1,394 research outputs found
Short-interval observational data to inform clinical trial design in Huntington's disease.
No full textOBJECTIVES: To evaluate candidate outcomes for disease-modifying trials in Huntington's disease (HD) over 6-month, 9-month and 15-month intervals, across multiple domains. To present guidelines on rapid efficacy readouts for disease-modifying trials. METHODS: 40 controls and 61 patients with HD, recruited from four EU sites, underwent 3 T MRI and standard clinical and cognitive assessments at baseline, 6 and 15 months. Neuroimaging analysis included global and regional change in macrostructure (atrophy and cortical thinning), and microstructure (diffusion metrics). The main outcome was longitudinal effect size (ES) for each outcome. Such ESs can be used to calculate sample-size requirements for clinical trials for hypothesised treatment efficacies. RESULTS: Longitudinal changes in macrostructural neuroimaging measures such as caudate atrophy and ventricular expansion were significantly larger in HD than controls, giving rise to consistently large ES over the 6-month, 9-month and 15-month intervals. Analogous ESs for cortical metrics were smaller with wide CIs. Microstructural (diffusion) neuroimaging metrics ESs were also typically smaller over the shorter intervals, although caudate diffusivity metrics performed strongly over 9 and 15 months. Clinical and cognitive outcomes exhibited small longitudinal ESs, particularly over 6-month and 9-month intervals, with wide CIs, indicating a lack of precision. CONCLUSIONS: To exploit the potential power of specific neuroimaging measures such as caudate atrophy in disease-modifying trials, we propose their use as (1) initial short-term readouts in early phase/proof-of-concept studies over 6 or 9 months, and (2) secondary end points in efficacy studies over longer periods such as 15 months
A new HgMn star HD 196821
No full textIn this study, we present the chemical abundance analysis of HD 196821. The spectra of HD 196821 was obtained at the TUBITAK National Observatory using the Coude Echelle spectrograph attached to the 1.5 m telescope. We determined the atmospheric parameters of HD 196821: T-eff=10600K, log g=3.6, nu(mic)=0 km/s, and [Fe/H]=0.16 dex. HD 196821 shows an overabundance of 85 times solar for Mn and 208,930 times solar for Hg. This strongly suggests that the star should be classified as an HgMn star
Radioimmunotherapy with radretumab in patients with relapsed hematologic malignancies.
No full textWe present here a systematic analysis of lymphoma and MM patients recruited into 2 clinical trials or treated with radretumab according to compassionate use, describing the biodistribution, dosimetry, safety, and clinical activity of radretumab. Methods: Uptake in lymphoma lesions, safety, and clinical activity of radretumab radioimmunotherapy (R-RIT) were evaluated in 18 relapsed lymphoma or multiple myeloma patients. Results: In 14 of 18 patients, selective tumor uptake was found; 11 of 15 lymphoma patients, including 9 of 11 with Hodgkin lymphoma (HL), were eligible for R-RIT (a priori criteria–based target-to-bone marrow ratio > 10:1 for EudraCT no. 2005-000545 or > 4:1 for EudraCT no. 2007-007241-12 at dosimetric imaging). Two HL and 1 diffuse large B cell lymphoma patient achieved complete response; 1 HL patient had partial response. Both multiple myeloma patients receiving R-RIT experienced stabilization of disease. Therefore, the overall objective response rate was 40%. Uncomplicated grade 3–4 thrombocytopenia or leukocytopenia was observed in 5 R-RIT patients, lasting 4–129 d. Conclusion: R-RIT showed a favorable benefit and risk profile in advanced relapsed lymphoma patients and induced complete response in 2 heavily pretreated, relapsed HL patients and in 1 diffuse large B cell lymphoma patient. These results warrant further exploration of R-RIT in larger phase II clinical trials
Combination of the immunocytokine F16-IL2 with doxorubicin or paclitaxel in patients with solid tumors: Results from two phase Ib trials
No full textBackground: F16-IL2 is a tumor-targeting immunocytokine composed of the antibody fragment F16 (specific to the tumor marker A1 domain of tenascin) and of human interleukin-2 (IL2). Thorough preclinical work showed that F16-IL2 localizes selectively at tumor tissues and enhances the activity of certain anticancer drugs. In these phase Ib studies, we investigated F16-IL2 in combination with doxorubicin or paclitaxel, defining the recommended dose (RD) and assessing safety, tolerability, and early signs of activity. Methods: Cohorts of pretreated patients with progressive solid tumors received weekly administrations of 6 escalating doses of doxorubicin (up to 25mg/m2) or 8 escalating doses of paclitaxel (up to 90mg/m2), combined with F16-IL2 (up to 25 MioIU of IL2 equivalent) for a maximum of 6 months. Safety and efficacy were evaluated using CTC v3.0 and RECIST criteria. Results: 18 and 28 patients, with a median age of 63 years (37-75) and 64 years (42-79), were treated in the doxorubicin and paclitaxel combination trials, respectively. Toxicity was manageable with only few reversible G4 events, no serious unexpected adverse reactions, and no treatment related deaths. The RD was defined as 25 MioIU of F16-IL2 given in combination with 25mg/m2 doxorubicin or 90mg/m2 paclitaxel weekly. Objective responses and long-lasting disease stabilizations were observed, including 4 partial responses, 2 of which in heavily pretreated NSCLC patients and 1 still ongoing after 17 months from beginning of treatment. Among the evaluable patients treated with the paclitaxel or doxorubicin combination respectively, PFS rate at 3 months is 50% and 44% (n=24 and n=16) and 1-year survival rate is 41% and 38% (n=17 and n=13). Conclusions: 25 Mio IU of F16-IL2 combined with full-dose doxorubicin or paclitaxel can be safely and repeatedly administered weekly to patients with solid tumors, and showed early signs of clinical activity. Based on preclinical evidence, these combination regimens are being administered to breast cancer patients in phase II trials. Moreover, starting from the observed promising signs of activity, a study of F16-IL2 in lung cancer patients is being planned
Expression of the oncofetal ED-B-containing fibronectin isoform in hematologic tumors enables ED-B-targeted 131I-L19SIP radioimmunotherapy in Hodgkin lymphoma patients
No full textCurrent treatment of hematologic malignancies involves rather unspecific chemotherapy, frequently resulting in severe adverse events. Thus, modern clinical research focuses on compounds able to discriminate malignant from normal tissues. Being expressed in newly formed blood vessels of solid cancers but not in normal mature tissues, the extradomain B of fibronectin (ED-B FN) is a promising target for selective cancer therapies. Using immunohistology with a new epitope retrieval technique for paraffin-embedded tissues, ED-B FN expression was found in biopsies from more than 200 Hodgkin and non-Hodgkin lymphoma patients of nearly all entities, and in patients with myeloproliferative diseases. ED-B FN expression was nearly absent in normal lymph nodes (n = 10) and bone marrow biopsies (n = 9). The extent of vascular ED-B FN expression in lymphoma tissues was positively correlated with grade of malignancy. ED-B FN expression was enhanced in lymph nodes with severe lymphadenopathy and in some hyperplastic tonsils. The in vivo accessibility of ED-B FN was confirmed in 3 lymphoma patients, in whom the lymphoma lesions were visualized on scintigraphy with (131)I-labeled L19 small immunoprotein ((131)I-L19SIP). In 2 relapsed Hodgkin lymphoma patients(131)I-L19SIP radioimmunotherapy induced a sustained partial response, qualifying ED-B FN as a promising target for antibody-based lymphoma therapies
Anonymous HD video streaming
No full textNo scalable privacy-enhancing technologies exists that is capable of anonymous HD video streaming. Our paper discusses the new anonymizer built into Tribler, a social content-sharing client. With anonymous HD-video streaming as the main objective requirements as at least 10 Mbit/s throughput, user bandwidth donations and NAT-traversal are defined. Using the Tribler API and related tools as Dispersy the ProxyCommunity is designed. This community of proxies provides peer discovery, onion routing and multi-tunnel proxying. Our system evolved through various stages. From the initial standalone routing prototype, to the first Tribler version. This was followed by profiling to achieve performance improvements. Finally the version with libtorrent and cryptography-readyness was implemented. Our performance evaluation shows that the proxy community is able to discover others on the network effectively and built circuits with them. Over these circuits the required 10 Mbit/s throughput for HD streaming has been achieved. Preliminary real-world testing shows that the system works in the wild. However more testing needs to be done and important work on our security model remains.Parallel and Distributed SystemsElectrical Engineering, Mathematics and Computer Scienc
Haploinsufficiency of the ESCRT Component HD-PTP Predisposes to Cancer
No full textSummaryEndosomal sorting complexes required for transport (ESCRT) drive cell surface receptor degradation resulting in attenuation of oncogenic signaling and pointing to a tumor suppressor function. Here, we show that loss of function of an ESCRT protein (HD-PTP encoded by the PTPN23 gene, located on the tumor suppressor gene cluster 3p21.3) drives tumorigenesis in vivo. Indeed, Ptpn23+/− loss predisposes mice to sporadic lung adenoma, B cell lymphoma, and promotes Myc-driven lymphoma onset, dissemination, and aggressiveness. Ptpn23+/−-derived tumors exhibit an unaltered remaining allele and maintain 50% of HD-PTP expression. Consistent with the role of HD-PTP in attenuation of integrin recycling, cell migration, and invasion, hemizygous Ptpn23+/− loss increases integrin β1-dependent B cell lymphoma survival and dissemination. Finally, we reveal frequent PTPN23 deletion and downregulation in human tumors that correlates with poor survival. Altogether, we establish HD-PTP/PTPN23 as a prominent haploinsufficient tumor suppressor gene preventing tumor progression through control of integrin trafficking
A Perfect Tidal Storm: HD 104067 Planetary Architecture Creating an Incandescent World
No full textThe discovery of planetary systems beyond the solar system has revealed a diversity of architectures, most of which differ significantly from our system. The initial detection of an exoplanet is often followed by subsequent discoveries within the same system as observations continue, measurement precision is improved, or additional techniques are employed. The HD 104067 system is known to consist of a bright K-dwarf host star and a giant planet in a ?55 days period eccentric orbit. Here we report the discovery of an additional planet within the HD 104067 system, detected through the combined analysis of radial velocity (RV) data from the High Resolution Echelle Spectrometer and High Accuracy Radial velocity Planet Searcher instruments. The new planet has a mass similar to Uranus and is in an eccentric ?14 days orbit. Our injection-recovery analysis of the RV data exclude Saturn-mass and Jupiter-mass planets out to 3 au and 8 au, respectively. We further present Transiting Exoplanet Survey Satellite observations that reveal a terrestrial planet candidate (R p = 1.30 ± 0.12 R ?) in a ?2.2 days period orbit. Our dynamical analysis of the three planet model shows that the two outer planets produce significant eccentricity excitation of the inner planet, resulting in tidally induced surface temperatures as high as ?2600 K for an emissivity of unity. The terrestrial planet candidate may therefore be caught in a tidal storm, potentially resulting in its surface radiating at optical wavelengths. © 2024. The Author(s). Published by the American Astronomical Society
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Polarized disk emission from Herbig AE/BE stars observed using Gemini planet imager: HD 144432, HD 150193, HD 163296, and HD 169142
No full textThis is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.In order to look for signs of on-going planet formation in young disks, we carried out the first J-band polarized emission imaging of the Herbig Ae/Be stars HD 150193, HD 163296, and HD 169142 using
the Gemini Planet Imager (GPI), along with new H band observations of HD 144432. We confirm the complex “double ring” structure for the nearly face-on system HD 169142 first seen in H-band, finding
the outer ring to be substantially redder than the inner one in polarized intensity. Using radiative transfer modeling, we developed a physical model that explains the full spectral energy distribution (SED) and J- and H-band surface brightness profiles, suggesting that the di↵erential color of the two rings could come from reddened starlight traversing the inner wall and may not require di↵erences in grain properties. In addition, we clearly detect an elongated, o↵-center ring in HD 163296 (MWC 275), locating the scattering surface to be 18 AU above the midplane at a radial distance of 77 AU, cospatial with a ring seen at 1.3mm by ALMA linked to the CO snow line. Lastly, we report a weak tentative detection of scattered light for HD 150193 (MWC 863) and a non-detection for HD 144432; the stellar companion known for each of these targets has likely disrupted the material in the outer disk of the primary star. For HD 163296 and HD 169142, the prominent outer rings we detect could be evidence for giant planet formation in the outer disk or a manifestation of large-scale dust growth processes possibly related to snow-line chemistry.Exeter’s STFC Consolidated Grant (ST/J001627/1). SK acknowledges support from an STFC Rutherford Fellowship
(ST/J004030/1) and a European Research Council (ERC) Starting Grant (Grant agreement No 639889).
This publication makes use of data products from the Two Micron All Sky Survey, which is a joint project of
the University of Massachusetts and the Infrared Processing and Analysis Center/California Institute of Technology,
funded by the National Aeronautics and Space Administration and the National Science Foundation. Based on
observations obtained at the Gemini Observatory (programs GS-2014A-SV-412, GS-2015A-Q-49), which is operated
by the Association of Universities for Research in Astronomy, Inc., under a cooperative agreement with the NSF on
behalf of the Gemini partnership: the National Science Foundation (United States), the National Research Council
(Canada), CONICYT (Chile), Ministerio de Ciencia, Tecnologa e Innovacin Productiva (Argentina), and Ministrio da
Cincia, Tecnologia e Inovao (Brazil)
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