1,725,926 research outputs found
Design and Synthesis of New GS-6207 Subtypes for Targeting HIV-1 Capsid Protein
No full textHIV-1 capsid protein (CA) is the molecular target of the recently FDA-approved long acting injectable (LAI) drug lenacapavir (GS-6207). The quick emergence of CA mutations resistant to GS-6207 necessitates the design and synthesis of novel sub-chemotypes. We have conducted the structure-based design of two new sub-chemotypes combining the scaffold of GS-6207 and the N-terminal cap of PF74 analogs, the other important CA-targeting chemotype. The design was validated via induced-fit molecular docking. More importantly, we have worked out a general synthetic route to allow the modular synthesis of novel GS-6207 subtypes. Significantly, the desired stereochemistry of the skeleton C2 was confirmed via an X-ray crystal structure of the key synthetic intermediate 22a. Although the newly synthesized analogs did not show significant potency, our efforts herein will facilitate the future design and synthesis of novel subtypes with improved potency
Linked collectors and determiners for: Helgeland Museum, Tabanidae.
No full textNatural history specimen data linked to collectors and determiners held within, "Helgeland Museum, Tabanidae". Claims or attributions were made on Bionomia by volunteer Scribes, <a href="http://bionomia.net/dataset/1f8694bd-6207-4685-921e-d29db4243947">https://bionomia.net/dataset/1f8694bd-6207-4685-921e-d29db4243947</a> using specimen data from the dataset aggregated by the Global Biodiversity Information Facility, <a href="https://gbif.org/dataset/1f8694bd-6207-4685-921e-d29db4243947">https://gbif.org/dataset/1f8694bd-6207-4685-921e-d29db4243947</a>. Formatted as a Frictionless Data package
Linked collectors and determiners for: Helgeland Museum, Tabanidae.
No full textNatural history specimen data linked to collectors and determiners held within, "Helgeland Museum, Tabanidae". Claims or attributions were made on Bionomia by volunteer Scribes, <a href="http://bionomia.net/dataset/1f8694bd-6207-4685-921e-d29db4243947">https://bionomia.net/dataset/1f8694bd-6207-4685-921e-d29db4243947</a> using specimen data from the dataset aggregated by the Global Biodiversity Information Facility, <a href="https://gbif.org/dataset/1f8694bd-6207-4685-921e-d29db4243947">https://gbif.org/dataset/1f8694bd-6207-4685-921e-d29db4243947</a>. Formatted as a Frictionless Data package
Frequency of capsid substitutions associated with GS-6207 in vitro resistance in HIV-1 from antiretroviral-naive and -experienced patients: Resistance to HIV capsid inhibitors
No full textInternational audienceBackground: GS-6207 is a first-in-class HIV capsid inhibitor, targeting several functions of the HIV capsid in the viral cycle, including viral particle assembly, capsid formation and nuclear entry. GS-6207 has demonstrated picomolar potency in vitro, activity confirmed by high potency in a Phase 1 clinical study, with a long-acting antiretroviral profile with potential dosing every 6 months. In vitro resistance selections previously conducted with increasing doses of GS-6207 have identified capsid variants with reduced susceptibility to GS-6207.Objectives: To study the prevalence of capsid mutations associated with in vitro resistance to GS-6207 in people living with HIV (PLWH).Methods: Plasma samples from ART-naive or -experienced PLWH, including PI-experienced people, were sequenced and analysed for the presence of capsid variants identified during in vitro resistance selection: L56I, M66I, Q67H, K70N, N74D, N74S and T107N.Results: Among the samples from the 1500 patients studied, none of the seven GS-6207 resistance mutations identified during in vitro selection experiments was detected, regardless of HIV subtype or PLWH treatment history.Conclusions: Out of the seven HIV capsid substitutions previously selected in vitro and shown to confer phenotypic resistance to GS-6207, none of these seven mutations was observed in this large dataset, suggesting that neither PLWH with previous PI failure nor PLWH with emergence of PI resistance mutations are anticipated to impact GS-6207 activity in these diverse HIV-infected populations
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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A phase 2 study of GI-6207 in patients with recurrent medullary thyroid cancer
No full textMedullary thyroid cancer (MTC) accounts for approximately 4% of thyroid carcinomas. Patients with unresectable, metastatic disease are candidates for approved agent targeted therapies such as vandetanib, cabozantinib, or selpercatinib, but toxicity is often an issue. Preclinical data supported the potential use of immunotherapy targeting carcinoembryonic antigen (CEA) in this indolent disease.
Patients with advanced/recurrent MTC were randomly assigned into a 1:1 ratio to receive a saccharomyces cerevisiae (yeast)-based immunotherapy (GI-6207) targeting CEA starting at the time of enrollment or 6 months after surveillance. The primary endpoint was to compare the calcitonin growth rate in the GI-6207 arm at 6 months, with patients in the surveillance arm at 6 months.
Between March 2013 and May 2018, 34 patients were randomly assigned to receive yeast-CEA vaccine (GI-6207) starting at the time of enrollment or 6 months after surveillance. Mean age was 51 years, and 82% of patients were diagnosed with sporadic MTC. There was no significant change in the calcitonin growth rates at 6 months when the immunotherapy group was compared with the surveillance group (-2.490042 vs. -2.526385; p = 0.3760). Treatment with GI-6207 was associated with increased peripheral CEA specific CD4 and/or CD8 T cells, with15/26 (58%) patients displaying increases after 3 months of treatment. One patient had a significant inflammatory event 17 months after the last vaccine at a known lymph node, perhaps related to a delayed immune response. There were no grade 3 or 4 adverse events. Grade 1 injection site reactions were most common.
The immunotherapy was well tolerated, but did not have an impact on tumor growth rate at 6 months as measured by calcitonin kinetics.
NCT01856920
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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