tbuckley/cabot-search huggingface dataset:
A comprehensive study of a 29-capsid AAV library in a non-human primate central nervous system
Authors: Oleksandr Kondratov, Liudmyla Kondratova, Ronald J. Mandel, Kirsten Coleman, Michael A. Savage, Heather L. Gray-Edwards, Timothy J. Ness, Edgar Rodriguez-Lebron, Robert D. Bell, Joseph Rabinowitz, Paul D. Gamlin, Sergei Zolotukhin
Journal: Molecular Therapy (2021)

Non-human primates (NHPs) are a preferred animal model for optimizing adeno-associated virus (AAV)-mediated CNS gene delivery protocols before clinical trials. In spite of its inherent appeal, it is challenging to compare different serotypes, delivery routes, and disease indications in a well-powered, comprehensive, multigroup NHP experiment. Here, a multiplex barcode recombinant AAV (rAAV) vector-tracing strategy has been applied to a systemic analysis of 29 distinct, wild-type (WT), AAV natural isolates and engineered capsids in the CNS of eight macaques. The report describes distribution of each capsid in 15 areas of the macaques' CNS after intraparenchymal (putamen) injection, or cerebrospinal fluid (CSF)-mediated administration routes (intracisternal, intrathecal, or intracerebroventricular). To trace the vector biodistribution (viral DNA) and targeted tissues transduction (viral mRNA) of each capsid in each of the analyzed CNS areas, quantitative next-generation sequencing analysis, assisted by the digital-droplet PCR technology, was used. The report describes the most efficient AAV capsid variants targeting specific CNS areas after each route of administration using the direct side-by-side comparison of WT AAV isolates and a new generation of rationally designed capsids. The newly developed bioinformatics and visualization algorithms, applicable to the comparative analysis of several mammalian brain models, have been developed and made available in the public domain.
Multi-omic profiling of primary mouse neutrophils predicts a pattern of sex- and age-related functional regulation
Authors: Ryan J. Lu, Shalina Taylor, Kévin Contrepois, Minhoo Kim, Juan I. Bravo, Mathew Ellenberger, Nirmal K. Sampathkumar, Bérénice A. Benayoun
Journal: Nature Aging (2021)
SO-27 Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142
Authors: T. André, S. Lonardi, K. Wong, H. Lenz, F. Gelsomino, M. Aglietta, M. Morse, E. Van Cutsem, R. McDermott, A. Hill, M. Sawyer, A. Hendlisz, B. Neyns, S. Abdullaev, A. Memaj, M. Lei, S. Kopetz, M. Overman
Journal: Annals of Oncology (2021)
Patient-centered Outcomes Research in Interstitial Lung Disease: An Official American Thoracic Society Research Statement
Authors: Kerri I. Aronson, Sonye K. Danoff, Anne-Marie Russell, Christopher J. Ryerson, Atsushi Suzuki, Marlies S. Wijsenbeek, Sabrina Bajwah, Pauline Bianchi, Tamera J. Corte, Joyce S. Lee, Kathleen O. Lindell, Toby M. Maher, Fernando J. Martinez, Paula M. Meek, Ganesh Raghu, Glenda Rouland, Rick Rudell, Monika M. Safford, Jamie S. Sheth, Jeffrey J. Swigris
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Section:ChooseTop of pageAbstract <<OverviewIntroductionMethodsDefinitionsConsiderations and Best P...Discussion of Specific Pa...Considerations for Use of...ConclusionsReferencesCITING ARTICLES
P25-9 The clinical courses of solid tumors with microsatellite instability-high (MSI-H)
Authors: Yuichiro Inagaki, Fumiya Ohara, Hirofumi Yokota, Yuki Takeuchi, Hitomi Sawa, Kotaro Miyao, Seki Takashi, Junko Arima, Eiji Yoneyama, Masashi Sawa
Journal: Annals of Oncology (2021)
Активність показників плазмового протеолізу та їх корекція у хворих на хронічне обструктивне захворювання легень із супутнім хронічним панкреатитом
Authors: T.M. Khrystych, Ya.M. Teleki, O.Yu. Olinyk, D.O Gontsaryuk
Journal: GASTROENTEROLOGY (2013)

У роботі досліджена зміна активності показників плазмового протеолізу у хворих на хронічне обструктивне захворювання легень, що поєднується з хронічним панкреатитом, у динаміці лікування.
Copy Number Aberration Analysis to Predict Response to Neoadjuvant Anti-HER2 Therapy: Results from the NeoALTTO Phase III Clinical Trial
Authors: David Venet, Mattia Rediti, Marion Maetens, Debora Fumagalli, David N. Brown, Samira Majjaj, Roberto Salgado, Lajos Pusztai, Nadia Harbeck, Sarra El-Abed, Yingbo Wang, Cristina Saura, Henry Gomez, Vladimir Fedorovich Semiglazov, Evandro de Azambuja, Jens Huober, Paolo Nuciforo, Serena Di Cosimo, Martine Piccart, Sherene Loi, Françoise Rothé, Christos Sotiriou
Journal: Clinical Cancer Research (2021)

Abstract Purpose: The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNA) in predicting pathologic complete response (pCR) and survival outcomes in the NeoALTTO trial. Experimental Design: The neoadjuvant phase III NeoALTTO trial enrolled 455 patients with HER2-positive early-stage breast cancer. DNA samples from 269 patients were assessed for genome-wide copy number profiling. Recurrent CNAs were found with GISTIC2.0. Results: CNA estimates were obtained for 184 patients included in NeoALTTO. Among those, matched transcriptome and whole-exome data were available for 154 and 181 patients, respectively. A significant association between gene copy number and pCR was demonstrated for ERBB2 amplification. Nevertheless, ERBB2 amplification ceased to be predictive once ERBB2 expression level was considered. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the estrogen receptor–positive subgroup. 6q23-24 deletion was significantly more frequent in TP53 wild-type (WT) compared with TP53-mutated, resulting in copy number levels significantly associated with lack of pCR only in the TP53 WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number. Conclusions: Our analysis identified ERBB2 copy number as well as 6q23-24 CNAs as predictors of response to anti–HER2-based treatment. ERBB2 expression outperformed ERBB2 amplification. The complexity of the 6q23-24 region warrants further investigation.
Strategies for controlling the innate immune activity of conventional and self-amplifying mRNA therapeutics: Getting the message across
Authors: An-Katrien Minnaert, Helena Vanluchene, Rein Verbeke, Ine Lentacker, Stefaan C. De Smedt, Koen Raemdonck, Niek N. Sanders, Katrien Remaut
Journal: Advanced Drug Delivery Reviews (2021)
Identification of Recurrent Non-Coding Driver Mutations in Non-Hodgkin Lymphomas through Integrative Genomic Analysis of 777 Patients
Authors: Aixiang Jiang, Bruno M. Grande, Sarah E Arthur, Miguel Alcaide, Daisuke Ennishi, Selin Jessa, Prasath Pararajalingam, Barbara Meissner, Merrill Boyle, Lauren Chong, Daniel Lai, Jordan Davidson, Anja Mottok, Kevin R Bushell, Laurie H. Sehn, Pedro Farinha, Sohrab P Shah, Andrew J. Mungall, Randy D. Gascoyne, Marco A Marra, Christian Steidl, Joseph M Connors, David W. Scott, Ryan D. Morin
Journal: Blood (2017)
Do Editorialists With Industry-Related Conflicts of Interest Write Unduly Favorable Editorials for Cancer Drugs in Top Journals?
Authors: Shubham Sharma, Christopher M. Booth, Elizabeth A. Eisenhauer, Bishal Gyawali
Journal: Journal of the National Comprehensive Cancer Network (2021)

Editorials accompanying the publication of trials in major oncology journals can have a substantial influence on clinical practice. We describe the prevalence of financial conflicts of interest (FCOIs) of authors writing such editorials and the extent to which FCOIs may shape the interpretation of clinical trials.We examined editorials published in 2018 alongside trial reports in the top 5 journals that publish cancer drug trials (New England Journal of Medicine, Lancet, Lancet Oncology, JAMA Oncology, and Journal of Clinical Oncology). An editorial was considered to have an FCOI if at least one of the editorialists had any disclosed FCOI. An FCOI with the same company whose drug was being discussed in the editorial was classified as a direct FCOI. Editorials were reviewed for their content and classified as being unduly favorable (defined as the presence of a positive spin without discussion of limitations) or not. Association of an FCOI and a direct FCOI with writing an unduly favorable editorial was assessed.Of the 90 editorials assessed, 74% (n=67) were classified as having an FCOI with the pharmaceutical industry, and 39% (n=35) had an FCOI with the same company whose product was being discussed in the editorial (direct FCOI). Editorials were classified as being unduly favorable toward the study drug in 12% (8 of 67) and 13% (3 of 23) (P=1.0) of those with and without FCOIs, respectively; corresponding rates with and without direct FCOI were 23% (8 of 35) and 5% (3 of 55), respectively (P=.009).Editorials in top oncology journals were frequently authored by experts with FCOIs, including direct FCOIs. Authoring an unduly favorable editorial for a new cancer drug was significantly associated with the author having a direct FCOI with the same company. These findings support the call for journals to ensure that authors of editorials have no direct FCOIs.
Skin-inspired gelatin-based flexible bio-electronic hydrogel for wound healing promotion and motion sensing
Authors: Manhui Zheng, Xuechuan Wang, Ouyang Yue, Mengdi Hou, Huijie Zhang, Sebastian Beyer, Anna Maria Blocki, Qin Wang, Guidong Gong, Xinhua Liu, Junling Guo
Journal: Biomaterials (2021)
Abstract 14897: Robust Reprogramming Of human Placenta derived Mesenchymal Stem Cells Into Spontaneously Contractile Cardiomyocytes
Authors: Xiaohu Ge, Ildiko Toma, I-Ning E. Wang, Vittorio Sebastiano, renee Reijo-Pera, Phillip C. Yang
Journal: Circulation (2011)

Background. Human placenta-derived mesenchymal stem cells (hPMSCs) represent a unique population of stem cells. They demonstrate partial pluripotency, immunomodulatory properties, and c-kit (CD117)...
Matt Morgan: Medicine, the never ending video game
Authors: Matt Morgan
Journal: BMJ (2021)

Sonic the Hedgehog was the first computer game I actually managed to complete. Although I may not have collected every one of the rings and I certainly died a lot while trying, I defeated Dr Robotnik in the final scene. Eventually. I felt a brief sense of achievement, but it was followed by a chasm of loss: what now? As I was 12 years old, my sense of purpose was quickly replaced by sports, riding my bike, and Street Fighter II .

A career in medicine can feel rather like a computer game. …
Acute coronary syndrome is associated with a substantial change in the platelet lipidome
Authors: Tobias Harm, Alexander Bild, Kristina Dittrich, Andreas Goldschmied, Jeremy Nestele, Madhumita Chatterjee, Xiaoqing Fu, Kyra Kolb, Tatsiana Castor, Oliver Borst, Tobias Geisler, Dominik Rath, Michael LäMmerhofer, Meinrad Gawaz
Journal: Cardiovascular Research (2021)

Platelets play a key role in the pathophysiology of coronary artery disease (CAD) and patients with enhanced platelet activation are at increased risk to develop adverse cardiovascular events. Beyond reliable cardiovascular risk factors such as dyslipoproteinaemia, significant changes of platelet lipids occur in patients with CAD. In this study, we investigate the platelet lipidome by untargeted liquid chromatography-mass spectrometry, highlighting significant changes between acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients. Additionally, we classify the platelet lipidome, spotlighting specific glycerophospholipids as key players in ACS patients. Furthermore, we examine the impact of significantly altered lipids in ACS on platelet-dependent thrombus formation and aggregation.In this consecutive study, we characterized the platelet lipidome in a CAD cohort (n = 139) and showed significant changes of lipids between patients with ACS and CCS. We found that among 928 lipids, 7 platelet glycerophospholipids were significantly up-regulated in ACS, whereas 25 lipids were down-regulated compared to CCS. The most prominent up-regulated lipid in ACS, PC18:0 (PC 10:0-8:0), promoted platelet activation and ex vivo platelet-dependent thrombus formation.Our results reveal that the platelet lipidome is altered in ACS and up-regulated lipids embody primarily glycerophospholipids. Alterations of the platelet lipidome, especially of medium chain lipids, may play a role in the pathophysiology of ACS.
Targeting glutamine utilization to block metabolic adaptation of tumor cells under the stress of carboxyamidotriazole-induced nutrients unavailability
Authors: Jing Shi, Rui Ju, Hongting Gao, Yuqing Huang, Lei Guo, Dechang Zhang
Journal: Acta Pharmaceutica Sinica B (2021)

Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells. Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment. Here, we show that carboxyamidotriazole (CAI), an anticancer drug, can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism. CAI suppressed glucose and lipid metabolism utilization, causing inhibition of mitochondrial respiratory chain complex I, thus producing reactive oxygen species (ROS). In parallel, activation of the aryl hydrocarbon receptor (AhR) increased glutamine uptake via the transporter SLC1A5, which could activate the ROS-scavenging enzyme glutathione peroxidase. As a result, combined use of inhibitors of GLS/GDH1, CAI could effectively restrict colorectal cancer (CRC) energy metabolism. These data illuminate a new antitumor mechanism of CAI, suggesting a new strategy for CRC metabolic reprogramming treatment.
<scp>Anti‐Cortactin</scp> Autoantibodies Are Associated With Key Clinical Features in Adult Myositis But Are Rarely Present in Juvenile Myositis
Authors: Iago Pinal‐Fernandez, Katherine Pak, Albert Gil‐Vila, Andres Baucells, Benjamin Plotz, Maria Casal‐Dominguez, Assia Derfoul, Maria Angeles Martinez‐Carretero, Albert Selva‐O'Callaghan, Sara Sabbagh, Livia Casciola‐Rosen, Jemima Albayda, Julie Paik, Eleni Tiniakou, Sonye K. Danoff, Thomas E. Lloyd, Frederick W. Miller, Lisa G. Rider, Lisa Christopher‐Stine, Andrew L. Mammen
Journal: Arthritis & Rheumatology (2021)

To define the prevalence and clinical phenotype of anti-cortactin autoantibodies in adult and juvenile myositis.In this longitudinal cohort study, anti-cortactin autoantibody titers were assessed by enzyme-linked immunosorbent assay in 670 adult myositis patients and 343 juvenile myositis patients as well as in 202 adult healthy controls and 90 juvenile healthy controls. The prevalence of anti-cortactin autoantibodies was compared among groups. Clinical features of patients with and those without anti-cortactin autoantibodies were also compared.Anti-cortactin autoantibodies were more common in adult dermatomyositis (DM) patients (15%; P = 0.005), particularly those with coexisting anti-Mi-2 autoantibodies (24%; P = 0.03) or anti-NXP-2 autoantibodies (23%; P = 0.04). In adult myositis, anti-cortactin was associated with DM skin involvement (62% of patients with anti-cortactin versus 38% of patients without anti-cortactin; P = 0.03), dysphagia (36% versus 17%; P = 0.02) and coexisting anti-Ro 52 autoantibodies (47% versus 26%; P = 0.001) or anti-NT5c1a autoantibodies (59% versus 33%; P = 0.001). Moreover, the titers of anti-cortactin antibodies were higher in patients with interstitial lung disease (0.15 versus 0.12 arbitrary units; P = 0.03). The prevalence of anti-cortactin autoantibodies was not different in juvenile myositis patients (2%) or in any juvenile myositis subgroup compared to juvenile healthy controls (4%). Nonetheless, juvenile myositis patients with these autoantibodies had a higher prevalence of "mechanic's hands" (25% versus 7%; P = 0.03), a higher number of hospitalizations (2.9 versus 1.3; P = 0.04), and lower peak creatine kinase values (368 versus 818 IU/liter; P = 0.02) than those without anti-cortactin.The prevalence of anti-cortactin autoantibodies is increased in adult DM patients with coexisting anti-Mi-2 or anti-NXP-2 autoantibodies. In adults, anti-cortactin autoantibodies are associated with dysphagia and interstitial lung disease.
Urgent Need to Reduce Heart Disease Among Women Worldwide
Authors: Bridget M. Kuehn
Journal: JAMA (2021)

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Chemotherapy and mismatch repair deficiency cooperate to fuel TP53 mutagenesis and ALL relapse
Authors: Fan Yang, Samuel W. Brady, Chao Tang, Huiying Sun, Lijuan Du, Malwine J. Barz, Xiaotu Ma, Yao Chen, Houshun Fang, Xiaomeng Li, Pandurang Kolekar, Omkar Pathak, Jiaoyang Cai, Lixia Ding, Tianyi Wang, Arend von Stackelberg, Shuhong Shen, Cornelia Eckert, Jeffery M. Klco, Hongzhuan Chen, Caiwen Duan, Yu Liu, Hui Li, Benshang Li, Renate Kirschner-Schwabe, Jinghui Zhang, Bin-Bing S. Zhou
Journal: Nature Cancer (2021)
Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets
Authors: Alexander P. Bye, Willianne Hoepel, Joanne L. Mitchell, Sophie Jégouic, Silvia Loureiro, Tanya Sage, Gestur Vidarsson, Jan Nouta, Manfred Wuhrer, Steven de Taeye, Marit van Gils, Neline Kriek, Nichola Cooper, Ian Jones, Jeroen den Dunnen, Jonathan M. Gibbins
Journal: Blood (2021)
Phase Ia/Ib dose-escalation study of IBI110 (anti-LAG-3 mAb) as a single agent and in combination with sintilimab (anti-PD-1 mAb) in patients (pts) with advanced solid tumors.
Authors: Cai Zhou, Yayi He, Shengxiang Ren, Wei Li, Jun Zhu, Jia Yu, Lei Wang, Anwen Xiong, Nong Xu, Chenyu Mao, Beiqing Pan, Ying Liu, Hui Zhou
Journal: Journal of Clinical Oncology (2021)

2589 Background: Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein that functions to control T cell response, activation and growth. Dual inhibition of PD-1 and LAG-3 may improve anti-tumor effect synergistically. In this first-in-human dose-escalation study, we report the preliminary safety and anti-tumor activity of IBI110 ± sintilimab in pts with advanced solid tumors. Methods: Enrolled pts, ECOG PS 0-1, had locally advanced, recurrent or metastatic solid tumors for whom standard therapy had failed. Pts received escalating doses of IBI110 (0.01/0.1/0.3/1/3/10/20mg/kg) IV Q3W in phase Ia and escalating doses of IBI110 (0.3/0.7/1.5/3/5 mg/kg) in combination with sintilimab 200 mg IV Q3W in phase Ib. Crossover from mono to combo was allowed at progression. The objectives were safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of IBI110 alone or IBI110+sintilimab (per RECIST v1.1). Results: Phase Ia: 21 pts (median age: 62 yr [range 43-72]; ECOG PS: 0 [n = 11], 1 [n = 10]) were enrolled. Dose escalation has completed and no dose-limiting toxicity (DLT) was observed in all dose cohorts. The most common treatment-related adverse event (TRAE) was anaemia (19.0%). TRAEs ≥G3 included anaemia (4.8%), ascites (4.8%) and hepatic function abnormal (4.8%). By investigator-assessment, best response was 1 confirmed partial response (PR) (ovarian cancer, 3 mg/kg IBI110 single agent) and 5 stable disease (SD) in monotherapy. After crossing from mono to combo at progression, 5 pts were observed to have SD. Phase Ib: 12 pts (median age: 60 yr [range 33-72]; ECOG PS: 0 [n = 7], 1 [n = 5]) were enrolled. All dose cohorts in dose escalation except IBI110 5mg/kg+ sintilimab have completed DLT observation and no DLT was observed. The most common TRAE was AST increased (41.7%). TRAEs ≥G3 included hyperglycaemia (8.3%), bilirubin conjugated increased (8.3%) and hepatic function abnormal (8.3%). By investigator-assessment, best response was 2 PR (small cell lung cancer and endometrial cancer) and 6 SD. Conclusions: IBI110 alone or plus sintilimab has acceptable toxicity and shows preliminary antitumor activity. Clinical trial information: NCT04085185.
Suppression of growth, progression and metastasis of breast cancer xenografts by orally administered complex sphingolipids
Authors: Shengli Ding, Kirk Simon, Eva Schmelz
Journal: Cancer Research (2008)

4663  Complex sphingolipids in the diet are hydrolyzed in the intestinal cells to bioactive metabolites that significantly reduced early and late stages of colon cancer in rodent models without causing severe side effects. In the present study, we investigated if bioactive metabolites generated from complex sphingolipids supplements can reach distant sites in the body in sufficient concentrations to suppress tumor formation, progression and possibly metastasis. Human breast epithelial cells representing early, intermediate, late and metastatic stages of breast cancer were injected subcutaneously into the mammary fat pad of nude mice. 0.1% sphingomyelin, or a combination with ceramide (0.08% SM, 0.02% ceramide) was added to the diet either before or after tumor implant to test both a preventive and an intervention approach. Orally administered sphingolipids affected tumor number and volume in a stage-dependent manner, with the less aggressive xenografts responding with both lower tumor incidence and tumor volume. This appears to correlate with the rate of proliferation that was more affected in xenografts representing earlier stages of breast cancer. Xenografts of more advanced breast cancer cells responded with a reduction of tumor size only; however, sphingolipid supplements significantly reduced metastases to the lungs (60-73%) and bone marrow (60-84%). These results suggest that sphingolipid supplements target fast growing but less aggressive tumors and metastases while they are relatively ineffective against solid, aggressive but slow growing tumors, indicating a promising potential as chemopreventive agents.  Supported by grant BCT0503453 from the Susan G. Komen Foundation and NIH/NCI R03 CA101125.
25144 Challenges in educating and counseling patients with psoriasis and psoriatic arthritis: results from a mixed-methods needs assessment in Canada and USA
Authors: Jeffrey Crowley, Suzanne Murray, Melinda J. Gooderham, Sacha Zahabi, Vinod Chandran, Alan Kivitz, Paul P. Doghramji, Christie Freeman, Patrice Lazure
Journal: Journal of the American Academy of Dermatology (2021)