Cost of medical care for malignant brain tumors at hospitals in the Japan Clinical Oncology Group brain-tumor study group.

BACKGROUND: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved. METHODS: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL. RESULTS: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month). CONCLUSIONS: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.

Application of elemental analysis-coupled isotope ratio mass spectrometry for protein turnover analysis using deuterium labeling: Purification and analysis of hydrogen isotope ratio of non-derivatized protein-bound alanine.

RATIONALE: Heavy water can be used as a tracer for the evaluation of protein turnover. By adding heavy water (D2 O) to the precursor pool, nonessential amino acids, including alanine, can be isotopically labeled in vivo. Protein turnover can then be quantified by measuring the hydrogen isotope ratio of protein-bound alanine. METHODS: In this study, we constructed a novel method to apply deuterium labeling of alanine to the evaluation of protein turnover using elemental analysis-coupled isotope ratio mass spectrometry (EA-IRMS). We established a preparative high-performance liquid chromatography method to isolate alanine from protein hydrolysates. EA-IRMS was then used to determine the hydrogen isotope ratio of alanine isolated from hydrolysates of protein from mouse myoblast C2C12 cells that had been treated with D2 O over the course of 72 h. RESULTS: In cells treated with 4% D2 O, the deuterium enrichment of alanine increased to approximately 0.9% over time, while that of cells treated with 0.017% D2 O increased to approximately 0.006%. The rate of protein synthesis calculated by fitting the increase of deuterium excess to rise-to-plateau kinetics was similar regardless of the concentration of D2 O. When C2C12 cells treated with insulin and rapamycin were analyzed 24 h after the addition of 0.017% D2 O, protein turnover was found to be accelerated by insulin, but this effect was offset by co-treatment with rapamycin. CONCLUSION: The derivative-free measurement of the hydrogen isotope ratio of protein-bound alanine using EA-IRMS can be applied to the evaluation of protein turnover. The proposed method is an accessible option for many laboratories to perform highly sensitive IRMS-based evaluations of protein metabolic turnover.

[Intraoperative Neurophysiological Monitoring in Pediatric Patients].

Because of technological advancements in preserving neurological function during surgery, intraoperative neurophysiological monitoring has become mandatory and increasingly common. Few studies have reported on the safety, feasibility, and reliability of intraoperative neurophysiological monitoring in children, especially infants. The maturation of nerve pathways is not fully achieved until 2 years of age. Moreover, it is often difficult to maintain stable anesthetic depth and hemodynamic status when operating on children. The interpretation of neurophysiological recordings in children is different from that in adults and requires further consideration.

Venous hypertension caused by a meningioma involving the sigmoid sinus: case report.

BACKGROUND: Intracranial venous hypertension has been associated with a few cases of meningioma secondary to compression of the venous sinus. This is the rare case of small meningioma involving the sigmoid sinus leading to intracranial venous hypertension mimicking venous thrombosis. CASE PRESENTATION: A 39-year-old woman suffered visual dysfunction due to bilateral papilledema. Noncontrast head computed tomography (CT) showed no intracranial space-occupying lesions or hydrocephalus. Cerebrospinal fluid examination revealed high opening pressure. Various image inspections such as three-dimensional CT angiography, magnetic resonance imaging, and cerebral angiography demonstrated a small 2.5-cm lesion causing subtotal occlusion of the dominant right sigmoid sinus. No improvement of clinical manifestations was observed after medical treatment for 6 months, so right presigmoid craniectomy was performed. Operative findings revealed that the tumor was located predominantly involving the sigmoid sinus. The pathological diagnosis was fibrous meningioma. Postoperative fundoscopic examination showed improvement of bilateral papilledema. CONCLUSIONS: We treated a patient presenting with intracranial hypertension due to a small meningioma involving the sigmoid sinus. This unusual case suggests that early surgical strategies should be undertaken to relieve the sinus obstruction.

Massive intracranial hemorrhage caused by intraventricular meningioma: case report.

BACKGROUND: Meningiomas are the most common benign intracranial tumors, and commonly comprise high-vascularizing but slow-growing tumors. On the other hand, meningiomas arising from the ventricular system are of rare occurrence, and spontaneous hemorrhage is an infrequent event. CASE PRESENTATION: We describe here the rare clinical manifestations of a 28-year-old female with acute intracranial hemorrhage located in the trigone of the lateral ventricle who was initially thought to have suffered an acute cerebrovascular accident, but was subsequently confirmed to have a benign intraventricular meningioma. To clarify the clinical features of such a rare course of meningioma, we also present a short literature review of acute intracranial hemorrhage caused by intraventricular meningioma. CONCLUSIONS: Ventricular meningioma presenting with hemorrhage such as acute stroke is a rare event, but recognition of such a pathogenesis is important. Although further accumulation of clinical data is needed, we suggest that early surgery should be undertaken in patients with lateral ventricular meningioma, even if it is not so large or asymptomatic.

Indoleamine 2,3-dioxygenase 1 is highly expressed in glioma stem cells.

Recent research has revealed that glioblastoma (GBM) avoids the immune system via strong expression of indoleamine 2,3-dioxygenase 1 (IDO1). IDO1, an enzyme involved in tryptophan metabolism, is now proposed as a new target in GBM treatment, since several reports have demonstrated that IDO1 expression is related to GBM malignancy. On the other hand, it is well known that glioma stem cells (GSCs) are strongly related to the malignancy of GBM. However, there is as yet no report evaluating the relationship between GSCs and IDO1. We therefore examined the expression levels of IDO1 in GSCs in order to identify a new therapeutic target for GBM based on the immune systems of GSCs. In the present study, we employed human GBM cell lines (U-138MG, U-251MG) and patient-derived GSC model cell lines (0125-GSC, 0222-GSC). GSC model cell lines Rev-U-138MG and Rev-U-251MG were established by culturing U-138MG and U-251MG in serum-free media, while differentiated GBM model cell lines 0125-DGC and 0222-DGC were established by culturing 0125-GSC and 0222-GSC in serum-containing media. The expression levels of stem cell markers (Nanog, Nestin, Oct4 and Sox2) and IDO1 protein and mRNA were determined. Rev-U-138MG and Rev-U-251MG formed spheres and their expression levels of stem cell markers were increased as compared to U-138MG and U-251MG. On the other hand, 0125-DGC and 0222-DGC suffered breakdown of sphere formation, despite the original 0125-GSC and 0222-GSC forming spheres, and their expression levels of the markers were decreased. IDO1 expressions were strongly recognized in Rev-U-138MG, Rev-U-251MG, 0125-GSC and 0222-GSC as compared to U-138MG, U-251MG, 0125-DGC and 0222-DGC. These findings demonstrate that GSCs exhibit treatment resistance with immunosuppression via high expression levels of IDO1, and could represent a novel target for GBM treatment.

Repeated stretch-shortening contraction of the triceps surae attenuates muscle atrophy and liver dysfunction in a rat model of inflammation.

NEW FINDINGS: What is the central question of this study? Is stretch-shortening contraction effective to attenuate skeletal muscle atrophy and hepatic dysfunction in a rat model of peptidoglycan-polysaccharide (PG-PS)-induced inflammation (PG-PS rat)? What are the main findings and their importance? Stretch-shortening contraction attenuates skeletal muscle atrophy in the trained leg and increases circulating interleukin-10 in PG-PS rats. Stretch-shortening contraction also ameliorates liver dysfunction in PG-PS rats, possibly via increased blood interleukin-10. These findings are important because they suggest that stretch-shortening contraction is effective to maintain liver function in addition to exercised skeletal muscle mass. ABSTRACT: Stretch-shortening contraction (SSC) is an effective modality to improve skeletal muscle mass. However, the beneficial effects of SSC in the presence of chronic inflammation remain unclear. Here, we imposed five SSC sessions unilaterally on the triceps surae in young female Lewis rats. Rats were injected with vehicle or peptidoglycan-polysaccharide (PG-PS) to induce long-lasting inflammation. The PG-PS reduced gastrocnemius muscle mass in both legs, but that of the SSC-trained leg was significantly greater than that of the contralateral leg. Circulating pro-inflammatory cytokines, such as IL-1ß, were significantly increased by PG-PS injection, even if carrying out SSC. The circulating anti-inflammatory cytokine IL-10 increased with SSC in both healthy and inflammatory conditions. Stretch-shortening contraction also prevented increases in serum aspartate aminotransferase activity and plasma free phenylalanine concentration induced by PG-PS, in comparison to the control resistance exercise consisting of isometric contractions. Moreover, aspartate aminotransferase and phenylalanine concentrations demonstrated a significant and negative correlation with IL-10/IL-1ß values (r = -0.61, P = 0.017, and r = -0.66, P = 0.008, respectively). These results suggest that SSC training is effective to reduce both muscle atrophy and the hepatic dysfunction induced by PG-PS, mediated, at least in part, through an increase in circulating IL-10.

Modified colored three-dimensional posterior and temporal cranial fossa model with mobility of the joint between C1 and occipital condyle.

BACKGROUND: Skull base surgery requires anatomical knowledge and appropriate surgical technique in bone drilling. We developed a newly modified three-dimensional (3D) model of the posterior cranial fossa as a learning tool that improves knowledge of skull base anatomy and surgical approaches, including skull base drilling techniques. METHODS: This bone model of the posterior cranial fossa was created based on computed tomography data using a 3D printer, and incorporates artificial cranial nerves, cerebral vessels, bony structures, dura mater, and cerebellar tentorial dura. These anatomical components are differentiated with various colors. In addition, the atlanto-occipital junction can be mobilized to fully expose the surface of the cartilage between the C1 condyle and occipital condyle to allow drilling to open the hypoglossal canal under a wide surgical field. The usefulness of the model for practicing skull base surgical approaches was evaluated. RESULTS: Experience of bone drilling, dural dissection, and 3D positioning of important structures, including cranial nerves and blood vessels, was identical to that in actual surgery. CONCLUSIONS: This model is designed to facilitate teaching anatomical knowledge and essential epidural procedure-related skills, and is useful for teaching the essential elements of posterior skull base surgery.

Unique advantages of dynamic l-[11C]methionine PET/CT for assessing the rate of skeletal muscle protein synthesis: A pilot trial in young men.

Although the standard method to evaluate skeletal muscle protein synthesis (MPS) is muscle biopsy, the method is invasive and problematic for multisite use. We conducted a small pilot study in volunteers to investigate changes in MPS according to skeletal muscle site using a noninvasive method in which 6 healthy young men were given yogurt (containing 20 g milk protein) or water, and 1 h later, l-[11C]methionine ([11C]Met) was administered intravenously. Dynamic PET/CT imaging of their thighs was performed for 60 min. The influx constant Ki of [11C]Met in skeletal muscle protein was calculated as an index of MPS using a Patlak plot, and found to be 0.6%-28% higher after ingesting yogurt than after water in 5 of the 6 volunteer participants, but it was 34% lower in the remaining participant. Overall, this indicated no significant increase in Ki after ingesting milk protein. However, when the quadriceps and hamstring muscles were analyzed separately, we found a significant difference in Ki. This demonstrates the potential of visualizing MPS by calculating the Ki for each voxel and reconstructing it as an image, which presents unique advantages of [11C]Met PET/CT for evaluating MPS, such as site-specificity and visualization.

Cacao Procyanidins-Induced Lifespan Extension in Caenorhabditis elegans in a Nervous System and CaMKII-Dependent Manner.

Procyanidins are gaining attention due to their potential health benefits. We found that cacao liquor procyanidin (CLPr) from Theobroma cacao seeds increased the lifespan of Caenorhabditis elegans, a representative model organism for aging studies. The genetic dependence of the lifespan-extending effect of CLPr was consistent with that of blueberry procyanidin, which is dependent on unc-43, osr-1, sek-1, and mev-1, but not on daf-16, sir-2.1, or skn-1. The lifespan-extending effect of CLPr was inhibited by neuron-specific RNA interference (RNAi) targeting unc-43 and pmk-1, and in worms with loss-of-function mutations in the odr-3, odr-1, or tax-4 genes, which are essential in sensory neurons, including AWC neurons. It was also inhibited in worms in which AWC neurons or AIB interneurons had been eliminated, and in worms with loss-of-function mutations in eat-4 or glr-1, which are responsible for glutamatergic synaptic transmission. These results suggest that the lifespan-extending effect of CLPr is dependent on the nervous system. In addition, it also requires unc-43 and pmk-1 expression in nonneuronal cells, as demonstrated by the experiments with RNAi in wild-type worms, the neuronal cells of which are not affected by systemic RNAi. The osr-1 gene is expressed in hypodermal and intestinal cells and regulates the response to osmotic stress along with unc-43/calcium/calmodulin-dependent protein kinase II and the p38 mitogen-activated protein kinase pathway. Consistent with this, CLPr improved osmotic stress tolerance in an unc-43- and pmk-1-dependent manner, and it was also dependent on AWC neurons. The lifespan-extending and osmotic-tolerance-improving activities were attributed to procyanidins with a tetrameric or higher-order oligomeric structure.

Fatal hemorrhage from AVM after DBS surgery: case report.

OBJECTIVES: Intracranial hemorrhage is a crucial complication of deep brain stimulation (DBS) surgery. The bleeding caused by mechanical tissue injury due to microelectrode and/or DBS electrode lead insertion has been well studied. However, hemorrhage caused by a congenital underlying disease such as vascular malformation has not been examined carefully. MATERIALS AND METHODS: We encountered a case of intracerebral hemorrhage from arteriovenous malformation (AVM) after DBS surgery. Preoperative magnetic resonance (MR) imaging did not show any abnormality in the patient. Computed tomography (CT) images taken immediately after the surgery did not show any intracranial hematoma and other abnormal findings. However, the patient did not recover from the general anesthesia, and hemorrhage in the left occipital lobe was detected by CT performed a day after the surgery. The location of the hematoma was markedly distant from the trajectory of DBS leads. Evacuation of the hematoma under general anesthesia was immediately performed. RESULTS: As an intraoperative finding, we noted the presence of abnormal vessels inside the hematoma in the occipital lobe. Tissue specimens including the abnormal vessels were obtained for histopathological analysis, results of which led to the diagnosis was AVM. CONCLUSION: Despite its low incidence, we would like to advise that such a type of hemorrhage could occur and measures should be taken to prevent its occurrence as much as possible. Preoperative detection of abnormal vessels by MR angiography and/or CT angiography might be helpful. Moreover, paying close attention to the possible leakage of cerebrospinal fluid during surgery might be important.

Simulation to locate burr hole sites in a patient for deep brain stimulation surgery and clipping of intracranial aneurysm.

BACKGROUND AND OBJECTIVE: Deep brain stimulation (DBS) candidates with neurologic diseases such as unruptured aneurysm present additional challenges to neurosurgeons when craniotomy must precede DBS surgery. Such craniotomy may potentially overlap with intended burr hole sites for the later insertion of DBS electrodes, and the skin incision for craniotomy may lie very close to or intersect with that for the burr holes. We report here a case of forehead craniotomy prior to DBS surgery in which we employed a neuronavigation system to simulate locations for the craniotomy and burr holes. METHOD: A 62-year-old male patient with Parkinson's disease was a candidate for DBS. He also had an aneurysm and was planned first to undergo frontal craniotomy for clipping before the DBS surgery. The locations of the craniotomy, burr holes, and skin incisions were therefore simulated using a neuronavigation system during craniotomy. RESULTS: Two weeks after the craniotomy, the patient underwent DBS surgery. Planning software confirmed the absence of cortical veins beneath the entry points of tentative burr holes and aided trajectory planning. The DBS surgery was performed without the interference of the burr holes and head pins and the craniotomy. CONCLUSION: Simulation of the locations of craniotomy and burr holes using a neuronavigation system proved valuable in the present case of frontal craniotomy before DBS surgery.

Nutritional Value of Yogurt as a Protein Source: Digestibility/Absorbability and Effects on Skeletal Muscle.

Yogurt is a traditional fermented food that is accepted worldwide for its high palatability and various health values. The milk protein contained in yogurt exhibits different physical and biological properties from those of non-fermented milk protein due to the fermentation and manufacturing processes. These differences are suggested to affect the time it takes to digest and absorb milk protein, which in turn will influence the blood levels of amino acids and/or hormones, such as insulin, and thereby, the rate of skeletal muscle protein synthesis via the activation of intracellular signaling, such as the mTORC1 pathway. In addition, based on the relationship between gut microbiota and skeletal muscle conditions, yogurt, including lactic acid bacteria and its metabolites, has been evaluated for its role as a protein source. However, the substantial value of yogurt as a protein source and the additional health benefits on skeletal muscle are not fully understood. The purpose of this review is to summarize the research to date on the digestion and absorption characteristics of yogurt protein, its effect on skeletal muscle, and the contribution of lactic acid bacterial fermentation to these effects.

Effect of subthalamic nucleus deep brain stimulation on the autonomic nervous system in Parkinson's disease patients assessed by spectral analyses of R-R interval variability and blood pressure variability.

OBJECTIVE: Autonomic nervous system impairment is an untoward symptom that is typically observed in advanced Parkinson's disease (PD) patients. However, details of the effects of subthalamic nucleus deep brain stimulation (STN-DBS) on the autonomic nervous system remain unclear. METHODS: Twenty-eight patients with advanced PD (12 males and 16 females) who underwent bilateral STN-DBS and 13 age-matched healthy controls were included in this study. We analyzed the dynamic cardiovascular autonomic function regulating the R-R interval and blood pressure by spectral and transfer function analyses of cardiovascular variability before and after STN-DBS. RESULTS: Vagally mediated arterial-cardiac baroreflex function improved after STN-DBS compared to that before STN-DBS (p < 0.05). However, there were no statistically significant differences in the results of the comparison of vagally mediated arterial-cardiac baroreflex function between on-stimulation and off-stimulation. CONCLUSIONS: The vagal component in cardiac autonomic dysfunction associated with PD is expected to improve after STN-DBS. We considered that the patients improved their lifestyle; in particular, increasing the amount of exercise by STN-DBS and the best pharmachological treatment may have positive effects on parasympathetic activities.

Anti­tumor effects of anti­epileptic drugs in malignant glioma cells.

Patients with glioblastoma frequently suffer epileptic seizures and often require anticonvulsant therapy during the treatment course. The present study investigated four common antiepileptic drugs, perampanel, carbamazepine (CBZ), sodium valproate (VPA) and levetiracetam (LEV), which are expected to have antitumor effects, and determined the most beneficial drug for the treatment of malignant glioma by comparing antitumor effects such as inhibition of cell proliferation and suppression of migration and invasion (using Transwell assays). The inhibition of cell growth was investigated using six malignant glioma cell lines (A­172, AM­38, T98G, U­138MG, U­251MG and YH­13). Significant inhibition of cell proliferation was observed in all six cell lines treated with perampanel, three cell lines treated with CBZ, four cell lines treated with VPA and two cell lines treated with LEV at the therapeutic blood concentration levels for the drugs to be used as antiepileptics. Further antitumor effects in combination with temozolomide were investigated using T98G and U­251MG cell lines, and were confirmed in both cell lines with perampanel and in T98G cells with LEV, but not observed with CBZ and VPA. Cell migration was significantly suppressed in both T98G and U­251MG cell lines with perampanel, but not with CBZ, VPA or LEV. To investigate the mechanisms by which perampanel suppresses the migration of malignant glioma cells, the expression of mRNA related to epithelial­mesenchymal transition following perampanel treatment was analyzed using reverse transcription­quantitative PCR in the T98G and U­251MG cell lines. The expression of Rac1 and RhoA, which constitute the cytoskeleton that enhances cell motility, were reduced in both cell lines. Furthermore, the expression of the mesenchymal marker N­cadherin, which promotes cell migration and infiltration, was decreased, but the expression of the epithelial marker E­cadherin, which strengthens cell­cell adhesion and reduces cell motility, was increased. Furthermore, the expression of matrix metalloproteinase­2, a proteolytic enzyme, was reduced. These effects may reduce cell motility and increase adhesion between cells, suggesting that perampanel treatment suppressed cell migration. In conclusion, the present study suggests that perampanel may be more beneficial in terms of antitumor efficacy than other antiepileptic drugs for the treatment of malignant glioma.

Evaluating Cranial Growth in Japanese Infants Using a Three-dimensional Scanner: Relationship between Growth-related Parameters and Deformational Plagiocephaly.

In this study, we aimed to evaluate the longitudinal changes in the cranial shape of healthy Japanese infants using a three-dimensional scanner and construct a normal values database for the growth process. Preterm infants (gestational age < 37 weeks), infants with neonatal asphyxia (5-minute Apgar score of <7), and patients who started helmet therapy for deformational plagiocephaly were excluded from this study. The first scan was performed at approximately 1 month of age, followed by two scans conducted at 3 and 6 months of age. The parameters considered were as follows: cranial length, width, height, circumference, volume, cranial vault asymmetry index, and cephalic index. A cranial vault asymmetry index >5% was defined as deformational plagiocephaly. Changes in each parameter were examined using repeated-measures analysis of variance classified by sex and deformational plagiocephaly status. The rate of increase in each parameter was also examined. In total, 88 infants (45 boys and 43 girls) were included in this study. All growth-related parameters were noted to increase linearly with time. Sex differences were observed in all parameters except cranial length. Deformational plagiocephaly was found to have no effect on growth-related parameters. Cranial volume increased by 60% from 1 to 6 months of age. The growth almost uniformly influenced the rate of increase in volume in each coordinate axis direction. Overall, the mean trends in three-dimensional parameters in infants up to 6 months of age were obtained using a three-dimensional scanner. These trends could be used as a guide by medical professionals involved in cranioplasty.

Anti-tumor effects of perampanel in malignant glioma cells.

Glioblastoma has a poor prognosis even after multimodal treatment, such as surgery, chemotherapy and radiation therapy. Patients with glioblastoma frequently develop epileptic seizures during the clinical course of the disease and often require antiepileptic drugs. Therefore, agents with both antiepileptic and antitumoral effects may be very useful for glioblastoma treatment. Perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist, is an antiepileptic drug that is widely used for intractable epilepsy. The present study aimed to assess the potential antitumoral effects of perampanel using malignant glioma cell lines. The cell proliferation inhibitory effect was evaluated using six malignant glioma cell lines (A-172, AM-38, T98G, U-138MG, U-251MG and YH-13). A dose-dependent inhibitory effect of perampanel on cell viability was demonstrated; however, the sensitivity of cells to perampanel varied and further antitumoral effects were demonstrated in combination with temozolomide (TMZ) in certain malignant glioma cells. Furthermore, cell cycle distribution and apoptosis induction analyses were performed in T98G and U-251MG cells using a fluorescence activated cell sorter (FACS) and the expression levels of apoptosis-related proteins were evaluated using western blotting. No significant change was demonstrated in the proportions of cells in the G0/G1, S and G2/M phases under 1.0 µM perampanel treatment, whereas induction of apoptosis was demonstrated using FACS at 10 µM perampanel and western blotting at 1.0 µM perampanel in both glioma cell lines. Overexpression of SERPINE1 may be related to poor prognosis in patients with gliomas. The combination of 1.0 µM perampanel and 5.0 µM tiplaxtinin, a SERPINE1 inhibitor, demonstrated further reduced cell viability in perampanel-resistant U-138MG cells, which have high expression levels of SERPINE1. These results indicated that the antitumor effect of perampanel may not be expected for malignant gliomas with higher expression levels of SERPINE1. The findings of the present study suggested that the antiepileptic drug perampanel may also have an antitumor effect through the induction of apoptosis, which is increased when combined with TMZ in certain malignant glioma cells. These findings also suggested that SERPINE1 expression may be involved in perampanel susceptibility. These results may lead to new therapeutic strategies for malignant glioma.

Inorganic Iron Supplementation Rescues Hematological Insufficiency Even Under Intense Exercise Training in a Mouse Model of Iron Deficiency with Anemia.

Iron deficiency anemia (IDA) due to malnutrition and/or blood loss is a common condition, especially in women of reproductive age. Intense exercise can induce anemia via an inflammatory response, but whether intense exercise affects the efficacy of iron supplementation to treat IDA is unclear. Here, we show in a mouse model of IDA that acute intense swimming increased IL-6 levels in the blood, but did not affect the maximum elevation of plasma iron following oral administration of 0.5 mg/kg Bw iron. However, compared with the control group without intense exercise, acute intense swimming was associated with a significant decrease in plasma iron 2 and 4 h after iron loading that could be attributed to rapid iron absorption in peripheral tissues. In the chronic experiment, IDA mice administered 0.36, 1.06, or 3.2 mg/kg Bw iron per day that were subjected to 11 intense swimming sessions over 3 weeks showed significantly decreased recovery levels for hemoglobin and red blood cell count during the early phase of the experimental period. At the end of the experimental period, significant, dose-dependent effects of iron, but not the main effect of intense exercise, were seen for recovery of hemoglobin and red blood cell counts, consistent with the acute exercise study. These results suggested that intense exercise in the presence of IDA does not inhibit iron absorption from the gastrointestinal tract and that iron supplementation can enhance the recovery process even after intense exercise.

α-Hydroxyisocaproic Acid Decreases Protein Synthesis but Attenuates TNFα/IFNγ Co-Exposure-Induced Protein Degradation and Myotube Atrophy via Suppression of iNOS and IL-6 in Murine C2C12 Myotube.

There is ongoing debate as to whether or not α-hydroxyisocaproic acid (HICA) positively regulates skeletal muscle protein synthesis resulting in the gain or maintenance of skeletal muscle. We investigated the effects of HICA on mouse C2C12 myotubes under normal conditions and during cachexia induced by co-exposure to TNFα and IFNγ. The phosphorylation of AMPK or ERK1/2 was significantly altered 30 min after HICA treatment under normal conditions. The basal protein synthesis rates measured by a deuterium-labeling method were significantly lowered by the HICA treatment under normal and cachexic conditions. Conversely, myotube atrophy induced by TNFα/IFNγ co-exposure was significantly improved by the HICA pretreatment, and this improvement was accompanied by the inhibition of iNOS expression and IL-6 production. Moreover, HICA also suppressed the TNFα/IFNγ co-exposure-induced secretion of 3-methylhistidine. These results demonstrated that HICA decreases basal protein synthesis under normal or cachexic conditions; however, HICA might attenuate skeletal muscle atrophy via maintaining a low level of protein degradation under cachexic conditions.