tbuckley/cabot-search huggingface dataset:
Reinforcement and Fatigue of a Bioinspired Mineral–Organic Bioresorbable Bone Adhesive
Authors: Alina Kirillova, Olivia Nillissen, Samuel Liu, Cambre Kelly, Ken Gall
Journal: Advanced Healthcare Materials (2020)

Bioresorbable bone adhesives may provide remarkable clinical solutions in areas ranging from fixation and osseointegration of permanent implants to the direct healing and fusion of bones without permanent fixation hardware. Mechanical properties of bone adhesives are critical for their successful application in vivo. Reinforcement of a tetracalcium phosphate-phosphoserine bone adhesive is investigated using three degradable reinforcement strategies: poly(lactic-co-glycolic) (PLGA) fibers, PLGA sutures, and chitosan lactate. All three approaches lead to higher compressive strengths of the material and better fatigue performance. Reinforcement with PLGA fibers and chitosan lactate results in a 100% probability of survival of samples at 20 MPa maximum compressive stress level, which is almost ten times higher compared to compressive loads observed in the intervertebral discs of the spine in vivo. High adhesive shear strength of 5.1 MPa is achieved for fiber-reinforced bone adhesive by tuning the surface architecture of titanium samples. Finally, biological and biomechanical performance of the fiber-reinforced adhesive is evaluated in a rabbit distal femur osteotomy model, showing the potential of the bone adhesive for clinical use.
Repurposing Nelarabine to Induce Differentiation of Acute Myeloid Leukemia
Authors: Hanying Wang, Xin He, Feiteng Huang, Haojie Dong, Wei Chen, Zheng Li, Jie Sun, Yinghui Zhu, Lei Zhang, Yuhui Wu, Lifeng Feng, Jing Zhang, Samer Khaled, Guido Marcucci, David Sykes, Hongchuan Jin, Xian Wang, Ling Li
Journal: Blood (2020)
A Molecular-Based Response Prediction Model to Romiplostim in Patients with Lower-Risk Myelodysplastic Syndrome and Severe Thrombocytopenia
Authors: Anne Sophie Kubasch, Aristoteles Giagounidis, Georgia Metzgeroth, Anna Jonasova, Regina Herbst, Jose Miguel Torregrosa Diaz, Benoit De Renzis, Katharina S. Götze, Marie-Luise Huetter-Kroenke, Marie-Pierre Gourin, Bohrane Slama, Sophie Dimicoli-Salazar, Pascale Cony-Makhoul, Kamel Laribi, Sophie Park, Katja Jersemann, Dorothea Schipp, Klaus H. Metzeler, Oliver Tiebel, Katja Sockel, Silke Gloaguen, Anna Mies, Fatiha Chermat, Christian Thiede, Rosa Sapena, Richard F. Schlenk, Pierre Fenaux, Uwe Platzbecker, Lionel Ades
Journal: Blood (2020)
Interleukin-2 Receptor Alpha Chain, Also Called CD25, Is a Potential Target in Acute Lymphoblastic Leukemia
Authors: Giovanna Carrà, Antonio Cartellà, Beatrice Maffeo, Paola Circosta, Alessandro Cignetti, Marisa Pautasso, Ubaldo Familiari, Marco Volante, Matteo Emidio Emidio Dragani, Giovanna Rege Cambrin, Giuseppe Saglio, Alessandro Morotti
Journal: Blood (2020)
Abstract MP170: Increased Ga <sub>o</sub> Expression Regulated by NRSF Plays a Key Role in the Development of Heart Failure Through the Impairment of Ca <sup>2+</sup> Homeostasis
Authors: Hideaki Inazumi, Yasuaki Nakagawa, Kenji Moriuchi, Koichiro Kuwahara
Journal: Circulation Research (2020)

Background: In the development of heart failure, pathological intracellular signaling reactivates fetal cardiac gene program, which leads to pathological cardiac remodeling. We previously reported that a transcriptional repressor, neuron restrictive silencer factor (NRSF) represses fetal cardiac gene program and maintains normal cardiac function, while pathological stimuli de-repress this NRSF mediated repression via activation of CaMKII. Molecular mechanisms by which NRSF maintains cardiac function remains to be determined, however. Purpose: To elucidate molecular mechanisms by which NRSF maintains normal cardiac function. Methods and Results: Newly generated cardiac-specific NRSF knockout mice (NRSF-cKO) showed cardiac dysfunction and premature deaths accompanied with lethal arrhythmias, as was observed in our previously reported cardiac-specific dominant-negative mutant of NRSF transgenic mice (dnNRSF-Tg). Expression of Gnao1 gene encoding Gα o , a member of inhibitory G proteins, was commonly increased in ventricles of dnNRSF-Tg and NRSF-cKO. ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay identified that NRSF transcriptionally regulates Gnao1 gene expression. Genetic Knockdown of Gα o in dnNRSF-Tg and NRSF-cKO ameliorated the reduced systolic function, increased arrhythmogenicity and reduced survival rates. Conversely cardiac-specific GNAO1 overexpression was sufficient to show impaired cardiac function. Mechanistically, Gα o increases current density in surface sarcolemmal L-type Ca 2 + channel and then activates CaMKII without affecting protein kinase A activity, which finally leads to impaired Ca 2+ handling and systolic dysfunction. Furthermore, expression of Gα o is also increased in ventricles of transverse aortic constriction model mice and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gα o prevented the progression of cardiac dysfunction. Conclusions: Increased expression of Gα o , induced by attenuation of NRSF-mediated repression forms a pathological circuit via activation of CaMKII and progresses heart failure by impairing Ca 2+ homeostasis. Gα o is a potential therapeutic target for heart failure.
Abstract PO-090: Protein-based immune profiles of basal-like vs luminal breast cancers
Authors: Andrea Walens, Linnea T. Olsson, Xiaohua Gao, Alina M. Hamilton, Erin L. Kirk, Stephanie M. Cohen, Bentley R. Midkiff, Yongjuan Xia, Mark E. Sherman, Nana Nikolaishvili-Feinberg, Katherine A. Hoadley, Melissa A. Troester, Benjamin C. Calhoun
Journal: Cancer Research (2020)

Abstract Background: Tumor infiltrating lymphocytes (TILs) play an important, but incompletely understood role in chemotherapy response and prognosis. In breast cancer, there appear to be distinct immune responses by subtype, but most studies have used limited numbers of protein markers or bulk sequencing of RNA to characterize immune response, in which spatial organization cannot be assessed. Methods: To identify immune phenotypes of Basal-like vs. Luminal breast cancer we used the GeoMx® (NanoString) platform to perform digital spatial profiling (DSP) of immune-related proteins in tumor whole sections and tissue microarrays (TMA). Visualization of CD45, CD68, or pan-Cytokeratin by immunofluorescence was used to select regions of interest (ROIs) in formalin-fixed paraffin embedded tissue sections. 44 antibodies representing stromal markers and multiple immune cell types were applied to quantify the tumor microenvironment. Results: In whole tumor slides, immune hot spots (CD45+) had increased expression of many immune markers, suggesting a diverse and robust immune response. In epithelium-enriched areas, immune signals were also detectable and varied by subtype, with Regulatory T cell (Treg) markers (CD4, CD25, FOXP3) being higher in Basal-like vs. Luminal breast cancer. Extending these findings to TMAs with more patients (n=75), we confirmed subtype-specific immune profiles, including enrichment of Treg markers in Basal-likes. Conclusion: This work demonstrated that immune responses can be detected in epithelium-rich tissue, and that TMAs are a viable approach for obtaining important immunoprofiling data. In addition, we found that immune marker expression is associated with BC subtype, suggesting possible prognostic or targetable differences. Citation Format: Andrea Walens, Linnea T. Olsson, Xiaohua Gao, Alina M. Hamilton, Erin L. Kirk, Stephanie M. Cohen, Bentley R. Midkiff, Yongjuan Xia, Mark E. Sherman, Nana Nikolaishvili-Feinberg, Katherine A. Hoadley, Melissa A. Troester, Benjamin C. Calhoun. Protein-based immune profiles of basal-like vs luminal breast cancers [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-090.
Bortezomib and Rituximab in Newly Diagnosed Adolescent and Adult CD20-Positive Philadelphia (Ph) Negative Precursor B-Cell Acute Lymphoblastic Leukemia: A Phase II Study
Authors: Vasu Babu Goli, Hasmukh Jain, Prashant Tembhare, Dhanlaxmi Lalit Shetty, Avinash Bonda, Lingaraj Nayak, Nikhil Patkar, Papagudi Ganesan Subramanian, Manju Sengar
Journal: Blood (2020)
Recurrent HNSCC Harbor an Immunosuppressive Tumor Immune Microenvironment Suggesting Successful Tumor Immune Evasion
Authors: Christian Watermann, Helen Pasternack, Christian Idel, Julika Ribbat-Idel, Johannes Brägelmann, Patrick Kuppler, Anne Offermann, Danny Jonigk, Mark Philipp Kühnel, Andreas Schröck, Eva Dreyer, Christian Rosero, Jacqueline Nathansen, Anna Dubrovska, Lars Tharun, Jutta Kirfel, Barbara Wollenberg, Sven Perner, Rosemarie Krupar
Journal: Clinical Cancer Research (2020)

Recurrent tumors (RT) of head and neck squamous cell carcinoma (HNSCC) occur in up to 60%, with poor therapeutic response and detrimental prognosis. We hypothesized that HNSCC RTs successfully evade antitumor immune response and aimed to reveal tumor immune microenvironment (TIME) changes of primary tumors (PT) and corresponding RTs.Tumor-infiltrating leukocytes (TIL) of 300 PTs and 108 RTs from two large independent and clinically well-characterized HNSCC cohorts [discovery cohort (DC), validation cohort (VD)] were compared by IHC. mRNA expression analysis of 730 immune-related genes was performed for 18 PTs and RTs after adjuvant chemoradiotherapy (CRT). The effect of chemotherapy and radiation resistance was assessed with an in vitro spheroid/immunocyte coculture model.TIME analysis revealed overall decrease of TILs with significant loss of CD8+ T cells (DC P = 0.045/VC P < 0.0001) and B lymphocytes (DC P = 0.036/VC P < 0.0001) in RTs compared with PTs in both cohorts. Decrease predominantly occurred in RTs after CRT. Gene expression analysis confirmed loss of TILs (P = 0.0004) and B lymphocytes (P < 0.0001) and showed relative increase of neutrophils (P = 0.018), macrophages (P < 0.0001), dendritic cells (P = 0.0002), and mast cells (P = 0.0057) as well as lower overall expression of immune-related genes (P = 0.018) in RTs after CRT. Genes involved in B-lymphocyte functions and number of tertiary lymphoid structures showed the strongest decrease. SPP1 and MAPK1 were upregulated in vivo and in vitro, indicating their potential suitability as therapeutic targets in CRT resistance.HNSCC RTs have an immunosuppressive TIME, which is particularly apparent after adjuvant CRT and might substantially contribute to poor therapeutic response and prognosis.
Injury and illness surveillance in sports: how golf, tennis, cycling and parasport extended the IOC consensus statement to tailor injury and illness surveillance to specific sports
Authors: Jiri Dvorak, Babette M Pluim
Journal: British Journal of Sports Medicine (2020)

For a sport to develop a meaningful injury prevention strategy, sound epidemiological data are crucial. This, in turn, needs to be based on the analysis of known risk factors involved in the sport so that mitigation strategies can be introduced by modifying the rules and laws if necessary. The key objective for medical advisors in sports is to reduce morbidity and to promote the sport as a health-enhancing leisure activity.1 In this editorial, we aimed to motivate other international sport federations to take similar action.

Insufficient physical activity greatly increases the risk of non-communicable diseases, and physical inactivity is one of the biggest public health threats of the 21st century.2 

Despite the incontrovertible evidence of the health benefits of physical activity, a WHO survey of 1.6 million participants in 146 countries revealed that 81% of children and adolescents aged 11–17 years participated in insufficient physical activity.3 In a climate dominated by COVID-19, obesity is clearly linked to poor outcome, along …
High-Dimensional and Single-Cell Transcriptome Analysis of AITL Tumor Microenvironment Reveals Gross Expansion of Novel Dysfunctional CD8+ T Cell Populations, Global Shift in B Cell Phenotypes
Authors: Joshua C. Pritchett, Zhi-Zhang Yang, Hyojin Kim, Jose C Villasboas, Andrew L. Feldman, James R. Cerhan, Stephen M. Ansell
Journal: Blood (2020)
Abstract 252: Adhesion GPCR, Latrophilin-2 Induces Cardiac Differentiation Through CDK5, Contributing to Repair After Myocardial Infarction
Authors: Hyun-jai Cho, Choon-Soo Lee, Jin-Woo Lee, Hyo-Soo Kim
Journal: Circulation Research (2020)

There has been an increasing demand for cardiomyocyte (CMC) for research into cardiovascular disease and the toxicology of drug metabolites. We identified a G protein-coupled receptor, latrophilin-2 (Lphn2), as a functional marker for cardiomyogenic lineage cells during both in vitro differentiation from ESCs/iPSCs and in vivo heart development. Lphn2 was selectively expressed on CPCs and CMCs during the differentiation of mouse and human PSCs, and cell sorting with an anti-Lphn2 antibody promoted the isolation of populations highly enriched in CPCs and CMCs. Lphn2 knock-down iPSCs did not express cardiac genes. Heterozygous Lphn2 -KO mice ( Lphn2 +/-) were alive and fertile. Homozygous Lphn2 -/- mice were embryonically lethal and showed underdevelopment of the ventricular myocardium. Interestingly, the hearts of Lphn2 -/- embryos revealed the disrupted conotruncal septation of ventricles at E13.5. Lphn2 induces the expression of the central transcription factors Gata4, Nkx2.5, and Tbx5 in mouse heart development. The amino acid sequence of Lphn2 is highly conserved across humans and mice (95.8% identical). For the purpose of cardiac regeneration, we transplanted PSC-derived Lphn2+ cells into the infarcted heart. Transplantation of Lphn2+ cells significantly reduced the fibrosis area and length compared with those in the PBS-injected control group and Lphn2- cells. Echocardiography revealed significantly small LV dimensions at the systole and diastole, and the LV systolic function was higher in the Lphn2+ cell group than in the control and Lphn2- cell groups. To investigate the molecular mechanism underlying the induction of cardiac differentiation by Lphn2, we used the Phospho Explorer Antibody Array, which encompasses nearly all known signaling pathways. Lphn2-dependent phosphorylation was strongest for CDK5 at Tyr15. We identified CDK5, Src, and P38MAPK as key downstream molecules of Lphn2. Our findings provide a valuable tool for identifying CPCs and CMCs differentiated from PSCs, as well as revealing novel insights into cardiac development. Furthermore, the results of this study could be of potential use in regenerative cell therapy for the restoration of cardiac muscle. Funding Source: This study was supported by "Strategic Center of Cell and Bio Therapy for Heart, Diabetes &amp; Cancer" (HI17C2085) through the Korea Health Industry Development Institute, funded by the Ministry of Health &amp; Welfare, Republic of Korea.
Nivolumab in Primary CNS Lymphoma and Primary Testicular Lymphoma with CNS Involvement: Single Center Experience
Authors: Andrey N. Gavrilenko, Nikita P. Volkov, Daniil I. Shmidt, Alexey Y. Polushin, Elena Kondakova, Kirill V. Lepik, Yuri R. Zalaylov, Marina O. Popova, Aleksandr D. Kulagin, Boris V. Afanasyev, Natalia B. Mikhailova
Journal: Blood (2020)
Central Nervous System (CNS) Involvement of Richter Transformation: A Single Center Experience
Authors: Yucai Wang, Marcella Tschautscher, Sameer A. Parikh, Timothy G. Call, Neil E. Kay, Patrick B. Johnston, Luis F. Porrata, Thomas M. Habermann, Thomas E. Witzig, Grzegorz S. Nowakowski, Stephen M. Ansell, Min Shi, Saad S. Kenderian, Eli Muchtar, Suzanne R. Hayman, Amber B. Koehler, Jose F. Leis, Wei Ding
Journal: Blood (2020)
Divergent Levels of CD112 and INKA1 Define a Subset of Human Hematopoietic Stem Cells That Resists Regenerative Stress to Preserve Stemness
Authors: Kerstin B Kaufmann, Andy G.X. Zeng, Etienne Coyaud, Laura Garcia Prat, Efthymia Papalexi, Estelle MN Laurent, Michelle Chan-Seng-Yue, Olga I. Gan, Kristele Pan, Jessica L. McLeod, Sasan Zandi, Shin-Ichiro Takayanagi, Rahul Satija, Brian Raught, Stephanie Zhi-Juan Xie, John E. Dick
Journal: Blood (2020)
CPX-351 Exposure-Response Analyses for Efficacy and Safety in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)
Authors: Qi Wang, Nathalie H. Gosselin, Michael J. Absalon, E. Anders Kolb, J.F. Marier, Todd A. Alonzo, Stefan Faderl, Todd M. Cooper
Journal: Blood (2020)
Outcomes of Multiple Myeloma Patients with Del 17p Undergoing Autologous Stem Cell Transplantation
Authors: Iuliana Vaxman, Alissa Visram, Prashant Kapoor, Abdullah S. Al Saleh, Shaji K. Kumar, Angela Dispenzieri, Francis K. Buadi, David Dingli, Eli Muchtar, Wilson I Gonsalves, S. Vincent Rajkumar, Taxiarchis Kourelis, Rahma M Warsame, Martha Q. Lacy, Morie A. Gertz
Journal: Blood (2020)
Correspondence on ‘Machine learning integration of scleroderma histology and gene expression identifies fibroblast polarisation as a hallmark of clinical severity and improvement’
Authors: Mirko Manetti
Journal: Annals of the Rheumatic Diseases (2020)

I read with great interest the article by Showalter et al 1 who, through an unbiased machine learning approach integrating skin biopsy histology and gene expression, describe the relevance of CD34 and α-smooth muscle actin (α-SMA) stains as biomarkers reflecting clinical severity and improvement in patients with diffuse cutaneous systemic sclerosis (dcSSc; scleroderma). Elegantly, the authors have shown that CD34 staining decreases with worsening clinical severity and subsequently increases with clinical improvement, while the opposite was observed for α-SMA myofibroblast marker staining.1 Moreover, CD34 and α-SMA immunostaining intensity appeared to be highly predictive of scleroderma gene expression subsets, with highest CD34 staining and lowest α-SMA staining being detectable in normal-like compared with fibroproliferative and inflammatory dcSSc skin samples.1 Further analyses revealed that clinically severe dcSSc skin exhibiting the α-SMAhigh/CD34low immunophenotype associates with a high inflammatory gene expression signature that can reverse over time in patients with clinical improvement, but not in those who do not improve.1 Mechanistically, the authors have suggested that differential CD34 and α-SMA stains may reflect distinct fibroblast polarisation states, with the α-SMAhigh/CD34 …
Quantifying the Size and Diversity of the Human Alloresponse Via High-Throughput T Cell Receptor Sequencing
Authors: Susan Dewolf, Boris Grinshpun, Thomas Savage, Sai ping Lau, Aleksandar Obradovic, Brittany Shonts, Suxiao Yang, Heather Morris, Julien Zuber, Robert Winchester, Megan Sykes, Yufeng Shen
Journal: Blood (2017)
Abstract 442: Epigenetic Regulation of Ezh2 in Direct Human Cardiac Reprogramming
Authors: Yang Zhou, Yawen Tang, Lianzhong Zhao, Rui Lu, Jianyi Zhang
Journal: Circulation Research (2020)

Cardiovascular disease is still the leading cause of death in the United States. Due to the limited regenerative capacity of adult hearts, the damage caused by heart injury could not be reversed and often progressed into heart failure. In need of cardiovascular disease treatment, many therapies aimed at either cell transplantation or cell regeneration have been proposed. Direct reprogramming of somatic cells into induced cardiomyocytes (iCMs) is considered to be a promising strategy for regenerative medicine. The induction of cardiomyocytes from non-myocytes has been achieved efficiently via ectopic expression of reprogramming factors both in vitro and in vivo with mice models. However, as human cells are more resistant to the reprogramming process, the generation of human iCMs (hiCMs) has been restricted by the factor that using more complex cocktails generated only functionally immature cells with lower efficiency and longer conversion time. The inefficiency of hiCMs production called for the identification and elucidation of underlying species-specific regulatory mechanisms in human, and removal of the additional epigenetic barriers which might be damping the hiCMs reprogramming. Here, we identified a human-specific epigenetic barrier, Enhancer of zesta homolog 2 (EZH2), via an unbiased loss-of-function screening. With the knockdown of EZH2, the hiCM reprogramming efficiency was significantly increased, accompanied with profound repression of collagen and extracellular matrix genes, which are related to the formation of fibrosis. Consistently, Inhibition of EZH2 catalytic activity via small molecules promotes hiCM reprogramming, suggesting that EZH2’s inhibitory effect was mediated by epigenetic regulation of histone modifications. Therefore, our study revealed a previously unrecognized regulatory mechanism of human cardiac reprogramming, which allows us to overcome the fibroblast fate barriers and ease the cardiac cell fate conversion.
Lenalidomide/RCHOP (R2CHOP) Produces High Response Rates and Overall Survival in New, Untreated Diffuse Large B Cell Lymphoma Transformed from Follicular Lymphoma- Results from MC078E
Authors: Sanjal H Desai, Betsy Laplant, William R. Macon, Rebecca L. King, Yucai Wang, David J. Inwards, Ivana Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, Thomas E. Witzig, Grzegorz S. Nowakowski
Journal: Blood (2020)
Abstract 312: The Tricuspid Valve Also Maladapts: Evidence From Sheep With Functional Tricuspid Regurgitation
Authors: Manuel K Rausch, William Meador, Marcin Malinowski, Tomasz Jazwiec, Mrudang Mathur, Tomasz Timek
Journal: Circulation Research (2020)

The objective of this work was to determine whether tricuspid valve leaflets maladapt to functional regurgitation as they do in the mitral valve. If they did, pharmacological control of the underlying mechanisms could open opportunities to support tricuspid valve surgery and improve currently poor outcomes. To this end, we used a biventricular heart failure model to induce functional tricuspid valve regurgitation in sheep. We sacrificed animals once they showed signs of heart failure (with in 2-3 weeks). In those animals (and controls), we measured tricuspid anterior leaflet area and thickness, collagen content via ELISAs, tissue stiffness via mechanical testing, and cellular changes via immunohistochemistry. We found a statistically significant increase with disease in leaflet area (p=0.004), thickness (p=0.037), collagen content (p=0.001), circumferential leaflet stiffness (p=0.001), and SMA (p=0.030), Figure 1. Our findings imply that in approximately 2-3 weeks of biventricular heart failure and associated functional tricuspid regurgitation, tricuspid valve leaflets underwent substantial remodeling. Specifically, it appears that activation of valvular interstitial cells increased collagen syntheses resulting in leaflet growth, thickening, and stiffening. No other previous study has demonstrated tissue maladaptation on all functional scales in the tricuspid valve. Our work is relevant as it implies that pharmacological control of this maladaptive response could allow for the promotion of the positive effects (e.g., area increase) while suppressing negative effects (e.g., fibrosis).