tbuckley/cabot-search huggingface dataset:
Abstract 256: mRNA-based Nanoparticles Are Highly Effective Agents For Cardiac Gene Therapy
Authors: Amy R Kontorovich, Ahmed A Eltoukhy, Irene C Turnbull, Timothy J Cashman, Satish K Rao, Daniel G Anderson, Roger J Hajjar, Kevin D Costa
Journal: Circulation Research (2013)

Gene therapy holds promise for repair and regeneration of damaged myocardium after infarction. Viral vectors used in most studies, while highly effective, carry concerns of safety and immunogenicity. Nanoparticle (NP)-enabled transfection using polymeric and lipidoid reagents mitigates some of the concerns related to the use of viral vectors. However, these agents have been less effective in transfecting cardiac myocytes, which are primarily post-mitotic and only weakly facilitate DNA entry to the nucleus. Because translation occurs in the cytosol, transfection with RNA obviates the need for nuclear entry. Recent work has shown that synthetic alterations to messenger RNA (mRNA) can prolong its half-life in the cytosol and diminish the host’s immune response. We hypothesized that transfection of cardiac myocytes with lipidoid NPs formed using modified mRNA would lead to high levels of protein expression. Neonatal rat (NRCM), adult rat (ARCM) and human embryonic stem cell-derived (hES-CM) cardiac myocytes were transfected with modified GFP-mRNA NPs using a lipidoid vehicle (Stemfect TM , Stemgent, Cambridge, MA) or Lipofectamine2000 (LF, Invitrogen) and GFP expression was assessed after 24 hours. Average transfection efficiency in NRCM was significantly higher using Stemfect versus LF as measured by flow cytometry (48.5% vs. 6.6% at 20ng mRNA; 47.4% vs. 11.8% at 40ng mRNA, 48.1% vs. 18.6% at 80ng mRNA; 48.1% vs. 28% at 160ng mRNA; n=3, p&lt;0.01 for each pair). In hES-CM transfection was also more robust with Stemfect NPs versus LF (91.6% vs. 62.2%, p&lt;0.05 at 40ng mRNA; 96.1 vs. 87.8%, p&lt;0.01 at 160ng mRNA; n=3). GFP expression was noted by fluorescence microscopy to be higher in ARCMs transfected with Stemfect NPs versus LF. In conclusion, we have shown that difficult-to-transfect cardiac myocytes are readily transfected with mRNA-based NPs in vitro and with significantly higher efficiency when using Stemfect rather than Lipofectamine. Gene therapy with mRNA represents a novel approach to cardiac repair and may be preferable to DNA because of the transient window of protein expression and lower side effect profile.
Association of young patient age with high-risk pathologic features and recurrence in papillary thyroid cancer.
Authors: Iris Wei, Sandra L. Wong, Barbra S. Miller, Paul G. Gauger, Mark Steven Cohen, Megan Rist Haymart, David T. Hughes
Journal: Journal of Clinical Oncology (2014)

6064 Background: Certain histopathologic features may be risk factors for recurrent disease after resection of papillary thyroid cancer (PTC). Age is also an important prognostic factor, with higher mortality in patients over 45. Our objective was to determine whether age was associated with these pathologic features and rates of recurrence. Methods: A retrospective analysis was performed for PTC patients who underwent anatomically complete resection at the University of Michigan between 2006 – 2012. Patients with known distant metastases were excluded. Demographics, high-risk pathologic features (capsular or vascular invasion, extrathyroidal extension, lymph node metastases, extranodal extension), and disease recurrence were examined. Results: A total of 623 PTC patients were included in the analysis; 141 (23%) were men, 482 (77%) women. Median age was 49 years (range 10–87). Twenty patients had recurrent disease, and all recurred locoregionally in the central or lateral neck, with a mean time to recurrence of 1.2 years. One patient was treated with radioactive iodine, while the rest underwent reoperation. By Kaplan-Meier analysis, there was no difference in recurrence rates between patients <45 and ≥45 years (p = 0.92). However, additional subgroup analysis revealed that patients ≤25 had a higher rate of recurrent disease compared to those >25 years (HR = 8.2, p = 0.02). The tumors of young patients (≤25 years) were also larger (p = 0.001), with higher rates of extranodal extension (p = 0.0004), vascular invasion (p < 0.0001), capsular invasion (p < 0.0001), and lymph node metastasis (p = 0.007). Overall, the presence of any aggressive pathologic features was associated with an increased risk of recurrence (HR = 18.5, p= 0.004). Using a Cox proportional hazards model, the most significant risk factors were tumor size, capsular invasion, extrathyroidal extension, and lymph node metastases. Conclusions: PTC patients ≤25 years old have significantly higher rates of recurrence and reoperation despite being classified as AJCC Stage I. This may be in part due to larger tumor sizes and presence of aggressive histopathologic features. Patients with these factors should be monitored with close surveillance.
Chronic activation of hypothalamic oxytocin neurons improves cardiac function during left ventricular hypertrophy-induced heart failure
Authors: Kara Garrott, Jhansi Dyavanapalli, Edmund Cauley, Mary Kate Dwyer, Sarah Kuzmiak-Glancy, Xin Wang, David Mendelowitz, Matthew W. Kay
Journal: Cardiovascular Research (2017)

A distinctive hallmark of heart failure (HF) is autonomic imbalance, consisting of increased sympathetic activity, and decreased parasympathetic tone. Recent work suggests that activation of hypothalamic oxytocin (OXT) neurons could improve autonomic balance during HF. We hypothesized that a novel method of chronic selective activation of hypothalamic OXT neurons will improve cardiac function and reduce inflammation and fibrosis in a rat model of HF.Two groups of male Sprague-Dawley rats underwent trans-ascending aortic constriction (TAC) to induce left ventricular (LV) hypertrophy that progresses to HF. In one TAC group, OXT neurons in the paraventricular nucleus of the hypothalamus were chronically activated by selective expression and activation of excitatory DREADDs receptors with daily injections of clozapine N-oxide (CNO) (TAC + OXT). Two additional age-matched groups received either saline injections (Control) or CNO injections for excitatory DREADDs activation (OXT NORM). Heart rate (HR), LV developed pressure (LVDP), and coronary flow rate were measured in isolated heart experiments. Isoproterenol (0.01 nM-1.0 µM) was administered to evaluate β-adrenergic sensitivity. We found that increases in cellular hypertrophy and myocardial collagen density in TAC were blunted in TAC + OXT animals. Inflammatory cytokine IL-1β expression was more than twice higher in TAC than all other hearts. LVDP, rate pressure product (RPP), contractility, and relaxation were depressed in TAC compared with all other groups. The response of TAC and TAC + OXT hearts to isoproterenol was blunted, with no significant increase in RPP, contractility, or relaxation. However, HR in TAC + OXT animals increased to match Control at higher doses of isoproterenol.Activation of hypothalamic OXT neurons to elevate parasympathetic tone reduced cellular hypertrophy, levels of IL-1β, and fibrosis during TAC-induced HF in rats. Cardiac contractility parameters were significantly higher in TAC + OXT compared with TAC animals. HR sensitivity, but not contractile sensitivity, to β-adrenergic stimulation was improved in TAC + OXT hearts.
“Sex up” general medicine to drive recruitment, says physicians’ leader
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Medical leaders must seek to boost the standing of general medicine to help improve the way clinical care is delivered on the front line, the president of the Royal College of Physicians has urged.

Jane Dacre said that medicine has placed too much emphasis on highly trained specialist care over the past two decades and not enough on generalists, who are increasingly needed to treat acutely ill patients with multiple problems.

Acknowledging the workforce pressures that act as a barrier to improving care, Dacre said that it was crucial to encourage more doctors to train as general physicians and geriatricians and that these specialities were valued in medicine. …
Organizational Practices Affecting Chronic Obstructive Pulmonary Disease Readmissions
Authors: Seppo T. Rinne, Paul L. Hebert, Edwin S. Wong, David H. Au, Lori A. Bastian, Ingrid M. Nembhard, Emily L. Neely, Christine A. Sulc, Chuan-Fen Liu
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Prescribing Quality and Prediction of Clinical Outcomes in Patients With Type 2 Diabetes: A Prospective Cohort Study
Authors: Kirsten P.J. Smits, Grigory Sidorenkov, Gerjan Navis, Margriet Bouma, Marianne A. Meulepas, Henk J.G. Bilo, Petra Denig
Journal: Diabetes Care (2017)

Prescribing quality indicators (PQIs) are used to assess whether patients are treated according to guideline recommendations. To ensure that the use of PQIs leads to improved patient outcomes, their predictive validity needs to be assessed (1). We assessed whether newly developed PQIs for diabetes care are associated with better intermediate cardiometabolic and renal outcomes in patients with type 2 diabetes. Special focus was on clinical action indicators that consider patients with elevated risk factor levels to be receiving adequate treatment when treatment is either started or intensified or when they return to control (2). Such indicators are considered more meaningful and fair than presently used indicators that focus on current medication use or on achieving risk factor control (3).

A cohort study was conducted using data from the Groningen Initiative to Analyze Type 2 Diabetes Treatment (GIANTT) database, including medical records data of 26,321 patients with type 2 diabetes in primary care. Eleven previously …
Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: preparation, characterization and application in a vaginal drug delivery system
Authors: Liqian Ci, Zhigang Huang, Yu Liu, Zhepeng Liu, Gang Wei, Weiyue Lu
Journal: Acta Pharmaceutica Sinica B (2017)

Lack of mucoadhesive properties is the major drawback to poloxamer 407 (F127)-based in situ hydrogels for mucosal administration. The objective of the present study was to construct a novel mucoadhesive and thermosensitive in situ hydrogel drug delivery system based on an amino-functionalized poloxamer for vaginal administration. First, amino-functionalized poloxamer 407 (F127-NH2) was synthesized and characterized with respect to its micellization behavior and interaction with mucin. Then using acetate gossypol (AG) as model drug, AG-loaded F127-NH2-based in situ hydrogels (NFGs) were evaluated with respect to rheology, drug release, ex vivo vaginal mucosal adhesion, in vivo intravaginal retention and local irritation after vaginal administration to healthy female mice. The results show that F127-NH2 is capable of forming a thermosensitive in situ hydrogel with sustained drug release properties. An interaction between positively charged F127-NH2 and negatively charged mucin was revealed by changes in the particle size and zeta potential of mucin particles as well as an increase in the complex modulus of NFG caused by mucin. Ex vivo and in vivo fluorescence imaging and quantitative analysis of the amount of AG remaining in mouse vaginal lavage all demonstrated greater intravaginal retention of NFG than that of an unmodified F127-based in situ hydrogel. In conclusion, amino group functionalization confers valuable mucoadhesive properties on poloxamer 407.
EULAR recommendations for management of fibromyalgia
Authors: Gary J Macfarlane, Caroline Kronisch, Fabiola Atzeni, Winfried Häuser, Ernest H Choy, Kirstine Amris, Jaime Branco, Fitnat Dincer, Paivi Leino-Arjas, Kathy Longley, Geraldine McCarthy, Suzi Makri, Serge Perrot, Piercarlo Sarzi Puttini, Ann Taylor, Gareth T Jones
Journal: Annals of the Rheumatic Diseases (2017)

h e u m di s-2 0 1 7-2 1
Therapeutic Inhibition of miR-4260 Suppresses Colorectal Cancer via Targeting MCC and SMAD4
Authors: Junjie Xiao, Dongchao Lv, Jinzhe Zhou, Yihua Bei, Ting Chen, Muren Hu, Qiulian Zhou, Siyi Fu, Qi Huang
Journal: Theranostics (2017)

Dysregulation of microRNAs (miRNAs, miRs) and their putative target genes have been increasingly reported to contribute to colorectal cancer. However, miRNAs that directly target the mutated in colorectal cancer (MCC) gene, a tumor suppressor which is downregulated or inactivated in colorectal cancer, remain largely unknown. By using an array-based miRNA analysis, we identified a group of miRNAs that were dysregulated in human metastatic versus non-metastatic colorectal cancer tissues. One of these miRNAs, miR-4260, was predicted to target MCC in the miRDB database. Results using human HCT116 and HT29 colorectal cancer cell lines showed that miR-4260 mimic enhanced cell proliferation and migration and reduced apoptosis induced by the chemotherapeutic agent 5-fluorouracil while miR-4260 inhibitor had inverse effects. Furthermore, miR-4260 negatively regulated MCC as well as SMAD4 by directly binding to the 3'untranslational region (3'UTR). Using siRNAs targeting MCC or SMAD4, we showed that upregulation of MCC and SMAD4 was essential to mediate the functional roles of miR-4260 inhibitor in colorectal cancer cells. Our in vivo experiments indicated that inhibition of miR-4260 reduced colorectal tumor growth in nude mice subcutaneously implanted with HCT116 cells. Significantly, miR-4260 was increased in human colorectal cancer tissues with simultaneous downregulation of MCC and SMAD4, strongly suggesting the clinical relevance of targeting miR-4260 in the treatment of colorectal cancer. In summary, we identified miR-4260 as a novel oncomiR for colorectal cancer that targets MCC and SMAD4. Inhibition of miR-4260 can, therefore, be a potential therapeutic strategy for colorectal cancer.
Alternate day fasting is no better for weight loss than conventional diets, study finds
Authors: Jacqui Wise
Journal: BMJ (2017)

Fasting on alternate days to lose weight seems no more effective than reducing the daily intake of calories, a study in JAMA Internal Medicine concludes.1

Alternate day fasting involves a “fast” day, when people are allowed to consume around 500 kcal, alternated with a “feast” day, when they can eat what they like. It has become increasingly popular during the past decade, with several bestselling diet books promoting this approach.

The randomised trial included 100 metabolically healthy obese adults with a mean body mass index of 34 and a mean age of 44. The participants were randomly allocated to one of three groups for a year: …
High Blood BAALC Copy Numbers Determined By Digital Droplet PCR at Timepoint of Allogeneic Transplantation in Complete Remission Predicts Relapse in Patients with Acute Myeloid Leukemia
Authors: Madlen Jentzsch, Marius Bill, Julia Schulz, Juliane Grimm, Stefanie Beinicke, Karoline Schubert, Janine Haentschel, Kathrin Wildenberger, Laura Katharina Schmalbrock, Lynn Baquiran Bonifacio, Wolfram Poenisch, Gerhard Behre, Georg-Nikolaus Franke, Thoralf Lange, Vladan Vucinic, Dietger Niederwieser, Sebastian Schwind
Journal: Blood (2016)
BAND 3CEINGE (Gly796Arg) Mutation Causes Dehydrated Hereditary Stomatocytosis (DHS) with Dyserythropoietic Phenotype
Authors: Luigia De Falco, Lucia De Franceschi, Frank Borgese, Carmelo Piscopo, Maria Rosaria Esposito, Rosa Anna Avvisati, Pietro Izzo, Helene Guizouarn, Andrea Biondani, Achille Iolascon
Journal: Blood (2008)
Analyzing Patient Characteristics Who Received (DA) EPOCH-R for High Risk Diffuse Large B-Cell Lymphoma: MD Anderson Cancer Center Experience
Authors: Kristin A. Simar, Vishwanath Sathyanarayanan, Amir K Issa, Mohamed Amin Ahmed, Mansoor Noorani, Michelle A Fanale, Yasuhiro Oki, F.B. Hagemeister, Sattva S. Neelapu, Loretta Nastoupil, Nathan Fowler, Francesco Turturro, Richard Eric Davis, Maria Alma Rodriguez, Michael Wang, Lei Feng, Ken H. Young, Timothy J. McDonnell, Chelsea C Pinnix, Luis E. Fayad, Jason R. Westin
Journal: Blood (2016)
The Nephila clavipes genome highlights the diversity of spider silk genes and their complex expression
Authors: Paul L Babb, Nicholas F Lahens, Sandra M Correa-Garhwal, David N Nicholson, Eun Ji Kim, John B Hogenesch, Matjaž Kuntner, Linden Higgins, Cheryl Y Hayashi, Ingi Agnarsson, Benjamin F Voight
Journal: Nature Genetics (2017)

Spider silks are the toughest known biological materials, yet are lightweight and virtually invisible to the human immune system, and they thus have revolutionary potential for medicine and industry. Spider silks are largely composed of spidroins, a unique family of structural proteins. To investigate spidroin genes systematically, we constructed the first genome of an orb-weaving spider: the golden orb-weaver (Nephila clavipes), which builds large webs using an extensive repertoire of silks with diverse physical properties. We cataloged 28 Nephila spidroins, representing all known orb-weaver spidroin types, and identified 394 repeated coding motif variants and higher-order repetitive cassette structures unique to specific spidroins. Characterization of spidroin expression in distinct silk gland types indicates that glands can express multiple spidroin types. We find evidence of an alternatively spliced spidroin, a spidroin expressed only in venom glands, evolutionary mechanisms for spidroin diversification, and non-spidroin genes with expression patterns that suggest roles in silk production.
Contribution of risk factors to excess mortality in isolated and lonely individuals: an analysis of data from the UK Biobank cohort study
Authors: Marko Elovainio, Christian Hakulinen, Laura Pulkki-Råback, Marianna Virtanen, Kim Josefsson, Markus Jokela, Jussi Vahtera, Mika Kivimäki
Journal: The Lancet Public Health (2017)

The associations of social isolation and loneliness with premature mortality are well known, but the risk factors linking them remain unclear. We sought to identify risk factors that might explain the increased mortality in socially isolated and lonely individuals.We used prospective follow-up data from the UK Biobank cohort study to assess self-reported isolation (a three-item scale) and loneliness (two questions). The main outcomes were all-cause and cause-specific mortality. We calculated the percentage of excess risk mediated by risk factors to assess the extent to which the associations of social isolation and loneliness with mortality were attributable to differences between isolated and lonely individuals and others in biological (body-mass index, systolic and diastolic blood pressure, and handgrip strength), behavioural (smoking, alcohol consumption, and physical activity), socioeconomic (education, neighbourhood deprivation, and household income), and psychological (depressive symptoms and cognitive capacity) risk factors.466 901 men and women (mean age at baseline 56·5 years [SD 8·1]) were included in the analyses, with a mean follow-up of 6·5 years (SD 0·8). The hazard ratio for all-cause mortality for social isolation compared with no social isolation was 1·73 (95% CI 1·65-1·82) after adjustment for age, sex, ethnic origin, and chronic disease (ie, minimally adjusted), and was 1·26 (95% CI 1·20-1·33) after further adjustment for socioeconomic factors, health-related behaviours, depressive symptoms, biological factors, cognitive performance, and self-rated health (ie, fully adjusted). The minimally adjusted hazard ratio for mortality risk related to loneliness was 1·38 (95% CI 1·30-1·47), which reduced to 0·99 (95% CI 0·93-1·06) after full adjustment for baseline risks.Isolated and lonely people are at increased risk of death. Health policies addressing risk factors such as adverse socioeconomic conditions, unhealthy lifestyle, and lower mental wellbeing might reduce excess mortality among the isolated and the lonely.Academy of Finland, NordForsk, and the UK Medical Research Council.
Abstract 17632: STIM1 Increases Calcium Stores in the Sarcoplasmic Reticulum of Adult Feline Ventricular Myocytes
Authors: Constantine Troupes, Hajime Kubo, Sadia Mohsin, Remus Berretta, Jonathan Soboloff, Steven Houser
Journal: Circulation (2015)

Background: STIM1 is a Sarcoplasmic Reticulum (SR) membrane resident protein implicated in sensing and maintaining SR Ca 2+ levels. The role of STIM1 in the regulation of SR Ca 2+ stores in the normal and diseased heart is not well described. Previous reports confirm that STIM1 is present at low levels in the healthy adult heart, but expression levels increase after cardiac injury. Objective: To determine if increased STIM1 expression after cardiac injury may be involved in the disturbed Ca 2+ cycling present within diseased cardiomyocytes. Results: Adenovirus was used to express either STIM1 or red fluorescent protein (RFP) in freshly isolated adult feline ventricular myocytes (AFMs). We found that in normally quiescent myocytes, STIM1 induced high resting SR Ca 2+ load and induced Ca 2+ sparks, which lead to spontaneous contractions by triggering action potentials. Concurrently, pacing of AFMs revealed STIM1 also increased fractional shortening and Ca 2+ transient amplitude. However, STIM1 also induced cell death (60% versus only 5% in RFP controls). Blockade of the L-type Ca 2+ channel (LTCC) with verapamil rescued the cell death caused by STIM1, but was unable to reduce SR load or Ca 2+ sparks. In contrast, inhibition of ORAI channels using BTP2 rescued cell death and abolished Ca 2+ sparks, while canonical transient receptor potential channel inhibition had no effect. STIM1 expression reduced baseline LTCC current amplitude by 20%, but there was no difference in current amplitude after Bay K8644 addition, suggesting channel number was not altered. Conclusions: STIM1 induced Ca 2+ influx can load the SR of large mammalian myocytes, causing Ca 2+ sparks and waves that can trigger action potentials. The induced APs lead to cell death and this effect could be blocked LTCC blockade. STIM1-mediated Ca 2+ influx was dependent on ORAI channel function. Similar to previous reports, we found that STIM1 reduced LTCC current but did not alter LTCC availability. These data show that after cardiac injury, STIM1 and ORAI may provide Ca 2+ influx that positively influences contractility but negatively impacts cell survival and arrhythmias.