tbuckley/cabot-search huggingface dataset:
Abstract 239: Augmented Cardiac Pyruvate Dehydrogenase Complex Flux During Hypoxia Increases Post-hypoxic Damage
Authors: Michal K Handzlik, Dumitru Constantin-Teodosiu, Paul L Greenhaff, Mark A Cole
Journal: Circulation Research (2015)

Modulation of cardiac pyruvate dehydrogenase complex (PDC) flux is known to alter post-ischemic myocardial injury. Hypoxia is intrinsic to ischemia, but its specific role in cardiac injury is unknown. We hypothesized that post-hypoxic cardiac injury would be attenuated with activation of the PDC complex during hypoxia. Mouse hearts were isolated and Langendorff perfused with 0.4mM palmitate and 11mM glucose. Following 30min of normoxia, hearts were subjected to 30min hypoxia (20% of normoxic pO2) followed by 30min of reoxygenation. PDC flux was increased by infusion of 1mM dichloroacetate (DCA), either from onset of hypoxia, or with onset of reoxygenation. Cardiac function was measured using an IV balloon, and fatty acid β-oxidation determined via 3H-labelling. Lactate efflux was assayed from timed buffer collections. Hearts were frozen at end-normoxia, end-hypoxia and end-reoxygenation, and assayed for PDC flux, and phosphate metabolites. Reactive oxygen species formation was assessed by Western blotting of protein carbonyls. End-hypoxic cardiac PDC flux fell to 41±5% of pre-hypoxic values (0.96 of 2.37 μmol/gdwt, p&lt;0.001) with β-oxidation also lower (25±11%, 0.06 of 0.24 μmol/min/gwwt, p&lt;0.025). Lactate efflux increased 2.3-fold (4.7 to 10.6 μmol/min/gwwt, p&lt;0.028) and AMP/ATP ratio 5.3-fold (0.04 to 0.21 p&lt;0.002). DCA infusion increased end-hypoxic PDC flux (170±16%, 1.64 of 0.96 μmol/gdwt, p&lt;0.003), reducing lactate efflux (47±8%, 5 of 11 μmol/min/gwwt, p&lt;0.021) and AMP/ATP ratio (43±12%, 0.09 of 0.21, p&lt;0.025). Control hearts were damaged by hypoxia, final recovery being 63±7% of pre-hypoxic function (18 of 29 bpm.mmHg.103). Hypoxic DCA infusion impaired recovery (49±4%, 15 of 31 bpm.mmHg.103), compared to DCA infusion during reoxygenation (63±3%, 19 of 30 bpm.mmHg.103, p&lt;0.023). Reactive oxygen species formation was not altered. Increasing PDC flux during hypoxia significantly modified myocardial substrate metabolism. In contrast to the reported beneficial effects of augmented PDC flux during ischemia, increasing PDC flux in the hypoxic heart exacerbated myocardial injury. These results indicate that the potentially therapeutic effects of increasing PDC flux are not dependent on the hypoxic aspect of myocardial ischemia.
Tyrosine phosphorylation of eNOS regulates myocardial survival after an ischaemic insult: role of PYK2
Authors: Sofia-Iris Bibli, Zongmin Zhou, Sven Zukunft, Beate Fisslthaler, Ioanna Andreadou, Csaba Szabo, Peter Brouckaert, Ingrid Fleming, Andreas Papapetropoulos
Journal: Cardiovascular Research (2017)

Endothelial nitric oxide (NO) synthase (eNOS) is known to play a cardioprotective protective. However, the molecular mechanisms regulating eNOS activity during ischaemia/reperfusion (I/R) injury are incompletely understood. eNOS is a substrate for several kinases that positively or negatively affect its enzymatic activity. Herein, we sought to correlate eNOS phosphorylation status with cardiomyocyte survival and we investigated the contribution of the proline-rich tyrosine kinase 2 (PYK2)/eNOS axis to the regulation of myocardial infarct size in vivo. Exposure of H9c2 cardiomyocytes to H2O2 lead to PYK2 phosphorylation on its activator site (Y402) and eNOS phosphorylation on the inhibitor site Y656 and the activator site S1176. Both H2O2–induced eNOS phosphorylation events were abolished by PYK2 pharmacological inhibition or gene knockdown. Activity assays demonstrated that phosphorylation of the tyrosine inhibitory site exerts a dominant effect over S1176. In cardiomyocytes subjected to oxidative stress or oxygen-glucose deprivation, inhibition of PYK2 limited cell injury; this effect was prevented by inhibition of NO production. In vivo, ischaemia-reperfusion induced an early activation of PYK2, leading to eNOS phosphorylation on Y656, which, in turn, reduced NO output, as judged by the low tissue levels of its downstream effector cGMP. Moreover, pharmacological blockade of PYK2 alleviated eNOS inhibition and prevented cardiac damage following I/R injury in wild-type, but not in eNOS KO mice. The current studies demonstrate that PYK2 is a pivotal regulator of eNOS function in myocardial infarction and identify PYK2 as a novel therapeutic target for cardioprotection.
PD-L1 serves as a double agent in separating GVL from GVHD
Authors: Todd V. Brennan, Yiping Yang
Journal: Journal of Clinical Investigation (2017)

Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative treatment for a variety of hematologic malignancies due to the well-recognized graft-versus-leukemia/lymphoma (GVL) effect that is mediated by donor-derived alloreactive T cells. However, graft-versus-host disease (GVHD) is mediated by the same T cells and remains a significant clinical problem associated with substantial morbidity and mortality. In this issue of the JCI, Ni and colleagues used several murine models of GVHD to evaluate the effect of CD4+ T cell depletion on GVL versus GVHD and revealed that depletion of CD4+ T cells leads to the upregulation of PD-L1 by recipient tissues and donor CD8+ T cells. Interaction of PD-L1 with PD-1 in GVHD-targeted tissues resulted in CD8+ T cell exhaustion and apoptosis, thereby preventing GVHD, whereas PD-L1 interactions with CD80 in lymphoid tissue promoted CD8+ T cell survival and expansion, thereby enhancing the GVL response. By separating these seemingly similar alloreactive T cell responses based on the context of interaction, the results of this study may lay the groundwork for the development of effective clinical strategies to enhance GVL while minimizing GVHD following allogeneic HCT.
Next-generation sequencing and FISH studies reveal the appearance of gene mutations and chromosomal abnormalities in hematopoietic progenitors in chronic lymphocytic leukemia
Authors: Miguel Quijada-Álamo, María Hernández-Sánchez, Cristina Robledo, Jesús-María Hernández-Sánchez, Rocío Benito, Adrián Montaño, Ana E. Rodríguez-Vicente, Dalia Quwaider, Ana-África Martín, María García-Álvarez, María Jesús Vidal-Manceñido, Gonzalo Ferrer-Garrido, María-Pilar Delgado-Beltrán, Josefina Galende, Juan-Nicolás Rodríguez, Guillermo Martín-Núñez, José-María Alonso, Alfonso García de Coca, José A. Queizán, Magdalena Sierra, Carlos Aguilar, Alexander Kohlmann, José-Ángel Hernández, Marcos González, Jesús-María Hernández-Rivas
Journal: Journal of Hematology & Oncology (2017)

Chronic lymphocytic leukemia (CLL) is a highly genetically heterogeneous disease. Although CLL has been traditionally considered as a mature B cell leukemia, few independent studies have shown that the genetic alterations may appear in CD34+ hematopoietic progenitors. However, the presence of both chromosomal aberrations and gene mutations in CD34+ cells from the same patients has not been explored. Amplicon-based deep next-generation sequencing (NGS) studies were carried out in magnetically activated-cell-sorting separated CD19+ mature B lymphocytes and CD34+ hematopoietic progenitors (n = 56) to study the mutational status of TP53, NOTCH1, SF3B1, FBXW7, MYD88, and XPO1 genes. In addition, ultra-deep NGS was performed in a subset of seven patients to determine the presence of mutations in flow-sorted CD34+CD19− early hematopoietic progenitors. Fluorescence in situ hybridization (FISH) studies were performed in the CD34+ cells from nine patients of the cohort to examine the presence of cytogenetic abnormalities. NGS studies revealed a total of 28 mutations in 24 CLL patients. Interestingly, 15 of them also showed the same mutations in their corresponding whole population of CD34+ progenitors. The majority of NOTCH1 (7/9) and XPO1 (4/4) mutations presented a similar mutational burden in both cell fractions; by contrast, mutations of TP53 (2/2), FBXW7 (2/2), and SF3B1 (3/4) showed lower mutational allele frequencies, or even none, in the CD34+ cells compared with the CD19+ population. Ultra-deep NGS confirmed the presence of FBXW7, MYD88, NOTCH1, and XPO1 mutations in the subpopulation of CD34+CD19− early hematopoietic progenitors (6/7). Furthermore, FISH studies showed the presence of 11q and 13q deletions (2/2 and 3/5, respectively) in CD34+ progenitors but the absence of IGH cytogenetic alterations (0/2) in the CD34+ cells. Combining all the results from NGS and FISH, a model of the appearance and expansion of genetic alterations in CLL was derived, suggesting that most of the genetic events appear on the hematopoietic progenitors, although these mutations could induce the beginning of tumoral cell expansion at different stage of B cell differentiation. Our study showed the presence of both gene mutations and chromosomal abnormalities in early hematopoietic progenitor cells from CLL patients.
Maternal and Fetal Outcomes of Admission for Delivery in Women With Congenital Heart Disease
Authors: Robert M. Hayward, Elyse Foster, Zian H. Tseng
Journal: JAMA Cardiology (2017)

Women with congenital heart disease (CHD) may be at increased risk for adverse events during pregnancy and delivery.To compare delivery outcomes between women with and without CHD.This retrospective study of inpatient delivery admissions in the Healthcare Cost and Utilization Project's California State Inpatient Database compared maternal and fetal outcomes between women with and without CHD by using multivariate logistic regression. Female patients with codes for delivery from the International Classification of Diseases, Ninth Revision, from January 1, 2005, through December 31, 2011, were included. The association of CHD with readmission was assessed to 7 years after delivery. Cardiovascular morbidity and mortality were hypothesized to be higher among women with CHD. Data were analyzed from April 4, 2014, through January 23, 2017.Noncomplex and complex CHD.Maternal outcomes included in-hospital arrhythmias, eclampsia or preeclampsia, congestive heart failure (CHF), length of stay, preterm labor, anemia complicating pregnancy, placental abnormalities, infection during labor, maternal readmission at 1 year, and in-hospital mortality. Fetal outcomes included growth restriction, distress, and death.Among 3 642 041 identified delivery admissions, 3189 women had noncomplex CHD (mean [SD] age, 28.6 [7.6] years) and 262 had complex CHD (mean [SD] age, 26.5 [6.8] years). Women with CHD were more likely to undergo cesarean delivery (1357 [39.3%] vs 1 164 509 women without CHD [32.0%]; P < .001). Incident CHF, atrial arrhythmias, ventricular arrhythmias, and maternal mortality were uncommon during hospitalization, with each occurring in fewer than 10 women with noncomplex or complex CHD (<0.5% each). After multivariate adjustment, noncomplex CHD (odds ratio [OR], 9.7; 95% CI, 4.7-20.0) and complex CHD (OR, 56.6; 95% CI, 17.6-182.5) were associated with greater odds of incident CHF. Similar odds were found for atrial arrhythmias in noncomplex (OR, 8.2; 95% CI, 3.0-22.7) and complex (OR, 31.8; 95% CI, 4.3-236.3) CHD, for fetal growth restriction in noncomplex (OR, 1.6; 95% CI, 1.3-2.0) and complex (OR, 3.5; 95% CI, 2.1-6.1) CHD, and for hospital readmission in both CHD groups combined (OR, 3.6; 95% CI, 3.3-4.0). Complex CHD was associated with greater adjusted odds of serious ventricular arrhythmias (OR, 31.8; 95% CI, 4.3-236.3) and maternal in-hospital mortality (OR, 79.1; 95% CI, 23.9-261.8).In this study of hospital admissions for delivery in California, CHD was associated with incident CHF, atrial arrhythmias, and fetal growth restriction and complex CHD was associated with ventricular arrhythmias and maternal in-hospital mortality, although these outcomes were rare, even in women with complex CHD. These findings may guide monitoring decisions and risk assessment for pregnant women with CHD at the time of delivery.
Impact of Body Weight Adjusted Dose on Efficacy and Safety of Radotinib in Chronic Myeloid Leukemia
Authors: Hayeon Noh, Su Young Jung, Jae-Yong Kwak, Sung-Hyun Kim, Suk Joong Oh, Dae Young Zang, Hye Lin Park, Dae Jin Jo, Jae Soo Shin, Young Rok Do, Dong-Wook Kim, Jangik I Lee
Journal: Blood (2016)
A Possible Early Biomarker for Bicuspid Aortopathy
Authors: Amalia Forte, Ciro Bancone, Gilda Cobellis, Marianna Buonocore, Giuseppe Santarpino, Theodor J.M. Fischlein, Marilena Cipollaro, Marisa De Feo, Alessandro Della Corte
Journal: Circulation Research (2017)

Rationale: The pathogenesis of bicuspid aortic valve (BAV)–associated aortopathy is poorly understood, and no prognostic biomarker is currently available. Objective: We aimed to identify putative circulating biomarkers pathogenetically and prognostically linked to bicuspid aortopathy. Methods and Results: By reverse transcription polymerase chain reaction, we evaluated gene expression variations (versus normal aorta) of transforming growth factor-β1 (TGF-β1), connective tissue growth factor, matrix metalloproteinase-2 (MMP-2), MMP-14, endoglin (ENG), and superoxide dismutase 3 in ascending aorta samples from 50 tricuspid and 70 patients with BAV undergoing surgery for aortic stenosis (aorta diameter ≤45 mm: BAV non-dil or &gt;45 mm: BAV dil ). Expression changes of the TGF-β1 active dimer and ENG were analyzed also by Western blot in ascending aorta samples from other 10 tricuspid aortic valve, 10 BAV non-dil , and 10 BAV dil patients. The serum concentration of study targets was assessed through ELISA and the ratio of serum TGF-β1/ENG (T/E) was evaluated. All BAV non-dil patients underwent follow-up echocardiography to assess aortic growth rate. In BAV non-dil patients, TGF-β1 and MMP-2 gene expression increased significantly, whereas MMP-14 and ENG expression decreased versus controls. Expression changes were confirmed at protein level for TGF-β1 and ENG. TGF-β1 serum concentration significantly decreased in tricuspid aortic valve and BAV non-dil patients versus healthy subjects. ENG serum concentration decreased in all patients, more markedly in BAV dil . A significant increase of the T/E ratio versus healthy subjects was unique of patients with BAV. In BAV non-dil patients, a T/E ≥9 was independently associated in multivariable analysis with higher MMP-2 and lower superoxide dismutase 3 gene expression, independent of age and aortic diameter. A significant correlation was observed between baseline T/E ratio and aortic diameter growth rate in BAV non-dil patients ( r =0.66, P &lt;0.001). Conclusions: The novel evidence of a possible value of the T/E ratio as a biomarker of BAV aortopathy was presented: further validation studies are warranted.
Erratum. Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide in Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin: The LixiLan-L Randomized Trial. Diabetes Care 2016;39:1972–1980
Authors: Vanita R. Aroda, Julio Rosenstock, Carol Wysham, Jeffrey Unger, Diego Bellido, Guillermo González-Gálvez, Akane Takami, Hailing Guo, Elisabeth Niemoeller, Elisabeth Souhami, Richard M. Bergenstal
Journal: Diabetes Care (2017)
TCTAP A-041 Safety and Efficacy of Sirolimus Coated Balloon for the Treatment of Coronary Small Vessel Disease: Results from Real World Multicenter Study
Authors: Bernardo Cortese, Sameer Dani, Keyur Parikh, Ranjan Shetty, N Prathap Kumar, Jagdish Hiremath
Journal: Journal of the American College of Cardiology (2017)
Splenic Ly6Ghigh mature and Ly6Gint immature neutrophils contribute to eradication of <i>S. pneumoniae</i>
Authors: Justin F. Deniset, Bas G. Surewaard, Woo-Yong Lee, Paul Kubes
Journal: The Journal of Experimental Medicine (2017)

The spleen plays an integral protective role against encapsulated bacterial infections. Our understanding of the associated mechanisms is limited to thymus-independent (TI) antibody production by the marginal zone (MZ) B cells, leaving the contribution of other splenic compartments such as the red pulp (RP) largely unexplored despite asplenic patients succumbing to the infection in the first 24 h, suggesting important antibody-independent mechanisms. In this study, using time-lapse intravital imaging of the spleen, we identify a tropism for Streptococcus pneumoniae in this organ mediated by tissue-resident MZ and RP macrophages and a protective role for two distinct splenic neutrophil populations (Ly6Ghi and Ly6Gintermediate) residing in the splenic RP. Splenic mature neutrophils mediated pneumococcal clearance in the spleen by plucking bacteria off the surface of RP macrophages that caught the majority of bacteria in a complement-dependent manner. This neutrophil phagocytic capacity was further enhanced after TI antibody production. Resident immature neutrophils (Ly6Gintermediate) in the spleen undergo emergency proliferation and mobilization from their splenic niche after pneumococcal stimulation to increase the effector mature neutrophil pool. We demonstrate that splenic neutrophils together with two macrophage populations and MZ B cells regulate systemic S. pneumoniae clearance through complementary mechanisms.
A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of LATS1
Authors: Wen Ni, Yuqin Zhang, Zetao Zhan, Feng Ye, Yonghao Liang, Jing Huang, Keli Chen, Longhua Chen, Yi Ding
Journal: Journal of Hematology & Oncology (2017)

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and tumor recurrence and metastasis are major factors that contribute to the poor outcome of patients with HCC. Long noncoding RNAs (lncRNAs) are known to regulate different tumorigenic processes, and a growing body of evidence indicates that Hippo kinase signaling is inactivated in many cancers. However, the upstream lncRNA regulators of Hippo kinase signaling in HCC are poorly understood.Using a lncRNA microarray, we identified a novel lncRNA, uc.134, whose expression was significantly decreased in the highly aggressive HCC cell line HCCLM3 compared with MHCC97L cells. Furthermore, we evaluated uc.134 expression in clinical samples using in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The full-length transcript of uc.134 was confirmed using rapid amplification of cDNA ends (RACE) analyses. To investigate the biological function of uc.134, we performed gain-of-function and loss-of-function studies both in vitro and in vivo. The underlying mechanisms of uc.134 in HCC were investigated using RNA pulldown, RNA immunoprecipitation, ubiquitination assays, Western blotting, mRNA microarray analyses, and qRT-PCR analyses.The ISH assay revealed that uc.134 expression was significantly decreased in 170 paraffin-embedded samples from patients with HCC compared with adjacent tissues and uc.134 expression directly correlated with patient prognosis. Furthermore, we defined a 1867-bp full-length transcript of uc.134 using 5'- and 3'-RACE analysis. The overexpression of uc.134 inhibited HCC cell proliferation, invasion, and metastasis in vitro and in vivo, whereas the knockdown of uc.134 produced the opposite results. Furthermore, we confirmed that uc.134 (1408-1867 nt) binds to CUL4A (592-759 aa region) and inhibits its nuclear export. Moreover, we demonstrated that uc.134 inhibits the CUL4A-mediated ubiquitination of LATS1 and increases YAPS127 phosphorylation to silence the target genes of YAP. Finally, a positive correlation between uc.134, LATS1, and pYAPS127 was confirmed in 90 paraffin-embedded samples by ISH and immunohistochemical staining.Our study identifies that a novel lncRNA, uc.134, represses hepatocellular carcinoma progression by inhibiting the CUL4A-mediated ubiquitination of LATS1 and increasing YAPS127 phosphorylation. The use of this lncRNA may offer a promising treatment approach by inhibiting YAP and activating Hippo kinase signaling.
Physicians Must Discuss Potential Long-Term Risks of Fecal Microbiota Transplantation to Ensure Informed Consent
Authors: Eline M. Bunnik, Nikkie Aarts, Lea Ann Chen
Journal: The American Journal of Bioethics (2017)

textabstractFecal microbiota transplantation (FMT) for patients with
multiply recurrent Clostridium difficile (C. difficile) infections
despite standard medical treatment is considered both
effective, with approximately 90% cured (Aroniadis et al.
2016), and acceptable regarding short-term safety concerns.
Doctors who perform FMT often also receive
requests for the treatment from patients suffering from a
range of other conditions, including irritable bowel syndrome
and inflammatory bowel diseases, such as Crohn’s
disease and ulcerative colitis. Sometimes patients request
FMT prior to accepting standard treatment options, and
thus seem to prefer it to standard of care. Other patients
request FMT for non-gastrointestinal disorders, in which
disease etiology and activity may be more tenuously
linked to gut bacteria. These examples highlight the growing
popularity of FMT, which in turn gives rise to concerns
regarding appropriate informed consent for the procedure.
Erratum: HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women (Nature Medicine 1, 59-64, (1995))
Authors: S Rowland-Jones, J Sutton, K Ariyoshi, T Dong, F Gotch, S McAdam, D Whitby, S Sabally, A Gallimore, T Corrah, M Takiguchi, T Schultz, A McMichael, H Whittle
Journal: Nature Medicine (1995)
TCTAP A-026 Circadian Rhythm in Southeast Asian Patients with ST-elevation Myocardial Infarction and the Differences in Clinical Characteristics and Outcomes
Authors: Kah Hua Peck, Violet Hoon, Wee Kiat Ang, Jason Kwok Kong Loh, Fahim Haider Jafary, David Foo, Timothy James Watson, Paul JL Ong, Hee Hwa Ho
Journal: Journal of the American College of Cardiology (2017)
Water-soluble chitosan inhibits nerve growth factor and attenuates allergic inflammation in mite allergen–induced allergic rhinitis
Authors: Pei-Chi Chen, Miao-Hsi Hsieh, Wen-Shuo Kuo, Hui-Fan Kao, Chih-Li Hsu, Jiu-Yao Wang
Journal: Journal of Allergy and Clinical Immunology (2017)
Performance of influenza case definitions for influenza community surveillance: based on the French influenza surveillance network GROG, 2009-2014
Authors: Jean-Sebastien Casalegno, Daniel Eibach, Martine Valette, Vincent Enouf, Isabelle Daviaud, Sylvie Behillil, Astrid Vabret, Jean Claude Soulary, Mehdi Benchaib, Jean Marie Cohen, Sylvie van der Werf, Anne Mosnier, Bruno Lina
Journal: Eurosurveillance (2017)

International case definitions recommended by the Centers for Disease Control and Prevention (CDC), the European Centre for Disease Prevention and Control (ECDC), and the World Health Organization (WHO) are commonly used for influenza surveillance. We evaluated clinical factors associated with the laboratory-confirmed diagnosis of influenza and the performance of these influenza case definitions by using a complete dataset of 14,994 patients with acute respiratory infection (ARI) from whom a specimen was collected between August 2009 and April 2014 by the Groupes Régionaux d’Observation de la Grippe (GROG), a French national influenza surveillance network. Cough and fever ≥ 39 °C most accurately predicted an influenza infection in all age groups. Several other symptoms were associated with an increased risk of influenza (headache, weakness, myalgia, coryza) or decreased risk (adenopathy, pharyngitis, shortness of breath, otitis/otalgia, bronchitis/ bronchiolitis), but not throughout all age groups. The WHO case definition for influenza-like illness (ILI) had the highest specificity with 21.4%, while the ECDC ILI case definition had the highest sensitivity with 96.1%. The diagnosis among children younger than 5 years remains challenging. The study compared the performance of clinical influenza definitions based on outpatient surveillance and will contribute to improving the comparability of data shared at international level.