tbuckley/cabot-search huggingface dataset:
Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes
Authors: Patrizia Benzoni, Giulia Campostrini, Sara Landi, Valeria Bertini, Eleonora Marchina, Maria Iascone, Gustav Ahlberg, Morten Salling Olesen, Elisabetta Crescini, Cristina Mora, Gianluigi Bisleri, Claudio Muneretto, Roberto Ronca, Marco Presta, Pier Luigi Poliani, Giovanna Piovani, Rosanna Verardi, Elisa Di Pasquale, Antonella Consiglio, Angel Raya, Eleonora Torre, Alessandra Maria Lodrini, Raffaella Milanesi, Marcella Rocchetti, Mirko Baruscotti, Dario DiFrancesco, Maurizio Memo, Andrea Barbuti, Patrizia Dell’Era
Journal: Cardiovascular Research (2019)

Abstract Aims Atrial fibrillation (AF) is the most common type of cardiac arrhythmias, whose incidence is likely to increase with the aging of the population. It is considered a progressive condition, frequently observed as a complication of other cardiovascular disorders. However, recent genetic studies revealed the presence of several mutations and variants linked to AF, findings that define AF as a multifactorial disease. Due to the complex genetics and paucity of models, molecular mechanisms underlying the initiation of AF are still poorly understood. Here we investigate the pathophysiological mechanisms of a familial form of AF, with particular attention to the identification of putative triggering cellular mechanisms, using patient’s derived cardiomyocytes (CMs) differentiated from induced pluripotent stem cells (iPSCs). Methods and results Here we report the clinical case of three siblings with untreatable persistent AF whose whole-exome sequence analysis revealed several mutated genes. To understand the pathophysiology of this multifactorial form of AF we generated three iPSC clones from two of these patients and differentiated these cells towards the cardiac lineage. Electrophysiological characterization of patient-derived CMs (AF-CMs) revealed that they have higher beating rates compared to control (CTRL)-CMs. The analysis showed an increased contribution of the If and ICaL currents. No differences were observed in the repolarizing current IKr and in the sarcoplasmic reticulum calcium handling. Paced AF-CMs presented significantly prolonged action potentials and, under stressful conditions, generated both delayed after-depolarizations of bigger amplitude and more ectopic beats than CTRL cells. Conclusions Our results demonstrate that the common genetic background of the patients induces functional alterations of If and ICaL currents leading to a cardiac substrate more prone to develop arrhythmias under demanding conditions. To our knowledge this is the first report that, using patient-derived CMs differentiated from iPSC, suggests a plausible cellular mechanism underlying this complex familial form of AF.
Art and the Scientist
Journal: JAMA (1961)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Equine-assisted interventions for veterans with service-related health conditions: a systematic mapping review
Authors: Adam R. Kinney, Aaron M. Eakman, Rebecca Lassell, Wendy Wood
Journal: Military Medical Research (2019)

Evidence-based treatments for service-related health conditions such as posttraumatic stress disorder (PTSD), depression, and traumatic brain injury (TBI) are not effective for all veterans. Equine-assisted interventions are emerging as an additional treatment modality, but little is known regarding the safe and effective delivery of these interventions. This study aimed to describe the following features of the body of literature concerning equine-assisted interventions among veterans: 1) veterans who have participated in equine-assisted interventions; 2) specific characteristics of equine-assisted interventions in veterans; and 3) the specific characteristics of research on equine-assisted interventions in veterans. We conducted a systematic mapping review of peer-reviewed literature reporting on equine-assisted interventions among veterans between 1980 and 2017. Searches of nine databases yielded 3336 unique records, six of which met the inclusion criteria and were reviewed. Data relevant to the study aims were extracted and analyzed. Equine-assisted interventions among veterans disproportionately targeted psychosocial outcomes and yielded promising results. The detailed methods of EAI varied in the reported studies, ranging from communicating with the horse to mounted exercises. There was also great diversity in outcome measurement. The state of theoretical development regarding the mechanisms by which equine-assisted interventions benefit the veteran population is currently underdeveloped. Studies provided insufficient detail with respect to the description of the intervention, reasons for attrition, and the dose-response relationship. Scientific development of equine-assisted interventions targeting psychosocial outcomes among veterans is warranted to establish their efficacy. Targeted outcomes should be expanded, including outcomes more closely aligned with the nature of polytraumatic injuries. Future research must also emphasize the theoretical development of equine-assisted interventions for veterans and thoroughly describe the participants, components of the intervention, factors contributing to attrition, and optimal dose-response relationships.
Fetal Gene Therapy Using a Single Injection of Recombinant AAV9 Rescued SMA Phenotype in Mice
Authors: Afrooz Rashnonejad, Gholamhossein Amini Chermahini, Cumhur Gündüz, Hüseyin Onay, Ayça Aykut, Burak Durmaz, Meral Baka, Qin Su, Guangping Gao, Ferda Özkınay
Journal: Molecular Therapy (2019)

Symptoms of spinal muscular atrophy (SMA) disease typically begin in the late prenatal or the early postnatal period of life. The intrauterine (IU) correction of gene expression, fetal gene therapy, could offer effective gene therapy approach for early onset diseases. Hence, the overall goal of this study was to investigate the efficacy of human survival motor neuron (hSMN) gene expression after IU delivery in SMA mouse embryos. First, we found that IU-intracerebroventricular (i.c.v.) injection of adeno-associated virus serotype-9 (AAV9)-EGFP led to extensive expression of EGFP protein in different parts of the CNS with a great number of transduced neural stem cells. Then, to implement the fetal gene therapy, mouse fetuses received a single i.c.v. injection of a single-stranded (ss) or self-complementary (sc) AAV9-SMN vector that led to a lifespan of 93 (median of 63) or 171 (median 105) days for SMA mice. The muscle pathology and number of the motor neurons also improved in both study groups, with slightly better results coming from scAAV treatment. Consequently, fetal gene therapy may provide an alternative therapeutic approach for treating inherited diseases such as SMA that lead to prenatal death or lifelong irreversible damage.
A phase I/II, open label trial of Lewis Y specific monoclonal antibody IGN311 to evaluate safety and efficacy in patients with malignant effusion
Authors: T. Bauernhofer, H. Samonigg, P. Regitnik, B. Lileg, W. Weizer, G. Waxenecker, M. Kainer, S. Wiederkum, H. Loibner, R. Kircheis
Journal: Journal of Clinical Oncology (2006)

2547 Background: Treatment of CRC patients (pts) with the humanized mAb IGN311 targeting the carbohydrate Lewis Y eliminated circulating tumor cells in blood and thereby confirmed the clinical profile of the parent murine antibody ABL364, which showed elimination of Lewis Y and cytokeratin positive cells in bone marrow of pts with breast cancer. Methods: An open-label, single treatment arm, uncontrolled study with IGN311 (100mg per dose, intravenously on day 1 and 7) in pts with malignant effusion (ascites or pleural effusion) is being conducted with the primary objective to examine safety and tolerability. Secondary objectives are volumetric measurement of the malignant effusion and to obtain data for several immunological parameters. Results: 4 pts (2 pts with gastric cancer and malignant ascites, 2 pts with breast cancer and malignant pleural effusion / ascites) have completed the study until December 2005. IGN311 was well tolerated with only one patient showing up to grade 2 nausea, vomiting and skin rashes as side effect after 1 st application which was easily managed. In all pts significant levels of IGN311 were measured followed by an increase in CD45 positive cells in the effusion. The patient with the highest level of Lewis Y expressing tumor cells showed a reduction of effusion volume during treatment. Conclusions: IGN311 was well tolerated, permeated into malignant effusion and attracted immune cells leading to decreased tumor cell counts in the effusion. In the case of strong Lewis Y expression of malignant cells in the effusion a reduction of the effusion volume could be demonstrated. [Table: see text]
What Is Christian Science?
Journal: JAMA (1922)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis screening in new entrants to the UK: a retrospective, population-based cohort study
Authors: Luis C Berrocal-Almanza, Ross Harris, Maeve K Lalor, Morris C Muzyamba, John Were, Anne-Marie O'Connell, Adil Mirza, Onn-Min Kon, Ajit Lalvani, Dominik Zenner
Journal: The Lancet Infectious Diseases (2019)
Impaired Awareness of Hypoglycemia Disrupts Blood Flow to Brain Regions Involved in Arousal and Decision Making in Type 1 Diabetes
Authors: Munachiso Nwokolo, Stephanie A. Amiel, Owen O’Daly, Megan L. Byrne, Bula M. Wilson, Andrew Pernet, Sally M. Cordon, Ian A. Macdonald, Fernando O. Zelaya, Pratik Choudhary
Journal: Diabetes Care (2019)

Impaired awareness of hypoglycemia (IAH) affects one-quarter of adults with type 1 diabetes and significantly increases the risk of severe hypoglycemia. Differences in regional brain responses to hypoglycemia may contribute to the susceptibility of this group to problematic hypoglycemia. This study investigated brain responses to hypoglycemia in hypoglycemia aware (HA) and IAH adults with type 1 diabetes, using three-dimensional pseudo-continuous arterial spin labeling (3D pCASL) functional MRI to measure changes in regional cerebral blood flow (CBF).Fifteen HA and 19 IAH individuals underwent 3D pCASL functional MRI during a two-step hyperinsulinemic glucose clamp. Symptom, hormone, global, and regional CBF responses to hypoglycemia (47 mg/dL [2.6 mmol/L]) were measured.In response to hypoglycemia, total symptom score did not change in those with IAH (P = 0.25) but rose in HA participants (P < 0.001). Epinephrine, cortisol, and growth hormone responses to hypoglycemia were lower in the IAH group (P < 0.05). Hypoglycemia induced a rise in global CBF (HA P = 0.01, IAH P = 0.04) but was not different between groups (P = 0.99). IAH participants showed reduced regional CBF responses within the thalamus (P = 0.002), right lateral orbitofrontal cortex (OFC) (P = 0.002), and right dorsolateral prefrontal cortex (P = 0.036) and a lesser decrease of CBF in the left hippocampus (P = 0.023) compared with the HA group. Thalamic and right lateral OFC differences survived Bonferroni correction.Responses to hypoglycemia of brain regions involved in arousal, decision making, and reward are altered in IAH. Changes in these pathways may disrupt IAH individuals' ability to recognize hypoglycemia, impairing their capacity to manage hypoglycemia effectively and benefit fully from conventional therapeutic pathways to restore awareness.
An Activatable Cancer-Targeted Hydrogen Peroxide Probe for Photoacoustic and Fluorescence Imaging
Authors: Judith Weber, Laura Bollepalli, Ana M. Belenguer, Marco Di Antonio, Nicola De Mitri, James Joseph, Shankar Balasubramanian, Christopher A. Hunter, Sarah E. Bohndiek
Journal: Cancer Research (2019)

Abstract Reactive oxygen species play an important role in cancer, however, their promiscuous reactivity, low abundance, and short-lived nature limit our ability to study them in real time in living subjects with conventional noninvasive imaging methods. Photoacoustic imaging is an emerging modality for in vivo visualization of molecular processes with deep tissue penetration and high spatiotemporal resolution. Here, we describe the design and synthesis of a targeted, activatable probe for photoacoustic imaging, which is responsive to one of the major and abundant reactive oxygen species, hydrogen peroxide (H2O2). This bifunctional probe, which is also detectable with fluorescence imaging, is composed of a heptamethine carbocyanine dye scaffold for signal generation, a 2-deoxyglucose cancer localization moiety, and a boronic ester functionality that specifically detects and reacts to H2O2. The optical properties of the probe were characterized using absorption, fluorescence, and photoacoustic measurements; upon addition of pathophysiologic H2O2 concentrations, a clear increase in fluorescence and red-shift of the absorption and photoacoustic spectra were observed. Studies performed in vitro showed no significant toxicity and specific uptake of the probe into the cytosol in breast cancer cell lines. Importantly, intravenous injection of the probe led to targeted uptake and accumulation in solid tumors, which enabled noninvasive photoacoustic and fluorescence imaging of H2O2. In conclusion, the reported probe shows promise for the in vivo visualization of hydrogen peroxide. Significance: This study presents the first activatable and cancer-targeted hydrogen peroxide probe for photoacoustic molecular imaging, paving the way for visualization of hydrogen peroxide at high spatiotemporal resolution in living subjects.
P031/O12 Sialic acids negatively affect the bone resorptive capacity of osteoclasts
Authors: AK Molhoek, RE Li, ID Jansen, T Schoenmaker, TJ de Vries, SJ van Vliet, Y van Kooyk
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> In rheumatoid arthritis the imbalance between osteoblasts and osteoclasts leads to an increased bone resorption, resulting in extensive bone destruction. Osteoclasts are multinucleated cells formed after fusion of macrophages. Macrophages are known to acquire an anti-inflammatory phenotype upon engagement of the carbohydrate sialic acid<sup>1</sup>, however whether triggering by sialic acids affects osteoclastogenesis is unknown. Therefore, we investigated the effect of sialic acids on osteoclastogenesis and their expression of the sialic acid binding receptors, called Siglecs. <h3>Methods</h3> Human monocytes were plated on either plastic, glass or bone slices and stimulated with M-CSF and RANK-L to generate osteoclasts. We designed a novel sorting methodology to separate the osteoclasts and the residual macrophages in our osteoclast-derived cultures. Purified osteoclasts were reanalyzed by microscopy and assessed for gene expression of osteoclast-specific genes by RT-PCR. Flow cytometry was used to obtain a full expression profile of the different siglec receptors in the osteoclasts, macrophages and monocytes precursor cells. Stimulation of pre-osteoclasts with sialic acids was done at day 7 and 10 of the culture. Supernatants were assessed for IL-6 and IL-10 production. <h3>Results</h3> Our novel osteoclast purification method resulted in pure osteoclasts expressing the classical genetic osteoclast markers such as cathepsin K and TRAP, while being negative for CD14. During the transition to osteoclasts, expression of siglec-1, −5/14 and −7 was lost, while siglec-6, –9 and −15 expression was maintained or gained. Osteoclasts are known for their effectively bone resorption, however after adding sialic acids to the pre-osteoclasts, both osteoclast formation and bone resorption were reduced, while an increase of IL-6 and IL-10 cytokines was observed. <h3>Conclusions</h3> Pre-osteoclasts stimulated with sialic acids display reduced osteoclast formation and bone resorption. Based on the siglec profiling we hypothesize that sialic acids engage siglec-9 on osteoclasts. Macrophages stimulated via siglec-9 produce IL-10 cytokine,<sup>1</sup> similarly as we observed in our stimulation experiments. Currently, we are addressing the role of siglec-9 in osteoclastogenesis. <h3>Reference</h3> Ando M, <i>et al</i>. Siglec-9 enhances IL-10 production in macrophages via tyrosine-based motifs. <i>Biochem Biophys Res Commun</i> 2008;369(3):878–83. <h3>Disclosure of Interest</h3> None declared.
Targeting Degradation of the Transcription Factor C/EBPβ Reduces Lung Fibrosis by Restoring Activity of the Ubiquitin-Editing Enzyme A20 in Macrophages
Authors: Shan-shan Liu, Xiao-xi Lv, Chang Liu, Jie Qi, Yun-xuan Li, Xu-peng Wei, Ke Li, Fang Hua, Bing Cui, Xiao-wei Zhang, Jiao-jiao Yu, Jin-mei Yu, Feng Wang, Shuang Shang, Chen-xi Zhao, Xue-ying Hou, Zhi-gang Yao, Ping-ping Li, Xia Li, Bo Huang, Zhuo-wei Hu
Journal: Immunity (2019)
Safety and Efficacy of a Six Month Full Dose Lenalidomide Consolidation Treatment After First-Line High-Dose Therapy in Patients with Multiple Myeloma
Authors: Roland Fenk, Julia Baier, Aristoteles Giagounidis, Mathias J. Rummel, Nicolaus Kröger, Tobias Strapatsas, Ariane Dienst, Esther Zipperer, Kathrin Nachtkamp, Alexander Burchardt, Thomas Schroeder, Lars Galonska, Norbert Gattermann, Rainer Haas, Guido Kobbe
Journal: Blood (2012)
Publisher Correction: Gut microbiota–bile acid–interleukin-22 axis orchestrates polycystic ovary syndrome
Authors: Xinyu Qi, Chuyu Yun, Lulu Sun, Jialin Xia, Qing Wu, Ying Wang, Lina Wang, Yangming Zhang, Xianyi Liang, Liying Wang, Frank J. Gonzalez, Andrew D. Patterson, Huiying Liu, Liangshan Mu, Zehong Zhou, Yue Zhao, Rong Li, Ping Liu, Chao Zhong, Yanli Pang, Changtao Jiang, Jie Qiao
Journal: Nature Medicine (2019)
Breast cancer growth rates in BRCA1/2 mutation carriers
Authors: K. Bosse, A. Goβmann, K. Rhiem, M. Warm, R. K. Schmutzler
Journal: Journal of Clinical Oncology (2007)

10575 Background: 1. Recent investigations suggest an accelerated growth rate in BRCA1/2-associated breast cancer. 2. This characteristic may have influence on screening policy. Patients and Methods: BRCA1/2 mutation carriers are regularly observed in a structured surveillance program that comprises annual mammography and MRI-scan in addition to sonography undertaken every six months. We performed a prospective study in approx. 2035 women participating in a breast cancer screening program from 01/1997 until 12/2006. In 9 carriers 10 BRCA-associated breast cancer cases were diagnosed of whom at least one previous examination was available. A calculation of the tumor volume doubling time was performed according to the following algorithm: VDT= log2 × (t 2 -t 1 )/logm 2 - logm 1 (VDT= Volume doubling time; t 1 and t 2 at the beginning and at the end of the observation period; m 1 and m 2 size of the tumor at point in time t 1 and t 2 ). Results: The 10 cases shown in table 1 prove both high growth rates with VDTs measuring on average 48 days and benign morphologic criteria in early stage disease by all 3 imaging procedures. The VDT for BRCA1-associated tumors was in average 42 days, while the single BRCA2 associated case had a VDT of 102 days. Conclusions: Our data demonstrate a short VDT of 48 days in BRCA1/2 mutation carriers. This is in line with another observational study which identified a tumor doubling time of 45 days for familial tumors in comparison to sporadic tumors with 82 days (Tilanus-Linthorst et al., 2005). These data underline the necessity for a closely meshed screening interval of 6 months. Lit: Tilanus- Linthorst et al., Eur J Cancer. 2005. Jul.41(11):1610–17 [Table: see text] No significant financial relationships to disclose.
Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy
Authors: Tongyan Liu, Chencheng Han, Siwei Wang, Panqi Fang, Zhifei Ma, Lin Xu, Rong Yin
Journal: Journal of Hematology & Oncology (2019)

Among all the stromal cells that present in the tumor microenvironment, cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor mesenchyme, which not only provide physical support for tumor cells but also play a key role in promoting and retarding tumorigenesis in a context-dependent manner. CAFs have also been involved in the modulation of many components of the immune system, and recent studies have revealed their roles in immune evasion and poor responses to cancer immunotherapy. In this review, we describe our current understanding of the tumorigenic significance, origin, and heterogeneity of CAFs, as well as the roles of different CAFs subtypes in distinct immune cell types. More importantly, we highlight potential therapeutic strategies that target CAFs to unleash the immune system against the tumor.