5-Aminolevulinic acid increases boronophenylalanine uptake into glioma stem cells and may sensitize malignant glioma to boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a high-LET particle radiotherapy clinically tested for treating malignant gliomas. Boronophenylalanine (BPA), a boron-containing phenylalanine derivative, is selectively transported into tumor cells by amino acid transporters, making it an ideal agent for BNCT. In this study, we investigated whether the amino acid 5-aminolevulinic acid (ALA) could sensitize glioma stem cells (GSCs) to BNCT by enhancing the uptake of BPA. Using human and mouse GSC lines, pre-incubation with ALA increased the intracellular accumulation of BPA dose-dependent. We also conducted in vivo experiments by intracerebrally implanting HGG13 cells in mice and administering ALA orally 24 h before BPA administration (ALA + BPA-BNCT). The ALA preloading group increased the tumor boron concentration and improved the tumor/blood boron concentration ratio, resulting in improved survival compared to the BPA-BNCT group. Furthermore, we found that the expression of amino acid transporters was upregulated following ALA treatment both in vitro and in vivo, particularly for ATB0,+. This suggests that ALA may sensitize GSCs to BNCT by upregulating the expression of amino acid transporters, thereby enhancing the uptake of BPA and improving the effectiveness of BNCT. These findings have important implications for strategies to improve the sensitivity of malignant gliomas to BPA-BNCT.

Influence of surgical position and registration methods on clinical accuracy of navigation systems in brain tumor surgery.

The aim of this study was to evaluate the influence of skin distortion due to surgical positioning on the clinical accuracy of the navigation system. The distance errors were measured in four fiducial markers (anterior, posterior, right, and left of the head) after the registration of the navigation system. The distance errors were compared between the surface-merge registration (SMR) method using preoperative imaging and the automatic intraoperative registration (AIR) method using intraoperative imaging. The comparison of the distance errors were performed in various surgical positions. The AIR method had the significant accuracy in the lateral markers than the SMR method (lateral position, 3.8 mm vs. 8.95 mm; p < 0.0001; prone position, 4.5 mm vs. 13.9 mm; p = 0.0001; 5.2 mm vs. 11.5 mm; p = 0.0070). The smallest distance errors were obtained close to the surgical field in the AIR method (3.25-3.85 mm) and in the forehead in the SMR method (3.3-8.1 mm). The AIR method was accurate and recommended for all the surgical positions if intraoperative imaging was available. The SMR method was only recommended for the supine position, because skin distortion was frequently observed in the lateral region.

Antihypertensive Drug Combinations Modify Cisplatin-induced Acute Kidney Injury.

BACKGROUND/AIM: There is limited evidence about the nephrotoxicity of calcium channel blockers (CCBs) and renin-angiotensin system (RAS) inhibitors with concomitant cisplatin (CDDP). We investigated whether combinations of antihypertensive drugs are associated with CDDP-related acute kidney injury (AKI) using the Japanese Adverse Drug Event Report database. PATIENTS AND METHODS: We analysed 544,864 reports in the database from 2004 to 2020. A reporting odds ratio (ROR) and confidence interval (CI) with adjustment for potential confounding factors was calculated for AKI for each drug and the combined use of the drugs and CDDP. RESULTS: CDDP, CCBs, and RAS inhibitors were all detected signals for AKI. The ROR in cases with concomitant use of CCBs, RAS inhibitors, and CDDP (adjusted ROR 7.28; 95% CI=5.56-9.54) was higher than that in cases with use of each drug. CONCLUSION: AKI may require more attention when patients receiving CDDP take CCBs and RAS inhibitors together.

Boron neutron capture therapy and add-on bevacizumab in patients with recurrent malignant glioma.

BACKGROUND: Although boron neutron capture therapy has shown excellent survival data, previous studies have shown an increase in radiation necrosis against recurrent malignant glioma. Herein, we proposed that bevacizumab may reduce radiation injury from boron neutron capture therapy by re-irradiation. We evaluated the efficacy and safety of a boron neutron capture therapy and add-on bevacizumab combination therapy in patients with recurrent malignant glioma. METHODS: Patients with recurrent malignant glioma were treated with reactor-based boron neutron capture therapy. Treatment with bevacizumab (10 mg/kg) was initiated 1-4 weeks after boron neutron capture therapy and was administered every 2-3 weeks until disease progression. Initially diagnosed glioblastomas were categorized as primary glioblastoma, whereas other forms of malignant glioma were categorized as non-primary glioblastoma. RESULTS: Twenty-five patients (14 with primary glioblastoma and 11 with non-primary glioblastoma) were treated with boron neutron capture therapy and add-on bevacizumab. The 1-year survival rate for primary glioblastoma and non-primary glioblastoma was 63.5% (95% confidence interval: 33.1-83.0) and 81.8% (95% confidence interval: 44.7-95.1), respectively. The median overall survival was 21.4 months (95% confidence interval: 7.0-36.7) and 73.6 months (95% confidence interval: 11.4-77.2) for primary glioblastoma and non-primary glioblastoma, respectively. The median progression-free survival was 8.3 months (95% confidence interval: 4.2-12.1) and 15.6 months (95% confidence interval: 3.1-29.8) for primary glioblastoma and non-primary glioblastoma, respectively. Neither pseudoprogression nor radiation necrosis were identified during bevacizumab treatment. Alopecia occurred in all patients. Six patients experienced adverse events ≥grade 3. CONCLUSIONS: Boron neutron capture therapy and add-on bevacizumab provided a long overall survival and a long progression-free survival in recurrent malignant glioma compared with previous studies on boron neutron capture therapy alone. The add-on bevacizumab may reduce the detrimental effects of boron neutron capture therapy, including pseudoprogression and radiation necrosis. Further studies of the combination therapy with a larger sample size and a randomized controlled design are warranted.

Reactor-based boron neutron capture therapy for 44 cases of recurrent and refractory high-grade meningiomas with long-term follow-up.

BACKGROUND: High-grade meningioma (HGM) is difficult to treat, and recurrent HGM after radiotherapy has an especially poor prognosis. We retrospectively analyzed the cases of 44 consecutive patients with recurrent and refractory HGM who were treated by reactor-based boron neutron capture therapy (BNCT). METHODS: In 2005-2019, we treated 44 recurrent and refractory HGMs by reactor-based BNCT. We analyzed the patients' tumor shrinkage, overall survival (OS) after initial diagnosis, OS after BNCT, progression-free survival (PFS) post-BNCT, and treatment failure patterns. RESULTS: The median OS (mOS) after BNCT and mOS after initial diagnosis were 29.6 (95% CI: 16.1-40.4) and 98.4 (95% CI: 68.7-169.4) months, respectively. The median follow-up after BNCT was 26 (6.4-103) months. The grade 2 (20 cases) and 3 (24 cases) post-BNCT mOS values were 44.4 (95% CI: 27.4-not determined) and 21.55 (10.6-30.6) months, respectively (P = .0009). Follow-up images were obtained from 36 cases at >3 months post-BNCT; 35 showed tumor shrinkage during the observation period. The post-BNCT median PFS (mPFS) of 36 cases was 13.7 (95% CI: 8.3-28.6) months. The post-BNCT mPFS values in patients with grade 2 and 3 disease were 24.3 (95% CI: 9.8-not determined) and 9.4 (6.3-14.4) months, respectively (P = .0024). Local recurrence was observed in only 22.2% of cases. These results showed good local tumor control and prolonged survival for recurrent HGM cases. CONCLUSIONS: Most of these cases had relatively large tumor volumes. The proportion of grade 3 patients was extremely high. Our patients thus seemed to have poor prognoses. Nevertheless, reactor-based BNCT exerted relatively good local control and favorable survival for recurrent and refractory HGMs.

Boron neutron capture therapy using dodecaborated albumin conjugates with maleimide is effective in a rat glioma model.

Introduction Boron neutron capture therapy (BNCT) is a biologically targeted, cell-selective particle irradiation therapy that utilizes the nuclear capture reaction of boron and neutron. Recently, accelerator neutron generators have been used in clinical settings, and expectations for developing new boron compounds are growing. Methods and Results In this study, we focused on serum albumin, a well-known drug delivery system, and developed maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) as a boron carrying system for BNCT. Our biodistribution experiment involved F98 glioma-bearing rat brain tumor models systemically administered with MID-AC and demonstrated accumulation and long retention of boron. Our BNCT study with MID-AC observed statistically significant prolongation of the survival rate compared to the control groups, with results comparable to BNCT study with boronophenylalanine (BPA) which is the standard use of in clinical settings. Each median survival time was as follows: untreated control group; 24.5 days, neutron-irradiated control group; 24.5 days, neutron irradiation following 2.5 h after termination of intravenous administration (i.v.) of BPA; 31.5 days, and neutron irradiation following 2.5 or 24 h after termination of i.v. of MID-AC; 33.5 or 33.0 days, respectively. The biological effectiveness factor of MID-AC for F98 rat glioma was estimated based on these survival times and found to be higher to 12. This tendency was confirmed in BNCT 24 h after MID-AC administration. Conclusion MID-AC induces an efficient boron neutron capture reaction because the albumin contained in MID-AC is retained in the tumor and has a considerable potential to become an effective delivery system for BNCT in treating high-grade gliomas.

Efficacy of Boron Neutron Capture Therapy in Primary Central Nervous System Lymphoma: In Vitro and In Vivo Evaluation.

BACKGROUND: Boron neutron capture therapy (BNCT) is a nuclear reaction-based tumor cell-selective particle irradiation method. High-dose methotrexate and whole-brain radiation therapy (WBRT) are the recommended treatments for primary central nervous system lymphoma (PCNSL). This tumor responds well to initial treatment but relapses even after successful treatment, and the prognosis is poor as there is no safe and effective treatment for relapse. In this study, we aimed to conduct basic research to explore the possibility of using BNCT as a treatment for PCNSL. METHODS: The boron concentration in human lymphoma cells was measured. Subsequently, neutron irradiation experiments on lymphoma cells were conducted. A mouse central nervous system (CNS) lymphoma model was created to evaluate the biodistribution of boron after the administration of borono-phenylalanine as a capture agent. In the neutron irradiation study of a mouse PCNSL model, the therapeutic effect of BNCT on PCNSL was evaluated in terms of survival. RESULTS: The boron uptake capability of human lymphoma cells was sufficiently high both in vitro and in vivo. In the neutron irradiation study, the BNCT group showed a higher cell killing effect and prolonged survival compared with the control group. CONCLUSIONS: A new therapeutic approach for PCNSL is urgently required, and BNCT may be a promising treatment for PCNSL. The results of this study, including those of neutron irradiation, suggest success in the conduct of future clinical trials to explore the possibility of BNCT as a new treatment option for PCNSL.

Advice on assistance and protection provided by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 3. On medical care and treatment of injuries from sulfur mustard.

Blister agents damage the skin, eyes, mucous membranes and subcutaneous tissues. Other toxic effects may occur after absorption. The response of the Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) to a request from the OPCW Director-General in 2013 on the status of medical countermeasures and treatments to blister agents is updated through the incorporation of the latest information. The physical and toxicological properties of sulfur mustard and clinical effects and treatments are summarised. The information should assist medics and emergency responders who may be unfamiliar with the toxidrome of sulfur mustard and its treatment.

Severity of constipation related to palonosetron during first-line chemotherapy: a retrospective observational study.

PURPOSE: Palonosetron, a long-acting 5-HT3 receptor antagonist, is an effective antiemetic agent for chemotherapy-induced nausea and vomiting; however, it sometimes causes severe constipation. The aim of the present study was to evaluate the severity of palonosetron-related constipation. METHODS: We retrospectively analyzed the incidence and severity of constipation after intravenous administration of 0.75-mg palonosetron in 150 chemotherapy-naïve patients who received first-line chemotherapy at Saga University Hospital. Constipation was classified into grades 1-5 according to the Common Terminology Criteria for Adverse Events version 5.0. Multiple logistic regression analysis was performed to identify factors associated with palonosetron-related worsening of constipation to grade 2 or higher. RESULTS: Palonosetron significantly increased the incidence and severity of constipation (incidence: before vs. after palonosetron, 35.4% vs. 74.0%, p < 0.0001, and severity: before vs. after palonosetron, 26.7% and 8.7% in grades 1 and 2, respectively, vs. 46.7%, 23.3%, and 4.0% in grades 1, 2, and 3, respectively, p < 0.0001). Despite the use of laxatives, 4.0% of patients had grade 3 constipation requiring manual evacuation. Combination treatment with aprepitant (odds ratio (OR), 10.9; 95% confidence interval (CI), 1.3-90.0; p = 0.026) and older age (OR, 1.25; 95% CI, 1.01-1.57; p = 0.039) were factors associated with the severity of constipation. CONCLUSION: Constipation was more severe in patients receiving combination treatment with aprepitant than in those treated with palonosetron alone. Older age was also associated with increased risk of severe palonosetron-related constipation. Identification of risk factors can help target risk-based laxative therapy.

The Therapeutic Effects of Dodecaborate Containing Boronophenylalanine for Boron Neutron Capture Therapy in a Rat Brain Tumor Model.

BACKGROUND: The development of effective boron compounds is a major area of research in the study of boron neutron capture therapy (BNCT). We created a novel boron compound, boronophenylalanine-amide alkyl dodecaborate (BADB), for application in BNCT and focused on elucidating how it affected a rat brain tumor model. METHODS: The boron concentration of F98 rat glioma cells following exposure to boronophenylalanine (BPA) (which is currently being utilized clinically) and BADB was evaluated, and the biodistributions in F98 glioma-bearing rats were assessed. In neutron irradiation studies, the in vitro cytotoxicity of each boron compound and the in vivo corresponding therapeutic effect were evaluated in terms of survival time. RESULTS: The survival fractions of the groups irradiated with BPA and BADB were not significantly different. BADB administered for 6 h after the termination of convection-enhanced delivery ensured the highest boron concentration in the tumor (45.8 µg B/g). The median survival time in the BADB in combination with BPA group showed a more significant prolongation of survival than that of the BPA group. CONCLUSION: BADB is a novel boron compound for BNCT that triggers a prolonged survival effect in patients receiving BNCT.

Synthesis and Evaluation of Dodecaboranethiol Containing Kojic Acid (KA-BSH) as a Novel Agent for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a form of tumor-cell selective particle irradiation using low-energy neutron irradiation of boron-10 (10B) to produce high-linear energy transfer (LET) alpha particles and recoiling 7Li nuclei (10B [n, alpha] 7Li) in tumor cells. Therefore, it is important to achieve the selective delivery of large amounts of 10B to tumor cells, with only small amounts of 10B to normal tissues. To develop practical materials utilizing 10B carriers, we designed and synthesized novel dodecaboranethiol (BSH)-containing kojic acid (KA-BSH). In the present study, we evaluated the effects of this novel 10B carrier on cytotoxicity, 10B concentrations in F98 rat glioma cells, and micro-distribution of KA-BSH in vitro. Furthermore, biodistribution studies were performed in a rat brain tumor model. The tumor boron concentrations showed the highest concentrations at 1 h after the termination of administration. Based on these results, neutron irradiation was evaluated at the Kyoto University Research Reactor Institute (KURRI) with KA-BSH. Median survival times (MSTs) of untreated and irradiated control rats were 29.5 and 30.5 days, respectively, while animals that received KA-BSH, followed by neutron irradiation, had an MST of 36.0 days (p = 0.0027, 0.0053). Based on these findings, further studies are warranted in using KA-BSH as a new B compound for malignant glioma.

Association of Genetic Polymorphisms With Afatinib-induced Diarrhoea.

BACKGROUND/AIM: Afatinib, a 2nd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used in treatment of non-small cell lung cancer (NSCLC), causes diarrhoea in over 90% of patients. The association of genetic background with diarrhoea is poorly understood. PATIENTS AND METHODS: We evaluated the roles of four single nucleotide polymorphisms (SNPs) in ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily G member 2 (ABCG2) genes-ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T, and ABCG2 421 C>A-on treatment-induced diarrhoea in 38 patients with NSCLC treated with afatinib. RESULTS: Diarrhoea occurred more frequently in patients with ABCB1 2677 T(A)/T(A) (14/16, 87.5%) than in patients with non-T(A)/T(A) alleles (8/22, 36.4%) (p=0.003). ABCB1 2677 T(A)/T(A) was significantly predictive of diarrhoea (p=0.002) by multivariable regression analysis. CONCLUSION: Afatinib-induced diarrhoea is associated with the SNP ABCB1 2677 T(A)/T(A).

Roles of Up-Regulated Expression of ASIC3 in Sex Difference of Acid-Induced Duodenal HCO3 - Responses.

Although the morbidity of ulcers is statistically higher in males than females, the mechanism of this difference remains unknown. Recent studies show that duodenal HCO3 - response to mucosal acidification is higher in females than males, and this may be a factor responsible for the sex difference in the mucosal protective mechanisms. In this article, we examined the duodenal HCO3 - responses to various stimuli in male and female rats, including estrogen, and reviewed the mechanisms responsible for the sex difference in the acid-induced HCO3 - secretion. Mucosal acidification was performed by exposing the duodenum to 10 mM HCl for 10 min. PGE2 was administered intravenously, while capsaicin was applied topically to the duodenum for 10 min. Tamoxifen was given s.c. 30 min before the acidification. Ovariectomy was performed 2 weeks before the experiments; half of the animals were given estrogen i.m. after the operation. Mucosal acidification increased duodenal HCO3 - secretion in male rats, and this response was inhibited by indomethacin and sensory deafferentation. Although no sex difference was found in HCO3 - responses to PGE2 and capsaicin, the response to acid was significantly greater in female than male rats. The different HCO3 - response to acid disappeared on ovariectomy, and this effect was totally reversed by the repeated administration of estrogen. The gene expression of ASIC3 in female rats was greater than in male rats and down-regulated by ovariectomy or tamoxifen treatment in an estradiol- dependent manner, while no sex difference was observed in TRPV1 and CFTR expressions. In conclusion, the acid-induced HCO3 - response is greater in female than male rats, and this phenomenon is not due to changes in PGE2 sensitivity or TRPV1/CFTR expressions but may be accounted for by increased expression of ASIC3 on sensory neurons, which is associated with the chronic influence of estrogen.

Other Hospital-onset Acute Ischemic Stroke Due to Large Vessel Occlusion Treated by Mechanical Thrombectomy after Inter-hospital Transfer.

The purpose of this study was to investigate the in-hospital acute ischemic stroke due to large vessel occlusion (LVO) that developed in another thrombectomy-incapable hospital, treated by mechanical thrombectomy after inter-hospital transfer. In eight other hospital-onset LVO patients, clinical characteristics, treatment results, and the timeline of thrombectomy were retrospectively investigated and compared to the results of 17 patients developed LVO at our own hospital and 18 developed in the community. In the analysis of timeline, the mean recognition-to-arrival time in other hospital-onset patients was 169 ± 78 min, significantly longer than for the community-onset patients (79 ± 78 min). Arrival-to-puncture time was 42 ± 19 min, significantly shorter than for the own hospital-onset patients (166 ± 80 min) and the community-onset patients (155 ± 76 min). Recognition-to-puncture times for the other hospital-onset patients, the own hospital-onset patients, and the community-onset patients were 212 ± 74, 166 ± 80, and 216 ± 83 min, respectively, and recognition-to-recanalization times were 285 ± 73, 200 ± 81, and 275 ± 125 min. Both these times were shorter for the own hospital-onset patients. The rates of modified Rankin Scale (mRS) of 0-2 in the three groups were 12%, 30%, and 23%, respectively. The rate of mRS 0-2 was lowest in the other hospital-onset patients. In conclusion, the other hospital-onset patients required additional time for their initial management and inter-hospital transfer although arrival-to-puncture time was shorter. Favorable outcomes were observed less frequently in them. Improving inter-hospital cooperation systems and to educate the medical staff in a thrombectomy-incapable hospital concerning stroke management is important measures for other hospital-onset stroke with LVO.

Newly Developed Aneurysm at the Anastomosis Site of a Superficial Temporal Artery to Middle Cerebral Artery Bypass Successfully Treated by Endovascular Embolization.

BACKGROUND: The superficial temporal artery (STA) to middle cerebral artery (MCA) bypass is an effective treatment procedure for steno-occlusive severe ischemic disease of the anterior circulation. The formation of an aneurysm at the anastomosis site is a rare complication, and the mechanism underlying this condition and the appropriate treatment strategy, have not yet been established. We describe a case of an unruptured anastomosis aneurysm that was treated by endovascular embolization 7 years after bypass surgery. CASE DESCRIPTION: A 62-year-old woman presented with slurred speech, with magnetic resonance imaging and angiography showing multiple infarctions in her left cerebral hemisphere and severe stenosis in the left internal carotid artery and left MCA. An STA-MCA anastomosis was performed without neurologic sequelae. Five years later, follow-up magnetic resonance imaging showed that an aneurysm had formed at the MCA side of the anastomosis site. After 2 years, the saccular aneurysm had grown and was embedded in the brain parenchyma. Because the patient had experienced repeated problems with surgical wound healing, an endovascular intervention was performed, achieving obliteration of the aneurysm by coil embolization. CONCLUSIONS: Endovascular treatment is a feasible and efficacious treatment option for an aneurysm at the anastomosis site of an STA-MCA bypass.

GPR40 full agonism exerts feeding suppression and weight loss through afferent vagal nerve.

GPR40/FFAR1 is a Gq protein-coupled receptor expressed in pancreatic ß cells and enteroendocrine cells, and mediates insulin and incretin secretion to regulate feeding behavior. Several GPR40 full agonists have been reported to reduce food intake in rodents by regulating gut hormone secretion in addition to their potent glucose-lowering effects; however, detailed mechanisms of feeding suppression are still unknown. In the present study, we characterized T-3601386, a novel compound with potent full agonistic activity for GPR40, by using in vitro Ca2+ mobilization assay in Chinese hamster ovary (CHO) cells expressing FFAR1 and in vivo hormone secretion assay. We also evaluated feeding suppression and weight loss after the administration of T-3601386 and investigated the involvement of the vagal nerve in these effects. T-3601386, but not a partial agonist fasiglifam, increased intracellular Ca2+ levels in CHO cells with low FFAR1 expression, and single dosing of T-3601386 in diet-induced obese (DIO) rats elevated plasma incretin levels, suggesting full agonistic properties of T-3601386 against GPR40. Multiple doses of T-3601386, but not fasiglifam, in DIO rats showed dose-dependent weight loss accompanied by feeding suppression and durable glucagon-like peptide-1 elevation, all of which were completely abolished in Ffar1-/- mice. Immunohistochemical analysis in the nuclei of the solitary tract demonstrated that T-3601386 increased the number of c-Fos positive cells, which also disappeared in Ffar1-/- mice. Surgical vagotomy and drug-induced deafferentation counteracted the feeding suppression and weight loss induced by the administration of T-3601386. These results suggest that T-3601386 exerts incretin release and weight loss in a GPR40-dependent manner, and that afferent vagal nerves are important for the feeding suppression induced by GPR40 full agonism. Our novel findings raise the possibility that GPR40 full agonist can induce periphery-derived weight reduction, which may provide benefits such as less adverse effects in central nervous system compared to centrally-acting anti-obesity drugs.

SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity.

The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca2+ signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1-/- ) mice. Treatment with SCO-267 activated Gq signaling in both high- and low-FFAR1-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1-/- mice, indicating a GPR40-dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.

Advice on assistance and protection provided by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 1. On medical care and treatment of injuries from nerve agents.

The Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) has provided advice on assistance and protection in relation to the Chemical Weapons Convention. In this, the first of several papers describing the SAB's work on this topic, we describe advice given in response to questions from the OPCW Director-General in 2013 and 2014 on the status of available medical countermeasures and treatments to organophosphorus nerve agents. This paper provides the evidence base for this advice which recommended to the OPCW pretreatments, emergency care, and long-term treatments that were available at the time of the request for this class of chemical warfare agent (CWA). It includes a bibliography of over 140 scientific references, which can be used as a platform for watching future medical countermeasure developments. The information provided in this paper should serve as a valuable reference for medical professionals and emergency responders who may have no knowledge of the symptoms and treatment options of exposure to nerve agents.

Advice on assistance and protection from the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 2. On preventing and treating health effects from acute, prolonged, and repeated nerve agent exposure, and the identification of medical countermeasures able to reduce or eliminate the longer term health effects of nerve agents.

The Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) has provided advice in relation to the Chemical Weapons Convention on assistance and protection. We present the SAB's response to a request from the OPCW Director-General in 2014 for information on the best practices for preventing and treating the health effects from acute, prolonged, and repeated organophosphorus nerve agent (NA) exposure. The report summarises pre- and post-exposure treatments, and developments in decontaminants and adsorbing materials, that at the time of the advice, were available for NAs. The updated information provided could assist medics and emergency responders unfamiliar with treatment and decontamination options related to exposure to NAs. The SAB recommended that developments in research on medical countermeasures and decontaminants for NAs should be monitored by the OPCW, and used in assistance and protection training courses and workshops organised through its capacity building programmes.

Boron Neutron Capture Therapy Combined with Early Successive Bevacizumab Treatments for Recurrent Malignant Gliomas - A Pilot Study.

Recurrent malignant gliomas (RMGs) are difficult to control, and no standard protocol has been established for their treatment. At our institute, we have often treated RMGs by tumor-selective particle radiation called boron neutron capture therapy (BNCT). However, despite the cell-selectivity of BNCT, brain radiation necrosis (BRN) may develop and cause severe neurological complications and sometimes death. This is partly due to the full-dose X-ray treatments usually given earlier in the treatment course. To overcome BRN following BNCT, recent studies have used bevacizumab (BV). We herein used extended BV treatment beginning just after BNCT to confer protection against or ameliorate BRN, and evaluated; the feasibility, efficacy, and BRN control of this combination treatment. Seven patients with RMGs (grade 3 and 4 cases) were treated with BNCT between June 2013 and May 2014, followed by successive BV treatments. They were followed-up to December 2017. Median overall survival (OS) and progression-free survival (PFS) after combination treatment were 15.1 and 5.4 months, respectively. In one case, uncontrollable brain edema occurred and ultimately led to death after BV was interrupted due to meningitis. In two other cases, symptomatic aggravation of BRN occurred after interruption of BV treatment. No BRN was observed during the observation period in the other cases. Common terminology criteria for adverse events grade 2 and 3 proteinuria occurred in two cases and necessitated the interruption of BV treatments. Boron neutron capture therapy followed by BV treatments well-prevented or well-controlled BRN with prolonged OS and acceptable incidence of adverse events in our patients with RMG.