tbuckley/cabot-search huggingface dataset:
Mll-Partial Tandem Duplication (Mll-PTD) Causes Pseudohypoxia and Hypermethylation of the Epigenome through Suppression of Mitochondrial Complex II
Authors: Asumi Yokota, Lulu Zhang, Xiaomei Yan, Xiaomin Feng, Lijun Wen, George Freudiger, Maria Rife, Ally Woeste, Yoshihiro Hayashi, Gang Huang
Journal: Blood (2018)
Quantitative Proteomics Identify Urinary Hgfl Protein As a Potential Marker for the Development of Chronic Kidney Disease in Sickle Cell Disease Patients
Authors: Xionghao Lin, Santosh L. Saraf, Simran Soni, Nowah Kokou Apeadoufia Afangbedji, Victor R. Gordeuk, Marina Jerebtsova, Sergei Nekhai
Journal: Blood (2017)
DHEA Can Inhibit the Proliferation of Myeloma Cells and the IL-6 Production of Bone Marrow Mononuclear Cells from the Myeloma Patients.
Authors: Ken-ichiro Otsuyama, Zi Ma, Shangqin Liu, Fu-Jun Li, Saeid Abroun, Xu Zheng, Yasuko Maki, Naohiro Tsuyama, Masanori Obata, Hideaki Ishikawa, Michio M. Kawano
Journal: Blood (2004)
A Somatostatin Receptor Subtype-3 (SST3) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors
Authors: Mari C. Vázquez-Borrego, Vandana Gupta, Alejandro Ibáñez-Costa, Manuel D. Gahete, Eva Venegas-Moreno, Álvaro Toledano-Delgado, David A. Cano, Cristóbal Blanco-Acevedo, Rosa Ortega-Salas, Miguel A. Japón, Ana Barrera-Martín, Alexandre Vasiljevic, Jason Hill, Shengwen Zhang, Heather Halem, Juan Solivera, Gérald Raverot, María A. Gálvez, Alfonso Soto-Moreno, Marcelo Paez-Pereda, Michael D. Culler, Justo P. Castaño, Raúl M. Luque
Journal: Clinical Cancer Research (2019)

Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST2 and SST5. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST2. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST3-agonists and characterize their effects on experimental NFPT models.Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST3-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST3-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST3-agonist.We successfully identified the first SST3-agonist peptides. SST3-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST3-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST3-agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs.This study demonstrates that SST3-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST3, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.
APRIL and BAFF: novel biomarkers for central nervous system lymphoma
Authors: Matthias Mulazzani, Marion Huber, Sabine Borchard, Sigrid Langer, Barbara Angele, Elisabeth Schuh, Edgar Meinl, Martin Dreyling, Tobias Birnbaum, Andreas Straube, Uwe Koedel, Louisa von Baumgarten
Journal: Journal of Hematology & Oncology (2019)

Abstract Background Early diagnosis of CNS lymphoma (CNSL) is essential for successful therapy of this rapidly progressing brain tumor. However, in patients presenting with focal brain lesions, fast and reliable diagnosis of PCNSL remains a challenge. A proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF) are important factors in the pathophysiology, diagnosis, and prognosis of systemic B cell malignancies. However, their utility as biomarkers for the diagnosis of CNSL and their effects on CNSL cells remain unclear. Methods In this prospective study, we analyzed the levels of APRIL and BAFF in the cerebrospinal fluid (CSF) of 116 patients with suspected focal brain lesions, including 53 CNSL patients. Additionally, we serially measured their levels during chemotherapy and relapse. Furthermore, we analyzed the effect of APRIL and BAFF on two B cell lymphoma cell lines using proliferation, viability, and chemotaxis assays. Results CSF levels of APRIL and BAFF reliably differentiated CNSL from other focal brain lesions (including primary and metastatic brain tumors, autoimmune-inflammatory lesions, and neuroinfectious lesions) with a specificity of 93.7% (APRIL, BAFF) and a sensitivity of 62.3% (APRIL) and 47.1% (BAFF). Serial CSF analysis of CNSL patients during chemotherapy and relapse demonstrates a close correlation of APRIL CSF levels and the course of this disease. In vitro, APRIL and BAFF showed anti-apoptotic effects during MTX treatment and mediated chemotaxis of malignant B cells. Conclusion This study extends the spectrum of valuable diagnostic biomarkers in CNSL. In patients with focal brain lesions, measurement of APRIL in CSF could help accelerating the diagnosis of CNSL. Moreover, our results highlight an important role of APRIL and BAFF in the pathophysiology of CNSL.
Molecular Monitoring of NPM1 Is a Useful Tool for Detecting Early-Stage Relapse and to Guide Pre-Emptive Treatment Approaches in Patients with NPM1-Mutated Acute Myeloid Leukemia
Authors: Francesca Schieppati, Angela Passi, Erika Borlenghi, Cinzia Lamorgese, Giuseppina Ruggeri, Marco Chiarini, Viviana Giustini, Michele Malagola, Chiara Cattaneo, Margherita Sciumé, Giuseppe Rossi
Journal: Blood (2017)
Effect of digital tumor board solutions on “failure-to-discuss” rates for patient cases during tumor boards.
Authors: Donna Fowler, Lincoln R Sheets, Matthew S Prime, Chaohui Guo, Athanasios Siadimas, Yariv Z Levy, Richard D Hammer
Journal: Journal of Clinical Oncology (2019)

308 Background: A multidisciplinary tumor board (MTB) provides an interdisciplinary approach for decision-making in cancer care. Efficient conduction of MTBs is importantfor optimal patient management. It is, however, often observed that prepared patient cases are not discussed during tumor boards due to limited time or incomplete information, which could cause delaytocaredecisions and/or the initiation of treatments. It remains unknown whether digital technologies canreduce the rate of failure to discuss during MTBs. Methods: A prospective cohort study was undertaken to evaluate the preparation &amp; conduction of MTBs pre- &amp; post-implementation of the NAVIFY Tumor Board (NTB) solution at Missouri University Health Care (MU), including the Ear, Nose &amp; Throat (ENT) MTB. The NTB is a cloud-based workflow product, integrated with the hospital EMR, that aggregates and displays relevant clinical information. NTB was introduced to theMUENT MTB on Oct 10, 2018. Results: Pre-NTB implementation, data was collected from 42 ENT MTBs. A total of 551 patient cases were prepared for MTBs, but only 423 patient cases were discussed. This was an average “failure-to-discuss” rate of 19.4% per meeting (SD = 15.6%). After NTB implementation, data was collected from 7 MTBs where a total of 70 patient cases were prepared and discussed. There were no instances of failure to discuss, and as such, was significantlyreduced after the implementation of NTB (Mann-Whitney U test, p = 0.0004). The average number of patient cases discussed per meeting pre- and post-NTB implementation did not change (Mann-Whitney U test, p &gt; 0.1) and meeting duration was the same. Conclusions: Introduction of the NTB did not change the weekly number of cases discussed, but did significantly reduce the failure to discuss rates for ENT MTB cases. Reducing failure to discuss rates could decrease the overall time to clinical decision and the initiation of treatment, which could potentially improve patient outcomes. Additional studies are needed to examine the impact of digital solutions on the quality of clinical care.
Bone Marrow-Derived Cells Restore Functional Integrity of the Gut Epithelial and Vascular Barriers in a Model of Diabetes and ACE2 Deficiency
Authors: Yaqian Duan, Ram Prasad, Dongni Feng, Eleni Beli, Sergio Li Calzi, Ana Leda F. Longhini, Regina Lamendella, Jason L. Floyd, Mariana Dupont, Sunil K. Noothi, Gopalkrishna Sreejit, Baskaran Athmanathan, Justin Wright, Amanda R. Jensen, Gavin Y. Oudit, Troy A. Markel, Prabhakara R. Nagareddy, Alexander G. Obukhov, Maria B. Grant
Journal: Circulation Research (2019)

There is incomplete knowledge of the impact of bone marrow cells on the gut microbiome and gut barrier function.We postulated that diabetes mellitus and systemic ACE2 (angiotensin-converting enzyme 2) deficiency would synergize to adversely impact both the microbiome and gut barrier function.Bacterial 16S rRNA sequencing and metatranscriptomic analysis were performed on fecal samples from wild-type, ACE2-/y, Akita (type 1 diabetes mellitus), and ACE2-/y-Akita mice. Gut barrier integrity was assessed by immunofluorescence, and bone marrow cell extravasation into the small intestine was evaluated by flow cytometry. In the ACE2-/y-Akita or Akita mice, the disrupted barrier was associated with reduced levels of myeloid angiogenic cells, but no increase in inflammatory monocytes was observed within the gut parenchyma. Genomic and metatranscriptomic analysis of the microbiome of ACE2-/y-Akita mice demonstrated a marked increase in peptidoglycan-producing bacteria. When compared with control cohorts treated with saline, intraperitoneal administration of myeloid angiogenic cells significantly decreased the microbiome gene expression associated with peptidoglycan biosynthesis and restored epithelial and endothelial gut barrier integrity. Also indicative of diabetic gut barrier dysfunction, increased levels of peptidoglycan and FABP-2 (intestinal fatty acid-binding protein 2) were observed in plasma of human subjects with type 1 diabetes mellitus (n=21) and type 2 diabetes mellitus (n=23) compared with nondiabetic controls (n=23). Using human retinal endothelial cells, we determined that peptidoglycan activates a noncanonical TLR-2 (Toll-like receptor 2) associated MyD88 (myeloid differentiation primary response protein 88)-ARNO (ADP-ribosylation factor nucleotide-binding site opener)-ARF6 (ADP-ribosylation factor 6) signaling cascade, resulting in destabilization of p120-catenin and internalization of VE-cadherin as a mechanism of deleterious impact of peptidoglycan on the endothelium.We demonstrate for the first time that the defect in gut barrier function and dysbiosis in ACE2-/y-Akita mice can be favorably impacted by exogenous administration of myeloid angiogenic cells.
TLR9 acts as a sensor for tumor-released DNA to modulate anti-tumor immunity after chemotherapy
Authors: Tae Heung Kang, Chih-Ping Mao, Young Seob Kim, Tae Woo Kim, Andrew Yang, Brandon Lam, Ssu-Hsueh Tseng, Emily Farmer, Yeong-Min Park, Chien-Fu Hung
Journal: Journal for ImmunoTherapy of Cancer (2019)

The tumor microenvironment exists in a state of dynamic equilibrium, in which a balance of agonist and antagonist signals govern the anti-tumor immune responses. Previous studies have shown that chemotherapy could shift this balance in favor of agonistic signals for the anti-tumor immune responses mounted by CD8+ cytotoxic T lymphocytes (CTL), providing sufficiently high antigen density within the tumor. We undertook the current study to characterize the anti-tumor immune response following chemotherapy and its underlying mechanisms. We show that this 'adjuvant effect' of chemotherapy is, at least partially, mediated by the release of tumor DNA and acts through the Toll-like receptor 9 (TLR9) pathway. We found that tumor-released DNA causes accumulation, antigen uptake, and maturation of dendritic cells (DCs) in the tumor in a TLR9-dependent manner. These DCs subsequently migrate into the draining lymph nodes and prime tumor-specific CTLs. Our study provides novel insights to the molecular and cellular mechanisms by which chemotherapy converts the tumor microenvironment into a site permissive for the activation of a potent tumor-specific adaptive immune response.
Autologous Hematopoietic Stem Cell Transplantation In Neuromyelitis Optica: A Retrospective Study Of The EBMT Autoimmune Diseases Working Party In Collaboration With The University Of Sao Paulo, Ribeirao Preto, Brazil
Authors: Raffaella Greco, Attilio Bondanza, Manuela Badoglio, Myriam Labopin, Maria Carolina Oliveira, Gian Luigi Mancardi, Simona Minguzzi, Joachim Burman, Fredrik Piehl, Hans Hagglund, Eva Krasulova, Giancarlo Comi, Fabio Ciceri, Dominique Farge
Journal: Blood (2013)
Unrelated Cord Blood Transplantation (UCBT) In Adults In The UK: Evolution, Experience and Outcomes. A Retrospective Analysis On Behalf Of The British Society of Blood and Marrow Transplantation (BSBMT) and Eurocord
Authors: John A Snowden, Robert Danby, Annalisa Ruggeri, David I Marks, Rachael E Hough, Antonio Pagliuca, Michael Potter, Nigel Russell, Charles Craddock, Andrew Clark, Eliane Gluckman, Gordon Cook, Bronwen E. Shaw, Vanderson Rocha
Journal: Blood (2013)
Untangling a web of Electronic Patient Reported Outcomes data to support quality improvement.
Authors: Meggan Davis, Erik Winters, Lisa Acomb, Matt Palmgren, Kerry K McMillen, Tracy Wong
Journal: Journal of Clinical Oncology (2019)

311 Background: Adoption of Electronic Patient Reported Outcomes (ePROs) as part of clinical care is aided by the ability to respond to feedback and develop solutions founded on data. This requires access to usage, volume, response, and system performance data, yet with limited resources the infrastructure needed to store and analyze these data is often an afterthought. The Seattle Caner Care Alliance followed an iterative process to create dashboards featuring content-specific metrics while improving the underlying infrastructure of patient-generated data collected via the ePRO program. Methods: For each dashboard, the project team followed 7 steps: 1) Clarify the purpose. 2) Brainstorm requirements with content-specific stakeholders. 3) Create initial drafts for review, testing, and validation. 4) Validate that metrics are clear and provide value. 5) Update dashboards and review with stakeholders. 6) Perform technical clean-up and improvement to data infrastructure. 7) Iterate until all stakeholders approve. Results: 27 data tables were linked to create four content-specific dashboards: Overall Key Performance Indicators (KPI), an experimental dashboard, and responses to chemotherapy symptom and distress screening surveys. The KPI dashboard featured completion rate, adoption rate, survey and intervention volumes with the ability to filter by ePRO type, diagnosis, and intervention. The experimental dashboard allowed the project team to test data points, visualizations and methodologies before creating dashboards or updating data structures. Chemotherapy symptom and distress screening dashboards displayed interventions by symptom or concern, severity, referrals, and response distribution. Conclusions: Data collected via an ePRO program offers an opportunity for improvement during implementation and ongoing program development. An iterative approach to analyzing these data and creating dashboards that engaged stakeholders and focused on data quality was an effective way to untangle a complex web of patient-generated data and to support program improvement. Future ePRO implementation would benefit from the inclusion of a flexible data development approach as part of planning and design.
Incidence Clinical Characteristics and Survival of Non Splenic Marginal Zone Lymphomas: A Population Based Study from a Cancer Registry in Northern Italy
Authors: Stefano Luminari, Ivan Rashid, Marina Cesaretti, Luigi Marcheselli, Alessandra Dondi, Stefano Madrigali, Gianluca Cervo, Monica Bellei, Antonella Montanini, Caterina Mammi, Maria Angela Sirotti, Massimo Federico
Journal: Blood (2008)
The Status of Multiple Myeloma in Colombia: First Report of the Colombian Registry for Hemato-Oncological Diseases (RENEHOC). Asociacion Colombiana De Hematologia y Oncologia (ACHO)
Authors: Virginia Abello, Henry Idrobo, Claudia Lucia Sossa, Kenny Mauricio Galvez, Domingo Saavedra, Maria Helena Solano, Rigoberto Gomez, Lina Gaviria, Jheremy Reyes, Monica Osuna, Luis Antonio Salazar, Angela María Peña, Claudia Patricia Casas, Daniel Espinosa, Paula A Lengerke Diaz, Januario E. Castro
Journal: Blood (2018)
Abstract 785: Modeling Congenital Heart Disease-Associated Variants in <i>GATA6</i> Using CRISPR/Cas9 and Human Induced Pluripotent Stem Cells
Authors: Arun Sharma, Lauren Wasson, Jon Willcox, Sarah U Morton, Joshua M Gorham, Daniel M DeLaughter, Meraj Neyazi, Manuel Schmid, Radhika Agarwal, Megan Jang, Christopher N Toepfer, Tarsha Ward, Yuri Kim, Alexandre C Pereira, Steven R DePalma, Angela Tai, Seongwon Kim, David Conner, Benoit Bruneau, Jon G Seidman, Christine E Seidman
Journal: Circulation Research (2019)

The discovery of damaging gene mutations in congenital heart disease (CHD) patients enables identification of regulators of cardiac development. Exome sequencing identified de novo heterozygous loss-of-function (LoF) and missense variants in GATA6 among CHD probands, most with outflow tract malformations. Other subjects with GATA6 LoF mutations developed pancreatic agenesis. To elucidate the molecular basis for the predominance of this heart defect, we modeled GATA6 mutations in cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs). GATA6 variants were introduced into isogenic hiPSCs using CRISPR/Cas9 genome editing. Genome-wide molecular profiles including chromatin accessibility (ATAC-Seq) and gene expression (single cell and bulk RNA-Seq) were evaluated during hiPSC-CM differentiation. Analyses of GATA6 mutant hiPSC-CMs showed deficits in hiPSC-CM differentiation, chromatin accessibility and transcriptional profiles. Heterozygous GATA6 LoF hiPSCs made hiPSC-CMs but exhibited reduced expression of second heart field genes. Homozygous GATA6 LoF hiPSCs failed to differentiate and adopted fibroblast expression profiles. hiPSCs carrying a homozygous GATA6 missense variant, R456G, which altered a DNA-binding domain residue, showed enhanced capacity to differentiate into neuroepithelial-like cells. Chromatin-accessibility studies confirmed that GATA6 normally binds to genes in the promoter region and other genes at distal enhancers. Human GATA6 haploinsufficiency disrupts developmental transcriptional responses driving cardiac morphogenesis. The HAND2 -dependent genetic program, operant during outflow tract development, is particularly sensitive to GATA6 dosage. The mixed differentiation patterns observed in mutation-carrying hiPSCs likely contributes to vascular phenotypes observed in CHD patients. GATA6 haploinsufficiency preferentially alters binding of distal enhancers to promoters in genes where GATA6 normally binds the enhancer rather than the promoter. We speculate that pathogenicity of GATA6 haploinsufficiency is mediated by weaker binding of GATA6 to distal enhancers than to promoter elements, altering expression of these genes in GATA6 haploinsufficient patients.
Stability of symptom clusters in patients with gastrointestinal cancers receiving chemotherapy.
Authors: Claire J. Han, Kerryn Reding, Bruce A. Cooper, Steven M. Paul, Yvette Conley, Marilyn J. Hammer, Fay Wright, Frances Cartwright, Jon Levine, Christine Miaskowski
Journal: Journal of Clinical Oncology (2019)

193 Background: Patients with gastrointestinal (GI) cancers who undergo chemotherapy (CTX) experience on average of thirteen symptoms. These co-occurring symptoms often cluster together and can influence various patient outcomes including quality of life (QOL). However, little evidence is available on how these symptoms change during a cycle of chemotherapy (CTX). An evaluation of how these symptom cluster together and how these symptom clusters change over time may provide useful information to guide symptom management strategies tailored to multiple symptoms. Objectives: The purpose of this study was to identify and compare symptom clusters using three symptom dimensions (i.e., occurrence, severity, and distress) at different time points during CTX (i.e., prior to CTX [T1], one week after CTX administration [T2], and two weeks after CTX administration [T3]) in patients with GI cancers. Methods: A modified version of the Memorial Symptom Assessment Scale was used to assess the occurrence, severity, and distress of 38 symptoms. Exploratory factor analyses were used to create the symptom clusters. Results: Five distinct symptom clusters were identified across the three symptom dimensions and the three assessments (i.e., psychological, CTX-related, weight change, GI, and epithelial). Psychological, CTX-related and weight change clusters were relatively stable for all three symptom dimensions as well as across time. GI cluster was identified only at T1, while epithelial cluster was identified at T2 and T3 for all three symptom dimensions. Conclusions: The number and types of symptom clusters appear to be relatively stable over time and across the symptom dimensions. Timely management of symptom clusters should be continued over the course of CTX including the recovery phases. Further studies are needed to explore the mechanisms of symptom clusters in patients with GI cancers undergoing CTX.
Abstract 849: Drp1-dependent Altered Mitochondrial Dynamics Contribute to Protein Aggregation and Mitochondrial Dysfunction in R120G αB-crystallin-induced Proteotoxicity
Authors: Shafiul Alam, Chowdhury S Abdullah, Richa Aishwarya, Mahboob Morshed, Sumitra Miriyala, Manikandan Panchatcharam, Md. S Bhuiyan
Journal: Circulation Research (2019)

Introduction: αB-crystallin (CryAB) is a chaperone protein that plays a pivotal role in the maintenance of the structural and mechanical integrity of the sarcomere. Mutation in αB-crystallin (CryAB R120G) causes sarcomere disorganization leading to protein aggregation. Accumulation of toxic protein aggregates causes cardiac contractile dysfunction and perturbed mitochondrial spatial organization. However, the role of mitochondria in the pathogenesis of protein aggregation-induced cardiomyopathies remain obscure. Objective: In this study, we investigated the role of mitochondrial dynamics and function in the development of R120G αB-crystallin induced cardiac proteotoxicity. Methods and Results: CryAB R120G Tg hearts showed accumulation of toxic protein aggregates resulting in disruption of the sarcomere structure, development of cardiomyocyte hypertrophy, and contractile dysfunction. Hearts obtained from CryAB R120G Tg mice showed increased expression and localization of Drp1 on the mitochondrial membrane. Alteration in the expression of mitochondrial dynamics regulatory proteins was observed at two months age when these mice exhibited normal cardiac morphometry and systolic function. Adenoviral-mediated expression of CryAB R120G in cardiomyocytes also showed increased mitochondrial fission, expression dependent inhibition of mitochondrial respiration and activation of cellular toxicity. Inhibition mitochondrial fission by Drp1 partial knockdown in CryABR120G expressing cardiomyocytes significantly decreased protein aggregation and improved mitochondrial respiration. Conclusion: Drp1-dependent excessive mitochondrial fission results in defects in mitochondrial respiration and accumulation of protein aggregates in CryABR120G expressing cardiomyocytes. Therefore, our study shows that maladaptive aberrant mitochondrial fission causes CryABR120G -induced mitochondrial dysfunction and cardiac proteotoxicity-associated cellular dysfunction.