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Cheal SM, Xu H, Guo HF, Patel M, Punzalan B, Fung EK, Lee SG, Bell M, Singh M, Jungbluth AA, Zanzonico PB, Piersigilli A, Larson SM, Cheung NKV
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Theranostic pretargeted radioimmunotherapy of internalizing solid tumor antigens in human tumor xenografts in mice: Curative treatment of HER2-positive breast carcinoma (opens in new window)

THERANOSTICS 2018; 8(18):5106-5125
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In recent reports, we have shown that optimized pretargeted radioimmunotherapy (PRIT) based on molecularly engineered antibody conjugates and Lu-177-DOTA chelate (DOTA-PRIT) can be used to cure mice bearing human solid tumor xenografts using antitumor antibodies to minimally internalizing membrane antigens, GPA33 (colon) and GD2 (neuroblastoma). However, many solid tumor membrane antigens are internalized after antibody binding and it is generally believed that internalizing tumor membrane antigens are not suitable targets for PRIT. In this study, we tested the hypothesis that DOTA-PRIT can be performed successfully to target HER2, an internalizing membrane antigen widely expressed in breast, ovarian, and gastroesophageal junction cancers. Methods: DOTA-PRIT was carried out in athymic nude mice bearing BT-474 xenografts, a HER2-expressing human breast cancer, using a three-step dosing regimen consisting of sequential intravenous administrations of: 1) a bispecific IgG-scFv (210 kD) format (BsAb) carrying the IgG sequence of the anti-HER2 antibody trastuzumab and the scFv "C825" with high-affinity, hapten-binding antibody for Bn-DOTA (metal) (BsAb: anti-HER2-C825), 2) a 500 kD dextran-based clearing agent, followed by 3) Lu-177-DOTA-Bn. At the time of treatment, athymic nude mice bearing established subcutaneous BT-474 tumors (medium- and smaller-sized tumors with tumor volumes of 209 +/- 101 mm(3) and ranging from palpable to 30 mm(3), respectively), were studied along with controls. We studied single- and multi-dose regimens. For groups receiving fractionated treatment, we verified quantitative tumor targeting during each treatment cycle using non-invasive imaging with single-photon emission computed tomography/computed tomography (SPECT/CT). Results: We achieved high therapeutic indices (TI, the ratio of radiation-absorbed dose in tumor to radiation-absorbed dose to critical organs, such as bone marrow) for targeting in blood (TI = 28) and kidney (TI = 7), while delivering average radiation-absorbed doses of 39.9 cGy/MBq to tumor. Based on dosimetry estimates, we implemented a curative fractionated therapeutic regimen for medium-sized tumors that would deliver approximately 70 Gy to tumors, which required treatment with a total of 167 MBq Lu-177-DOTA-Bn/mouse (estimated absorbed tumor dose: 66 Gy). This regimen was well tolerated and achieved 100% complete responses (CRs; defined herein as tumor volume equal to or smaller than 4.2 mm(3)), including 62.5% histologic cure (5/8) and 37.5% microscopic residual disease (3/8) at 85 days (d). Treatment controls showed tumor progression to 207 +/- 201% of pre-treatment volume at 85 d and no CRs. Finally, we show that treatment with this curative Lu-177 regimen leads to a very low incidence of histopathologic abnormalities in critical organs such as bone marrow and kidney among survivors compared with non-treated controls. Conclusion: Contrary to popular belief, we demonstrate that DOTA-PRIT can be successfully adapted to an internalizing antigen-antibody system such as HER2, with sufficient Tls and absorbed tumor doses to achieve a high probability of cures of established human breast cancer xenografts while sparing critical organs of significant radiotoxicity.
Fins JJ
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Mosaic Decisionmaking and Reemergent Agency after Severe Brain Injury (opens in new window)

CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS 2018 JAN; 27(1):163-174
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In this article, I will discuss the challenge posed by the reemergent agency of individuals with severe brain injury whose ability to communicate has been partially restored by neuroprosthetics, drugs, and rehabilitation. Instead of categorically distinguishing patients as either competent or incompetent, these technologies necessitate a more nuanced approach to intermediate states of decisionmaking capacity. This indeterminacy is addressed through a mosaic approach to decisionmaking, which seeks to achieve a proportionate and prudent balance between unbridled self-determination and conventional surrogate representation.
Gonda KJ, Domar AD, Gleicher N, Marrs RP
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Insights from clinical experience in treating IVF poor responders (opens in new window)

REPRODUCTIVE BIOMEDICINE ONLINE 2018 JAN; 36(1):12-19
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'Poor responders' is a term used to describe a subpopulation of IVF patients who do not respond well to ovarian stimulation with gonadotrophins. While there is no standard definition of a poor responder, these patients tend to be of advanced maternal age (>= 40 years), have a history of poor ovarian response with conventional stimulation protocols, and/or have low ovarian reserve. Despite the heterogeneity of this patient group, there are characteristics and needs common to many poor responders that can be addressed through a holistic approach. Stimulation during the earlier stages of follicle maturation may help synchronize follicle development for improved response to later gonadotrophin stimulation, and supplementation with dehydroepiandrosterone or human growth hormone may promote early follicle development in poor responders. IVF protocols should be specifically tailored to poor responders to complement the patient's natural cycle. Because poor responders tend to have high levels of stress and anxiety, patients should receive psychological counselling and support, both prior to and during IVF cycles, to ensure optimal outcomes and improve patients' experience. It is important to set realistic expectations with poor responders and their partners to help patients make informed decisions and better manage their distress and anxiety. (c) 2017 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
Yao NY, O'Donnell ME
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Replication fork convergence at termination: A multistep process (opens in new window)

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2018 JAN 9; 115(2):237-239
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Harden JL, Guo HY, Bertrand M, Shendruk TN, Ramakrishnan S, Leheny RL
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Enhanced gel formation in binary mixtures of nanocolloids with short-range attraction (opens in new window)

JOURNAL OF CHEMICAL PHYSICS 2018 JAN 28; 148(4):? Article 044902
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Colloidal suspensions transform between fluid and disordered solid states as parameters such as the colloid volume fraction and the strength and nature of the colloidal interactions are varied. Seemingly subtle changes in the characteristics of the colloids can markedly alter the mechanical rigidity and flow behavior of these soft composite materials. This sensitivity creates both a scientific challenge and an opportunity for designing suspensions for specific applications. In this paper, we report a novel mechanism of gel formation in mixtures of weakly attractive nanocolloids with modest size ratio. Employing a combination of x-ray photon correlation spectroscopy, rheometry, and molecular dynamics simulations, we find that gels are stable at remarkably weaker attraction in mixtures with size ratio near two than in the corresponding monodisperse suspensions. In contrast with depletion-driven gelation at larger size ratio, gel formation in the mixtures is triggered by microphase demixing of the species into dense regions of immobile smaller colloids surrounded by clusters of mobile larger colloids that is not predicted by mean-field thermodynamic considerations. These results point to a new route for tailoring nanostructured colloidal solids through judicious combination of interparticle interaction and size distribution. Published by AIP Publishing.
Tomasini MD, Wang YJ, Karamafrooz A, Li G, Beuming T, Gao JL, Taylor SS, Veglia G, Simon SM
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Conformational Landscape of the PRKACA-DNAJB1 Chimeric Kinase, the Driver for Fibrolamellar Hepatocellular Carcinoma (opens in new window)

SCIENTIFIC REPORTS 2018 JAN 15; 8(?):? Article 720
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In fibrolamellar hepatocellular carcinoma a single genetic deletion results in the fusion of the first exon of the heat shock protein 40, DNAJB1, which encodes the J domain, with exons 2-10 of the catalytic subunit of protein kinase A, PRKACA. This produces an enzymatically active chimeric protein J-PKAca. We used molecular dynamics simulations and NMR to analyze the conformational landscape of native and chimeric kinase, and found an ensemble of conformations. These ranged from having the J-domain tucked under the large lobe of the kinase, similar to what was reported in the crystal structure, to others where the J-domain was dislodged from the core of the kinase and swinging free in solution. These simulated dislodged states were experimentally captured by NMR. Modeling of the different conformations revealed no obvious steric interactions of the J-domain with the rest of the RII beta holoenzyme.
Jenness C, Giunta S, Muller MM, Kimura H, Muir TW, Funabiki H
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HELLS and CDCA7 comprise a bipartite nucleosome remodeling complex defective in ICF syndrome (opens in new window)

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2018 JAN 30; 115(5):E876-E885
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Mutations in CDCA7, the SNF2 family protein HELLS (LSH), or the DNA methyltransferase DNMT3b cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. While it has been speculated that DNA methylation defects cause this disease, little is known about the molecular function of CDCA7 and its functional relationship to HELLS and DNMT3b. Systematic analysis of how the cell cycle, H3K9 methylation, and the mitotic kinase Aurora B affect proteomic profiles of chromatin in Xenopus egg extracts revealed that HELLS and CDCA7 form a stoichiometric complex on chromatin, in a manner sensitive to Aurora B. Although HELLS alone fails to remodel nucleosomes, we demonstrate that the HELLS-CDCA7 complex possesses nucleosome remodeling activity. Furthermore, CDCA7 is essential for loading HELLS onto chromatin, and CDCA7 harboring patient ICF mutations fails to recruit the complex to chromatin. Together, our study identifies a unique bipartite nucleosome remodeling complex where the functional remodeling activity is split between two proteins and thus delineates the defective pathway in ICF syndrome.
Kleiner RE, Hang LE, Molloy KR, Chait BT, Kapoor TM
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A Chemical Proteomics Approach to Reveal Direct Protein-Protein Interactions in Living Cells (opens in new window)

CELL CHEMICAL BIOLOGY 2018 JAN; 25(1):110-120.e3
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Protein-protein interactions mediate essential cellular processes, however the detection of native interactions is challenging since they are often low affinity and context dependent. Here, we develop a chemical proteomics approach in vivo CLASPI [iCLASPI] (in vivo crosslinking-assisted and stable isotope labeling by amino acids in cell culture [SILAC]-based protein identification) relying upon photo-crosslinking, amber suppression, and SILAC-based quantitative proteomics to profile context-dependent protein-protein interactions in living cells. First, we use iCLASPI to profile in vivo binding partners of the N-terminal tails of soluble histone H3 or H4. We identify known histone chaperones and modifying proteins, thereby validating our approach, and find an interaction between soluble histone H3 and UBR7, an E3 ubiquitin ligase, mediated by UBR7's PHD domain. Furthermore, we apply iCLASPI to profile the context-dependent protein-protein interactions of chromatin-associated histone H3 at different cell-cycle stages, and identify ANP32A as a mitosis-specific interactor. Our results demonstrate that the iCLASPI approach can provide a general strategy for identifying native, context-dependent direct protein-protein interactions using photo-crosslinking and quantitative proteomics.
Bieniasz P, Telesnitsky A
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Multiple, Switchable Protein: RNA Interactions Regulate Human Immunodeficiency Virus Type 1 Assembly (opens in new window)

ANNUAL REVIEW OF VIROLOGY, VOL 5 2018; 5(?):165-183
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Human immunodeficiency virus type 1 (HIV-1) particle assembly requires several protein: RNA interactions that vary widely in their character, from specific recognition of highly conserved and structured viral RNA elements to less specific interactions with variable RNA sequences. Genetic, biochemical, biophysical, and structural studies have illuminated how virion morphogenesis is accompanied by dramatic changes in the interactions among the protein and RNA virion components. The 5' leader RNA element drives RNA recognition by Gag upon initiation of HIV-1 assembly and can assume variable conformations that influence translation, dimerization, and Gag recognition. As Gag multimerizes on the plasma membrane, forming immature particles, its RNA binding specificity transiently changes, enabling recognition of the A-rich composition of the viral genome. Initiation of assembly may also be regulated by occlusion of the membrane binding surface of Gag by tRNA. Finally, recent work has suggested that RNA interactions with viral enzymes may activate and ensure the accuracy of virion maturation.
Mathews DJH, Fins JJ, Racine E
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The Therapeutic "Mis"conception: An Examination of its Normative Assumptions and a Call for its Revision (opens in new window)

CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS 2018 JAN; 27(1):154-162
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This article examines some of the assumptions and implications associated with the Belmont era context in which the concept of therapeutic misconception was forged. We argue that the justification of therapeutic misconception should be reconsidered based on less paternalistic and more participatory models of research. Finally, we identify conceptual and practical approaches that might better reflect contemporary research practice.