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The master epigenetic regulator lysine acetyltransferase (KAT) p300/CBP plays a pivotal role in neuroplasticity and cognitive functions. Recent evidence has shown that in several neurodegenerative diseases, including Alzheimer's disease (AD), the expression level and function of p300/CBP are severely compromised, leading to altered gene expression causing pathological conditions. Here, we show that p300/CBP activation by a small‐molecule TTK21, conjugated to carbon nanosphere (CSP) ameliorates Aβ‐impaired long‐term potentiation (LTP) induced by high‐frequency stimulation, theta burst stimulation, and synaptic tagging/capture (STC). This functional rescue was correlated with CSP‐TTK21‐induced changes in transcription and translation. Mechanistically, we observed that the expression of a large number of synaptic plasticity‐ and memory‐related genes was rescued, presumably by the restoration of p300/CBP mediated acetylation. Collectively, these results suggest that small‐molecule activators of p300/CBP could be a potential therapeutic molecule for neurodegenerative diseases like AD. [ABSTRACT FROM AUTHOR]

Background: Hearing and vision impairments are highly prevalent in people with dementia (PwD) and may have a negative impact on quality of life and other dementia‐related outcomes. Intervening to optimise sensory impairment and support sensory function may be a means of improving dementia‐related outcomes. The SENSE‐cog Trial evaluated whether a home‐based multi‐part 'sensory support' intervention (SSI) is effective in improving quality of life and other key outcomes in PwD (including hearing and/or vision problems), and their partners. Method: This was a pan‐European, multi‐centre, observer blind, randomised controlled trial (RCT), of PwD with hearing and/or vision impairment and their partners. We evaluated a multi‐part complex intervention of hearing and vision rehabilitation tailored to each participant dyad, compared to care as usual (CAU). The intervention included at a minimum: assessment and correction of hearing and/or vision impairments; home‐based, therapist‐delivered sensory support (i.e., adherence with devices; improving the sensory environment (i.e., lighting), communication training, and signposting to other support agencies. Result: Across 7 centres in the UK, Ireland, Greece, France and Cyprus, 291 participants with dementia were randomised from May 2018 to May 2021 to receive either 'care as usual', or a multi‐component sensory intervention (10 visits over 18 weeks). Mitigating strategies to adapt study procedure to the COVID‐19 pandemic were implemented. Significant difference in Quality of Life at 36 weeks was not seen; however, significant differences at 18 weeks were seen, with average DEMQoL scores being lower (poorer QoL) in the CAU group by between 2.6 and 2.7 units/ points at this time point, adjusted for covariates. The focus of this presentation will be on secondary outcomes including activities of daily living and functional ability (dementia‐ or sensory‐related) across the two groups. No serious adverse effects were related to the intervention; low grade adverse effects related to the intervention were reported by five participants only. Conclusion: Hearing and vision support and rehabilitation in PwD living at home is a potentially important means of improving the lived experience of dementia and may represent a critical step in the diagnostic and post‐diagnostic care pathway. However, effects may not be sustained over the longer term. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions High‐intensity end‐of‐life (EOL) care, marked by admission to intensive care units (ICUs) or in‐hospital death, can be costly and burdensome. Recent trends in use of ICUs, life‐sustaining treatments (LSTs), and noninvasive ventilation (NIV) during EOL hospitalizations among older adults with advanced cancer and patterns of in‐hospital death are unknown.We used SEER‐Medicare data (2003–2017) to identify beneficiaries with advanced solid cancer (summary stage 7) who died within 3 years of diagnosis. We identified EOL hospitalizations (within 30 days of death), classifying them by increasing intensity of care into: (1) without ICU; (2) with ICU but without LST (invasive mechanical ventilation, tracheostomy, gastrostomy, acute dialysis) or NIV; (3) with ICU and NIV but without LST; and (4) with ICU and LST use. We constructed a multinomial regression model to evaluate trends in risk‐adjusted hospitalization, overall and across hospitalization categories, adjusting for sociodemographics, cancer characteristics, comorbidities, and frailty. We evaluated trends in in‐hospital death across categories.Of 226,263 Medicare beneficiaries with advanced cancer, 138,305 (61.1%) were hospitalized at EOL [Age, Mean (SD):77.9(7.1) years; 45.5% female]. Overall, EOL hospitalizations remained high throughout, from 78.1% (95% CI: 77.4, 78.7) in 2004 to 75.5% (95% CI: 74.5, 76.2) in 2017. Hospitalizations without ICU use decreased from 49.3% (95% CI: 48.5, 50.2) to 35.0% (95% CI: 34.2, 35.9) while hospitalizations with more intensive care increased, from 23.7% (95% CI: 23.0, 24.4) to 28.7% (95% CI: 27.9, 29.5) for ICU without LST or NIV, 0.8% (95% CI: 0.6, 0.9) to 3.8% (95% CI: 3.4, 4.1) for ICU with NIV but without LST, and 4.3% (95% CI: 4.0, 4.7) to 8.0% (95% CI: 7.5, 8.5) for ICU with LST use. Among those who experienced in‐hospital death, the proportion receiving ICU care increased from 46.5% to 65.0%.Among older adults with advanced cancer, EOL hospitalization rates remained stable from 2004–2017. However, intensity of care during EOL hospitalizations increased as evidenced by increasing use of ICUs, LSTs, and NIV. [ABSTRACT FROM AUTHOR]

Background: Hearing and vision impairments are highly prevalent in people with dementia (PwD) and may have a negative impact on quality of life and other dementia‐related outcomes. Intervening to optimize sensory function improve these outcomes. The SENSE‐cog Trial evaluated whether a home‐based multi‐part 'sensory support' intervention (SSI) is effective in improving quality of life and other key outcomes in PwD (including hearing and/or vision problems), and their care partners. Methods: This was a pan‐European, multi‐centre, observer blind, randomized controlled trial (RCT), of PwD with hearing and/or vision impairment and their companions. We compared 'care as usual' (CAU) to a multi‐part complex intervention of hearing and vision rehabilitation (SSI) tailored to each participant dyad. The SSI included: assessment and correction of hearing and/or vision impairments; home‐based, therapist‐delivered sensory support (i.e., adherence with devices; improving the sensory environment, communication training, and signposting to other support agencies). Outcomes were collected at baseline, intervention end (18 weeks) and post‐intervention (36 weeks – the primary endpoint) and included: quality of life, sensory and cognitive functional ability, relationship satisfaction, neuropsychiatric symptoms, and mental well‐being. Health resource utilization was measured to estimate cost‐effectiveness of the intervention. Results: Across 7 European centers (UK, France, Cyprus, Greece), 252 participants with dementia (median age 80 years, 53% female, 59% hearing impairment only, 4% visual impairment only and 37% both impairments) were randomized from May 2018 to May 2021 to receive either CAU or SSI (10 visits over 18 weeks). Mitigating strategies to adapt study procedures to the COVID‐19 pandemic were implemented. Over 75% of participants completed the primary outcome, the DEM‐QoL scale, at 36 weeks. An initial feasibility study yielded positive results for this outcome revealing an average improvement in the DEM‐QoL of 4.9 points (> minimum important clinical change). Conclusions: Hearing and vision support in PwD is a potentially important and cost‐effective means of improving the lived experience of dementia, representing a critical step in the diagnostic and care pathway. Main RCT results will be available in May 2022. Trial registration: ISRCTN17056211 [ABSTRACT FROM AUTHOR]

Alveolar rhabdomyosarcoma ( ARMS) is an aggressive paediatric cancer of skeletal muscle with poor prognosis. A PAX3-FOXO1 fusion protein acts as a driver of malignancy in ARMS by disrupting tightly coupled but mutually exclusive pathways of proliferation and differentiation. While PAX3-FOXO1 is an attractive therapeutic target, no current treatments are designed to block its oncogenic activity. The present work shows that the histone acetyltransferase P/ CAF ( KAT2B) is overexpressed in primary tumours from ARMS patients. Interestingly, in fusion-positive ARMS cell lines, P/ CAF acetylates and stabilizes PAX3-FOXO1 rather than MyoD, a master regulator of muscle differentiation. Silencing P/ CAF, or pharmacological inhibition of its acetyltransferase activity, down-regulates PAX3-FOXO1 levels concomitant with reduced proliferation and tumour burden in xenograft mouse models. Our studies identify a P/ CAF-PAX3-FOXO1 signalling node that promotes oncogenesis and may contribute to MyoD dysfunction in ARMS. This work exemplifies the therapeutic potential of targeting chromatin-modifying enzymes to inhibit fusion oncoproteins that are a frequent event in sarcomas. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Experience with non-antigenic galactose α1,3 galactose (αGal) polymers and development of αGal deficient pigs has reduced or eliminated the significance of this antigen in xenograft rejection. Despite these advances, delayed xenograft rejection (DXR) continues to occur most likely due to antibody responses to non-Gal endothelial cell (EC) antigens. Methods:  To gauge the diversity of the non-Gal antibody response we used antibody derived from CD46 transgenic heterotopic cardiac xenografts performed without T-cell immunosuppression, Group A (n = 4) and Gal knockout (GT-KO) heart transplants under tacrolimus and sirolimus immunosuppression, Group B (n = 8). Non-Gal antibody was measured by flow cytometry and by western blots using GT-KO EC membrane antigens. A nanoLC/MS/MS analysis of proteins recovered from 2D gels was used to identify target antigens. Results:  Group A recipients exhibited a mixed cellular and humoral rejection. Group B recipients mainly exhibited classical DXR. Western blot analysis showed a non-Gal antibody response induced by GT+ and GT-KO hearts to an overlapping set of pig aortic EC membrane antigens. Proteomic analysis identified 14 potential target antigens but failed to define several immunodominant targets. Conclusions:  These experiments indicate that the non-Gal antibody response is directed to a number of stress response and inflammation related pig EC antigens and a few undefined targets. Further analysis of these antibody specificities using alternative methods is required to more fully define the repertoire of non-Gal antibody responses. [ABSTRACT FROM AUTHOR]

Xenotransplantation using porcine organs may resolve a chronic shortage of donor organs for clinical transplantation if significant immunological barriers can be overcome. To determine the potential role of T lymphocytes in Xenograft (Xg) rejection, we transplanted transgenic hCD46 porcine hearts heterotopically into baboon recipients. Methods: Recipients were treated to deplete anti-Gal antibody with a non-antigenic α-Gal polyethylene glycol polymer (TPC) (n=2), TPC plus rituximab (anti-CD20) (n=1) or were untreated (n=1). None of the recipients received T-cell immunosuppression. Results: All Xgs failed within 7 days and showed evidence of a mixed humoral and cellular rejection process. Cellular infiltration consisting primarily of CD4+ T cells and few CD8+ T cells. Proliferation and cytotoxicity assays showed sensitization of CD4+ and CD8+ T cells that reacted with porcine IFN-γ (pIFN-γ)-stimulated porcine aortic endothelial cells (PAEC). The CD4+ lymphocytes displayed greater cytotoxicity than CD8+ cells. An increased frequency of PAEC-specific interleukin (IL) 2 and IFN-γ-secreting T cells was observed, suggesting a Th1 cytokine bias. An increase in the percentage of circulating CD4+CD28− cells was observed at the time of rejection and over 50% of the CD4+ cells recovered from residual pig tissue at necropsy lacked CD28 expression. Conclusions: These findings show that lymphocytes are efficiently stimulated by PAEC antigens and can mediate direct tissue destruction. These studies (1) provide an insight into the potential of cellular-mediated cardiac Xg rejection, (2) show for the first time the induction of cytotoxic pig-specific CD4+CD28− lymphocytes and (3) provide a rational basis for determining different modes of immunosuppression to treat Xg rejection. [ABSTRACT FROM AUTHOR]

The article outlines the study conducted on xenotransplantation using GT-KO pigs in the U.S. It reveals that one of the fundamental advantages of xenotransplantation is the donor organ, because it is derived from a pig which can be genetically modified to relieve the patient of immunosuppressive burden. The donor organs eliminated the need for systemic complement inhibition and reduced the immunosuppressive burden of the recipient.

Methanobactin (mb) is a chalkophore produced by Methylosinus trichosporium OB3b. Mb has been shown to bind to many metals in addition to Cu(II) and Cu(1). There seem to be two general families of CD spectra associated with different types of metals. The first is common to soft metal ions and includes Au(III), Cu(II), Pb(II), AG(I), and Hg(II). The second is common to hard metal ions and includes Zn(II), Mn(II), Co(II), and Ni(II). All metals can be displaced by Cu(II) except for Au(III), Cu(I), and Ag(I) which seem to inactivate rob, possibly irreversibly. This may be because mb is known to reduce Cu(II), Au(III), and AGO), and the oxidation of mb may impair subsequent metal binding. Alternatively, Pb(II) and all other metals on this list, can be displaced by Cu(II) suggesting that they cannot be reduced. Kinetic CD spectra of immediate and long-term changes in mb may be indicative of metal-reduction processes or changes in ligand binding and aggregation state. We find that most metals bind more rapidly than the dead time of the instrument (∼10 msec) and lead to stable conformations, but Au(III) and Cu(II) show longer-term changes that may be associated with oxidation and/or alteration of mb ligands. [ABSTRACT FROM AUTHOR]

Methanobactin (mb) is a chalkophore produced by Methylosinus trichosporium OB3b. This chromopeptide appears to be a part of the copper acquisition system of these methane-oxidizing bacteria. We have obtained detailed NMR spectra of mb after titration with Cu(II). This is only possible because mb reduces Cu(II) to Cu(I) upon binding and thus becomes diamagnetic as well as slightly less soluble. Cu(I) in solution is typically unstable; however, it remains stable in solution when bound to rob. We have not yet identified the specific reductant which is also capable of reducing Hg(II), Ag(I), and Au(III). Mb is thought to bind metal ions using nitrogen, sulfur and possibly oxygen ligands from its 4-thiocarbonyl-5-hydroxy imidazole (THI), 4-hydroxy-5-thiocarbonyl imidazole (HTI), and possibly its tyrosine. Our experiments show that there are considerable changes in these residue environments denoted by significant changes in the proton NMR spectra of mb when it is bound to copper versus copper-free mb. Residue assignments have been made using COSY and TOCSY measurements. Protons on the nitrogens of HTI and THI have been identified using HSQC 15N NMR. [ABSTRACT FROM AUTHOR]

Objective: Left atrio-ventricular valve (LAVV) regurgitation after repair of an atrio-ventricular septal defect (AVSD) may necessitate further surgery. However, redo-LAVV repair remains challenging. We sought to determine if more LAVV valves are preserved in the current era, and analyze early and longer-term results., Patients: All consecutive patients with repaired AVSD who underwent redo-LAVV surgery from January 2004 to April 2017 were included. Patients with single ventricles, atrial isomerism, and complex associated anomalies were excluded., Methods: This was a single-center study using retrospective chart review and an institutional database for follow-up information. Data analyzed included number and year of primary AVSD and redo-LAVV operation, presence of trisomy 21, morphology of AVSD, mortality, and reoperation. Univariate analysis included repair and replacement rates and early and long-term survival., Results: During the study period 36 redo-LAVV operations were performed, with repair in 28 and replacement in eight. The number of redo-operations increased from 13 in the first part to 23 in the second part of the study. The rate of LAVV preservation significantly increased over time (54% vs 91%, P < 0.01), and was not affected by morphology of AVSD or trisomy 21. There was one in-hospital death at Day 42 and overall estimated survival was 94.5% at 5 years. Freedom from reoperation after redo-LAVV repair was 87% at 5 years with no significant difference between repair and replacement groups., Conclusion: In the current era, more LAVVs can be preserved at the time of redo-operation with excellent early and long-term survival and acceptable reoperation rates. LAVV morphology and presence of trisomy 21 did not affect outcome., (© 2018 Wiley Periodicals, Inc.)