tbuckley/cabot-search huggingface dataset:
Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics
Authors: Makan Khoshnejad, Ami Patel, Krzysztof Wojtak, Sagar B. Kudchodkar, Laurent Humeau, Nicholas N. Lyssenko, Daniel J. Rader, Kar Muthumani, David B. Weiner
Journal: Molecular Therapy (2018)

Elevated low-density lipoprotein cholesterol (LDL-C) is one of the major contributors to cardiovascular heart disease (CHD), the leading cause of death worldwide. Due to severe side effects of statins, alternative treatment strategies are required for statin-intolerant patients. Monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown great efficacy in LDL-C reduction. Limitations for this approach include the need for multiple injections as well as increased costs associated with patient management. Here, we engineered a DNA-encoded mAb (DMAb) targeting PCSK9 (daPCSK9), as an alternative approach to protein-based lipid-lowering therapeutics, and we characterized its expression and activity. A single intramuscular administration of mouse daPCSK9 generated expression in vivo for over 42 days that corresponded with a substantial decrease of 28.6% in non-high-density lipoprotein cholesterol (non-HDL-C) and 10.3% in total cholesterol by day 7 in wild-type mice. Repeated administrations of the DMAb plasmid led to increasing expression, with DMAb levels of 7.5 μg/mL at day 62. daPCSK9 therapeutics may provide a novel, simple, less frequent, cost-effective approach to reducing LDL-C, either as a stand-alone therapy or in combination with other LDL-lowering therapeutics for synergistic effect. Elevated low-density lipoprotein cholesterol (LDL-C) is one of the major contributors to cardiovascular heart disease (CHD), the leading cause of death worldwide. Due to severe side effects of statins, alternative treatment strategies are required for statin-intolerant patients. Monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown great efficacy in LDL-C reduction. Limitations for this approach include the need for multiple injections as well as increased costs associated with patient management. Here, we engineered a DNA-encoded mAb (DMAb) targeting PCSK9 (daPCSK9), as an alternative approach to protein-based lipid-lowering therapeutics, and we characterized its expression and activity. A single intramuscular administration of mouse daPCSK9 generated expression in vivo for over 42 days that corresponded with a substantial decrease of 28.6% in non-high-density lipoprotein cholesterol (non-HDL-C) and 10.3% in total cholesterol by day 7 in wild-type mice. Repeated administrations of the DMAb plasmid led to increasing expression, with DMAb levels of 7.5 μg/mL at day 62. daPCSK9 therapeutics may provide a novel, simple, less frequent, cost-effective approach to reducing LDL-C, either as a stand-alone therapy or in combination with other LDL-lowering therapeutics for synergistic effect.
Abstract 15592: Role of Electroanatomic Voltage Mapping for Risk Stratification in Patients With Repaired Congenital Heart Disease Involving the Right Ventricle
Authors: Vincenzo Pazzano, Rosalinda Palmieri, Corrado Di Mambro, Mario S Russo, Massimo S Silvetti, Fabrizio Gimigliano, Salvatore Giannico, Benedetta Leonardi, Fabrizio Drago
Journal: Circulation (2015)

Introduction: Among adult patients with previous surgical correction for Tetralogy of Fallot or other repaired Congenital Heart Disease (rCHD) involving the RV, ventricular arrhythmias (VA) and sudden cardiac death (SCD) represent a late complication. The imparied haemodynamics that lead to RV dilatation and overload could also alterate its electroanatomic structure. Hypothesis: 3D electroanatomic mapping (EAM) of the RV could confirm the presence of myocardial electrical abnormalities, allowing to better identify patients at risk for life-threatening arrhythmias. Methods: 146 patients (age 19.2 ±7.0) with rCHD involving the RV were selected from a population undergoing routine post-surgical follow-up, according to the presence of VA or severe RV dilatation. These patients underwent 3D EAM of the RV. We tested the correlation between size of scar tissue (areas with voltage &lt; 0.5 mV) and several parameters universally accepted by the literature as risk factors for VA in this particular patient population. Results: In 125 (85.6%) patients, EAM demonstrated areas of low voltage in the antero-lateral RVOT. In 20 of these (16%, 13.7% of the total) the scar extended to the septum. 72 (49.3%) had a peritricuspid scar, and in 20 (13.7%) other areas of the RV were interested. Total low-voltage area, expressed as % of total endocardial area, was significantly higher in patients with history of PVCs [3.2% (±2.6) vs 2.2% (±1.8), p&lt;0.05], complex PVCs at 24h-Holter ECG (Lown class ≥2) [3.4 (±2.5) vs 2.6 (±2.3), p&lt;0.05], exercise-inducible PVCs [3.8 (±2.4) vs 2.6 (±2.2), p=0.01] and history of previous shunt [4.0 (±2.7) vs 2.6 (±2.2), p=0.01]. Scar size was also positively correlated with age (p=0.01), age at correction (p=0.01) and QRS duration on surface ECG (p&lt;0.05). Conclusions: In patients with rCHD involving the RV it is common to observe endocardial low-voltage areas with variable distribution, not always corresponding to the sites of surgical lesion. Morover, the size of the scar tissue area correlates with some of the parameters which have been already identified as risk factors for life-threatening arrhythmias and SCD in adult patients with CHD. We suggest that EAM should become part of the routine tests for the stratification of arrhythmic risk in this population.
FRI0435 Clinicopathological correlation in inflammatory myositis: analysis of the remicam cohort (REGISTRY OF INFLAMMATORY MYOSITYS FROM MADRID, SPAIN)
Authors: B.E. Joven, F. Lozano, L. Nuño, F.J. López-Longo, O. Toldos, E. Rabadán, A. Hernández, J. Martínez-Barrios, C. Larena, M. Blazquez, C. Barbadillo, I. Llorente, A. Pérez, T. Cobo, R. Almodovar, L. Lojo, R. Calvo, M.J. García de Yébenes, P.E. Carreira
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Associations between muscle pathology and clinical features in inflammatory myositis(IM) are not well defined <h3>Objectives</h3> to describe the pathological findings in REMICAM<sup>1</sup> muscle biopsies, and analyse their associations with clinical features <h3>Methods</h3> All patients with available biopsy were included. According to the score proposed by ENMC workshop<sup>2</sup>, from muscle biopsy reports was extracted: inflammatory cells and location (endomysial, perimysial, perivascular), rimmed vacuola, fibre atrophy, necrosis, regeneration, and HLA expression. Descriptive analysis and association studies between histology and clinical features were performed (t and chi square tests, univariate logistic regression with OR) <h3>Results</h3> From 479 patients, 244 (51%) had available biopsy. Most frequent findings were: inflammatory infiltrates(75%): endomysial(44%), perimysial(49%) perivascular(26%); fibre atrophy(54%), perifascicular(27%); necrosis(55%) and regeneration(47%). HLA expression was +in 60/75 cases(80%). Endomysial infiltrate was associated with PM (OR 0.4;p&lt;0.0001), cardiac involvement (OR 2.2;p=0.014), less arthritis (OR 0,5;p=0.01) and older age (51 vs 42 y;p&lt;0.01); perimysial infiltrate and perifascicular atrophy with DM (OR 3.8;p&lt;0.0001) and younger age (40 vs 48 y;p&lt;0.05); necrosis with cardiac involvement (OR 2.1;p=0.035), neoplasia (OR 2.5;p=0.02) and no connective tissue disease (OR 0.4;p=0.01); and HLA with PM (OR 0.1;p=0.003) <h3>Conclusions</h3> most frequent histologic findings in IM muscle are inflammatory infiltrates, necrosis, HLA expression and perifascicular atrophy. Endomysial infiltration and HLA are characteristic of PM, and perimysial infiltration/perifascicular atrophy of DM. Endomysial infiltrates are associated with cardiac involvement. Necrosis is more frequent in neoplasia and less in connective tissue diseases, and is associated with cardiac involvement and older age. Our data suggest that muscle biopsy might help to identify those IM patients at higher risk of severe complications, as neoplasia or cardiac involvement <h3>References</h3> [1] Nuño L. Rheumatol Clin2017. [2] De Bleecker JL. Neuromuscular Disorders2015. <h3>Disclosure of Interest</h3> None declared
Case 36-2018: A 29-Year-Old Man with an Incidentally Discovered Renal Mass
Authors: Douglas M. Dahl, Joseph F. Simeone, Othon Iliopoulos, Philip J. Saylor, Chin-Lee Wu
Journal: New England Journal of Medicine (2018)

A 29-year-old man was evaluated for a new, self-identified left testicular mass. Genitourinary ultrasonography revealed a varicocele on the left side and an incidental complex right renal mass measuring 11 cm in diameter. Diagnostic and management decisions were made.
IgM’s exit route
Authors: Anne Reversat, Michael Sixt
Journal: The Journal of Experimental Medicine (2018)

In this issue of JEM, Thierry et al. (https://doi.org/10.1084/jem.20180344) demonstrate that, once secreted by freshly activated plasmablasts, IgM leaves the lymph node via the microarchitecture of the fibroblastic reticular cell conduit. This work demonstrates how the very peculiar stromal compartment of lymphatic organs optimizes the systemic distribution of immune effectors.
High COPD prevalence at high altitude: does household air pollution play a role?
Authors: Evelyn A. Brakema, Aizhamal Tabyshova, Marise J. Kasteleyn, Eveline Molendijk, Rianne M.J.J. van der Kleij, Job F.M. van Boven, Berik Emilov, Meerim Akmatalieva, Maamed Mademilov, Mattijs E. Numans, Sian Williams, Talant Sooronbaev, Niels H. Chavannes
Journal: European Respiratory Journal (2018)

Studies comparing chronic obstructive pulmonary disease (COPD) prevalence across altitudes report conflicting results. However, household air pollution (HAP), a major COPD risk factor, was mostly not accounted for in previous analyses and never objectively measured. We aimed to compare the prevalence of COPD and its risk factors between low-resource highlands and lowlands, with a particular focus on objectively measured HAP. We conducted a population-based, observational study in a highland (∼2050 m above sea level) and a lowland (∼750 m above sea level) setting in rural Kyrgyzstan. We performed spirometry in randomly selected households, measured indoor particulate matter with an aerodynamic diameter &lt;2.5 µm (PM 2.5 ) and administered a questionnaire on other COPD risk factors. Descriptive statistics and multivariable logistic regressions were used for analyses. We included 392 participants: 199 highlanders and 193 lowlanders. COPD was more prevalent among highlanders (36.7% versus 10.4%; p&lt;0.001). Their average PM 2.5 exposure was also higher (290.0 versus 72.0 µg·m −3 ; p&lt;0.001). In addition to high PM 2.5 exposure (OR 3.174, 95% CI 1.061–9.493), the altitude setting (OR 3.406, 95% CI 1.483–7.825), pack-years of smoking (OR 1.037, 95% CI 1.005–1.070) and age (OR 1.058, 95% CI 1.037–1.079) also contributed to a higher COPD prevalence among highlanders. COPD prevalence and HAP were highest in the highlands, and were independently associated. Preventive interventions seem warranted in these low-resource, highland settings. With this study being one of the first spirometry-based prevalence studies in Central Asia, generalisability needs to be assessed.
Interaction of Mitochondrial and Epigenetic Regulation in Hepatocellular Carcinoma
Authors: Victoria Chagoya de Sánchez, Enrique Chávez, Gabriela Velasco- Loyden, María Guadalupe Lozano-Rosas, Alejandro Rusbel Aparicio-Cadena
Journal: Liver Cancer (2018)

Hepatocellular carcinoma (HCC) is a pathology preceded mainly by cirrhosis of diverse etiology and is associated with uncontrolled dedifferentiation and cell proliferation processes. Many cellular functions are dependent on mitochondrial function, among which we can mention the enzymatic activity of PARP-1 and sirtuin 1, epigenetic regulation of gene expression, apoptosis, and so on. Mitochondrial dysfunction is related to liver diseases including cirrhosis and HCC; the energetic demand is not properly supplied and mitochondrial morphologic changes have been observed, resulting in an altered metabolism. There is a strong relationship between epigenetics and mitochondrion since the first one is dependent on the correct function of the last one. There is an interest to improve or to maintain mitochondrial integrity in order to prevent or reverse HCC; such is the case of IFC-305 that has a beneficial effect on mitochondrial function in a sequential model of cirrhosis-HCC. In this model, IFC-305 downregulates the expression of PCNA, thymidylate synthase, HGF and its receptor c-Met and upregulates the cell cycle inhibitor p27, thereby decreasing cell proliferation. Both effects, improvement of mitochondria function and reduction of tumor proliferation, suggest its use as HCC chemoprevention or as an adjuvant in chemotherapy.
Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse
Authors: Selma Osmanagic-Myers, Attila Kiss, Christina Manakanatas, Ouafa Hamza, Franziska Sedlmayer, Petra L. Szabo, Irmgard Fischer, Petra Fichtinger, Bruno K. Podesser, Maria Eriksson, Roland Foisner
Journal: Journal of Clinical Investigation (2018)

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by accelerated cardiovascular disease with extensive fibrosis. It is caused by a mutation in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus. To investigate the contribution of the endothelium to cardiovascular HGPS pathology, we generated an endothelium-specific HGPS mouse model with selective endothelial progerin expression. Transgenic mice develop interstitial myocardial and perivascular fibrosis and left ventricular hypertrophy associated with diastolic dysfunction and premature death. Endothelial cells show impaired shear stress response and reduced levels of endothelial nitric oxide synthase (eNOS) and NO. On the molecular level, progerin impairs nucleocytoskeletal coupling in endothelial cells through changes in mechanoresponsive components at the nuclear envelope, increased F-actin/G-actin ratios, and deregulation of mechanoresponsive myocardin-related transcription factor-A (MRTFA). MRTFA binds to the Nos3 promoter and reduces eNOS expression, thereby mediating a profibrotic paracrine response in fibroblasts. MRTFA inhibition rescues eNOS levels and ameliorates the profibrotic effect of endothelial cells in vitro. Although this murine model lacks the key anatomical feature of vascular smooth muscle cell loss seen in HGPS patients, our data show that progerin-induced impairment of mechanosignaling in endothelial cells contributes to excessive fibrosis and cardiovascular disease in HGPS patients.
Abstract 12773: Association of Opioid Use With Atrial Fibrillation in a Post-9/11 Veteran Population
Authors: Jonathan D Stock, Philip Chui, Lindsey Rosman, Brian J Malm, Lori Bastian, Matthew M Burg
Journal: Circulation (2018)

Introduction: Risks of the current opioid epidemic have traditionally focused on overdoses, but recent studies have shown opioid use is an independent risk factor for cardiovascular mortality. One ...
Surgeon who endangered patients’ lives at abortion clinic is struck off
Authors: Clare Dyer
Journal: BMJ (2018)

An independently contracted surgeon with the British Pregnancy Advisory Service who exposed patients to the risk of life threatening conditions during abortions carried out in May and June 2017 has been struck off by a medical practitioners tribunal.

In one case, James Olobo-Lalobo failed to diagnose a molar pregnancy even though it had been suggested by the ultrasonographer in a preoperative assessment. He failed to initiate the follow-up care that is essential with molar pregnancies. “Patient A,” a 44 year old woman whom Olobo-Lalobo saw at Merseyside BPAS for an abortion by vacuum aspiration, ultimately took matters into her own hands when she called the clinic …
ADTH-07 Deep learning based classification of intrapapillary capillary loops for detection of early oesophageal squamous neoplasia
Authors: Martin Everson, Luis Garcia Peraza Herrera, Wenqi Li, Imanol Luengo Muntion, Omer Ahmad, David Graham, Matthew Banks, Laurence Lovat, Tom Vercauteren, Seb Ourselin, HP Wang, Warren Wang, Rehan Haidry
Journal: Endoscopy (2018)

<h3>Introduction</h3> Narrow band imaging with magnification endoscopy (ME-NBI) allows detailed assessment of microvascular patterns within early squamous cell neoplasia (ESCN). The Japanese Endoscopy Society (JES) <b>AB</b> classification describes ESCN and predicts invasion depth based on the intrapapillary capillary loop (IPCL) pattern. Early lesions are amenable to endoscopic therapy (EET). We have designed a novel deep convolutional network (CNN) able to classify IPCL patterns as normal (A) or abnormal (B1/B2/B3), in order to alert endoscopists to abnormal areas in ESCN during lesion assessment. <h3>Methods</h3> 17 patients were recruited at a referral centre in Taiwan. Endoscopies were performed using ME-NBI (Olympus). IPCLs were classified for each video by 2 experts as normal (type A), or abnormal (type B1/B2/B3), using the JES classification. Matched tissue was obtained by ESD for histologic evaluation of invasion depth. Images were quality controlled to remove uninformative (blurred) images. Our full dataset consisted of 7046 images. A CNN was developed with five-fold cross validation. On average, each fold used 3962 images for training, and 1637 unseen images (846 normal and 791 abnormal) for testing. Accuracy, F1 scores, sensitivity and specificity for abnormal IPCL detection were calculated. <h3>Results</h3> 17 patients were included (10 had early neoplasia [1 high grade intra-epithelial neoplasia (HGIN) 4 carcinoma <i>in situ</i> (CIS) invading to the lamina propria, 4 to the muscularis mucosa and 1 to the submucosa] and 7 were normal). Our algorithm operates at video rate and had an accuracy for differentiating abnormal IPCL patterns (type B1, B2, B3) from normal (type A) of 93.69%. The average F1 score for identifying abnormal areas of ESCN based on IPCL classification was similarly high at 92.2%. Our network also achieved a sensitivity and specificity for abnormal IPCL detection of 89.3% and 98% respectively. <h3>Conclusion</h3> We introduce a novel application of deep learning by developing a real-time CNN, with promising results in classifying squamous mucosa as normal or neoplastic based on the JES IPCL classification. Our system demonstrates impressive accuracy, sensitivity and specificity for differentiating type A from type B1/2/3 IPCLs. Further work is underway to develop a multiclass classifier to distinguish between the subtypes of IPCL patterns. Such a validated system could be used <i>in vivo</i> to alert endoscopists to the presence of ESCN and direct planning of appropriate EET.
Staging Systems to Predict Metastatic Cutaneous Squamous Cell Carcinoma
Authors: Ivo Abraham, Clara Curiel-Lewandrowski
Journal: JAMA Dermatology (2018)

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 Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Dermatology journal
Exacerbations of severe asthma in patients treated with mepolizumab
Authors: Rahul Shrimanker, Ian D. Pavord, Steve Yancey, Liam G. Heaney, Ruth H. Green, Peter Bradding, Beverley Hargadon, Chris E. Brightling, Andrew J. Wardlaw, Pranabashis Haldar
Journal: European Respiratory Journal (2018)

<b>Exacerbations on mepolizumab are associated with a lower sputum eosinophil level appear less severe in terms of symptoms compared to placebo. These findings raise the possibility that an alternative treatment approach may be needed for these events.</b>http://ow.ly/SoFX30md6of
MicroRNAs and mild cognitive impairment: A systematic review
Authors: Paola Piscopo, Eleonora Lacorte, Marco Feligioni, Flavia Mayer, Alessio Crestini, Laura Piccolo, Ilaria Bacigalupo, Melania Filareti, Elena Ficulle, Annamaria Confaloni, Nicola Vanacore, Massimo Corbo
Journal: Ageing Research Reviews (2018)
Investigation of charge ratio variation in mRNA – DEAE-dextran polyplex delivery systems
Authors: C. Siewert, H. Haas, T. Nawroth, A. Ziller, S.S. Nogueira, M.A. Schroer, C.E. Blanchet, D.I. Svergun, A. Radulescu, F. Bates, Y. Huesemann, M.P. Radsak, U. Sahin, P. Langguth
Journal: Biomaterials (2018)

mRNA pharmaceuticals represent a new class of therapeutics, with applications, in cancer vaccination, tumour therapy and protein substitution. Formulations are required to deliver messenger RNA (mRNA) to the target sites where induction of genetic transfection following receptor mediated cell uptake & translation is required. In the current study, the cationic polysaccharide diethylaminoethylen (DEAE) - Dextran was selected as a model system carrier for the investigation of polyplex nanoparticle formation together with mRNA as a function of the molar ratio of the components. The structure of the mRNA/Dextran colloids was investigated as a function of the polymer-to-mRNA ratio and correlated with the biological activity determined by cellular transfection with luciferase coding mRNA. Dynamic light scattering (DLS), small angle x-ray scattering (SAXS), and small angle neutron scattering (SANS) with deuterium contrast variation were used to achieve structural insight into the systems. Similarly to previously investigated lipid based systems, colloidally stable particles with confined size were obtained with either excess of positive or negative charge. Highest activity was obtained with positive charge excess. From the scattering experiments information on the internal organization inside the polymer/mRNA systems was derived. Indication for the presence of structural elements in the length scale of ten to 20 nm were found in the excess of dextran, which could be due to either excess or particulate polymer. Information on the molecular organization of the mRNA nanoparticle products may provide a valuable basis for defining critical quality attributes of drug products for pharmaceutical application.