Search

Previous studies have not clearly identified a prognostic factor for desmoid tumours (DT). Whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) were performed in 64 cases of DT to investigate the molecular profiles in combination with the clinicopathological characteristics. CTNNB1 mutations with specific hotspots were identified in 56 cases (87.5%). A copy number loss in chromosome 6 (chr6) was identified in 14 cases (21.9%). Clustering based on the mRNA expression profiles was predictive of the patients' prognoses. The risk score generated by the expression of a three-gene set (IFI6, LGMN, and CKLF) was a strong prognostic marker for recurrence-free survival (RFS) in our cohort. In risk groups stratified by the expression of IFI6, the hazard ratio for recurrence-free survival in the high-risk group relative to the low-risk group was 12.12 (95% confidence interval: 1.56-94.2; p = 8.0 × 10 6 ). In conclusion, CTNNB1 mutations and a chr6 copy number loss are likely the causative mutations underlying the tumorigenesis of DT while the gene expression profiles may help to differentiate patients who would be good candidates for wait-and-see management and those who might benefit from additional systemic or radiation therapies., Competing Interests: Conflict of interest statement The authors certify that no actual or potential conflict of interest in relation to this article exists., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The circadian rhythms are endogenous rhythms of about 24 h, and are driven by the circadian clock. The clock centre locates in the suprachiasmatic nucleus. Light signals from the retina shift the circadian rhythm in the suprachiasmatic nucleus, but there is a robust part of the suprachiasmatic nucleus that causes jet lag after an abrupt shift of the environmental lighting condition. To examine the effect of attenuated circadian rhythm on the duration of jet lag, we established a transgenic rat expressing BMAL1 dominant negative form under control by mouse Prnp-based transcriptional regulation cassette [BMAL1 DN (+)]. The transgenic rats became active earlier than controls, just after light offset. Compared to control rats, BMAL1 DN (+) rats showed smaller circadian rhythm amplitudes in both behavioural and Per2 promoter driven luciferase activity rhythms. A light pulse during the night resulted in a larger phase shift of behavioural rhythm. Furthermore, at an abrupt shift of the light-dark cycle, BMAL1 DN (+) rat showed faster entrainment to the new light-dark cycle compared to controls. The circadian rhythm has been regarded as a limit cycle phenomenon, and our results support the hypothesis that modification of the amplitude of the circadian limit cycle leads to alteration in the length of the phase shift., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Synovial sarcoma is a rare tumor requiring new treatment methods. A 46-year-old woman with primary monophasic synovial sarcoma in the left thigh involving the sciatic nerve, declining surgery because of potential dysfunction of the affected limbs, received two courses of BNCT. The tumor thus reduced was completely resected with no subsequent recurrence. The patient is now able to walk unassisted, and no local recurrence has been observed, demonstrating the applicability of BNCT as adjuvant therapy for synovial sarcoma. Further study and analysis with more experience accumulation are needed to confirm the real impact of BNCT efficacy for its application to synovial sarcoma., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Management of bone metastasis is becoming increasingly important. Thus, local and systemic treatment options have been developed for control. Although systemic administration of anticancer agents is effective for bone metastasis, it is often stopped because of poor general conditions or side effects. Therefore, it is highly desirable to develop a more effective and safer local treatment for bone metastasis. The purpose of the current study was to investigate the antitumor effects and safety of gelatin hydrogel microspheres incorporating cisplatin (GM-CDDP), which we developed as a sustained release system without harmful substances. First, we assessed GM-CDDP for its in vitro degradability and potential for sustained release. Second, in vivo antitumor and side effects were evaluated using a murine bone metastasis model of MDA-MB-231 human breast cancer cells incorporating GFP. In vitro, initial bursts were observed within 2 h and CDDP was released gradually with gelatin hydrogel degradation, which reached 100% at 48 h. In vivo, local administration of GM-CDDP (2 mg/kg) significantly suppressed tumor growth and bone osteolysis compared with the control, and local and systemic administration of free CDDP (2 mg/kg; p < 0.05). Local administration of GM-CDDP significantly reduced loss of body weight and elevation of blood urea nitrogen compared with the systemic administration of free CDDP (p < .05). The current study suggests that local administration of GM-CDDP achieves higher antitumor effects with a potential for lesser side effects compared with local or systemic administration of free CDDP., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Background: Skeletal related events due to metastatic bone tumors markedly affect the activities of daily living (ADL) and quality of life (QOL) in cancer patients. We focused on multidisciplinary therapy for metastatic bone tumors. This study aimed to evaluate the outcomes of surgical treatment for metastatic bone tumors in the extremities., Methods: We retrospectively reviewed 114 patients who underwent surgical treatment for metastatic bone tumors of the extremities between 2008 and 2019 and 69 patients were reassessed for more than 6 months after surgery. The most common primary tumor was renal, followed by lung, thyroid, and breast cancers. We assessed 69 patients' performance status (PS), Barthel Index (BI) for ADL, EuroQol 5 Dimensions (EQ-5D) for QOL, and numerical rating scale (NRS) for pain and analyzed these postoperative values relative to preoperative values using Friedman's test. The postoperative overall survival and the prognostic factors were evaluated using the Kaplan-Meier method, the log-rank test and Cox proportional hazards analysis., Results: The 1-year overall survival rate was 59%, and the median survival time after surgery was 20 months. Primary tumor, visceral metastasis, and surgical procedure were risk factors correlated with overall survival. PS, BI, EQ-5D, and NRS improved at 3 months after surgery and these improvements were maintained for 6 months after surgery regardless of the surgical procedure., Conclusions: The significant factors affecting survival after surgical treatment for bone metastases included the primary tumor, presence of visceral metastases, and internal fixation without tumor resection or curettage. Surgical treatment for metastatic bone tumors effectively reduced pain and improved PS, ADL, and QOL postoperatively after 3 months., Competing Interests: 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., (© 2021 The Authors.)

Background/aim: This study aimed to evaluate the association of clinical characteristics with treatment outcomes to ascertain the appropriate treatment options for soft tissue sarcomas (STS) patients with brain metastasis (BM)., Patients and Methods: Medical records of STS patients with BM who were treated in our institutions were retrospectively reviewed, and analyzed to identify the factors associated with post-BM survival., Results: Among the 509 STS patients, BM occurred in five patients (0.98%). The median survival after BM was 1.5 months. Histological subtypes of the primary lesions in the five BM patients were: two synovial sarcomas, one myxoid liposarcoma, one alveolar soft part sarcoma, and one rhabdomyosarcoma. Among the five BM patients, the post-BM survival of two patients, who underwent surgery and postoperative radiotherapy, was longer than that of the other patients (p<0.01)., Conclusion: Combined surgery and postoperative radiotherapy effectively managed symptoms and prolonged survival in STS patients with BM., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Chondrolipoma is, based on the limited case reports available, an extremely rare histological variant of lipoma with the proliferation of mature adipocytes containing an area of true hyaline cartilage. Chondrolipoma is characterized by adult onset and is often identified in the breast, pharynx and tongue. The current study presents a case of chondrolipoma of the finger in an 11 year-old girl. Physical examination indicated a well-defined elastic soft mass, measuring 2.5x2 cm, on the dorsal aspect of the proximal phalanx of the left middle finger. Magnetic resonance imaging (MRI) revealed a well-circumscribed lesion with heterogeneous signal intensity. On T1- and T2-weighted images, the lesion indicated a predominantly marked hyperintense signal containing linear hypointense regions, and on fat-suppressed short-tau inversion recovery sequences, the lesion indicated a predominant hypointensity, with linear regions displaying hyperintensity. Marginal excision of the tumor was performed. Histologically, the major component of the tumor was mature adipose tissue containing a limited area of mature hyaline cartilage matrix, without lipoblasts or malignancy. The postoperative course of the patient was excellent, with no local recurrence three years after surgery. To the best of our knowledge, the current study outlines the first pediatric case of chondrolipoma arising in the finger., (Copyright: © Mitani et al.)

Malignant melanoma is an aggressive tumor with a high potential for distant metastases. Autopsy studies have shown that gallbladder metastases are found in 15% of patients. However, metastatic melanoma of the gallbladder is rarely discovered in living patients. A 73-year-old man was reported. The patient underwent surgical removal of malignant melanoma on his back and lymphadenectomy of the axillary lymph nodes. In addition, the patient developed cutaneous metastases to the right axillary and the middle of the chest 1.5 years after the surgery. Consequently, nivolumab chemotherapy was started. A computed tomography (CT) scan showed a well-enhanced mass in the gallbladder 4 months after. Abdominal ultrasonography revealed a 13-mm hypoechoic heterogeneous mass in the gallbladder with a hyperechoic layer on the mass surface. Magnetic resonance imaging demonstrated that the gallbladder tumor showed high signal intensity on T1-weighted images, low signal intensity on T2-weighted images, and high signal intensity on diffusion-weighted images. Positron emission tomography-CT revealed the slight uptake of fluorodeoxyglucose at the tumor. Endoscopic ultrasonography showed a hypoechoic tumor infiltrating the submucosal layer. The patient underwent open cholecystectomy. Examination of the resected specimens revealed a black, nodular-type tumor in the gallbladder body. The histopathological diagnosis was malignant melanoma. It was judged as metastatic melanoma of the gallbladder.

The blood-brain barrier (BBB) prevents the permeability of drugs into the brain, and as such limits the management of various brain diseases. To overcome this barrier, drug-encapsulating nanoparticles or vesicles, drug conjugates, and other types of drug delivery systems (DDSs) have been developed. However, the brain-targeting ability of nanoparticles or vesicles is still insufficient. Recently, among the various brain-targeting ligands previously studied for facilitating transcellular BBB transport, several sugar-appended nanocarriers for brain delivery were identified. Meanwhile, cyclodextrins (CyDs) have been used as nanocarriers for drug delivery since they can encapsulate hydrophobic compounds with high biocompatibility. Therefore, in this study, we created various sugar-appended β-cyclodextrins (β-CyDs) to discover novel brain-targeting ligands. As a result, of the six sugar-appended CyDs, lactose-appended β-CyD (Lac-β-CyD) showed greater cellular uptake in hCMEC/D3 cells, human brain microvascular endothelial cells, than other sugar-appended β-CyDs did. In addition, the permeability of Lac-β-CyD within the in vitro human BBB model was greater than that of other sugar-appended β-CyDs. Moreover, Lac-β-CyD significantly accumulated in the mouse brain after intravenous administration. Thus, Lac-β-CyD efficiently facilitated the accumulation of the model drug into the mouse brain. These findings suggest that Lac-β-CyD has the potential to be a novel carrier for drugs across the BBB., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Clear cell sarcoma of tendons and aponeuroses (CCS) is a rare, malignant tumor arising in lower extremities with no effective treatment other than wide surgical resection. Here described is a case of primary CCS in the peroneal tendon of the right foot of a 54-year-old woman enrolled to undergo BNCT. The tumor mass post-BNCT disappeared totally without damage to other normal tissue, demonstrating, for the first time, the potential efficacy of BNCT in complete local control of CCS., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We herein describe soft tissue tumor arising in the lower extremity of a pediatric patient. The tumor displayed a unique and wide range of histological features, sheet-like and cohesive growth pattern consisting of enlarged round to epithelioid atypical cells with a large alveolar and pseudopapillary histological architecture, focally mimicking alveolar soft part sarcoma and MiT family translocation renal cell carcinoma. Tumor cells were focally immunoreactive for cytokeratin, S-100, and EMA. RNA sequencing identified a novel in-frame NR1D1 (exon 5)-MAML1 (exon 2) gene rearrangement resulting in the formation of a putative chimeric protein containing the N-terminal C4-type zing finger domains of NR1D1 and the C-terminal MAML1 protein, which was confirmed by subsequent RT-PCR, Sanger sequencing, and FISH assay. To the best of our knowledge, NR1D1-MAML1 fusion has not yet been described in any neoplasms, suggesting the emergence of a novel tumor entity.

The cAMP-response element (CRE) is critical in the formation of long-term memory. To prove the pharmacological effects of the methoxyflavones-rich residue (MRR) and its constituent methoxyflavones (1-9) extracted from the rhizomes of Kaempferia parviflora on the nervous system, we examined the effects of the MRR and methoxyflavones (1-9) on CRE-mediated transcription in PC12D cells. The MRR increased CRE-mediated transcription in PC12D cells. In addition, among methoxyflavones (1-9) isolated from MRR, compounds 1-4 increased CRE-mediated transcription. These results suggest that K. parviflora and methoxyflavone might be very useful materials for preventing and recovering from cognitive decline., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Marine macroscopic colony-forming filamentous (MMCFF) cyanobacteria are considered as prolific producers of bioactive compounds. Thus, knowledge of the diversity of MMCFF cyanobacteria as related to bioactive compound production has become very important. However, basic taxonomic studies of MMCFF cyanobacteria are lacking. Many cyanobacterial taxa are still misidentified or undescribed. In this study, a total of 32 cyanobacterial colonies from nine coastal regions of Okinawa Prefecture were investigated for a diversity assessment. A polyphasic approach including morphological and molecular studies based on 16S rRNA gene sequences was performed to characterize Okinawan MMCFF cyanobacteria. Both morphological and molecular phylogenetic results showed that MMCFF cyanobacteria from Okinawan coasts are very diverse. We found morphotypes of Lyngbya-like, Phormidium-like, and Leptolyngbya-like groups among Okinawan cyanobacterial samples. Genetically, samples were distributed in various clades in the phylogenetic tree, including within Moorena, Okeania, Caldora, Neolyngbya, Dapis, as well as several unknown clades. In addition, cytotoxic activities of three samples from Kiyan coast were tested against HeLa cells. All three crude extracts of these samples showed strong cytotoxic activity with IC 50  < 1 μg/ml.

Introduction: Diabetes mellitus (DM) negatively affects fracture repair by inhibiting endochondral ossification, chondrogenesis, callus formation, and angiogenesis. We previously reported that transcutaneous CO 2 application accelerates fracture repair by promoting endochondral ossification and angiogenesis. The present study aimed to determine whether CO 2 treatment would promote fracture repair in cases with type I DM., Research Design and Methods: A closed femoral shaft fracture was induced in female rats with streptozotocin-induced type I DM. CO 2 treatment was performed five times a week for the CO 2 group. Sham treatment, where CO 2 was replaced with air, was performed for the control group. Radiographic, histologic, genetic, and biomechanical measurements were taken at several time points., Results: Radiographic assessment demonstrated that fracture repair was induced in the CO 2 group. Histologically, accelerated endochondral ossification and capillary formation were observed in the CO 2 group. Immunohistochemical assessment indicated that early postfracture proliferation of chondrocytes in callus was enhanced in the CO 2 group. Genetic assessment results suggested that cartilage and bone formation, angiogenesis, and vasodilation were upregulated in the CO 2 group. Biomechanical assessment revealed enhanced mechanical strength in the CO 2 group., Conclusions: Our findings suggest that CO 2 treatment accelerates fracture repair in type I DM rats. CO 2 treatment could be an effective strategy for delayed fracture repair due to DM., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Studies showing that individuals with non-small cell lung cancer (NSCLC) and diabetes mellitus (DM) have reported poor outcomes after pulmonary resection with varying results. Therefore, we investigated the clinical impact of preoperative DM on postoperative morbidity and survival in individuals with resectable NSCLC., Patients and Methods: Data of individuals who underwent pulmonary resection for NSCLC from 2000 to 2015 were extracted from the database of Kyoto University Hospital. The primary endpoint was the incidence of postoperative complications, and secondary endpoints were postoperative length of hospital stay and overall survival. The survival rate was analyzed using the Kaplan-Meier method., Results: A total of 2,219 patients were eligible for the study. The median age of participants was 67 years. Among them, 39.5% were women, and 259 (11.7%) presented with DM. The effect of DM on the incidence of postoperative complications and postoperative length of hospital stay was not significant. Although the 5-year survival rates were similar in both patients with and without DM (80.2% versus 79.4%; p = 0.158), those with DM who had a hemoglobin A1c level ≥ 8.0% had the worst survival., Conclusions: In individuals with resectable NSCLC, preoperative DM does not influence the acute phase postoperative recovery. However, poorly controlled preoperative DM could lead to low postoperative survival rates., Competing Interests: The authors have declared that no competing interests exist.

Despite growing evidence that high creativity leads to mental well-being in older individuals, the neurophysiological bases of creativity remain elusive. Creativity reportedly involves multiple brain areas and their functional interconnections. In particular, functional magnetic resonance imaging (fMRI) is used to investigate the role of patterns of functional connectivity between the default network and other networks in creative activity. These interactions among networks play the role of integrating various neural processes to support creative activity and involve attention, cognitive control, and memory. The electroencephalogram (EEG) enables researchers to capture a pattern of band-specific functional connectivity, as well as moment-to-moment dynamics of brain activity; this can be accomplished even in the resting-state by exploiting the excellent temporal resolution of the EEG. Furthermore, the recent advent of functional connectivity analysis in EEG studies has focused on the phase-difference variable because of its fine spatio-temporal resolution. Therefore, we hypothesized that the combining method of EEG signals having high-temporal resolution and the phase synchronization analysis having high-spatio-temporal resolutions brings a new insight of functional connectivity regarding high creative activity of older participants. In this study, we examined the resting-state EEG signal in 20 healthy older participants and estimated functional connectivities using the phase lag index (PLI), which evaluates the phase synchronization of EEG signals. Individual creativity was assessed using the S-A creativity test in a separate session before the EEG recording. In the analysis of associations of EEG measures with the S-A test scores, the covariate effect of the intelligence quotient was evaluated. As a result, higher individual S-A scores were significantly associated with higher node degrees, defined as the average PLI of a node (electrode) across all links with the remaining nodes, across all nodes at the alpha band. A conventional power spectrum analysis revealed no significant association with S-A scores in any frequency band. Older participants with high creativity exhibited high functional connectivity even in the resting-state, irrespective of intelligence quotient, which supports the theory that creativity entails widespread brain connectivity. Thus, PLIs derived from EEG data may provide new insights into the relationship between functional connectivity and creativity in healthy older people., (Copyright © 2020 Nobukawa, Yamanishi, Ueno, Mizukami, Nishimura and Takahashi.)

Metabolites in human biofluids document the physiological status of individuals. We conducted comprehensive, non-targeted, non-invasive metabolomic analysis of urine from 27 healthy human subjects, comprising 13 young adults (30 ± 3 years) and 14 seniors (76 ± 4 years). Quantitative analysis of 99 metabolites revealed 55 that displayed significant differences in abundance between the two groups. Forty-four did not show a statistically significant relationship with age. These include 13 standard amino acids, 5 methylated, 4 acetylated, and 9 other amino acids, 6 nucleosides, nucleobases, and derivatives, 4 sugar derivatives, 5 sugar phosphates, 4 carnitines, 2 hydroxybutyrates, 1 choline, and 1 ethanolamine derivative, and glutathione disulfide. Abundances of 53 compounds decreased, while 2 (glutathione disulfide, myo-inositol) increased in elderly people. The great majority of age-linked markers were highly correlated with creatinine. In contrast, 44 other urinary metabolites, including urate, carnitine, hippurate, and betaine, were not age-linked, neither declining nor increasing in elderly subjects. As metabolite profiles of urine and blood are quite different, age-related information in urine offers additional valuable insights into aging mechanisms of endocrine system. Correlation analysis of urinary metabolites revealed distinctly inter-related groups of compounds., Competing Interests: The authors declare that they have no competing interests., (© 2020 The Authors. FASEB BioAdvances published by the Federation of American Societies for Experimental Biology.)

A 61-year-old Japanese man with the pure spinal form of cerebrotendinous xanthomatosis developed dysesthesia of the lower limbs and gait disturbance at 57 years of age. At 61 years old, he was unable to walk without support. A neurological examination showed spasticity and sensory disturbance in the lower limbs. Spinal MRI showed long hyperintense lesions involving the lateral and posterior funiculus in the cervical and thoracic cord on T2-weighted images. His serum cholestanol level was markedly elevated. A CYP27A1 gene analysis identified two missense variants, p.R474W, and a novel p.R262C variant. Combination therapy with chenodeoxycholic acid and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase decreased his serum cholestanol level.

Bone mass is regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Osteoporosis is a bone metabolism disorder in which bone mass decreases due to increased bone resorption rather than bone formation. We focused on the traditional plant Alpinia zerumbet in Okinawa, Japan, and searched for promising compounds for the prevention and treatment of osteoporosis. Pinocembrin isolated from the leaves of A. zerumbet showed enhanced alkaline phosphatase (ALP) activity and mineralization and increased mRNA expression of osteoblast-related genes Alp and Osteocalcin (Ocn) in MC3T3-E1 cells. Pinocembrin increased the mRNA expression of Runx2 and Osterix, which are important transcription factors in osteoblast differentiation, and the mRNA expression of Dlx5 and Msx2, which are enhancers of these transcription factors. The bone morphogenetic protein (BMP) antagonist noggin, its receptor kinase inhibitor LDN-193189 and p38 MAPK inhibitor SB203580 attenuated pinocembrin-promoted ALP activity. Pinocembrin increased the mRNA of Bmp-2 and its target gene Id1. In addition, the estrogen receptor (ER) inhibitor ICI182780 suppressed pinocembrin-stimulated ALP activity. Pinocembrin may increase BMP-2 expression via ER. Then, the BMP-2 promotes osteoblast specific genes expression and mineralization through both Smad-dependent and independent pathway following Runx2 and Osterix induction. Our findings suggest that pinocembrin has bone anabolic effects and may be useful for the prevention and treatment of bone metabolic diseases such as osteoporosis.

Background: Cancer stem cells (CSCs) are considered to be responsible for tumor initiation, formation, and poor prognosis of cancer patients. However, the rarity of CSCs in clinical samples makes it difficult to elucidate characteristics of CSCs, especially in osteosarcoma (OS). The aim of this study is to verify whether it is possible to generate CSC-like cells by transducing defined factors into an OS cell line., Methods: We retrovirally transduced the Octamer-binding transcription factor 3/4 (OCT3/4), Kruppel-like factor 4 (KLF4), and SRY-box transcription factor 2 (SOX2) genes into the MG-63 human OS cell line (MG-OKS). Parental and GFP-transduced MG-63 cells were used as negative control. We assessed the properties of the generated cells in vitro and in vivo. Multiple comparisons among groups were made using a one-way analysis of variance (ANOVA) followed by post hoc testing with Tukey's procedure., Results: MG-OKS cells in vitro exhibited the significantly increased mRNA expression levels of CSC markers (CD24, CD26, and CD133), decreased cell growth, increased chemoresistance and cell migration, and enhanced sphere formation. Notably, MG-OKS cells cultured under osteogenic differentiation conditions showed strongly positive staining for both Alizarin Red S and alkaline phosphatase, indicating osteogenesis of the cells. Gene ontology analysis of microarray data revealed significant upregulation of epidermal-related genes. Tumors derived from MG-OKS cells in vivo were significantly larger than those from other cells in μCT analysis, and immunohistochemical staining showed that Ki-67, osteocalcin, and HIF-1α-positive cells were more frequently detected in the MG-OKS-derived tumors., Conclusions: In this study, we successfully generated OS CSC-like cells with significantly enhanced CSC properties following transduction of defined factors.

To explore the further possibilities of nanometer-thick ferromagnetic films (ultrathin ferromagnetic films), we investigated the ferromagnetic resonance (FMR) of 1 nm-thick Co film. Whilst an FMR signal was not observed for the Co film grown on a SiO 2 substrate, the insertion of a 3 nm-thick amorphous Ta buffer layer beneath the Co enabled the detection of a salient FMR signal, which was attributed to the smooth surface of the amorphous Ta. This result implies the excitation of FMR in an ultrathin ferromagnetic film, which can pave the way to controlling magnons in ultrathin ferromagnetic films.

HIV-1 often acquires drug-resistant mutations in spite of the benefits of antiretroviral therapy (ART). HIV-1 integrase (IN) is essential for the concerted integration of HIV-1 DNA into the host genome. IN further contributes to HIV-1 RNA binding, which is required for HIV-1 maturation. Non-catalytic-site integrase inhibitors (NCINIs) have been developed as allosteric IN inhibitors, which perform anti-HIV-1 activity by a multimodal mode of action such as inhibition of the IN-lens epithelium-derived growth factor (LEDGF)/p75 interaction in the early stage and disruption of functional IN multimerization in the late stage of HIV-1 replication. Here, we show that IN undergoes an adaptable conformational change to escape from NCINIs. We observed that NCINI-resistant HIV-1 variants have accumulated 4 amino acid mutations by passage 26 (P26) in the IN-encoding region. We employed high-performance liquid chromatography (HPLC), thermal stability assays, and X-ray crystallographic analysis to show that some amino acid mutations affect the stability and/or dimerization interface of the IN catalytic core domains (CCDs), potentially resulting in the severely decreased multimerization of full-length IN proteins (IN undermultimerization). This undermultimerized IN via NCINI-related mutations was stabilized by HIV-1 RNA and restored to the same level as that of wild-type HIV-1 in viral particles. Recombinant HIV-1 clones with IN undermultimerization propagated similarly to wild-type HIV-1. Our study revealed that HIV-1 can eventually counteract NCINI-induced IN overmultimerization by IN undermultimerization as one of the escape mechanisms. Our findings provide information on the understanding of IN multimerization with or without HIV-1 RNA and may influence the development of anti-HIV-1 strategies. IMPORTANCE Understanding the mechanism of HIV-1 resistance to anti-HIV-1 drugs could lead to the development of novel drugs with increased efficiency, resulting in more effective ART. ART composed of more potent and long-acting anti-HIV-1 drugs can greatly improve drug adherence and also provide HIV-1 prevention such as preexposure prophylaxis. NCINIs with a multimodal mode of action exert potent anti-HIV-1 effects through IN overmultimerization during HIV-1 maturation. However, HIV-1 can acquire some mutations that cause IN undermultimerization to alleviate NCINI-induced IN overmultimerization. This undermultimerized IN was efficiently stabilized by HIV-1 RNA and restored to the same level as that of wild-type HIV-1. Our findings revealed that HIV-1 eventually acquires such a conformational escape reaction to overcome the unique NCINI actions. The investigation into drug-resistant mutations associated with HIV-1 protein multimerization may facilitate the elucidation of its molecular mechanism and functional multimerization, allowing us to develop more potent anti-HIV-1 drugs and unique treatment strategies., (Copyright © 2020 American Society for Microbiology.)

Since ancient days, human fasting has been performed for religious or political reasons. More recently, fasting has been employed as an effective therapy for weight reduction by obese people, and numerous studies have investigated the physiology of fasting by obese subjects. Well-established fasting markers (butyrates, BCAAs and carnitines) were considered essential energy substitutes after glycogen storage depletion. However, a recently developed metabolomic approach has unravelled previously unappreciated aspects of fasting. Surprisingly, one-third (44) of 120 metabolites investigated increase during 58 h of fasting, including antioxidative metabolites (carnosine, ophthalmic acid, ergothioneine and urates) and metabolites of entire pathways, such as the pentose phosphate pathway. Signalling metabolites (3-hydroxybutyrate and 2-oxoglutarate) and purines/pyrimidines may also serve as transcriptional modulators. Thus, prolonged fasting activates both global catabolism and anabolism, reprogramming metabolic homeostasis.

Background: Carbon dioxide therapy has been reported to be effective in treating certain cardiac diseases and skin problems. Although a previous study suggested that transcutaneous carbon dioxide application accelerated fracture repair in association with promotion of angiogenesis, blood flow, and endochondral ossification, the influence of the duration of carbon dioxide application on fracture repair is unknown. The aim of this study was to investigate the effect of the duration of transcutaneous carbon dioxide application on rat fracture repair., Methods: A closed femoral shaft fracture was created in each rat. Animals were randomly divided into four groups: the control group; 1w-CO 2 group, postoperative carbon dioxide treatment for 1 week; 2w-CO 2 group, postoperative carbon dioxide treatment for 2 weeks; 3w-CO 2 group, postoperative carbon dioxide treatment for 3 weeks. Transcutaneous carbon dioxide application was performed five times a week in the carbon dioxide groups. Sham treatment, where the carbon dioxide was replaced with air, was performed for the control group. Radiographic, histological, and biomechanical assessments were performed at 3 weeks after fracture., Results: The fracture union rate was significantly higher in the 3w-CO 2 group than in the control group (p < 0.05). Histological assessment revealed promotion of endochondral ossification in the 3w-CO 2 group than in the control group. In the biomechanical assessment, all evaluation items related to bone strength were significantly higher in the 3w-CO 2 group than in the control group (p < 0.05)., Conclusions: The present study, conducted using an animal model, demonstrated that continuous carbon dioxide application throughout the process of fracture repair was effective in enhancing fracture healing., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

We discovered that majusculamide A ( 1 ) and majusculamide B ( 2 ), isolated from a marine cyanobacterium collected in Okinawa, induced osteoblast differentiation in MC3T3-E1 cells. Although majusculamide A ( 1 ) has a different configuration only at the C-19 stereocenter, bearing a methyl group, compared to majusculamide B ( 2 ), the effect of 1 was stronger than that of 2 . We synthesized some analogues of the majusculamides ( 3 - 15 ) and evaluated osteogenic activities of these analogues. The structure-activity relationship study of majusculamide analogues suggested that the number of methyls and configuration at C-19 and the nature of the substituent at C-20 of majusculamide A ( 1 ) may be important for the osteoblast differentiation-inducing effect of 1 .

Soft tissue sarcomas (STSs) are rare heterogeneous malignancies of mesenchymal origin. Pulmonary metastases develop in approximately 50% of the patients with high-grade STS, being the major cause of mortality in patients with metastatic STS. Pulmonary metastasectomy has been reported to contribute to long-term survival; however, an appropriate treatment has not been established. We aimed to identify factors associated with post-metastasis survival in STS patients with pulmonary metastasis and determine the appropriate treatment for each patient. We retrospectively reviewed the records of metastatic STS patients treated between 2000 and 2017 and analyzed the clinico-pathologic variables to identify factors associated with the survival. The median survival after pulmonary metastasis was 20.6 months, and the 1-, 3-, and 5-year survival rates were 68.6%, 36.0%, and 25.1%, respectively. The survival was significantly greater in patients who underwent pulmonary metastasectomy than in those without surgery (38.9 months vs. 10.5 months; p < 0.0001). Among those who did not undergo surgery, the survival was significantly greater in patients who received chemotherapy than in those without chemotherapy (19.1 months vs. 6.3 months, p = 0.037). Multivariate analysis identified pulmonary metastasectomy as the most important prognostic factor for post-metastasis survival (Hazard ratio 5.623; 95% Confidence Interval 2.733-11.572; p < 0.0001). In conclusion, pulmonary metastasectomy was the most important prognostic factor for post-metastasis survival in patients with metastatic STS. In addition, chemotherapy could prolong survival in patients who were not eligible for pulmonary resection. Although we should carefully weigh the risks and benefits, appropriate treatment for pulmonary metastases could contribute to long-time survival.

We study spin transport through a suspended Cu channel by an electrical non-local 4-terminal measurement for future spin mechanics applications. A magnetoresistance due to spin transport through the suspended Cu channel is observed, and its magnitude is comparable to that of a conventional fixed Cu lateral spin valve. The spin diffusion length in the suspended Cu channel is estimated to be 340 nm at room temperature from the spin signal dependence on the distance between the ferromagnetic injector and detector electrodes. This value is found to be slightly shorter than in a fixed Cu. The decrease in the spin diffusion length in the suspended Cu channel is attributed to an increase in spin scattering originating from naturally oxidized Cu at the bottom of the Cu channel.

Background: Heterotopic pancreas (HP) is defined as pancreatic tissue in organs with no anatomical continuity with the orthotopic pancreas. Based on the number of cases reported in the literature between the year 2000 and 2020, HP is rarely found causing malignant transformation of the duodenum. We herein report a case of adenocarcinoma arising from the HP in the first portion of the duodenum., Case Presentation: A 77-year-old Japanese man presented to our hospital with epigastric pain. Despite having undergone laparoscopic surgery for early sigmoid colon cancer a month earlier, serum levels of tumor-specific antigens, such as CA19-9, were elevated. After undergoing a series of radiologic examinations, the first portion of the duodenum was found thickened. However, a biopsy of the lesion showed no malignancy. Four months later, follow-up computed tomography (CT) scans showed that the lesion was thicker and involved the gastroduodenal artery (GDA), suggesting tumor invasion. A new biopsy did not detect the malignancy. However, serum tumor-specific antigen levels increased, especially duke pancreatic monoclonal antigen type 2 (5287 U/mL), in the absence of tumor in the orthotopic pancreas. The follow-up CT imaging showed a malignant tumor in the first portion of the duodenum. Five months later, we performed a subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) for duodenal or HP cancer in the first portion of the duodenum, finding a lesion from the pyloric bulbs to the first portion of the duodenum, which invaded the adjacent pancreas and GDA. The pathological examination of the specimens revealed adenocarcinoma arising from HP. Nine months after surgery, no recurrence was found by radiologic imaging or tumor-specific antigen laboratory testing., Conclusions: HP adenocarcinoma is rare and difficult to diagnose preoperatively due to its submucosal location. Therefore, a careful follow-up with blood testing and radiologic imaging, as well as diagnostic surgery, is recommended.

Three new antimalarial compounds, clonocoprogens A, B, and C, were isolated from the static culture of an Okinawan fungus, Clonostachys compactiuscula FKR-0021. These compounds were new analogs of N 14 -palmitoylcoprogen, reported as a siderophore. They showed moderate antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with IC 50 values ranging from 1.7 to 9.9 µM.

Objective: The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system has been validated to predict wound healing and limb salvage of patients with peripheral artery disease (PAD). Our goal was to evaluate the association between WIfI stage and wound healing, limb salvage, and survival in a select cohort of patients with PAD and tissue loss undergoing an attempt of wound healing without immediate revascularization (conservative approach) in a multidisciplinary wound program., Methods: Veterans with PAD and tissue loss were prospectively enrolled in our Prevention of Amputation in Veterans Everywhere (PAVE) program. Limbs were stratified to a conservative, revascularization, primary amputation, and palliative limb care approach based on the patient's fitness, ambulatory status, perfusion evaluation, and validated pathway of care. Rates of wound healing, wound recurrence, limb salvage, and survival were retrospectively analyzed by WIfI clinical stages (stage 1-4) in the conservative group. Cox regression modeling was used to estimate clinical outcomes by WIfI stage., Results: Between January 2006 and October 2017, there were 961 limbs prospectively enrolled in our PAVE program. A total of 233 limbs with 277 wounds were stratified to the conservative approach. WIfI staging distribution included 19.7% stage 1, 20.2% stage 2, 38.6% stage 3, and 21.5% stage 4. All ischemia scores were classified as 1 or 2. Advanced wound interventions and minor amputations were performed on 40 limbs (16.6%) and 57 limbs (23.7%), respectively. Average long-term follow-up was 41.4 ± 29.0 months. Complete wound healing without revascularization was achieved in 179 limbs (76.8%) during 4.4 ± 4.1 months. Thirty-four limbs (14%) underwent deferred revascularization because of a lack of complete wound healing. At long-term follow-up, wound recurrence per limb was 39%. Overall limb salvage at long-term follow-up was 89.3%. Stratified by WIfI stage, there was no statistically significant difference between groups for wound healing (P = .64), wound recurrence (P = .55), or limb salvage (P = .66) after adjustment for significant patient, limb, and wound characteristics., Conclusions: In select patients with mild to moderate ischemia and tissue loss, a stratified approach can achieve acceptable rates of wound healing and limb salvage, with limited need for deferred revascularization. WIfI clinical staging did not predict wound healing, limb salvage, or survival in this cohort., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Irijimasides A-E ( 1 - 5 ), a series of new 14-membered macrolide glycosides, were isolated from a marine cyanobacterium collected in Okinawa. The gross structures of 1 - 5 were established by spectroscopic analysis, including 2D NMR, while absolute stereostructures were determined based on NOESY spectra, chemical derivatization, and ECD data. All five macrolides suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP) activity in mouse RAW264 macrophage cells, indicating that these compounds inhibit osteoclast formation.

The outcomes of osteosarcoma with poor prognostic factors, such as poor responders, metastatic disease at diagnosis, and relapsed or refractory disease, are poor. We reviewed the clinical records of the patients diagnosed with osteosarcoma at our institute between 2004 and 2018 who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in our institute. Ten patients of osteosarcoma with poor responder, refractory status, and metastatic disease at diagnosis received high-dose chemotherapy followed by ASCT. Four patients underwent high-dose chemotherapy followed by ASCT with the conditioning regimen consisted of thiotepa and melphalan (MEL). Five patients underwent high-dose chemotherapy followed by ASCT with the conditioning regimen consisted of intravenous busulfan (BU) and MEL. One patient underwent tandem high-dose chemotherapy followed by ASCT with BU and MEL followed by carboplatin and etoposide. None of the ten patients died of regimen related toxicities. None of the five patients with poor responders who underwent high-dose chemotherapy followed by ASCT as part of consolidation therapy died of disease after ASCT. High-dose chemotherapy followed by ASCT might be effective for poor responders in osteosarcoma.

As human society ages globally, age-related disorders are becoming increasingly common. Due to decreasing physiological reserves and increasing organ system dysfunction associated with age, frailty affects many elderly people, compromising their ability to cope with acute stressors. Frail elderly people commonly manifest complex clinical symptoms, including cognitive dysfunction, hypomobility, and impaired daily activity, the metabolic basis of which remains poorly understood. We applied untargeted, comprehensive LC-MS metabolomic analysis to human blood from 19 frail and nonfrail elderly patients who were clinically evaluated using the Edmonton Frail Scale, the MoCA-J for cognition, and the TUG for mobility. Among 131 metabolites assayed, we identified 22 markers for frailty, cognition, and hypomobility, most of which were abundant in blood. Frailty markers included 5 of 6 markers specifically related to cognition and 6 of 12 markers associated with hypomobility. These overlapping sets of markers included metabolites related to antioxidation, muscle or nitrogen metabolism, and amino acids, most of which are decreased in frail elderly people. Five frailty-related metabolites that decreased-1,5-anhydroglucitol, acetyl-carnosine, ophthalmic acid, leucine, and isoleucine-have been previously reported as markers of aging, providing a metabolic link between human aging and frailty. Our findings clearly indicate that metabolite profiles efficiently distinguish frailty from nonfrailty. Importantly, the antioxidant ergothioneine, which decreases in frailty, is neuroprotective. Oxidative stress resulting from diminished antioxidant levels could be a key vulnerability for the pathogenesis of frailty, exacerbating illnesses related to human aging., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Electroencephalography (EEG) has long been studied as a potential diagnostic method for Alzheimer's disease (AD). The pathological progression of AD leads to cortical disconnection. These disconnections may manifest as functional connectivity alterations, measured by the degree of synchronization between different brain regions, and alterations in complex behaviors produced by the interaction among wide-spread brain regions. Recently, machine learning methods, such as clustering algorithms and classification methods, have been adopted to detect disease-related changes in functional connectivity and classify the features of these changes. Although complexity of EEG signals can also reflect AD-related changes, few machine learning studies have focused on the changes in complexity. Therefore, in this study, we compared the ability of EEG signals to detect characteristics of AD using different machine learning approaches one focused on functional connectivity and the other focused on signal complexity. We examined functional connectivity, estimated by phase lag index (PLI) in EEG signals in healthy older participants [healthy control (HC)] and patients with AD. We estimated signal complexity using multi-scale entropy. Utilizing a support vector machine, we compared the identification accuracy of AD based on functional connectivity at each frequency band and complexity component. Additionally, we evaluated the relationship between synchronization and complexity. The identification accuracy of functional connectivity of the alpha, beta, and gamma bands was significantly high (AUC 1.0), and the identification accuracy of complexity was sufficiently high (AUC 0.81). Moreover, the relationship between functional connectivity and complexity exhibited various temporal-scale-and-regional-specific dependency in both HC participants and patients with AD. In conclusion, the combination of functional connectivity and complexity might reflect complex pathological process of AD. Applying a combination of both machine learning methods to neurophysiological data may provide a novel understanding of the neural network processes in both healthy brains and pathological conditions., (Copyright © 2020 Nobukawa, Yamanishi, Kasakawa, Nishimura, Kikuchi and Takahashi.)

Case: We present a rare case of extraskeletal para-articular osteochondroma (ESPAOC) in the ankle of a 9-year-old boy, which was causing pain and limiting the range of motion of the ankle joint. The lesion might have also contributed to the deformity of the medial aspect of the talus. Total resection resolved all of the symptoms, with no recurrence at 1-year postoperatively., Conclusion: Operative excision should be considered when ESPAOC directly restricts ankle motion because it can lead to chronic pain and joint degeneration if left untreated.

Soft tissue myoepithelial tumors are very rare mesenchymal tumors that are currently categorized as miscellaneous neoplasms with uncertain differentiation. Although the molecular pathogenesis of soft tissue myoepithelial tumors remains unclear, EWSR1 gene fusions with a variety of partner genes are regarded as one of the major pathogenic driver events in these tumors. We herein present a case of a deep soft tissue malignant myoepithelial tumor arising in the thigh with multiple pulmonary metastases. This tumor displayed diverse and unique histological features, namely, an epithelioid glandular growth pattern, pseudorosette-like formation, and a diffuse nest and cord-like pattern within an abundant myxoid matrix. Next-generation RNA sequencing identified a novel fusion transcript, in which the in-frame junctional reads contained exon 9 of EWSR1 and exon 2 of VGLL1, resulting in the formation of a putative chimeric protein with the N-terminal transcriptional activation domain of EWSR1 and C-terminal full length of the VGLL1 protein. EWSR1-VGLL1 fusion has not been described in neoplasm before. Further molecular and functional experiments on the present EWSR1-VGLL1 fusion gene are required to elucidate its tumorigenic effect., (© 2019 Wiley Periodicals, Inc.)

TRAF-interacting protein with a forkhead-associated (FHA) domain (TIFA), originally identified as an adaptor protein of TRAF6, has recently been shown to be involved in innate immunity, induced by a pathogen-associated molecular pattern (PAMP). ADP-β-D-manno-heptose, a newly identified PAMP, binds to alpha-kinase 1 (ALPK1) and activates its kinase activity to phosphorylate TIFA. Phosphorylation triggers TIFA oligomerisation and formation of a subsequent TIFA-TRAF6 oligomeric complex for ubiquitination of TRAF6, eventually leading to NF-κB activation. However, the structural basis of TIFA-dependent TRAF6 signalling, especially oligomer formation of the TIFA-TRAF6 complex remains unknown. In the present study, we determined the crystal structures of mouse TIFA and two TIFA mutants-Thr9 mutated to either Asp or Glu to mimic the phosphorylation state-to obtain the structural information for oligomer formation of the TIFA-TRAF6 complex. Crystal structures show the dimer formation of mouse TIFA to be similar to that of human TIFA, which was previously reported. This dimeric structure is consistent with the solution structure obtained from small angle X-ray scattering analysis. In addition to the structural analysis, we examined the molecular assembly of TIFA and the TIFA-TRAF6 complex by size-exclusion chromatography, and suggested a model for the TIFA-TRAF6 signalling complex.

Background: Primary osteosarcoma in elderly patients are rare malignant tumors. Its optimal treatment has not yet been determined., Methods: This retrospective study included 104 patients aged >50 years with resectable, non-metastatic osteosarcoma treated by the members of the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group. The effects of adjuvant chemotherapy were estimated by comparing outcomes in patients who received surgery plus chemotherapy with those who underwent surgery alone., Results: Median age at presentation was 59 years. Neoadjuvant and adjuvant chemotherapy was administered to 83 (79.8%) patients. Patients who underwent surgery plus chemotherapy and those who underwent surgery alone had 5-year overall survival (OS) rates of 68.6% and 71.7%, respectively (p = 0.780), and 5-year relapse free survival (RFS) rates of 48.2% and 43.6%, respectively (p = 0.64). Univariate analysis showed that resection with wide margins was significantly correlated with better prognosis., Conclusions: The addition of chemotherapy to surgery did not improve OS or RFS in patients aged >50 years with resectable, non-metastatic osteosarcoma. Surgery with wide margins was only significantly prognostic of improved survival. The effect of chemotherapy in elderly osteosarcoma patients was unclear., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Surgical strategy for significant carotid artery stenosis complicated with severe aortic valve stenosis is still controversial. Herein, we report a case of 80-year-old female in whom 78% stenosis by the NASCET criteria in left internal carotid artery was pointed out during preoperative checkup for symptomatic severe aortic stenosis. Carotid endarterectomy was done concomitantly with aortic valve replacement. No neurological complication occurred perioperatively.

The phytotoxic potential of the leaves and twigs of Schumannianthus dichotomus , discarded in the mat-making industry against four test plants (lettuce ( Lactuca sativa L.), rapeseed ( Brassica napus L.), foxtail fescue ( Vulpia myuros (L.) C.C. Gmel.) and timothy ( Phleum pratense L.)) was investigated and found strong phytotoxic activity. An assay-guided fractionation of S. dichotomus extarcts against cress ( Lepidium sativum L.) through a series of column chromatography steps yielded two compounds, 8-(5-oxo-2,5-dihydrofuran-2-yl) octanoic acid (ODFO) and ( E )-6-hydroxy-2,6-dimethylocta-2,7-dienoic acid (8-carboxylinalool). ODFO and 8-carboxylinalool showed strong phytotoxic activity against cress and timothy. The concentrations required for 50% growth inhibition ( I 50 value) of the seedlings of cress and timothy were 111.94-128.01 and 36.30-91.75 µM, respectively, for ODFO, but the values were much higher at 315.98-379.13 and 107.92-148.41 µM, respectively, for 8-carboxylinalool, indicating the stronger phytotoxic activity of ODFO. This study is the first to isolate ODFO and 8-carboxylinalool from S. dichotomus and their phytotoxic potential while ODFO is firstly encountered from any natural source. The growth inhibitory activity of the identified compounds may explain their role in the phytotoxic activity of S. dichotomus , which suggests the possible use of its leaves and twigs or its active constituents as natural bioherbicides.

Cyatheaceae (tree ferns) appeared during the Jurassic period and some of the species still remain. Those species may have some morphological and/or physiological characteristics for survival. A tree fern was observed to suppress the growth of other ligneous plants in a tropical forest. It was assumed that the fern may release toxic substances into the forest floor, but those toxic substances have not yet been identified. Therefore, we investigated the phytotoxicity and phytotoxic substances of Cyathea lepifera (J. Sm. ex Hook.) Copel. An aqueous methanol extract of C. lepifera fronds inhibited the growth of roots and shoots of dicotyledonous garden cress ( Lepidum sativum L.), lettuce ( Lactuca sativa L.), and alfalfa ( Medicago sativa L.), and monocotyledonous ryegrass ( Lolium multiflorum Lam.), timothy ( Phleum pratense L.), and barnyardgrass ( Echinochloa crus-galli (L.) P. Beauv.). The results suggest that C. lepifera fronds may have phytotoxicity and contain some phytotoxic substances. The extract was purified through several chromatographic steps during which inhibitory activity was monitored, and p -coumaric acid and (-)-3-hydroxy- β -ionone were isolated. Those compounds showed phytotoxic activity and may contribute to the phytotoxic effects caused by the C. lepifera fronds. The fronds fall and accumulate on the forest floor through defoliation, and the compounds may be released into the forest soils through the decomposition process of the fronds. The phytotoxic activities of the compounds may be partly responsible for the fern's survival.

The bioassay-guided fractionation of an Okeania sp. marine cyanobacterium collected in Okinawa led to the isolation of the lipopeptide mabuniamide ( 1 ). The gross structure of 1 was determined by spectroscopic analyses, and its absolute configuration was determined using Marfey's analysis of the acid hydrolysate of 1 . The absolute configuration of 1 was confirmed by total synthesis. Mabuniamide ( 1 ) stimulated glucose uptake in cultured rat L6 myotubes. In addition, mabuniamide ( 1 ) and its stereoisomer ( 2 ) exhibited moderate antimalarial activity.