tbuckley/cabot-search huggingface dataset:
Abstract 214: Effect of Matrix Stiffness on Adult Cardiomyocytes Using Dynamic, Tunable, and Reversible Magnetorheological PDMS Substrates
Authors: Alexia Vite, Matthew A. Caporizzo, Elise Corbin, Kenneth Bedi, Christina Yingxian Chen, Benjamin L. Prosser, Kenneth B. Margulies
Journal: Circulation Research (2019)

The physical properties of the extracellular matrix (ECM), including stiffness and viscoelasticity, play a key role in the development of hypertensive and hypertrophic cardiac diseases at the cellular level, affecting the morphology and function of heart tissue. The ECM is a dynamic structure that is continuously changing in both normal and diseased tissue. In an extension of prior studies examining how substrates of fixed stiffness affect cardiac cells, we introduce a novel experimental model that allows exploration of cardiomyocyte functional alterations in response to rapid and reversible matrix stiffness modulation. We fabricated a biocompatible magneto-rheological elastomer (MRE) culture substrate by adding iron particles to a PDMS elastomer. In the presence of an applied magnetic field, this substrate stiffens reversibly and nearly instantaneously from 10 kPa to 50 kPa: the range observed in normal and diseased myocardium, respectively. Adult cardiomyocytes isolated from non-failing human hearts (unused organ donors) or adult rats were cultured for 24 - 48 hours on the tunable MREs. Cardiomyocytes cultured on a stiffened MRE (~50 kPa) exhibited time-dependent reductions in cell shortening and peak Ca 2+ transient amplitude compared with cardiomyocytes cultured on a soft MRE (~10 kPa). Rates of cardiomyocyte shortening and re-lengthening were also slowed by culture on 50 kPa substrates. Using super-resolution imaging, we found that cardiomyocytes cultured on a stiffened MRE exhibited an increased microtubule network density and demonstrated increased cellular stiffness and viscoelasticity, as measured by nanoindentation. These studies indicate that adult human and rat cardiomyocytes are acutely sensitive to changes in extracellular stiffness within the pathophysiological range and tend to adapt their own stiffness to match that of their surroundings via dynamic changes in microtubule architecture. These mechanisms may contribute to the regulation of mechanical homogeneity within the myocardium. Our method provides a unique in vitro platform for studying mechanosensing, mechanotransduction and mechanical memory in isolated adult cardiomyocytes.
A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation–Positive NSCLC Patients
Authors: Giorgio Scagliotti, Denis Moro-Sibilot, Jens Kollmeier, Adolfo Favaretto, Eun Kyung Cho, Heidrun Grosch, Martin Kimmich, Nicolas Girard, Chun-Ming Tsai, Te-Chun Hsia, Matteo Brighenti, Christian Schumann, Xuejing Aimee Wang, Sameera R. Wijayawardana, Aaron M. Gruver, Johan Wallin, Kambiz Mansouri, Volker Wacheck, Gee-Chen Chang
Journal: Journal of Thoracic Oncology (2019)
Profiling of Circulating Free DNA Using Targeted and Genome-wide Sequencing in Patients with SCLC
Authors: Sumitra Mohan, Victoria Foy, Mahmood Ayub, Hui Sun Leong, Pieta Schofield, Sudhakar Sahoo, Tine Descamps, Bedirhan Kilerci, Nigel K. Smith, Mathew Carter, Lynsey Priest, Cong Zhou, T. Hedley Carr, Crispin Miller, Corinne Faivre-Finn, Fiona Blackhall, Dominic G. Rothwell, Caroline Dive, Gerard Brady
Journal: Journal of Thoracic Oncology (2019)

SCLC accounts for approximately 250,000 deaths worldwide each year. Acquisition of adequate tumor biopsy samples is challenging, and liquid biopsies present an alternative option for patient stratification and response monitoring.
Increased SERUM VON Willebrand Levels in Chronic Lymphocytic Leukemia (CLL) Patients Are Related to a Shorter Time to Treatment
Authors: Thommais Tryfou, Paraskevi Papaioannou, Panagiotis Repousis, Annita Ioanna Gkioka, Sotirios Sachanas, Aikaterini Bitsani, Maria Dimou, Dimitrios Maltezas, Aspasia Koudouna, Anastasia Kopsaftopoulou, Konstantina Chamoulkou, Ioannis Grafakos, Styliani Kokori, Argyrios Tsantes, Gerasimos Pangalis, Panayiotis Panayiotidis, Marie-Christine Kyrtsonis
Journal: Blood (2018)
An Open Label, Multi Center Study on the Efficacy and Safety of a Liquid, Ready-to-Use Intravenously Administered Anti-D Immunoglobulin in Patients with Chronic Immune Thrombocytopenic Purpura.
Authors: Louis M. Aledort, Abdulgabar Salama, Lidia Kovaleva, Tadeusz Robak, Benjamin Brenner, Adrian Newland, Simon Davies, Diane J. Nugent, Alphonse Hubsch, Irmgard Andresen, Othmar Zenker
Journal: Blood (2004)
Abstract 543: The Metabolites of Human Cardiac Precursors Enhanced Cardiomyogenic Differentiation of hiPSC
Authors: Wen-Pin Chen, You-Yi Li
Journal: Circulation Research (2019)

Background: Wnt signaling pathways are involved in cardiomyogenic differentiation. Besides that, nutrients and metabolism may also influence cell differentiation. However, it is still unclear whether the cell lineage commitment could be controlled by the metabolites of its precursor cells. The aim of this study is to examine whether the metabolites of cardiac precursors could determine cardiomyogenic differentiation fate of hiPSC. Methods: hiPSC was maintained in serum-free and feeder-free monolayer condition. After CHIR99021-induced mesendodermal differentiation for two days, IWP4 was added to inhibit Wnt signaling and to induce myogenic differentiation for another two days. After wash, the culture medium was collected during cell differentiation period of day 5-10 (d5-10-diff-medium). ExoQuick-TC kit was used to extract the exosomes in the medium. Cardiomyocytes were identified by immunocytochemistry staining with mouse monoclonal antibody against cardiac sarcomeric actinin alpha, and were counted the percentage by flow cytometry. Results: The exosome-free d5-10-diff-medium was found to be able to dramatically induce cardiomyogenic differentiation only in CHIR99021-induced mesendodermal cells, rather than directly in hiPSC, in the absence of Wnt inhibitor. The metabolic profiling of the exosome-free d5-10-diff-medium was further characterized by LC-MS. After functional validation, the effective metabolites for the induction of cardiomyogenic differentiation were identified and the possible signaling pathways were analyzed. Conclusion: This study demonstrated that the metabolites of cardiac precursors could control cardiac cell commitment by driving the development of cardiac metabolic system.
Molecular Analysis of Factor V, Prothrombin and Methylenetetrahydrofolate Redutase in Thrombolic Patients
Authors: Aldair Sousa Paiva, Hugo Diogenes De Oliveira Paiva, Geraldo Barroso Cavalcanti, Gioconda DR Leão, Marcos Dias Leão, Frank Bahia, Roberto C Vasconcelos, Andrea LAC Fernandes, Erica Aires Gil, Victor lima Soares, Geisa Januario, Karla Cristina Santos, Telma Araujo Lemos, Alessandra Suelen Jardim
Journal: Blood (2018)
Impact of Conditioning Regimen Intensity On the Outcomes of Allogeneic Hematopoietic Cell Transplantation for Refractory Grade-III Follicular (FL-III) and Diffuse Large B-Cell Lymphomas (DLBCL): A Cibmtr Analysis
Authors: Mehdi Hamadani, Wael Saber, Jeanette Carreras, Kwang W. Ahn, Ginna G. Laport, Silvia Montoto, David G. Maloney, Hillard M. Lazarus
Journal: Blood (2012)
Epoxyketone-Based Proteasome Inhibitors Carfilzomib and Orally Bioavailable ONX 0912 Have Anti-Resorptive and Bone-Anabolic Activity in Addition to Anti-Myeloma Effects
Authors: Michelle A Hurchla, Antonio Garcia-Gomez, Mary C Hornick, Enrique M Ocio, Aixiao Li, Juan F Blanco, Lynne Collins, Christopher J Kirk, David Piwnica-Worms, Ravi Vij, Michael H Tomasson, Atanasio Pandiella, Jesús F San Miguel, Mercedes Garayoa, Katherine N Weilbaecher
Journal: Blood (2011)
Abstract 882: The Valosin-containing Protein Resists Pathological Cardiac Calcium Overload via Inhibiting Mitochondrial Calcium Uptake
Authors: Shaunrick Stoll, Ben Ma, Erick J. Behringer, Hongyu Qiu
Journal: Circulation Research (2019)

Stress-induced mitochondrial calcium (Ca 2+ ) overload is a trigger of cardiomyocyte death though the opening of mitochondrial permeability transition pore (mPTP) during cardiac ischemic injury. We previously found that the valosin-containing protein (VCP), an ATPase-associated protein, protects cardiomyocytes against stress-induced death and also inhibits mPTP opening in vitro. However, the underlying molecular mechanisms are not fully understood. Here, we tested our hypothesis that VCP protects cardiomyocytes against stress-induced mPTP opening through resisting excessive mitochondrial Ca 2+ uptake. By using a cardiac-specific transgenic (TG) mouse model in which VCP is overexpressed by 3.5 folds in the hearts, we found that, under the pathological extra-mitochondrial Ca 2+ overload (10-70μM), Ca 2+ entered into cardiac mitochondriawas much lessin VCP TG mice compared to little-matched WT mice, subsequently preventing mPTP opening and ATP depletion under the Ca 2+ challenge. Mechanistically, overexpression of VCP in the heart results in post-translational protein degradation of the mitochondrial Ca 2+ uptake protein 1 (MICU1), an activator of the mitochondria Ca 2+ uniporter (MCU) which is responsible for mitochondrial calcium uptake. Together, our results reveal a new regulatory role of VCP in cardiac mitochondrial Ca 2+ homeostasis and unlocks the potential mechanism by which VCP confers its cardioprotection.
New artificial intelligence system: first validation study versus experienced endoscopists for colorectal polyp detection
Authors: Cesare Hassan, Michael B Wallace, Prateek Sharma, Roberta Maselli, Vincenzo Craviotto, Marco Spadaccini, Alessandro Repici
Journal: Gut (2019)

To improve colorectal polyp detection, a new artificial intelligence (AI) system (GI-Genius, Medtronic) was trained and validated on a dataset of white-light endoscopy videos from a high-quality randomised controlled trial in comparison to the detection rate and the reaction time (RT) on a lesion basis (n=337/338, sensitivity: 99.7%); false-positive frames were seen in less than 1% of frames from the whole colonoscopy. The RT was faster by AI system as compared with endoscopists in 82% of cases (n=277/337; difference 1.27+3.81 s). This promising system will be tested in clinical studies.

Despite its efficacy in colorectal cancer prevention, colonoscopy is affected by a high miss rate of neoplastic lesions and unacceptable variability in adenoma detection rate among individual endoscopists.1 2 By aiding polyp detection on colonoscopy images (figure 1), artificial intelligence (AI) can reduce performance variability. AI algorithms for object detection usually comprise a convolutional neural network trained using as ground truth images annotated by experts. Once trained, these AI systems are able to detect and pinpoint objects in real time, such as colorectal polyps. A new AI system (GI-Genius, Medtronic) was trained and validated using a series of videos of 2684 histologically confirmed polyps from 840 patients who underwent high-definition white-light colonoscopy as part of a previous randomised controlled study with centralised pathology.3 A total of 1.5 million images showing these polyps from different perspectives were extracted from videos and manually annotated by expert endoscopists. For the purpose of the study, patients were randomised between a validation group and a training group. In detail, for the validation phase, 338 polyps (168/338 adenomas or sessile serrated adenomas, 49.7%) from 105 patients were used. For each of these polyps, a video clip was cut starting 5 s before polyp appearance and ending when the snare/biopsy forceps appeared. To assess sensitivity, a true-positive per …
Low-Dose Clofarabine Has Significant Activity in High-Risk Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia Post-MDS (sAML) After Azacitidine (AZA) Failure: Interim Results of the GFM Clo08 Dose Escalating Phase I/II Study (NCT0106325)
Authors: Thorsten Braun, Emmanuel Raffoux, Thomas Prebet, Sabine Brechignac, Aspasia Stamatoullas, Francois Dreyfus, Zehaira Hebibi, Lionel Ades, Norbert Vey, Hervé Dombret, Pierre Fenaux, Claude Gardin
Journal: Blood (2011)
Abstract 164: Hypoxia-Induced Cardiomyocyte Mitophagy and Mitochondrial Permeability Transition are Inhibited by Bnip3 Phosphorylation
Authors: Matthew D Martens, Jared T Field, Wajihah Mughal, Christof Rampitsch, Tammy Ivanco, William Diehl-Jones, Joseph W Gordon
Journal: Circulation Research (2019)

Bnip3 is a hypoxia-inducible initiator of cardiomyocyte cell death and has also been implicated as a mitochondrial receptor for the cellular mitophagy machinery. Previous work from our group demonstrates that the prostaglandin E1 analogue, misoprostol, prevents hypoxia-induced mitochondrial dysfunction and is a potent activator of PKA. We hypothesize that misoprostol alters the phosphorylation status of Bnip3, inhibiting its ability to induce cardiomyocyte mitophagy, mitochondrial dysfunction and cell death. Using a rodent model of neonatal hypoxia, in combination with rat primary ventricular neonatal cardiomyocytes (PVNC’s) and H9c2 cells, we assessed the effect of hypoxia and misoprostol drug treatments on mitochondrial function, mitophagy, and cell viability. In postnatal day 5 rats, hypoxia caused a 30% increase in the concentration of serum cardiac troponin-I, a clinically relevant marker for cardiomyocyte cell death, which was absent with the addition of misoprostol drug treatments (n=3). Using PVNC’s we further demonstrated that hypoxia reduced measures of mitochondrial function including membrane potential (47%) and maximal respiration (46%), which were restored back to control levels with the addition of misoprostol (p&lt;0.01). Furthermore, hypoxia induced a 36% increase in mitophagy, concurrent with a 210% increase in mitochondrial permeability transition, both of which were reversed with misoprostol drug treatment (p&lt;0.01). Using a combination of mass spectrometry and mutagenesis, we also show that PKA directly phosphorylates the transmembrane domain of Bnip3 to inhibit its function. Mechanistically, when the PKA phosphorylation site on Bnip3 was neutralized, the protective effect of misoprostol on mitochondrial membrane potential, mitophagy and permeability transition was lost. Taken together, these results demonstrate a foundational role for Bnip3 phosphorylation in the molecular regulation of cardiomyocyte mitochondrial dysfunction. These findings further identify a pharmacological mechanism, through PKA, which may ultimately be able to prevent hypoxia-induced myocardial injury.
Improving the chemotherapy consent: From paper to tablet.
Authors: Aarti Sonia Bhardwaj, Jessica Parra, Kavita Rampertaap, Katherine FitzPatrick, Raina Caridi, Mark Liu, Victoria Casani, Donna Berizzi, Luis M. Isola, Cardinale B. Smith
Journal: Journal of Clinical Oncology (2019)

298 Background: A comprehensive chemotherapy informed consent process improves shared decision-making. Additionally, the Oncology Care Model (OCM) emphasizes providing patients with a documented care plan that contains the 13 components in the Institute of Medicine Care Management Plan. Within our health system, we incorporated the care plan into our existing chemotherapy consent process and utilized technology to increase compliance and reduce administrative burden. Methods: Our 2 phase PDSA included: 1) updating our existing paper chemotherapy form with the 13 components of the IOM care plan and then 2) piloting an electronic version of the chemotherapy consent form. We updated our new chemotherapy consent with the addition of Prognosis, Expected Response to Treatment, Potential Effect on Quality of Life, Potential Benefits/Goals of Treatment, and added more options for potential side effects/harm. Given the increased administrative burden, we created and piloted the use of an electronic version of the consent form in our breast oncology program. Results: Baseline, monthly random chart audit of 20-40 patients revealed compliance with completing every question of the paper chemotherapy consent at 30% of all patients receiving IV chemotherapy at our cancer center that month- 7/2018. When the new chemotherapy consent incorporating the IOM elements was rolled out, compliance initially rose to 50% (8/2018), however the following months dropped to 10-20% (9-11/2018) and then back up to 41% briefly (12/2018). The results were low and inconsistent. A pareto chart confirmed that redundancy and too many questions were the reasons for under-completion. By auto-populating fields for certain questions on the paper consent, compliance increased to 75% (2/2019). Finally within our breast cancer pilot group our compliance rose to 100% (3-4/2019), by converting to an electronic form with the maximum options for auto-population and drop-down selections for certain fields. Conclusions: Incorporating regulatory requirements into an existing workflow can reduce administrative burden. The use of innovative technology can further increase clinician and OCM compliance while delivering value to patients.
Cytogenetic Clonal Evolution in Myeloproliferative Neoplasms: Contexts and Prognostic Impact Among 650 Patients with Serial Bone Marrow Biopsies
Authors: Maura Nicolosi, Domenico Penna, Mythri Mudireddy, Natasha Szuber, Rangit Vallapureddy, Terra L. Lasho, Christy Finke, Curtis A. Hanson, Animesh Pardanani, Naseema Gangat, Rhett P. Ketterling, Ayalew Tefferi
Journal: Blood (2018)
Abstract 581: Hyperglycemia Acutely Increases Cytosolic Reactive Oxygen Species (ROS) via O-linked GlcNAcylation Activation of CaMKII in Mouse Ventricular Myocytes
Authors: Shan Lu, Zhandi Liao, Julie Bossuyt, Donald Bers
Journal: Circulation Research (2019)

Diabetes mellitus (DM) is a complex, multisystem disease, affecting large populations worldwide. Chronic CaMKII activation in autonomous states can occur in DM and contribute to arrhythmogenesis. Diabetic hyperglycemia has been shown to activate CaMKII by (1) O-linked attachment of N-acetylglucosamine (O-GlcNAc) at S280 leading to arrhythmia and (2) a ROS-CaMKII pathway, and these can increase post-infarction mortality. However, the mechanism by which high extracellular [glucose] (Hi-Glu) promotes ROS generation that may synergize with CaMKII activation remains unknown. Here we tested the mechanism by which extracellular Hi-Glu influences ROS production in adult ventricular myocytes, using H 2 DCFDA to measure ROS. Hi-Glu (30 mM) significantly increased the rate of ROS generation, which was prevented in myocytes pretreated with CaMKII inhibitor KN-93 or from both global CaMKIIδ-KO and cardiac specific CaMKIIδ-KO. CaMKII-KO or inhibition prevented Hi-Glu induced sarcoplasmic reticulum (SR) Ca 2+ release events (Ca 2+ sparks and waves). Thus, CaMKII activation is required for Hi-Glu induced ROS generation in cardiomyocytes. Next, we tested the involvement of O-GlcNAc-CaMKII pathway. Inhibition of de- GlcNAcylation by 100nM Thiamet G (Thm-G) mimicked the effect of Hi-Glu, enhancing the rate of ROS. Also, inhibition of GlcNAcylation (OSMI-1) blocked the ROS induction triggered by either Hi-Glu or Thm-G. Moreover, in new CRSPR-based knock-in mouse in which the functional GlcNAc site on CaMKIIδ was ablated (S280A) neither Hi-Glu nor Thm-G induced myocyte ROS generation. So CaMKIIδ-S280 is required for the Hi-Glu-induced (and GlcNAc-dependent) ROS production. To identify the ROS source(s), we used different inhibitors: NOX2 inhibitor (Gp91-ds-tat peptide), NOX4 inhibitors (GKT137831), Mito Tempo and NOS pathway inhibitors (L-NAME, L-NIO and L-NPA). Only NOX2 inhibition prevented Hi-Glu/Thm-G induced ROS generation. In summary, our data suggests that diabetic hyperglycemia acutely induces ROS production via an O-GlcNAc-CaMKII dependent pathway and the ROS induced by hyperglycemia is mainly from cytosolic NOX2 complex.
Abstract 512: Extracellular Matrix Components Isolated From Diabetic Mice Alters Cardiac Fibroblast Function Through the AGE/RAGE Signaling Cascade
Authors: Stephanie Burr, James A Stewart
Journal: Circulation Research (2019)

Roughly 30 million Americans suffer from diabetes and these individuals are at an increased risk of developing cardiovascular complications. A common complication is heart failure which occurs due to the stiffening of the left ventricle brought on by cardiac fibroblast “activation” that results in the remodeling the extracellular matrix (ECM). Fibroblast “activation” can be triggered by the AGE/RAGE signaling cascade. Advanced Glycated End products (AGEs) are produced and accumulate in the ECM overtime, but under hyperglycemic conditions this process is accelerated. We aim to investigate how the presence of AGEs in the either diabetic or non-diabetic ECM can affect fibroblast ECM remodeling as well as determine the role of AGE/RAGE signaling during this process. In order to assess this question diabetic and non-diabetic fibroblasts were embedded in 3D matrices composed of collagen isolated from either diabetic or non-diabetic mice. Non-diabetic fibroblasts displayed similar matrix contraction and α-SMA expression to diabetic fibroblasts when embedded in diabetic collagen. In addition, increasing the AGE/RAGE cascade leads to increase gel contraction indicating increase in fibroblast “activation”. These results indicate 1) the ECM from diabetic and non-diabetic mice differ from one another, 2) diabetic ECM can impact fibroblast function and shift them towards an “active” state, and 3) that fibroblasts can modify the ECM through activation of the AGE/RAGE signaling cascade. These results suggest the importance of understanding the impact diabetes has on the ECM and fibroblast function.
N-Myc Is Overexpressed In Both Murine and Human Early T-Cell Precursor Leukemia and Is Sufficient To Initiate this Leukemia In Multipotent Primitive Arf-/- thymocytes
Authors: Louise M. Treanor, Sheng Zhou, Yu Fukuda, Nandakumar Satish, David Finkelstein, John D. Schuetz, Charles G. Mullighan, Brian P. Sorrentino
Journal: Blood (2013)
Abstract 750: Gene Signatures to Distinguish Amyloid Cardiomyopathy Risk in Multiple Myeloma Patients
Authors: Alokkumar Jha, Isabel Morgado, Dian J Lee, Kevin Alexander, Cheng-Yu Tsai, Katharina Schimmel, Jennifer Ward, R Witteles, Michaela Liedtke, Ronglih Liao, Seema Dangwal
Journal: Circulation Research (2019)

Amyloid light chain (AL) amyloidosis results from tissue deposition of clonal light chains, most commonly produced by clonal plasma cells. AL amyloidosis is closely associated with multiple myeloma (MM), another disease which arises from clonal plasma cell proliferation. Here we aim to identify gene signatures to distinguish AL cardiomyopathy (AL-CM) risk in MM patients. We utilized publicly available data sets and applied Graph Cluster Perturbation approach to cluster the co-expression networks based on pathways in MM and AL-CM utilizing 225 samples from four datasets: GSE42955 study (12 dilated CM, 12 ischemic CM and 5 control LV human heart tissues), GSE95077 study (16 amiloride drug treated/untreated myeloma cell line samples), GSE24128 study (16 newly diagnosed AL with monoclonal plasma cell samples over- or under-expressing cyclin D1), and GSE6477 study (76 primary bone marrow samples from hyper-diploid myeloma patients and 80 non-hyperdiploid MM patients). From these data sets, the networks for extracellular matrix organization, immune system, innate immune system, metabolism, and neutrophil degranulation pathways for MM and amyloid CM were extracted. Summary: Ranking of the perturbed genes based on pathways similarity index in MM and AL resulted in a panel of genes: CD44, NRAS, GRAP2, CTLA4, GSN, CCND1, NFKB1, and IRF1 (p= &lt;0.01). As shown in Figure , the high hazard ratio of this gene cluster in MM with AL-CM (3.76; p=0.021) compared to MM without CM (0.96; p=0.032) suggests the potential of this gene panel to distinguish high or low risk groups in MM based on survival.
Nitric Oxide Scavenging, Abnormal Vasoregulation and Oxidative Damage in sph/sph Mice with Severe Hereditary Spherocytosis: Possible Consequences of Red Blood Cell Hemolysis.
Authors: Anne C. Schraufnagel, Barb Piknova, Kirkwood A. Pritchard, Neil Hogg, Nancy J. Wandersee
Journal: Blood (2005)