tbuckley/cabot-search huggingface dataset:
Abstract 3553: Echocardiographic Mechanisms and Clinical Impact of Significant Mitral Regurgitation After Percutaneous Mitral Valvuloplasty
Authors: Mi-Jeong Kim, Young-Hoon Jung, Se-Whan Lee, Jon Suh, Hyuk Ko, Young-Hak Kim, Jong-Min Song, Duk-Hyun Kang, Myeong-Ki Hong, Jae-Joong Kim, Seong-Wook Park, Seung-Jung Park, Jae-Kwan Song
Journal: Circulation (2006)

To assess the incidence and clinical impact of different mechanisms of significant traumatic mitral regurgitation (MR) after percutaneous mitral valvuloplasty (PMV), echocardiographic and clinical ...
Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects
Authors: Atar Lev, Yu Nee Lee, Guangping Sun, Enas Hallumi, Amos J. Simon, Keren S. Zrihen, Shiran Levy, Tal Beit Halevi, Maria Papazian, Neta Shwartz, Ido Somekh, Sarina Levy-Mendelovich, Baruch Wolach, Ronit Gavrieli, Helly Vernitsky, Ortal Barel, Elisheva Javasky, Tali Stauber, Chi A. Ma, Yuan Zhang, Ninette Amariglio, Gideon Rechavi, Ayal Hendel, Deborah Yablonski, Joshua D. Milner, Raz Somech
Journal: The Journal of Experimental Medicine (2020)

The T cell receptor (TCR) signaling pathway is an ensemble of numerous proteins that are crucial for an adequate immune response. Disruption of any protein involved in this pathway leads to severe immunodeficiency and unfavorable clinical outcomes. Here, we describe an infant with severe immunodeficiency who was found to have novel biallelic mutations in SLP76. SLP76 is a key protein involved in TCR signaling and in other hematopoietic pathways. Previous studies of this protein were performed using Jurkat-derived human leukemic T cell lines and SLP76-deficient mice. Our current study links this gene, for the first time, to a human immunodeficiency characterized by early-onset life-threatening infections, combined T and B cell immunodeficiency, severe neutrophil defects, and impaired platelet aggregation. Hereby, we characterized aspects of the patient's immune phenotype, modeled them with an SLP76-deficient Jurkat-derived T cell line, and rescued some consequences using ectopic expression of wild-type SLP76. Understanding human diseases due to SLP76 deficiency is helpful in explaining the mixed T cell and neutrophil defects, providing a guide for exploring human SLP76 biology.
429P Demographics, pattern of care, and outcome analysis of malignant melanoma cases from a tertiary care centre in India
Authors: A. Agarwal, J. Bajpai, A. Chatterjee, A. Kapoor, A. Saklani, S. Mokal, P. Mondal, P. Eaga, P.G. Bhargava, A. Desouza, V.S. Ostwal, A. Ramaswamy, S. Dandekar, B. Reiki, M. Bal, K. Prabhash, S. Gupta, S. Banawali
Journal: Annals of Oncology (2020)
Legumain-induced intracerebrally crosslinked vesicles for suppressing efflux transport of Alzheimer's disease multi-drug nanosystem
Authors: Fuxin Jiang, Jian Ren, Yachai Gao, Jinna Wang, Yiping Zhao, Fengying Dai
Journal: Bioactive Materials (2020)

Brain barrier is both a protective permeability hurdle and a limitation site where therapeutic agents are excluded to enter the target region. Designing drug vehicle to overcome this notorious barrier bottle is challenging. Herein, we construct a stimuli-responsive self-assembled nanovesicle that delivers water-soluble drugs to prevent the efflux transport of brain barriers by responding to the endogenously occurring signals in Alzheimer's disease (AD) brain microenvironment. Once stimuli-responsive vesicles are accumulated in intracerebrally, the intrinsically occurring legumain endopeptidase cleaves the Ac-Ala-Ala-Asn-Cys-Asp (AK) short peptide on the drug vesicles to expose the 1,2 thiol amino group to cyclize with the cyano groups on 2-cyano-6-aminobenzothiazole (CABT) of the chaperone vesicles, thus triggering the formation of cross-linked micrometre-scale vesicles. Such a structural alteration completely prevents further brain barriers efflux. The superior neuroprotective capacity of cross-linked vesicles is validated in senescence accelerated mouse prone 8 (SAMP8). This smart multi-drug delivery vesicle is promising to serve as a powerful system for AD treatment and can be adapted for the therapy of other central nervous system (CNS) disorders.
Docosahexaenoic acid-induced apoptotic cell death is correlated with inhibition of β-catenin/wnt signaling pathway and Cox-2 in human pancreatic cancer cells
Authors: Kyoung-Sub Song, Eun-Jin Yun, Jong-Seok Kim, Jun-Young Heo, Yeon-Joo Jung, Chang Han, Tong Wu, Jong-Il Park, Gi-Ryang Kweon, Seung-Kiel Park, Wan-Hee Yoon, Byung-Doo Hwang, Kyu Lim
Journal: Cancer Research (2008)

2705  ω3-Polyunsaturated fatty acids (ω3-PUFAs) including docosahexaenoic acid (DHA) has been known to inhibit the cell growth through apoptosis in various cancer cells. However, the mechanism of ω3-PUFAs-induced cell death is still unclear. The β-catenin/wnt signaling pathway plays a critical role in cell proliferation and has been found to be chronically activated in variety of human cancers. In this study, we have investigated the cytotoxic mechanism of ω3-PUFAs in pancreatic cancer cells (SW1990 and PANC-1). Treatment of cells with two ω3-PUFAs, DHA and eicosapentaenoic acid (EPA), significantly induced inhibition of cell growth with a dose-dependent and increases of sub-G1 population in SW1990 cells. The effect of ω3-PUFAs due to induction of apoptosis, given that DHA induced cleavage form of PARP and inhibition of caspase-3; in contrast arachidonic acid (AA) has no effect. Moreover, DHA treatment reduced the level of β-catenin in SW1990 and PANC-1 cells. DHA also induced the association of β-catenin/Axin/GSK-3β complex, which serves as a parallel mechanism for β-catenin degradation. In immunocytochemical stain of β-catenin, the cytosolic and nuclear β-catenin expression was reduced in the DHA-treated SW1990 cells, compared to control cells. The TCF/LEF reporter activity, a β-catenin-controlled downstream signal, was also decreased by DHA treatment. DHA also inhibited Cox-2 reporter activity in a dose-dependent manner. These findings suggest that DHA induce apoptotic cell death through the Cox-2 and β-catenin/Axin/GSK-3β signaling pathway in human pancreatic cancer cells. Therefore, utilization of ω3-PUFAs may represent a potential effective therapy for the chemoprevention and treatment of human pancreatic cancer.
When a House Is Not a Home: A Survey of Antimetastatic Niches and Potential Mechanisms of Disseminated Tumor Cell Suppression
Authors: Sarah B. Crist, Cyrus M. Ghajar
Journal: Annual Review of Pathology Mechanisms of Disease (2020)

Over the last four decades, the cancer biology field has concentrated on cellular and microenvironmental drivers of metastasis. Despite this focus, mortality rates upon diagnosis of metastatic disease remain essentially unchanged. Would a small change in perspective help? Knowing what constitutes an inhospitable, rather than hospitable, microenvironment could provide the inspiration necessary to develop better therapies and preventative strategies. In this review, we canvas the literature for hints about what characteristics four common antimetastatic niches-skeletal muscle, spleen, thyroid, and yellow bone marrow-have in common. We posit that thorough molecular and mechanistic characterization of antimetastatic tissues may inspire reimagined therapies that inhibit metastatic development and/or progression in an enduring manner.
Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches
Authors: Lei Zhang, Ryan Mack, Peter Breslin, Jiwang Zhang
Journal: Journal of Hematology & Oncology (2020)

Abstract Aging drives the genetic and epigenetic changes that result in a decline in hematopoietic stem cell (HSC) functioning. Such changes lead to aging-related hematopoietic/immune impairments and hematopoietic disorders. Understanding how such changes are initiated and how they progress will help in the development of medications that could improve the quality life for the elderly and to treat and possibly prevent aging-related hematopoietic diseases. Here, we review the most recent advances in research into HSC aging and discuss the role of HSC-intrinsic events, as well as those that relate to the aging bone marrow niche microenvironment in the overall processes of HSC aging. In addition, we discuss the potential mechanisms by which HSC aging is regulated.
Trends in Relative Incidence and Prevalence of Dementia Across Non-Hispanic Black and White Individuals in the United States, 2000-2016
Authors: Melinda C. Power, Erin E. Bennett, Robert W. Turner, N. Maritza Dowling, Adam Ciarleglio, M. Maria Glymour, Kan Z. Gianattasio
Journal: JAMA Neurology (2020)

In the US, dementia risk is higher in non-Hispanic Black individuals than in non-Hispanic White individuals. To evaluate progress toward reducing such disparities, tracking secular trends in racial disparities in dementia prevalence is essential.To examine whether relative racial disparities in dementia prevalence or incidence have changed in the US from 2000 to 2016.The Health and Retirement Study (HRS) is a nationally representative study of adults 50 years or older. New participants are recruited every 6 years, and study visits occur biennially. Approximately 17 000 to 22 000 respondents have been surveyed at each wave since 2000, achieving response rates of 81% to 89%. Data for this cohort study were obtained from non-Hispanic White and non-Hispanic Black participants aged 70 years and older from the 2000 to 2016 waves. For analyses of secular trends in racial disparities in dementia prevalence, each HRS wave was considered separately (range of participants meeting eligibility criteria in each wave, 6322-7579). For analyses of secular trends in racial disparities in dementia incidence, 7 subcohorts were created (range of participants meeting eligibility criteria in each subcohort, 5322-5961) following up people without dementia for 4 years from subcohort baseline visits in 2000, 2002, 2004, 2006, 2008, 2010, and 2012. Data were analyzed from October 2019 to August 2020.Race based on self-response to closed-ended survey questions.Dementia status was determined using 3 algorithms with similar sensitivity and specificity across non-Hispanic White and Black participants. Disparities were characterized using ratio measures.In this study, the mean age and percentage of male participants eligible for inclusion in analyses of racial disparities in dementia prevalence increased over time among non-Hispanic White participants (from 78.2 years and 40% in 2000 to 78.7 years and 44% in 2016) but remained steady in non-Hispanic Black participants during the same period (from 78.0 years and 37% in 2000 to 77.9 years and 38% in 2016). Prevalence ratios comparing Black and White participants ranged from approximately 1.5 to 1.9 across algorithms and years, whereas hazard ratios ranged from approximately 1.4 to 1.8. Although results suggest stable or declining dementia risk overall, there was no evidence suggesting change in relative racial disparities in dementia prevalence or incidence during follow-up.This study did not find evidence to suggest that the ratio of dementia risk across Black and White individuals changed in the US between 2000 and 2016. Additional efforts to identify and mitigate the source of these disparities is warranted.
Abstract 13031: Sex Differences in Prevalence and Association of Sleep and Psychological Disturbances in Patients Hospitalized With Cardiovascular Diseases
Authors: Yuichi Jono, Takashi Kohno, Hiroki Kitakata, Ryoma Fukuoka, Yasuyuki Shiraishi, Yoshinori Katsumata, Kentaro Hayashida, Shinsuke Yuasa, Shun Kohsaka, Seiji Takatsuki, Keiichi Fukuda
Journal: Circulation (2018)

Introduction: Sleep and psychological disturbances contribute to the development of various cardiovascular (CV) diseases. However, there is not enough data regarding the evaluation of insomnia, exc...
In Utero and Early Life Exposure to the Great Chinese Famine and Risk of Rheumatoid Arthritis in Adulthood
Authors: Hannah VanEvery, Wen‐hao Yang, Nancy Olsen, Xinyuan Zhang, Rong Shu, Bing Lu, Shouling Wu, Liufu Cui, Xiang Gao
Journal: Arthritis & Rheumatology (2020)

To investigate whether early life exposure to the Great Chinese Famine of 1959-1961 is associated with the risk of RA development in adulthood.This study included 101,510 participants who were enrolled in the Kailuan Study in 2006. RA cases were confirmed by medical record review. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) for RA according to famine exposure status (exposed in utero or between ages 0 and 3 years, between ages 3 and 6 years, or at age 6 years or older), in comparison to participants born after 1961 who were not exposed to famine.During 12 years of follow-up (2006-2018), we identified 187 RA cases. Individuals exposed to famine in utero or between ages 0 and 3 years had a higher prevalence of RA relative to other groups (0.2-0.35% versus 0.08-0.20%). After adjustment for potential confounders, the OR for RA was 2.95 (95% CI 1.55-5.59) for individuals exposed in utero, 4.53 (95% CI 2.72-7.54) for those exposed between ages 0 and 3 years, 2.55 (95% CI 1.43-4.57) for those exposed between ages 3 and 6 years, and 2.72 (95% CI 1.70-4.36) for those exposed at age 6 years or older versus individuals born after 1961. Similar associations with the risk of RA were observed for men and women when subjects were stratified by sex (P for interaction = 0.89).Individuals exposed to famine in utero or in early childhood (between ages 0 and 3 years) were more likely to develop RA in adulthood, highlighting the importance of early life as a vulnerable developmental period.
204P Prospective observational study on pazopanib in patients treated for advanced or metastatic renal cell carcinoma (RCC) in Asia, North Africa and Middle East countries: Final analysis of PARACHUTE study
Authors: R. Kanesvaran, B. Biswas, P. Danchaivijitr, L. Chen, Y.F. Wong, T. Hashem, C.S. Lim, B. Karabulut, H-J. Chung, C. Chikatapu, S. Ingles, K. Silmane, M. Erman
Journal: Annals of Oncology (2020)
Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma
Authors: Kohei Shigeta, Aya Matsui, Hiroto Kikuchi, Sebastian Klein, Emilie Mamessier, Ivy X Chen, Shuichi Aoki, Shuji Kitahara, Koetsu Inoue, Ayako Shigeta, Tai Hato, Rakesh R Ramjiawan, Daniel Staiculescu, Dieter Zopf, Lukas Fiebig, Gabriela S Hobbs, Alexander Quaas, Simona Dima, Irinel Popescu, Peigen Huang, Lance L Munn, Mark Cobbold, Lipika Goyal, Andrew X Zhu, Rakesh K Jain, Dan G Duda
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background and purpose Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models. Basic procedures We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib—dosed orally at 5, 10 or 20 mg/kg daily—combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer. Main findings Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells ( Rag1 -deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10—a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes—in murine HCC and in blood of patients with HCC. Using Cxcr3 -deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy. Principal conclusions Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.
Abstract IA17: CAR T cells for T-cell lymphoma
Authors: Maksim Mamonkin
Journal: Blood Cancer Discovery (2020)

Abstract Development of CAR T-cell therapies for T-cell lymphoma has been hampered by a limited range of targetable antigens. Shared expression of most T-lineage antigens between malignant and normal T cells promotes fratricide of CAR T cells and increases the risk of T-cell aplasia. We developed a CAR targeting CD5, a pan-T cell antigen commonly expressed in T-cell lymphoma. CD5 CAR T cells evade fratricide by rapidly downregulating CD5 protein expression and retain high cytotoxicity against T-cell lymphoma. An ongoing phase I clinical trial demonstrates curative potential of autologous CD5 CAR T cells in patients with peripheral T-cell lymphoma. CD5 CAR T-cell infusions were well tolerated and did not produce prolonged ablation of endogenous T cells. Other CAR T cell-based approaches for T-cell lymphoma will also be discussed. Citation Format: Maksim Mamonkin. CAR T cells for T-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA17.
18239 Secukinumab treatment results in sustained improvement in absolute PASI and drug survival: 24-month follow-up from the British Association of Dermatologists Biologics and Immunomodulators Register
Authors: Emma Riley, Anthony Bewley, Philip Hampton, Jenny Hughes, Robin May, Andrew Franklin, Suja George, Joannah Whitehead, Laura Steven
Journal: Journal of the American Academy of Dermatology (2020)
Missing Self-Induced Activation of NK Cells Combines with Non-Complement-Fixing Donor-Specific Antibodies to Accelerate Kidney Transplant Loss in Chronic Antibody-Mediated Rejection
Authors: Alice Koenig, Sarah Mezaache, Jasper Callemeyn, Thomas Barba, Virginie Mathias, Antoine Sicard, Béatrice Charreau, Maud Rabeyrin, Frédérique Dijoud, Cécile Picard, Vannary Meas-Yedid, Jean-Christophe Olivo-Marin, Emmanuel Morelon, Maarten Naesens, Valérie Dubois, Olivier Thaunat
Journal: Journal of the American Society of Nephrology (2020)

Background Binding of donor-specific antibodies (DSAs) to kidney allograft endothelial cells that does not activate the classic complement cascade can trigger the recruitment of innate immune effectors, including NK cells. Activated NK cells contribute to microvascular inflammation leading to chronic antibody-mediated rejection (AMR). Recipient NK cells can also trigger antibody-independent microvascular inflammation by sensing the absence of self HLA class I molecules (“missing self”) on allograft endothelial cells. This translational study investigated whether the condition of missing self amplifies DSA-dependent NK cell activation to worsen chronic AMR. Methods and Results Among 1682 kidney transplant recipients who underwent an allograft biopsy at Lyon University Hospital between 2004 and 2017, 135 fulfilled the diagnostic criteria for AMR and were enrolled in the study. Patients with complement-fixing DSAs identified by a positive C3d binding assay ( n =73, 54%) had a higher risk of transplant failure ( P =0.002). Among the remaining patients with complement-independent chronic AMR ( n =62, 46%), those in whom missing self was identified through donor and recipient genotyping exhibited worse allograft survival ( P =0.02). In multivariable analysis, only proteinuria (HR: 7.24; P =0.01) and the presence of missing self (HR: 3.57; P =0.04) were independent predictors for transplant failure following diagnosis of chronic AMR. Cocultures of human NK cells and endothelial cells confirmed that addition of missing self to DSA-induced NK cell activation increased endothelial damage. Conclusions The assessment of missing self at the time of diagnosis of chronic AMR identifies patients at higher risk for kidney transplant failure.
MR Imaging and Cardiac Amyloidosis: Where to Go From Here?⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Joseph B. Selvanayagam, Darryl P. Leong
Journal: JACC. Cardiovascular imaging (2010)
YAP Circular RNA, circYap, Attenuates Cardiac Fibrosis via Binding with Tropomyosin-4 and Gamma-Actin Decreasing Actin Polymerization
Authors: Nan Wu, Jindong Xu, William W. Du, Xiangmin Li, Faryal Mehwish Awan, Feiya Li, Sema Misir, Esra Eshaghi, Juanjuan Lyu, Le Zhou, Kaixuan Zeng, Aisha Adil, Sheng Wang, Burton B. Yang
Journal: Molecular Therapy (2020)

Cardiac fibrosis is a common pathological feature of cardiac hypertrophy. This study was designed to investigate a novel function of Yes-associated protein (YAP) circular RNA, circYap, in modulating cardiac fibrosis and the underlying mechanisms. By circular RNA sequencing, we found that three out of fifteen reported circYap isoforms were expressed in nine human heart tissues, with the isoform hsa_circ_0002320 being the highest. The levels of this isoform in the hearts of patients with cardiac hypertrophy were found to be significantly decreased. In the pressure overload mouse model, the levels of circYap were reduced in mouse hearts with transverse aortic constriction (TAC). Upon circYap plasmid injection, the cardiac fibrosis was attenuated, and the heart function was improved along with the elevation of cardiac circYap levels in TAC mice. Tropomyosin-4 (TMP4) and gamma-actin (ACTG) were identified to bind with circYap in cardiac cells and mouse heart tissues. Such bindings led to an increased TPM4 interaction with ACTG, resulting in the inhibition of actin polymerization and the following fibrosis. Collectively, our study uncovered a novel molecule that could regulate cardiac remodeling during cardiac fibrosis and implicated a new function of circular RNA. This process may be targeted for future cardio-therapy. Cardiac fibrosis is a common pathological feature of cardiac hypertrophy. This study was designed to investigate a novel function of Yes-associated protein (YAP) circular RNA, circYap, in modulating cardiac fibrosis and the underlying mechanisms. By circular RNA sequencing, we found that three out of fifteen reported circYap isoforms were expressed in nine human heart tissues, with the isoform hsa_circ_0002320 being the highest. The levels of this isoform in the hearts of patients with cardiac hypertrophy were found to be significantly decreased. In the pressure overload mouse model, the levels of circYap were reduced in mouse hearts with transverse aortic constriction (TAC). Upon circYap plasmid injection, the cardiac fibrosis was attenuated, and the heart function was improved along with the elevation of cardiac circYap levels in TAC mice. Tropomyosin-4 (TMP4) and gamma-actin (ACTG) were identified to bind with circYap in cardiac cells and mouse heart tissues. Such bindings led to an increased TPM4 interaction with ACTG, resulting in the inhibition of actin polymerization and the following fibrosis. Collectively, our study uncovered a novel molecule that could regulate cardiac remodeling during cardiac fibrosis and implicated a new function of circular RNA. This process may be targeted for future cardio-therapy.