First decay study of the very neutron-rich isotope Br-93

The decay of the mass-separated, very neutron-rich isotope Br-93 has been studied by gamma-spectroscopy. A level scheme of its daughter Kr-93 has been constructed. Level energies, gamma-ray branching ratios and multipolarities suggest spins and parities which are in accord with a smooth systematics of the N=57 isotones for Z less-equal 40, suggesting the N=56 shell closure still to be effective in Kr isotopes. So far, there is no indication of a progressive onset of deformation in neutron-rich Kr isotopes.Comment: 17 pages, 3 figures, Phys. Rev. C, in prin

IAP inhibitors enhance co-stimulation to promote tumor immunity

The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell–dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

Findings From a Process Evaluation of an Indigenous Holistic Housing Support and Mental Health Case Management Program in Downtown Toronto

While urban Indigenous populations in Canada are increasing and represent many diverse and culturally vibrant communities, disparities between Indigenous and non-Indigenous people’s experiences of the social determinants of health are significant. The Mino Kaanjigoowin (MK) program at Na-Me-Res (Native Men’s Residence) in Toronto, Ontario, Canada, supports Indigenous men who are experiencing homelessness or are precariously housed and who have complex health and social needs. Using a community-partnered approach that aligns with wise practices for conducting Indigenous health research, a mixed-methods process evaluation of the MK program was conducted in 2017‒2018 by the Well Living House in partnership with Na-Me-Res. Thematic analysis of qualitative data gathered through two focus groups with community members who access the MK program (n = 9) and key informant interviews with staff (n = 11) was carried out using a decolonizing lens. Results indicate that the MK program provides a unique healing model that is grounded in trust, honour, and respect. Strengths of the program include a harm reduction framework, meeting basic needs, and person-centred care. The program could be enhanced through increased human resource capacity and improved infrastructure, including a separate space for MK staff and activities. The evaluation findings demonstrate how the MK program provides specialized and culturally safe services as a best- practice model to meet the complex health and social needs of urban Indigenous people

The Public Repository of Xenografts (ProXe) enables discovery and randomized phase II-like trials in mice

Over 90% of drugs with preclinical activity fail to ultimately benefit patients. We hypothesized that adequately sized and appropriately powered, randomized phase II-like trials of patient-derived xenografts (PDX) could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment and made them available through an open-source web portal (www.PRoXe.org) that includes all de-identified information relevant to the xenografted specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs designed to mimic human randomized phase II trials are feasible and can generate transcriptional, functional and proteomic biomarkers as well as large numbers of in vivo models with acquired resistance. Investigators from >50 institutions have already accessed PRoXe.org and models have been shared between >20 centers

Potent, selective, and orally bioavailable inhibitors of VPS34 provide chemical tools to modulate autophagy in vivo

Autophagy is a dynamic process that regulates lysosomal-dependent degradation of cellular components. Until recently the study of autophagy has been hampered by the lack of reliable pharmacological tools but selective inhib-itors are now available to modulate the PI 3-kinase VPS34 which is required for autophagy. Here we describe the discovery of potent and selective VPS34 inhibitors, their pharmacokinetic (PK) properties, and ability to inhibit autophagy in cellular and mouse models

Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors

Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1R132H. This letter describes SAR exploration focused on improving both the in vitro and in vivo metabolic stability of the compounds, leading to the identification of 19 as a potent and selective mutant IDH1 inhibitor that has demonstrated brain penetration and excellent oral bioavailability in rodents. In a preclinical patient-derived IDH1 mutant xenograft tumor model study, 19 efficiently inhibited the production of the biomarker, 2-HG

Identification of NVP-TNKS656: The use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor

Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure-based design and LipE-based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient, but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19, and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic signature of binding, highly favorable physicochemical properties, and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies. © 2013 American Chemical Society

Identification and Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1R132H. Synthesis of the 4 diastereomers identified the (S,S)-diastereomer (IDH125) as the most potent isomer, with reasonable cellular activity and excellent selectivity vs IDH1wt. Initial SAR exploration identified the key tolerances and potential for optimization. X-ray crystallography of IDH125 in the homodimer of IDH1R132H identified the allosteric binding site and aided the rationalization for excellent mutant selective inhibition, as well as the lack of activity vs mutant IDH2. Potency improvement and modulation of the in-vitro ADME profile identified (S)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (IDH889) with good in-vivo exposure and in-vivo activity in a mutant IDH1 mouse xenograft model