tbuckley/cabot-search huggingface dataset:
sEVs from tonsil-derived mesenchymal stromal cells alleviate activation of hepatic stellate cells and liver fibrosis through miR-486-5p
Authors: Jieun Kim, Chanbin Lee, Yongbo Shin, Sihyung Wang, Jinsol Han, Minju Kim, Ji Min Kim, Sung-Chan Shin, Byung-Joo Lee, Tae-Jin Kim, Youngmi Jung
Journal: Molecular Therapy (2020)

Mesenchymal stromal cells (MSCs) are considered as a promising therapeutic tool for liver fibrosis, a main feature of chronic liver disease. Because small extracellular vesicles (sEVs) harboring a variety of proteins and RNAs are known to have similar functions with their derived cells, MSC-derived sEVs carry out the regenerative capacities of MSCs. Human tonsil-derived MSCs (T-MSCs) are reported as a novel source of MSCs, but their effects on liver fibrosis remain unclear. In the present study, we investigated the effects of T-MSC-derived sEVs on liver fibrosis. The expression of profibrotic genes decreased in human primary hepatic stellate cells (pHSCs) co-cultured with T-MSCs. Treatment of T-MSC-sEVs inactivated human and mouse pHSCs. Administration of T-MSC-sEVs ameliorated hepatic injuries and fibrosis in chronically damaged liver induced by carbon tetrachloride (CCl4). miR-486-5p highly enriched in T-MSC-sEVs targeting the hedgehog receptor, smoothened (Smo), was upregulated, whereas Smo and Gli2, the hedgehog target gene, were downregulated in pHSCs and liver tissues treated with T-MSC-sEVs or miR-486-5p mimic, indicating that sEV-miR-486 inactivates HSCs by suppressing hedgehog signaling. Our results showed that T-MSCs attenuate HSC activation and liver fibrosis by delivering sEVs, and miR-486 in the sEVs inactivates hedgehog signaling, suggesting that T-MSCs and their sEVs are novel anti-fibrotic therapeutics for treating chronic liver disease.
Drug design targeting active posttranslational modification protein isoforms
Authors: Fanwang Meng, Zhongjie Liang, Kehao Zhao, Cheng Luo
Journal: Medicinal Research Reviews (2020)

Abstract Modern drug design aims to discover novel lead compounds with attractable chemical profiles to enable further exploration of the intersection of chemical space and biological space. Identification of small molecules with good ligand efficiency, high activity, and selectivity is crucial toward developing effective and safe drugs. However, the intersection is one of the most challenging tasks in the pharmaceutical industry, as chemical space is almost infinity and continuous, whereas the biological space is very limited and discrete. This bottleneck potentially limits the discovery of molecules with desirable properties for lead optimization. Herein, we present a new direction leveraging posttranslational modification (PTM) protein isoforms target space to inspire drug design termed as “Post‐translational Modification Inspired Drug Design (PTMI‐DD).” PTMI‐DD aims to extend the intersections of chemical space and biological space. We further rationalized and highlighted the importance of PTM protein isoforms and their roles in various diseases and biological functions. We then laid out a few directions to elaborate the PTMI‐DD in drug design including discovering covalent binding inhibitors mimicking PTMs, targeting PTM protein isoforms with distinctive binding sites from that of wild‐type counterpart, targeting protein‐protein interactions involving PTMs, and hijacking protein degeneration by ubiquitination for PTM protein isoforms. These directions will lead to a significant expansion of the biological space and/or increase the tractability of compounds, primarily due to precisely targeting PTM protein isoforms or complexes which are highly relevant to biological functions. Importantly, this new avenue will further enrich the personalized treatment opportunity through precision medicine targeting PTM isoforms.
Targeted proteomics of right heart adaptation to pulmonary arterial hypertension
Authors: Myriam Amsallem, Andrew J. Sweatt, Jennifer Arthur Ataam, Julien Guihaire, Florence Lecerf, Mélanie Lambert, Maria Rosa Ghigna, Md Khadem Ali, Yuqiang Mao, Elie Fadel, Marlene Rabinovitch, Vinicio de Jesus Perez, Edda Spiekerkoetter, Olaf Mercier, Francois Haddad, Roham T. Zamanian
Journal: European Respiratory Journal (2020)

No prior proteomic screening study has centred on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH. Plasma proteomic profiling was performed using multiplex immunoassay in 121 (discovery cohort) and 76 (validation cohort) PAH patients. The association between proteomic markers and RHMP, defined by the Mayo right heart score (combining RV strain, New York Heart Association (NYHA) class and N-terminal pro-brain natriuretic peptide (NT-proBNP)) and Stanford score (RV end-systolic remodelling index, NYHA class and NT-proBNP), was assessed by partial least squares regression. Biomarker expression was measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice. High levels of hepatocyte growth factor (HGF), stem cell growth factor-β, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams. High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk of heart failure who warrant closer follow-up and intensified therapy.
Response by Mahmood et al to Letter Regarding Article, “Impact of Left Atrial Appendage Exclusion on Short-Term Outcomes in Isolated Coronary Artery Bypass Graft Surgery”
Authors: Eitezaz Mahmood, Aidan Sharkey, Robina Matyal, Feroze Mahmood, Omar Chaudhary, Kamal Khabbaz
Journal: Circulation (2020)
Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants
Authors: Haresh Kirpalani, Edward F. Bell, Susan R. Hintz, Sylvia Tan, Barbara Schmidt, Aasma S. Chaudhary, Karen J. Johnson, Margaret M. Crawford, Jamie E. Newman, Betty R. Vohr, Waldemar A. Carlo, Carl T. D’Angio, Kathleen A. Kennedy, Robin K. Ohls, Brenda B. Poindexter, Kurt Schibler, Robin K. Whyte, John A. Widness, John A.F. Zupancic, Myra H. Wyckoff, William E. Truog, Michele C. Walsh, Valerie Y. Chock, Abbot R. Laptook, Gregory M. Sokol, Bradley A. Yoder, Ravi M. Patel, C. Michael Cotten, Melissa F. Carmen, Uday Devaskar, Sanjay Chawla, Ruth Seabrook, Rosemary D. Higgins, Abhik Das
Journal: New England Journal of Medicine (2020)

Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia. We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity. A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively. In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Heart, Lung, and Blood Institute and others; TOP ClinicalTrials.gov number, NCT01702805.).
Coronary Artery Calcification and Myocardial Perfusion: Kissing Cousins or Distant Relatives?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Robert A. Vogel
Journal: Journal of the American College of Cardiology (2006)
Injury patterns differ with age in male youth football: a four-season prospective study of 1111 time-loss injuries in an elite national academy
Authors: Eirik Halvorsen Wik, Lorenzo Lolli, Karim Chamari, Olivier Materne, Valter Di Salvo, Warren Gregson, Roald Bahr
Journal: British Journal of Sports Medicine (2020)

To describe age group patterns for injury incidence, severity and burden in elite male youth football.
The pharmacological IGF1R-IRS1/2 inhibitor NT157 presents multiple anti-neoplastic effects in myeloproliferative neoplasms
Authors: Bruna Alves Fenerich, João Agostinho Machado-Neto, Ana Paula Nunes Rodrigues Alves, Paula De Melo Campos, Jaqueline Cristina Fernandes, Juan Luiz Coelho-Silva, Renata Scopim Ribeiro, Fernanda B da Silva, Priscila Santos Scheucher, Lorena Lobo Figueiredo-Pontes, Eduardo Magalhães Rego, Fabiola Traina
Journal: Blood (2017)
Genome Methylation Accurately Predicts Neuroendocrine Tumor Origin: An Online Tool
Authors: Wenzel M. Hackeng, Koen M.A. Dreijerink, Wendy W.J. de Leng, Folkert H.M. Morsink, Gerlof D. Valk, Menno R. Vriens, G. Johan A. Offerhaus, Christoph Geisenberger, Lodewijk A.A. Brosens
Journal: Clinical Cancer Research (2020)

The primary origin of neuroendocrine tumor metastases can be difficult to determine by histopathology alone, but is critical for therapeutic decision making. DNA methylation-based profiling is now routinely used in the diagnostic workup of brain tumors. This has been enabled by the availability of cost-efficient array-based platforms. We have extended these efforts to augment histopathologic diagnosis in neuroendocrine tumors.Methylation data was compiled for 69 small intestinal, pulmonary, and pancreatic neuroendocrine tumors. These data were used to build a ridge regression calibrated random forest classification algorithm (neuroendocrine neoplasm identifier, NEN-ID). The model was validated during 3 × 3 nested cross-validation and tested in a local and an external cohort (n = 198 cases).NEN-ID predicted the origin of tumor samples with high accuracy (>95%). In addition, the diagnostic approach was determined to be robust across a range of possible confounding experimental parameters, such as tumor purity and array quality. A software infrastructure and online user interface were built to make the model available to the scientific community.This DNA methylation-based prediction model can be used in the workup for patients with neuroendocrine tumors of unknown primary. To facilitate validation and clinical implementation, we provide a user-friendly, publicly available web-based version of NEN-ID.
Recurrent NR3C1 Aberrations at First Diagnosis Relate to Steroid Resistance in Pediatric T-Cell Acute Lymphoblastic Leukemia Patients
Authors: Jordy C. G. van der Zwet, Willem Smits, Jessica G. C. A. M. Buijs-Gladdines, Rob Pieters, Jules P. P. Meijerink
Journal: HemaSphere (2020)

The glucocorticoid receptor NR3C1 is essential for steroid-induced apoptosis, and deletions of this gene have been recurrently identified at disease relapse for acute lymphoblastic leukemia (ALL) patients. Here, we demonstrate that recurrent NR3C1 inactivating aberrations—including deletions, missense, and nonsense mutations—are identified in 7% of pediatric T-cell ALL patients at diagnosis. These aberrations are frequently present in early thymic progenitor-ALL patients and relate to steroid resistance. Functional modeling of NR3C1 aberrations in pre-B ALL and T-cell ALL cell lines demonstrate that aberrations decreasing NR3C1 expression are important contributors to steroid resistance at disease diagnosis. Relative NR3C1 messenger RNA expression in primary diagnostic patient samples, however, does not correlate with steroid response.
Assessing Drug Development Risk Using Big Data and Machine Learning
Authors: Vangelis Vergetis, Dimitrios Skaltsas, Vassilis G. Gorgoulis, Aristotelis Tsirigos
Journal: Cancer Research (2020)

Identifying new drug targets and developing safe and effective drugs is both challenging and risky. Furthermore, characterizing drug development risk, the probability that a drug will eventually receive regulatory approval, has been notoriously hard given the complexities of drug biology and clinical trials. This inherent risk is often misunderstood and mischaracterized, leading to inefficient allocation of resources and, as a result, an overall reduction in R&D productivity. Here we argue that the recent resurgence of Machine Learning in combination with the availability of data can provide a more accurate and unbiased estimate of drug development risk.
Parkinson’s Disease — What’s the FUS?
Authors: Joel S. Perlmutter, Mwiza Ushe
Journal: New England Journal of Medicine (2020)

Parkinson's disease causes progressive motor and cognitive dysfunction. Medications aim to replace deficient dopamine in the brain and reduce the characteristic slowness, stiffness, and tremor. However, as the disorder progresses, medications provide shorter duration of benefit and produce involuntary dyskinetic movements. Surgical approaches to Parkinson's disease that can provide additional benefit at these later stages include deep-brain stimulation and ablative lesions in the nuclei of the basal ganglia.1,2 These procedures are considered to produce clinical benefit by modulation of pathologic oscillatory signals.3 Deep-brain stimulation for the treatment of Parkinson's disease has predominantly targeted the subthalamic nucleus or the internal segment . . .
Emerging Evidence of the Direct Association Between COVID-19 And Chilblains—Reply
Authors: Marie Baeck, Anne Herman
Journal: JAMA Dermatology (2020)

Pembrolizumab is a monoclonal antibody directed against PD-1.We report what is to our knowledge the first case of CP associated with a PD-1 inhibitor.Programmed cell death 1 inhibitors are associated with numerous cutaneous adverse effects, including lichen planus-like, psoriasiform, and vitiligo-like rashes. 5Mucosal adverse effects are increasingly recognized, including severe mucositis. 6The adverse effects are considered immune-related adverse events, as pembrolizumab and other PD-1 inhibitors release the checkpoints that regulate the function of the immune system.Using a PD-1 inhibitor for this patient possibly activated native T cells, leading to differentiation and proliferation of polyclonal plasma cells.It is unclear why the proliferation was localized to the oral mucosa, and whether the development of CP, like some other mucocutaneous adverse effects of PD-1 inhibitors, portends an improved prognosis.Dermatologists and oral health care clinicians should be able to recognize the growing number of mucocutaneous adverse effects of these increasingly used agents, including CP.
Tralokinumab for atopic dermatitis: a promising new therapy
Authors: D.E. Morra, A.M. Drucker
Journal: British Journal of Dermatology (2020)

Linked Articles: Wollenberg et al. Br J Dermatol 2021; 184:437–449. Silverberg et al. Br J Dermatol 2021; 184:450–463.
Causes, effects, and clinical implications of perturbed patterns within the cancer epigenome
Authors: Urszula Oleksiewicz, Marta Machnik
Journal: Seminars in Cancer Biology (2020)

Somatic mutations accumulating over a patient's lifetime are well-defined causative factors that fuel carcinogenesis. It is now clear, however, that epigenomic signature is also largely perturbed in many malignancies. These alterations support the transcriptional program crucial for the acquisition and maintenance of cancer hallmarks. Epigenetic instability may arise due to the genetic mutations or transcriptional deregulation of the proteins implicated in epigenetic signaling. Moreover, external stimulation and physiological aging may also participate in this phenomenon. The epigenomic signature is frequently associated with a cell of origin, as well as with tumor stage and differentiation, which all reflect its high heterogeneity across and within various tumors. Here, we will overview the current understanding of the causes and effects of the altered and heterogeneous epigenomic landscape in cancer. We will focus mainly on DNA methylation and post-translational histone modifications as the key regulatory epigenetic signaling marks. In addition, we will describe how this knowledge is translated into the clinic. We will particularly concentrate on the applicability of epigenetic alterations as biomarkers for improved diagnosis, prognosis, and prediction. Finally, we will also review current developments regarding epi-drug usage in clinical and experimental settings.
Randomized Trial of Focused Ultrasound Subthalamotomy for Parkinson’s Disease
Authors: Raúl Martínez-Fernández, Jorge U. Máñez-Miró, Rafael Rodríguez-Rojas, Marta del Álamo, Binit B. Shah, Frida Hernández-Fernández, José A. Pineda-Pardo, Mariana H.G. Monje, Beatriz Fernández-Rodríguez, Scott A. Sperling, David Mata-Marín, Pasqualina Guida, Fernando Alonso-Frech, Ignacio Obeso, Carmen Gasca-Salas, Lydia Vela-Desojo, W. Jeffrey Elias, José A. Obeso
Journal: New England Journal of Medicine (2020)

The subthalamic nucleus is the preferred neurosurgical target for deep-brain stimulation to treat cardinal motor features of Parkinson's disease. Focused ultrasound is an imaging-guided method for creating therapeutic lesions in deep-brain structures, including the subthalamic nucleus.We randomly assigned, in a 2:1 ratio, patients with markedly asymmetric Parkinson's disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure. The primary efficacy outcome was the between-group difference in the change from baseline to 4 months in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (i.e., part III) for the more affected body side (range, 0 to 44, with higher scores indicating worse parkinsonism) in the off-medication state. The primary safety outcome (procedure-related complications) was assessed at 4 months.Among 40 enrolled patients, 27 were assigned to focused ultrasound subthalamotomy (active treatment) and 13 to the sham procedure (control). The mean MDS-UPDRS III score for the more affected side decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points; 95% confidence interval [CI], 8.6 to 11.1) and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points; 95% CI, 0.0 to 3.5); the between-group difference was 8.1 points (95% CI, 6.0 to 10.3; P<0.001). Adverse events in the active-treatment group were dyskinesia in the off-medication state in 6 patients and in the on-medication state in 6, which persisted in 3 and 1, respectively, at 4 months; weakness on the treated side in 5 patients, which persisted in 2 at 4 months; speech disturbance in 15 patients, which persisted in 3 at 4 months; facial weakness in 3 patients, which persisted in 1 at 4 months; and gait disturbance in 13 patients, which persisted in 2 at 4 months. In 6 patients in the active-treatment group, some of these deficits were present at 12 months.Focused ultrasound subthalamotomy in one hemisphere improved motor features of Parkinson's disease in selected patients with asymmetric signs. Adverse events included speech and gait disturbances, weakness on the treated side, and dyskinesia. (Funded by Insightec and others; ClinicalTrials.gov number, NCT03454425.).
mRNA loading into ATP-responsive polyplex micelles with optimal density of phenylboronate ester crosslinking to balance robustness in the biological milieu and intracellular translational efficiency
Authors: Naoto Yoshinaga, Satoshi Uchida, Anjaneyulu Dirisala, Mitsuru Naito, Kensuke Osada, Horacio Cabral, Kazunori Kataoka
Journal: Journal of Controlled Release (2020)
Optimization of approaches for DNA isolation and copy number analysis from formalin-fixed paraffin-embedded tissues using high-density SNP microarrays identifies novel genomic regions of gain/loss in early-stage breast cancer
Authors: Musaffe Tuna, Patricia Thompson, Sharoni Jacobs, Walter Lee, Rahul Mitra, Aysegul Sahin, Gordon Mills, Melissa Bondy, Ralf Krahe
Journal: Cancer Research (2007)

2930  DNA copy number changes are common to breast tumors. High-density single nucleotide polymorphism (SNP) microarrays and array-based comparative genomic hybridization are used to detect such chromosomal aberrations and loss of heterozygosity (LOH). Archived formalin-fixed paraffin-embedded (FFPE) tissues with follow-up data constitute an invaluable resource for retrospective studies of disease and treatment outcomes. However, technical issues associated with FFPE samples have limited their general use in genomic profiling studies. Using tumor and normal matched DNAs from nine early-stage breast cancer patients (FFPE tumor, fresh frozen tumor and normal tissue, and peripheral blood leukocytes), we compared two novel methods of genomic DNA extraction to the Qiagen DNeasy method and devised an optimized strategy for DNA copy number and LOH determination using Affymetrix® high-density oligo-based SNP microarrays. Standard PCR and RAPD PCR (50-750 bp amplicons) used for quality control proved good predictors of the genotyping call rate and accuracy for DNA copy number and LOH detection. The use of unmatched normal controls derived from the HapMap Project as references for copy number analysis also proved valid in comparative studies to use of patient matched normal tissue. Genotyping efficiency and accuracy was improved using our novel extraction methods. After censoring the data for probe sets that rely on the presence of longer amplicons not present in fragmented FFPE DNA, call rates for FFPE DNA were equivalent to call rates for fresh frozen tissue DNA, and concordance rates between FFPE and fresh frozen tumor reached >99%. Identical DNA copy number changes were obtained between FFPE and fresh frozen tumor samples. We observed and validated by additional methodologies a heterogeneous pattern of shared gains and losses across the sample set, including the amplification of EGFR (in chromosome 7p11.2, 11%), gains in 16p13.3 (MAPK8IP3, 33%) and 11q13.3 (CCND1, 33%), and losses in 12q24.33 (FZD10, 67%), 13q13.3 (CCNA1, 56%), 16q23.3 (CDH13, 44%) and 17p13.1 (TP53, 33%). These data demonstrate that optimization of the DNA extraction procedure from FFPE and removal of probe sets requiring longer amplicons from the analyses yielded highly concordant calls enabling the identification of DNA copy number changes from FFPE DNAs relevant to early stage breast cancers.