A temperate Earth-sized planet with tidal heating transiting an M6 star.

Temperate Earth-sized exoplanets around late-M dwarfs offer a rare opportunity to explore under which conditions planets can develop hospitable climate conditions. The small stellar radius amplifies the atmospheric transit signature, making even compact secondary atmospheres dominated by N2 or CO2 amenable to characterization with existing instrumentation1. Yet, despite large planet search efforts2, detection of low-temperature Earth-sized planets around late-M dwarfs has remained rare and the TRAPPIST-1 system, a resonance chain of rocky planets with seemingly identical compositions, has not yet shown any evidence of volatiles in the system3. Here we report the discovery of a temperate Earth-sized planet orbiting the cool M6 dwarf LP 791-18. The newly discovered planet, LP 791-18d, has a radius of 1.03 ± 0.04 R⊕ and an equilibrium temperature of 300-400 K, with the permanent night side plausibly allowing for water condensation. LP 791-18d is part of a coplanar system4 and provides a so-far unique opportunity to investigate a temperate exo-Earth in a system with a sub-Neptune that retained its gas or volatile envelope. On the basis of observations of transit timing variations, we find a mass of 7.1 ± 0.7 M⊕ for the sub-Neptune LP 791-18c and a mass of [Formula: see text] for the exo-Earth LP 791-18d. The gravitational interaction with the sub-Neptune prevents the complete circularization of LP 791-18d's orbit, resulting in continued tidal heating of LP 791-18d's interior and probably strong volcanic activity at the surface5,6.

Clinicopathologic Analysis of Primary Adrenal Diffuse Large B-Cell Lymphoma: A Reappraisal of 23 Japanese Patients Based on EBV Association and PD-L1 Expression in Tumor Cells.

Primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) is rare. We investigate 23 Japanese patients with PA-DLBCL to understand the clinicopathologic features and biological behavior of this disease. The 17 males and 6 females had a median age of 74 years (range: 40 to 86 y). Tumor cells harbored Epstein-Barr virus-encoded small RNA (EBER) in 9 (39%) samples, including samples from the 2 patients with methotrexate-associated B-cell lymphoproliferative disorder. Programmed cell death ligand 1 (PD-L1) expression was detected in tumor cells of 6 (26%) samples, including 1 EBER+ and 5 EBER- samples. Four (17%) patients exhibited an intravascular proliferating pattern, and all 4 patient samples showed positive staining for PD-L1 in tumor cells. Among those patients, 3 showed intravascular proliferating pattern accompanied by a diffuse extravascular proliferation of tumor cells, and 1 patient was diagnosed with intravascular large B-cell lymphoma. We divided the 23 patients into 3 groups: EBER+ (n=9, 39%), EBER-PD-L1+ (n=5, 22%), and EBER-PD-L1- (n=9, 39%). A comparison of the outcomes among the 3 groups showed significant differences in overall survival (P=0.034). The EBER+ group had the worst prognosis, and the EBER-PD-L1- group had the best prognosis. We also compared the outcomes among the 3 groups that received rituximab-containing chemotherapies. Both the overall survival and progression-free survival were significantly different among these groups (P<0.001 and P=0.002, respectively). In conclusion, we evaluated 3 types of PA-DLBCL and found that each had unique clinical, pathologic, and prognostic features. Our results suggested that immune senescence, iatrogenic immunodeficiency, and immune evasion contribute to the development of PA-DLBCL.

Removal of Aß Oligomers from the Blood: A Potential Therapeutic System for Alzheimer's Disease.

PURPOSE: Amyloid-ß protein (Aß) is one of the causative proteins of Alzheimer's disease. We have been developing extracorporeal blood Aß-removal systems as a method for enhancing Aß clearance from the brain. We reported previously that medical adsorbents and hemodialyzers removed Aß monomers from peripheral blood, which was associated with influx of Aß monomers from the brain into the bloodstream. Our intent here was to develop a method to promote clearance of Aß oligomers and to provide an estimate of the molecular size of intact Aß oligomers in plasma. METHODS: Two hollow-fiber devices with different pore sizes (Membranes A and B) were evaluated as removers of Aß oligomers with human plasma in vitro. The concomitant removal of Aß oligomers and monomers was investigated by using Membrane B and hexadecyl alkylated cellulose beads or polysulfone hemodialyzers. Double-filtration plasmapheresis with Membrane A was investigated as an approach for the removal of plasma Aß oligomers in humans. RESULTS: Aß oligomers were effectively removed by both Membranes A and B. The increase of Aß oligomers in plasma was observed just after the removal of plasma Aß oligomers in humans. The intact molecular size of major Aß oligomers in the plasma was estimated to be larger than albumin at approximately 60 kDa or more. Additionally, the concomitant removal of Aß monomers and oligomers evoked dissociation of larger Aß oligomers into smaller ones and monomers. CONCLUSION: Aß oligomers were cleared from plasma both in vitro and in human subjects by using hollow-fiber membranes with large pores, indicating that their intact sizes were mostly larger than 60 kDa. Aß oligomers in peripheral circulation were increased after some clearances in human. Further investigation will determine whether the Aß oligomers detected in circulation after clearance were via influx from the brain.

Concentration and Glycoform of Rituximab in Plasma of Patients with B Cell Non-Hodgkin's Lymphoma.

PURPOSE: Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. METHODS: Twenty B cell non-Hodgkin's lymphoma patients who were treated with rituximab for the first time or after more than one year's abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. RESULTS: Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. CONCLUSION: Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.

[Clinical Efficacy of Prone Positioning in Elderly Patients with Respiratory Failure after Thoracic Aortic Surgery].

In order to demonstrate the clinical efficacy of prone positioning(PP), we reviewed 2 elderly patients with respiratory failure who underwent thoracic aortic surgery. Case 1:An 80-year-old man with true thoracic aortic aneurysm (TAA) underwent total arch replacement under moderate hypothermia. Two days after surgery, PP was conducted for 3 hours to treat atelectasis and poor oxygenation. His respiratory state and oxygenation subsequently improved and he was weaned from ventilator assistance. Case 2:An 82-year-old woman with early thrombosed acute type A aortic dissection and cardiac tamponade underwent emergency primary repair of the ascending aorta under moderate hypothermia. Six days after surgery, PP was conducted for approximately 3 hours to improve oxygenation. She was weaned from the ventilator 7 days after surgery. The clinical courses of both cases after PP were uneventful. In order to improve the respiratory state of elderly patients after TAA surgery, PP is effective and useful.

Analysis of pulmonary nodules in patients with high-grade soft tissue sarcomas.

Nowadays, small pulmonary nodules are easily detectable in patients with soft tissue sarcomas (STSs) because of highly improved computed tomography (CT) technologies. The purpose of this study was to determine the frequency and significance of the pulmonary nodules detected by CT in high-grade STS patients. 124 patients with high-grade STS were retrospectively reviewed. There were 72 males (57%) and 52 females (43%). Patients' average age was 61 years (median (quartiles) 66 years (48-75), range 8-94 years). Pulmonary nodules were detected in 49 (39.5%) of 124 patients by CT scanning at first presentation. Of 49 patients with nodules at first presentation, 34 (69.4%) had benign lesions, and 13 (26.5%) had metastatic nodules. One patient (2%) had primary lung cancer and the remaining one with one nodule could not be definitively diagnosed due to a short follow-up time. 30 patients (24.1%) of 124 patients developed pulmonary nodules during their clinical progression. Seven (23.3%) had benign lesions, whereas 21 (70%) had metastatic lesions. Primary lung cancer was detected in two patients (6.7%). The size and timing of detection of a pulmonary nodule significantly affected the final clinical diagnosisby multivariate analysis. We conclude that pulmonary nodules can be detected highly frequently in patients with high-grade STSs because of improved CT technologies. Careful follow-up is needed if nodules are detected after initial treatment or during the clinical course of the disease.

Generation of thymine radicals from 6-alkoxy-5-bromo-5,6-dihydrothymine derivatives by radiolytic reduction and photolytic dehalogenation.

The reduction of 6-alkoxy-5-bromo-5,6-dihydrothymine derivatives ( 1a, b) by hydrated electrons (e aq (-)) generated in the radiolysis of deoxygenated aqueous solution was investigated. As the major products, 1-(6'-alkoxy-5',6'-dihydrothymin-5'-yl)thymines ( 6a, b), 5-(hydroxymethyl)uracil ( 8), 6-alkoxy-5,6-dihydrothymines ( 9a, b), and thymine ( 10) were produced in sufficient yields. This product distribution is indicative of the generation of 6-alkoxy-5,6-dihydrothymin-5-yl radicals ( 2a, b) as primary intermediates that undergo elimination of alkoxide ions (RO (-)) into thymine radical cations ( 3) followed by deprotonation at the N1 to form N-centered thymine radicals ( 4). The transient absorption spectra of the 5-yl radicals 2a- c were observed by means of nanosecond laser flash photolysis of 1a, b and 5-bromo-6-ethoxy-5,6-dihydrothymidine ( 1c) in deoxygenated aqueous solution, in which homolytic C5-Br bond dissociation occurred. In contrast to the reaction characteristics in aqueous solutions, the dimeric products were not obtained in acetonitrile, probably because in-cage hydrogen abstraction from the C5 methyl group by bromine atom leads to formation of methide type intermediates 20.

Product and pulse radiolysis studies on radical-ion splitting of N(1)-C(5')-linked dimer hydrates of 5-substituted uracils by one-electron reduction in anoxic aqueous solution.

Steady-state gamma-radiolysis, pulse radiolysis, and cyclic voltammetry have been performed to identify the mechanism by which N(1)-C(5')-linked homodimer hydrates [1-(6'-hydroxy-5',6'-dihydrothymin-5'-yl)thymine (2a) and [1-(5'-fluoro-6'-hydroxy-5',6'-dihydrouracil-5'-yl)-5-fluorouracil (2b)], N(1)-C(6')-linked dimer hydrate [1-(5'-hydroxy-5',6'-dihydrothymin-6'-yl)thymine (3a)], and N(1)-C(5')-linked heterodimer hydrate [1-(6'-hydroxy-5',6'-dihydrothymin-5'-yl)-5-fluorouracil (2ba)] undergo radiolytic reductive splitting to regenerate the parent monomers in anoxic aqueous solution. Radiolytic reductions of the thymine homodimer hydrates 2a and 3a by hydrated electrons (e(aq)-) regenerated the parent thymine (1a) almost quantitatively, while the 5-fluorouracil homodimer hydrates cis-2b and trans-2b afforded 1-(uracil-5'-yl)-5-fluorouracil efficiently along with a small amount of the parent 5-fluorouracil (1b). In contrast to 2b, the heterodimer hydrate analogue 2ba with noneliminating 5'-methyl substituent releases 5-fluorouracil 1b almost quantitatively in the radiolytic reduction. The pulse radiolysis studies suggested that the electron adducts are produced primarily at the thymine and 5-fluorouracil structural unit in the dimer hydrates 2a,b, respectively, in which the resulting dimer hydrate radical anion of 2b (2b*-) was more stable than that of 2a (2a*-). As characterized by pulse radiolysis and cyclic voltammetry, the 5-fluorouracil homodimer hydrate 2b bearing F-substituent at C(5') undergoes one-electron reduction to eliminate exclusively fluoride ion along with the formation of dimer hydrate C(5') radical (2b(-F)*) with oxidizing property. The formation of a possible dimer hydrate radical intermediate 2b(-F)* was also supported by the effect of amines as the reducing additives on the yields of 1b and 4b in the radiolytic reduction of 2b.

NMR structures of anti-HIV D-peptides derived from the N-terminus of viral chemokine vMIP-II.

The viral macrophage inflammatory protein-II (vMIP-II) encoded by Kaposi's sarcoma-associated herpesvirus has unique biological activities in that it blocks the cell entry by several different human immunodeficiency virus type 1 (HIV-1) strains via chemokine receptors including CXCR4 and CCR5. In this paper, we report the solution structure of all-d-amino acid peptides derived from the N-terminus of vMIP-II, which have been shown to have strong CXCR4 binding activity and potently inhibit HIV-1 entry via CXCR4, by using long mixing time two-dimensional nuclear Overhauser enhancement spectroscopy experiments. Both of all-d-peptides vMIP-II (1-10) and vMIP-II (1-21), which are designated as DV3 and DV1, respectively, have higher CXCR4 binding ability than their l-peptide counterparts. They are partially structured in aqueous solution, displaying a turn-like structure over residues 5-8. The small temperature coefficients of His-6 amide proton for both peptides also suggest the formation of a small hydrophobic pocket centered on His-6. The structural features of DV3 are very similar to the reported solution structure of all-l-peptide vMIP-II (1-10) [M.P. Crump, E. Elisseeva, J. Gong, I. Clark-Lewis, B.D. Sykes, Structure/function of human herpesvirus-8 MIP-II (1-71) and the antagonist N-terminal segment (1-10), FEBS Lett. 489 (2001) 171], which is consistent with the notion that d- and l-enantiomeric peptides can adopt mirror image conformations. The NMR structures of the d-peptides provide a structural basis to understand their mechanism of action and design new peptidomimetic analogs to further explore the structure-activity relationship of d-peptide ligand binding to CXCR4.

One-electron reduction characteristics of N(3)-substituted 5-fluorodeoxyuridines synthesized as radiation-activated prodrugs.

We designed and synthesized N(3)-substituted 5-fluorodeoxyuridines as radiation-activated prodrugs of the antitumor agent, 5-fluorodeoxyuridine (5-FdUrd). A series of 5-FdUrd derivatives possessing a 2-oxoalkyl group at the N(3)-position released 5-FdUrd in good yield via one-electron reduction initiated by hypoxic irradiation. Cytotoxicity of the 5-FdUrd derivative possessing the 2-oxocyclopentyl group (3d) was low, but was enhanced by hypoxic irradiation resulting in 5-FdUrd release.