tbuckley/cabot-search huggingface dataset:
Abstract 627: Primary Cilia of the Cardiac Neural Crest Orchestrate Critical Aspects of Ventricular Maturation and Postnatal Cardiac Function: A Role for Hedgehog Signaling
Authors: Lindsey A Fitzsimons, Adrian M Moran, Kerry L Tucker
Journal: Circulation Research (2019)

Primary cilia are tiny, plasma-membrane bound organelles that function to modulate intra- and extracellular signaling, in particular Hedgehog signaling, implicated in both normal development as well as in various disease pathologies, including congenital heart disease (CHD). Cardiac neural crest cells (CNCC) display primary cilia and function as a major progenitor cell population contributing to the developing heart. We hypothesized that damage to or loss of primary cilia in CNCC would impair normal heart development, leading to CHD. We present 1) a precise description of CHD’s resulting from loss of primary cilia of CNCC in vivo ; 2) characterization of the functional, electrophysiological aspects of the perinatal phenotype; and 3) a preliminary investigation of the molecular mechanisms leading to this phenotype. Using a Wnt1:Cre-2, Ift88-targeted conditional elimination of primary cilia, and a Td-tomato reporter to track CNCC, we observed loss of cilia in CNCC at embryonic day E9.5, with notable CNCC contribution to the ventricular myocardium and pronounced disorganization of the endocardium by E10.5.The phenotype resulting from cilia loss in CNCC was characterized by a variety predicted CHDs in addition to disorganization of the ventricular endocardium, pronounced noncompaction of the ventricular myocardium, and perinatal lethality. To investigate potential changes in Hedgehog signaling resulting from cilia loss, we implemented an in vivo conditional knockout in which Wnt1:Cre-2 drives expression of a mutant, constitutively-active Hedgehog receptor. Noncompaction observed in all Wnt1:Cre-2/Ift88 mutants became exacerbated in a primary-cilia dependent fashion with the introduction of forced Hedgehog signaling in CNCC. These results support a critical role for both primary cilia and Hedgehog signaling in the development of the ventricular myocardium. Further electrophysiological assessments of Wnt1:Cre-2/Ift88 newborn mutant mice revealed bradycardia, conduction defects, and ECG tracings consistent with ventricular hypertrophy. These data collectively support a role for Hedgehog signaling via primary cilia of CNCC in the pathogenesis of outflow tract defects, VSD, and most notably, ventricular maturation CHDs.
Thiopurine Methyltransferase Genotype Modulates Early Treatment Response to 6-Mercaptopurine as Measured by Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia.
Authors: Martin Stanulla, Elke Schaffeler, Thomas Flohr, Gunnar Cario, Karl Welte, Bartram R. Claus, Eichelbaum Michel, Zanger Ulrich, Schrappe Martin, Schwab Matthias
Journal: Blood (2004)
Abstract 650: Dose-response Effect of Hyperglycemia in Maternal Diabetes Mediated Congenital Heart Defects
Authors: Corrin Mansfield, Sathiyanarayanan Manivannan, Emily M Cameron, Vidu Garg, Madhumita Basu
Journal: Circulation Research (2019)

Congenital heart defects (CHDs) are the leading cause of infant morbidity and mortality. The etiology is multifactorial and maternal pre-existing diabetes is a non-genetic risk factor, which perturbs embryonic development and increases the risk of CHDs by 3-to 5-fold. We have previously demonstrated that maternal hyperglycemia (matHG) leads to an increase in reactive oxygen species and reduced nitric oxide bioavailability and found an epigenetic mechanism for altered expression of Notch1 , a gene critical for endocardial cushion formation, cardiomyocyte (CM) differentiation, outflow tract development, and ventricular trabeculation. We also noted spectrum of cardiac defects in developing embryos when exposed to increased severity of matHG, the underlying molecular basis of which remains unclear. To this end, we hypothesized that matHG alters gene-expression of cardiac progenitor cells in a spatiotemporal manner to predispose embryos to diabetes-induced CHDs. To test cell-specific responses to HG, murine embryonic cell-lines [AVM, atrioventricular cushion mesenchymal and ECC1, endothelial] were cultured in normal (NG, 5.5mM) and different doses of HG (10, 25 and 40mM). RNA-seq was performed after 48hrs of treatment and gene-set enrichment analysis of AVM NG and HG (25mM) identified genes associated with metabolic processes, response to oxidative-stress (OS), chromatin regulation and altered Wnt/Notch signaling pathways with HG. Similarly, RNA-seq analysis of protein-coding genes in ECC1-HG revealed increasing numbers (8, 311, 1072) of differentially expressed genes compared to NG, and associated with OS, ATP-synthesis, cardiac development, suggesting a dose-response relationship. Additionally, a streptozotocin-induced murine model of diabetes was used to characterize the influence of matHG dose on CHD susceptibility. Examination of E9.5, E11.5, E13.5 embryos displayed defects in CM proliferation, ventricular trabeculation, thin ventricular myocardium and septal defects with matHG. Together, our in vitro transcriptomic analysis and in vivo histologic characterization support a variable molecular and phenotypic response to hyperglycemic stress during cardiac development that contribute to matHG associated CHDs.
Response Rates of High and Low Dose Estrogen and Their Combination with DDAVP and/or Aminocaproic Acid in Patients with Menorrhagia and Type I Von Willebrand’s Disease.
Authors: Vasundhara Kailasnath, S. Paige Hertweck, Salvatore Bertolone, Sanjay P Ahuja
Journal: Blood (2008)
Discontinuation of Imatinib Therapy in Chronic Myeloid Leukemia Patients with Sustained Complete Molecular Response4.5 (CMR4.5)
Authors: Hyun-Gyung Goh, Soo-Young Choi, Ju-Hee Bang, Soo-Hyun Kim, Eun-Jung Jang, Dongho Kim, Ji-Young Byeun, Joon Seong Park, Hyeoung-Joon Kim, Hawk Kim, Dong-Wook Kim
Journal: Blood (2011)
Think First, Cut Last — Lessons from a Clinical Trial of Refractory Heartburn
Authors: Nicholas J. Talley
Journal: New England Journal of Medicine (2019)

Conceptualizing gastroesophageal reflux disease (GERD) as a single disease process that will respond to higher and higher doses of acid suppression is a mistake.1 The underlying mechanisms that can lead to reflux of stomach contents into the esophagus and subsequent symptoms or esophagitis are probably diverse and contribute in varying combinations.1 These range from increased transient relaxations of the esophageal sphincter, promoting increased acid or bile reflux, to anatomical derangements of the esophageal sphincter, with or without esophageal hypersensitivity plus psychological distress.1 It is also possible that disordered gastric accommodation increases esophageal sphincter relaxation, which may occur in functional dyspepsia . . .
Abstract 709: DNA Damage-free iPS-cardiomyocyte Reduces Cardiac Fibrosis Through Downmodulation of Exosomal miR-101
Authors: Ramaswamy Kannappan, Jessica M Miller, Vasanthi Rajasekaran, Namakkal Rajasekaran Soorappan, Jianyi Zhang
Journal: Circulation Research (2019)

With the growing field of myocardial repair through transplantation of cardiomyocytes (CM) derived from human induced pluripotent stem cells (iPSC) calls for a method for reducing fibrotic tissue development at the site of cell transplantation. We tested the hypothesis of whether transplanting CMs derived from DNA damage-free (DdF) iPSCs could reduce the recruitment of myofibroblasts and reduce fibrosis at the site of transplantation. Transcription factor p53 functions are DNA damage-dependent: induce apoptosis in DNA damaged cells while promoting cell cycle in normal cells. Utilizing this discriminating nature of p53 we selected iPSCs that are DdF and differentiated them into CMs. Control CMs (Ctrl-CM) and DdF-CMs were tested for transplantation induced fibrosis in a mouse model. The inflammatory markers such as accumulation of ROS, superoxide and DNA damage were significantly reduced in DdF cells. RNA sequencing revealed that, in DdF-CMs, the inflammatory and fibrosis signaling pathways are significantly different compared to Ctrl-CMs. Transplantation of both CMs into the myocardium of ischemia-induced mice resulted in fibrosis around the transplantation site. However, the fibrotic area around transplanted sites and total fibrosis were significantly reduced in mice hearts that received DdF-CMs as evidenced by collagen accumulation and Sirus red staining of fibrotic tissue. Importantly, the number of myofibroblasts at the site of DdF-CM transplantation was significantly reduced compared to Ctrl-CM sites. In an in vitro migration study, fibroblasts preferentially migrated towards the Ctrl-CMs. Human fibroblast treatment with DdF-CM exosomes (DdF-Exo) resulted in reduced expression of fibrotic markers than Ctrl-CM exosomes (Ctrl-Exo) treatment. miRNA analysis in exosomes showed that the anti-inflammatory miR-26a is upregulated and the inflammatory miRNA101 is downregulated in DdF-Exo. Overexpression of miR-101 mimic in DdF-Exo abrogated the anti-fibrotic potential property of DdF-Exo. Our results clearly demonstrate that DdF-CMs has anti-fibrotic potential. Transplanting DdF-CMs attracted reduced myofibroblast to the engraft site and Ctrl-CMs transplantation induce fibrosis through the expression of exosomal miR-101.
Abstract 934: Physical and Genetic Interaction Analyses in Human Pluripotent Stem Cell-Derived Cardiomyocytes to Study Protein Quality Control Disease in the Heart
Authors: Juan A Perez-Bermejo, Luke M Judge, Kenneth Wu, Christina L Jensen, Robyn M Kaake, Danielle Swaney, Po-Lin So, Nevan J Krogan, Bruce R Conklin
Journal: Circulation Research (2019)

Cardiomyocytes must maintain constant contractile function of the heart throughout a human lifetime. To achieve this, a complex network of chaperones and other proteins maintains the homeostasis of the proteins in the cell. Protein quality control pathways are increasingly recognized for their importance in both inherited and sporadic cardiac disease, and as potential therapeutic targets. The co-chaperone BAG3 is particularly interesting, because genetic evidence suggests that variants of BAG3 can be both pathologic and protective. However, understanding the molecular mechanism underlying most of these disease-genetic variant associations remains a major challenge. Unbiased analysis of physical and genetic interaction networks holds the potential to provide critical information to fill in this knowledge gap. Using genome engineering tools, we have generated a series of isogenic human induced pluripotent (iPS) cell lines bearing different variants on the BAG3 gene, along with an epitope tag fusion. Using mass spectrometry methods, we have been able to identify interacting partners for the BAG3 protein expressed at endogenous levels in iPS-derived cardiomyocytes. Our results show a surprisingly high number of cardiac-specific interactions. In addition, some BAG3 protein variants present distinct gain or loss of specific interactions, allowing us to narrow down the list of candidate hits. Using microscopy image analysis, we performed a targeted knockdown screening on BAG3 interaction partners to dissect pathways of BAG3 interactors that are involved in the development disease phenotype.We hope the information obtained from this study will improve our understanding of the heart proteostasis network, enable the identification of potential therapeutic targets, and provide clues towards a broader understanding of the role of genetic variation in complex disease.
Abstract 480: A Novel Role for Telomerase in Calcific Aortic Valve Disease
Authors: Luis Hortells, Camille Boufford, Cailyn Regan, Claire Chu, William J Moorhead, Genevieve Doyon, Dennis Bruemmer, Cynthia St Hilaire
Journal: Circulation Research (2019)

Intro: Telomerase (TERT) is an enzyme best known for its telomere-extending activities on the ends of chromosomes, however, less known are the non-canonical, transcriptional and epigenetic actitivies of TERT. We sought to assess if TERT, through non-canonical activities, contributes to the progression of calcific aortic valve disease (CAVD). It has been established that overexpression of TERT in mesenchymal stem cells primes these cells to differentiate into osteoblasts. Other studies have identified non-canonical roles for TERT in inducing the transcription of genes in inflammatory and cell differentiation pathways. Methods: Using mesenchymal stem cells, primary valve interstitial cells (VICs) from control and CAVD patients, and smooth muscle cells (SMCs) from WT and TERT knockout mice, we performed in vitro biochemical assays to study the role of TERT in the calcification process. Results: Our data shows that TERT is highly expressed in CAVD valves compared to Control valves. Under osteogenic differentiation conditions Control valve interstitial cells (VICs) upregulate TERT protein levels and calcify. Inflammatory signals induce TERT expression in VICs and exacerbates calcification. Similarly, WT vascular VSMCs readily calcify in vitro, but VSMCs from TERT knockout mice do not, and TERT deletion also reduced valve calcification in LDLR/TERT double knock mice. These studies provide evidence that TERT is necessary is the osteogenic switch of a healthy to a calcifying VIC. Knocking down TERT reduces expression of the osteogenic transcription factor RUNX2 and we further provided evidence that STAT5 may help to mediate TERTs effects on osteogenic gene transcription. Conclusion: From these data we suggest that TERT is required for valve calcification by inducing the osteogenic transition of quiescent valve interstitial cells (VICs) into calcifying VICs, and that TERT and STAT5 co-regulate transcription of osteogenic genes. These results indicate that TERT is an active contributor to the calcification process of valve tissues and our futures studies will delineate the mechanisms involved.
Association of early postnatal transfer and birth outside a tertiary hospital with mortality and severe brain injury in extremely preterm infants: observational cohort study with propensity score matching
Authors: Kjell Helenius, Nicholas Longford, Liisa Lehtonen, Neena Modi, Chris Gale
Journal: BMJ (2019)

Abstract Objective To determine if postnatal transfer or birth in a non-tertiary hospital is associated with adverse outcomes. Design Observational cohort study with propensity score matching. Setting National health service neonatal care in England; population data held in the National Neonatal Research Database. Participants Extremely preterm infants born at less than 28 gestational weeks between 2008 and 2015 (n=17 577) grouped based on birth hospital and transfer within 48 hours of birth: upward transfer (non-tertiary to tertiary hospital, n=2158), non-tertiary care (born in non-tertiary hospital; not transferred, n=2668), and controls (born in tertiary hospital; not transferred, n=10 866). Infants were matched on propensity scores and predefined background variables to form subgroups with near identical distributions of confounders. Infants transferred between tertiary hospitals (horizontal transfer) were separately matched to controls in a 1:5 ratio. Main outcome measures Death, severe brain injury, and survival without severe brain injury. Results 2181 infants, 727 from each group (upward transfer, non-tertiary care, and control) were well matched. Compared with controls, infants in the upward transfer group had no significant difference in the odds of death before discharge (odds ratio 1.22, 95% confidence interval 0.92 to 1.61) but significantly higher odds of severe brain injury (2.32, 1.78 to 3.06; number needed to treat (NNT) 8) and significantly lower odds of survival without severe brain injury (0.60, 0.47 to 0.76; NNT 9). Compared with controls, infants in the non-tertiary care group had significantly higher odds of death (1.34, 1.02 to 1.77; NNT 20) but no significant difference in the odds of severe brain injury (0.95, 0.70 to 1.30) or survival without severe brain injury (0.82, 0.64 to 1.05). Compared with infants in the upward transfer group, infants in the non-tertiary care group had no significant difference in death before discharge (1.10, 0.84 to 1.44) but significantly lower odds of severe brain injury (0.41, 0.31 to 0.53; NNT 8) and significantly higher odds of survival without severe brain injury (1.37, 1.09 to 1.73; NNT 14). No significant differences were found in outcomes between the horizontal transfer group (n=305) and controls (n=1525). Conclusions In extremely preterm infants, birth in a non-tertiary hospital and transfer within 48 hours are associated with poor outcomes when compared with birth in a tertiary setting. We recommend perinatal services promote pathways that facilitate delivery of extremely preterm infants in tertiary hospitals in preference to postnatal transfer.
A Phase 2 Study of Carfilzomib Plus Elotuzumab Plus Dexamethasone for Myeloma Patients Relapsed after 1-3 Prior Treatment Lines
Authors: Raija Helena Silvennoinen, Dimitrios Tsallos, Hareth Nahi, Pekka Anttila, Perttu Koskenvesa, Juha Lievonen, Anu Räsänen, Ville Varmavuo, Anu Sikiö, Marita Nurmi, Marjaana Säily, Anu Partanen, Marja Sankelo, Sini Luoma, Sorella Ilveskero, Tarja-Terttu Pelliniemi, Esa Jantunen, Muntasir M Majumder, Samuli Eldfors, Maija Leppä, Caroline A Heckman
Journal: Blood (2018)
Reversibility of the Resistance to Lenalidomide and Pomalidomide and Absence of Cross-Resistance in a Murine Model of MM
Authors: Enrique M Ocio, Diego Fernández-Lázaro, Laura San-Segundo, Lorena González-Méndez, Montserrat Martín-Sánchez, Mercedes Garayoa, Teresa Paíno, Antonio Garcia-Gomez, Norma C. Gutierrez, Manuel Delgado, Juan C. Montero, Nuria Quintana, Jose Luis García, Atanasio Pandiella, Jesús F. San Miguel
Journal: Blood (2011)
Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study
Authors: Pamela T. Soliman, Shannon N. Westin, David A. Iglesias, Bryan M. Fellman, Ying Yuan, Qian Zhang, Melinda S. Yates, Russell R. Broaddus, Brian M. Slomovitz, Karen H. Lu, Robert L. Coleman
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second-line chemotherapy with a response rate &amp;gt;13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent EEC. Patients and Methods: A Simon two-stage design was employed. Women with ≤2 prior chemotherapy regimens for recurrence were eligible. Pretreatment biopsy was required, followed by everolimus 10 mg orally, letrozole 2.5 mg orally, and metformin 500 mg orally twice a day on a 4-week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity. Results: Sixty-two patients were enrolled. Median age was 62 years (40–77) with 401 cycles completed, median of 6 cycles (1–31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received &amp;gt;12 cycles. Median follow-up was 17.9 months (2–47). Median progression-free survival was 5.7 [95% confidence interval (CI), 3.0–8.1] and OS was 19.6 months (95% CI, 14.2–26.3). Positive progesterone receptor expression was associated with CB (89.5% vs. 27.3%, P = 0.001). Conclusions: Everolimus, letrozole, and metformin resulted in 50% CB and 28% OR in women with recurrent EEC. Progesterone receptor–positive tumors may have better response; validation studies are needed. See related commentary by Madariaga et al., p. 523
Outcomes and care patterns for advanced pancreatic cancer patients treated in tertiary vs regional/community cancer centres in Northern Alberta.
Authors: Matthew Anaka, Minji Lee, Sunita Ghosh, Winson Y. Cheung, Jennifer L. Spratlin
Journal: Journal of Clinical Oncology (2019)

163 Background: Cancer care in Northern Alberta (Canada) is delivered at a single tertiary cancer centre, and 11 regional and community cancer centres (RCCC). We compared outcomes and care patterns for patients with advanced pancreatic cancer (APC; locally advanced or metastatic) in Northern Alberta treated with palliative chemotherapy at either the tertiary centre or an RCCC. Methods: This is a retrospective cohort analysis of APC patients treated with palliative chemotherapy from 2012-2015 in Northern Alberta (Canada). Data were obtained from outpatient medical oncology and palliative care notes and the provincial cancer registry. Survival analysis used a multivariate Cox-regression model. All other tests were Chi-squared/Fisher’s Exact. Results: We identified 106 patients, 90 treated in the tertiary centre, and 16 in a RCCC. Baseline characteristics were not significantly different. There were significant differences in first line chemotherapy regimen use (P = 0.037), with patients treated at RCCC more likely to receive gemcitabine during the study period (68.8% vs 36.6%), and less likely gemcitabine/nab-paclitaxel (12.5% vs 36.5%) or FOLFIRINOX (18.8% vs 28.7%). Patients treated at RCCC were less likely to see an outpatient palliative care physician (P = 0.020, 6.3% vs 35.6%), or have a documented goals of care designation (P = 0.005, 12.5% vs 52.2%). There was no significant difference in overall survival in a multivariate analysis (median 199 vs 232 days, HR = 1.080, 95% CI 0.594 – 1.966). Conclusions: We found that survival was not different for APC patients treated at the tertiary vs RCCC in Northern Alberta. However there were significant differences in the use of palliative care resources and 1 st line chemotherapy regimens, which represent important disparities that should be the focus for future quality improvement.