tbuckley/cabot-search huggingface dataset:
Abstract IA09: The dynamics of cancer cell heterogeneity
Authors: Guido Lenz, Giovana R. Onzi, Luiza C. Pereira, Karen Breitenbach, Luana s. Lenz, Brunnet G. Leonardo, Eloisa Dalsin
Journal: Clinical Cancer Research (2018)

Abstract Cancer cells behave heterogeneously regarding proliferation and survival to therapy. This heterogeneity is not static, fluctuating over time with different frequencies and amplitudes. Here we set out to measure the dynamics of the proliferative and tolerant phenotype of untreated and glioma cell lines treated with temozolomide (TMZ) and/or cisplatin. For this, we followed single clones of glioma cells and measured the number of cells in each clone for three consecutive time points. The larger the clone, the more similar is their proliferation rate among clones of the same size, indicating that division shuffled the proliferation phenotypes of the cells. The response to TMZ or cisplatin is highly variable in small clones, but this response becomes more homogeneous with the increase in colony size, due to small heritability of the phenotype that controls the response to these drugs. The reduction in variance in relation to colony size is twice as high for the response to TMZ or cisplatin when compared to untreated colonies. Inhibition of HDAC prior to treatment freezes the variability of the response to TMZ, but not cisplatin, so that small and large colonies respond with the same variance. This indicates that the response to TMZ is phenocopied over generations of cells in the presence of HDAC inhibition, but rapidly fluctuates in its absence. With the aid of a computational model of the mother-daughter and sister-sister differences in proliferation and survival in the presence of the chemotherapeutic drugs, we described the dynamics of these phenotypes in response to TMZ, cisplatin, and their combination. We conclude that the proliferative and response to chemotherapeutic phenotypes fluctuate with time and can be stabilized with inhibition of HDACs, with important insights into drug combination to improve therapeutic potential. Citation Format: Guido Lenz, Giovana R. Onzi, Luiza C. Pereira, Karen Breitenbach, Luana s. Lenz, Brunnet G. Leonardo, Eloisa Dalsin. The dynamics of cancer cell heterogeneity [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA09.
Geoffrey Harold Greatrex
Authors: Peter P Dawson
Journal: BMJ (2018)

Geoffrey Harold Greatrex lived most of his childhood in Earls Colne, Essex. His grandfather, Thomas, was a sergeant major who had served in the Boer war and lived near the gunnery ranges at Shoeburyness. His father, Harold, was the local headmaster of the village primary school. Harold was an enterprising man on a very modest income. He supplemented this by rough shooting for the pot and running evening ballroom dancing classes. To do that, he bought a disused chapel in the village and the oak floor of another chapel and married the two together. Initially the bicycle was the only means of transport, and father was known to cycle to Cambridge and back (100 miles) when a bargain was found. Geoffrey’s love of cycling came from this period. By the age of 7 he was a crack shot with the air rifle, and his early diaries detail the demise of unlucky sparrows and starlings shot around the village—no health and safety regs in those days. It was a very rural and wartime existence, and to earn pocket money, Geoffrey would work in the fields for local farmers for a few pence. With his marvellous memory he would relate all the names and occupations of the villagers. His younger brother, Tim, made up the family. The boys were always close, and it was a great loss for Geoffrey when Tim predeceased him a few years ago.

In 1952 Geoffrey enrolled at Durham University to study medicine. This took place at Newcastle. Here he met many new students, some of whom he is still in contact with. Money was always tight, and for one summer term, he saved on accommodation by living in a small tent in a farmer’s field. As winter approached, a colleague induced him to join him in very …
Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rheumatoid arthritis: development and validation of clinical predictors
Authors: Xavier M Teitsma, Johannes W G Jacobs, Paco M J Welsing, Pascal H P de Jong, Johanna M W Hazes, Angelique E A M Weel, Attila Pethö-Schramm, Michelle E A Borm, Jacob M van Laar, Floris P J G Lafeber, Johannes W J Bijlsma
Journal: Annals of the Rheumatic Diseases (2018)

To identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA).In U-Act-Early, 108 disease-modifying antirheumatic drug (DMARD)-naive patients with RA were randomised to initiate MTX therapy and treated to target until sustained remission (disease activity score assessing 28 joints (DAS28) <2.6 with four or less swollen joints for ≥24 weeks) was achieved. If no remission, hydroxychloroquine was added to the treatment regimen (ie, 'MTX+') and replaced by tocilizumab if the target still was not reached thereafter. Regression analyses were performed to identify clinical predictors for IR, defined as needing addition of a biological DMARD, to 'MTX+'. Data from the treatment in the Rotterdam Early Arthritis Cohort were used for external validation of the prediction model.Within 1 year, 56/108 (52%) patients in U-Act-Early showed IR to 'MTX+'. DAS28 (adjusted OR (ORadj) 2.1, 95% CI 1.4 to 3.2), current smoking (ORadj 3.02, 95% CI 1.1 to 8.0) and alcohol consumption (ORadj 0.4, 95% CI 0.1 to 0.9) were identified as baseline predictors. The area under the receiver operator characteristic curve (AUROC) of the prediction model was 0.75 (95% CI 0.66 to 0.84); the positive (PPV) and negative predictive value (NPV) were 65% and 80%, respectively. When applying the model to the validation cohort, the AUROC slightly decreased to 0.67 (95% CI 0.55 to 0.79) and the PPV and NPV to 54% and 80%, respectively.Higher DAS28, current smoking and no alcohol consumption are predictive factors for IR to step-up 'MTX+' in DMARD-naive patients with new-onset RA.NCT01034137; Post-results, ISRCTN26791028; Post-results.
Abstract 20865: Experience From the First-in-Human Case--A Phase I Clinical Trial Evaluating the Safety of Allogeneic Adipose Tissue-Derived Multilineage Progenitor Cells-Transplantation Therapy in Severe Familial Hypercholesterolemia Patients
Authors: Masahiro Koseki, Ayami Saga, Takeshi Okada, Koutaro Kanno, Kouichi Tomita, Keigo Osuga, Sachiko Ezoe, Makoto Nishida, Yasushi Sakata, Shizuya Yamashita
Journal: Circulation (2016)

Introduction:  Familial hypercholesterolemia (FH) is an inherited disorder, mainly caused by defects in low-density lipoprotein (LDL) receptor gene. Although most of heterozygous FH patients are able to be treated with statin, ezetimibe, bile acid sequestrants and anti-PCSK9 antibody, homozygous FH patients are resistant to drug therapy.   Hypothesis:  With the increase of the evidence about the safety of mesenchymal stem cells and percutaneous transhepatic portal approach in islet transplantation, we hypothesized that cell-transplantation therapy with allogeneic adipose tissue-derived multilineage progenitor cells, could be an alternative treatment instead of liver transplantation for severe FH patients.   Methods and Results:  We have first performed a couple of pre-clinical studies. 1) Adipose tissue were harvested from healthy donor and multi-lineage progenitor cells (ADMPCs) were isolated. ADMPCs were able to differentiate into hepatocyte-like cells by appropriate growth factor stimulation, which expressed albumin and incorporated DiI-labeled LDL particles. 2) Xenogenic ADMPCs were transplanted into WHHL rabbits, an animal model of FH, via portal vein (3x10 7  cells / rabbit). Serum total cholesterol levels were reduced significantly within four weeks and maintained to the end of study. 3) Pravastatin were administrated into WHHL rabbits after ADMPCs transplantation. Administration of statin enhanced the effect of ADMPCs transplantation by up-regulation of LDL-receptor activity and resulted in significant additional reduction in total cholesterol. Based on these evidences, we generated a protocol for the first-in-human clinical trial. Briefly, 1). 50-100 ml of subcutaneous adipose-tissue are harvested from the donor under local anesthesia. 2). ADMPCs are isolated and cultured for 3-4 weeks. 3). Allogeneic ADMPCs (1.0 x 10 7 /kg) are transplanted into FH patients via portal vein under local anesthesia. Here, we have transplanted allogeneic 4.8 x 10 8  ADMPCs into a 54 y.o. female FH patient on Feb, 2016 and the patient are currently under observation.   Conclusion:  We have experienced the first-in-human case of allogeneic ADMPCs transplantation in a severe FH patient.
Activation of β-catenin signaling in aggrecan-expressing cells in temporomandibular joint causes osteoarthritis-like defects
Authors: Tianqian Hui, Yachuan Zhou, Tingyu Wang, Jun Li, Shanxing Zhang, Lifan Liao, Jianhong Gu, Ling Ye, Lan Zhao, Di Chen
Journal: International Journal of Oral Science (2018)

β-Catenin plays a critical role in cartilage formation and development. To further understand the role of β-catenin in osteoarthritis (OA) development in temporomandibular joint (TMJ), we have generated β-catenin conditional activation mice (β-cat(ex3) Agc1CreER ) by breeding Agc1-CreER mice with β-cateninflox(ex3)/+ mice. Results of histologic analysis showed the progressive TMJ defects in 3- and 6-month-old β-cat(ex3) Agc1CreER mice (tamoxifen induction was performed at 2 weeks of age), including decreased chondrocyte numbers in the superficial layer associated with less Alcian blue staining, increased numbers of hypertrophic chondrocytes in deep layers, and rough articular surface. Compared to the TMJ phenotype of β-cat(ex3) Col2CreER mice, β-cat(ex3) Agc1CreER mice showed much severe morphological defects in the superficial layer of TMJ. This may reflect that Agc1-CreER mice could efficiently target cells in the superficial layer of TMJ. Results of immunostaining showed significantly increased expression of MMP13, Col-X, Adamts4, and Adamts5 in TMJ of β-cat(ex3) Agc1CreER mice. Results of proliferating cell nuclear antigen (PCNA), Ki67, and terminal deoxinucleotidyl transferase-mediated dUTP-fluorescein nick end labeling (TUNEL) staining further demonstrated that cell proliferation was decreased and cell apoptosis was increased in condylar cartilage of β-cat(ex3) Agc1CreER mice. Our findings indicate that abnormal upregulation of β-catenin in TMJ leads to defects assembling to OA-like phenotype, further demonstrating that β-catenin plays a critical role in TMJ pathogenesis.
New developments in patients with eosinophilic gastrointestinal diseases presented at the CEGIR/TIGERS Symposium at the 2018 American Academy of Allergy, Asthma &amp; Immunology Meeting
Authors: Jonathan M. Spergel, Seema S. Aceves, Kara Kliewer, Nirmala Gonsalves, Mirna Chehade, Joshua B. Wechsler, Marion Groetch, Joshua Friedlander, Evan S. Dellon, Wendy Book, Ikuo Hirano, Amanda B. Muir, Antonella Cianferoni, Lisa Spencer, Chris A. Liacouras, Edaire Cheng, Leah Kottyan, Ting Wen, Thomas Platts-Mills, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2018)
Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes
Authors: Fabrizio De Benedetti, Marco Gattorno, Jordi Anton, Eldad Ben-Chetrit, Joost Frenkel, Hal M. Hoffman, Isabelle Koné-Paut, Helen J. Lachmann, Seza Ozen, Anna Simon, Andrew Zeft, Inmaculada Calvo Penades, Michel Moutschen, Pierre Quartier, Ozgur Kasapcopur, Anna Shcherbina, Michael Hofer, Philip J. Hashkes, Jeroen Van der Hilst, Ryoki Hara, Segundo Bujan-Rivas, Tamas Constantin, Ahmet Gul, Avi Livneh, Paul Brogan, Marco Cattalini, Laura Obici, Karine Lheritier, Antonio Speziale, Guido Junge
Journal: New England Journal of Medicine (2018)

Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor–associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares.
Abstract P098: Slower Gait Speed is Associated with Increased Mortality Risk in Chronic Kidney Disease.
Authors: Baback Roshanravan, Cassiane Robinson-Cohen, Kushang V Patel, Greg Levin, Ian H de Boer, Jonathan Himmelfarb, Bryan Kestenbaum
Journal: Circulation (2012)

Objective: Skeletal muscle dysfunction (sarcopenia) is an under-recognized complication of chronic kidney disease (CKD) that may have important clinical consequences. Gait speed is associated with sarcopenia and comorbid disease burden among older adults; however, little is known about the prognostic significance of gait speed in CKD. We determined the association of gait speed with all-cause mortality in a prospective cohort of non-dialysis CKD patients. Methods: We measured usual gait speed over 4-meters in 309 participants from a prospective study of non-dialysis CKD. Included subjects had an estimated glomerular filtration rate (eGFR ckdepi ) &lt;90mL/min/1.73m 2 , were stroke-free and did not require a wheelchair for ambulation. Study coordinators assessed mortality during follow-up by phone contacts, medical record review, and the social security death index. We evaluated gait speed continuously, and using a cut point of 0.8 m/s, consistent with previous studies. We used Cox's proportional hazards to estimate the association of gait speed with mortality after adjustment for age, sex, race, smoking, diabetes, pre-existing CAD, BMI, eGFR and hemoglobin. Results: Median follow-up time was 2.7 years; range 27 days to 4.8 years. The mean age was 58.9 ± 13 years and mean eGFR by cystatin C (eGFR cysc ) was 48.5 ± 23mL/min/1.73m 2 . There were a total of 31 deaths (10.4%) during follow-up. Unadjusted mortality rates were 23 and 80 deaths per 1,000 person-years among participants who had a gait speed of &gt;0.8m/s versus ≤0.8m/s, respectively. After full adjustment, gait speed ≤0.8m/s was associated with a 2.8-fold greater risk of death compared to a gait speed &gt;0.8 m/s. Gait speed was also strongly associated with mortality when analyzed as a continuous variable ( Table ) and a stronger predictor of death than age, history of CAD, or diabetes. No. Deaths (%) Model 1 + Model 2 # Hazard Ratio 95% CI Hazard Ratio 95% CI Gait speed * 32(10) 0.74 (0.64-0.86) 0.75 (0.64-0.87) &gt;0.8m/s 13 (6) Reference Reference ≤0.8m/s 19(19) 3.49 (1.54-7.95) 2.84 (1.25-6.48) * Gait speed analyzed continuously per 10cm/s increase in speed. +Model 1: Adjusted for age, sex, race, study site #Model 2: adds smoking, BMI, eGFR cysc , diabetes, prevalent coronary disease. Conclusion: Gait speed is strongly associated with death in a cohort of middle-aged CKD patients.
Multidomain Quantitative Recovery Following Radical Cystectomy for Patients Within the Robot-assisted Radical Cystectomy with Intracorporeal Urinary Diversion Versus Open Radical Cystectomy Randomised Controlled Trial: The First 30 Patients
Authors: James W.F. Catto, Pramit Khetrapal, Gareth Ambler, Rachael Sarpong, Ingrid Potyka, Muhammad Shamim Khan, Melanie Tan, Andrew Feber, Liam Bourke, Aidan P. Noon, Simon Dixon, Louise Goodwin, Norman R. Williams, Edward Rowe, Anthony Kouparis, John McGrath, Chris Brew-Graves, John D. Kelly
Journal: European Urology (2018)
Epithelial proliferation in inflammatory skin disease is regulated by tetratricopeptide repeat domain 7 (Ttc7) in fibroblasts and lymphocytes
Authors: Ursina Nüesch, Andrea A. Mauracher, Lennart Opitz, Benjamin Volkmer, Katarzyna Michalak-Mićka, Jivko Kamarashev, Tom Hartwig, Ernst Reichmann, Burkhard Becher, Stefano Vavassori, Jana Pachlopnik Schmid
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 18093: Effect of Left Ventricular Function on Post Transcatheter Aortic Valve Replacement Hemodynamics
Authors: Allan Chen, Vishal Parikh, Allen Brown, Gregory Coffman, Fadi Matar, Christiano Caldeira, John Sullebarger, Robert Hooker, Kevin Kip, Arthur Labovitz, Aarti Patel
Journal: Circulation (2016)

Introduction: Transcatheter aortic valve replacement (TAVR) causes immediate and long term hemodynamic effects that have not yet been clearly defined. This study sought to identify the effect of TA...
Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers
Authors: Brian R. Untch, Vanessa Dos Anjos, Maria E.R. Garcia-Rendueles, Jeffrey A. Knauf, Gnana P. Krishnamoorthy, Mahesh Saqcena, Umeshkumar K. Bhanot, Nicholas D. Socci, Alan L. Ho, Ronald Ghossein, James A. Fagin
Journal: Cancer Research (2018)

Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers (Tpo-Cre/HrasG12V/p53flox/flox ) with the FTI tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS-MAPK signaling was abrogated in vitro by selective RTK (i.e., EGFR, FGFR) inhibitors, but responses were ineffective in vivo, whereas combination of tipifarnib with the MEK inhibitor AZD6244 improved outcomes. A subset of tumor-bearing mice treated with tipifarnib developed acquired resistance. Whole-exome sequencing of resistant tumors identified a Nf1 nonsense mutation and an activating mutation in Gnas at high allelic frequency, supporting the on-target effects of the drug. Cell lines modified with these genetic lesions recapitulated tipifarnib resistance in vivo This study demonstrates the feasibility of targeting Ras membrane association in cancers in vivo and predicts combination therapies that confer additional benefit.Significance: Tipifarnib effectively inhibits oncogenic HRAS-driven tumorigenesis and abrogating adaptive signaling improves responses. NF1 and GNAS mutations drive acquired resistance to Hras inhibition, supporting the on-target effects of the drug. Cancer Res; 78(16); 4642-57. ©2018 AACR.
Protective effect of breastfeeding on recurrent cough in adulthood
Authors: Kimberly D Gerhart, Debra A Stern, Stefano Guerra, Wayne J Morgan, Fernando D Martinez, Anne L Wright
Journal: Thorax (2018)

Rationale Breastfeeding protects from respiratory infections in early life but its relationship to recurrent cough and other respiratory outcomes in adult life is not well established. Methods Infant feeding practices were assessed prospectively in the Tucson Children’s Respiratory Study, a non-selected birth cohort and categorised into formula from birth or introduced &lt;1 month, formula introduced ≥1 to &lt;4 months and exclusive breastfeeding for ≥4 months. Infant feeding was assessed as an ordinal variable representing an increasing dose of breastmilk across the three categories. Recurrent cough was defined at 22, 26 and 32 years as ≥2 episodes of cough without a cold lasting 1 week during the past year. Covariates included participant sex, race/ethnicity and smoking as well as parental smoking, education, age and asthma. Covariates were evaluated as potential confounders for the relation between infant feeding and adult outcomes. Results Of the 786 participants, 19% breastfed &lt;1 month, 50% breastfed ≥1 to &lt;4 months and 31% breastfed ≥4 months. The prevalence of recurrent cough at 22, 26 and 32 years was 17%, 15% and 16%, respectively. Each ordinal increase in breastfeeding duration was associated with a decreased risk of recurrent cough in adult life: adjusted OR=0.71, (95% CI: 0.56 to 0.89), p=0.004. Additional adjustment for concurrent adult asthma, wheeze, smoking and lung volume did not change these results. Conclusion Longer duration of breastfeeding reduces the risk of recurrent cough in adult life, regardless of smoking and other respiratory symptoms, suggesting long-term protective effects on respiratory health.
The protective role of macrophage migration inhibitory factor in acute kidney injury after cardiac surgery
Authors: Christian Stoppe, Luisa Averdunk, Andreas Goetzenich, Josefin Soppert, Arnaud Marlier, Sandra Kraemer, Jil Vieten, Mark Coburn, Ana Kowark, Bong-Song Kim, Gernot Marx, Steffen Rex, Akinobu Ochi, Lin Leng, Gilbert Moeckel, Andreas Linkermann, Omar El Bounkari, Alexander Zarbock, Jürgen Bernhagen, Sonja Djudjaj, Richard Bucala, Peter Boor
Journal: Science Translational Medicine (2018)

Clinical data after cardiac surgery and experimental mouse models of acute kidney injury suggest a renoprotective role of macrophage migration inhibitory factor (MIF).
A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease
Authors: Daria V. Ilatovskaya, Gregory Blass, Oleg Palygin, Vladislav Levchenko, Tengis S. Pavlov, Michael N. Grzybowski, Kristen Winsor, Leonid S. Shuyskiy, Aron M. Geurts, Allen W. Cowley, Lutz Birnbaumer, Alexander Staruschenko
Journal: Journal of the American Society of Nephrology (2018)

Background Loss of glomerular podocytes is an indicator of diabetic kidney disease (DKD). The damage to these cells has been attributed in part to elevated intrarenal oxidative stress. The primary source of the renal reactive oxygen species, particularly H 2 O 2 , is NADPH oxidase 4 (NOX4). We hypothesized that NOX4-derived H 2 O 2 contributes to podocyte damage in DKD via elevation of podocyte calcium. Methods We used Dahl salt-sensitive (SS) rats with a null mutation for the Nox4 gene (SS Nox4−/− ) and mice with knockout of the nonselective calcium channel TRPC6 or double knockout of TRPC5 and TRPC6. We performed whole animal studies and used biosensor measurements, electron microscopy, electrophysiology, and live calcium imaging experiments to evaluate the contribution of this pathway to the physiology of the podocytes in freshly isolated glomeruli. Results Upon induction of type 1 diabetes with streptozotocin, SS Nox4−/− rats exhibited significantly lower basal intracellular Ca 2+ levels in podocytes and less DKD-associated damage than SS rats did. Furthermore, the angiotensin II–elicited calcium flux was blunted in glomeruli isolated from diabetic SS Nox4−/− rats compared with that in glomeruli from diabetic SS rats. H 2 O 2 stimulated TRPC-dependent calcium influx in podocytes from wild-type mice, but this influx was blunted in podocytes from Trpc 6-knockout mice and, in a similar manner, in podocytes from Trpc 5/6 double-knockout mice. Finally, electron microscopy revealed that podocytes of glomeruli isolated from Trpc 6-knockout or Trpc 5/6 double-knockout mice were protected from damage induced by H 2 O 2 to the same extent. Conclusions These data reveal a novel signaling mechanism involving NOX4 and TRPC6 in podocytes that could be pharmacologically targeted to abate the development of DKD.