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Background: Amide proton transfer (APT) imaging has been proposed as a technique to assess tumor metabolism. However, the relationship between APT imaging and other quantitative modalities including positron emission tomography (PET) has not been investigated in detail. This study aimed to evaluate the clinical usefulness of APT imaging in determining the metabolic status of malignant glioma and to compare findings with those from 11 C-methionine (Met)-PET., Methods: This research analyzed APT imaging data from 20 consecutive patients with malignant glioma treated between January 2022 and July 2023. Patients underwent tumor resection and correlations between tumor activity and intensity of APT signal were investigated. We also compared 11 C-Met-PET and APT imaging for the same regions of the perifocal tumor invasion area., Results: Clear, diagnostic APT images were obtained from all 20 cases. Mean APT intensity (APT mean ) was significantly higher in the glioblastoma (GBM), IDH wild type group (27.2 ± 12.8%) than in other gliomas (6.0 ± 4.7%; p < 0.001). The cut-off APT mean to optimally distinguish between GBM and other malignant gliomas was 12.8%, offering 100% sensitivity and 83.3% specificity. These values for APT mean broadly matched the tumor-to-contralateral normal brain tissue ratio from 11 C-Met-PET analysis (r = 0.66). The APT signal was also observed in the gadolinium non-contrast region on T1-weighted imaging, appearing to reflect the surrounding tumor-infiltrated area., Conclusions: APT imaging can be used to evaluate the area of tumor invasion, similar to 11 C-Met-PET. APT imaging revealed low invasiveness in patients and was useful in preoperative planning for tumor resection, facilitating maximum tumor resection including the tumor invasive area., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Life cycle assessments of microalgal cultivation systems are often conducted to evaluate the sustainability and feasibility factors of the entire production chain. Unlike widely reported conventional microalgal cultivation systems, the present work adopted a microalgal-bacterial cultivation approach which was upscaled into a pilot-scale continuous photobioreactor for microalgal biomass production into biodiesel from wastewater resources. A multiple cradle-to-cradle system ranging from microalgal biomass-to-lipid-to-biodiesel was evaluated to provide insights into the energy demand of each processes making up the microalgae-to-biodiesel value chain system. Energy feasibility studies revealed positive NER values (4.95-8.38) for producing microalgal biomass but deficit values for microalgal-to-biodiesel (0.14-0.23), stemming from the high energy input requirements in the downstream processes for converting biomass into lipid and biodiesel accounting to 88-90% of the cumulative energy demand. Although the energy balance for microalgae-to-biodiesel is in the deficits, it is comparable with other reported biodiesel production case studies (0.12-0.40). Nevertheless, the approach to using microalgal-bacterial cultivation system has improved the overall energy efficiency especially in the upstream processes compared to conventional microalgal cultivation systems. Energy life cycle assessments with other microalgal based biofuel systems also proposed effective measures in increasing the energy feasibility either by utilizing the residual biomass and less energy demanding downstream extraction processes from microalgal biomass. The microalgal-bacterial cultivation system is anticipated to offer both environmental and economic prospects for upscaling by effectively exploiting the low-cost nutrients from wastewaters via bioconversion into valuable microalgal biomass and biodiesel., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

High invasiveness is a characteristic of glioblastoma (GBM), making radical resection almost impossible, and thus, resulting in a tumor with inevitable recurrence. GBM recurrence may be caused by glioma stem-like cells (GSCs) that survive many kinds of therapy. GSCs with high expression levels of CD44 are highly invasive and resistant to radio-chemotherapy. CD44 is a multifunctional molecule that promotes the invasion and proliferation of tumor cells via various signaling pathways. Among these, paired pathways reciprocally activate invasion and proliferation under different hypoxic conditions. Severe hypoxia (0.5-2.5% O 2 ) upregulates hypoxia-inducible factor (HIF)-1α, which then activates target genes, including CD44, TGF-β, and cMET, all of which are related to tumor migration and invasion. In contrast, moderate hypoxia (2.5-5% O 2 ) upregulates HIF-2α, which activates target genes, such as vascular endothelial growth factor (VEGF)/VEGFR2, cMYC, and cyclin D1. All these genes are related to tumor proliferation. Oxygen environments around GBM can change before and after tumor resection. Before resection, the oxygen concentration at the tumor periphery is severely hypoxic. In the reparative stage after resection, the resection cavity shows moderate hypoxia. These observations suggest that upregulated CD44 under severe hypoxia may promote the migration and invasion of tumor cells. Conversely, when tumor resection leads to moderate hypoxia, upregulated HIF-2α activates HIF-2α target genes. The phenotypic transition regulated by CD44, leading to a dichotomy between invasion and proliferation according to hypoxic conditions, may play a crucial role in GBM recurrence.

A rapid preparation method for the analysis of the urine from a cannabis user was established. Generally, 11-nor-9-carboxy-∆ 9 -tetrahydrocannabinol (THC-COOH), which is one of the main metabolites of ∆ 9 -tetrahydorocannabinol (THC), must be detected from a user's urine to verify cannabis use. However, existing preparation methods are usually multistep and time-consuming processes. Before the analysis by liquid-chromatography tandem mass spectrometry (LC-MS/MS), deconjugation by treatment with β-glucuronidase or alkaline solution, liquid-liquid extraction or solid-phase extraction (SPE), and evaporation are generally performed. In addition, subsequent derivatization (silylation or methylation) are certainly necessary for gas-chromatography mass spectrometry (GC/MS) analysis. Here, we focused on the phenylboronic-acid (PBA) SPE, which selectively binds compounds with a cis-diol moiety. THC-COOH is metabolized as a glucuronide conjugate (THC-COOGlu) which has cis-diol moieties, therefore, we investigated the conditions of its retention and elution to reduce the operating time. We developed four elution conditions, which afford the following derivatives: acidic elution for THC-COOGlu, alkaline elution for THC-COOH, methanolysis elution for the THC-COOH methyl ester (THC-COOMe), and methanolysis elution and following methyl etherification for O-methyl-THC-COOMe (O-Me-THC-COOMe). All repeatability and recovery rates were evaluated by LC-MS/MS in this study. As a result, these four pathways required short times (within 10-25 min) and exhibited good repeatability and recovery rates. Detection limits of pathway I-IV were 10.8, 1.7, 18.9, and 13.8 ng mL -1 , respectively. Lower limits of quantification were 62.5, 31.25, 57.3, and 62.5 ng mL -1 , respectively. When proof of cannabis use is required, any elution condition can be selected to match the possessing reference standards and analytical instruments. To our knowledge, this is the first report of using PBA SPE for the preparation of the urine samples containing cannabis and achieving partial derivatization when eluting from a PBA carrier. Our method can provide a new and practical solution for the preparation of the urine samples from cannabis users. Although the PBA SPE method cannot recover THC-COOH in urine because of its lack of a 1,2-diol moiety, this method has technological advantages for simplifying the process and reducing the operating time, thereby avoiding human errors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Recurrent glioblastoma multiforme (GBM) is largely attributed to peritumoral infiltration of tumor cells. As higher CD44 expression in the tumor periphery correlates with higher risk of GBM invasion, the present study analyzed the relationship between CD44 expression and magnetic resonance imaging (MRI)-based invasiveness of GBM on a large scale. We also quantitatively evaluated GBM invasion using 5-aminolevulinic acid (5-ALA) spectroscopy to investigate the relationship between CD44 expression and tumor invasiveness as evaluated by intraoperative 5-ALA intensity. Based on MRI, GBM was classified as high-invasive type in 28 patients and low-invasive type in 22 patients. High-invasive type expressed CD44 at a significantly higher level than low-invasive type and was associated with worse survival. To quantitatively analyze GBM invasiveness, the relationship between tumor density in the peritumoral area and the spectroscopic intensity of 5-ALA was investigated. Spectroscopy showed that the 5-ALA intensity of infiltrating tumor cells correlated with tumor density as represented by the Ki-67 staining index. No significant correlation between CD44 and degree of 5-ALA-based invasiveness of GBM was found, but invasiveness of GBM as evaluated by 5-ALA matched the classification from MRI in all except one case, indicating that CD44 expression at the GBM periphery could provide a reliable biomarker for invasiveness in GBM.

Background: The efficacy of perioperative prophylactic antiepileptic drug therapy in "seizure-naïve" patients with brain tumor, including glioblastoma (GBM), remains controversial. This study investigated whether perampanel (PER) is effective and safe for preventing perioperative onset of epileptic seizures, so-called early seizure, in patients with brain tumors., Methods: Forty-five patients underwent tumor resection through craniotomy for a primary supratentorial brain tumor at Ehime University Hospital between April 2021 and July 2022. PER was administered from the 1 st to the 6th day after surgery for seizure prophylaxis. Occurrence of early seizure, hematological toxicities, and various side effects were recorded on postoperative days 7 and 14. In addition, the clinical course of these patients was compared with 42 brain tumor patients under the same treatment protocol who received levetiracetam (LEV) for seizure prophylaxis between April 2017 and October 2018., Results: In 45 patients with brain tumor, including GBM, who received PER administration, no early seizures were identified within 7 days postoperatively. No adverse drug reactions such as hematological toxicity, liver or kidney dysfunction, or exanthematous drug eruption were observed in any cases. As side effects, somnolence was reported in 14 patients (31.1%), vertigo in 3 patients (6.7%), and headache in 3 patients (6.7%). Although somnolence and vertigo were difficult to assess in the case of intraparenchymal tumors, particularly GBM, these side effects were not identified in patients with extraparenchymal tumors such as meningiomas, epidermoid cysts, and pituitary adenomas. In addition, no significant differences were identified compared to patients who received LEV., Conclusion: The efficacy and safety of PER in preventing early seizures among patients with brain tumors were retrospectively evaluated. Perioperative administration of PER to patients with brain tumors may reduce the risk of early seizures without incurring serious side effects, showing no significant differences compared to patients who received LEV., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Surgical Neurology International.)

Background: The role of surgery in primary central nervous system lymphoma (PCNSL) is to allow pathological diagnosis from tumor biopsy. However, PCNSL is often difficult to distinguish from other tumors, particularly glioblastoma multiforme (GBM). Quantitative evaluations to facilitate differentiation between PCNSL and GBM would be useful. Here, we investigated the best examinations for exact differentiation of PCNSL from GBM among preoperative examinations, including imaging studies and tumor markers., Methods: Various examinations were performed for 68 patients with PCNSL , including serum soluble interleukin 2 receptor, β2-microglobulin (MG) in cerebrospinal fluid (CSF), diffusion-weighted imaging, 11 C-methionine-positron emission tomography (PET), and 18 F-fluorodeoxyglucose (FDG)-PET. These results were compared with findings from 28 patients with consecutive GBM who underwent the same examinations to evaluate the utility and accuracy of different investigations., Results: CSF β2-MG ≥2.0 mg/L was relatively specific for PCNSL, offering 95.0% sensitivity and 85.7% specificity. Tumor-to-contralateral normal brain tissue ratio ≥2.4 on 18 F-FDG-PET was also quite specific for PCNSL, offering 83.8% sensitivity and 95.2% specificity. No other examinations displayed any significant differences in quantitative differential markers between PCNSL and GBM., Conclusions: Both β2-MG ≥2.0 mg/dL in CSF and tumor-to-contralateral normal brain tissue ratio ≥2.4 from 18 F-FDG-PET allow quantitative differentiation of PCNSL from GBM, potentially representing clinically useful indicators. These findings could lead to innovative methods for differentiating PCNSL from GBM as well as new treatment strategies for other brain tumors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Various synthetic drugs have appeared over the past years across the world, and phenethylamine derivatives are among them; indeed, aromatic fluoro analogs of methamphetamine and amphetamine have been in the illicit drug market since the early 2000s. Although they are currently widely abused across the world, little information is available on their metabolism and toxicology. Recently, we came across an alleged 2-fluoromethamphetamine (2-FMA) drug abuse case. The urine obtained from the alleged abuser was analyzed as part of a criminal investigation. 2-FMA, 2-fluoroamphetamine (2-FAP) and some related compounds were detected by liquid chromatography-tandem mass spectrometry. In forensic science, both an "unchanged" drug and its metabolite(s) need to be detected in urine to verify the illicit drug use. Notably, the detection of 2-FAP, which is a plausible 2-FMA metabolite, is insufficient as evidence of 2-FMA use because 2-FAP is widely available and may be present as such in taken liquids. In this study, we synthesized analytical standards for N-hydroxy 2-FMA (N-OH-2-FMA) and two diastereomers of 2-fluoroephedrine, which are plausible metabolites of 2-FMA. Using these standards, the urine specimen was found to contain N-OH-2FMA and one diastereomer of 2-fluoroephedrine; moreover, the concentrations of these compounds were successfully determined. The results of our study suggest that N-hydroxylation and aliphatic hydroxylation are the characteristic metabolic pathways of 2-FMA compared with that of methamphetamine. This evidence indicates that both N-OH-2-FMA and 2-fluoroephedrine are plausible candidates as analytical targets for drug-use certification in forensic science., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

BACKGROUND Chronic graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantations. Due to fibrotic changes, patients with GVHD are at risk for difficult airway management. We encountered a case of chronic GVHD that went into a "cannot intubate, cannot ventilate" (CICV) condition after induction of general anesthesia and was managed using cricothyrotomy. CASE REPORT A 45-year-old man with uncontrolled chronic GVHD developed pneumothorax of the right lung. Thoracoscopic dissection of the adhesions, closure of the pneumostomy, and drainage under general anesthesia were planned. In the preoperative airway assessment, we concluded that using a video laryngoscope or endotracheal fiber would be sufficient to intubate the patient after sedation and that airway management after the loss of consciousness would not be difficult. Therefore, general anesthesia was induced by rapid induction; however, the patient developed difficult mask ventilation. Intubation was attempted via a video laryngoscope or bronchofiber but failed. Ventilating using a supraglottic instrument was difficult. The patient was evaluated to have a CICV condition. Thereafter, because of a rapid decrease in oxygen saturation (SpO2) and bradycardia, a cricothyrotomy was performed. Subsequently, ventilation became adequate, SpO2 increased immediately and drastically, and respiration and circulatory dynamics recovered. CONCLUSIONS We believe that anesthesiologists should practice, prepare, and simulate airway emergencies that can be experienced during surgery. In this case, we recognized that skin sclerosis in the neck and chest could lead to CICV. It may be suitable for airway management of scleroderma-like patients to select conscious intubation with a bronchoscope as a first choice.

Background: Increased extracellular glutamate is known to cause epileptic seizures in patients with glioblastoma (GBM). However, predicting whether the seizure will be refractory is difficult. The present study investigated whether evaluation of the levels of various metabolites, including glutamate, can predict the occurrence of refractory seizure in GBM by quantitative measurement of metabolite concentrations on magnetic resonance spectroscopy (MRS)., Methods: Forty patients were treated according to the same treatment protocol for primary GBM at Ehime University Hospital between April 2017 and July 2021. Of these patients, 23 underwent MRS to determine concentrations of metabolites, including glutamate, N-acetylaspartate, creatine, and lactate, in the tumor periphery by applying LC-Model. The concentration of each metabolite was expressed as a ratio to creatine concentration. Patients were divided into three groups: Type A, patients with no seizures; Type B, patients with seizures that disappeared after treatment; and Type C, patients with seizures that remained unrelieved or appeared after treatment (refractory seizures). Relationships between concentrations of metabolites and seizure types were investigated., Results: In 23 GBMs, seizures were confirmed in 11 patients, including Type B in four and Type C in seven. Patients with epilepsy (Type B or C) showed significantly higher glutamate and N-acetylaspartate values than did non-epilepsy patients (Type A) (p < 0.05). No significant differences in glutamate or N-acetylaspartate levels were seen between Types B and C. Conversely, Type C showed significantly higher concentrations of lactate than did Type B (p = 0.001). Cutoff values of lactate-to-creatine, glutamate-to-creatine, and N-acetylaspartate-to-creatine ratios for refractory seizure were > 1.25, > 1.09, and > 0.88, respectively., Conclusions: Extracellular concentrations of glutamate, N-acetylaspartate, and lactate in the tumor periphery were significantly elevated in patients with GBM with refractory seizures. Measurement of these metabolites on MRS may predict refractory epilepsy in such patients and could be an indicator for continuing the use of antiepileptic drugs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

In this paper, we explored stable states in the system of 2,4,6-trinitrotoluene (TNT) crystal with a few additional hydrogen radicals (H add 's) using a structure-search scheme based on first-principles calculations and an evolutionary algorithm (EA) to get insights into the decomposition process of TNT. We introduced three evolutionary operators acting on H add 's and transforming only local structures of TNT molecules: "displacement", "permutation", and "mating". We searched for stable structures by increasing the number of H add 's ( n ) from 1 to 2, 3, 4, 6, and 8 and constructed a convex-hull diagram for the formation energy from solid TNT and solid hydrogen. We showed that the system of n = 6 had the largest energy reduction, in which five of the eight TNT molecules in the calculation cell were transformed into NO, H 2 O, C 2 H 3 N, C 2 NO 3 H 3 , C 8 N 2 O 4 H 7 , C 9 N 2 O 8 H 5 , and C 14 N 7 O 12 H 11 . Analysis of the structural transformations observed during the EA search indicates that (1) the H add 's approaching the TNT molecules react with C, forming a six-membered ring, and with N and O in nitro groups, leaving the TNT molecules as NO, H 2 O, C 2 H 3 N, and C 2 NO 3 H 3 , and (2) the partially decomposed TNT molecules are bonded to one another via C, N, and O.

Background: Hemangioblastoma originates in the central nervous system (CNS), usually in the cerebellum, and sporadic cases in the supratentorial region are extremely rare. In addition, there have been no previous reports of cases showing hyperintensity on diffusion weighted image (DWI) on magnetic resonance imaging (MRI) and negative immunostaining for inhibin-alpha. Here, we report a rare case of sporadic supratentorial hemangioblastoma arising in the parasagittal region and suggest a useful indicator for the exact diagnosis and pitfalls for surgical procedures., Case Description: A 66-year-old woman was admitted to our hospital with a 6-month history of progressive numbness in the right lower extremities and gait disturbance. Neurological findings on admission revealed mild right-sided hemiparesis of the lower limbs (manual muscle test: 4/V). Neuroimaging demonstrated an abnormal lesion with clear boundaries in the left frontal lobe appearing hypointense on T1-weighted image (WI), hyperintense on T2-WI, and hyperintense on DWI, with strong enhancement on gadolinium (Gd)-enhanced T1-WI. Computed tomography (CT) showed no calcification, and cerebral angiography revealed strong staining from bilateral middle meningeal arteries and the left anterior cerebral artery (ACA). Surgical excision of the lesion was performed and gross total resection was achieved. Histological findings revealed a marked increase in vascular structures, and the round stroma contained tumor cells. Silver impregnation stains demonstrated abundant reticulin fibers. In addition, immunohistochemistry revealed that most tumor cells stained negatively for epithelial membrane antigen (EMA) and inhibin-alpha, and positively stained for podoplanin (D2-40), and the tumor was diagnosed as hemangioblastoma. The postoperative course was uneventful and follow-up neuroimaging after one year revealed no signs of recurrence., Conclusions: Supratentorial hemangioblastomas are extremely rare and display a strong infiltrative and aggressive nature. Careful identification from preoperative image and histopathological study for appropriate treatment selection are warranted for supratentorial hemangioblastoma., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-851/coif). The authors have no conflicts of interest to declare., (2022 Translational Cancer Research. All rights reserved.)

Background: Posterior pelvic ring injuries are challenging for surgeons to treat adequately due to difficulties with reduction and stabilization. Surgical intervention is a beneficial option to protect neurological structures and provide sufficient stability for early mobilization. The gull wing plate (GWP) is a pre-contoured anatomical locking plate with six screws, and its design is unique among posterior transiliac tension-band plates. The purpose of this study was to investigate clinical results of the GWP., Methods: Patients who had an unstable posterior pelvic ring injury and underwent internal fixation with GWP were retrospectively analyzed at a trauma center. Demographic data, fracture type, perioperative data, and radiological evaluation with computed tomography (CT) were collected. Clinical outcomes were graded using the functional independence measure (FIM) and Majeed outcome score., Results: Twenty-six patients were enrolled (mean age, 54 years), and the mean follow-up period was 23 months. The mean Injury Severity Score was 24 points, and internal fixation was performed 6.6 days post-trauma. CT evaluation showed the lateral surface angle of the uninjured ilium was approximately 68°. The GWP pre-contoured anatomical design closely matched this angle. The mean FIM and Majeed score were 119 and 76 points, respectively, which were graded as excellent (n = 14), good (n = 9), or fair (n = 3)., Conclusions: With the retrospective single-center data available, the GWP seems to be a minimally-invasive alternative, provides reliable stability of the posterior pelvic ring and allows for rehabilitation within normal ranges., (© 2022. The Author(s).)

The adsorbed structure of 1-pyrenebutanoic acid succinimidyl ester (PASE) on graphene was investigated based on density functional theory. We found two locally stable structures: a straight structure with the chainlike part of butanoic acid succinimidyl ester (BSE) lying down and a bent structure with the BSE part directed away from graphene, keeping the pyrene (Py) part adsorbed on graphene. Then, to elucidate the adsorption mechanism, we separately estimated the contributions of the Py and BSE parts to the entire PASE adsorption, and the adsorption effect of the BSE part was found to be secondary in comparison to the contribution of the Py. Next, the mobility of the BSE part at room temperature was confirmed by the activation energy barrier between straight and bent structures. To take account of the external environment, we considered the presence of amino acids and the hydration effect by a three-dimensional reference interaction site model. The contributions of glycine molecules and the solvent environment to stabilizing the bent PASE structure relative to the straight PASE structure were found. Therefore, the effect of the external environment around PASE is of importance when the standing-up process of the BSE part from graphene is considered., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Posterior pelvic ring injuries commonly involve sacral fractures, which are difficult to reduce and stabilize. Because conservative treatment requires long-term bedrest and leads to unsatisfactory outcomes, surgical intervention is a beneficial option to protect neurological structures and provide sufficient stability for early mobilization. Several studies have investigated a variety of internal fixation techniques, such as iliosacral screws, transiliac bars, spinal instruments, and transiliac plates. The gull wing plate (GWP) is a pre-contoured anatomical locking plate with two cancellous screws (φ6.5 mm) and four locking screws (φ5.0 mm), the design of which is unique among posterior tension-band plates. The GWP provides reliable stability of the posterior construct of the pelvic ring and accelerates rehabilitation. Compared to alternative surgical techniques for posterior fixation, the simple surgical procedure of the GWP is minimally invasive and highly reproducible, which leads to fewer complications and less radiation exposure., Competing Interests: The authors have no conflicts of interest to disclose., (© 2022 The Authors.)

Background: The incidence of brain metastasis of pancreatic cancer has been reported to be approximately 0.3%. The blood-brain barrier of the central nervous system restricts the transfer of substances, including chemotherapeutic agents, from the bloodstream. It is hypothesized that brain metastasis may occur despite successful chemotherapy for the primary tumor. Herein, we report a case of brain metastases of pancreatic cancer that occurred after chemotherapy and discuss relevant literature., Case Presentation: A 64-year-old man underwent distal pancreatectomy with D2 lymph node dissection for resectable pancreatic tail cancer. Invasive ductal carcinoma of pancreas, pT3N2M0 pStageIII (TNM Classification of Malignant Tumors, UICC 8th edition) was diagnosed. S-1 adjuvant chemotherapy was initiated. Three months postoperatively, CA19-9 had increased to 619 U/mL. Additionally, contrast-enhanced computed tomography (CT) and fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT revealed local recurrence in the para-aortic lymph nodes. Chemotherapy was revised to a combined regimen of gemcitabine and nab-paclitaxel. After 4 cycles, tumor markers were normalized. After 5 cycles, recurrence could not be identified on contrast-enhanced CT; therefore, the patient was adjudged to be in complete remission. However, after 29 cycles of chemotherapy, the patient had symptoms of raised intracranial pressure. Magnetic resonance imaging showed two metastatic lesions of 20 mm and 32 mm in the left frontal lobe and cerebellum, respectively. Quasi-emergency resection of the metastatic brain tumors was performed. Pathological examination revealed that the resected specimens originated from primary pancreatic cancer. The patient was discharged on postoperative day 12, without any complications. Postoperatively, a total of 53 Gy of local brain radiation therapy was added. On postoperative day 30, blood carcinoembryonic antigen level had decreased to 5.4 ng/dl and all other tumor markers were negative. Additionally, tumor markers of the cerebrospinal fluid were markedly reduced and the cytology was negative for tumor cells. These results suggested complete resection of the metastatic brain tumors., Conclusions: Aggressive resection and salvage stereotactic radiotherapy for metastatic brain tumors may lead to complete cure and a good long-term prognosis., (© 2022. The Author(s).)

In this study, we present a theoretical study on the in-plane conductance of graphene partially sandwiched between Ni(111) nanostructures with a width of ∼12.08 Å. In the sandwiched part, the gapped Dirac cone of the graphene was controlled using a pseudospin by changing the magnetic alignment of the Ni(111) nanostructures. Upon considering the antiparallel configuration of Ni(111) nanostructures, the transmission probability calculation of the in-plane conductance of graphene shows a gap-like transmission at E - E F = 0.2 and 0.65 eV from the pd-hybridization and controllable Dirac cone of graphene, respectively. In the parallel configuration, the transmission probability calculation showed a profile similar to that of the pristine graphene. High and colossal magnetoresistance ratios of 284% and 3100% were observed at E - E F = 0.65 eV and 0.2 eV, respectively. Furthermore, a magnetoresistance beyond 3100% was expected at E - E F = 0.65 eV when the width of the Ni(111) nanostructures on the nanometer scale was considered., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

To solve the issue of narrow micropores in traditional protonic type Zeolite Socony Mobil-5 (HZSM-5) catalysts in the restricting of large-molecular reactants/products diffusion, hollow HZSM-5 with a mesoporous shell was prepared using a hydrothermal method combined with a tetrapropylammonium hydroxide (TPAOH) treatment process. Applying for in-situ catalyst upgrading of bio-oil from rapid pyrolysis of biomass, the obtained most efficient catalyst of Hollow(30)-TP resulted in aromatic hydrocarbon yields in the range of 78.49-78.67% for cellulose and hemicellulose, which is much greater than those using the traditional HZSM-5 (61.06-68.26%). Furthermore, in the case using real biomass (cedar) with an optimal biomass/catalyst weight ratio of 1:2, the aromatic hydrocarbon yield reached up to 80.16%. In addition, this catalyst exhibited excellent reusability and regeneration property due to the increased accessibility to the acid sites in the hollow HZSM-5 for the improving of the reaction rate as well as the reducing of coking., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Catalytic hydrolysis of sodium borohydride (NaBH 4 ) is a promising method to provide clean hydrogen (H 2 ) energy for portable devices. Therefore, designing a non-noble metal catalyst that performs well in this hydrolysis is essential. Cobalt-nanoparticles (Co-NPs) supported on magnesium-aluminium layered double hydroxide (LDH) with various mean diameter were synthesized by changing concentration of cobalt-citrate anion (Co-citrate) precursor used for ion exchange with the LDH host. Then the Co-citrate intercalated LDHs were reduced with NaBH 4 to form Co-NPs. Evidence of successful intercalation was shown by X-ray diffraction (XRD) and Fourier-Transform Infrared spectroscopy (FT-IR). Transmission Electron Microscope (TEM) and Scanning TEM (STEM) observations revealed that Co-NPs were in metallic state and their mean diameter increased with the concentration of Co-citrate solution. Nitrogen physisorption isotherms showed that the surface structure of LDHs transformed from non-porous to mesoporous after chemical reduction, which indicated that the Co-NPs were formed in the interlayer of LDHs. Catalytic hydrolysis of NaBH 4 at 25 °C clarified that the catalyst synthesized from 6 mM Co-citrate solution showed the highest H 2 generation rate of 4520 ± 251 mL min -1 ·g Co -1 , indicating the catalyst had the optimum size of Co-NP. This activity could be considered relatively higher compared to unsupported cobalt and many other supported cobalt-base catalysts previously reported. It was also clearly shown that size of Co-NPs supported on LDH could be a significant parameter as it allowed better accessibility of reactants to the active catalyst surface to obtain maximum activity. For this optimum catalyst, the activation energy was evaluated to be 56.9 kJ mol -1 . Although the catalyst was able to achieve almost the same conversion when the catalyst was repeatedly tested five times under the same condition, the catalytic activity decreased gradually. Overall, it could be revealed that Co-NPs supported on LDHs have a huge potential to be used for H 2 energy production., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Effective business networks, experienced mentors, and access to financial and business knowledge are crucial for small-scale entrepreneurs to overcome challenges and barriers towards growth. Women entrepreneurs have limited access to information, training, credit, and networks compared to that of men entrepreneurs. Business Associations (BAs) are self-governing bodies designed to meet the needs of entrepreneurs in a specific local, national and regional socio-economic-cultural context. This study investigates firstly the potential of BAs to support and empower women entrepreneurs and the difficulties encountered by women in taking up leadership positions in BAs., Methods: Three sub-sectors from among tourism enterprises in Hikkaduwa Urban Council, Galle District, in Sri Lanka were studied. A questionnaire survey among 390 respondents (195 women, 195 men) was conducted aiming to understand the profile of entrepreneurs. Employing 24 in-depth interviews (12 women, 12 men), a further investigation was taken to ascertain the underlying reasons of their decisions in business and family., Findings: Determined to overcome the challenges, women entrepreneurs join BAs thus gaining access to business resources such as financial, information and connections. They become members of multiple BAs seeking tenacities to address difficulties they face as women entrepreneurs. However, women's participation is restricted to low-level positions while significant leadership positions in BAs tend to be dominated by male thereby obstructing a great deal of potential benefits yieldable by women., Recommendations: We recommend that BAs promote women across the entire hierarchy of organization making BAs more relevant to women members who are in greater need of its services., Research Limitations/and Future Research: This study covers three sub-sectors of the tourism industry in one district in Sri Lanka wherein more research is demanded covering larger industries and geographies to develop nuanced theories about the potentially powerful roles that BAs could play to support women entrepreneurs. Business/trade associations hold enormous potential to support women entrepreneurs with critically important resources, i.e., mentoring and networking. Further research is required to further analyze how to promote women's leadership in BAs. Since the study was done before Covid-19 pandemic, gender impact of the pandemic could not be integrated., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

This work presents an ab initio study of a few-layer hexagonal boron nitride (hBN) and hBN-graphene heterostructure sandwiched between Ni(111) layers. The aim of this study is to understand the electron transmission process through the interface. Spin-polarized density functional theory calculations and transmission probability calculations were conducted on Ni(111)/ n hBN/Ni(111) with n = 2, 3, 4, and 5 as well as on Ni(111)/hBN-Gr-hBN/Ni(111). Slabs with magnetic alignment in an anti-parallel configuration (APC) and parallel configuration (PC) were considered. The pd-hybridizations at both the upper and lower interfaces between the Ni slabs and hBN were found to stabilize the system. The Ni/ n hBN/Ni magnetic tunnel junction (MTJ) was found to exhibit a high tunneling magnetoresistance (TMR) ratio at ∼0.28 eV for n = 2 and 0.34 eV for n > 2, which are slightly higher than the Fermi energy. The observed shifting of this high TMR ratio originates from the transmission of electrons through the surface states of the d z 2 -orbital of Ni atoms at interfaces which are hybridized with the p z -orbital of N atoms. In the case of n > 2, the proximity effect causes an evanescent wave, contributing to decreasing transmission probability but increasing the TMR ratio. However, the TMR ratio, as well as transmission probability, was found to be increased upon replacing the unhybridized hBN layer of the Ni/3hBN/Ni MTJ with graphene, thus yielding Ni/hBN-Gr-hBN/Ni. A TMR ratio as high as ∼1200% was observed at an energy of 0.34 eV, which is higher than the Fermi energy. Furthermore, a design is proposed for a device based on a new reading mechanism using the high TMR ratio observed just above the Fermi energy level., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Aim: Vertebral artery injury associated with blunt traumatic cervical spine injury sometimes causes severe cerebellar and brain stem infarction. No treatment guidelines for vertebral artery injury aimed at preventing stroke have been decided. We have conducted endovascular embolization in patients with up to Denver grade IV cerebrovascular injury complicated by unstable cervical spine injury before open reduction and fixation surgery. The purpose of this study was to validate the clinical course of vertebral artery injury and especially endovascular treatment for grade IV patients in our hospital., Methods: Participants comprised of patients diagnosed as having traumatic cervical spine injury in our hospital between January 2015 and April 2018. Among these patients, we selected those with vertebral artery injury and retrospectively examined the background characteristics of the patients, details of treatment, and complications with or without stroke., Results: Traumatic cervical spine injury was diagnosed in 89 patients. Among these patients, 15 (16.7%) showed a complicating vertebral artery injury. Mean age was 62.6 years, and almost 50% of the patients were injured in falls. Three types of cervical spine injury caused vertebral artery injury: subluxation, Jefferson fracture, and fracture involving the foramen transversarium. Vertebral artery injury was classified as grade IV in 12 patients, of whom nine required spinal surgery. All patients who needed spinal surgery underwent endovascular therapy before surgery, and none experienced a stroke., Conclusion: Endovascular embolization of the vertebral artery occlusion in patients with unstable cervical spine injury before open reduction and fixation surgery can be a treatment option to prevent stroke., Competing Interests: Approval of Research Protocol: This study was approved by the ethics committee of our hospital as a retrospective review and prognostic study of stroke complications (acceptance number: 30‐44, 2019‐021). Informed Consent: We disclosed information about this study based on the opt‐out approach. Registry and the registration no. of the study/trial: Not applicable. Animal Study: Not applicable. Conflict of Interest: None declared., (© 2021 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

The penetration mechanism of choline chloride-glycerol deep eutectic solvent (DES) through the stratum corneum (SC) as a potential solvent for a novel enhancer of protein penetration into the skin was investigated in a wide and small angle X-ray diffraction study. We found that DES penetrated through intercellular lipids but not the corneocytes. DES seemed to extract a portion of lipids of the short lamellae in the SC. Hydrated DES with a DES to water weight ratio of 9 to 1 (9DES-1H 2 O) showed the strongest interaction with the lipids in the SC compared with water, DES, and hydrated DESs with another weight ratio of DES to water (DES : water=8 : 2). In a skin penetration test with a fluorescently labelled lysozyme, 9DES-1H 2 O increased the amount of penetration through the SC by two-fold compared with HEPES buffer., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

Pyrrolidinophenones (PPs) are synthetic cathinones containing a pyrrolidine ring that are used recreationally worldwide. Recently, many studies on the metabolism and cytotoxicity of PPs have been published. Here, we focus on new designer drug containing an indan skeleton, 1-(2,3-dihydro-1H-inden-5-yl)-2-(pyrrolidine-1-yl)butan-1-one (5-PPDI), because there have been no reports to date regarding the metabolism of indan-type cathinones. The identification of 5-PPDI phase I metabolites in human urine enables us to determine whether a person has taken 5-PPDI. This metabolite detection approach plays a very important role in the field of forensic science. We synthesized analytical standards of 5-PPDI and four proposed metabolites. A urine sample was prepared by salting-out assisted liquid-liquid extraction with acetonitrile. Analyses of all standards and the urine sample were performed by liquid chromatography high resolution tandem mass spectrometry. As a result, we were able to detect 5-PPDI and its metabolites in the urine specimen. Two diastereomers of synthesized 1-OH metabolites were successfully separated, and only one diastereomer was observed in the urine specimen. To the best of our knowledge, this is the first report on the stereoselective reduction of PPs in humans. Further, we performed quantitative analyses of 5-PPDI and its metabolites in the urine. We identified three characteristic features of 5-PPDI phase I metabolism: (1) hydroxylation at the indan skeleton, (2) stereoselective reduction of the carbonyl group, and (3) hydroxylation of the indan skeleton possibly proceeding more preferentially than any other metabolization. In addition, several structural isomers and diastereomers of 2'-OH metabolites were detected. Based on these data, we propose phase I metabolic pathways of 5-PPDI, which will be essential in understanding the metabolism of other PPs with an indan skeleton., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Various new psychoactive substances, such as cathinone and its analogs, possess similar chemical structures. Accurate identification of structurally similar drugs of abuse is important in forensic drug analysis. Chromatographic differentiation is a powerful analytical technique for this purpose. In this study, we applied supercritical fluid chromatography to differentiate ring-substituted regioisomers of six synthetic cathinone analogs (fluoro-α-pyrrolidinovalerophenone, methyl-α-pyrrolidinovalerophenone, methoxy-α-pyrrolidinovalerophenone, fluoro-α-pyrrolidinooctanophenone, fluoropentedrone, and fluorooctedrone). The examined cathinone analogs were weakly retained on the stationary phase (possessing diol functional group) and eluted quickly. We optimized the conditions to retain the examined cathinone analogs to achieve sufficient separation, and found that the types of functional groups on the stationary phase greatly affected the retention and separation. Systematic examination of the chromatographic conditions showed that the two stationary phases possessing anthracene and pentafluorobenzyl groups had good separation capabilities for the examined 2-, 3-, and 4-regioisomers of six cathinone analogs, which had different skeletal structures. Interestingly, the two stationary phases showed different selectivities, and alteration of the elution order was observed. The developed method was validated and its discrimination ability was investigated by measuring mass spectra and absorption spectra. Supercritical fluid chromatography-ultraviolet absorption spectroscopy/mass spectrometry is a powerful analytical technique for differentiation of ring-substituted cathinone analogs., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Analytical Science Advances published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Neomacrophorins I-III (1-3) and X have previously been isolated from Trichoderma sp. 1212-03. Their mode of action against cancer cells and the mechanism of biosynthesis of the characteristic [4.4.3] propellane framework in neomacrophorin X have not been reported. The isolation and characterization of neomacrophorins IV (4), V (5), and VI (6) is reported. Epoxyquinones 1, 4, and 6 potently induced apoptotic cell death in human acute promyelocytic leukemia HL60 cells, while epoxysemiquinols 2, 3, and 5 showed weak activity. This indicates that the epoxyquinone moiety is crucial for apoptosis-inducing activities of neomacrophorins. We also found that neomacrophorins inhibit proteasome in vitro, and 1, 4, and 6 induced significant accumulation of ubiquitinated proteins in HL60 cells. These activities were completely suppressed by a nucleophile, N-acetyl-l-cysteine (NAC). The analysis of reaction mechanisms using LC-MS suggested that C2' and C7' of neomacrophorins could be Michael acceptors in the reaction with NAC methyl ester (NACM). These findings indicated that the electrophilic properties of neomacrophorins are responsible for both their potent biological effects and the biosynthesis of unique [4.4.3] propellane framework in neomacrophorin X., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The β-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as β-secretase) is a promising target for the treatment of Alzheimer's disease. A pK a lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF 3 dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aβ reduction in dog even at 0.16 mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [ 14 C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1 mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Lumbar vertebral fracture (LVF) infrequently produces massive retroperitoneal hematoma (RPH). This study aimed to systematically review the clinical and radiographic characteristics of RPH resulting from LVF., Methods: For 193 consecutive patients having LVF who underwent computed tomography (CT), demographic data, physiological conditions, and outcomes were reviewed from their medical records. Presence or absence of RPH, other bone fractures, or organ/vessel injury was evaluated in their CT images, and LVF or RPH, if present, was classified according to either the Orthopaedic Trauma Association classification or the concept of interfascial planes., Results: RPH resulting only or dominantly from LVF was found in 66 (34.2%) patients, whereas among the others, 64 (33.2%) had no RPH, 38 (19.7%) had RPH from other injuries, and 25 (13.0%) had RPH partly attributable to LVF. The 66 RPHs resulting only or dominantly from LVF were radiologically classified into mild subtype of minor median (n = 35), moderate subtype of lateral (n = 11), and severe subtypes of central pushing-up (n = 13) and combined (n = 7). Of the 20 patients with severe subtypes, 18 (90.0%) were in hemorrhagic shock on admission, and 6 (30.0%) were clinically diagnosed as dying due to uncontrollable RPH resulting from vertebral body fractures despite no anticoagulant medication., Conclusions: LVF can directly produce massive RPH leading to hemorrhagic death. A major survey of such pathology should be conducted to establish appropriate diagnosis and treatment.

Microemulsions (MEs) containing deep eutectic solvents (DESs) and water in the inner phase for use in transdermal delivery of poorly soluble drugs were prepared using a mixture of polyoxyethylene sorbitan monooleate (Tween-80) and sorbitan laurate (Span-20) as surfactants. We investigated the effects of the ratios of surfactant (Tween-80/Span-20) and solvents (DES components/water) on the ME structure determined by the analysis of small-angle X-ray scattering profiles with the core-corona model. Tween-80 with an unsaturated long alkyl chain induced a structural transition of MEs from a sphere to a cylinder. DESs caused the aggregation of surfactants due to the solvophobic interactions between DESs and the alkyl chains of surfactants. Transmittance electron microscopy images of MEs indicated the presence of aggregates of the dispersed ME particles with each shape.

Medulloepithelioma is a rare and highly malignant primitive neuroectodermal tumor that usually occurs in childhood. The diagnosis of this entity required only morphological analysis until the World Health Organization classification of central nervous system (CNS) tumors was revised, and now genetic analysis is necessary. We report a case of medulloepithelioma in the posterior cranial fossa that was diagnosed by both morphological and genetic analyses based on this classification. A 10-month-old girl was admitted to our hospital with consciousness disturbance and vomiting. Neuroimaging revealed a partially calcified mass and cyst formation in the posterior cranial fossa. Partial resection of the tumor was performed and histological findings revealed multilayered rosettes with LIN28A staining, but genetic analysis showed no amplification of the C19MC microRNA cluster at 19q14.32. Therefore, we diagnosed the tumor as medulloepithelioma belonging to other CNS embryonal tumors. The patient was immediately treated with systemic high-dose chemotherapy. Follow-up neuroimaging 10 months later showed no signs of recurrence. Medulloepitheliomas are difficult to diagnose by routine HE staining and require combined morphological, immunohistochemical and genetic analyses to provide an accurate diagnosis., (© 2017 Japanese Society of Neuropathology.)

Small and broad-necked aneurysms are generally very difficult to treat using endovascular therapy. The arrival of the low-profile stent (e.g., Low-profile Visualized Intraluminal Support; LVIS) has enabled reconstructive treatment for these aneurysms. In addition, the bulging technique using LVIS is an effective and attractive technique for performing stent-assisted coiling to preserve parent arteries and achieve neck coverage. We report here a patient with a small and wide-necked ruptured basilar artery (BA) top aneurysm, in whom successful treatment was achieved by stent-assisted coiling with LVIS Jr. using the bulging technique. A 74-year-old woman with moderate hypertension consulted for treatment of subarachnoid hemorrhage with a ruptured BA top aneurysm measuring 2.7 mm in height with a 4.3 mm neck. We initially tried emergency balloon-assisted coiling, but coiling proved difficult. We therefore performed stent-assisted coiling with LVIS Jr. using the bulging technique. The postoperative course was uneventful, with no aggravation of neurological symptoms, and the patient was discharged 14 days postoperatively. This treatment strategy with LVIS Jr. using the bulging technique may be very useful for patients with a ruptured aneurysm with a small and broad neck that would otherwise require treatment with intravascular devices or open surgery.

We have developed a tumor environment-responsive polymeric anticancer prodrug containing pirarubicin (THP) conjugated to N-(2-hydroxypropyl) methacrylamide copolymer (PHPMA), [P-THP], through a spacer containing pH-sensitive hydrazone bond, that showed remarkable therapeutic effect against various tumor models and in a human pilot study. Toward clinical development, here we report THP release profile from its HPMA copolymer conjugate, the conjugate stability, protein and cell-binding and solubility of P-THP. Size exclusion chromatography of P-THP (molecular weight 38 kDa) showed similar hydrodynamic volume as bovine serum albumin (BSA) in aqueous solution, with no apparent interactions with BSA, nor aggregation by itself. pH-responsive release of free THP was reconfirmed at pHs 6.5 and lower. The drug release was significantly affected by a type of used buffer. Phosphate buffer seems to facilitate faster hydrazone bond cleavage at pH 7.4 whereas higher stability was achieved in L-arginine solution which yielded only little cleavage and THP release, approx. 15% within 2 weeks at the same pH at 25 °C. Furthermore, ex vivo study using sera of different animal species showed very high stability of P-THP. Incubation with blood showed high stability of P-THP during circulation, without binding to blood cells. These findings revealed that L-arginine solution provides appropriate media for formulation of P-THP infusion solution as tumor-targeted polymeric anticancer drug based on EPR effect., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare and treatable variant of cerebral amyloid angiopathy, lacks specific imaging and clinical features, and requires invasive brain biopsy to confirm the diagnosis. We report the case of a patient with nonconvulsive status epilepticus (NCSE) caused by CAA-ri in the right occipital lobe., Presentation of Case: A 78-year-old man with a history of hypertension and rheumatoid arthritis was admitted to our hospital following an episode of seizures. CT scan showed a low-attenuating subcortical lesion in the right occipital lobe. MRI revealed the lesion as hypointense on T1-weighted imaging (WI) and hyperintense on T2-WI, showing no enhancement on T1-WI contrast-enhanced with gadolinium. In addition, T2*-weighted gradient-recalled echo (T2*-GRE) and susceptibility-weighted imaging (SWI) revealed extensive cortical microbleeds. Biopsy to determine the exact diagnosis revealed histological findings of reactive changes and perivascular inflammatory infiltration associated with amyloid deposition in vessel walls. These findings were consistent with CAA-ri. Corticosteroid therapy with dexamethasone was initiated for a short period as a diagnostic and therapeutic maneuver, resulting in marked reductions in the lesion., Discussion: CAA is generally associated with intracerebral hemorrhage, dementia, and small cerebral infarctions in the elderly population, but in a small proportion of cases is related to inflammatory responses to vascular deposits of Aβ, as so-called CAA-ri., Conclusion: CAA-ri should be considered among the differential diagnoses for causes of unprovoked seizure onset in elderly individuals, when associated with petechial hemorrhages on T2*-GRE and SWI sequences on MRI., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neomacrophorin X (1) was isolated from Trichoderma sp. 1212-03. Heteronuclear multiple bond correlation (HMBC) spectral analysis indicated a unique [4.4.3]propellane framework, which was verified by the 1 H and 13 C chemical shift calculations based on density functional theory (DFT) and subsequent comparison with experimental data obtained in CDCl 3 . The DFT-based electronic circular dichroism (ECD) calculations were effective in not only determining the absolute configuration but also confirming the relative structure. The predominant conformation of 1 was found to be solvent-dependent, with different conformations presenting different NMR and ECD profiles. Introduction of J-based analysis with a J-resolved HMBC aided in this investigation. This conformational alternation was reproduced by considering the solvation with the SM5.4 model in the calculation, although it was not sufficiently quantitative. Although the calculations without solvent effects suggested a conformer that satisfies the spectral profiles in CDCl 3 , postcalculations with the SM5.4 solvation protocol stabilized the second major conformer, which reproduces the NMR and ECD profiles in polar solvents. Neomacrophorin X (1) is assumed to be biosynthesized by a coupling between the reduced form of anthraquinone and a neomacrophorin derivative. This hypothesis was supported experimentally by the isolation of pachybasin and chrysophanol, as well as acyclic premacrophorin (2), from the same fungus. Some biological properties of 1 are described.

The electronic and magnetic properties of chemically modified graphene armchair edges are studied using a combination of tight-binding calculations, first-principles modelling, and low temperature scanning tunneling microscopy (STM) experiments. The atomically resolved STM images of the hydrogen etched graphitic edges suggest the presence of localized states at the Fermi level for certain armchair edges. We demonstrate theoretically that the topological zero-energy edge mode may emerge at armchair boundaries with asymmetrical chemical termination of the two outermost atoms in the unit cell. We particularly focus our attention on armchair edges terminated by various combinations of the hydrogen (H, H 2 ) and methylene (CH 2 ) groups. The inclusion of the spin component in our calculations reveals the appearance of π-electron-based magnetism at the armchair edges under consideration.

Group A1 heat shock transcription factors (HsfA1s) are the master regulators of the heat stress response (HSR) in plants. Upon heat shock, HsfA1s trigger a transcriptional cascade that is composed of many transcription factors. Despite the importance of HsfA1s and their downstream transcriptional cascade in the acquisition of thermotolerance in plants, the molecular basis of their activation remains poorly understood. Here, domain analysis of HsfA1d, one of several HsfA1s in Arabidopsis thaliana, demonstrated that the central region of HsfA1d is a key regulatory domain that represses HsfA1d transactivation activity through interaction with HEAT SHOCK PROTEIN70 (HSP70) and HSP90. We designated this region as the temperature-dependent repression (TDR) domain. We found that HSP70 dissociates from HsfA1d in response to heat shock and that the dissociation is likely regulated by an as yet unknown activation mechanism, such as HsfA1d phosphorylation. Overexpression of constitutively active HsfA1d that lacked the TDR domain induced expression of heat shock proteins in the absence of heat stress, thereby conferring potent thermotolerance on the overexpressors. However, transcriptome analysis of the overexpressors demonstrated that the constitutively active HsfA1d could not trigger the complete transcriptional cascade under normal conditions, thereby indicating that other factors are necessary to fully induce the HSR. These complex regulatory mechanisms related to the transcriptional cascade may enable plants to respond resiliently to various heat stress conditions., (© 2016 American Society of Plant Biologists. All rights reserved.)

Mps1, also known as TTK, is a dual-specificity kinase that regulates the spindle assembly check point. Increased expression levels of Mps1 are observed in cancer cells, and the expression levels correlate well with tumor grade. Such evidence points to selective inhibition of Mps1 as an attractive strategy for cancer therapeutics. Starting from an aminopyridine-based lead 3a that binds to a flipped-peptide conformation at the hinge region in Mps1, elaboration of the aminopyridine scaffold at the 2- and 6-positions led to the discovery of 19c that exhibited no significant inhibition for 287 kinases as well as improved cellular Mps1 and antiproliferative activities in A549 lung carcinoma cells (cellular Mps1 IC₅₀=5.3 nM, A549 IC₅₀=26 nM). A clear correlation between cellular Mps1 and antiproliferative IC₅₀ values indicated that the antiproliferative activity observed in A549 cells would be responsible for the cellular inhibition of Mps1. The X-ray structure of 19c in complex with Mps1 revealed that this compound retains the ability to bind to the peptide flip conformation. Finally, comparative analysis of the X-ray structures of 19c, a deamino analogue 33, and a known Mps1 inhibitor bound to Mps1 provided insights into the unique binding mode at the hinge region., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.

DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN2A (DREB2A) is a key transcription factor for drought and heat stress tolerance in Arabidopsis thaliana. DREB2A induces the expression of dehydration- and heat stress-inducible genes under the corresponding stress conditions. Target gene selectivity is assumed to require stress-specific posttranslational regulation, but the mechanisms of this process are not yet understood. Here, we identified DNA POLYMERASE II SUBUNIT B3-1 (DPB3-1), which was previously annotated as NUCLEAR FACTOR Y, SUBUNIT C10 (NF-YC10), as a DREB2A interactor, through a yeast two-hybrid screen. The overexpression of DPB3-1 in Arabidopsis enhanced the expression of a subset of heat stress-inducible DREB2A target genes but did not affect dehydration-inducible genes. Similarly, the depletion of DPB3-1 expression resulted in reduced expression of heat stress-inducible genes. Interaction and expression pattern analyses suggested the existence of a trimer comprising NF-YA2, NF-YB3, and DPB3-1 that could synergistically activate a promoter of the heat stress-inducible gene with DREB2A in protoplasts. These results suggest that DPB3-1 could form a transcriptional complex with NF-YA and NF-YB subunits and that the identified trimer enhances heat stress-inducible gene expression during heat stress responses in cooperation with DREB2A. We propose that the identified trimer contributes to the target gene selectivity of DREB2A under heat stress conditions., (© 2014 American Society of Plant Biologists. All rights reserved.)

Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase that is activated by fibrillar collagens, which act as its endogenous ligand. DDR2 regulates cell proliferation, cell adhesion, migration, extracellular matrix remodeling and reproductive functions. Both DDR2 null allele mice and mice with a recessive, loss-of-function allele for Ddr2 exhibit dwarfing and a reduction in body weight. However, the detailed mechanisms by which DDR2 exerts its positive systemic regulation of whole body size, local skeletal size and fat tissue volume remain to be clarified. To investigate the systemic role of DDR2 in body size regulation, we produced transgenic mice in which the DDR2 protein is overexpressed, then screened the transgenic mice for abnormalities using systematic mouse abnormality screening. The modified-SHIPRA screen revealed that only the parameter of body size was significantly different among the genotypes. We also discovered that the body length was significantly increased, while the body weight was significantly decreased in transgenic mice compared to their littermate controls. We also found that the epididymal fat pads were significantly decreased in transgenic mice compared to normal littermate mice, which may have been the cause of the leptin decrement in the transgenic mice. The new insight that DDR2 might promote metabolism in adipocyte cells is very interesting, but more experiments will be needed to elucidate the direct relation between DDR2 and adipose-derived hormones. Taken together, our data demonstrated that DDR2 might play a systemic role in the regulation of body size thorough skeletal formation and fat metabolism.

The geometry and chemistry of graphene nanostructures significantly affects their electronic properties. Despite a large number of experimental and theoretical studies dealing with the geometrical shape-dependent electronic properties of graphene nanostructures, experimental characterisation of their chemistry is clearly lacking. This is mostly due to the difficulties in preparing chemically-modified graphene nanostructures in a controlled manner and in identifying the exact chemistry of the graphene nanostructure on the atomic scale. Herein, we present scanning probe microscopic and first-principles characterisation of graphene nanostructures with different edge geometries and chemistry. Using the results of atomic scale electronic characterisation and theoretical simulation, we discuss the role of the edge geometry and chemistry on the electronic properties of graphene nanostructures with hydrogenated and oxidised linear edges at graphene boundaries and the internal edges of graphene vacancy defects. Atomic-scale details of the chemical composition have a strong impact on the electronic properties of graphene nanostructures, i.e., the presence or absence of non-bonding π states and the degree of resonance stability.

In order to understand the improvement effect of potassium (K) on the catalytic activity of iron-loaded calcined scallop shell (CS) for the steam reforming tar derived from biomass, various K precursors were applied for the catalyst preparation. It is found that pompom-like iron-based particles with a mesoporous structure were easily formed on the surface of calcined scallop shell (CS) when K2CO3 was used as K precursor while no such kind of microsphere was formed when other kinds of K precursors such as KOH and KNO3 were applied. The optimum K-loading amount for the preparation of this catalyst was investigated. Based on the experimental results obtained, a mechanism for the formation of these microspheres was proposed. This pompom-like potassium-promoted iron-based catalyst showed a better catalytic activity and reusability for the steam reforming of tar derived from lignin., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively.

The CB2 receptor has emerged as a potential target for the treatment of pruritus as well as pain without CB1-mediated side effects. We previously identified 2-pyridone derivatives 1 and 2 as potent CB2 agonists; however, this series of compounds was found to have unacceptable pharmacokinetic profiles with no significant effect in vivo. To improve these profiles, we performed further structural optimization of 1 and 2, which led to the discovery of bicyclic 2-pyridone 18e with improved CB2 affinity and selectivity over CB1. In a mouse pruritus model, 18e inhibited compound 48/80 induced scratching behavior at a dose of 100 mg/kg. In addition, the docking model of 18e with an active-state CB2 homology model indicated the structural basis of its high affinity and selectivity over CB1., (Copyright © 2013. Published by Elsevier Ltd.)

Selective CB2 agonists have the potential for treating pain without central CB1-mediated adverse effects. Screening efforts identified 1,2-dihydro-3-isoquinolone 1; however, this compound has the drawbacks of being difficult to synthesize with two asymmetric carbons on an isoquinolone scaffold and of having a highly lipophilic physicochemical property. To address these two major problems, we designed the 2-pyridone-based lead 15a, which showed moderate affinity for CB2. Optimization of 15a led to identification of 39f with high affinity for CB2 and selectivity over CB1. Prediction of the binding mode of 39f in complex with an active-state CB2 homology model provided structural insights into its high affinity for CB2., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Thellungiella salsuginea (formerly T. halophila), a species closely related to Arabidopsis (Arabidopsis thaliana), is tolerant not only to high salt levels, but also to chilling, freezing, and ozone. Here, we report that T. salsuginea also shows greater heat tolerance than Arabidopsis. We identified T. salsuginea HsfA1d (TsHsfA1d) as a gene that can confer marked heat tolerance on Arabidopsis. TsHsfA1d was identified via Full-length cDNA Over-eXpressing gene (FOX) hunting from among a collection of heat-stress-related T. salsuginea cDNAs. Transgenic Arabidopsis overexpressing TsHsfA1d showed constitutive up-regulation of many genes in the Arabidopsis AtHsfA1 regulon under normal growth temperature. In Arabidopsis mesophyll protoplasts, TsHsfA1d was localized in both the nucleus and the cytoplasm. TsHsfA1d also interacted with AtHSP90, which negatively regulates AtHsfA1s by forming HsfA1-HSP90 complexes in the cytoplasm. It is likely that the partial nuclear localization of TsHsfA1d induced the expression of the AtHsfA1d regulon in the transgenic plants at normal temperature. We also discovered that transgenic Arabidopsis plants overexpressing AtHsfA1d were more heat-tolerant than wild-type plants and up-regulated the expression of the HsfA1d regulon, as was observed in TsHsfA1d-overexpressing plants. We propose that the products of both TsHsfA1d and AtHsfA1d function as positive regulators of Arabidopsis heat-stress response and would be useful for the improvement of heat-stress tolerance in other plants.

Diamond is the stiffest known material. Here we report that nanopolycrystal diamond synthesized by direct-conversion method from graphite is stiffer than natural and synthesized monocrystal diamonds. This observation departs from the usual thinking that nanocrystalline materials are softer than their monocrystals because of a large volume fraction of soft grain-boundary region. The direct conversion causes the nondiffusional phase transformation to cubic diamond, producing many twins inside diamond grains. We give an ab initio-calculation twinned model that confirms the stiffening. We find that shorter interplane bonds along [111] are significantly strengthened near the twinned region, from which the superstiff structure originates. Our discovery provides a novel step forward in the search for superstiff materials.

Soybean (Glycine max) is an important crop around the world. Abiotic stress conditions, such as drought and heat, adversely affect its survival, growth, and production. The DEHYDRATION-RESPONSIVE ELEMENT-BINDING PROTEIN2 (DREB2) group includes transcription factors that contribute to drought and heat stress tolerance by activating transcription through the cis-element dehydration-responsive element (DRE) in response to these stress stimuli. Two modes of regulation, transcriptional and posttranslational, are important for the activation of gene expression by DREB2A in Arabidopsis (Arabidopsis thaliana). However, the regulatory system of DREB2 in soybean is not clear. We identified a new soybean DREB2 gene, GmDREB2A;2, that was highly induced not only by dehydration and heat but also by low temperature. GmDREB2A;2 exhibited a high transactivation activity via DRE and has a serine/threonine-rich region, which corresponds to a negative regulatory domain of DREB2A that is involved in its posttranslational regulation, including destabilization. Despite the partial similarity between these sequences, the activity and stability of the GmDREB2A;2 protein were enhanced by removal of the serine/threonine-rich region in both Arabidopsis and soybean protoplasts, suggestive of a conserved regulatory mechanism that involves the recognition of serine/threonine-rich sequences with a specific pattern. The heterologous expression of GmDREB2A;2 in Arabidopsis induced DRE-regulated stress-inducible genes and improved stress tolerance. However, there were variations in the growth phenotypes of the transgenic Arabidopsis, the induced genes, and their induction ratios between GmDREB2A;2 and DREB2A. Therefore, the basic function and regulatory machinery of DREB2 have been maintained between Arabidopsis and soybean, although differentiation has also occurred.

Many patients with POEMS syndrome have osteosclerotic plasmacytoma. Radiation therapy is useful for patients who have localized lesions, although chemotherapy is necessary for patients who have widespread lesions. Thus, evaluation of these lesions is important to determine the therapeutic strategy. We evaluated the activities of lesions in two patients with POEMS syndrome by (18)F-FDG positron emission tomography (PET)/computed tomography (CT) scan. In the first patient, PET/CT scan revealed osteosclerotic lesions, which were not detected by Ga-scintigraphy or plain X-ray. It also detected residual disease activity and relapse. In the second patient, lymph node involvement was suggested by (18)F-FDG uptake, and plasmacytoma was confirmed by subsequent biopsy. In the extramedullary lesions of this case, FDG uptake was as marked as in myeloma, whereas bone lesion was only detectable by CT scan. In POEMS syndrome, the PET and CT are complementary, and the combined PET/CT scan is considered to be very useful for evaluation of involved lesions.