. Thirteen cases of WCS have been reported in the literature. These were thought to be caused by reperfusion due to decompression.

Late Effects of Chronic Low Dose Rate Total Body Irradiation on the Heart Proteome of ApoE-/- Mice Resemble Premature Cardiac Ageing.

Recent epidemiologic studies support an association between chronic low-dose radiation exposure and the development of cardiovascular disease (CVD). The molecular mechanisms underlying the adverse effect of chronic low dose exposure are not fully understood. To address this issue, we have investigated changes in the heart proteome of ApoE deficient (ApoE-/-) C57Bl/6 female mice chronically irradiated for 300 days at a very low dose rate (1 mGy/day) or at a low dose rate (20 mGy/day), resulting in cumulative whole-body doses of 0.3 Gy or 6.0 Gy, respectively. The heart proteomes were compared to those of age-matched sham-irradiated ApoE-/- mice using label-free quantitative proteomics. Radiation-induced proteome changes were further validated using immunoblotting, enzyme activity assays, immunohistochemistry or targeted transcriptomics. The analyses showed persistent alterations in the cardiac proteome at both dose rates; however, the effect was more pronounced following higher dose rates. The altered proteins were involved in cardiac energy metabolism, ECM remodelling, oxidative stress, and ageing signalling pathways. The changes in PPARα, SIRT, AMPK, and mTOR signalling pathways were found at both dose rates and in a dose-dependent manner, whereas more changes in glycolysis and ECM remodelling were detected at the lower dose rate. These data provide strong evidence for the possible risk of cardiac injury following chronic low dose irradiation and show that several affected pathways following chronic irradiation overlap with those of ageing-associated heart pathology.

A case of CD74-ROS1-positive lung adenocarcinoma diagnosed by next-generation sequencing achieved long-term survival with pemetrexed regimens.

Previously, cytotoxic drugs were the only option for patients with non-small cell lung cancer (NSCLC) and the prognosis was poor. However, molecularly targeted therapies and immune checkpoint inhibitors represent a breakthrough in the treatment of advanced NSCLC and have improved survival rates. In addition, advances in next-generation sequencing (NGS) have revealed the landscape of genomic alterations in patients with different cancers, aiding in the development of new molecularly targeted drugs. The patient reported here was a 54-year-old woman with left lower lung adenocarcinoma. The lung cancer was staged as T2aN3M1a stageIVA 11 years ago. She had received seven regimens of chemotherapy for 11 years. Among these, pemetrexed (PEM) regimens particularly showed long-term effects totaling more than 5 years. We performed NGS after disease progression of the seventh treatment. NGS revealed CD74-ROS1 fusion and she was treated with entrectinib. She has been taking entrectinib for over 20 months now. Herein, we report a rare case of CD74-ROS1-positive lung adenocarcinoma diagnosed by NGS that achieved long-term survival with cytotoxic drugs, especially PEM regimens. In patients showing favorable clinical response to PEM regimens, physicians should consider testing for ROS1/ALK rearrangement.

Ninety-day mortality of extremely elderly patients undergoing hip fracture surgery and its association with preoperative cardiac function: a single-center retrospective study.

PURPOSE: We investigated the 90-day mortality rate in elderly patients who underwent hip fracture surgery and the association of preoperative cardiac function with mortality. METHODS: We retrospectively enrolled 133 consecutive patients aged 80 years or older who underwent hip fracture surgery. We obtained information for patient sex, age, comorbidities, medications, anesthesia method, left ventricular systolic and diastolic functions assessed by echocardiography, and preoperative brain natriuretic peptide (BNP) levels. Multivariate logistic regression analysis was performed. RESULTS: The 90-day mortality rate in patients with a mean age of 88.9 years was 7.5% (10/133). More than half of the patients had diastolic dysfunction of the left ventricle. There were no significant differences in preoperative cardiac systolic and diastolic functions between the mortality group and non-mortality group. The preoperative BNP level in the mortality group was significantly higher than that in the non-mortality group (p = 0.038). Preoperative BNP level was not an independent risk factor for 90-day mortality (p = 0.081) in the primary multivariate logistic regression analysis but was an independent risk factor (p = 0.039) with an odds ratio of 1.004 (95% CI 1.000-1.008) in the sensitivity analysis with different explanatory variables. CONCLUSION: The 90-day mortality rate in patients over 80 years old after hip fracture surgery was 7.5%. There were no significant differences in preoperative cardiac function assessed by echocardiography between the mortality and non-mortality groups. Our results suggest that there is no association or only a weak association of high BNP level with 90-day mortality in this age population.

[Motor Evoked Potential].

Motor evoked potential(MEP)is the most widely used intraoperative neurophysiological monitoring measure. It includes cortical direct stimulation MEP(dMEP), which directly stimulates the primary motor cortex of the frontal lobe identified by short-latency somatosensory evoked potentials, and transcranial MEP(tcMEP), which involves high-current or high-voltage transcranial stimulation using cork-screw electrodes installed in the scalp. dMEP is performed in brain tumor surgery close to the motor area. tcMEP is simple, safe, and widely used in spinal and cerebral aneurysm surgeries. The increase in sensitivity and specificity with compound muscle action potential(CMAP)after peripheral nerve stimulation normalization performed in MEP to remove the effect of muscle relaxants is unclear. However, tcMEP for decompression in compressive spinal and spinal nerve diseases may predict the recovery of postoperative neurological symptoms with CMAP normalization. The anesthetic fade phenomenon can be avoided with CMAP normalization. The cutoff rate of loss of amplitude that causes postoperative motor paralysis in intraoperative MEP monitoring is 70%-80%, and setting an alarm at each facility based on this is necessary.

Anesthetic Fade in Intraoperative Transcranial Motor Evoked Potential Monitoring Is Mainly due to Decreased Synaptic Transmission at the Neuromuscular Junction by Propofol Accumulation.

BACKGROUND: We previously reported that normalization of motor evoked potential (MEP) monitoring amplitude by compound muscle action potential (CMAP) after peripheral nerve stimulation prevented the expression of anesthetic fade (AF), suggesting that AF might be due to reduced synaptic transfer in the neuromuscular junction. METHODS: We calculated the time at which AF began for each of craniotomy and spinal cord surgery, and examined whether AF was avoided by CMAP after peripheral nerve stimulation normalization in each. Similar studies were also made with respect to the upper and lower limb muscles. RESULTS: AF was observed in surgery lasting 160 minutes for craniotomy and 260 minutes or more for spinal surgery, and 195 minutes in the upper limb muscles and 135 minutes in the lower limb muscles. In all the series, AF could be avoided by CMAP after peripheral nerve stimulation normalization. CONCLUSION: AF of MEP occurred in both craniotomy and spinal cord surgery, and it was also corrected by CMAP after peripheral nerve stimulation. AF is considered to be mainly due to a decrease in synaptic transfer of the neuromuscular junction due to the accumulation of propofol because of the avoidance by CMAP normalization. However, it may be partially due to a decrease in the excitability of pyramidal tracts and α-motor neurons, because AF occurred earlier in the lower limb muscles than in the upper limb muscles.

Inflammation and subsequent nociceptor sensitization in the bone marrow are involved in an animal model of osteoarthritis pain.

AIMS: This study aimed to determine whether pathological changes in the bone marrow cause Osteoarthritis (OA) pain based on magnetic resonance imaging (MRI), immunohistochemistry, and electrophysiology. MAIN METHODS: Adjuvant-induced arthritis (AIA) was achieved by injecting 150 µL of complete Freund's adjuvant into the right knee joints of male Sprague-Dawley rats. AIA rats were compared with saline-injected rats. KEY FINDINGS: AIA significantly induced mechanical hyperalgesia and spontaneous pain in the right hind paw 1-14 days after induction. Intratibial injection of 50 µL of 1 % lidocaine significantly suppressed AIA-induced mechanical hyperalgesia (p = 0.0001) and spontaneous pain (p = 0.0006) 3 days after induction. In T2-weighted MRI, AIA induced high-signal intensity within the proximal tibial metaphysis, and the mean T2 values in this area significantly increased on days 3 (p = 0.0043) and 14 (p = 0.0012) after induction. AIA induced intraosseous edema and significantly increased the number of intraosseous granulocytes on days 3 (p < 0.0001) and 14 (p < 0.0001) after induction. The electrophysiological study on days 3-7 after induction showed significantly increased spontaneous firing rates (p = 0.0166) and evoked responses to cutaneous stimuli (brush, p < 0.0001; pinching, p = 0.0359) in the right hind paw plantar surface and intratibial stimuli (p = 0.0002) in wide-dynamic-range neurons of the spinal dorsal horn. SIGNIFICANCE: Intraosseous changes caused by OA induce hypersensitivity in the sensory afferents innervating bone marrow may be involved in OA pain. Novel bone marrow-targeted therapies could be beneficial for treating OA pain.

Effect of cerebrospinal fluid drainage pressure in descending and thoracoabdominal aortic repair: a prospective multicenter observational study.

PURPOSE: Cerebrospinal fluid drainage (CSFD) is recommended during open or endovascular thoracic aortic repair. However, the incidence of CSFD complications is still high. Recently, CSF pressure has been kept high to avoid complications, but the efficacy of CSFD at higher pressures has not been confirmed. We hypothesize that CSFD at higher pressures is effective for preventing motor deficits. METHODS: This prospective observational study included 14 hospitals that are members of the Japanese Society of Cardiovascular Anesthesiologists. Patients who underwent thoracic and thoracoabdominal aortic repair were divided into four groups: Group 1, CSF pressure around 10 mmHg; Group 2, CSF pressure around 15 mmHg; Group 3, CSFD initiated when motor evoked potential amplitudes decreased; and Group 4, no CSFD. We assessed the association between the CSFD group and motor deficits using mixed-effects logistic regression with a random intercept for the institution. RESULTS: Of 1072 patients in the study, 84 patients (open surgery, 51; thoracic endovascular aortic repair, 33) had motor deficits at discharge. Groups 1 and 2 were not associated with motor deficits (Group 1, odds ratio (OR): 1.53, 95% confidence interval (95% CI): 0.71-3.29, p = 0.276; Group 2, OR: 1.73, 95% CI: 0.62-4.82) when compared with Group 4. Group 3 was significantly more prone to motor deficits than Group 4 (OR: 2.56, 95% CI: 1.27-5.17, p = 0.009). CONCLUSION: CSFD is not associated with motor deficits in thoracic and thoracoabdominal aortic repair with CSF pressure around 10 or 15 mmHg.

Epidermal growth factor represses differentiation of mouse trophoblast stem cells into spongiotrophoblast cells via epidermal growth factor receptor.

The mouse placenta is composed of three different trophoblast layers that are occupied by particular trophoblast subtypes to maintain placental function and pregnancy. Accurate control of trophoblast differentiation is required for proper placental function; however, the molecular mechanisms underlying cell fate decisions in trophoblast stem cells remain poorly understood. Epidermal growth factor (EGF) signaling is involved in multiple biological processes including cell survival, proliferation, and differentiation. The effect of EGF on trophoblast function has been reported in various species; however, the role of EGF signaling in mouse trophoblast specification remains unclear. In this study, we aimed to elucidate the role of EGF signaling in mouse trophoblast differentiation using mouse trophoblast stem cells (mTSCs) in an in vitro culture system. EGF stimulation at the early stage of differentiation repressed mTSC differentiation into spongiotrophoblast cells (SpT). Gene deletion and inhibitor experiments showed that the effect of EGF exposure went through epidermal growth factor receptor (Egfr) activity in mTSCs. EGF stimuli induced acute downstream activation of MAPK/ERK, PI3K/AKT, and JNK pathways, and inhibition of the MAPK/ERK pathway, but not others, alleviated EGF-mediated repression of SpT differentiation. Moreover, expression of Mash2, a master regulator of SpT differentiation, was repressed by EGF stimulation, and MAPK/ERK inhibition counteracted this repression. The Mash2 overexpression recovered SpT marker expression, indicating that the decrease in Mash2 expression was due to abnormal SpT differentiation in EGF-treated mTSCs. Our findings suggest that the EGF-Egfr-MAPK/ERK-Mash2 axis is a core regulatory mechanism for the EGF-mediated repression of SpT differentiation.

Case report: Electrocardiographic changes in pembrolizumab-induced fatal myocarditis.

Immune checkpoint inhibitor (ICI)-induced myocarditis is rare but fatal. Because of the rapid course of ICI-induced myocarditis, understanding of clinical course is only possible through information from case reports. We report a case of pembrolizumab-induced myocarditis in which we were able to document the course of electrocardiographic changes from onset to death. A 58-year-old woman with stage IV lung adenocarcinoma, who had completed her first cycle of pembrolizumab, carboplatin, and pemetrexed, was admitted with pericardial effusion. She underwent pericardiocentesis after admission. A second cycle of chemotherapy was administered 3 weeks after the first cycle. Twenty-two days after admission, she developed a mild sore throat and tested positive for SARS-CoV-2 antigen. She was diagnosed with mild coronavirus disease 2019 (COVID-19), isolated, and treated with sotrovimab. Thirty-two days after admission, an electrocardiogram showed monomorphic ventricular tachycardia (VT). Suspecting myocarditis caused by pembrolizumab, the patient was started on daily methylprednisolone after coronary angiography and endocardial biopsy. Eight days after the start of methylprednisolone administration, she was considered to have passed the acute stage. However, four days later, R-on-T phenomenon triggered polymorphic VT and she died. The impact of viral infections such as COVID-19 on patients be treated with immune checkpoint inhibitors is still unknown and we need to be careful with systemic management after viral infections.

ATP and its metabolite adenosine cooperatively upregulate the antigen-presenting molecules on dendritic cells leading to IFN-γ production by T cells.

Dendritic cells (DCs) present foreign antigens to T cells via the major histocompatibility complex (MHC), thereby inducing acquired immune responses. ATP accumulates at sites of inflammation or in tumor tissues, which triggers local inflammatory responses. However, it remains to be clarified how ATP modulates the functions of DCs. In this study, we investigated the effects of extracellular ATP on mouse bone marrow-derived dendritic cells (BMDCs) as well as the potential for subsequent T cell activation. We found that high concentrations of ATP (1 mM) upregulated the cell surface expression levels of MHC-I, MHC-II, and co-stimulatory molecules CD80 and CD86 but not those of co-inhibitory molecules PD-L1 and PD-L2 in BMDCs. Increased surface expression of MHC-I, MHC-II, CD80, and CD86 was inhibited by a pan-P2 receptor antagonist. In addition, the upregulation of MHC-I and MHC-II expression was inhibited by an adenosine P1 receptor antagonist and by inhibitors of CD39 and CD73, which metabolize ATP to adenosine. These results suggest that adenosine is required for the ATP-induced upregulation of MHC-I and MHC-II. In the mixed leukocyte reaction assay, ATP-stimulated BMDCs activated CD4 and CD8T cells and induced interferon-γ (IFN-γ) production by these T cells. Collectively, these results suggest that high concentrations of extracellular ATP upregulate the expression of antigen-presenting and co-stimulatory molecules but not that of co-inhibitory molecules in BMDCs. Cooperative stimulation of ATP and its metabolite adenosine was required for the upregulation of MHC-I and MHC-II. These ATP-stimulated BMDCs induced the activation of IFN-γ-producing T cells upon antigen presentation.