Successful treatment of pediatric patients with high-grade gliomas featuring leptomeningeal metastases by targeting BRAF V600E mutations with dabrafenib plus trametinib: two illustrative cases.

A combination of BRAF and MEK inhibitors is reported to be effective for gliomas with the BRAF V600E mutation; however, its efficacy in gliomas with leptomeningeal metastases (LMM) is still unknown. In this report, we describe two pediatric patients with high-grade glioma featuring the BRAF V600E mutation who were treated with dabrafenib and trametinib for LMM. Both 2 cases underwent craniotomy for primary intracranial lesions and were diagnosed as a high-grade glioma with BRAF V600E mutation; one case was consistent with anaplastic pleomorphic xanthoastorocytoma, the other was epithelioid glioblastoma. They received standard treatment for the lesions but subsequently were found to have new lesions including multiple spinal dissemination. We started administering dabrafenib and trametinib. Within a few days of starting treatment, the symptoms improved dramatically and MRI performed one month after the prescription of the two drugs demonstrated remission of both brain and spinal lesions. This report shows that dabrafenib and trametinib are effective not only for recurrent lesions but also for LMM in pediatric patients.

Unmanageable Cerebrospinal Fluid Leakage With Eosinophilic Meningitis in a Gliadel Wafer Implant Patient.

Gliadel wafer implants (Eisai Inc., Woodcliff Lake, NJ, USA) have shown their efficacy in prolonging survival in patients with malignant gliomas. The safety of Gliadel wafers has also been reported; however, there is a certain risk of adverse events. We present a rare case of refractory cerebrospinal fluid (CSF) leakage with eosinophilic meningitis in a patient with glioblastoma who underwent tumor resection with Gliadel wafer implants. A 60-year-old man presented with a glioblastoma in the right temporal lobe. The patient underwent tumor resection with Gliadel wafer implants. During the postoperative course, the patient presented with intractable CSF leakage and the development of a pseudomeningocele. A delayed rise in blood and CSF eosinophil count (a few weeks after the primary operation) and positive drug-induced lymphocyte stimulation test (DLST) results against the Gliadel wafer led to the diagnosis of an allergic reaction to these implants. Removal of the Gliadel wafers resolved the eosinophilic reaction; however, the patient subsequently required a shunt procedure for persistent hydrocephalus. This case highlights the importance of investigating rare causes of refractory CSF leakage and hydrocephalus due to allergic reactions to Gliadel wafers. Delayed elevations of eosinophils in blood and CSF tests may lead to a diagnosis of eosinophilic meningitis. DLST against Gliadel wafers is also useful for diagnosis when it is available. To control the hydrocephalus, not only the shunt procedure but also wafer removal must be considered; however, patients with limited life expectancy are generally hesitant to undergo such additional procedures.

How I do it: Sternocleidomastoid sparing approach for the right vertebral artery to common carotid artery transposition.

BACKGROUND: Direct surgery is an important option to treat vertebral artery (VA) stenosis. METHOD: A patient with symptomatic stenosis at the origin of the right VA underwent transposition of the right VA to the common carotid artery (CCA). Using the sternocleidomastoid sparing approach, the VA was anastomosed to the posterior wall of the CCA by twisting the CCA to expose its posterior wall to face the operative field. CONCLUSION: This approach, consisting of securing the proximal VA and then following it to its distal end, not only preserves the sternocleidomastoid muscle but also protects the sympathetic chains and thoracic duct.

Brain-derived neurotrophic factor (BDNF) induces antagonistic action to Nogo signaling by the upregulation of lateral olfactory tract usher substance (LOTUS) expression.

Neurons in the central nervous system (CNS) have limited capacity for axonal regeneration after trauma and neurological disorders due to an endogenous nonpermissive environment for axon regrowth in the CNS. Lateral olfactory tract usher substance (LOTUS) contributes to axonal tract formation in the developing brain and axonal regeneration in the adult brain as an endogenous Nogo receptor-1 (NgR1) antagonist. However, how LOTUS expression is regulated remains unclarified. This study examined molecular mechanism of regulation in LOTUS expression and found that brain-derived neurotrophic factor (BDNF) increased LOTUS expression in cultured hippocampal neurons. Exogenous application of BDNF increased LOTUS expression at both mRNA and protein levels in a dose-dependent manner. We also found that pharmacological inhibition with K252a and gene knockdown by siRNA of tropomyosin-related kinase B (TrkB), BDNF receptor suppressed BDNF-induced increase in LOTUS expression. Further pharmacological analysis of the TrkB signaling pathway revealed that BDNF increased LOTUS expression through mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) cascades, but not phospholipase C-γ (PLCγ) cascade. Additionally, treatment with c-AMP response element binding protein (CREB) inhibitor partially suppressed BDNF-induced LOTUS expression. Finally, neurite outgrowth assay in cultured hippocampal neurons revealed that BDNF treatment-induced antagonism for NgR1 by up-regulating LOTUS expression. These findings suggest that BDNF may acts as a positive regulator of LOTUS expression through the TrkB signaling, thereby inducing an antagonistic action for NgR1 function by up-regulating LOTUS expression. Also, BDNF may synergistically affect axon regrowth through the upregulation of LOTUS expression.

The uric acid-urea distribution volume ratio is a potential marker of hydration status in patients on hemodialysis.

The distribution volume of uric acid is affected by the amount of extracellular water (ECW), while urea distribution volume can be considered as total body water (TBW). Thus, the ratio of distribution volumes of uric acid and urea can be paralleled to and be considered as the proxy of ECW/TBW. A total of 108 patients at our facility was included. The uric acid and urea distribution volume ratio (UUVdR) calculated from the single-pool model, which was measured within 1 month of the time when the bioimpedance index was measured. ECW/TBW at the end of the HD session was measured by InBody S10. We investigated the association between the UUVdR and the ECW/TBW values and the factors affecting the residuals of the regression equation. We also evaluated the predictive ability of overhydration or dehydration in randomly selected two groups, i.e., the training group and the validation group. ECW/TBW correlated highly with UUVdR. Multivariate analysis demonstrated that only creatinine and ECW/TBW were significantly associated with regression residuals. The cutoff values of UUVdR for overhydration and dehydration were 0.666 and 0.579, respectively, in the training group. Their AUC were 0.872 and 0.898, respectively. The sensitivity and specificity values in the validation group were 0.571 and 0.868 for overhydration, and 0.444 and 0.953 for dehydration, respectively. UUVdR might be a proxy of hydration status in hemodialysis patients. It may be possible to predict hydration status without dedicated devices in the epidemiological study.

LOTUS suppresses amyloid ß-induced dendritic spine elimination through the blockade of amyloid ß binding to PirB.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide but has no effective treatment. Amyloid beta (Aß) protein, a primary risk factor for AD, accumulates and aggregates in the brain of patients with AD. Paired immunoglobulin-like receptor B (PirB) has been identified as a receptor of Aß and Aß-PirB molecular interactions that cause synapse elimination and synaptic dysfunction. PirB deletion has been shown to suppress Aß-induced synaptic dysfunction and behavioral deficits in AD model mice, implying that PirB mediates Aß-induced AD pathology. Therefore, inhibiting the Aß-PirB molecular interaction could be a successful approach for combating AD pathology. We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of type1 Nogo receptor and PirB and that LOTUS overexpression promotes neuronal regeneration following damage to the central nervous system, including spinal cord injury and ischemic stroke. Therefore, in this study, we investigated whether LOTUS inhibits Aß-PirB interaction and Aß-induced dendritic spine elimination. METHODS: The inhibitory role of LOTUS against Aß-PirB (or leukocyte immunoglobulin-like receptor subfamily B member 2: LilrB2) binding was assessed using a ligand-receptor binding assay in Cos7 cells overexpressing PirB and/or LOTUS. We assessed whether LOTUS inhibits Aß-induced intracellular alterations and synaptotoxicity using immunoblots and spine imaging in a primary cultured hippocampal neuron. RESULTS: We found that LOTUS inhibits the binding of Aß to PirB overexpressed in Cos7 cells. In addition, we found that Aß-induced dephosphorylation of cofilin and Aß-induced decrease in post-synaptic density-95 expression were suppressed in cultured hippocampal neurons from LOTUS-overexpressing transgenic (LOTUS-tg) mice compared with that in wild-type mice. Moreover, primary cultured hippocampal neurons from LOTUS-tg mice improved the Aß-induced decrease in dendritic spine density. Finally, we studied whether human LOTUS protein inhibits Aß binding to LilrB2, a human homolog of PirB, and found that human LOTUS inhibited the binding of Aß to LilrB2 in a similar manner. CONCLUSIONS: This study implied that LOTUS improved Aß-induced synapse elimination by suppressing Aß-PirB interaction in rodents and inhibited Aß-LilrB2 interaction in humans. Our findings revealed that LOTUS may be a promising therapeutic agent in counteracting Aß-induced AD pathologies.

Impact of Dissipation on Universal Fluctuation Dynamics in Open Quantum Systems.

Recent theoretical and experimental works have explored universal dynamics related to surface growth physics in isolated quantum systems. In this Letter, we theoretically elucidate that dissipation drastically alters universal particle-number-fluctuation dynamics associated with surface-roughness growth in one-dimensional free fermions and bosons. In a system under dephasing that causes loss of spatial coherence, we numerically find that a universality class of surface-roughness dynamics changes from the ballistic class to a class with the Edwards-Wilkinson scaling exponents and an unconventional scaling function. We provide the analytical derivation of the diffusion equation from the dephasing Lindblad equation via a renormalization-group technique and succeed in explaining the drastic change. Furthermore, we numerically find the same change of the universality class under a more nontrivial dissipation, i.e., symmetric incoherent hopping.

A case of early recurrent immunoglobulin A nephropathy and T-cell-mediated rejection in a transplant patient with Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is an X-chromosome recessive immunodeficiency disease characterized by the triad of thrombocytopenia, eczema, and susceptibility to infection owing to WAS protein gene abnormalities. Kidney transplantation is rarely offered to WAS patients with end-stage renal disease because of concerns that thrombocytopenia and immune disorders may affect the clinical outcome. Here, we report the case of a 20-year-old kidney transplant patient who developed end-stage renal disease owing to immunoglobulin (Ig)A nephropathy caused by WAS. Despite recurrent IgA nephropathy and T-cell-mediated rejection 7 months after transplantation, two rounds of steroid pulse therapy attenuated his renal function and urinary abnormality. His serum creatinine level was maintained at approximately 1.5 mg/dL 1 year after transplantation. No other WAS-related complications were observed throughout the clinical course. Although WAS can cause poor prognosis in kidney transplant patients, careful follow-up may allow kidney transplantation to be performed.

Dynamical Scaling of Surface Roughness and Entanglement Entropy in Disordered Fermion Models.

Localization is one of the most fundamental interference phenomena caused by randomness, and its universal aspects have been extensively explored from the perspective of one-parameter scaling mainly for static properties. We numerically study dynamics of fermions on disordered one-dimensional potentials exhibiting localization and find dynamical one-parameter scaling for surface roughness, which represents particle-number fluctuations at a given length scale, and for entanglement entropy when the system is in delocalized phases. This dynamical scaling corresponds to the Family-Vicsek scaling originally developed in classical surface growth, and the associated scaling exponents depend on the type of disorder. Notably, we find that partially localized states in the delocalized phase of the random-dimer model lead to anomalous scaling, where destructive interference unique to quantum systems leads to exponents unknown for classical systems and clean systems.

Observation of domain wall bimerons in chiral magnets.

Topological defects embedded in or combined with domain walls have been proposed in various systems, some of which are referred to as domain wall skyrmions or domain wall bimerons. However, the experimental observation of such topological defects remains an ongoing challenge. Here, using Lorentz transmission electron microscopy, we report the experimental discovery of domain wall bimerons in chiral magnet Co-Zn-Mn(110) thin films. By applying a magnetic field, multidomain structures develop, and simultaneously, chained or isolated bimerons arise as the localized state between the domains with the opposite in-plane components of net magnetization. The multidomain formation is attributed to magnetic anisotropy and dipolar interaction, and domain wall bimerons are stabilized by the Dzyaloshinskii-Moriya interaction. In addition, micromagnetic simulations show that domain wall bimerons appear for a wide range of conditions in chiral magnets with cubic magnetic anisotropy. Our results promote further study in various fields of physics.

LOTUS, an endogenous Nogo receptor antagonist, is involved in synapse and memory formation.

The Nogo signal is involved in impairment of memory formation. We previously reported the lateral olfactory tract usher substance (LOTUS) as an endogenous antagonist of the Nogo receptor 1 that mediates the inhibition of axon growth and synapse formation. Moreover, we found that LOTUS plays an essential role in neural circuit formation and nerve regeneration. However, the effects of LOTUS on synapse formation and memory function have not been elucidated. Here, we clearly showed the involvement of LOTUS in synapse formation and memory function. The cultured hippocampal neurons derived from lotus gene knockout (LOTUS-KO) mice exhibited a decrease in synaptic density compared with those from wild-type mice. We also found decrease of dendritic spine formation in the adult hippocampus of LOTUS-KO mice. Finally, we demonstrated that LOTUS deficiency impairs memory formation in the social recognition test and the Morris water maze test, indicating that LOTUS is involved in functions of social and spatial learning and memory. These findings suggest that LOTUS affects synapse formation and memory function.

Family-Vicsek Scaling of Roughness Growth in a Strongly Interacting Bose Gas.

Family-Vicsek scaling is one of the most essential scale-invariant laws emerging in surface-roughness growth of classical systems. In this Letter, we theoretically elucidate the emergence of the Family-Vicsek scaling even in a strongly interacting quantum bosonic system by introducing a surface-height operator. This operator is comprised of a summation of local particle-number operators at a simultaneous time, and thus the observation of the surface roughness in the quantum many-body system and its scaling behavior are accessible to current experiments of ultracold atoms.

Donor-Recipient Body Weight Mismatch May Affect Glomerular Basement Membrane Thinning in Electron Microscopic Examination of 1-Hour Renal Allograft Biopsy Specimens.

BACKGROUND: Although an association between body weight mismatch and impaired graft function has been reported, few histologic studies have evaluated this issue, especially using electric microscopic analysis. During routine observations, we have noted a thin glomerular basement membrane (GBM) in the 1-hour biopsy specimen in cases with an overweight recipient and a lightweight donor. Therefore, we hypothesized that donor-recipient body weight mismatch affects the GBM thickness in the 1-hour biopsy specimen. The aim of the present study was to clarify the effect of donor-recipient body weight mismatch on the GBM thickness of the 1-hour biopsy specimen measured using electron microscopy. METHODS: We used an electron microscope to measure the GBM thickness of specimens at 1-hour post-transplantation (n = 24) and at 1 year post-transplantation (n = 17). The GBM thickness of cases with donor-recipient body weight mismatch was compared with those without mismatch. In accordance with a previous study, we defined a donor/recipient body weight ratio of less than 0.9 as donor-recipient body weight mismatch and a ratio of more than 0.9 as no mismatch. RESULTS: At 1-hour post-transplantation, the mean GBM was significantly thinner in the mismatch group than in the nonmismatch group. However, at 1-year post-transplantation, the mean GBM thickness did not significantly differ between the 2 groups. CONCLUSIONS: The GBM thickness at 1-hour post-transplantation is thinner in cases with donor-recipient body weight mismatch than in cases without mismatch. This implies that donor-recipient body weight mismatch may have to be considered when assessing donor-derived thin GBM disease using the 1-hour biopsy specimen.

Can Lipofuscin Deposition on Renal Allograft Tubular Epithelium Be a Surrogate Marker for Kidney Allograft Aging?

BACKGROUND: Lipofuscin is an indicator of aging. We examined the clinicopathologic significance of lipofuscin deposition in the renal tubules of renal allografts. METHOD: We analyzed allograft biopsy specimens from living kidney transplantations from January to December 2015. For controls, we analyzed native kidney biopsy specimens obtained from January 2015 to December 2016. We identified granules with a yellow-to-tan shade in renal tubules as lipofuscin. RESULTS: The donor age at transplantation was significantly older in lipofuscin deposition biopsy specimens than in those without, whereas the time after transplantation age was not different between the 2 groups with renal allografts. In native kidney biopsies, age at biopsy was significantly older in lipofuscin deposition biopsy specimens than in those without. We compared "massive lipofuscin deposition," defined as lipofuscin deposition on both sides of 3 or more renal tubules, and donor-age matched control allograft biopsies without lipofuscin deposition. Comparing these 2 groups, recipient age at transplantation was significantly older in the massive lipofuscin deposition group. CONCLUSION: Lipofuscin deposition on tubular epithelium is not a surrogate marker of aging of kidneys allografts, although lipofuscin deposition was significantly greater in older tissues from native kidneys. The older age of recipients may be associated with massive lipofuscin deposition in renal allografts.

Vasa recta hyalinosis reflects severe arteriolopathy in renal allografts.

AIM: We examined the clinicopathologic significance of hyalinosis in the vasa recta in the medulla of allograft kidney biopsies. METHOD: We analyzed biopsy specimens from January 2010 to December 2015, obtained from both the cortex and medulla (including the vasa recta) ≥ 1 year after living-donor kidney transplantation. We excluded biopsy specimens from recipients who had undergone transplantation due to diabetic nephropathy or who had diabetes mellitus after transplantation. We evaluated hyaline arteriolopathy in the cortex using the aah score determined by the Banff 2007 classification. RESULT: Among 381 biopsy specimens obtained from 248 transplant recipients ≥ 1 year after transplantation, 36 specimens obtained from 34 recipients showed vasa recta hyalinosis (VRH) in the medulla. Among these 36 specimens, 17 had a score of aah3, 16 had a score of aah2, and 3 had a score of aah1. The incidence of VRH was 1.9% at ≥ 1 to < 4 years, 7.1% at ≥ 4 to < 8 years, and 50.0% at ≥ 8 years. The aah scores and the proportion of hyalinosis in the arteriolar media among all muscular arterioles in the cortex were significantly higher in the VRH group at ≥ 8 years in the late-phase biopsy (P < 0.01). The graft survival was worse in the VRH group (P = 0.024), although there was no significant difference in the graft survival between the ≥ aah2 and < aah2 groups at ≥ 8 years in the late-phase biopsy (P = 0.159). CONCLUSION: VRH in renal allografts reflects severe arteriolopathy of the cortex. VRH in the late-phase biopsy may be a prognostic factor for graft survival.

Spin-Orbital-Angular-Momentum Coupled Bose-Einstein Condensates.

We demonstrate coupling between the atomic spin- and orbital-angular momentum (OAM) of the atom's center-of-mass motion in a Bose-Einstein condensate (BEC). The coupling is induced by Raman-dressing lasers with a Laguerre-Gaussian beam and creates coreless vortices in an F=1 ^{87}Rb spinor BEC. We observe correlations between spin and OAM in the dressed state and characterize the spin texture; the result is in good agreement with the theory. In the presence of the Raman field, our dressed state is stable for 0.1 s or longer, and it decays due to collision-induced relaxation. As we turn off the Raman beams, the vortex cores in the bare spin |m_{F}=1⟩ and |-1⟩ split. These spin-OAM coupled systems with the Raman-dressing approach have great potential for exploring new topological textures and quantum states.

Structure-associated Functional Control of TX-1877 Series by Glyco-conjugation.

BACKGROUND/AIM: Sugar molecules are often used as a tool to structurally modify chemical compounds. The features of synthesized sugar-conjugated TX-1877 derivatives were herein examined. MATERIALS AND METHODS: The molecular stabilities (reactivity) and hydrophobicities of sugar (e.g., monosaccharide and tetra-O-acetylated monosaccharide)-conjugated TXs were analyzed using a molecular simulation (e.g. molecular mechanics (MM) and molecular orbital (MO) analysis). RESULTS: The hydrophobicities of TX-1877 derivatives were increased by tetra-O-acetylation, and TX-2244 exhibited the most potent radiosensitizing activity (enhancement ratio: ER=2.30). CONCLUSION: The conformations and hydrophobicities of chemical compounds may be controlled by adding monosaccharide- and tetra-O-acetyl-conjugated sugars to TX-1877.

Interlobular hyaline arteriopathy reflects severe arteriolopathy in renal allografts.

AIM: The present study was performed to examine the clinicopathological significance of hyaline deposits in the smooth muscle of the interlobular artery (interlobular hyaline arteriopathy [IHA]) in renal allografts. METHODS: Tissue specimens that included the interlobular artery from biopsies performed from January 2012 to December 2015, as well as specimens from biopsies performed ≥1 year after living kidney transplantation were analyzed. Biopsies of recipients with new-onset diabetes mellitus after transplantation were excluded, as well as those of recipients who had undergone transplantation because of diabetic nephropathy. Arteriolopathy was evaluated using the aah score determined by the Banff 2007 classification. RESULTS: In total, 51 specimens with IHA lesions were identified among 381 biopsies obtained from 243 recipients performed ≥1 year after kidney transplantation. Among these 51 biopsies, 18 specimens had a score of aah3, 29 had a score of aah2, and four had a score of aah1. The incidence of IHA lesions was 3.6% at ≥1 to <4 years, 18.5% at ≥4 to <8 years, and 54.1% at ≥8 years. Older kidney grafts exhibited more IHA lesions. Among the biopsy specimens obtained ≥8 years after transplantation, no significant differences in the recipient or donor age, duration after transplantation, or prevalence of hypertension were observed between the IHA and non-IHA groups. The aah scores were significantly higher in the IHA group ≥8 years after transplantation as determined by the mean score test (P < 0.01). CONCLUSION: IHA in renal allografts is associated with severe arteriolopathy.

Interactive Analysis of TX-1123 with Cyclo-oxygenase: Design of COX2 Selective TX Analogs.

BACKGROUND: To date, two cyclo-oxygenase (COX) isoforms, COX1 and COX2, have been identified. In the present study, the COX-inhibitory activities of TX-1123 derivatives with the 2-hydroxyarylidene-4-cyclopentene-1,3-dione structure were examined, and the binding profiles of TX-1123 to COXs were analyzed using docking simulations. MATERIALS AND METHODS: X-Ray data on COX1 [protein data bank (PDB) ID=1PGG] and COX2 (PDB ID=3LN1) were used for molecular interactive simulations. The interactive profiles of TX-1123 derivatives with COXs were examined using a molecular simulation technique with Molegro Virtual Docker (CLC bio, Aarhus, Denmark). RESULTS: TX-1123 exhibited COX1-inhibitory activity [half-maximal-inhibitory concentration (IC50)=1.57×10-5 M]. The COX2 inhibitory activity of TX-1123 was potent (IC50=1.16×10-6 M), and the ratio of COX1/COX2 inhibition was 13.5. TX-1123 bound to the COX2 molecule, and the oxygen atom of the 4-cyclopentene-1,3-dione region of TX-1123 interacted with Cys26 and Gln447 of COX2. CONCLUSION: The TX-1123-binding pocket of COX2 differs from that of the COX2-selective celecoxib-binding pocket. TX-1123 exhibited a different COX2-interactive mechanism from that of celecoxib.

Fabrication of Conductive Copper Films on Flexible Polymer Substrates by Low-Temperature Sintering of Composite Cu Ink in Air.

The development of a thermal sintering method for Cu-based inks under an air atmosphere could greatly expand their application for printed electronics. However, it is well-known that Cu-based inks cannot produce conductive Cu films when sintered at low temperatures in air because Cu readily oxidizes under such conditions. In this study, we have successfully demonstrated air atmosphere sintering at low temperatures (less than 150 °C) via a simple hot plate heat treatment for producing conductive Cu films on flexible polymer substrates, using a novel Cu-based composite ink with sub-10 nm Cu nanoparticles protected with 1-amino-2-propanol with micrometer-sized Cu particles and submicrometer-sized Cu particles; oxalic acid was also added to prevent the oxidation of the Cu during sintering. The Cu films showed a minimum resistivity of 5.5 × 10-5 Ω·cm when sintered in air at 150 °C for a very short period of 10 s. To the best of our knowledge, this is the first report of sintering of Cu-based inks in air at less than 150 °C. Another novel property of the present Cu-based composite ink is the lowest reported resistivity at 80 °C under N2 flow (5.3 × 10-5 Ω·cm at 80 °C and 8.4 × 10-6 Ω·cm at 120 °C). This fast, efficient, and inexpensive technology for thermal sintering in ambient air using composite inks could be a commercially viable method for fabricating printed electronics on flexible substrates.