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As a standard therapy for Fabry disease, enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (α-Gal) has been successfully used, and the instructions for this drug state that “it should not be co-administrated with cationic amphiphilic drugs such as hydroxychloroquine (HCQ) and amiodarone (AMI), since these drugs have the potential to inhibit intracellular α-Gal activity”. However, there would be cases in which HCQ or AMI is required for patients with Fabry disease, considering their medical efficacy and application.Thus, we examined the impact of HCQ/AMI on recombinant human α-Gal by in vitro, cellular, and animal experiments. The results revealed that HCQ/AMI affected the enzyme activity of α-Gal incorporated into cultured fibroblasts from a Fabry mouse when the cells were cultured in medium containing these drugs and the enzyme, although their direct inhibitory effect on the enzyme is not strong. These lysosomotropic drugs may be trapped and concentrated in lysosomes, followed by inhibition of α-Gal.On the other hand, no reduction of α-Gal activity incorporated into the organs and tissues, or acceleration of glycoshingolipid accumulation was observed in Fabry mice co-administered with HCQ/AMI and the enzyme, compared with in the case of usual ERT. As HCQ/AMI administered are catabolized in the liver, these drugs possibly do not affect ERT for Fabry mice, different from in the case of cultured cells in an environment isolated from the surroundings.

Abstract Objective Sepsis is a lethal condition characterized by systemic inflammation and multiple organ failure; this condition was initially defined as systemic inflammatory response syndrome (SIRS) due to infection. We previously reported that the hypothalamic neuropeptide orexin improved survival in a murine model of sepsis by mainly acting in the medullary raphe nucleus through orexin type-2 receptors. We hypothesized that orexin treatment enhances recovery from sepsis by reversing the reduction in orexin levels in the cerebrospinal fluid (CSF). We recently reported a case in which CSF orexin levels were reduced in a patient with sepsis. Herein, we attempted to further investigate CSF orexin levels in rats and patients with systemic inflammation. This patient study was a single-center, retrospective observational study. Results CSF orexin levels were low in rats with lipopolysaccharide-induced systemic inflammation. We enrolled 14 patients with meningitis/encephalitis. Six patients were diagnosed with SIRS, of whom 5 patients had infections (“sepsis” by the previous definition). CSF orexin levels were low in SIRS patients. The results support the hypothesis that orexin treatment enhances recovery from sepsis by reversing the reduction in CSF orexin levels.

Background Neuromyelitis optica spectrum disorder (NMOSD) diagnostic criteria for inflammatory demyelinating central nervous system diseases included symptomatic narcolepsy; however, no relevant case‐control studies exist. We aimed to examine the relationship among cerebrospinal fluid orexin‐A (CSF‐OX) levels, cataplexy and diencephalic syndrome; determine risk factors for low-and-intermediate CSF‐OX levels (≤200 pg/mL) and quantify hypothalamic intensity using MRI.Methods This ancillary retrospective case‐control study included 50 patients with hypersomnia and 68 controls (among 3000 patients) from Akita University, the University of Tsukuba and community hospitals (200 facilities). Outcomes were CSF‐OX level and MRI hypothalamus‐to‐caudate‐nucleus‐intensity ratio. Risk factors were age, sex, hypersomnolence and MRI hypothalamus‐to‐caudate‐nucleus‐intensity ratio >130%. Logistic regression was performed for the association between the risk factors and CSF‐OX levels ≤200 pg/mL.Results The hypersomnia group (n=50) had significantly more cases of NMOSD (p130% (AOR 6.33; 95% CI 1.18 to 34.09; p=0.032). The latter was less sensitive in predicting CSF-OX levels ≤200 pg/mL. Cases with MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% had a higher rate of diencephalic syndrome (p

Abstract Background Although the combination of rehabilitation and nutrition may be important for the prevention of intensive care unit (ICU)-acquired weakness, a protocolized intervention of this combination has not yet been reported. We herein developed an original combined protocol and evaluated its efficacy. Methods In this single-center historical control study, we enrolled adult patients admitted to the ICU. Patients in the control group received standard care, while those in the intervention group received the protocol-based intervention. The ICU mobility scale was used to set goals for early mobilization and a neuromuscular electrical stimulation was employed when patients were unable to stand. The nutritional status was assessed for nutritional therapy, and target calorie delivery was set at 20 or 30 kcal/kg/day and target protein delivery at 1.8 g/kg/day in the intervention group. The primary endpoint was a decrease in femoral muscle volume in 10 days assessed by computed tomography. Results Forty-five patients in the control group and 56 in the intervention group were included in the analysis. Femoral muscle volume loss was significantly lower in the intervention group (11.6 vs 14.5%, p = 0.03). The absolute risk difference was 2.9% (95% CI 0.1–5.6%). Early mobilization to a sitting position by day 10 was achieved earlier (p = 0.03), and mean calorie delivery (20.1 vs. 16.8 kcal/kg/day, p = 0.01) and mean protein delivery (1.4 vs. 0.8 g/kg/day, p

Abstract Background This study aimed to clarify P‐wave duration (PWD) ability before pacemaker implantation to predict worsening atrial fibrillation (AF) burden after the procedure. Methods We retrospectively investigated 75 patients who underwent permanent pacemaker implantation due to sick sinus syndrome (SSS) at Komaki City Hospital between January 2006 and May 2019. Worsening AF burden was defined as an increase in the number of AF episodes, each lasting ≥5.5 hours a day. Results In the study population, 17 patients (23%) had worsening AF burden during the follow‐up period. These patients had significantly longer PWD in lead Ⅱ (117.9 ± 19.9 ms vs 101.3 ± 20.0 ms, P = .002) than the patients without worsening AF burden. The best discriminative cutoff value for PWD in lead Ⅱ was 108 ms (sensitivity, 77%; specificity, 67%). In multivariate analysis, PWD in lead II ≥108 ms (hazard ratio, 5.395; 95% confidence interval, 1.352‐21.523; P = .017) was an independent predictor of worsening AF burden. Patients with PWD in lead II

Sepsis is a potentially lethal condition characterized by systemic inflammation and multiple organ failure, and sepsis-associated encephalopathy (SAE) is an independent risk factor for mortality in patients with sepsis. We previously reported that orexin improved survival in an animal model of sepsis by acting in the brain. Peripherally administered orexin entered the brain under the conditions of systemic inflammation because of BBB dysfunction and produced survival-related effects. As a therapeutic concept, we hypothesized that orexin treatment enhances recovery from sepsis by restoring reduced orexin levels in cerebrospinal fluid (CSF). Here, we report that CSF orexin levels were reduced in a 63-year-old woman with sepsis. The patient presented with coma, fever, headache, vomiting, and seizures upon arrival at the emergency room. She had a history of subarachnoid hemorrhage which led to the development of hydrocephalus, and as a consequence, a ventriculoperitoneal shunt (VP shunt) tube had been installed to ameliorate the complication. Physical examinations showed dehydration and abnormality of circulation, arterial blood gas analysis showed insufficient oxygenation, blood tests showed an inflammatory response, liver injury, kidney injury, hyperkalemia, and hyperglycemia, and radio graphical examinations showed mild hydrocephalus and several old microinfarctions. She was diagnosed with sepsis because her Sequential Organ Failure Assessment (SOFA) score was 13 and Enterococcus faecalis was isolated form her blood and CSF. Status epilepticus, hyperglycemia, and sepsis-associated encephalopathy were considered possible causes of coma. Her CSF could be safely sampled because she had a VP shunt, although it is ethically difficult to sample CSF routinely from patients with sepsis. Reduced CSF orexin levels gradually recovered as she recovered from sepsis. Unexpectedly, orexin was detected in the blood, which is unusual in healthy humans. Blood orexin was not detected after recovery from sepsis. This result may imply that orexin leaks into the blood because of BBB dysfunction. To the best of our knowledge, this is the first report investigating orexin levels in the CSF and blood of a patient with sepsis, and the data obtained from this case may provide a new understanding of the pathophysiology of SAE.

Drug-induced lysosomal storage disease (DILSD) caused by cationic amphiphilic drugs (CADs), which exhibits toxic manifestations and pathological findings mimicking Fabry disease (α-galactosidase A deficiency), has attracted the interests of clinicians and pathologists. Although the affected region is lysosomes in both the diseases, DILSD is characterized by intralysosomal accumulation of phospholipids and Fabry disease that of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). However, it is unknown whether administration of CADs affects the catabolism of Gb3 and Lyso-Gb3 in Fabry disease. In this study, we independently administered hydroxychloroquine/amiodarone to wild-type and Fabry mice and examined the effects of the drugs on the enzyme activity and substrates accumulated in organs and tissues. The results revealed that the administration of the drugs induced accumulation of phosphatidylcholine in both the wild-type and Fabry mice. However, reduction of α-galactosidase A activity in the organs and tissues of the wild-type mice was not found, and the storage of Gb3 and Lyso-Gb3 was not accelerated by these drugs in the Fabry mice. This suggests that hydroxychloroquine/amiodarone do not have any significant impact on the catabolism of Gb3 and Lyso-Gb3 in organs and tissues of both wild-type and Fabry mice.

Astrocyte-microglia communication influences the onset and progression of central nervous system (CNS) disorders. In this study, we determined how chronic inflammation by activated astrocytes affected and regulated CNS functions in Sandhoff disease (SD), a CNS lysosomal storage disorder. SD triggers intense CNS inflammation such as microglial activation and astrogliosis. It is caused by mutation of the HEXB gene, which reduces β-hexosaminidase (Hex) enzymatic activity in lysosomes, leading to accumulation of the substrate GM2 ganglioside in neuronal cells. Hexb−/− mice display a phenotype similar to human patients that suffer from chronic inflammation characterized by activation of astrocytes and microglia. In Hexb−/− mice, tremors and loss of muscle coordination begins at ~12 weeks. Interestingly, we found that reactive astrocytes expressed adenosine A2A receptor in the cerebral cortices of Hexb−/− mice at the later inflammatory phase. In cultured astrocytes, expression of A2A receptor could be induced by astrocyte defined medium, and then the activation of the A2A receptor induced ccl2 expression. In Hexb−/− mice, inhibition of the A2A receptor antagonized by istradefylline decreased the number of activated microglial cells and inflammatory cytokines/chemokines at 13 weeks. Thus, the astrocytic A2A receptor is an important sensor that regulates microglial activation in the late phase of inflammation.

The Japanese government has promoted dissemination of Japanese legal information to the world, and it has released English translations of Japanese statutes as well as a Japanese-English bilingual dictionary for statutory terms. However, the number of these translations is insufficient. The bilingual dictionary, the Japanese-English Standard Legal Terms Dictionary, contains only 3782 entries. To expand this key reference work, we focused on the Japanese Official Gazette, English Edition, which was published from 1946 to 1952 under order of the Supreme Commander for the Allied Powers. We conducted an experiment on targeted phrase extraction to acquire legal translations and confirm the usefulness of the Japanese Official Gazette, English Edition.

Aims: This study sought to conduct additional analyses of the Cognitive Test for Severe Dementia (CTSD) using the COSMIN checklist to ensure the development of adequate outcome measures. Methods: The following analyses were conducted: (1) factor analyses were used to evaluate construct validity; (2) the standard error of measurement (SEM) and minimal detectable change (MDC) were assessed to evaluate reliability and interpretability; and (3) longitudinal change was assessed to evaluate responsiveness. Results: The CTSD factor analysis yielded 2 factors, each of which was dichotomized by the passage rate of each item. We calculated a SEM and MDC of 1.6 and 3.6 points, respectively. Finally, the mean CTSD score showed a significant reduction (p < 0.001) over time, and the change in score exceeded the SEM and MDC. Conclusion: Our results indicate that the CTSD could provide a reliable outcome measure in severe dementia.

In Sandhoff disease (SD), the activity of the lysosomal hydrolytic enzyme, β-hexosaminidase (Hex), is lost due to a Hexb gene defect, which results in the abnormal accumulation of the substrate, GM2 ganglioside (GM2), in neuronal cells, causing neuronal loss, microglial activation, and astrogliosis. We established induced pluripotent stem cells from the cells of SD mice (SD-iPSCs). In the present study, we investigated the occurrence of abnormal differentiation and development of a neural lineage in the asymptomatic phase of SD in vitro using SD mouse fetus-derived neural stem cells (NSCs) and SD-iPSCs. It was assumed that the number of SD mouse fetal brain-derived NSCs was reduced and differentiation was promoted, resulting in the inhibition of differentiation into neurons and enhancement of differentiation into astrocytes. The number of SD-iPSC-derived NSCs was also reduced, suggesting that the differentiation of NSCs was promoted, resulting in the inhibition of differentiation into neurons and enhancement of that into astrocytes. This abnormal differentiation of SD-iPSCs toward a neural lineage was reduced by the glucosylceramide synthase inhibitor, miglustat. Furthermore, abnormal differentiation toward a neural lineage was reduced in SD-iPSCs with Hexb gene transfection. Therefore, differentiation ability along the time axis appears to be altered in SD mice in which the differentiation ability of NSCs is promoted and differentiation into neurons is completed earlier, while the timing of differentiation into astrocytes is accelerated. These results clarified that the abnormal differentiation of SD-iPSCs toward a neural lineage in vitro was shown to reflect the pathology of SD.

This paper, which aims to increment the vocabulary of an existing thesaurus using hyponymy relations, focuses on an agricultural thesaurus called AGROVOC. Our main goal is to acquire AGROVOC-qualified candidates from the hyponymy relations of legal texts and tables. We propose a pattern-based approach to hyponymy relation acquisition. Our experimental result showed that 222 and 868 candidates are extracted from statutory sentences with 67.1% precision and tables with 37.0% precision, respectively.

Sepsis is a systemic inflammatory response to infection, accounting for the most common cause of death in intensive care units. Here, we report that peripheral administration of the hypothalamic neuropeptide orexin improves the survival of mice with lipopolysaccharide (LPS) induced endotoxin shock, a well-studied septic shock model. The effect is accompanied by a suppression of excessive cytokine production and an increase of catecholamines and corticosterone. We found that peripherally administered orexin penetrates the blood-brain barrier under endotoxin shock, and that central administration of orexin also suppresses the cytokine production and improves the survival, indicating orexin’s direct action in the central nervous system (CNS). Orexin helps restore body temperature and potentiates cardiovascular function in LPS-injected mice. Pleiotropic modulation of inflammatory response by orexin through the CNS may constitute a novel therapeutic approach for septic shock.

Neural crest (NC) cells are a migratory, multipotent cell population that arises at the neural plate border, and migrate from the dorsal neural tube to their target tissues, where they differentiate into various cell types. Abnormal development of NC cells can result in severe congenital birth defects. Because only a limited number of cells can be obtained from an embryo, mechanistic studies are difficult to perform with directly isolated NC cells. Protein zero (P0) is expressed by migrating NC cells during the early embryonic period. In the P0-Cre;Z/EG transgenic mouse, transient activation of the P0 promoter induces Cre-mediated recombination, indelibly tagging NC-derived cells with enhanced green fluorescent protein (EGFP). Induced pluripotent stem cell (iPSC) technology offers new opportunities for both mechanistic studies and development of stem cell-based therapies. Here, we report the generation of iPSCs from the P0-Cre;Z/EG mouse. P0-Cre;Z/EG mouse-derived iPSCs (P/G-iPSCs) exhibited pluripotent stem cell properties. In lineage-directed differentiation studies, P/G-iPSCs were efficiently differentiated along the neural lineage while expressing EGFP. These results suggest that P/G-iPSCs are useful to study NC development and NC-associated diseases.

BACKGROUND:Reduced hippocampal volume in schizophrenia is a well-replicated finding. New imaging techniques allow delineation of hippocampal subfield volumes. Studies including predominantly chronic patients demonstrate differences between subfields in sensitivity to illness, and in associations with clinical features. We carried out a cross-sectional and longitudinal study of first episode, sub-chronic, and chronic patients, using an imaging strategy that allows for the assessment of multiple hippocampal subfields. METHODS:Hippocampal subfield volumes were measured in 34 patients with schizophrenia (19 first episode, 6 sub-chronic, 9 chronic) and 15 healthy comparison participants. A subset of 10 first episode and 12 healthy participants were rescanned after six months. RESULTS:Total left hippocampal volume was smaller in sub-chronic (p = 0.04, effect size 1.12) and chronic (p = 0.009, effect size 1.42) patients compared with healthy volunteers. The CA2-3 subfield volume of chronic patients was significantly decreased (p = 0.009, effect size 1.42) compared to healthy volunteers. The CA4-DG volume was significantly reduced in all three patient groups compared to healthy group (all p < 0.005). The two affected subfield volumes were inversely correlated with severity of negative symptoms (p < 0.05). There was a small, but statistically significant decline in left CA4-DG volume over the first six months of illness (p = 0.01). CONCLUSIONS:Imaging strategies defining the subfields of the hippocampus may be informative in linking symptoms and structural abnormalities, and in understanding more about progression during the early phases of illness in schizophrenia.

Sandhoff disease (SD) is a glycosphingolipid storage disease that arises from mutations in the Hexb gene and the resultant deficiency in β-hexosaminidase activity. This deficiency results in aberrant lysosomal accumulation of the ganglioside GM2 and related glycolipids, and progressive deterioration of the central nervous system. Dysfunctional glycolipid storage causes severe neurodegeneration through a poorly understood pathogenic mechanism. Induced pluripotent stem cell (iPSC) technology offers new opportunities for both elucidation of the pathogenesis of diseases and the development of stem cell-based therapies. Here, we report the generation of disease-specific iPSCs from a mouse model of SD. These mouse model-derived iPSCs (SD-iPSCs) exhibited pluripotent stem cell properties and significant accumulation of GM2 ganglioside. In lineage-directed differentiation studies using the stromal cell-derived inducing activity method, SD-iPSCs showed an impaired ability to differentiate into early stage neural precursors. Moreover, fewer neurons differentiated from neural precursors in SD-iPSCs than in the case of the wild type. Recovery of the Hexb gene in SD-iPSCs improved this impairment of neuronal differentiation. These results provide new insights as to understanding the complex pathogenic mechanisms of SD.

Background: To identify the clinical factors affecting activities of daily living (ADL) at baseline and after 6 months. Methods: We conducted a single-centre observational study at two time points across 6 months (baseline and after 6 months) from April 2015 to March 2017. in a 270-bed rural recuperation hospital at Hyogo prefecture in Japan. The total number of participants was 131 (male 33, female 98; mean age: 87.0 ± 7.0; mild and moderate dementia, 38; severe dementia, 93). Measurement scales used were Personal Self-Maintenance Scale (PSMS) for assessing ADL, Mini-Mental State Examination and Cognitive Test in Severe Dementia (CTSD) for cognitive function, Neuropsychiatric Inventory- Nursing Home version and Cornell Scale for Depression in Dementia (CSDD) for behavioural/psychological symptoms of dementia, Mini Nutritional Assessment Short form (MNA-SF) for nutritional status, Pain Assessment in Advanced Dementia for pain, and Charlson comorbidity index (CCI) and the number of illness categories based on Cumulative Illness Rating Scale Geriatrics for comorbidities. Multiple regression analyses identified the association between PSMS score as the dependent variable and other variables as independent variables. Results: In participants with severe dementia, the PSMS scores at baseline were significantly associated with CTSD, CCI, MNA-SF, and CSDD scores. In the longitudinal analysis, only CTSD score was significantly associated with PSMS score after 6 months. It is noteworthy that for participants with severe dementia, the only factor associated with ADL after 6 months was cognitive function, as assessed by CTSD score. Conclusions: The most important factor predicting functional decline is cognitive function, even at the severe and profound stage. [ABSTRACT FROM AUTHOR]

We recently developed Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas (KORTUC) as a strategy to increase intratumoral oxygen concentrations and degrade antioxidant enzymes such as peroxidase and catalase. We then developed KORTUC II, which uses sodium hyaluronate containing hydrogen peroxide as a radiosensitizer. KORTUC II requires twice-weekly administration to sustain its effects, but decreasing the frequency of radiosensitizer injections to once-weekly would reduce the burden on the patients and the physicians. The goal of this study was thus to develop a new formulation of KORTUC (New KORTUC) that only requires once-weekly administration. We performed experimental studies using a mouse tumor model and biodegradable hydrogel. C3H/He mice were allocated to control, KORTUC, or hydrogel groups. At 72 h after injection, each tumor was irradiated with a 6 MeV electron beam to a total dose of 30 Gy. During a 62-day observation period, changes in tumor volume and survival rates were assessed in each group. Tumor growth rate was slowest in the hydrogel groups. These data suggest that hydrogel could represent a useful adjunct as a long-acting radiosensitizer in place of sodium hyaluronate. New KORTUC, which contains hydrogen peroxide and hydrogel, exerted a radiosensitizing effect that persisted beyond 72 h following injection of the agent. Use of this new formulation allows radiosensitizer injections to be performed once-weekly with good effect. [ABSTRACT FROM AUTHOR]

Background: We have developed a new radiosensitization treatment called Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II). Using KORTUC II, we performed breast-conserving treatment (BCT) without any surgical procedure for elderly patients with breast cancer in stages I/II or patients refusing surgery. Since surgery was not performed, histological confirmation of the primary tumor region following KORTUC II treatment was not possible. Therefore, to precisely evaluate the response to this new therapy, a detailed diagnostic procedure is needed. The goal of this study was to evaluate the therapeutic response to KORTUC II treatment in patients with stage I/II breast cancer using annual breast contrast-enhanced (CE) magnetic resonance imaging (MRI). Methods: Twenty-one patients with stage I/II breast cancer who were elderly and/or refused surgery were enrolled in this study. All patients underwent MRI prior to and at 3 to 6 months after KORTUC II, and then approximately biannually thereafter. Findings from MRI were compared with those from other diagnostic modalities performed during the same time period. Results: KORTUC II was well tolerated, with minimal adverse effects. All of 21 patients showed a clinically complete response (cCR) on CE MRI. The mean period taken to confirm cCR on the breast CE MRI was approximately 14 months. The mean follow-up period for the patients was 61.9 months at the end of October 2014. Conclusions: The therapeutic effect of BCT using KORTUC II without surgery could be evaluated by biannual CE MRI evaluations. Approximately 14 months were required to achieve cCR in response to this therapy. [ABSTRACT FROM AUTHOR]

We previously developed a new enzyme-targeting radiosensitization treatment named Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II), which contains hydrogen peroxide and sodium hyaluronate for injection into various types of tumors. For breast cancer treatment, the radiosensitization agent was injected into the tumor tissue twice a week under ultrasonographic guidance, immediately prior to each administration of radiation therapy. At approximately three hours after the second or third injection, computed tomography (CT) was performed to confirm the production and distribution of oxygen gas generated from the KORTUC radiosensitization agent by catalysis of peroxidases contained mainly in tumor tissue. The purpose of this study was to demonstrate that tumor hypoxia could be overcome by such a procedure and to evaluate the method of intratumoral injection in terms of confirming oxygen distribution in the target tumor tissue and around the tumor to be visualized on dedicated CT imaging. Three-dimensional reconstructed maximum intensity projection imaging of contrast-enhanced breast magnetic resonance imaging was used to compare the position of the tumor and that of the generated oxygen. Distributed oxygen gas was confirmed in the tumor tissue and around it in all 10 patients examined in the study. A region of oxygen gas was measured as an average value of -457.2 Hounsfield units (HU) as a region of interest. A slightly increased HU value compared to the density of air or oxygen was considered due to the presence of tumor tissue in the low-density area on 5-mm-thick reconstructed CT imaging. The results of this study showed that intratumoral oxygen was successfully produced by intratumoral KORTUC injection under ultrasonographic guidance, and that tumor hypoxia, which is considered a main cause of radioresistance in currently used Linac (linear accelerator) radiation therapy for malignant neoplasms, could be resolved by this method. [ABSTRACT FROM AUTHOR]

We have conducted rapid thermal annealing (RTA) for improving the two-dimensional (2D) arrangement of electronic states in the epitaxial nitrogen (N) δ-doped layer in GaAs. RTA rearranged the N-pair configurations in the GaAs (001) plane and reduced the number of non-radiative recombination centers. Furthermore, a Landau shift, representing the 2D delocalized electronic states in the (001) plane, was observed at around zero magnetic field intensity in the Faraday configuration. [ABSTRACT FROM AUTHOR]

Most radiation biologists/radiation oncologists have long accepted the concept that the biologic effects of radiation principally involve damage to deoxyribonucleic acid (DNA), which is the critical target, as described in “Radiobiology for the Radiologist”, by E.J. Hall and A.J. Giaccia [1]. Although the concepts of direct and indirect effects of radiation are fully applicable to low-LET (linear energy transfer) radioresistant tumor cells/normal tissues such as osteosarcoma cells and chondrocytes, it is believed that radiation-associated damage to DNA does not play a major role in the mechanism of cell death in low-LET radiosensitive tumors/normal tissues such as malignant lymphoma cells and lymphocytes. Hall and Giaccia describe lymphocytes as very radiosensitive, based largely on apoptosis subsequent to irradiation. As described in this review, apoptosis of lymphocytes and lymphoma cells is actually induced by the “hydrogen peroxide (H2O2) effect”, which I propose in this review article for the first time. The mechanism of lymphocyte death via the H2O2 effect represents an ideal model to develop the enhancement method of radiosensitivity for radiation therapy of malignant neoplasms. In terms of imitating the high radiosensitivity of lymphocytes, osteosarcoma cells (representative of low-LET radioresistant cells) might be the ideal model for indicating the conversion of cells from radioresistant to radiosensitive utilizing the H2O2 effect. External beam radiation such as X-rays and high-energy electrons for use in modern radiotherapy are generally produced using a linear accelerator. We theorized that when tumors are irradiated in the presence of H2O2, the activities of anti-oxidative enzymes such as peroxidases and catalase are blocked and oxygen molecules are produced at the same time via the H2O2 effect, resulting in oxidative damage to low-LET radioresistant tumor cells, thereby rendering them highly sensitive to irradiation. In this review, this potential paradigm shift in modern radiation biology/radiation oncology is discussed in detail in terms of overcoming drug/radiation resistance in radiation therapy and/or anti-cancer chemotherapy. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to establish a non-surgical breast-conserving treatment (BCT) using KORTUC II radiosensitization treatment. A new radiosensitizing agent containing 0.5% hydrogen peroxide and 0.83% sodium hyaluronate (a CD44 ligand) has been developed for intra-tumoral injection into various tumors. This new method, named KORTUC II, was approved by our local ethics committee for the treatment of breast cancer and metastatic lymph nodes. A total of 72 early-stage breast cancer patients (stage 0,1 patient; stage I,23; stage II, 48) were enrolled in the KORTUC II trial after providing fully informed consent. The mean age of the patients was 59.7 years. A maximum of 6 mL (usually 3 mL for tumors of less than approximately 3 cm in diameter) of the agent was injected into breast tumor tissue twice a week under ultrasonographic guidance. For radiotherapy, hypofraction radiotherapy was administered using a tangential fields approach including an ipsilateral axillary region and field-in-field method; the energy level was 4 MV, and the total radiation dose was 44 Gy administered as 2.75 Gy/fraction. An electron boost of 3 Gy was added three times. Treatment was well tolerated with minimal adverse effects in all 72 patients. No patients showed any significant complications other than mild dermatitis. A total of 24 patients under 75 years old with stage II breast cancer underwent induction chemotherapy (EC and/or taxane) prior to KORTUC II treatment, and 58 patients with estrogen receptor-positive tumors also received hormonal therapy following KORTUC II. The mean duration of follow-up as of the end of September 2014 was 51.1 months, at which time 68 patients were alive without any distant metastases. Only one patient had local recurrence and died of cardiac failure at 6.5 years. Another one patient had bone metastases. For two of the 72 patients, follow-up ended after several months following KORTUC II treatment. In conclusion, non-surgical BCT can be performed using KORTUC II, which has three major characteristics: imaging guidance; enzyme-targeting; and targeting of breast cancer stem cells via the CD44 receptor. [ABSTRACT FROM AUTHOR]

Linac-based stereotactic radiotherapy has little effect on the majority of advanced neoplasms. Therefore, the novel radiosensitizer Kochi oxydol-radiation therapy for unresectable carcinomas (KORTUC) II, which contains hydrogen peroxide and sodium hyaluronate, was developed. The effectiveness of KORTUC II for the treatment of chemotherapy-resistant supraclavicular lymph node metastases, recurrent breast cancer and stage IV primary breast cancer has previously been demonstrated. The present study evaluated the safety and efficacy of KORTUC II for patients with stage I primary breast cancer. A total of 15 patients (age range, 40-76 years) were enrolled. The injection of 3 ml of KORTUC II agent was initiated from the sixth radiotherapy fraction and was performed twice a week, under ultrasonographic guidance. The therapeutic effects were evaluated by PET-CT and/or MRI examinations prior to and following KORTUC II treatment. All patients exhibited complete responses and the overall survival rate was 100% after a follow-up period of five years. The mean duration of follow-up at the end of March 2015 was 53 months. Based on these results, KORTUC II treatment exhibited marked therapeutic effects with satisfactory treatment outcomes and an acceptable extent of adverse events. [ABSTRACT FROM AUTHOR]

Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablatedmice, but not in orexin receptor-deficient mice. Peripherally administered YNT-185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexindeficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists. [ABSTRACT FROM AUTHOR]

Linac-based radiotherapy has a negligible effect on the majority of advanced neoplasms. Therefore, a novel radiosensitization treatment Kochi Oxydol Radiation Therapy for Unresectable Carcinomas II (KORTUC II), which utilizes hydrogen peroxide and sodium hyaluronate was developed. The effectiveness of KORTUC II for the treatment of chemotherapy-resistant supraclavicular lymph node metastases and recurrent breast cancers has previously been demonstrated. The present study evaluated the safety and efficacy of KORTUC II in patients with stage IV primary breast cancer. Seven patients (age range, 36-65 years) were enrolled. All patients received induction chemotherapy prior to KORTUC II treatment and underwent positron emission tomography-computed tomography (PET-CT) examinations prior to and 2-7 months following KORTUC II treatment, and every six months thereafter where possible. The radiotherapy regimen (x-ray irradiation) was 2.75 gray (Gy)/fraction, 5 fractions/week for 16-18 fractions with a total radiation dose of 44-49.5 Gy. Administration of the KORTUC II agent (3-6 ml: 3 ml for a lesion <3 cm in diameter and 6 ml for a lesion =3 cm) was initiated from the sixth radiotherapy fraction, and was conducted twice a week under ultrasonographic guidance. The therapeutic effects were evaluated by PET-CT examinations prior to and following KORTUC II treatment. Of the seven lesions from the seven patients, five exhibited complete responses, two exhibited partial responses and none exhibited stable disease or progressive disease. The overall survival rate was determined to be 100% at 1 and 86% at 2 years post-treatment. The mean duration of follow-up by December 2014 was 51 months. The results of the PET-CT studies indicated that KORTUC II treatment demonstrated marked therapeutic effects with satisfactory treatment outcomes and acceptable adverse effects. [ABSTRACT FROM AUTHOR]