Allogeneic natural killer (NK) cell adoptive transfer is a promising treatment for several cancers but is less effective for the treatment of multiple myeloma. In this study, we report on quadruple ...gene-engineered induced pluripotent stem cell (iPSC)-derived NK cells designed for mass production from a renewable source and for dual targeting against multiple myeloma through the introduction of an NK cell-optimized chimeric antigen receptor (CAR) specific for B cell maturation antigen (BCMA) and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity when combined with therapeutic anti-CD38 antibodies. Additionally, these cells express a membrane-bound interleukin-15 fusion molecule to enhance function and persistence along with knock out of CD38 to prevent antibody-mediated fratricide and enhance NK cell metabolic fitness. In various preclinical models, including xenogeneic adoptive transfer models, quadruple gene-engineered NK cells consistently demonstrate durable antitumor activity independent of exogenous cytokine support. Results presented here support clinical translation of this off-the-shelf strategy for effective treatment of multiple myeloma.
Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson's disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), ...Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles suggest dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of two genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced retinal degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible, albeit ineffective, compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in αSyn-mediated neurotoxicity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aim
Colorectal cancer is the second commonest cause of cancer death worldwide. Colonoscopy plays a key role in the control of colorectal cancer and, in that regard, maximizing detection (and removal) ...of pre‐cancerous adenomas at colonoscopy is imperative. GI Genius™ (Medtronic Ltd) is a computer‐aided detection system that integrates with existing endoscopy systems and improves adenoma detection during colonoscopy. COLO‐DETECT aims to assess the clinical and cost effectiveness of GI Genius™ in UK routine colonoscopy practice.
Methods and analysis
Participants will be recruited from patients attending for colonoscopy at National Health Service sites in England, for clinical symptoms, surveillance or within the national Bowel Cancer Screening Programme. Randomization will involve a 1:1 allocation ratio (GI Genius™‐assisted colonoscopy:standard colonoscopy) and will be stratified by age category (<60 years, 60–<74 years, ≥74 years), sex, hospital site and indication for colonoscopy. Demographic data, procedural data, histology and post‐procedure patient experience and quality of life will be recorded. COLO‐DETECT is designed and powered to detect clinically meaningful differences in mean adenomas per procedure and adenoma detection rate between GI Genius™‐assisted colonoscopy and standard colonoscopy groups. The study will close when 1828 participants have had a complete colonoscopy. An economic evaluation will be conducted from the perspective of the National Health Service. A patient and public representative is contributing to all stages of the trial. Registered at ClinicalTrials.gov (NCT04723758) and ISRCTN (10451355).
What will this trial add to the literature?
COLO‐DETECT will be the first multi‐centre randomized controlled trial evaluating GI Genius™ in real world colonoscopy practice and will, uniquely, evaluate both clinical and cost effectiveness.
The protein O-glucosyltransferase Rumi/POGLUT1 regulates Drosophila Notch signaling by adding O-glucose residues to the Notch extracellular domain. Rumi has other predicted targets including Crumbs ...(Crb) and Eyes shut (Eys), both of which are involved in photoreceptor development. However, whether Rumi is required for the function of Crb and Eys remains unknown. Here we report that in the absence of Rumi or its enzymatic activity, several rhabdomeres in each ommatidium fail to separate from one another in a Notch-independent manner. Mass spectral analysis indicates the presence of O-glucose on Crb and Eys. However, mutating all O-glucosylation sites in a crb knock-in allele does not cause rhabdomere attachment, ruling out Crb as a biologically-relevant Rumi target in this process. In contrast, eys and rumi exhibit a dosage-sensitive genetic interaction. In addition, although in wild-type ommatidia most of the Eys protein is found in the inter-rhabdomeral space (IRS), in rumi mutants a significant fraction of Eys remains in the photoreceptor cells. The intracellular accumulation of Eys and the IRS defect worsen in rumi mutants raised at a higher temperature, and are accompanied by a ∼50% decrease in the total level of Eys. Moreover, removing one copy of an endoplasmic reticulum chaperone enhances the rhabdomere attachment in rumi mutant animals. Altogether, our data suggest that O-glucosylation of Eys by Rumi ensures rhabdomere separation by promoting proper Eys folding and stability in a critical time window during the mid-pupal stage. Human EYS, which is mutated in patients with autosomal recessive retinitis pigmentosa, also harbors multiple Rumi target sites. Therefore, the role of O-glucose in regulating Eys may be conserved.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ubiquitylation targets proteins for proteasome-mediated degradation and plays important roles in many biological processes including apoptosis. However, non-proteolytic functions of ubiquitylation ...are also known. In Drosophila, the inhibitor of apoptosis protein 1 (DIAP1) is known to ubiquitylate the initiator caspase DRONC in vitro. Because DRONC protein accumulates in diap1 mutant cells that are kept alive by caspase inhibition ("undead" cells), it is thought that DIAP1-mediated ubiquitylation causes proteasomal degradation of DRONC, protecting cells from apoptosis. However, contrary to this model, we show here that DIAP1-mediated ubiquitylation does not trigger proteasomal degradation of full-length DRONC, but serves a non-proteolytic function. Our data suggest that DIAP1-mediated ubiquitylation blocks processing and activation of DRONC. Interestingly, while full-length DRONC is not subject to DIAP1-induced degradation, once it is processed and activated it has reduced protein stability. Finally, we show that DRONC protein accumulates in "undead" cells due to increased transcription of dronc in these cells. These data refine current models of caspase regulation by IAPs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•iDuo NK cells prevent antigen escape by targeting both CD19+ and CD19− lymphoma cells.•iDuo NK cells demonstrate enhanced anti-tumor activity and persistence without the need for cytokine support.
...Display omitted
Substantial numbers of B cell leukemia and lymphoma patients relapse due to antigen loss or heterogeneity after anti-CD19 chimeric antigen receptor (CAR) T cell therapy. To overcome antigen escape and address antigen heterogeneity, we engineered induced pluripotent stem cell-derived NK cells to express both an NK cell-optimized anti-CD19 CAR for direct targeting and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity. In addition, we introduced a membrane-bound IL-15/IL-15R fusion protein to promote in vivo persistence. These engineered cells, termed iDuo NK cells, displayed robust CAR-mediated cytotoxic activity that could be further enhanced with therapeutic antibodies targeting B cell malignancies. In multiple in vitro and xenogeneic adoptive transfer models, iDuo NK cells exhibited robust anti-lymphoma activity. Furthermore, iDuo NK cells effectively eliminated both CD19+ and CD19− lymphoma cells and displayed a unique propensity for targeting malignant cells over healthy cells that expressed CD19, features not achievable with anti-CAR19 T cells. iDuo NK cells combined with therapeutic antibodies represent a promising approach to prevent relapse due to antigen loss and tumor heterogeneity in patients with B cell malignancies.
Cichocki et al report on a novel CAR-natural killer (CAR-NK) cell therapy for B-cell lymphoma that addresses antigen loss, tumor heterogeneity, and failed CAR-cell persistence. The authors engineered induced pluripotent stem cell (iPSC)-derived NK cells with anti-CD19 CAR and a noncleavable CD16 that augments toxicity in the presence of anti-CD20 therapy and added an IL-15/IL-15R fusion to promote cytokine-independent persistence. In vitro and xenograft models treated with the engineered NK cells plus rituximab had robust activity and may represent a promising “off the shelf” approach to targeting B-cell malignancies.
Abstract
Oxide solid electrolytes (OSEs) have the potential to achieve improved safety and energy density for lithium-ion batteries, but their high grain-boundary (GB) resistance generally is a ...bottleneck. In the well-studied perovskite oxide solid electrolyte, Li
3
x
La
2/3-
x
TiO
3
(LLTO), the ionic conductivity of grain boundaries is about three orders of magnitude lower than that of the bulk. In contrast, the related Li
0.375
Sr
0.4375
Ta
0.75
Zr
0.25
O
3
(LSTZ0.75) perovskite exhibits low grain boundary resistance for reasons yet unknown. Here, we use aberration-corrected scanning transmission electron microscopy and spectroscopy, along with an active learning moment tensor potential, to reveal the atomic scale structure and composition of LSTZ0.75 grain boundaries. Vibrational electron energy loss spectroscopy is applied for the first time to reveal atomically resolved vibrations at grain boundaries of LSTZ0.75 and to characterize the otherwise unmeasurable Li distribution therein. We find that Li depletion, which is a major reason for the low grain boundary ionic conductivity of LLTO, is absent for the grain boundaries of LSTZ0.75. Instead, the low grain boundary resistivity of LSTZ0.75 is attributed to the formation of a nanoscale defective cubic perovskite interfacial structure that contained abundant vacancies. Our study provides new insights into the atomic scale mechanisms of low grain boundary resistivity.
PurposeThe objective of this paper is to investigate how firms react to cybersecurity information sharing environment where government organizations disseminate cybersecurity threat information ...gathered by individual firms to the private entities. The overall impact of information sharing on firms' cybersecurity investment decision has only been game-theoretically explored, not giving practical implication. The authors therefore leverage the Cybersecurity Information Sharing Act of 2015 (CISA) to observe firms' attitudinal changes toward investing in cybersecurity.Design/methodology/approachThe authors design a quasi-experiment where they set US cybersecurity firms as an experimental group (a proxy for total investment in cybersecurity) and nonsecurity firms as a control group to measure the net effect of CISA on overall cybersecurity investment. To enhance the robustness of the authors’ difference-in-difference estimation, the authors employed propensity score matched sample test and reduced sample test as well.FindingsFor the full sample, the authors’ empirical findings suggest that US security firms' overall performance (i.e. Tobin's Q) improved following the legislation, which indicates that more investment in cybersecurity was followed by the formation of information sharing environment. Interestingly, big cybersecurity firms are beneficiaries of the CISA when the full samples are divided into small and large group. Both Tobin's Q and sales growth rate increased for big firms after CISA.Research limitations/implicationsThe authors’ findings shed more light on the research stream of cybersecurity and information sharing, a research area only explored by game-theoretical approaches. Given that the US government has tried to enforce cybersecurity defensive measures by building cooperative architecture such as CISA 2015, the policy implication of this study is far-reaching.Originality/valueThe authors’ study contributes to the research on the economic benefits of sharing cybersecurity information by finding the missing link (i.e. empirical evidence) between “sharing” and “economic impact.” This paper confirms that CISA affects the cybersecurity industry unevenly by firm size, a previously unidentified relationship.
A platform for capture and release of circulating tumor cells (CTCs) is demonstrated by utilizing aptamer grafted silicon nanowires. Here, single‐stranded DNA‐aptamers are generated via the ...Cell‐SELEX process to serve as capture agents, allowing specific capture and release of non‐small cell lung cancer (NSCLC) CTCs from whole‐blood samples with minimum contamination and negligible disruption to CTC viability and functions.
PDF
