Small Cell Carcinoma of the Tonsil Treated with Irinotecan and Cisplatin: A Case Report and Literature Review

We report a rare case of extrapulmonary small cell carcinoma arising in the palatine tonsil treated by combined chemotherapy with irinotecan/cisplatin following irradiation therapy. This chemotherapy regimen was recently found to be effective for small cell lung carcinoma. Our case is the first report of combined irinotecan/cisplatin chemotherapy to treat extrapulmonary small cell carcinoma of the oropharynx

AlzPathway: a comprehensive map of signaling pathways of Alzheimer’s disease

BACKGROUND: Alzheimer’s disease (AD) is the most common cause of dementia among the elderly. To clarify pathogenesis of AD, thousands of reports have been accumulating. However, knowledge of signaling pathways in the field of AD has not been compiled as a database before. DESCRIPTION: Here, we have constructed a publicly available pathway map called “AlzPathway” that comprehensively catalogs signaling pathways in the field of AD. We have collected and manually curated over 100 review articles related to AD, and have built an AD pathway map using CellDesigner. AlzPathway is currently composed of 1347 molecules and 1070 reactions in neuron, brain blood barrier, presynaptic, postsynaptic, astrocyte, and microglial cells and their cellular localizations. AlzPathway is available as both the SBML (Systems Biology Markup Language) map for CellDesigner and the high resolution image map. AlzPathway is also available as a web service (online map) based on Payao system, a community-based, collaborative web service platform for pathway model curation, enabling continuous updates by AD researchers. CONCLUSIONS: AlzPathway is the first comprehensive map of intra, inter and extra cellular AD signaling pathways which can enable mechanistic deciphering of AD pathogenesis. The AlzPathway map is accessible at http://alzpathway.org/

Counts-in-Cylinders in the Sloan Digital Sky Survey with Comparisons to N-body Simulations

Environmental statistics provide a necessary means of comparing the properties of galaxies in different environments and a vital test of models of galaxy formation within the prevailing, hierarchical cosmological model. We explore counts-in-cylinders, a common statistic defined as the number of companions of a particular galaxy found within a given projected radius and redshift interval. Galaxy distributions with the same two-point correlation functions do not necessarily have the same companion count distributions. We use this statistic to examine the environments of galaxies in the Sloan Digital Sky Survey, Data Release 4. We also make preliminary comparisons to four models for the spatial distributions of galaxies, based on N-body simulations, and data from SDSS DR4 to study the utility of the counts-in-cylinders statistic. There is a very large scatter between the number of companions a galaxy has and the mass of its parent dark matter halo and the halo occupation, limiting the utility of this statistic for certain kinds of environmental studies. We also show that prevalent, empirical models of galaxy clustering that match observed two- and three-point clustering statistics well fail to reproduce some aspects of the observed distribution of counts-in-cylinders on 1, 3 and 6-Mpc/h scales. All models that we explore underpredict the fraction of galaxies with few or no companions in 3 and 6-Mpc/h cylinders. Roughly 7% of galaxies in the real universe are significantly more isolated within a 6 Mpc/h cylinder than the galaxies in any of the models we use. Simple, phenomenological models that map galaxies to dark matter halos fail to reproduce high-order clustering statistics in low-density environments.Comment: 17 pages, 10 figures. Accepted, Ap

Identification of candidate molecular targets of the novel antineoplastic antimitotic NP-10

We previously reported the identification of a novel antimitotic agent with carbazole and benzohydrazide structures: N′-[(9-ethyl-9H-carbazol-3-yl)methylene]-2-iodobenzohydrazide (code number NP-10). However, the mechanism(s) underlying the cancer cell-selective inhibition of mitotic progression by NP-10 remains unclear. Here, we identified NP-10-interacting proteins by affinity purification from HeLa cell lysates using NP-10-immobilized beads followed by mass spectrometry. The results showed that several mitosis-associated factors specifically bind to active NP-10, but not to an inactive NP-10 derivative. Among them, NUP155 and importin β may be involved in NP-10-mediated mitotic arrest. Because NP-10 did not show antitumor activity in vivo in a previous study, we synthesized 19 NP-10 derivatives to identify more effective NP-10-related compounds. HMI83-2, an NP-10-related compound with a Cl moiety, inhibited HCT116 cell tumor formation in nude mice without significant loss of body weight, suggesting that HMI83-2 is a promising lead compound for the development of novel antimitotic agents

Leishmania major Strain-Dependent Macrophage Activation Contributes to Pathogenicity in the Absence of Lymphocytes

Infection of C57BL/6 wild-type mice with Leishmania major 5-ASKH or Friedlin strains results in relatively similar pathogenicity with self-healing lesions within weeks. Parasite clearance depends on nitric oxide production by activated macrophages in response to cytokines produced mainly by CD41 Th1 cells. In contrast, C57BL/6 Rag2 knockout mice, which lack T and B lymphocytes, show distinct pathologies during infection with these strains. Despite of the similar parasite number, the 5-ASKH infection induced severe inflammation rather than the Friedlin. To determine the immunological factors behind this phenomenon, we infected C57BL/6 Rag2 knockout mice with these two strains and compared immune cell kinetics and macrophage activation status. Compared with the Friedlin strain, the 5-ASKH strain elicited increased pathology associated with the accumulation of CD11bhigh, Ly6Ghigh neutrophils by week four and increased the expression of macrophage activation markers. We then analyzed the differentially expressed transcripts in infected bone marrow-derived macrophages by RNA sequencing. It showed upregulation of multiple inflammatory transcripts, including Toll-like receptor 1/2 (TLR1/2), CD69, and CARD14, upon 5-ASKH infection. Our findings suggest that different L. major strains can trigger distinct macrophage activation, contributing to the disease outcome observed in the absence of lymphocytes but not in the presence of lymphocytes

Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)

Human glucosylcerebrosidase 2 (GBA2) of the CAZy family GH116 is responsible for the breakdown of glycosphingolipids on the cytoplasmic face of the endoplasmic reticulum and Golgi apparatus. Genetic defects in GBA2 result in spastic paraplegia and cerebellar ataxia, while cross-talk between GBA2 and GBA1 glucosylceramidases may affect Gaucher disease. Here, we report the first three-dimensional structure for any GH116 enzyme, Thermoanaerobacterium xylanolyticum TxGH116 β-glucosidase, alone and in complex with diverse ligands. These structures allow identification of the glucoside binding and active site residues, which are shown to be conserved with GBA2. Mutagenic analysis of TxGH116 and structural modeling of GBA2 provide a detailed structural and functional rationale for pathogenic missense mutations of GBA2

The Galaxy Content of SDSS Clusters and Groups

Imaging data from the Sloan Digital Sky Survey are used to characterize the population of galaxies in groups and clusters detected with the MaxBCG algorithm. We investigate the dependence of Brightest Cluster Galaxy (BCG) luminosity, and the distributions of satellite galaxy luminosity and satellite color, on cluster properties over the redshift range 0.1 < z < 0.3. The size of the dataset allows us to make measurements in many bins of cluster richness, radius and redshift. We find that, within r_200 of clusters with mass above 3e13 h-1 M_sun, the luminosity function of both red and blue satellites is only weakly dependent on richness. We further find that the shape of the satellite luminosity function does not depend on cluster-centric distance for magnitudes brighter than ^{0.25}M_i - 5log(h) < -19. However, the mix of faint red and blue galaxies changes dramatically. The satellite red fraction is dependent on cluster-centric distance, galaxy luminosity and cluster mass, and also increases by ~5% between redshifts 0.28 and 0.2, independent of richness. We find that BCG luminosity is tightly correlated with cluster richness, scaling as L_{BCG} ~ M_{200}^{0.3}, and has a Gaussian distribution at fixed richness, with sigma_{log L} ~ 0.17 for massive clusters. The ratios of BCG luminosity to total cluster luminosity and characteristic satellite luminosity scale strongly with cluster richness: in richer systems, BCGs contribute a smaller fraction of the total light, but are brighter compared to typical satellites. This study demonstrates the power of cross-correlation techniques for measuring galaxy populations in purely photometric data.Comment: 22 pages, 14 figures, submitted to Ap

SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression

臓器チップ技術を用いて新型コロナウイルスが血管へ侵入するメカニズムを解明 --Claudin-5発現抑制による呼吸器の血管内皮バリア破壊--. 京都大学プレスリリース. 2022-09-22.A study using an organ-on-a-chip reveals a mechanism of SARS-CoV-2 invasion into blood vessels --Disruption of vascular endothelial barrier in respiratory organs by decreasing Claudin-5 expression--. 京都大学プレスリリース. 2022-09-27.In the initial process of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects respiratory epithelial cells and then transfers to other organs the blood vessels. It is believed that SARS-CoV-2 can pass the vascular wall by altering the endothelial barrier using an unknown mechanism. In this study, we investigated the effect of SARS-CoV-2 on the endothelial barrier using an airway-on-a-chip that mimics respiratory organs and found that SARS-CoV-2 produced from infected epithelial cells disrupts the barrier by decreasing Claudin-5 (CLDN5), a tight junction protein, and disrupting vascular endothelial cadherin–mediated adherens junctions. Consistently, the gene and protein expression levels of CLDN5 in the lungs of a patient with COVID-19 were decreased. CLDN5 overexpression or Fluvastatin treatment rescued the SARS-CoV-2–induced respiratory endothelial barrier disruption. We concluded that the down-regulation of CLDN5 expression is a pivotal mechanism for SARS-CoV-2–induced endothelial barrier disruption in respiratory organs and that inducing CLDN5 expression is a therapeutic strategy against COVID-19