tbuckley/cabot-search huggingface dataset:
Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for <i>SOD1</i> ALS
Authors: Timothy Miller, Merit Cudkowicz, Pamela J. Shaw, Peter M. Andersen, Nazem Atassi, Robert C. Bucelli, Angela Genge, Jonathan Glass, Shafeeq Ladha, Albert L. Ludolph, Nicholas J. Maragakis, Christopher J. McDermott, Alan Pestronk, John Ravits, François Salachas, Randall Trudell, Philip Van Damme, Lorne Zinman, C. Frank Bennett, Roger Lane, Alfred Sandrock, Heiko Runz, Danielle Graham, Hani Houshyar, Alexander McCampbell, Ivan Nestorov, Ih Chang, Manjit McNeill, Laura Fanning, Stephanie Fradette, Toby A. Ferguson
Journal: New England Journal of Medicine (2020)

Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose.In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).
Whole exome sequencing analyses reveal gene–microbiota interactions in the context of IBD
Authors: Shixian Hu, Arnau Vich Vila, Ranko Gacesa, Valerie Collij, Christine Stevens, Jack M Fu, Isaac Wong, Michael E Talkowski, Manuel A Rivas, Floris Imhann, Laura Bolte, Hendrik van Dullemen, Gerard Dijkstra, Marijn C Visschedijk, Eleonora A Festen, Ramnik J Xavier, Jingyuan Fu, Mark J Daly, Cisca Wijmenga, Alexandra Zhernakova, Alexander Kurilshikov, Rinse K Weersma
Journal: Gut (2020)

Objective Both the gut microbiome and host genetics are known to play significant roles in the pathogenesis of IBD. However, the interaction between these two factors and its implications in the aetiology of IBD remain underexplored. Here, we report on the influence of host genetics on the gut microbiome in IBD. Design To evaluate the impact of host genetics on the gut microbiota of patients with IBD, we combined whole exome sequencing of the host genome and whole genome shotgun sequencing of 1464 faecal samples from 525 patients with IBD and 939 population-based controls. We followed a four-step analysis: (1) exome-wide microbial quantitative trait loci (mbQTL) analyses, (2) a targeted approach focusing on IBD-associated genomic regions and protein truncating variants (PTVs, minor allele frequency (MAF) &gt;5%), (3) gene-based burden tests on PTVs with MAF &lt;5% and exome copy number variations (CNVs) with site frequency &lt;1%, (4) joint analysis of both cohorts to identify the interactions between disease and host genetics. Results We identified 12 mbQTLs, including variants in the IBD-associated genes IL17REL , MYRF , SEC16A and WDR78 . For example, the decrease of the pathway acetyl-coenzyme A biosynthesis, which is involved in short chain fatty acids production, was associated with variants in the gene MYRF (false discovery rate &lt;0.05). Changes in functional pathways involved in the metabolic potential were also observed in participants carrying rare PTVs or CNVs in CYP2D6 , GPR151 and CD160 genes. These genes are known for their function in the immune system. Moreover, interaction analyses confirmed previously known IBD disease-specific mbQTLs in TNFSF15 . Conclusion This study highlights that both common and rare genetic variants affecting the immune system are key factors in shaping the gut microbiota in the context of IBD and pinpoints towards potential mechanisms for disease treatment.
Adenovirus as a platform for selective assembly and targeted delivery of gold nanoparticles to tumor cells
Authors: Vaibhav Saini, Dmitri Martyshkin, Sergei Mirov, Victoria Towner, Hongju Wu, Larisa Pereboeva, Anton Borovjagin, Guy Perkins, Mark Ellisman, David Curiel, Maaike Everts
Journal: Cancer Research (2008)

5605  Nanotechnology holds great promise for the treatment of diseases like cancer. In this regard, gold nanoparticles (AuNPs) have biomedical applications such as drug delivery, imaging, and hyperthermic tumor cell ablation. However, lack of AuNP targeting to tumor cells is a major impediment for realization of these therapeutic possibilities. Therefore, we propose to use targeted adenoviral (Ad) gene therapy vector as a platform for selective assembly and specific delivery of AuNPs to tumors. This would also allow a combination of gene therapy and nanotechnology for the treatment of cancer. We have previously demonstrated that AuNPs can be coupled to Ad vectors. We herein aim to further this paradigm by coupling AuNPs to specific Ad capsid locations and thus avoiding detrimental effects on Ad infectivity and targeting that were observed with the non-specific approach. Towards this goal, 1.8 nm Ni-NTA-AuNPs were coupled to Ad vectors expressing a 6-His tag at different capsid locations, including fiber fibritin (FF, ~9 copies), pIX (240 copies) or hexon (720 copies). Upon coupling AuNPs to Ad, the molecular weight of the hexon virus increased in a CsCl density gradient indicating successful attachment of the AuNPs. However, no increase in the density of FF and pIX viruses was observed. Transmission electron microscopy confirmed the presence of AuNPs in the hexon virus and its absence in the FF and the pIX viruses. This corroborates with the fact that that FF virus has few 6-His (~9) tags for AuNP binding. With respect to pIX, this protein is structurally located 65 A below the main surface of the Ad capsid and might therefore be inaccessible to AuNPs. Atomic absorption spectroscopy was utilized to determine that 56±4 AuNPs were bound per hexon virus. This indicates that hexon is the optimal location for AuNP binding to the capsid. Also, specifically AuNP-labeled Ad vector infectivity for native Ad vector receptor expressing HeLa cells was 2-fold higher as compared to the non-specifically labeled vectors. Importantly, unlike the non-specifically AuNP-labeled Ad vectors, no adverse effects on Ad vector tumor targeting ability were observed after specific coupling of AuNPs to the hexon virus. Therefore, Ad can provide a versatile platform for selective assembly of AuNPs, resulting in a multifunctional agent capable of simultaneous targeting and treatment of cancer by utilizing gene therapy and nanotechnology approaches.
P-160 A phase II study of resection followed capecitabine plus oxaliplatin for liver metastasis of colorectal cancer (REX study): Safety analysis
Authors: T. Watanabe, N. Sugimoto, H. Tamagawa, A. Hasegawa, H. Satake, K. Kataoka, K. Kamei, M. Kobayashi, K. Munakata, M. Fukunaga, M. Kotaka, T. Satoh, A. Kanazawa, T. Kurata, T. Yamanaka, N. Tomita
Journal: Annals of Oncology (2020)
SARS‐CoV‐2, COVID‐19, skin and immunology – What do we know so far?
Authors: Natalijia Novak, Wenming Peng, Mirjam C. Naegeli, Christina Galvan, Isabel Kolm‐Djamei, Charlotte Brüggen, Beatriz Cabanillas, Peter Schmid‐Grendelmeier, Alba Catala
Journal: Allergy (2020)

Abstract The pandemic condition coronavirus disease (COVID‐19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), can take asymptomatic, mild, moderate, and severe courses. COVID‐19 affects primarily the respiratory airways leading to dry cough, fever, myalgia, headache, fatigue, and diarrhea and can end up in interstitial pneumonia and severe respiratory failure. Reports about the manifestation of various skin lesions and lesions of the vascular system in some subgroups of SARS‐CoV‐2‐positive patients as such features outside the respiratory sphere, are rapidly emerging. Vesicular, urticarial, and maculopapular eruptions and livedo, necrosis, and other vasculitis forms have been reported most frequently in association with SARS‐CoV‐2 infection. In order to update information gained, we provide a systematic overview of the skin lesions described in COVID‐19 patients, discuss potential causative factors, and describe differential diagnostic evaluations. Moreover, we summarize current knowledge about immunologic, clinical, and histologic features of virus‐ and drug‐induced lesions of the skin and changes to the vascular system in order to transfer this knowledge to potential mechanisms induced by SARS‐CoV‐2.
Bromodomain-Selective BET Inhibitors Are Potent Antitumor Agents against MYC-Driven Pediatric Cancer
Authors: P. Jake Slavish, Liying Chi, Mi-Kyung Yun, Lyudmila Tsurkan, Nancy E. Martinez, Barbara Jonchere, Sergio C. Chai, Michele Connelly, M. Brett Waddell, Sourav Das, Geoffrey Neale, Zhenmei Li, William R. Shadrick, Rachelle R. Olsen, Kevin W. Freeman, Jonathan A. Low, Jeanine E. Price, Brandon M. Young, Nagakumar Bharatham, Vincent A. Boyd, Jun Yang, Richard E. Lee, Marie Morfouace, Martine F. Roussel, Taosheng Chen, Daniel Savic, R. Kiplin Guy, Stephen W. White, Anang A. Shelat, Philip M. Potter
Journal: Cancer Research (2020)

Inhibition of members of the bromodomain and extraterminal (BET) family of proteins has proven a valid strategy for cancer chemotherapy. All BET identified to date contain two bromodomains (BD; BD1 and BD2) that are necessary for recognition of acetylated lysine residues in the N-terminal regions of histones. Chemical matter that targets BET (BETi) also interact via these domains. Molecular and cellular data indicate that BD1 and BD2 have different biological roles depending upon their cellular context, with BD2 particularly associated with cancer. We have therefore pursued the development of BD2-selective molecules both as chemical probes and as potential leads for drug development. Here we report the structure-based generation of a novel series of tetrahydroquinoline analogs that exhibit >50-fold selectivity for BD2 versus BD1. This selective targeting resulted in engagement with BD-containing proteins in cells, resulting in modulation of MYC proteins and downstream targets. These compounds were potent cytotoxins toward numerous pediatric cancer cell lines and were minimally toxic to nontumorigenic cells. In addition, unlike the pan BETi (+)-JQ1, these BD2-selective inhibitors demonstrated no rebound expression effects. Finally, we report a pharmacokinetic-optimized, metabolically stable derivative that induced growth delay in a neuroblastoma xenograft model with minimal toxicity. We conclude that BD2-selective agents are valid candidates for antitumor drug design for pediatric malignancies driven by the MYC oncogene. SIGNIFICANCE: This study presents bromodomain-selective BET inhibitors that act as antitumor agents and demonstrates that these molecules have in vivo activity towards neuroblastoma, with essentially no toxicity.
Noninvasive Risk Stratification After HCV Eradication in Patients With Advanced Chronic Liver Disease
Authors: Georg Semmler, Teresa Binter, Karin Kozbial, Philipp Schwabl, Stefanie Hametner‐Schreil, Alberto Zanetto, Sabrina Gavasso, David Chromy, David J.M. Bauer, Benedikt Simbrunner, Bernhard Scheiner, Theresa Bucsics, Albert F. Stättermayer, Matthias Pinter, Petra Steindl‐Munda, Rainer Schöfl, Francesco Paolo Russo, Paolo Simioni, Michael Trauner, Peter Ferenci, Thomas Reiberger, Mattias Mandorfer
Journal: Hepatology (2020)

Risk stratification after cure from hepatitis C virus (HCV) infection remains a clinical challenge. We investigated the predictive value of noninvasive surrogates of portal hypertension (liver stiffness measurement [LSM] by vibration-controlled transient elastography and von Willebrand factor/platelet count ratio [VITRO]) for development of hepatic decompensation and hepatocellular carcinoma in patients with pretreatment advanced chronic liver disease (ACLD) who achieved HCV cure.
Quality of Life Assessed Using Skindex-16 Scores Among Patients With Acne Receiving Isotretinoin Treatment
Authors: Aaron M. Secrest, Zachary H. Hopkins, Zachary E. Frost, Vanina L. Taliercio, LaVar D. Edwards, Joshua E. Biber, Suephy C. Chen, Mary-Margaret Chren, Laura K. Ferris, Jacob Kean, Rachel Hess
Journal: JAMA Dermatology (2020)

<h3>Importance</h3> Acne is a common dermatologic condition and significantly affects psychosocial health and quality of life. An international task force recommended routine use of quality-of-life measures for clinic visits associated with acne management, but this has yet to translate into clinical practice. <h3>Objective</h3> To assess mean Skindex-16 scores over time among patients with moderate to severe acne receiving isotretinoin treatment. <h3>Design, Setting, and Participants</h3> A longitudinal, retrospective case series study of Skindex-16 data collected at monthly visits from 57 consecutive patients with acne receiving isotretinoin; data were collected and evaluated between November 23, 2016, and January 22, 2019. Continuous variables were compared using quantile regression. Multivariable linear mixed models evaluated mean (95% CI) score trajectory over time. <h3>Main Outcomes and Measure</h3> Skindex-16 scores, including normalized scores for the emotional, symptomatic, and functional aspects of having skin disease as well as an overall score. <h3>Results</h3> Fifty-seven patients (31 [54.4 %] males, with median [interquartile range] age of 17.2 [15.9-18.1] years) in this case series study completed the Skindex-16 at baseline and at least once during follow-up. Baseline Skindex-16 scores were similar by sex but worse with increasing age. Emotional impact was more bothersome to patients with acne requiring isotretinoin treatment than either symptoms or functioning. Improvements of greater than 50% in overall and Emotional domain scores were seen by month 2 of receiving isotretinoin treatment (eg, overall scores decreased from 39.4 to 17.5 by month 2; a decrease of 22.0;<i>P</i> &lt; .001). Qualitatively, Skindex-16 scores reached their nadir between months 3 and 5; at month 4, overall Skindex-16 scores showed a 4.4-fold improvement (from 39.4 at baseline to 8.9;<i>P</i> &lt; .001) and Emotional domain scores showed a 4.8-fold improvement (from 57.7 at baseline to 11.9;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> The findings of this case series suggest that patients receiving isotretinoin treatment achieve greater than a 50% improvement in quality of life by month 2 and can expect approximately 4-fold to 5-fold improvements from baseline with a full course of isotretinoin. This study shows the potential of routine administration of quality of life measures to assess patient care in dermatology.
SO-29 Long-term survival after hyperthermic intraperitoneal chemotherapy using mitomycin C or oxaliplatin in colorectal cancer patients with synchronous peritoneal metastases: A nationwide comparative study
Authors: C. Bakkers, F. van Erning, K. Rovers, S. Nienhuijs, J. Burger, V. Lemmens, A. Aalbers, N. Kok, D. Boerma, A. Brandt-Kerkhof, P. Hemmer, W. van Grevenstein, P. de Reuver, P. Tanis, J. Tuynman, I. de Hingh
Journal: Annals of Oncology (2020)
P-86 Comparison of the pharmacokinetics of donafenib and sorafenib in patients with advanced hepatocellular carcinoma: An open-label, randomized, parallel-controlled, multicentre phase II/III trial
Authors: S. Qin, F. Bi, J. Xu, C. Du, Q. Fan, L. Zhang, M. Tao, D. Jiang, S. Wang, Y. Chen, J. Sheng, X. Zhuang, J. Wu, B. Lv
Journal: Annals of Oncology (2020)
Omics-based exploration and functional validation of neurotrophic factors and histamine as therapeutic targets in ALS
Authors: Cinzia Volonté, Giovanna Morello, Antonio Gianmaria Spampinato, Susanna Amadio, Savina Apolloni, Velia D’Agata, Sebastiano Cavallaro
Journal: Ageing Research Reviews (2020)

A plethora of genetic and molecular mechanisms have been implicated in the pathophysiology of the heterogeneous and multifactorial amyotrophic lateral sclerosis (ALS) disease, and hence the conventional "one target-one drug" paradigm has failed so far to provide effective therapeutic solutions, precisely because of the complex nature of ALS. This review intends to highlight how the integration of emerging "omics" approaches may provide a rational foundation for the comprehensive exploration of molecular pathways and dynamic interactions involved in ALS, for the identification of candidate targets and biomarkers that will assist in the rapid diagnosis and prognosis, lastly for the stratification of patients into different subgroups with the aim of personalized therapeutic strategies. To this purpose, particular emphasis will be placed on some potential therapeutic targets, including neurotrophic factors and histamine signaling that both have emerged as dysregulated at different omics levels in specific subgroups of ALS patients, and have already shown promising results in in vitro and in vivo models of ALS. To conclude, we will discuss about the utility of using integrated omics coupled with network-based approaches to provide additional guidance for personalization of medicine applications in ALS.
ドキソルビシン(DOX)抵抗性腫瘍もつマウスにおけるPEGリポソーマルDOXのin vivo抗腫瘍作用:血管内皮細胞に対する細胞毒性作用の関与 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Ogawara Ken-ichi, UN Keita, Tanaka Ken-ichi, Higaki Kazutaka, Kimura Toshikiro
Journal: Journal of Controlled Release (2009)
Abstract 12952: The Usefulness of Echo-Estimated Diastolic Late Mitral Annular Velocity in Heart Failure (HF) With Preserved Left Ventricular (LV) Ejection Fraction (EF)
Authors: Eiichiro Yamamoto, Fumi Oike, Taiki Nishihara, Masafumi Takae, Koichiro Fujisue, Daisuke Sueta, Seiji Takashio, Kenji Sakamoto, Koichi Kaikita, Kenichi Tsujita
Journal: Circulation (2018)

Introduction: Left atrial (LA) structure are altered in the majority of HF with preserved LVEF (HFpEF) patients. Because diastolic late mitral annular velocity (a’) measured by transthoracic-echoca...
A Defining Moment for Pediatric Primary Care Telehealth
Authors: Alexander G. Fiks, Brian P. Jenssen, Kristin N. Ray
Journal: JAMA Pediatrics (2020)

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 Pediatrics 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 Pediatrics journal
Machine Learning for Clinical Outcome Prediction
Authors: Farah Shamout, Tingting Zhu, David A. Clifton
Journal: IEEE Reviews in Biomedical Engineering (2020)

Clinical decision-making in healthcare is already being influenced by predictions or recommendations made by data-driven machines. Numerous machine learning applications have appeared in the latest clinical literature, especially for outcome prediction models, with outcomes ranging from mortality and cardiac arrest to acute kidney injury and arrhythmia. In this review article, we summarize the state-of-the-art in related works covering data processing, inference, and model evaluation, in the context of outcome prediction models developed using data extracted from electronic health records. We also discuss limitations of prominent modeling assumptions and highlight opportunities for future research.
Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus
Authors: Kenji Kabashima, Takayo Matsumura, Hiroshi Komazaki, Makoto Kawashima
Journal: New England Journal of Medicine (2020)

Nemolizumab is a subcutaneously administered humanized monoclonal antibody against interleukin-31 receptor A, which is involved in pruritus and inflammation in atopic dermatitis. In phase 2 studies, nemolizumab lessened the severity of atopic dermatitis.
Abstract 12865: An Increased Left Ventricular Trabeculation Provides the Prognostic Information With a Close Relationship With BNP in Non-Ischemic Cardiomyopathy
Authors: Takayuki Kawamura, Yoshitaka Iwanaga, Kazuyoshi Kakehi, Yoshinori Kagioka, Mana Okune, Takashi Nakamura, Shunichi Miyazaki
Journal: Circulation (2018)

Introduction: The clinical significance of left ventricular (LV) trabeculation remains uncertain in cardiomyopathy of a broad spectrum of etiologies and clinical features. B-type natriuretic peptid...
P-99 Pembrolizumab in combination with gemcitabine and cisplatin for the treatment of advanced biliary tract cancer: phase 3 KEYNOTE-966 trial in progress
Authors: A. Vogel, R. Finn, R. Kelley, J. Furuse, J. Edeline, Z. Ren, S. Su, U. Malhotra, A. Siegel, J. Valle
Journal: Annals of Oncology (2020)