tbuckley/cabot-search huggingface dataset:
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Authors: James A. Thomas, John P. Iredale, Stuart J. Forbes
Journal: Hepatology (2011)

We thank Liu and colleagues for their comments; however, it is important to clarify a number of points. This was not a comparative study of stem cells versus differentiated cells.1 Bone marrow (BM) contains a wide range of cell types with potentially diverse actions when delivered during liver injury. Positive effects have been detected following the application of stem/progenitor cell containing BM fractions of varying purity and potency.2, 3 In our experiments, unfractionated BM delivery caused a net increase in murine liver fibrosis.1 This phenotype is likely to be the result of several (interacting and opposing) BM cell populations. BM stem cells, including hematopoietic and mesenchymal stem cells, constitute a numerically small minority of BM cells. Importantly, injected mesenchymal stem cells can give rise to profibrogenic liver cell populations,4, 5 highlighting the potential risks of uncharacterized cell populations. The advantages of a single differentiated cell type in terms of predictability and mechanistic clarity do not preclude the potential therapeutic benefits of mixed cell fractions. However, for the field to progress, we need to understand the precise activities of individual donor cell lineages before we can make sense of the potentially diverse effects of mixed BM fractions. BM stem cells or their derivatives may have benefit in chronic liver disease. However, to date, clinical studies have been small or uncontrolled, hence larger, randomized controlled trials are now required to determine whether there are positive or negative clinical effects. Indeed, adverse events have already been detected following autologous BM cell infusion.6 To this effect, we are part of a multicenter randomized trial testing CD133+ hematopoietic stem cells in cirrhosis that has already opened in the United Kingdom (ISRCTN: 91288089). Regarding the possibility of BM stem cells transdifferentiating in vivo into hepatocytes, this has repeatedly been shown not to occur to any meaningful degree, if at all. Therefore, paracrine mechanisms of action are more plausible.7, 8 The chronology of human cirrhosis is measured in years, so clinically useful disease-modifying treatments may require repeat administration. Furthermore, it is possible that cell-based treatments will ultimately be tailored to parameters such as disease etiology and stage of disease, necessitating a broad and well-understood therapeutic arsenal. Thomas James*, John Iredale*, Stuart J. Forbes*, * MRC/University of Edinburgh, Center for Inflammation Research, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
Analytical protein measurements from 400 tumor-derived stem cells
Authors: Arunashree Bhamidipati, Keith Syson Chan, Wilhelm Lachnit, Irving Weissman, David Voehringer
Journal: Clinical Cancer Research (2007)

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

C11 

The discovery of tumor stem cells in acute myeloid leukemia a decade ago initiated a field of research has accelerated growth in the past few years. Researchers are now describing tumor stem cells in a variety of hematopoietic and solid tumors. The impetus for much of this research is the desire to identify targets for drug intervention in these critical tumor populations. The molecular pathways that functionally define these cells are important therapeutic targets. Tumor stem cells are rare and with insufficient material to use standard assay methods. Although DNA microarray and/or qPCR are used to study tumor stem cells, their rare nature limits quantitative protein analysis. This creates a gap in our knowledge since many proteins, such as β-catenin or MAPK signaling proteins, are not regulated at the transcriptional level, but through post-translational modifications (phosphorylation, ubiquitination, etc ¼). Here we describe a technique utilizing a nanoimmunoassay platform (FireflyTM) to measure tumor stem cell proteins. Transitional tumor stem cells (TCC+) were sorted from a patient tumor and lysed for analysis. A lysate of 400 cells was subjected to isoelectric focusing and immobilization. Immunodetection was performed and quantitation of signal was measured using HRP-labeled secondary chemiluminescence reagents. Here we report β-catenin protein concentrations of 192 ng/mg of total protein in the tumor stem cells, which was undetectable in ‘non-stem’ tumor cells. Comparisons of protein levels and the degree of phosphorylation are made between these samples, other tumor cell lines and hematopoetic stem cells.
MicroRNAs as novel players in skin development, homeostasis and disease
Authors: M.R. Schneider
Journal: British Journal of Dermatology (2011)

Journal Article MicroRNAs as novel players in skin development, homeostasis and disease Get access M.R. Schneider M.R. Schneider Gene Center, LMU Munich, Feodor‐Lynen‐Strasse 25, 81377 Munich, Germany Marlon R. Schneider. E‐mail: schnder@lmb.uni‐muenchen.de Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 166, Issue 1, 1 January 2012, Pages 22–28, https://doi.org/10.1111/j.1365-2133.2011.10568.x Published: 01 January 2012 Article history Accepted: 02 August 2011 Published: 01 January 2012
639. Gene Expression Analysis of LPS Stimulated THP-1 Cells Treated with Antisense IRAK1 Delivered Using a pH-Sensitive, Membrane Disruptive Polymer
Authors: Rachel E. Johns, Allan S. Hoffman, Patrick S. Stayton
Journal: Molecular Therapy (2004)

Goals and Significance: The inflammatory response, which is initiated upon trauma, infection, or in the presence of a foreign body, is necessary for normal wound healing. However, during chronic inflammation, control of this response becomes clinically advantageous. The interleukin-1 (IL-1) pathway to nuclear transcription factor κB (NF-κB) is a major contributor to the inflammatory response. IL-1 Receptor Associated Kinase-1 (IRAK1) is a central kinase in this pathway and is a target molecule for controlling NF-κB activation and the subsequent production of inflammatory mediators. Decreasing the expression of IRAK1 has been accomplished through the use of an antisense oligonucleotide. By delivering an 18-mer oligodeoxynucleotide (ODN) complimentary to the mRNA sequence of IRAK1, production of this kinase was inhibited. ODN uptake generally occurs through endocytosis, after which molecules are trafficked to the lysosome and degraded, resulting in loss of the therapeutic ODN. In an effort to improve the delivery of ODNs and other biological molecules, a family of pH-sensitive membrane disruptive polymers has been developed in our lab. These polymers are able to enhance cytoplasmic delivery of therapeutics by releasing them from the endosome. The polymer used in this study consisted of a hydrophobic, membrane disruptive backbone linked via acid degradable acetal bonds to hydrophilic poly(ethylene glycol) (PEG). The PEG groups mask the hydrophobic backbone until the acetal bonds degrade at the low pH of the endosome or lysosome, freeing the hydrophobic backbone to disrupt the endosomal membrane and deliver the therapeutic cargo to the cytoplasm of the cell.
Website of the week: Dealing with depression
Authors: J. O'N. Roach
Journal: BMJ (2000)

My cousin committed suicide a year ago aged 27, but seemed remarkably calm just before the event. Of course feeling suddenly happier and calmer can be a danger sign, as described at the Suicide Awareness\Voices of Education (SA\VE) site, www.save.org/symptoms.html. Informing relatives of the warning signs, tragically missed on this occasion, is clearly a key point in the management of patients …
Abstract 14584: Exercise Capacity and Stroke Volume are Preserved Even with a Severely Dilated Right Ventricle, Late After Tetralogy Repair
Authors: Shamus O'Meagher, David S Celermajer, Rajesh Puranik
Journal: Circulation (2011)

Introduction:  Pulmonary regurgitation (PR) with progressive right ventricle (RV) dilatation is very common late after repair of Tetralogy of Fallot (TOF) in childhood. Guidelines recommend pulmonary valve replacement (PVR) when indexed RV end diastolic volume (RVEDVi) exceeds 150ml/m 2 , even in asymptomatic patients. As PVR, however, has limited durability, this should be deferred as long as possible. We compared subjects with RVEDVi below versus above this cut-point, measuring cardiac function and exercise capacity objectively.   Hypothesis:  That left ventricular (LV) stroke volume and exercise capacity deteriorate when RVEDVi increases above 150ml/m 2 , in patients with repaired TOF.   Methods:  Of 60 patients with repaired TOF (mean age at repair 2.6 ± 2.5 years; age at MRI study 24.5 ± 9.5 years; range 11 to 48 years; 36 males), 32 had RVEDVi below and 28 had RVEDVi above 150ml/m 2 , at time of referral. Cardiac MRIs (1.5T) and cardiopulmonary exercise tests were performed.   Results:  In the >150ml/m 2  group, RVEDVi was 185 ± 38 ml/m 2  compared to 117 ± 23 ml/m 2  in the other subjects (p=0.0001). RV ejection fraction was lower (47 ± 7% vs 52 ± 7%, p=0.0066), fractional PR was higher (41 ± 12% vs 24 ± 14%, p=0.0001) but RV stroke volume was larger (154 ± 33 ml vs 107 ± 27 ml, p=0.0001) in the >150ml/m 2  group. There were no significant differences in LV stroke volume (86 ± 17 ml vs 77 ± 21 ml, p=0.06), LV ejection fraction (57 ± 7% vs 56 ± 7%, p=0.86) or exercise capacity (% predicted Wpeak: 92 ± 20% vs 89 ± 17%, p=0.50 and; % predicted VO2peak: 84 ± 18% vs 88 ± 16%, p=0.44). Fibrosis was rarely detected in the RV body (n=1) and more frequently in the RV outflow (n=33, p=NS).   Conclusions:  Exercise capacity and stroke volume are maintained with RVEDVi above compared to below the currently recommended cut-off for PVR surgery. Optimal timing for PVR thus remains unclear, given these observations.
Granulocyte Colony-Stimulating Factor (Filgrastim) Accelerates Granulocyte Recovery After Intensive Postremission Chemotherapy for Acute Myeloid Leukemia With Aziridinyl Benzoquinone and Mitoxantrone: Cancer and Leukemia Group B Study 9022
Authors: Joseph O. Moore, Richard K. Dodge, Philip C. Amrein, Jonathan Kolitz, Edward J. Lee, Bayard Powell, Scott Godfrey, Francisco Robert, Charles A. Schiffer
Journal: Blood (1997)
A Comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast Cancer
Authors: Beat Thürlimann, Aparna Keshaviah, Alan S Coates, Henning Mouridsen, Louis Mauriac, John F Forbes, Robert Paridaens, Monica Castiglione-Gertsch, Richard D Gelber, Manuela Rabaglio, Ian Smith, Andrew Wardley, Karen N Price, Aron Goldhirsch
Journal: New England Journal of Medicine (2005)

The aromatase inhibitor letrozole is a more effective treatment for metastatic breast cancer and more effective in the neoadjuvant setting than tamoxifen. We compared letrozole with tamoxifen as adjuvant treatment for steroid-hormone-receptor-positive breast cancer in postmenopausal women.The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial that compared five years of treatment with various adjuvant endocrine therapy regimens in postmenopausal women with hormone-receptor-positive breast cancer: letrozole, letrozole followed by tamoxifen, tamoxifen, and tamoxifen followed by letrozole. This analysis compares the two groups assigned to receive letrozole initially with the two groups assigned to receive tamoxifen initially; events and follow-up in the sequential-treatment groups were included up to the time that treatments were switched.A total of 8010 women with data that could be assessed were enrolled, 4003 in the letrozole group and 4007 in the tamoxifen group. After a median follow-up of 25.8 months, 351 events had occurred in the letrozole group and 428 events in the tamoxifen group, with five-year disease-free survival estimates of 84.0 percent and 81.4 percent, respectively. As compared with tamoxifen, letrozole significantly reduced the risk of an event ending a period of disease-free survival (hazard ratio, 0.81; 95 percent confidence interval, 0.70 to 0.93; P=0.003), especially the risk of distant recurrence (hazard ratio, 0.73; 95 percent confidence interval, 0.60 to 0.88; P=0.001). Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the tamoxifen group. Women given letrozole had a higher incidence of skeletal and cardiac events and of hypercholesterolemia.In postmenopausal women with endocrine-responsive breast cancer, adjuvant treatment with letrozole, as compared with tamoxifen, reduced the risk of recurrent disease, especially at distant sites. (ClinicalTrials.gov number, NCT00004205.)
Abstract 12075: Whole-Genome Sequencing at 10-Days of Life in Perinatal Long-QT Syndrome Yields New Insights Into Disease Pathogenesis
Authors: James R Priest, Charles Gawad, Kris Kahlig, Scott Ceresnak, Lindsey Malloy-Walton, Kyla Dunn, Megan P Grove, Marco Perez, Katsuhide Maeda, Anne Dubin, Luiz Belardinelli, Rich Chen, Tom Quertermous, Stephen Quake, Euan A Ashley
Journal: Circulation (2014)

Introduction: Perinatal LQTS represents a severe form of long-QT syndrome with poor outcomes and early genotype-specific treatment is limited by the 2 month turnaround time of standard panel genetic testing. Hypothesis: We aimed to provide a molecular diagnosis within a clinically actionable timeframe. Methods: We performed rapid CLIA-certified whole genome sequencing on two infants with perinatal long-QT syndrome delivering a molecular diagnosis at 10-days of life. Whole cell patch clamping and single cell genotyping were also performed. Results: In Case #1 we discovered a previously characterized variant in KCNH2 which was paternally inherited, however whole genome sequencing provided an unbiased assessment of the entire catalog of human genes revealing a second maternally inherited modifier variant in RNF207. In Case #2 we discovered a novel mutation leucine replacing valine (V1762L) at residue 1762 in the SNC5A sodium channel. Whole-cell patch clamping experiments show the V1762L mutation causes a profound defect in late sodium current ~4.5 fold greater than the wild-type channel. A single cell analysis demonstrated that the mutation was present in the genome of only 3 of 36 individually isolated and genotyped patient cells, suggesting mosaicism. Conspicuously, standard panel genetic testing was negative. Conclusions: We report here the earliest molecular diagnoses of LQTS, and demonstrate that rapid whole genome sequencing may be fruitfully applied to perinatal LQTS. In case #1 we hypothesize that a polygenic inheritance may explain the early and severe perinatal presentation, and have identified a putative modifier gene for LQTS in RNF207. The observation of mosaicism in case #2 suggests that in studies of inherited disease, mosaicism represents a common mechanism by which causal variation may be missed.
Abstract 13836: Accessory Renal Arteries Perfuse a Substantial Fraction of Renal Mass: Studies in Renal Denervation Patients
Authors: Thomas Houghland, Jason J Hamann, Naohiko T Nemoto, Ross F Garberich, Kristi Rosenthal, John R Lesser, Robert S Schwartz
Journal: Circulation (2014)

Introduction: Renal denervation is an emerging therapy for resistant hypertension, but has a non-response rate of roughly 15-30%. Untreated accessory renal arteries may have a potentially causative role in non-response. Prior data show a strongly proportional relationship between individual renal mass and cross sectional area of the principal artery perfusing that kidney, analogous to the relations between myocardial mass and coronary artery area. Because accessory renal arteries are prevalent (up to 65%) in patients undergoing renal denervation, we questioned whether accounting for their presence would further strengthen the correlation between renal mass and artery cross sectional area. Methods: High resolution CT scans from 34 participants in the REDUCE-HTN Clinical study were measured for kidney volume and main renal artery area (TRAA). Areas of all visible accessory arteries were measured separately. Standard linear regression was used to determine the quantitative relationship among these parameters...
Hospitalized heart failure patients with preserved vs. reduced ejection fraction in Dubai, United Arab Emirates: a prospective study
Authors: Narjes Saheb Sharif‐Askari, Syed Azhar Syed Sulaiman, Fatemeh Saheb Sharif‐Askari, Ali Al Sayed Hussain, Sadeq Tabatabai, Arif Abdullatif Al‐Mulla
Journal: European Journal of Heart Failure (2014)
Abstract 15357: Washout Rate of 123I-Metaiodobenzylguanidine and Dose of Carvedilol are Independently Associated With Central Sleep Apnea in Chronic Heart Failure
Authors: Akira Tamura, Shinichi Ando, Yoshiyuki Kawano, Yukie Goto, Kazuhiro Shinozaki, Munenori Kotoku, Junichi Kadota
Journal: Circulation (2010)

Background: Central sleep apnea (CSA) is observed in 20 - 40% of patients with chronic heart failure (CHF) and is associated with increased morbidity and mortality in those patients. The genesis of...
Antidepressant Response Trajectories and Associated Clinical Prognostic Factors Among Older Adults
Authors: Stephen F. Smagula, Meryl A. Butters, Stewart J. Anderson, Eric J. Lenze, Mary Amanda Dew, Benoit H. Mulsant, Francis E. Lotrich, Howard Aizenstein, Charles F. Reynolds
Journal: JAMA Psychiatry (2015)

IMPORTANCE More than 50% of older adults with late-life major depressive disorder fail to respond to initial treatment with first-line pharmacological therapy.OBJECTIVES To assess typical patterns of response to an open-label trial of extended-release venlafaxine hydrochloride (venlafaxine XR) for late-life depression and to evaluate which clinical factors are associated with the identified longitudinal response patterns.DESIGN, SETTING, AND PARTICIPANTS Group-based trajectory modeling was applied to data from a 12-week open-label pharmacological trial conducted in specialty care as part of the Incomplete Response in Late Life: Getting to Remission Study.Clinical prognostic factors, including domain-specific cognitive performance and individual depression symptoms, were examined in relation to response trajectories.Participants included 453 adults aged 60 years or older with current major depressive disorder.The study was conducted between August 2009 and August 2014.INTERVENTION Open-label venlafaxine XR (titrated up to 300 mg/d) for 12 weeks.MAIN OUTCOMES AND MEASURES Subgroups exhibiting similar response patterns were derived from repeated measures of overall depression severity obtained using the Montgomery-Asberg Depression Rating Scale.RESULTS Among the 453 study participants, 3 subgroups with differing baseline depression severity clearly responded to treatment: one group with the lowest baseline severity had a rapid response (n = 69 [15.23%]), and distinct responses were also apparent among groups starting at moderate (n = 108 [23.84%]) and higher (n = 25 [5.52%]) baseline symptom levels.Three subgroups had nonresponding trajectories: 2 with high baseline symptom levels (totaling 35.98%: high, nonresponse 1, n = 110 [24.28%]; high, nonresponse 2, n = 53 [11.70%]) and 1 with moderate baseline symptom levels (n = 88 [19.43%]).Several factors were independently associated with having a nonresponsive trajectory, including greater baseline depression severity, longer episode duration, less subjective sleep loss, more guilt, and more work/activity impairment (P < .05).Higher delayed memory (list recognition) performance was independently associated with having a rapid response (adjusted odds ratio = 2.22; 95% CI, 1.18-4.20).CONCLUSIONS AND RELEVANCE Based on the observed trajectory patterns, patients who have late-life depression with high baseline depression severity are unlikely to respond after 12 weeks of treatment with venlafaxine XR.However, high baseline depression severity alone may be neither a necessary nor sufficient predictor of treatment nonresponse.
Polymorphisms in CCR5 confer susceptibility to Löfgren's syndrome and may regulate the immune response
Authors: B. Karakaya, C.H.M. van Moorsel, G.T. Rijkers, A.H.M. van der Helm, T.W.J. Huizinga, J.M.M. van den Bosch, J.C. Grutters
Journal: European Respiratory Journal (2011)

Rationale: Lofgren's syndrome is an acute and usually self-remitting phenotype of sarcoidosis. Several studies have found associations between specific gene polymorphisms and susceptibility to sarcoidosis.

Chemokines are small peptides that mediate monocyte, lymphocyte and neutrophil chemotactic activity by binding to specific G-protein coupled receptors, such as CCR5. A study showed that the HHC haplotype of CCR5, with single nucleotide polymorphism (SNP) rs1799987, was associated with Lofgren's syndrome.

Objective: We investigated if SNPs of the CCR5 gene were associated with Lofgren's syndrome and had an effect on the B-lymphocyte response of patients.

Methods: Hunderd and twenty patients with Lofgren's syndrome were characterized and genotyped for 4 SNPs in CCR5. Our control cohort consisted of 313 self-reported healthy individuals.

Calcium mobilization response to MIP-1a, a ligand of CCR5, was measured in peripheral blood B-lymphocytes of 18 Lofgren's syndrome patients (3 male and 15 female) and 3 controls.

Results: Carriage of the G-allele was significantly higher in patients with Lofgren's syndrome than in healthy controls (p=0.00557, CI 1.13-2.01, OR 1.505).

Twelve out of 18 patients with Lofgren's syndrome showed no calcium response, of which 11 were carriers of the G-allele: 7 GG, 4 GA, 1 AA. Nine of these 12 patients where women. All controls showed a calcium mobilization response upon stimulation with MIP-1a.

Conclusions: The SNP rs1799987 in the CCR5 genes is associated with Lofgren's syndrome. Functionality assays showed that polymorphisms of the CCR5 have an impact on cellular processes that may regulate the response of B-lymphocytes.