We demonstrate controllable excitation of the center-of-mass longitudinal motion of a thermal antiproton plasma using a swept-frequency autoresonant drive. When the plasma is cold, dense, and highly ...collective in nature, we observe that the entire system behaves as a single-particle nonlinear oscillator, as predicted by a recent theory. In contrast, only a fraction of the antiprotons in a warm plasma can be similarly excited. Antihydrogen was produced and trapped by using this technique to drive antiprotons into a positron plasma, thereby initiating atomic recombination.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Abstract
KAT6A is a lysine histone acetyltransferase (HAT) of the MYST family of HATs. KAT6A, and its paralog KAT6B, have been shown to acetylate histone H3K23Ac and regulate diverse biological ...processes, including transcription, cell-cycle progression, stem cell maintenance and development. Molecular dysregulation of KAT6A has been observed in several cancers, including amplifications in breast, lung, ovarian cancer along with oncogenic fusions in AML. In breast cancer, KAT6A is amplified as part of the 8p11 amplicon in 10-15% of the patient population, which correlates with a worse clinical outcome in the estrogen receptor+ (ER+) subtype. Here we present identification of a first-in-class potent KAT6A/KAT6B tool inhibitor CTx-648 (PF-9363), that possesses high selectivity versus other MYST family members (KAT7, KAT5, KAT8) and other KATs, demonstrating anti-tumor activity in breast cancer. Using genetic and pharmacological approaches, we have demonstrated several ER+ breast cancer cell lines including KAT6A amplified and over-expressing models, are dependent on KAT6A enzymatic function. Epigenomic profiling studies using bulk and nascent RNA-seq combined with ATAC-seq revealed CTx-648 leads to downregulation of a specific set of genes involved in ESR1 pathway, cell cycle and stem cell pathways. In vivo target validation studies showed strong anti-tumor activity of CTx-648 in several ER+ breast cancer cell line and patient-derived xenograft models, including models harboring endocrine therapy resistance ESR1 mutations, highlighting promise for this novel therapy in ER+ breast cancer population. Based on the strength of the pre-clinical data, a selective KAT6 inhibitor (PF-07248144) is now commencing a Phase 1 clinical study in Advanced or Metastatic Solid Tumors.
Citation Format: Shikhar Sharma, Jay Chung, Sean Uryu, Amanda Rickard, Natalie Nady, Showkhin Khan, Zhenxiong Wang, Yong Zhang, Haikuo Zhang, Pei-Pei Kung, Eric Greenwald, Karen Maegley, Patrick Bingham, Hieu Lam, Ylva E. Bozikis, Hendrik Falk, Elizabeth Allan, Vicky M. Avery, Miriam S. Butler, Michelle A. Camerino, Catalina Carrasco-Pozo, Susan A. Charman, Melissa J. Davis, Mark A. Dawson, Dawson Sarah-Jane, Melanie de Silva, Matthew L. Dennis, Olan Dolezal, Rachel Lagiakos, Geoffrey J. Lindeman, Laura MacPherson, Stewart Nuttall, Thomas S. Peat, Bin Ren, Alexandra E. Stupple, Elliot Surgenor, Chin Wee Tan, Tim Thomas, Jane E. Visvader, Anne K. Voss, Francois Vaillant, Karen L. White, James Whittle, Yuqing Yang, Soroor Hediyeh-Zadeh, Paul A. Stupple, Ian P. Street, Brendon J. Monahan, Thomas Paul. First-in-class KAT6A/KAT6B inhibitor CTx-648 (PF-9363) demonstrates potent anti-tumor activity in ER+ breast cancer with KAT6A dysregulation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1130.
The authors sought to evaluate 2 approaches with varying time and complexity in engaging adolescents with an Internet-based preventive intervention for depression in primary care. The authors ...conducted a randomized controlled trial comparing primary care physician motivational interview (MI, 5-10 minutes) + Internet program versus brief advice (BA, 1-2 minutes) + Internet program.
Adolescent primary care patients in the United States, aged 14 to 21 years.
Eighty-four individuals (40% non-white) at increased risk for depressive disorders (subthreshold depressed mood >3-4 weeks) were randomly assigned to either the MI group (n = 43) or the BA group (n = 40).
Patient Health Questionnaire-Adolescent and Center for Epidemiologic Studies Depression Scale (CES-D).
Both groups substantially engaged the Internet site (MI, 90.7% vs BA 77.5%). For both groups, CES-D-10 scores declined (MI, 24.0 to 17.0, p < .001; BA, 25.2 to 15.5, p < .001). The percentage of those with clinically significant depression symptoms based on CES-D-10 scores declined in both groups from baseline to 12 weeks, (MI, 52% to 12%, p < .001; BA, 50% to 15%, p < .001). The MI group demonstrated declines in self-harm thoughts and hopelessness and was significantly less likely than the BA group to experience a depressive episode (4.65% vs 22.5%, p = .023) or to report hopelessness (MI group of 2% vs 15% for the BA group, p = .044) by 12 weeks.
An Internet-based prevention program in primary care is associated with declines in depressed mood and the likelihood of having clinical depression symptom levels in both groups. Motivational interviewing in combination with an Internet behavior change program may reduce the likelihood of experiencing a depressive episode and hopelessness.
Mutation detection accuracy has been described extensively; however, it is surprising that pre-PCR processing of formalin-fixed paraffin-embedded (FFPE) samples has not been systematically assessed ...in clinical context. We designed a RING trial to (i) investigate pre-PCR variability, (ii) correlate pre-PCR variation with EGFR/BRAF mutation testing accuracy and (iii) investigate causes for observed variation.
13 molecular pathology laboratories were recruited. 104 blinded FFPE curls including engineered FFPE curls, cell-negative FFPE curls and control FFPE tissue samples were distributed to participants for pre-PCR processing and mutation detection. Follow-up analysis was performed to assess sample purity, DNA integrity and DNA quantitation.
Rate of mutation detection failure was 11.9%. Of these failures, 80% were attributed to pre-PCR error. Significant differences in DNA yields across all samples were seen using analysis of variance (p<0.0001), and yield variation from engineered samples was not significant (p=0.3782). Two laboratories failed DNA extraction from samples that may be attributed to operator error. DNA extraction protocols themselves were not found to contribute significant variation. 10/13 labs reported yields averaging 235.8 ng (95% CI 90.7 to 380.9) from cell-negative samples, which was attributed to issues with spectrophotometry. DNA measurements using Qubit Fluorometry demonstrated a median fivefold overestimation of DNA quantity by Nanodrop Spectrophotometry. DNA integrity and PCR inhibition were factors not found to contribute significant variation.
In this study, we provide evidence demonstrating that variation in pre-PCR steps is prevalent and may detrimentally affect the patient's ability to receive critical therapy. We provide recommendations for preanalytical workflow optimisation that may reduce errors in down-stream sequencing and for next-generation sequencing library generation.
BACKGROUND—There are limited data on comparison of contemporary drug-eluting stent (DES) platforms, previous generation DES, and bare-metal stents (BMS) for percutaneous coronary intervention in ...saphenous vein grafts (SVG). We aimed to assess clinical outcomes following percutaneous coronary intervention to SVG in patients receiving bare-metal stents (BMS), first-generation DES, and newer generation DES in a large unselected national data set from the BCIS (British Cardiovascular Intervention Society).
METHODS AND RESULTS—Patients undergoing percutaneous coronary intervention to SVG in the United Kingdom from January 2006 to December 2013 were divided into 3 groups according to stent useBMS, first-generation DES, and newer generation DES group. Study outcomes included in-hospital major adverse cardiovascular events, 30-day mortality, and 1-year mortality. Patients (n=15 003) underwent percutaneous coronary intervention to SVG in England and Wales during the study period. Of these, 38% received BMS, 15% received first-generation DES, and 47% received second-generation DES. The rates of in-hospital major adverse cardiovascular events were significantly lower in patients treated with second-generation DES (odds ratio, 0.51; 95% confidence interval, 0.38–0.68; P<0.001), but not with first-generation DES, compared with BMS-treated patients. Similarly, 30-day mortality (odds ratio, 0.43; 95% confidence interval, 0.32–0.59; P<0.001) and 1-year mortality (odds ratio, 0.60; 95% confidence interval, 0.51–0.71; P<0.001) were lower in patients treated with second-generation DES, but not with first-generation DES, compared with the patients treated with BMS.
CONCLUSIONS—Patients receiving second-generation DES for the treatment SVG disease have lower rates of in-hospital major adverse cardiovascular events, 30-day mortality, and 1-year mortality, compared with those receiving BMS.
Background The Millennium Cohort Study of UK babies born this century obtained maternal report of birth weight and data on the family's characteristics, including parental ethnicity, education, and ...social circumstances. Parental permission to link babies to their birth registration data provided the opportunity to investigate factors affecting accuracy of maternal recall of birth weight and to determine possible causes of error. Methods Logistic regression was used to investigate the relationship between maternal factors and recall of birth weight. Numerical and graphical methods were used to identify potential causes for birth weight discrepancies. Results Data were obtained from the birth registry and Millennium Cohort Study for 11 890 of the 14 294 cohort children born in England and Wales. Weight was reported in imperial units by 84% of mothers and this was more common in younger mothers. Accuracy within 100 g was 92% overall, varying from 94% among British/Irish white mothers to 69–89% for other ethnic groups and was lower among the long-term unemployed and those living in disadvantaged or ethnic wards. Explanations (mostly rounding and transcription errors) were identified for 27% of the discrepancies of 100 g or more. Conclusion Mothers' reports of their infants' birth weight showed high level of agreement with registration data, the mean discrepancy being consistently close to zero. However, the variance of the discrepancy differed according to ethnic group, ward type, and socioeconomic status. These sources of differential variability should be taken into account in analyses using birth weight, and possibly other reported data, from socially mixed populations.
This study sought to determine the effect of percutaneous mitral valve annuloplasty with the Carillon device versus guideline-directed medical therapy (GDMT) alone in patients with secondary mitral ...regurgitation (MR) and severe left ventricular (LV) enlargement.
The clinical impact of the Carillon device in patients with severe LV dilation is not well established.
This is a pooled analysis involving 3 prospective trials (TITAN Transcatheter Implantation of Carillon Mitral Annuloplasty Device, TITAN II, and REDUCE FMR CARILLON Mitral Contour System for Reducing Functional Mitral Regurgitation trials) in which patients with functional MR and severe LV enlargement (LV end-diastolic diameter >65 mm) were treated with GDMT and the Carillon device versus GDMT alone. Key outcomes of this analysis were changes over 1 year of follow-up in mitral valve and LV echocardiographic parameters, functional outcome, quality of life, mortality, and heart failure hospitalization (HFH).
A total of 95 patients (67 in the Carillon group, 28 in the GDMT group) with severe LV enlargement were included. In the Carillon group, all mitral valve and LV morphology parameters were significantly improved at 1 year. Regurgitant volume decreased by 12 ml (p < 0.001), MR grade decreased by 0.6 U (p < 0.001), LV end-diastolic volume decreased by 25 cm3 (p = 0.005), and LV end-systolic volume decreased by 21 cm3 (p = 0.01). Significant functional improvement differences were also noted between the Carillon group and the GDMT group including an improvement of Kansas City Cardiomyopathy Questionnaire score (15 ± 4 vs. 6 ± 6; p = 0.03). The incidence of HFH was 29.9% versus 50.0% and the cumulative rate of HFH was 0.43 versus 0.75 (p < 0.001).
In patients with functional MR and severe LV enlargement, the Carillon device improved mitral valve function, LV morphology, and functional outcome compared with patients receiving GDMT only. Preoperative LV dimension should not be a limiting factor when evaluating patient eligibility or anticipated response to therapy with the Carillon device.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose To identify factors associated with best-corrected visual acuity (BCVA) presentation and 2-year outcome in 479 intermediate, posterior, and panuveitic eyes. Design Cohort study using ...randomized controlled trial data. Methods Multicenter Uveitis Steroid Treatment (MUST) Trial masked BCVA measurements at baseline and at 2 years follow-up used gold-standard methods. Twenty-three clinical centers documented characteristics per protocol, which were evaluated as potential predictive factors for baseline BCVA and 2-year change in BCVA. Results Baseline factors significantly associated with reduced BCVA included age ≥50 vs <50 years; posterior vs intermediate uveitis; uveitis duration >10 vs <6 years; anterior chamber (AC) flare >grade 0; cataract; macular thickening; and exudative retinal detachment. Over 2 years, eyes better than 20/50 and 20/50 or worse at baseline improved, on average, by 1 letter ( P = .52) and 10 letters ( P < .001), respectively. Both treatment groups and all sites of uveitis improved similarly. Factors associated with improved BCVA included resolution of active AC cells, resolution of macular thickening, and cataract surgery in an initially cataractous eye. Factors associated with worsening BCVA included longer duration of uveitis (6–10 or >10 vs <6 years), incident AC flare, cataract at both baseline and follow-up, pseudophakia at baseline, persistence or incidence of vitreous haze, and incidence of macular thickening. Conclusions Intermediate, posterior, and panuveitis have a similarly favorable prognosis with both systemic and fluocinolone acetonide implant treatment. Eyes with more prolonged/severe inflammatory damage and/or inflammatory findings initially or during follow-up have a worse visual acuity prognosis. The results indicate the value of implementing best practices in managing inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Ronald Lewis Graham (1935–2020) Buhler, Joe; Butler, Steve; Spencer, Joel ...
Notices of the American Mathematical Society,
12/2021, Volume:
68, Issue:
11
Journal Article
β-Thalassemias are a group of inherited blood disorders caused by loss of β-globin synthesis and are characterized by anemia, extramedullary hematopoiesis and ineffective erythropoiesis leading to ...secondary iron overload. Increased iron absorption is due to inappropriately low levels of the liver hormone, hepcidin (HAMP). The membrane serine protease Matriptase-2 (TMPRSS6) attenuates BMP-mediated HAMP induction by cleaving the BMP co-receptor, hemojuvelin (HJV). Previously, we demonstrated that an RNAi-therapeutic targeting Tmprss6 elevates hepcidin expression and reduces disease severity in the Hbbth3/+ mouse model of β-Thalassemia intermedia (Blood. 2013; 14;121(7):1200-8). To further interrogate the efficacy of this therapeutic approach, Hbbth3/+ animals were treated with a siRNA directed against Tmprss6 on a replete 50ppm iron diet, a low iron diet (3-5ppm iron) or a 50ppm iron diet containing deferiprone.
Systemic administration of an siRNA directed against Tmprss6 in the three diet conditions leads to significant inhibition of Tmprss6 mRNA in the livers of Hbbth3/+ mice with concomitant elevation in hepcidin expression. In correspondence with earlier studies, we demonstrate here that Tmprss6 silencing in animals under each of the three diet regimens leads to a significant improvement in the anemia of Hbbth3/+ mice as evidenced by increased total hemoglobin. Furthermore, hallmarks of ineffective erythropoiesis, including splenomegaly and reticulocytosis, were decreased in all Tmprss6 silenced Hbbth3/+ animals. If untreated, excessive iron loading in humans with β-Thalassemia leads to tissue iron deposition and eventual organ damage and failure. Importantly, here we demonstrate that the total body iron burden of Hbbth3/+ mice, as assessed by non-heme liver iron, is decreased by almost 30% in animals chelated with oral deferiprone and treated with Tmprss6 siRNA. A similar diminution of iron deposition is not evident in animals on a low iron diet or in mice fed deferiprone alone. Taken together, this data suggest that siRNA suppression of Tmprss6, in conjunction with chelation therapy, may provide an improved modality for treatment of the anemia and secondary iron loading seen in hemoglobinopathies such as β-Thalassemia.
Racie:Alnylam Pharmaceutical, Inc: Employment. Butler:Alnylam Pharmaceutical, Inc: Employment. Fitzgerald:Alnylam: Employment. Fleming:Alnylam Pharmaceutical, Inc: Research Funding.
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