tbuckley/cabot-search huggingface dataset:
Abstract 12656: Phosphodiesterase 4 (PDE4) Inhibition Induces Weight Loss and Improves Insulin Resistance via cAMP-EPAC-AMPK Mediated Reprogramming of Macrophages
Authors: Chaoneng Wu, Andrei Maiseyeu, Jeffrey A Deiuliis, Jixin Zhong, Xiaoquan Rao, Zhekang Ying, Vaishali Bagalkot, Sanjay Rajagopalan
Journal: Circulation (2015)

Objective: Recent evidence suggests an important role for cAMP-dependent pathways in modulation of innate immune function. Phosphodiesterase 4 (PDE4) is widely expressed in innate immune cells such as macrophages/dendritic cells with potent anti-inflammatory effects on pharmacologic inhibition of the enzyme. We investigated the importance of PDE4 in diet-induced obesity (DIO) and hypothesized that PDE4 inhibition will improve insulin sensitivity and reduce inflammation. Methods and Results: PDE4 was upregulated in both visceral and subcutaneous (SubQ) white adipose tissue (WAT) in DIO mice (12 weeks of high-fat diet, HFD, 60% fat) compared to normal-chow diet (NCD) mice (↑4∼10-folds, p&lt;0.01). The degree of expression was correlated with macrophage infiltration in stromal vascular fraction from WAT (CD11b + F4/80 + cells, r=0.56, p&lt;0.05). Treatment with Roflumilast (3mg/kg/day), a high affinity inhibitor of PDE4 (IC 50 0.39 nM) versus vehicle control (n=6∼10 in each group) for 21 days concomitant with HFD, resulted in rapid and substantial weight loss (↓45.8% fat content), enhanced thermogenesis [(∼20% higher oxygen consumption and heat production, 0.7∼1.1°C higher core body temperature in a cold environment (4°C)], brown adipose reprogramming, improvement in insulin resistance (HOMA-IR ↓ from 0.69±0.04 to 0.44±0.01, p&lt;0.01) and hepatic steatosis. These changes were paralleled by increased alternative macrophage activation (Altf), reduced inflammation in WAT [↑CD206 and CD301 by flow cytometry with ↓ TNF/IL-6 gene expression] and activation of thermogenic genes in brown adipose tissue. In-vitro treatment of mouse bone marrow-derived macrophages (BMDM) promoted Altf and increased expression of tyrosine hydroxylase (↑2.5 folds) and catecholamines secretion. Additional experiments with agents that augment/reduce intracellular cAMP/EPAC/AMPK revealed an essential role for this cascade in Altf activation and catecholamine release. Conclusions: PDE4 antagonism improves obese diabetic symptoms through convergent pathways involving Altf activation and enhancing thermogenesis via cAMP dependent modulation of macrophage catecholamine release.
Sonic hedgehog promotes tumor growth, metastasis and desmoplasia in pancreatic cancer
Authors: Jennifer Bailey, Michel Ouellette, Michael Hollingsworth
Journal: Cancer Research (2007)

5366  Sonic hedgehog (Shh) is tightly regulated throughout development, with expression restricted to patterns within specific organs of a developing embryo. Aberrant expression of Shh is associated with the development and progression of pancreatic cancer. A current model posits that pancreatic cancer results from an accumulation of genetic and epigenetic events including mutations that activate Kras and p21, followed by decreased expression and/or mutations of tumor suppressor genes including p53 and p16INK4A. We investigated the role of interactions between these pathways and Shh during the stepwise transformation of primary pancreatic epithelial cells.  	A normal pancreatic epithelial cell line was immortalized by stable expression of recombinant human telomerase, hTert-HPNE, and several sub-lines were established that contain additional genetic insults in pathways that lead to pancreatic cancer progression. One sub-line expresses mutant K-ras, another the human papillomavirus E6/E7 proteins, a third line has mutant K-ras and E6/E7 in combination, and a fourth cell line expresses K-ras, E6/E7 and the SV40 small T antigen (transformed HPNE). We transduced a retroviral vector into all of these cell lines that causes overexpression of Shh.  	Shh expression in vivo significantly decreased the time-to-tumor-progression of the transformed HPNE cell line. In an orthotopic model of tumor challenge, Shh increased tumor size and incidence of metastasis to the spleen, peritoneum and liver. Primary tumors expressing Shh displayed increased desmoplasia, and showed significant infiltration of myofibroblasts as evidenced by analysis of cellular morphology and IHC staining of tumor sections for both vimentin and α-smooth muscle actin. Additional analysis showed evidence of responses to Shh signaling by myofibroblasts (Gli expression). In vitro invasion experiments with Shh and a human pancreatic myofibroblast cell line suggested that Shh can act as a chemoattractant, increasing the invasive potential of human pancreatic myofibroblasts. These data suggest that Shh, secreted from pancreatic epithelia, may be a critical player in the tumor microenvironment and progression of pancreatic cancer.
Abstract 17460: Phenotypic Correlates of Incidentally Discovered Pathogenic Variants in Aortopathy Genes
Authors: Zi Ye, Robyn L Fossey, Iftikhar J Kullo
Journal: Circulation (2017)

Introduction:  The ACMG recommends reporting incidentally discovered pathogenic variants in aortopathy genes. We investigated the electronic health records (EHR) to assess phenotypic correlates of pathogenic/likely pathogenic (P/LP) variants in 10 genes related to hereditary aortopathy.   Methods:  The 10 aortopathy genes (Table) were sequenced in 2,344 individuals participating in the Mayo Return of Actionable Variants Empirical (RAVE) study. Of 1092 individuals with transthoracic echocardiography (TTE) data in the EHR, 26 were P/LP variant carriers including one with Marfan syndrome (MFS). After excluding this patient, for each P/LP variant carrier, we randomly selected 2 to 5 non-carriers matching by referral diagnoses, sex and age (± 5 years) at most recent TTE evaluation, and compared aortic root dimension, presence of aneurysms and tortuous arteries on imaging reports, and EHR traits between two groups (Table).   Results:  Participant characteristics and clinical features are summarized in Table. Although none of the P/LP variant carriers had an aortic aneurysm on TTE, they had larger aortic root size, and were more likely to have tortuous arteries, temporomandibular dysfunction, varicose vein, movement disorders than non-carriers (Table). In a separate analysis of all individuals with TTE (1 with MFS excluded), aortic root size was larger in individuals carrying a P/LP variant in 10 genes than in non-carriers during a mean follow- up of 12.8 ±7.8 years [assessed by a mix-effects model, mean difference (95%) in z-score: 0.6 (0.18-1.02) unit].   Conclusions:  None of the individuals carrying a P/LP variant in aortopathy genes had an ascending aortic aneurysm or history of aortic dissection. However, P/LP variant carriers were more likely to have clinical features related to hereditary aortopathy than non-carriers. Further work is warranted to determine the clinical implications after such incidental genomic findings returned.
Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study)
Authors: João Figueira, Emily Fletcher, Pascale Massin, Rufino Silva, Francesco Bandello, Edoardo Midena, Monica Varano, Sobha Sivaprasad, Haralabos Eleftheriadis, Geeta Menon, Miguel Amaro, Sarah Ayello Scheer, Catherine Creuzot-Garcher, João Nascimento, Dalila Alves, Sandrina Nunes, Conceição Lobo, José Cunha-Vaz
Journal: Ophthalmology (2018)
Venoms of Neotropical wasps lack cross-reactive carbohydrate determinants enabling reliable protein-based specific IgE determination
Authors: Amilcar Perez-Riverol, Michaela Miehe, Frederic Jabs, Henning Seismman, Luís Gustavo Romani Fernandes, Ricardo de Lima Zollner, Thilo Jakob, Marcia R. Brochetto Braga, Edzard Spillner
Journal: Journal of Allergy and Clinical Immunology (2018)
MHC-Matching at 5 Loci Results in Higher Levels of Engraftment of Allogeneic Cord Blood (CB) Hematopoietic Stem Cells (HSC) Following Neonatal Transplantation.
Authors: Graca Almeida-Porada, Christopher D. Porada, Christine LeBlanc, Joao L. Ascensao, Ian K. McNiece, Esmail D. Zanjani
Journal: Blood (2008)
Pilot Study of Imatinib Discontinuation in Patients with Chronic Myeloid Leukemia with Deep Molecular Response (EDI-PIO) — Evaluation of Pioglitazone in Treatment-Free Remission
Authors: Katia B Pagnano, Eliana C Miranda, Marcia Torresan Delamain, Gislaine Oliveira Duarte, Bruna Virgilio, Jessica Vianna, Erich Vinicius De Paula, Carmino Antonio De Souza
Journal: Blood (2017)
Trends in use of radiation therapy from 2000 to 2012 using National Cancer Database (NCDB): Is less the new more?
Authors: Gaurav Goyal, Peter T. Silberstein, James O. Armitage
Journal: Journal of Clinical Oncology (2015)

e19501 Background: Hodgkin Lymphoma (HL) is one of the few malignancies that have been converted from a disease with high mortality to a cure rate of almost 75% over the past years. Since most of the patients are cured, treatment- related toxicities have become a major concern (secondary malignancies, thyroid dysfunction, cardiac toxicities). Current guidelines recommend combined modality therapy (radiation and chemotherapy) or chemotherapy alone in early stage (I-II) HL and combination chemotherapy for advanced stage (III-IV) HL. Our aim was to analyze NCDB for trends in radiation therapy (RT) use among all stages of HL from 2000 to 2012. Methods: It is a retrospective study of patients diagnosed with HL (Stage I-IV) between the years 2000 and 2012 utilizing NCDB (n= 77840). NCDB contains ~70% of all new cancer diagnoses from >1,500 American College of Surgeons-accredited cancer programs in the United States and Puerto Rico. Patients who received radiation therapy were eligible for the study (n=24,118). Chi- square test was used as the test of significance (p- value<0.05). Results: Between the years 2000 and 2012, use of RT declined among all stages of HL; Stage I (53% to 40%, p-value 0.0002), Stage II (52% to 36%, p value <0.0001), Stage III (21% to 10%, p-value <0.0001), Stage IV (17% to 9%, p-value 0.0002) (Table 1). Conclusions: This is the largest study evaluating radiation therapy in patients with stage I-IV Hodgkin lymphoma. There has been a significant decline in the use of RT from 2000 to 2012 among all stages of HL.The degree of decline seems more for advanced stage as compared to early stage HL. Reduction in RT use could be attributed partly to studies showing similar patient survival with its omission, and partly to its long-term toxicities. The selection of therapy must balance the goal of high cure rate and the need to reduce long-term complications. Radiation therapy use in stage I-IV Hodgkin Lymphoma from 2000-2012. Year of Diagnosis Stage I(%) Stage II(%) Stage III(%) Stage IV(%) 2000 53 52 21 17 2001 52 57 21 14 2002 52 55 21 16 2003 49 54 23 15 2004 52 52 20 16 2005 44 47 20 18 2006 47 49 19 16 2007 43 44 14 13 2008 45 44 14 16 2009 44 44 13 14 2010 46 44 15 14 2011 45 41 11 10 2012 40 36 10 9 p-value 0.0002 < 0.0001 <0.0001 0.0002
Bortezomib plus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 Trial.
Authors: B Coiffier, Ea Osmanov, X Hong, A Scheliga, J Mayer, F Offner, S Rule, A Teixeira, J Walewski, S de Vos, M Crump, O Shpilberg, Dl Esseltine, E Zhu, C Enny, P Theocharous, H van de Velde, Ya Elsayed, Pl Zinzani, Lym study investigators, Marina. Liberati Anna
Journal: The Lancet Oncology (2011)
Effect of Topical Cyclosporine Rinse on Oral Lichen Planus
Authors: Drore Eisen, Charles N. Ellis, Elizabeth A. Duell, Christopher E.M. Griffiths, John J. Voorhees
Journal: New England Journal of Medicine (1990)

Oral lichen planus is a relatively common disorder of the mouth that can be debilitating. It is frequently palliated with topical or systemic corticosteroids and retinoids. These treatments require prolonged use, however, and are not always effective.
Distinct genetic alteration profiles of acute myeloid leukemia between Caucasian and Eastern Asian population
Authors: Hui Wei, Ying Wang, Chunlin Zhou, Dong Lin, Bingcheng Liu, Kaiqi Liu, Shaowei Qiu, Benfa Gong, Yan Li, Guangji Zhang, Shuning Wei, Xiaoyuan Gong, Yuntao Liu, Xingli Zhao, Runxia Gu, Yingchang Mi, Jianxiang Wang
Journal: Journal of Hematology & Oncology (2018)

Racial and ethnic disparities in malignancies attract extensive attention. To investigate whether there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population, data from several prospective AML trials were retrospectively analyzed in this study. We found that there were more patients with core binding factor (CBF) leukemia in Eastern Asian cohorts and there were different CBF leukemia constitutions between them. The ratios of CBF leukemia are 27.7, 22.1, 21.1, and 23.4%, respectively, in our (ChiCTR-TRC-10001202), another Chinese, Korean, and Japanese Eastern Asian cohorts, which are significantly higher than those in ECOG1900, MRC AML15, UK NCRI AML17, HOVON/SAKK AML-42, and German AML2003 (15.5, 12.5, 9.3, 10.2, and 12%, respectively). And CBFbeta-MYH11 occurred more prevalently in HOVON/SAKK AML- 42 and ECOG1900 trials (50.0 and 54.3% of CBF leukemia, respectively) than in Chinese and Japanese trials (20.1 and 20.8%, respectively). The proportion of FLT3-ITD mutation is 11.2% in our cohort, which is lower than that in MRC AML15 and UK NCRI AML17 (24.6 and 17.9%, respectively). Even after excluding the age bias, there are still different incidence rates of mutation between Caucasian and Eastern Asian population. These data suggest that there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population.
The Immunomodulatory Drugs, through Loss of Ikaros and Aiolos, Derepress CD38 and Functionally Synergise with Daratumumab
Authors: Pasquale L. Fedele, Simon Willis, Michael S. Low, Jai Rautela, David H. Segal, Jianan Gong, Yang Liao, Nicholas Huntington, Wei Shi, David Huang, George Grigoriadis, Julie Tellier, Stephen Nutt
Journal: Blood (2017)
Flu infection raises risk of heart attack in first seven days
Authors: Jacqui Wise
Journal: BMJ (2018)

The risk of myocardial infarction is six times higher within the first seven days of a laboratory confirmed influenza diagnosis, according to research published in the New England Journal of Medicine .1 The risk is highest for older adults, patients with influenza B infections, and patients having their first heart attack.

The Canadian researchers said that their findings reinforce the importance of vaccination and that patients should not delay evaluation for heart symptoms, particularly in the first week of an acute respiratory infection. The study comes as the UK continues to see a rise in flu hospitalisations and GP consultations.

Previous studies …
Friends and family test should no longer be mandatory
Authors: Glenn Robert, Jocelyn Cornwell, Nick Black
Journal: BMJ (2018)

Background  Recently, a patient with maternal uniparental disomy of chromosome 16 (UPD(16)mat) presenting with Silver-Russell syndrome (SRS) phenotype was reported. SRS is characterised by growth failure and dysmorphic features.  Objective  To clarify the prevalence of UPD(16)mat in aetiology-unknown patients with SRS phenotype and phenotypic differences between UPD(16)mat and SRS.  Methods  We studied 94 patients with SRS phenotype of unknown aetiology. Sixty-three satisfied the Netchine-Harbison clinical scoring system (NH-CSS) criteria, and 25 out of 63 patients showed both protruding forehead and relative macrocephaly (clinical SRS). The remaining 31 patients met only three NH-CSS criteria, but were clinically suspected as having SRS. To detect UPD(16)mat, we performed methylation analysis for the ZNF597:TSS-differentially methylated region (DMR) on chromosome 16 and subsequently performed microsatellite, SNP array and exome analyses in the patients with hypomethylated ZNF597:TSS-DMR.  Results  We identified two patients (2.1%) with a mixture of maternal isodisomy and heterodisomy of chromosome 16 in 94 aetiology-unknown patients with SRS phenotype. Both patients exhibited preterm birth and prenatal and postnatal growth failure. The male patient had ventricular septal defect and hypospadias. Whole-exome sequencing detected no gene mutations related to their phenotypes.  Conclusion  We suggest considering genetic testing for UPD(16)mat in SRS phenotypic patients without known aetiology.
Differential gene expression profiles of normal human bronchial epithelial (NHBE) cells following exposure to mainstream cigarette smoke and smoke condensate from tobacco-burning and primarily tobacco-heating cigarettes
Authors: Wanda Fields, Mary Borgeding, Pamela Odom, Betsy Bombick, David Doolittle
Journal: Cancer Research (2008)

1755   Cigarette mainstream smoke (MSS), a complex chemical mixture consisting of particulate and vapor phases, has been shown to affect genes in multiple signal transduction pathways including those involved in inflammation and oxidative stress. Our laboratory previously reported that the particulate phase of smoke (cigarette smoke condensate, CSC) from cigarettes that primarily heat tobacco produce less molecular effects in normal human bronchial epithelial (NHBE) cells than CSC from tobacco-burning cigarettes. The objective of this study was to compare the effects of MSS from tobacco-burning and tobacco-heating cigarettes on gene expression and proliferation in NHBE cells using quantitative RT/PCR and neutral red uptake assays. Kentucky 2R4F cigarettes (K2R4F), designed to represent the average low “tar” cigarette in the US market, served as the reference cigarette and Eclipse, a cigarette that primarily heats tobacco, was the test cigarette. Mainstream smoke was generated under Federal Trade Commission conditions (35 ml puff of 2 second duration, taken once per minute). NHBE cells were exposed to filtered air or 0.03 - 0.12 mg wet total particulate matter (WTPM)/L of MSS from K2R4F or Eclipse. K2R4F MSS resulted in temporal up-regulation of HO-1, HSP-70, COX-2, IL-8 and CYP1B1 compared to filtered air. K2R4F elicited statistically significant (p
Case 2-2018: A 41-Year-Old Woman with Vision Disturbances and Headache
Authors: Dean M. Cestari, Mary E. Cunnane, Joseph F. Rizzo, John H. Stone
Journal: New England Journal of Medicine (2018)

A 41-year-old woman with systemic lupus erythematosus presented with worsening headache, pulsatile tinnitus, and transient vision loss. Ophthalmologic examination revealed bilateral optic-disk edema with splinter and subretinal hemorrhages. A diagnosis was made.
Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation
Authors: Jennifer M. Felton, Christopher D. Lucas, David A. Dorward, Rodger Duffin, Tiina Kipari, Sonja Vermeren, Calum T. Robb, Kenneth G. MacLeod, Bryan Serrels, Jürgen Schwarze, Christopher Haslett, Ian Dransfield, Adriano G. Rossi
Journal: Journal of Allergy and Clinical Immunology (2018)

BackgroundEosinophils play a central role in propagation of allergic diseases, including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia, but the question of whether alterations in apoptotic cell clearance by phagocytes contributes directly to resolution of allergic airway inflammation remains unexplored.ObjectivesIn this study we investigated the role of the receptor tyrosine kinase Mer in mediating apoptotic eosinophil clearance and allergic airway inflammation resolution in vivo to establish whether apoptotic cell clearance directly affects the resolution of allergic airway inflammation.MethodsAlveolar and bone marrow macrophages were used to study Mer-mediated phagocytosis of apoptotic eosinophils. Allergic airway inflammation resolution was modeled in mice by using ovalbumin. Fluorescently labeled apoptotic cells were administered intratracheally or eosinophil apoptosis was driven by administration of dexamethasone to determine apoptotic cell clearance in vivo.ResultsInhibition or absence of Mer impaired phagocytosis of apoptotic human and mouse eosinophils by macrophages. Mer-deficient mice showed delayed resolution of ovalbumin-induced allergic airway inflammation, together with increased airway responsiveness to aerosolized methacholine, increased bronchoalveolar lavage fluid protein levels, altered cytokine production, and an excess of uncleared dying eosinophils after dexamethasone treatment. Alveolar macrophage phagocytosis was significantly Mer dependent, with the absence of Mer attenuating apoptotic cell clearance in vivo to enhance inflammation in response to apoptotic cells.ConclusionsWe demonstrate that Mer-mediated apoptotic cell clearance by phagocytes contributes to resolution of allergic airway inflammation, suggesting that augmenting apoptotic cell clearance is a potential therapeutic strategy for treating allergic airway inflammation.
Combined Ectopic Expression of Homologous Recombination Factors Promotes Embryonic Stem Cell Differentiation
Authors: Eui-Hwan Choi, Seobin Yoon, Keun P. Kim
Journal: Molecular Therapy (2018)

Homologous recombination (HR), which ensures accurate DNA replication and strand-break repair, is necessary to preserve embryonic stem cell (ESC) self-renewal. However, little is known about how HR factors modulate ESC differentiation and replication stress-associated DNA breaks caused by unique cell-cycle progression. Here, we report that ESCs utilize Rad51-dependent HR to enhance viability and induce rapid proliferation through a replication-coupled pathway. In addition, ESC differentiation was shown to be enhanced by ectopic expression of a subset of recombinases. Abundant expression of HR proteins throughout the ESC cycle, but not during differentiation, facilitated immediate HR-mediated repair of single-stranded DNA (ssDNA) gaps incurred during S-phase, via a mechanism that does not perturb cellular progression. Intriguingly, combined ectopic expression of two recombinases, Rad51 and Rad52, resulted in efficient ESC differentiation and diminished cell death, indicating that HR factors promote cellular differentiation by repairing global DNA breaks induced by chromatin remodeling signals. Collectively, these findings provide insight into the role of key HR factors in rapid DNA break repair following chromosome duplication during self-renewal and differentiation of ESCs.Graphical abstract
Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence
Authors: Giovanna Cutrona, Claudio Tripodo, Serena Matis, Anna Grazia Recchia, Carlotta Massucco, Marina Fabbi, Monica Colombo, Laura Emionite, Sabina Sangaletti, Alessandro Gulino, Daniele Reverberi, Rosanna Massara, Simona Boccardo, Daniela de Totero, Sandra Salvi, Michele Cilli, Mariavaleria Pellicanò, Martina Manzoni, Sonia Fabris, Irma Airoldi, Francesca Valdora, Silvano Ferrini, Massimo Gentile, Ernesto Vigna, Sabrina Bossio, Laura De Stefano, Angela Palummo, Giovanni Iaquinta, Martina Cardillo, Simonetta Zupo, Giannamaria Cerruti, Adalberto Ibatici, Antonino Neri, Franco Fais, Manlio Ferrarini, Fortunato Morabito
Journal: Science Translational Medicine (2018)

Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rβ1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rβ1 chain when cocultured with activated T cells or CD40L+ cells. CLL cells activated in vitro in this context produced IL-23, a finding that, together with the presence of IL-23 in CLL lymphoid tissues, suggests the existence of an autocrine/paracrine loop inducing CLL cell proliferation. Interference with the IL-23R/IL-23 axis using an anti-IL-23p19 antibody proved effective in controlling disease onset and expansion in xenografted mice, suggesting potential therapeutic strategies.