tbuckley/cabot-search huggingface dataset:
Flies in the ointment: AAV vector preparations and tumor risk
Authors: Junping Zhang, Xiangping Yu, Roland W. Herzog, R. Jude Samulski, Weidong Xiao
Journal: Molecular Therapy (2021)

In an article previously published in Molecular Therapy, a high incidence of cancer formation was reported in mice transduced with adeno-associated viral (AAV) vector. 1 Rosas L.E. Grieves J.L. Zaraspe K. La Perle K.M. Fu H. McCarty D.M. Patterns of scAAV vector insertion associated with oncogenic events in a mouse model for genotoxicity. Mol. Ther. 2012; 20: 2098-2110 Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Tumors from hepatectomized mice transduced with a self-complementary AAV (scAAV) vector containing a strong enhancer/promoter (CMV/beta-actin) but lacking a transgene or polyadenylation signal ("CBA-null," Figure 1A) were more frequently associated with vector DNA than tumors in the control group that had been transduced with a conventional scAAV vector expressing a reporter gene. Most tumors caused by CBA-null vector insertions in the host chromosome were associated with common proto-oncogenes or tumor suppressors. These studies were performed in the tumor-prone mouse strain C3H/HeJ and in mice with severe combined immunodeficiency (SCID). Facilitated by the specific design of the CBA-null vector, proto-oncogene activation in liver tumors was linked to readthrough transcription or transcriptional enhancer effects on the target gene caused by rAAV integration.
Magnetic Resonance Imaging Screening for Postinfarct Life-Threatening Ventricular Arrhythmia
Authors: Christian de Chillou, Damien Voilliot, Sana Amraoui, Josselin Duchateau, Eloi Marijon, Estelle Gandjbakhch, Philippe Maury, Jean-Marc Sellal, Gabriela Hossu, Hubert Cochet, Pierre-Yves Marie, Damien Mandry, Elie Mousseaux, Alban Redheuil, Anne Rollin, Olivier Lairez, Victor Waldmann, Gilles Soulat, Xavier Waintraub, Maheshwar Pauriah, Faiez Zannad, Nicolas Girerd, Isabelle Magnin-Poull, Marine Beaumont, Pierre Jaïs, Frédéric Sacher, Mélèze Hocini, Pierre Bordachar, Hugues Blangy, Nicolas Sadoul, Jacques Felblinger, Michel Haïssaguerre, Freddy Odille
Journal: JACC. Cardiovascular imaging (2021)
Prevalence and Trends in Suicidal Behavior Among US Military Veterans During the COVID-19 Pandemic
Authors: Brandon Nichter, Melanie L. Hill, Peter J. Na, Alexander C. Kline, Sonya B. Norman, John H. Krystal, Steven M. Southwick, Robert H. Pietrzak
Journal: JAMA Psychiatry (2021)

The COVID-19 pandemic has raised considerable concerns about increased risk for suicidal behavior among US military veterans, who already had elevated rates of suicide before the pandemic.To examine longitudinal changes in suicidal behavior from before the COVID-19 pandemic to nearly 10 months into the pandemic and identify risk factors and COVID-related variables associated with new-onset suicide ideation (SI).This population-based prospective cohort study used data from the first and second wave of the National Health and Resilience in Veterans Study, conducted from November 18, 2019, to December 19, 2020. Median dates of data collection for the prepandemic and peripandemic assessments were November 21, 2019, and November 14, 2020, nearly 10 months after the start of the COVID-19 public health emergency in the US. A total of 3078 US military veterans aged 22 to 99 years were included in the study.Past-year SI and suicide attempts.In this cohort study of 3078 US veterans (mean [SD] age, 63.2 [14.7] years; 91.6% men; 79.3% non-Hispanic White veterans, 10.3% non-Hispanic Black veterans, and 6.0% Hispanic veterans), 233 (7.8%) reported past-year SI, and 8 (0.3%) reported suicide attempts at the peripandemic assessment. Past-year SI decreased from 10.6% prepandemic (95% CI, 9.6%-11.8%) to 7.8% peripandemic (95% CI, 6.9%-8.8%). A total of 82 veterans (2.6%) developed new-onset SI over the follow-up period. After adjusting for sociodemographic and military characteristics, the strongest risk factors and COVID-19-related variables for new-onset SI were low social support (odds ratio [OR], 2.77; 95% CI, 1.46-5.28), suicide attempt history (OR, 6.31; 95% CI, 2.71-14.67), lifetime posttraumatic stress disorder and/or depression (OR, 2.25; 95% CI, 1.16-4.35), past-year alcohol use disorder severity (OR, 1.06; 95% CI, 1.01-1.12), COVID-19 infection (OR, 2.41; 95% CI, 1.41-5.01), and worsening of social relationships during the pandemic (OR, 1.47; 95% CI, 1.16-1.88).The results of this cohort study suggest that despite grim forecasts that the COVID-19 pandemic would exacerbate suicidality among US military veterans, the rate of SI decreased at the population level nearly 10 months into the pandemic. Veterans who were infected with COVID-19 were more than twice as likely to report SI, which suggests the need for future research to examine the potential link between COVID-19 infection and suicidal behavior.
26592 Characterization of response clusters identified by unsupervised machine learning: A post hoc analysis of the head-to-head ECLIPSE trial of guselkumab and secukinumab in patients with moderate-to-severe psoriasis
Authors: Diamant Thaçi, Curdin Conrad, Alexander Egeberg, Andreas Pinter, Kristian Reich, Bethany Hyde, Ye-Jin Eun, Sven Wegner, Maria Jazra, Bülent Öztürk, Knut Schäkel
Journal: Journal of the American Academy of Dermatology (2021)
Differential roles of FOXO transcription factors on insulin action in brown and white adipose tissue
Authors: Erica P. Homan, Bruna B. Brandão, Samir Softic, Abdelfattah El Ouaamari, Brian T. O’Neill, Rohit N. Kulkarni, Jason K. Kim, C. Ronald Kahn
Journal: Journal of Clinical Investigation (2021)

Insulin and IGF-1 are essential for adipocyte differentiation and function. Mice lacking insulin and IGF-1 receptors in fat (FIGIR-KO, fat-specific IGF-1 receptor and insulin receptor–KO) exhibit complete loss of white and brown adipose tissue (WAT and BAT), glucose intolerance, insulin resistance, hepatosteatosis, and cold intolerance. To determine the role of FOXO transcription factors in the altered adipose phenotype, we generated FIGIR-KO mice with fat-specific KO of fat-expressed Foxos [Foxo1, Foxo3, Foxo4] (F-Quint–KO). Unlike FIGIR-KO mice, F-Quint–KO mice had normal BAT, glucose tolerance, insulin-regulated hepatic glucose production, and cold tolerance. However, loss of FOXOs only partially rescued subcutaneous WAT and hepatosteatosis, did not rescue perigonadal WAT or systemic insulin resistance, and led to even more marked hyperinsulinemia. Thus, FOXOs play different roles in insulin/IGF-1 action in different adipose depots, being most important in BAT, followed by subcutaneous WAT and then by visceral WAT. Disruption of FOXOs in fat also led to a reversal of insulin resistance in liver, but not in skeletal muscle, and an exacerbation of hyperinsulinemia. Thus, adipose FOXOs play a unique role in regulating crosstalk between adipose depots, liver, and β cells.
High-performance SOD mimetic enzyme Au@Ce for arresting cell cycle and proliferation of acute myeloid leukemia
Authors: Yuxiang Sun, Xin Liu, Lei Wang, Li Xu, Kunliang Liu, Lei Xu, Fangfang Shi, Yu Zhang, Ning Gu, Fei Xiong
Journal: Bioactive Materials (2021)

SOD-like activity of CeO2 nanoparticles (Ce NPs) is driven by Ce3+/Ce4+, high oxidative stress can oxidize Ce3+ to reduce the ratio of Ce3+/Ce4+, inactivating the SOD activity of Ce NPs. Herein, we found Au@Ce NPs, assembled by Au NPs and Ce NPs, exhibited high-performance of SOD mimetic enzyme activity even upon the oxidation of H2O2. Ce NPs supported by nano-Au can acquire the electrons from Au NPs through the enhanced localized surface plasmon resonance (LSPR), maintaining the stability of Ce3+/Ce4+ and SOD-like activity. Meanwhile, Au@Ce NPs retained the peroxidase function and catalase function. As a result, Au@Ce NPs effectively scavenged O2•- and the derived ROS in AML cells, which are the important signaling source that drives AML cell proliferation and accelerates cell cycle progression. When HL-60 cells were treated by Au@Ce NPs, the removal of endogenous ROS signal significantly arrested cell cycle at G1 phase and suppressed the cell proliferation by blocking the mitogen-activated protein kinases (MAPKs) signaling and the Akt/Cyclin D1 cell cycle signaling. Importantly, this treatment strategy showed therapeutic effect for subcutaneous transplantation of AML model as well as a satisfactory result in diminishing the leukocyte infiltration of liver and spleen particularly. Thus, assembled Au@Ce NPs show the high-performance SOD-like activity, promising the potential in treating AML and regulating abnormal ROS in other diseases safely and efficiently.
Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk
Authors: Melissa M. Clemens, Stefanie Kennon-McGill, Joel H. Vazquez, Owen W. Stephens, Erich A. Peterson, Donald J. Johann, Felicia D. Allard, Eric U. Yee, Sandra S. McCullough, Laura P. James, Brian N. Finck, Mitchell R. McGill
Journal: Acta Pharmaceutica Sinica B (2021)

We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity. Here, we hypothesized that exogenous PA is also beneficial. To test that, we treated mice with a toxic APAP dose at 0 h, followed by PA or vehicle (Veh) post-treatment. We then collected blood and liver at 6, 24, and 52 h. Post-treatment with PA 2 h after APAP protected against liver injury at 6 h, and the combination of PA and N-acetyl-l-cysteine (NAC) reduced injury more than NAC alone. Interestingly, PA did not affect canonical mechanisms of APAP toxicity. Instead, transcriptomics revealed that PA activated interleukin-6 (IL-6) signaling in the liver. Consistent with that, serum IL-6 and hepatic signal transducer and activator of transcription 3 (Stat3) phosphorylation increased in PA-treated mice. Furthermore, PA failed to protect against APAP in IL-6-deficient animals. Interestingly, IL-6 expression increased 18-fold in adipose tissue after PA, indicating that adipose is a source of PA-induced circulating IL-6. Surprisingly, however, exogenous PA did not alter regeneration, despite the importance of endogenous PA in liver repair, possibly due to its short half-life. These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model.
28522 The impact of the SARS-CoV-2 pandemic on phototherapy utilization
Authors: Aunna Pourang, Hailey Olds, Nneamaka Ezekwe, Henry W. Lim, Iltefat Hamzavi
Journal: Journal of the American Academy of Dermatology (2021)

Phototherapy is a mainstay of treatment for several dermatologic conditions. Patients often require multiple treatments per week for several weeks to months to achieve treatment efficacy. The SARS-CoV-2 global pandemic caused many dermatology clinics to close completely or significantly reduce patient volumes, which may have limited patient access to this beneficial treatment. This retrospective study examines the pandemic's impact on phototherapy treatment rates and reimbursement at one major tertiary care center and five locations of a private dermatology clinic in Southeast Michigan. Phototherapy CPT reimbursement data from March 1-June 30, 2020 was compared with the same timeframe in 2019. Units of phototherapy performed decreased by an average of 84%, and there was an average decrease of 43% in the number of unique patients receiving treatments. Reimbursement for phototherapy decreased by an average of 83%. The drastic decline in phototherapy reimbursement is a reflection of the pandemic's financial impact and likely correlates to a larger scale of revenue loss in dermatology practices. Adequate phototherapy treatment was also likely delayed for many patients. As the pandemic continues, implementation of home phototherapy treatments may be necessary for patients to receive proper treatment and to minimize the impact of loss of revenue due to limited in-office phototherapy. Precautions will need to be taken to guarantee the safety of patients and the care team for patients to receive optimal in-office phototherapy treatment. The pandemic's impact on medical dermatology finances could potentially destabilize access to patients who need this safe and effective treatment.
Utilizing biomarkers in atrial fibrillation: the pros and cons
Authors: Wern Yew Ding, Garry McDowell, Gregory Y H Lip
Journal: Cardiovascular Research (2021)

This editorial refers to ‘Using multimarker screening to identify biomarkers associated with cardiovascular death in patients with atrial fibrillation’ by T. Pol et al., doi:10.1093/cvr/cvab262. The interplay of atrial fibrillation (AF) with various conditions such as chronic kidney disease, obstructive sleep apnoea, and chronic obstructive pulmonary disease is well recognized, reinforcing the notion that AF rarely occurs in isolation and that this is in fact a multisystem disorder. Accordingly, the approach to AF care has moved beyond mere therapeutics aimed at the disease itself to greater focus on holistic and integrated management, as well as the upstream management of risk factors, given the improved outcomes with such an approach.1,2 A real-world observational study previously reported an annual mortality rate in patients with AF of 5.5%, the majority of which were attributable to cardiovascular causes3; however, a significant proportion of this cohort of patients were...
SPLUNC1 is a novel marker of disease severity and airway infection in bronchiectasis
Authors: Holly R. Keir, Amelia Shoemark, Jeffrey T.J. Huang, James D. Chalmers
Journal: European Respiratory Journal (2021)

<b>Having been shown to be a biomarker of severity in cystic fibrosis, this study shows SPLUNC1 is also a novel marker of severity and lung infections in non-CF bronchiectasis</b>https://bit.ly/3ABzEdc
Immune signatures reveal tumor escape targets in mice and man
Authors: Rebecca Sadun, Suzanne Sachsman, William Morris, Xiaoying Chen, Alan Epstein
Journal: Cancer Research (2007)

2743  Immunotherapy represents a powerful tool for reversing the immune system’s tolerance to cancer. The success of a given immunotherapy regimen in a particular cancer, however, depends on the treatment’s ability to reverse the escape mechanism(s) being employed by that cancer. We sought to determine the molecules involved in the tumor escape strategies of specific cancers by measuring the expression levels of immunomodulatory molecules in five BALB/c mouse tumors (4TI breast, A20 lymphoma, C26 colon, MAD109 lung, and RENCA renal cell carcinoma) and two human counterparts (breast and colon cancers). For the murine studies, groups of tumor-bearing mice were treated with an immunotherapy regimen, LEC/chTNT-3 + PC61, known to produce significant tumor regression in a tumor model-dependent fashion. Real-time rtPCR was used to measure the expression profiles of a panel T cell activation/inhibition genes at the tumor site. Gene expression was compared between control mice (no treatment), mice completely responsive to treatment (A20, C26), mice moderately responsive to treatment (4TI), and mice poorly responsive to treatment (MAD109, RENCA). The Treg transcription factor FoxP3 was found to be high in untreated 4TI, A20, and C26 tumor signatures, but not in the immune signatures of untreated MAD109 or RENCA tumors. This insight could predict the preferable response of C26, A20, and 4TI tumors to Treg depletion using PC61 treatment. Genes like PD-L2 were profoundly increased in all five cancers and may thus represent a more universal target for immunotherapy. To determine the clinical utility of these gene signatures, murine 4TI and C26 tumors were compared to their human counterparts (breast and colorectal adenocarcinomas). Remarkably, all tested cases of breast cancer (n=8) displayed a homogenous signature, a signature also consistent with that of murine breast tumor. Human colorectal cases (n=12), however, displayed marked heterogeneity, suggesting that while a single immunotherapeutic reagent may be appropriate for the majority of ductal breast carcinomas, subgroups of colorectal cancers may require different immunotherapeutic strategies, despite their similar histology. These data underscore the importance of attaining immune signatures of the common human cancers, which would facilitate both the design of immunotherapies capable of targeting and reversing immune abnormalities and the determination of which patients are likely to respond to which immunotherapeutic regimens.
Reasons, Respect, and Identity in Public Health Decision Making
Authors: Søren Holm
Journal: The American Journal of Bioethics (2021)

argues in the paper 'Neutrality and perfectionism in public health' that the state can legitimately implement public health policies that protect capabilities, even if these policies to some extent infringe the liberty of citizens (M'hamdi 2021).I completely agree with the conclusion, probably in part because I am a liberal, Scandinavian welfare state supporter at heart, but I think some of M'hamdi's arguments to this conclusion are fundamentally problematic.The core of my concern is that two distinctions that are made in the arguments developing criteria for which liberties the state should respect and which it can infringe are much more complicated to make than it initially seems.The first is the distinction between liberties that are essential to our
Associations of BNT162b2 vaccination with SARS-CoV-2 infection and hospital admission and death with covid-19 in nursing homes and healthcare workers in Catalonia: prospective cohort study
Authors: Carmen Cabezas, Ermengol Coma, Nuria Mora-Fernandez, Xintong Li, Montse Martinez-Marcos, Francesc Fina, Mireia Fabregas, Eduardo Hermosilla, Angel Jover, Juan Carlos Contel, Yolanda Lejardi, Belen Enfedaque, Josep Maria Argimon, Manuel Medina-Peralta, Daniel Prieto-Alhambra
Journal: BMJ (2021)

Abstract Objective To determine associations of BNT162b2 vaccination with SARS-CoV-2 infection and hospital admission and death with covid-19 among nursing home residents, nursing home staff, and healthcare workers. Design Prospective cohort study. Setting Nursing homes and linked electronic medical record, test, and mortality data in Catalonia on 27 December 2020. Participants 28 456 nursing home residents, 26 170 nursing home staff, and 61 791 healthcare workers. Main outcome measures Participants were followed until the earliest outcome (confirmed SARS-CoV-2 infection, hospital admission or death with covid-19) or 26 May 2021. Vaccination status was introduced as a time varying exposure, with a 14 day run-in after the first dose. Mixed effects Cox models were fitted to estimate hazard ratios with index month as a fixed effect and adjusted for confounders including sociodemographics, comorbidity, and previous medicine use. Results Among the nursing home residents, SARS-CoV-2 infection was found in 2482, 411 were admitted to hospital with covid-19, and 450 died with covid-19 during the study period. In parallel, 1828 nursing home staff and 2968 healthcare workers were found to have SARS-CoV-2 infection, but fewer than five were admitted or died with covid-19. The adjusted hazard ratio for SARS-CoV-2 infection after two doses of vaccine was 0.09 (95% confidence interval 0.08 to 0.11) for nursing home residents, 0.20 (0.17 to 0.24) for nursing home staff, and 0.13 (0.11 to 0.16) for healthcare workers. Adjusted hazard ratios for hospital admission and mortality after two doses of vaccine were 0.05 (0.04 to 0.07) and 0.03 (0.02 to 0.04), respectively, for nursing home residents. Nursing home staff and healthcare workers recorded insufficient events for mortality analysis. Conclusions Vaccination was associated with 80-91% reduction in SARS-CoV-2 infection in all three cohorts and greater reductions in hospital admissions and mortality among nursing home residents for up to five months. More data are needed on longer term effects of covid-19 vaccines.
Effects of Dapagliflozin in Patients With Kidney Disease, With and Without Heart Failure
Authors: John J.V. McMurray, David C. Wheeler, Bergur V. Stefánsson, Niels Jongs, Douwe Postmus, Ricardo Correa-Rotter, Glenn M. Chertow, Fan Fan Hou, Peter Rossing, C. David Sjöström, Scott D. Solomon, Robert D. Toto, Anna Maria Langkilde, Hiddo J.L. Heerspink
Journal: JACC Heart Failure (2021)

The purpose of this paper was to investigate the effects of dapagliflozin in chronic kidney disease (CKD) patients, with and without heart failure (HF).Patients with CKD, with and without type 2 diabetes, were enrolled in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial. Some patients had HF at baseline.A total of 4,304 participants were randomized to dapagliflozin 10 mg daily or placebo. The primary composite endpoint was ≥50% decline in estimated glomerular filtration rate, end-stage kidney disease, or kidney/cardiovascular death. Secondary endpoints were a kidney composite (primary endpoint minus cardiovascular death), the composite of cardiovascular death/HF hospitalization, and all-cause death. Analysis of outcomes according to HF history was prespecified.HF patients (n = 468; 11%) were older and had more coronary disease, atrial fibrillation, and type 2 diabetes. Mean estimated glomerular filtration rate was similar in patients with and without HF. Rates of HF hospitalization/cardiovascular death and death from any cause were higher in HF patients, but the secondary kidney failure outcome occurred at the same rate in people with and without HF. Dapagliflozin reduced the risk of the primary outcome equally in patients with HF (HR: 0.58 [95% CI: 0.37-0.91]) and without HF (HR: 0.62 [95% CI: 0.51-0.75]) (P interaction = 0.59). The proportional risk-reductions were similar in patients with and without HF for the cardiovascular death/HF hospitalization composite (HR: 0.68 [95% CI: 0.44-1.05] vs HR: 0.70 [95% CI: 0.51-0.97], respectively; P interaction = 0.90), and all-cause death (HR: 0.56 [95% CI: 0.34-0.93] vs HR: 0.73 [95% CI: 0.54-0.97], respectively; P interaction = 0.39), although absolute risk reductions were larger in HF patients. Adverse event rates were low and did not differ among patients with or without HF.Dapagliflozin reduced the risk of kidney failure and cardiovascular death/HF hospitalization and prolonged survival in CKD patients with or without type 2 diabetes, independently of history of HF. (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease [DAPA-CKD]; NCT03036150).
A high-affinity human TCR-like antibody detects celiac disease gluten peptide–MHC complexes and inhibits T cell activation
Authors: Rahel Frick, Lene S. Høydahl, Jan Petersen, M. Fleur du Pré, Shraddha Kumari, Grete Berntsen, Alisa E. Dewan, Jeliazko R. Jeliazkov, Kristin S. Gunnarsen, Terje Frigstad, Erik S. Vik, Carmen Llerena, Knut E.A. Lundin, Sheraz Yaqub, Jørgen Jahnsen, Jeffrey J. Gray, Jamie Rossjohn, Ludvig M. Sollid, Inger Sandlie, Geir Åge Løset
Journal: Science Immunology (2021)

A human TCR-like antibody blocks gluten-dependent activation of celiac disease T cells in vitro and in HLA-DQ2.5 humanized mice.