tbuckley/cabot-search huggingface dataset:
Circular RNA FOXP1 promotes tumor progression and Warburg effect in gallbladder cancer by regulating PKLR expression
Authors: Shouhua Wang, Yongjie Zhang, Qiang Cai, Mingzhe Ma, Long Yang Jin, Mingzhe Weng, Di Zhou, Zhaohui Tang, Jian Dong Wang, Zhiwei Quan
Journal: Molecular Cancer (2019)

Abstract Background Circular RNAs (circRNAs) have recently been identified as potential functional modulators of the cellular physiology processes. The study aims to uncover the potential clinical value and driving molecular mechanisms of circRNAs in gallbladder cancer (GBC). Patients and methods We performed RNA sequencing from four GBC and paired adjacent normal tissues to analyze the circRNA candidates. Quantitative real-time polymerase chain reaction (QRT-PCR) was used to measure the circFOXP1 expression from 40 patient tissue samples. Short hairpin RNA mediated knockdown or exogenous expression of circFOXP1 combined with in vitro and in vivo assays were performed to prove the functional significance of circFOXP1. Double luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays were also performed. Results By performing RNA sequencing from GBC and paired adjacent normal tissues to analyze the circRNA candidates, we identified that circFOXP1 (hsa_circ_0008234) expression was significantly upregulated in GBC tissues and positively associated with lymph node metastasis, advanced TNM stage and poor prognosis in patients. Short hairpin RNA mediated knockdown or exogenous expression of circFOXP1 combined with in vitro assays demonstrated that circFOXP1 has pleiotropic effects, including promotion of cell proliferation, migration, invasion, and inhibition of cell apoptosis in GBC. In vivo, circFOXP1 promoted tumor growth. Mechanistically, double luciferase reporter, RNA immunoprecipitation (RIP) and biotin-labeled RNA pull-down assays clarified that circFOXP1 interacted with PTBP1 that could bind to the 3’UTR region and coding region (CDS) of enzyme pyruvate kinase, liver and RBC (PKLR) mRNA (UCUU binding bites) to protect PKLR mRNA from decay. Additionally, circFOXP1 acted as the sponge of miR-370 to regulate PKLR, resulting in promoting Warburg effect in GBC progression. Conclusions These results demonstrated that circFOXP1 serve as a prognostic biomarker and critical regulator in GBC progression and Warburg effect, suggesting a potential target for GBC treatment.
Very Low Dose of Anti-T-Lymphocyte Globulin Protects Against Severe Forms of Graft Versus Host Disease in High Risk Patients: The Experience in Our Center
Authors: Joan Manuel Mora, Arancha Bermúdez, Miguel Angel Cortés, Yolanda González Romero, Mercedes Colorado, Cristina Fernández Martínez, Almudena Cabero Martínez, David Gómez, Sara Fernández Luis, Sara García Ávila, Lucrecia Yáñez, Irati Ormazabal, Guillermo Martín Sánchez, Jose Luis Arroyo, Javier Núñez, Iñigo Romón, Eulogio Conde, Carlos Richard
Journal: Blood (2018)
Association between Charlson-Deyo Score and delay to colonoscopy in veterans subsequently diagnosed with colorectal cancer.
Authors: Thi Khuc, Christian Jackson
Journal: Journal of Clinical Oncology (2019)

288 Background: Colorectal cancer (CRC) is the second most common cause of cancer deaths in the United States and expected to cause 51,020 deaths in 2019. Early detection with yearly fecal occult blood test (FOBT) has been proven to decrease CRC mortality. A 30-day delay from positive FOBT to colonoscopy is associated with increased risk of CRC. The Veterans Affairs Health System (VAHS) treats approximately 11% of CRCs in the United States. The effects of an aging population, physician shortage, and increased military personnel entering the VAHS may increase demands on VAHS resources. The primary aim of this study was to determine risk factors that caused delay to colonoscopy. Methods: We retrospectively reviewed records of 600 patients referred for colonoscopy from January 1999 to January 2009, who were subsequently diagnosed with CRC. Patients with a prior CRC diagnosis were excluded. The final study cohort consisted of 530 patients. We analyzed the relationship between 10 variables and delay in time from initial consultation to colonoscopy. Variables consisted of age, sex, race, ethnicity, CRC location, marital status, history of mental health diagnosis, tobacco use, substance abuse, Charlson/Deyo (C/D) score and season of referral for colonoscopy. A delay in time was defined as 30 days or greater. Logistic regression analysis adjusted for age, race, CRC location and C/D score. Results: A total of 87.17% of patients experienced a delay in time from initial consultation to colonoscopy. When analyzed with a predictive variable of delay to colonoscopy, C/D score of ≥ 2 versus 0, was associated with higher odds of delay in time to colonoscopy (OR = 2.18, p = 0.02). African American race and Hispanic ethnicity was associated with a higher odds of delay in time to colonoscopy, but was not statistically significant (OR = 1.47, p = 0.47, OR = 1.37, p = 0.48). Conclusions: Patients with a C/D score ≥ 2 were 218% more likely to have delay in time from initial consult to colonoscopy, resulting in a delayed CRC diagnosis. C/D score may be used to determine which patients should have more frequent reminders to schedule their colonoscopy to prevent delays in care. Randomized and prospective studies will need to be performed.
Description of a knock-in mouse model of JAK2V617F MPN emerging from a minority of mutated hematopoietic stem cells
Authors: Olivier Mansier, Badr Kilani, Amélie V. Guitart, Alexandre Guy, Virginie Gourdou-Latyszenok, Caroline Marty, Marie Parrens, Isabelle Plo, William Vainchenker, Chloé James
Journal: Blood (2019)
Diet as a Source of Exposure to Environmental Contaminants for Pregnant Women and Children from Six European Countries
Authors: Eleni Papadopoulou, Line Småstuen Haug, Amrit Kaur Sakhi, Sandra Andrusaityte, Xavier Basagaña, Anne Lise Brantsaeter, Maribel Casas, Sílvia Fernández-Barrés, Regina Grazuleviciene, Helle Katrine Knutsen, Lea Maitre, Helle Margrete Meltzer, Rosemary R. C. McEachan, Theano Roumeliotaki, Remy Slama, Marina Vafeiadi, John Wright, Martine Vrijheid, Cathrine Thomsen, Leda Chatzi
Journal: Environmental Health Perspectives (2019)

Pregnant women and children are especially vulnerable to exposures to food contaminants, and a balanced diet during these periods is critical for optimal nutritional status.Our objective was to study the association between diet and measured blood and urinary levels of environmental contaminants in mother-child pairs from six European birth cohorts (n=818 mothers and 1,288 children).We assessed the consumption of seven food groups and the blood levels of organochlorine pesticides, polybrominated diphenyl ethers, polychlorinated biphenyls (PCBs), per- and polyfluoroalkyl substances (PFAS), and heavy metals and urinary levels of phthalate metabolites, phenolic compounds, and organophosphate pesticide (OP) metabolites. Organic food consumption during childhood was also studied. We applied multivariable linear regressions and targeted maximum likelihood based estimation (TMLE).Maternal high (≥4 times/week) versus low (<2 times/week) fish consumption was associated with 15% higher PCBs [geometric mean (GM) ratio=1.15; 95% confidence interval (CI): 1.02, 1.29], 42% higher perfluoroundecanoate (PFUnDA) (GM ratio=1.42; 95% CI: 1.20, 1.68), 89% higher mercury (Hg) (GM ratio=1.89; 95% CI: 1.47, 2.41) and a 487% increase in arsenic (As) (GM ratio=4.87; 95% CI: 2.57, 9.23) levels. In children, high (≥3 times/week) versus low (<1.5 times/week) fish consumption was associated with 23% higher perfluorononanoate (PFNA) (GM ratio=1.23; 95% CI: 1.08, 1.40), 36% higher PFUnDA (GM ratio=1.36; 95% CI: 1.12, 1.64), 37% higher perfluorooctane sulfonate (PFOS) (GM ratio=1.37; 95% CI: 1.22, 1.54), and >200% higher Hg and As [GM ratio=3.87 (95% CI: 1.91, 4.31) and GM ratio=2.68 (95% CI: 2.23, 3.21)] concentrations. Using TMLE analysis, we estimated that fish consumption within the recommended 2-3 times/week resulted in lower PFAS, Hg, and As compared with higher consumption. Fruit consumption was positively associated with OP metabolites. Organic food consumption was negatively associated with OP metabolites.Fish consumption is related to higher PFAS, Hg, and As exposures. In addition, fruit consumption is a source of exposure to OPs. https://doi.org/10.1289/EHP5324.
Cyclin D1 Maintains Mantle Cell Lymphoma Through CDK4-Independent Regulation Of DNA Replicative Checkpoints
Authors: Suchismita Mohanty, Atish Mohanty, Natalie Sandoval, Victoria Bedell, Joyce Murata-Collins, Jun Wu, Anna Scuto, Dennis D. Weisenburger, Vu N Ngo
Journal: Blood (2013)
Abstract 858: NAD(H) Redox Imbalance in the Heart Accelerates Diabetic Cardiomyopathy
Authors: Ying Ann Chiao, Christine Light, Rong Tian, Junichi Sadoshima, Chi Fung Lee
Journal: Circulation Research (2019)

Diabetes is linked to NAD(H) redox imbalance and lowered NAD + levels, but the roles of NAD + metabolism in diabetic cardiomyopathy are not established. We induced diabetes in C57BL6 wild type mice (WT) by streptozotocin (STZ) injections to cause depletion in serum insulin levels and elevation in fasting glucose levels. Hyperglycemic, male WT mice showed gradual declines in systolic and diastolic functions (FS, 50% vs 30%; E’/A’ ratio, 1.5 vs 1.0; 16-week after STZ), without causing cardiac hypertrophy. Dysfunctions in diabetic hearts were associated with lowered NAD + /NADH ratio and protein hyperacetylation, suggesting the roles of NAD(H) redox imbalance in diabetic cardiomyopathy. To test if NAD(H) redox imbalance promotes dysfunctions of diabetic hearts, we employed cardiac-specific Ndufs4-KO mice (cKO), which exhibit lowered NAD + /NADH ratio without overt cardiac dysfunction at baseline. Changes in cardiac functions at 2-, 4-, and 8-week after STZ injections, insulin and fasting glucose levels of control and cKO male mice were measured. Similar insulin depletion and hyperglycemia (~450 mg/dL) were observed in diabetic control and cKO mice. Systolic and diastolic dysfunctions were worsened in diabetic cKO mice (control vs cKO: FS 37% vs 22%; E’/A’ 1.25 vs 0.95, 8-week after STZ). Cardiac fibrosis levels were slightly elevated in diabetic control and cKO hearts, but were not different between the two groups (~4% in both group of mice). The results suggested that the accelerated declines in cardiac functions contributed by NAD(H) redox imbalance are not due to the altered extracellular matrix environment. To restore the NAD(H) redox balance in diabetic hearts, we elevated NAD + levels in male control and cKO mice with cardiac-specific NAMPT overexpression. Elevations in cardiac NAD + levels alleviated systolic and diastolic dysfunctions in diabetic control and cKO mice, despite similar levels of hyperglycemia among groups. Similar exacerbation of cardiac dysfunction was observed in female diabetic cKO mice, while NAMPT overexpression similarly improved cardiac function in female diabetic control and cKO mice. Our findings showed that NAD(H) redox imbalance promotes the progression of diabetic cardiomyopathy, via a fibrosis-independent mechanism.
Preclinical Studies for Sickle Cell Disease Gene Therapy Using Bone Marrow CD34+ Cells Modified with a βAS3-Globin Lentiviral Vector
Authors: Fabrizia Urbinati, Zulema Romero Garcia, Sabine Geiger, Rafael Ruiz de Assin, Gabriela Kuftinec, Roger P. Hollis, Satiro N. De Oliveira, Jennifer Wherley, Aaron Cooper, Tim M. Townes, Gay M. Crooks, Elizabeth J Read, Mark C. Walters, Herbert J. Meiselman, Thomas D. Coates, Victor J. Marder, Donald B. Kohn
Journal: Blood (2011)
Study Of Activity Of E6201, a Dual FLT3 and MEK Inhibitor, In Acute Myelogenous Leukemia With FLT3 Or RAS Mutation
Authors: Weiguo Zhang, Gautam Borthakur, Chen Gao, Ye Chen, Yong S. Lan, Vivian R Ruvolo, Kenichi Nomoto, Nanding Zhao, Marina Konopleva, Michael Andreeff
Journal: Blood (2013)
Abstract 566: Branched Chain Ketoacid Dehydrogenase Kinase Inhibition Alters Substrate Utilization and Gene Expression in Myocytes
Authors: Parker Siddall, Eliza Bollinger, Matthew Peloquin, Bina Albuquerque, Zhongyuan Sun, Gang Xing, Michelle Clasquin, Darren Dumlao, Mary Piotrowski, Jake Delmore, Evanthia Pashos, Angela Hadjipanayis, Teresa Cunio, Chang Zou, Bei B. Zhang, Russell A. Miller, Rachel J. Roth Flach
Journal: Circulation Research (2019)

Circulating increases in branched chain amino acid (BCAA) levels have long been associated with type II diabetes and metabolic syndrome. Emerging data also suggest that impaired BCAA catabolism may play a role in heart failure progression. BCAA are catabolized via the branched chain ketoacid (BCKA) dehydrogenase enzyme complex (BCKDH). BCKD kinase (BCKDK) is a negative regulator of BCAA catabolism through its inhibitory phosphorylation of the BCKDHE1a subunit, and the phosphatase PPM1k dephosphorylates this same site to activate BCAA catabolism. Using an inhibitor of BCKDK (BT2), BCAA catabolism is increased in vivo. Here, we utilized metabolomics to evaluate the contribution of BCAA catabolism to substrate preference in heart and skeletal muscle. Surprisingly, BCKDK inhibition with BT2 had no effect on incorporation of glucose into TCA cycle intermediates in heart or skeletal muscle. Because others have recently shown that the primary site of BCAA catabolism is skeletal muscle, we knocked down BCKDK and PPM1k in human skeletal myocytes to further investigate how BCKDK loss or inhibition affects substrate utilization. Similar to our in vivo observations, knockdown of BCKDK and PPM1k had no effect on glucose and pyruvate utilization in a mitochondrial function assay. However, an increase in maximal respiration was observed after BCKDK knockdown when fatty acids were used. To evaluate the mechanisms underlying this increase we then performed RNAseq in these cells after BCKDK and PPM1K knockdown and observed changes in a number of genes that may explain these alterations in substrate utilization. Finally, we performed C13 BCAA metabolomics in human skeletal myocytes after BT2 treatment or knockdown of BCKDK and PPM1k. Using BT2, we observed a dose-responsive reduction in BCKA production from C13 BCAA by the muscle cells as expected; however, though BCKA production was increased after PPM1k was knocked down, we surprisingly did not observe a decrease in BCKA production after BCKDK knockdown. Collectively these data suggest that BCKDK inhibition may improve metabolism and cardiac function by altering substrate preference in skeletal myocytes.
Potent Anti-Leukemic Activity of a Novel Cdk9 Inhibitor in Preclinical CLL Mouse Models
Authors: Joachim Rudolf Göthert, Roze Imsak, Michael Möllmann, Stefanie Weber, Mandy Necke, Ulrich Dührsen, Jan Eickhoff, Matthias Baumann, Anke Unger, Carsten Schultz-Fademrecht, Jan Dürig
Journal: Blood (2011)
Human Extramedullary Bone and Bone Marrow in Mice: First In Vivo Model of a Genetically Controlled Hematopoietic Environment
Authors: Ye Chen, Rodrigo O Jacamo, Nicole A. Hofmann, Yue-xi Shi, Rui-yu Wang, Sergej Konoplev, Dirk Strunk, Marina Konopleva, Michael Andreeff
Journal: Blood (2011)
Myelofibrosis Drug Development through the Decade: Novel JAK Inhibitors
Authors: Ali Younas Khan, Muhammad Junaid Tariq, Muhammad Usman, Awais Ijaz, Abdul Rafae, Mustafa Nadeem Malik, Hafiz Muhammad Fazeel, Nadia Carenina Nunes Cavalcante Parr, Muhammad Asad Fraz, Muhammad Jahanzeb Khalil, Jemin Aby Jose, Seren Durer, Ceren Durer, Faiz Anwer
Journal: Blood (2018)
The Prognostic Impact of t(14;20) in Multiple Myeloma - a Multicenter Retrospective Study of 26 Patients
Authors: Artur Jurczyszyn, Sarah Goldman-Mazur, Jorge J. Castillo, Anna Waszczuk-Gajda, Norbert Grząśko, Max Bittrich, Andrew J Yee, Anna Suska, Deepu Madduri, Saurabh Chhabra, Ariel Kleman, Parameswaran Hari, Stuart L. Goldberg, Aimee Chappell, Massimo Gentile, David H. Vesole
Journal: Blood (2018)
Abstract 716: 2D and 3D Assessment of Angiogenesis in Cardiac Engineered Tissues Implanted on Infarcted Rat Hearts
Authors: Fabiola Munarin, Rajeev J Kant, Cassady E Rupert, Amelia Khoo, Kareen L Coulombe
Journal: Circulation Research (2019)

A lack of efficient vessel perfusion in cardiac engineered tissues affects cell viability and limits the success of implanted cardiac tissues. To address the need for vascular infiltration, we have developed a collagen-based cardiac construct releasing pro-angiogenic growth factors. The constructs were implanted in a rodent model of myocardial infarction four days after ischemia/reperfusion injury. Angiogenesis assessment was performed 4 weeks after implantation by 2D histological analysis with RECA-1 antibody and with Microfil® (Flow Tech, MA) perfusion followed by 3D microCT analysis (voxel dimensions 10x10x10 μm). Cross-registration of microCT z-stacks with histological images allows segmentation of remote, infarct and implant regions. The heart vasculature was reconstructed in 3D with ImageJ and Imaris software, and Image J volume calculator and skeletonization algorithm have been used to measure vessels volume, length and number of branch points in each region of interest. Results from 2D histological analysis confirmed the development of capillary-like structures in the implants, visible in both cross and longitudinal sections in the histological slides. The density of cross-sectional vessels measured in the cardiac tissues was comparable to the density of vessels present in the infarct region (118 ± 77 and 93 ±74 vessels/mm 2 counted in infarct and implant regions, respectively). Furthermore, a 1.5-fold increase in vessels density was detected in the infarct zone of the treatment group with respect to the sham rats at 4 weeks. 3D reconstruction of rat heart vasculature showed evidence of the formation of new, perfused vessels in cardiac implants and presumably host-to graft connections. However, perfused vessels volume was not very different in the implants compared to the infarct regions. To the best of our knowledge, this is the first study where a 3D reconstruction of the perfused vasculature of a repaired rat heart has been conducted with a resolution of 10 μm, and that evidence of host-to-graft connections and vascular integration were shown 4 weeks after implantation. The automated quantification proposed is this study represents a non-biased method that can be further adopted by other groups to assess angiogenesis in cardiac implants.
Negative CD19 Expression Is Associated with Inferior Relapse-Free Survival in RUNX1-RUNX1T1-Positive Acute Myeloid Leukemia; The Japanese Pediatric Leukemia/Lymphoma Study Group Experience from the AML-05 Study
Authors: Toshihiko Imamura, Kenichi Sakamoto, Norio Shiba, Takao Deguchi, Nobutaka Kiyokawa, Yoshiko Hashii, Akiko Saito, Daisuke Tomizawa, Takashi Taga, Souichi Adachi
Journal: Blood (2018)
Abstract 908: Mechanism of Calcium Sensitivity Modulation of Cardiac Troponin C by Small Molecules Illuminated by Umbrella Sampling Simulations
Authors: Steffen Lindert
Journal: Circulation Research (2019)

Cardiac troponin C (cTnC) binds intracellular calcium and subsequently cardiac troponin I (cTnI), initiating cardiac muscle contraction. Due to its role in contraction, cTnC has been a therapeutic target in the search for small molecules to treat cardiomyopathies that interfere with normal muscle contraction. Structural studies have shown the binding location of small molecules such as bepridil, dfbp-o, 3-methyldiphenylamine (DPA) and W7 to be a hydrophobic pocket in the regulatory domain of cTnC (cNTnC) but have not shown the influence of these small molecules on the dynamics of opening this domain. Here we describe an application of an umbrella sampling method used to elucidate the impact these calcium sensitivity modulators have on the free energy of cNTnC hydrophobic patch opening. We found that all these molecules lowered the free energy of opening in the absence of the cTnI, with bepridil facilitating the least endergonic transformation. In the presence of cTnI, however, we saw a stabilization of the open configuration due to DPA and dfbp-o binding, and a destabilization of the open configuration imparted by bepridil and W7. Predicted poor binding molecule NSC34337 left the hydrophobic immediately in conventional MD simulations suggesting that only hydrophobic patch binders stabilized the open conformation. Additionally, differences in the free energy of hydrophobic patch opening of hypertrophic (HCM) and dilated cardiomyopathy (DCM) cTnC systems were investigated. Molecular dynamics and umbrella sampling simulations revealed a lower free energy of opening for the HCM mutations A8V and A31S, as well as the calcium-sensitizing mutation L48Q. The DCM mutations, Y5H, Q50R, and E59D/D75Y, all exhibited a higher free energy of opening. In conclusion, our developed simulation protocol presents a novel approach to study calcium sensitivity modulation by small molecules and mutations and facilitates a molecular understanding of cardiac muscle contraction.
Abstract 862: SGK-1 Metabolically Reprograms VSMC Energy Metabolism by Modulation of Substrate Utilization and Mitochondrial Structure
Authors: Krystal Roggerson, Wei Zhong, Oguljahan Babayewa, Sharon Francis
Journal: Circulation Research (2019)

Obesity is associated with vascular remodeling which increases the risk of developing heart disease; the leading cause of death world-wide. The mechanisms underlying vascular remodeling during obesity are not completely understood, but impaired cellular energy metabolism is thought to play an important role. Oxidative phosphorylation (OXPHOS) and glycolysis are the cell’s two main energy generating pathways that rely on energy substrate availability. Glucose is the primary substrate for glycolysis, whereas, pyruvate which is metabolized from glucose, long chain fatty acids (LCFAs) and glutamine are the substrates metabolized for OXPHOS. Previously, we reported that serum and glucocorticoid-inducible kinase 1 (SGK-1) is up-regulated in the vasculature of diet-induced obese mice, implicating a role for this serine/threonine kinase in obesity-related vascular remodeling. Indeed, our current data demonstrate that deletion of serum and glucocorticoid-inducible kinase 1 (SGK-1) specifically in vascular smooth muscle cells (VSMC) protects against obesity-induced vascular remodeling. Further, protection from remodeling was concomitant with metabolic reprogramming of VSMCs due to a metabolic shift from glycolysis towards OXPHOS in SGK-1 knockout (KO) VSMCs compared to wildtype (WT) VSMCs. Interestingly, metabolic reprogramming was also evident in SGK-1 KO VSMC under basal conditions, suggesting a novel role for SGK-1 in cellular energy metabolism. Inhibition of glycolysis was due to an overall reduction in glucose uptake, whereas, an increase in OXPHOS was associated with redistribution of mitochondria and altered levels of the mitochondrial fusion and fission regulatory proteins, suggesting that SGK-1 reprograms energy metabolism through modulation of energy substrate utilization and mitochondrial structure. Altogether, our data point to SGK-1 inhibition as a novel therapy for obesity-related vascular pathology.
Role of Serial Positron Emission Tomography (PET) Scans in Indolent Lymphomas' Management - Interim Results from an Ongoing Prospective Study at King Fahd Medical City, Riyadh, Saudi Arabia
Authors: Nawal Faiez Alshehry, Musab Ahmed, Shahid Iq bal, Atta Munawar Gill, Mohammad E Dawiama, Ahmed Ali Butt, Belal Albtoosh, Ibraheem H. Motabi, Mubarak S. AlGhamdi, Imran Khan Tailor, Syed Altaf, Syed Ziauddin A. Zaidi, Shanker Raja
Journal: Blood (2018)
Role of the Transcription Factor LYL-1 in the Adult and Fetal Hematopoietic Stem Cells.
Authors: Claude Capron, Catherine Lacout, Yann Lecluse, Isabelle Poullion, Fedor Svinarchouk, Fred Sablitzky, William Vainchenker, Annelise Bennaceur-Griscelli, Dominique Dumenil
Journal: Blood (2004)
Outcome of Early Introduction of Hypertransfusion/Chelation Program in Children with Thalassemia Intermedia
Authors: Yasser Wali, A. Hakim Al-Rawas, Shoaib Al Zadjali, Murtadha K. Al-Khabori, Wafa Bashir, Mathew Zachariah, Taimoora Sulaiman, Surekha Tony
Journal: Blood (2012)