tbuckley/cabot-search huggingface dataset:
Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates
Authors: Donald J. Foster, Christopher R. Brown, Sarfraz Shaikh, Casey Trapp, Mark K. Schlegel, Kun Qian, Alfica Sehgal, Kallanthottathil G. Rajeev, Vasant Jadhav, Muthiah Manoharan, Satya Kuchimanchi, Martin A. Maier, Stuart Milstein
Journal: Molecular Therapy (2018)

Significant progress has been made in the advancement of RNAi therapeutics by combining a synthetic triantennary N-acetylgalactosamine ligand targeting the asialoglycoprotein receptor with chemically modified small interfering RNA (siRNA) designs, including the recently described Enhanced Stabilization Chemistry. This strategy has demonstrated robust RNAi-mediated gene silencing in liver after subcutaneous administration across species, including human. Here we demonstrate that substantial efficacy improvements can be achieved through further refinement of siRNA chemistry, optimizing the positioning of 2′-deoxy-2′-fluoro and 2′-O-methyl ribosugar modifications across both strands of the double-stranded siRNA duplex to enhance stability without compromising intrinsic RNAi activity. To achieve this, we employed an iterative screening approach across multiple siRNAs to arrive at advanced designs with low 2′-deoxy-2′-fluoro content that yield significantly improved potency and duration in preclinical species, including non-human primate. Liver exposure data indicate that the improvement in potency is predominantly due to increased metabolic stability of the siRNA conjugates. Significant progress has been made in the advancement of RNAi therapeutics by combining a synthetic triantennary N-acetylgalactosamine ligand targeting the asialoglycoprotein receptor with chemically modified small interfering RNA (siRNA) designs, including the recently described Enhanced Stabilization Chemistry. This strategy has demonstrated robust RNAi-mediated gene silencing in liver after subcutaneous administration across species, including human. Here we demonstrate that substantial efficacy improvements can be achieved through further refinement of siRNA chemistry, optimizing the positioning of 2′-deoxy-2′-fluoro and 2′-O-methyl ribosugar modifications across both strands of the double-stranded siRNA duplex to enhance stability without compromising intrinsic RNAi activity. To achieve this, we employed an iterative screening approach across multiple siRNAs to arrive at advanced designs with low 2′-deoxy-2′-fluoro content that yield significantly improved potency and duration in preclinical species, including non-human primate. Liver exposure data indicate that the improvement in potency is predominantly due to increased metabolic stability of the siRNA conjugates.
A Woman With a Large Ulcerated Nodule on the Finger
Authors: Ramya Vangipuram, Christopher Haley, Stephen K. Tyring
Journal: JAMA (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 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
Abstract 12039: Health Literacy Mediates the Relationship Between Perceived Control and Cardiac Event-free Survival in Patients With Heart Failure
Authors: Jia-rong Wu, Jennifer L Miller, Debra K Moser
Journal: Circulation (2016)

Introduction: Lower levels of perceived control and health literacy are independently associated with morbidity (higher levels of anxiety and depression or rehospitalizations) in individuals with heart failure (HF). However, little is known about the interrelationship of these two predictors. Low health literacy impairs engagement in the health care process and in doing so may play a role between perceived control and outcomes. Objective: The purpose of this study was to examine the relationships among perceived control, health literacy and cardiac event-free survival in patients with HF. Methods: This was a prospective study of 575 rural patients with HF (female 41%, age 66±13, married 57%). Perceived control was assessed using the Control Attitude Scale-Revised. Health literacy was measured by the Short Test of Functional Health Literacy in Adults. Cardiac events were followed for 24 months by patient/family interview and hospital database review. Linear/logistic regression and survival analyses were used to examine the associations among health literacy, perceived control, and cardiac event-free survival. Results: Patients with higher perceived control had higher health literacy. Higher perceived control and higher health literacy were associated with better cardiac event-free survival before and after adjusting for covariates (e.g. age, marital status, B-type Natriuretic Peptide) ( p &lt;.05). Perceived control was not a significant predictor of health outcomes ( p =.10) after entering health literacy ( p &lt;.001) in the model demonstrating mediation (Figure). Conclusions: Lower perceived control was associated with worse outcomes and health literacy was a mediator between perceived control and health outcomes. Our results suggest that interventions intended to improve health outcomes in adults with HF need to increase their perceived control of HF care and also take into account patients’ level of health literacy.
GPs forced to turn away patients because of winter pressures
Authors: Gareth Iacobucci
Journal: BMJ (2018)

GPs are being forced to turn away patients because they do not have the capacity to safely treat the number of people seeking care this winter, doctors have warned.

General practice leaders said that the pressures reported in NHS hospitals are equally prevalent in GP surgeries, which are struggling to cope with an “overwhelming” demand for appointments and home visits, and a spike in respiratory illnesses and flu.

Dean Eggitt, a GP in Doncaster and medical secretary of Doncaster Local Medical Committee, told The BMJ , “I have never worked so hard and seen so many patients in my entire life. We’re getting to the …
Evolution of Herpes Zoster Vaccines and Their Economic Value
Authors: Mehdi Najafzadeh
Journal: JAMA Internal Medicine (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 Internal Medicine 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 Internal Medicine journal
miRNAs — novel regulators in skin cancer
Authors: M. Teresa Villanueva
Journal: Nature reviews. Cancer (2014)

mi RNAs -novel regulators in skin cancerZhang, Ge and Fuchs have provided new insights into the role of microRNA-125b (miR-125b) in the initiation, progression and maintenance of squamous cell carcinoma (SCC).Using an inducible mouse model, they found that miR-125b overexpression in skin epithelium promoted spontaneous tumour formation as well as sensitizing skin to chemically-induced carcinogenesis.Furthermore, miR-125b expression maintained tumour growth by repressing differentiation and promoting a cancer stem-cell-like transcriptional programme.By identifying and validating miR-125b targets specifically associated with tumorigenesis, they found that miR-125b directly represses stress-responsive MAPK transcripts.It also indirectly maintains epidermal growth factor receptor (EGFR) signalling, by repressing vacuolar protein-sorting 4 homologue B (Vps4b), which encodes a protein that promotes endocytic degradation of phosphorylated EGFR.
Gastritis staging in the endoscopic follow-up for the secondary prevention of gastric cancer: a 5-year prospective study of 1755 patients
Authors: Massimo Rugge, Alberto Meggio, Cecilia Pravadelli, Mattia Barbareschi, Matteo Fassan, Maria Gentilini, Manuel Zorzi, Giovanni De Pretis, David Y Graham, Robert M Genta
Journal: Gut (2018)

Objective Operative link on gastritis assessment (OLGA) staging for gastritis ranks the risk for gastric cancer (GC) in progressive stages (0–IV). This prospective study aimed at quantifying the cancer risk associated with each gastritis stage. Design A cohort of 1755 consecutive patients with dyspepsia underwent initial (T-0) oesophagogastroduodenoscopy with mapped gastric biopsies, OLGA staging and assessment of Helicobacter pylori infection. Patients were followed for 55 months (median); patients with stages II III and IV underwent a second endoscopy/restaging (T-1), and those with stages 0 and I were followed clinically and through in-depth clinical and record checking. Endpoints were OLGA stage at T-1 and development of gastric epithelial neoplasia. Results At T-0, 77.6% of patients had stage 0, 14.4% stage I, 5.1% stage II, 2.1% stage III and 0.85% stage IV. H. pylori infection was detected in 603 patients at T-0 and successfully eradicated in 602 of them; 220 had a documented history of H. pylori eradication; and 932 were H. pylori naïve-negative. Incident neoplastic lesions (prevalence=0.4%; low-grade intraepithelial neoplasia (IEN)=4; high-grade IEN=1; GC=2) developed exclusively in patients with stages III–IV. The risk for epithelial neoplasia was null in patients at stages 0, I and II (95% CI 0 to 0.4), 36.5 per 1000 person-years in patients at stage III (95% CI 13.7 to 97.4) and 63.1 per 1000 person-years in patients at stage IV (95% CI 20.3 to 195.6). Conclusions This prospective study confirms that OLGA staging reliably predicts the risk for development of gastric epithelial neoplasia. Although no neoplastic lesions arose in H. pylori- naïve patients, the H. pylori eradication in subjects with advanced stages (III–IV) did not abolish the risk for neoplastic progression.
Facial Papules in a Patient With Lichen Planopilaris
Authors: Athena J. Manatis-Lornell, Maryanne M. Senna
Journal: JAMA Dermatology (2018)

A woman in her 50s with biopsy-proven scalp lichen planopilaris presented with slightly pruritic facial papules that coincided with the start of her hair loss condition; she denied a history of severe acne or other inflammatory skin disorders and had no health problems. What is your diagnosis?
Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade
Authors: Adel Samson, Karen J. Scott, David Taggart, Emma J. West, Erica Wilson, Gerard J. Nuovo, Simon Thomson, Robert Corns, Ryan K. Mathew, Martin J. Fuller, Timothy J. Kottke, Jill M. Thompson, Elizabeth J. Ilett, Julia V. Cockle, Philip van Hille, Gnanamurthy Sivakumar, Euan S. Polson, Samantha J. Turnbull, Elizabeth S. Appleton, Gemma Migneco, Ailsa S. Rose, Matthew C. Coffey, Deborah A. Beirne, Fiona J. Collinson, Christy Ralph, D. Alan Anthoney, Christopher J. Twelves, Andrew J. Furness, Sergio A. Quezada, Heiko Wurdak, Fiona Errington-Mais, Hardev Pandha, Kevin J. Harrington, Peter J. Selby, Richard G. Vile, Stephen D. Griffin, Lucy F. Stead, Susan C. Short, Alan A. Melcher
Journal: Science Translational Medicine (2018)

Intravenous infusion of oncolytic reovirus in patients leads to infection of brain tumors, infiltration by cytotoxic T cells, and up-regulation of PD-L1.
The interaction of sex, height, and QRS duration on the effects of cardiac resynchronization therapy on morbidity and mortality: an individual‐patient data meta‐analysis
Authors: Cecilia Linde, John G.F. Cleland, Michael R. Gold, J. Claude Daubert, Anthony S.L. Tang, James B. Young, Lou Sherfesee, William T. Abraham
Journal: European Journal of Heart Failure (2018)
Abstract 12939: 18F-Sodium Fluoride Positron Emission Tomography for Molecular Imaging of Coronary Atherosclerosis Based on Computed Tomography Analysis
Authors: Toshiro Kitagawa, Hideya Yamamoto, Shinya Toshimitsu, Ko Sasaki, Atsuhiro Senoo, Yutaka Hirokawa, Yasuki Kihara
Journal: Circulation (2016)

Background: Arterial 18F-sodium fluoride (18F-NaF) uptake on positron emission tomography (PET) has been reported to reflect active atherosclerosis with osteogenesis and inflammatory stimulus. We e...
Extracellular matrix as a driver of progressive fibrosis
Authors: Jeremy Herrera, Craig A. Henke, Peter B. Bitterman
Journal: Journal of Clinical Investigation (2018)

The extracellular matrix (ECM) is dynamically tuned to optimize physiological function. Its major properties, including composition and mechanics, profoundly influence cell biology. Cell-ECM interactions operate through an integrated set of sensor and effector circuits that use several classes of receptors and signal transduction pathways. At the single-cell level, the ECM governs differentiation, metabolism, motility, orientation, proliferation, and survival. At the cell population level, the ECM provides higher-order guidance that is essential for physiological function. When pathological changes in the ECM lead to impairment of organ function, we use the term “fibrosis.” In this Review, we differentiate fibrosis initiation from progression and focus primarily on progressive lung fibrosis impairing organ function. We present a working model to explain how the altered ECM is not only a consequence but also a driver of fibrosis. Additionally, we advance the concept that fibrosis progression occurs in a fibrogenic niche that is composed of a fibrogenic ECM that nurtures fibrogenic mesenchymal progenitor cells and their fibrogenic progeny.
Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans
Authors: Kendra L. Marks, David T. Martel, Calvin Wu, Gregory J. Basura, Larry E. Roberts, Kara C. Schvartz-Leyzac, Susan E. Shore
Journal: Science Translational Medicine (2018)

Noninvasive bimodal auditory stimulation targets the dorsal cochlear nucleus and reduces tinnitus in guinea pigs and humans.
The impact of aging on primate hematopoiesis as interrogated by clonal tracking
Authors: Kyung-Rok Yu, Diego A. Espinoza, Chuanfeng Wu, Lauren Truitt, Tae-Hoon Shin, Shirley Chen, Xing Fan, Idalia M. Yabe, Sandhya Panch, So Gun Hong, Samson Koelle, Rong Lu, Aylin Bonifacino, Allen Krouse, Mark Metzger, Robert E. Donahue, Cynthia E. Dunbar
Journal: Blood (2018)
The Public and the Opioid-Abuse Epidemic
Authors: Robert J. Blendon, John M. Benson
Journal: New England Journal of Medicine (2018)

The Public and the Opioid-Abuse Epidemic A majority of the U.S. public considers addiction to prescription pain medication a major problem but does not deem it a national emergency. And only about half of the public believes there’s a treatment for prescription-painkiller addiction that’s effective in the long term.
Datamonkey 2.0: A Modern Web Application for Characterizing Selective and Other Evolutionary Processes
Authors: Steven Weaver, Stephen D Shank, Stephanie J Spielman, Michael Li, Spencer V Muse, Sergei L Kosakovsky Pond
Journal: Molecular Biology and Evolution (2017)

Inference of how evolutionary forces have shaped extant genetic diversity is a cornerstone of modern comparative sequence analysis. Advances in sequence generation and increased statistical sophistication of relevant methods now allow researchers to extract ever more evolutionary signal from the data, albeit at an increased computational cost. Here, we announce the release of Datamonkey 2.0, a completely re-engineered version of the Datamonkey web-server for analyzing evolutionary signatures in sequence data. For this endeavor, we leveraged recent developments in open-source libraries that facilitate interactive, robust, and scalable web application development. Datamonkey 2.0 provides a carefully curated collection of methods for interrogating coding-sequence alignments for imprints of natural selection, packaged as a responsive (i.e. can be viewed on tablet and mobile devices), fully interactive, and API-enabled web application. To complement Datamonkey 2.0, we additionally release HyPhy Vision, an accompanying JavaScript application for visualizing analysis results. HyPhy Vision can also be used separately from Datamonkey 2.0 to visualize locally executed HyPhy analyses. Together, Datamonkey 2.0 and HyPhy Vision showcase how scientific software development can benefit from general-purpose open-source frameworks. Datamonkey 2.0 is freely and publicly available at http://www.datamonkey.org, and the underlying codebase is available from https://github.com/veg/datamonkey-js.
Understanding Comorbidity Profiles and Their Effect on Treatment and Survival in Patients With Colorectal Cancer
Authors: Erin E. Hahn, Michael K. Gould, Corrine E. Munoz-Plaza, Janet S. Lee, Carla Parry, Ernest Shen
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Patients with colorectal cancer (CRC) commonly present at an older age with multiple comorbid conditions and complex care needs at the time of diagnosis. Clusters of comorbid conditions, or profiles, have not been systematically identified in this patient population. This study aimed to identify clinically distinct comorbidity profiles in a large sample of patients with CRC from an integrated healthcare system, and to examine the effect of comorbidity profiles on treatment and survival. Methods: In this retrospective cohort study, we used latent class analysis (LCA) to identify comorbidity profiles in a sample of 7,803 patients with CRC diagnosed between 2008 and 2013. We identified treatment received from electronic health records and used Cox proportional hazards analysis to examine the effect of comorbidity class on survival. We also examined the effect of comorbidity profile on receipt of guideline-recommended treatment. Results: Median age at diagnosis was 66 years, 52% of patients were male, and 48% were nonwhite. A plurality had stage 0-I disease (42%), with 22% stage II, 22% stage III, and 14% stage IV. More than half (59%) had ≤1 comorbid condition, whereas 19% had ≥4 comorbidities. LCA identified 4 distinct comorbidity classes. Classes were distinguished by the presence or absence of vascular and/or respiratory disease and diabetes with complications, as well as progressively greater Charlson comorbidity index scores. Comorbidity class was independently associated with treatment selection (P<.001) and survival (P<.001). Conclusions: Patients with CRC can be described by 4 distinct comorbidity profiles that are independent predictors of treatment and survival. These results provide insight into how comorbidities cluster within patients with CRC. This work represents a shift away from simple counting of comorbid conditions and toward a more nuanced understanding of how comorbidities cluster within groups of patients with CRC.
Abstract 19338: Sustained Release of Endothelial Progenitor Cell Derived Exosomes From Shear-Thinning Hydrogel Improves Angiogenesis and Promotes Function After Myocardial Infarction
Authors: Carol W Chen, Chantel M Venkataraman, Leo L Wang, George Hung, Ann C Gaffey, Jennifer J Chung, Anthony Liccardi, Alen Trubelja, Steven H Seeholzer, Jason A Burdick, Pavan Atluri
Journal: Circulation (2016)

Introduction: Previous studies showed that administration of endothelial progenitor cells (EPCs) into ischemic myocardium improved cardiac function after myocardial infarction (MI). A growing body ...
Which is your choice? Neoadjuvant doxorubicin hydrochloride and doxetaxel (AD) versus doxorubicin hydrochloride, cyclophosphamide, and paclitaxel (AC-T) in locally advanced breast cancer.
Authors: Seok Yun Kang, Jin-Hyuk Choi, Ku Sang Kim
Journal: Journal of Clinical Oncology (2012)

e11559 Background: It is well known that neoadjuvnat chemotherapy is acceptable for women with locally advanced breast cancer. However, it is not achieving consensus that what kind of regimen is most effective and tolerable, although lots of regimens and dosages were clinically used. Methods: We compared the patients who were received adriamycine and doxetaxel (AD) and adriamycin, cyclophosphamide followed by paclitaxel (AC-T) as neoadjuvant chemotherapy and then received operation from 1 January 2006 to 30 September 2011. The group of AD regimen was scheduled for 3 cycles of AD (50mg/m2 and 75mg/m2, respectively) with 3 weeks interval and then completes resection. The group of AC-T was scheduled for 4 cycles of AC regimen (50mg/m2 and 500mg/m2, respectively) and then 4 cycles of paclitaxel(175mg/m2) with 3 weeks interval and then completes resection. Results: The patients who were enrolled in this study were totally 78(AD and AC-T were equally 38.) The significant differences of patients’ characteristics between two groups were not observed. However, the significant differences were identified in hematologic toxicity including neutropenia more than grade 3 p&lt;0.001), neutropenic fever p&lt;0.001), dose reduction rate due to hematologic toxicity (p=0.012) and chemotherapy induced anemia (p=0.012)), although chemotherapy induced thrombocytopenia (p=1.0) was not different between two groups. No differences were identified in non-hematologic toxicity including hepatic toxicity, gastrointestinal toxicity and peripheral neuropathy. The response of chemotherapy was no difference between two groups, which was estimated by conversion rate of breast conserving surgery, clinical response of chemotherapy (p=0.148), clinically downstaging rate (p=0.464) and pathologic complete response rate (p=1.0). There is no factor to predicting pathologic complete response or conversion to breast conservation in this study. Conclusions: The neoadjuvant AC-T regimen is more tolerable with similar clinical outcome compared to AD regimen.
Abstract 18832: Local Expression of Coagulation Factor X (FXa) is Increased in Response to Pressure Overload and Mediates Cardiac Hypertrophy and Fibrosis
Authors: Xinji Guo, Mikhail Kolpakov, Bahman Hooshdaran, Liudmila Vlasenko, William Schappell, Tao Wang, Shaojun Liu, David Crandall, Patricia Andrade-Gordon, Steven R Houser, Abdelkarim Sabri
Journal: Circulation (2016)

Introduction: Factor Xa (FXa) is a key components of the coagulation cascade leading to thrombin generation and clot formation. FXa inhibition has been proven to be viable targets for effective ant...