tbuckley/cabot-search huggingface dataset:
Blinatumomab for the Treatment of Philadelphia Chromosome–Negative, Precursor B-cell Acute Lymphoblastic Leukemia
Authors: Ofir Wolach, Richard M. Stone
Journal: Clinical Cancer Research (2015)

Blinatumomab is a CD19/CD3 bispescific antibody designed to redirect T cells toward malignant B cells and induce their lysis. It recently gained accelerated approval by the FDA for the treatment of relapsed or refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (RR-ALL). In the phase II trial that served as the basis for approval, blinatumomab demonstrated significant single-agent activity and induced remission [complete remission (CR) and CR with incomplete recovery of peripheral blood counts (CRh)] in 43% of 189 adult patients with RR-ALL; the majority of responders (82%) also attained negative minimal residual disease (MRD(-)) status that did not generally translate into long-term remissions in most cases. Additional studies show that blinatumomab can induce high response rates associated with lasting remissions in patients in first remission treated for MRD positivity, suggesting a role for blinatumomab in the upfront, MRD-positive setting. Blinatumomab infusion follows a predictable immunopharmacologic profile, including early cytokine release that can be associated with a clinical syndrome, T-cell expansion, and B-cell depletion. Neurologic toxicities represent a unique toxicity that shares similarities with adverse effects of other T-cell engaging therapies. Further studies are needed to clarify the optimal disease setting and timing for blinatumomab therapy. Additional insights into the pathogenesis, risk factors, and prevention of neurologic toxicities as well as a better understanding of the clinical consequences and biologic pathways that are associated with drug resistance are needed.
Hepatic manifestations of autoimmune rheumatic diseases
Authors: S Abraham
Journal: Annals of the Rheumatic Diseases (2004)

Hepatic manifestations in autoimmune disease include chronic active hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and nodular regenerative hyperplasia. These diseases are rare and may occur concomitantly or serially. Clinicians must be aware of the possibility of liver disease so that it can be treated as soon as possible.
Effect of Estrogen on Brain Activation Patterns in Postmenopausal Women During Working Memory Tasks
Authors: S E Shaywitz, B A Shaywitz, K R Pugh, R K Fulbright, P Skudlarski, W E Mencl, R T Constable, F Naftolin, S F Palter, K E Marchione, L Katz, D P Shankweiler, J M Fletcher, C Lacadie, M Keltz, J C Gore
Journal: JAMA (1999)

ContextPreclinical studies suggest that estrogen affects neural structure and function in mature animals; clinical studies are less conclusive with many, but not all, studies showing a positive influence of estrogen on verbal memory in postmenopausal women.ObjectiveTo investigate the effects of estrogen on brain activation patterns in postmenopausal women as they performed verbal and nonverbal working memory tasks.DesignRandomized, double-blind, placebo-controlled, crossover trial from 1996 through 1998.SettingCommunity volunteers tested in a hospital setting.PatientsForty-six postmenopausal women aged 33 to 61 years (mean [SD] age, 50.8 [4.7] years).InterventionTwenty-one-day treatment with conjugated equine estrogens, 1.25 mg/d, randomly crossed over with identical placebo and a 14-day washout between treatments.Main Outcome MeasuresBrain activation patterns measured using functional magnetic resonance imaging during tasks involving verbal and nonverbal working memory.ResultsTreatment with estrogen increased activation in the inferior parietal lobule during storage of verbal material and decreased activation in the inferior parietal lobule during storage of nonverbal material. Estrogen also increased activation in the right superior frontal gyrus during retrieval tasks, accompanied by greater left-hemisphere activation during encoding. The latter pattern represents a sharpening of the hemisphere encoding/retrieval asymmetry (HERA) effect. Estrogen did not affect actual performance of the verbal and nonverbal memory tasks.ConclusionsEstrogen in a therapeutic dosage alters brain activation patterns in postmenopausal women in specific brain regions during the performance of the sorts of memory function that are called upon frequently during any given day. These results suggest that estrogen affects brain organization for memory in postmenopausal women.
Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets
Authors: Valeria Sordi, Maria Luisa Malosio, Federica Marchesi, Alessia Mercalli, Raffaella Melzi, Tiziana Giordano, Nathalie Belmonte, Giuliana Ferrari, Biagio Eugenio Leone, Federico Bertuzzi, Gianpaolo Zerbini, Paola Allavena, Ezio Bonifacio, Lorenzo Piemonti
Journal: Blood (2005)
Emphysema, COPD and lung cancer screening. Update of an ongoing study
Authors: Pablo Sanchez Salcedo, Maria Sanchez-Carpintero, Juan Bertó, Pilar Rivera, Ana Belén Alcaide, Juan Pablo de Torres, Arantxa Campo, Jorge Zagaceta, Javier Zulueta
Journal: European Respiratory Journal (2012)

Recently, screening with low-dose CT (LDCT) has been shown to reduce mortality from lung cancer. We reported that emphysema on a LDCT, but not COPD (FEV1/FVC<70%), is associated with an increased risk of lung cancer. We present an update of our screening study.

Data comes from a prospective cohort of an ongoing lung cancer screening study held at our center. From 2000 to 2011, current and former smokers of at least 40 years of age and at least 10 pack-years of smoking were recruited. All had annual LDCTs and most a baseline spirometry. Lung cancer incidence density and its association with risk factors were calculated with logistic regression.

From a cohort of 2697 subjects, 1925 (25% females) who had LDCTs and a spirometry were analyzed. Median age and smoking history were 55 and 33 pack-yrs, respectively. Emphysema on LDCT and airway obstruction on spirometry were found in 25% and 28%, respectively. Lung cancer was diagnosed in 38 subjects, 26 on the baseline LDCT and 12 in annual follow-ups. The most frequent hystologic types were adenocarcinoma (53%) and squamous cell carcinoma (21%). There were 4 (11%) small cell carcinomas (all in stages IIIB or IV). The majority of NSCLC were identified in stage I (79%). The incidence density for lung cancer in subjects with emphysema, COPD, or with none was 36.1, 24.7 and 2.5 per 1000 person-yrs, respectively. Adjusting for age, sex and smoking, emphysema (OR 4.76; IC95% 2.32-9.77) and airway obstruction (OR 2.65; IC 95% 1.26-5.57) were independent risk factors for lung cancer.

In a cohort of individuals participating in a lung cancer screening study, emphysema and airway obstruction are significantly associated with a greater risk of lung cancer.
Costs of occupational asthma in the UK
Authors: J. G. Ayres, R. Boyd, H. Cowie, J. F. Hurley
Journal: Thorax (2010)

<h3>Objectives</h3> To estimate the social costs of occupational asthma in the UK. <h3>Methods</h3> A desk-top approach using cost-of-illness methodology was employed, defining direct and indirect lifetime costs for six scenarios: a male and a female worker each exposed to isocyanates, latex and biocides (eg, glutaraldehyde) or flour. The numbers of new cases annually in each industry were estimated from Survey of Work-related and Occupational Respiratory Disease (SWORD) data. The main outcome measure was the current value total working lifetime costs of new cases annually for each scenario. <h3>Results</h3> Assuming 209 new cases of occupational asthma in the six scenarios in the year 2003, the present value total lifetime costs were estimated to be £25.3–27.3 million (2004 prices). Grossing up for all estimated cases of occupational asthma in the UK in 2003, this came to £70–100 million. About 49% of these costs were borne by the individual, 48% by the state and 3% by the employer. <h3>Conclusions</h3> The cost to society of occupational asthma in the UK is high. Given that the number of newly diagnosed cases is likely to be underestimated by at least one-third, these costs may be as large as £95–135 million. Each year a new stream of lifetime costs will be added as a newly diagnosed cohort is identified. Approaches to reduce the burden of occupational asthma have a strong economic justification. However, the economic burden falls on the state and the individual, not on the employer. The incentive for employers to act is thus weak.
Mechanisms of epithelial dysfunction in giardiasis
Authors: A. G Buret
Journal: Gut (2007)

A better understanding of the pathophysiological processes of Giardia may lead to understanding the diseases it causes and to identifying new therapeutic agents

Infection with the ubiquitous intestinal parasite Giardia lamblia (synonymous G duodenalis or G intestinalis ) may cause acute or chronic diarrhoea, dehydration, abdominal discomfort and weight loss.1–4 Despite the prevalence of this disease, the pathophysiological features underlying intestinal disturbances in giardiasis remain incompletely understood. Giardia causes disease without penetrating the epithelium, invading the surrounding tissues or entering the blood stream. Interestingly, the epithelial abnormalities responsible for intestinal malabsorption and diarrhoea in giardiasis seem to share similarities with those observed in other enteric disorders, such as bacterial enteritis, chronic food anaphylaxis, Crohn’s disease and coeliac disease.5–9 Therefore, a better understanding of these pathophysiological processes may help identify new therapeutic targets for a variety of gastrointestinal diseases. In an attempt to unravel the mechanisms by which Giardia exerts its clinical effects, researchers have relied on a variety of cell systems and animal models. This issue of Gut presents data from an elegant human clinical study by Troeger et al 10 ( see page 328 ) that sheds new light on these processes. In view of the limited space available, this commentary only highlights selected mechanisms whereby Giardia -induced epithelial dysfunction may contribute to disease development.

Previous studies using models in vivo and in vitro have established that Giardia causes malabsorption of glucose, sodium and water, and reduced disaccharidase activity, due to loss of epithelial absorptive surface area. …
CDK5 regulates cell-cell and cell-matrix adhesion in human keratinocytes
Authors: N. Nakano, A. Nakao, K. Ishidoh, R. Tsuboi, E. Kominami, K. Okumura, H. Ogawa
Journal: British Journal of Dermatology (2005)

Journal Article CDK5 regulates cell–cell and cell–matrix adhesion in human keratinocytes Get access N. Nakano, N. Nakano Atopy (Allergy) Research Center, Departments of Nobuhiro Nakano. E‐mail: nbnakano@med.juntendo.ac.jp Search for other works by this author on: Oxford Academic Google Scholar A. Nakao, A. Nakao Atopy (Allergy) Research Center, Departments ofDepartment of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan Search for other works by this author on: Oxford Academic Google Scholar K. Ishidoh, K. Ishidoh Biochemistry Search for other works by this author on: Oxford Academic Google Scholar R. Tsuboi, R. Tsuboi Dermatology, Juntendo University School of Medicine, Tokyo, Japan Search for other works by this author on: Oxford Academic Google Scholar E. Kominami, E. Kominami Biochemistry Search for other works by this author on: Oxford Academic Google Scholar K. Okumura, K. Okumura Atopy (Allergy) Research Center, Departments of Search for other works by this author on: Oxford Academic Google Scholar H. Ogawa H. Ogawa Atopy (Allergy) Research Center, Departments ofDermatology, Juntendo University School of Medicine, Tokyo, Japan Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 153, Issue 1, 1 July 2005, Pages 37–45, https://doi.org/10.1111/j.1365-2133.2005.06583.x Published: 01 July 2005 Article history Accepted: 23 June 2004 Published: 01 July 2005
Lower Adiponectin Levels at First Trimester of Pregnancy Are Associated With Increased Insulin Resistance and Higher Risk of Developing Gestational Diabetes Mellitus
Authors: Marilyn Lacroix, Marie-Claude Battista, Myriam Doyon, Julie Ménard, Jean-Luc Ardilouze, Patrice Perron, Marie-France Hivert
Journal: Diabetes Care (2013)

OBJECTIVE To evaluate the associations between adiponectin levels and 1) the risk of developing gestational diabetes mellitus (GDM), and 2) insulin resistance/sensitivity, β-cell function, and compensation indices in a prospective cohort representative of the general population of pregnant women. RESEARCH DESIGN AND METHODS We performed anthropometric measurements and collected blood samples at 1st (6–13 weeks) and 2nd (24–28 weeks) trimesters. Diagnosis of GDM was made at 2nd trimester based on a 75-g oral glucose tolerance test (International Association of the Diabetes and Pregnancy Study Groups criteria). Insulin was measured (ELISA; Luminex) to estimate homeostasis model assessment of insulin resistance (HOMA-IR), β-cell function (HOMA-B), insulin sensitivity (Matsuda index), insulin secretion (AUCinsulin/glucose), and β-cell compensation (insulin secretion sensitivity index-2). Adiponectin was measured by radioimmunoassay. RESULTS Among the 445 participants included in this study, 38 women developed GDM. Women who developed GDM had lower 1st-trimester adiponectin levels (9.67 ± 3.84 vs. 11.92 ± 4.59 µg/mL in women with normal glucose tolerance). Lower adiponectin levels were associated with higher risk of developing GDM (OR, 1.12 per 1 µg/mL decrease of adiponectin levels; P = 0.02, adjusted for BMI and HbA1c at 1st trimester). Adiponectin levels at 1st and 2nd trimesters were associated with HOMA-IR (both: r = −0.22, P &amp;lt; 0.0001) and Matsuda index (r = 0.28, P &amp;lt; 0.0001, and r = 0.29, P &amp;lt; 0.0001). After adjustment for confounding factors, we found no significant association with HOMA-B and AUCinsulin/glucose. CONCLUSIONS Pregnant women with lower adiponectin levels at 1st trimester have higher levels of insulin resistance and are more likely to develop GDM independently of adiposity or glycemic measurements.
The effect of surgery on lung volume and conventional monitoring parameters in ventilated newborn infants
Authors: H. Proquitte, O. Freiberger, S. Yilmaz, C. Bamberg, P. Degenhardt, C. C. Roehr, R. R. Wauer, G. Schmalisch
Journal: European Respiratory Journal (2009)

In newborn infants, thoraco-abdominal surgery is a serious intervention with respect to gas exchange and lung mechanics. This prospective clinical study compared surgery-induced changes in functional residual capacity (FRC) and ventilation inhomogeneity (VI) indices with changes in conventional monitoring parameters. Of 29 ventilated newborns (mean weight 2,770+/-864 g at surgery), 13, nine and seven underwent thoracic, abdominal or congenital diaphragmatic hernia (CDH) surgery, respectively. The multiple breath washout (MBWO) technique using heptafluoropropane as tracer gas (Babylog 8000; Dräger, Lübeck, Germany) was performed <6 h before surgery, 22-24 h after surgery and <6 h before extubation. Gas exchange, respiratory mechanics, FRC and VI index data were recorded. Thoraco-abdominal surgery resulted in changes to FRC and VI indices in a procedure-specific manner; however, these changes were not reflected in conventional mechanical or ventilatory monitoring parameters. FRC decreased in non-CDH infants, while FRC increased and VI indices decreased in CDH infants. Despite improvements, the differences in FRC and VI between CDH and non-CDH infants indicated persistent impaired lung function in CHD infants. MBWO can be advantageously used to measure the effect of surgery on the lung. While FRC and VI indices changed following surgery, conventional monitoring parameters did not.
Biochemical and Pharmacological Properties of SANORG 34006, a Potent and Long-Acting Synthetic Pentasaccharide
Authors: J.M. Herbert, J.P. Hérault, A. Bernat, R.G.M. van Amsterdam, J.C. Lormeau, M. Petitou, C. van Boeckel, P. Hoffmann, D.G. Meuleman
Journal: Blood (1998)
A Universal Method for the Study of CR1 Retroposons in Nonmodel Bird Genomes
Authors: A. Suh, J. O. Kriegs, S. Donnellan, J. Brosius, J. Schmitz
Journal: Molecular Biology and Evolution (2012)

Presence/absence patterns of retroposon insertions at orthologous genomic loci constitute straightforward markers for phylogenetic or population genetic studies. In birds, the convenient identification and utility of these markers has so far been mainly restricted to the lineages leading to model birds (i.e., chicken and zebra finch). We present an easy-to-use, rapid, and cost-effective method for the experimental isolation of chicken repeat 1 (CR1) insertions from virtually any bird genome and potentially nonavian genomes. The application of our method to the little grebe genome yielded insertions belonging to new CR1 subfamilies that are scattered all across the phylogenetic tree of avian CR1s. Furthermore, presence/absence analysis of these insertions provides the first retroposon evidence grouping flamingos + grebes as Mirandornithes and several markers for all subsequent branching events within grebes (Podicipediformes). Five markers appear to be species-specific insertions, including the hitherto first evidence in birds for biallelic CR1 insertions that could be useful in future population genetic studies.
BAFF Regulates Follicular Helper T Cells and Affects Their Accumulation and Interferon‐γ Production in Autoimmunity
Authors: Christine M. Coquery, William M. Loo, Nekeithia S. Wade, Annelise G. Bederman, Kenneth S. Tung, Janet E. Lewis, Henry Hess, Loren D. Erickson
Journal: Arthritis & Rheumatology (2014)

Objective Follicular helper T (Tfh) cells are critical for the development of protective antibodies via germinal center (GC) B cell responses; however, uncontrolled Tfh cell expansion activates autoreactive B cells to produce antibodies that cause autoimmunity. The mechanisms that control Tfh cell homeostasis remain largely unknown. The aim of this study was to determine the contribution of BAFF to Tfh cell responses in autoimmunity. Methods We analyzed the properties of Tfh cells in lupus‐prone mice sufficient or deficient in BCMA. Adoptive transfer studies and mixed bone marrow chimeras were used to test BCMA signaling in T cells. We assessed BAFF stimulation of Tfh cells through in vitro cell cocultures and in vivo depletion studies using flow cytometry. Results In Nba2 mice, Tfh cells expressed the BAFF receptors BCMA and B lymphocyte stimulator receptor 3 (BR‐3) and accumulated in the spleen when BCMA was absent. BCMA deficiency in T cells promoted the expansion of Tfh cells, GC formation, autoantibody production, and interferon‐γ (IFNγ) production by Tfh cells through BR‐3. IFNγ‐producing Tfh cells increased BAFF expression in dendritic cells. Blocking BAFF or IFNγ in vivo reduced Tfh cell accumulation and reduced autoimmunity in BCMA‐deficient animals. Moreover, circulating Tfh‐like cells that expressed BR‐3 (but not BCMA) were elevated in patients with systemic lupus erythematosus, and this correlated with serum BAFF and IFNγ levels. Conclusion In Nba2 mice, BCMA negatively regulates Tfh cell expansion, while BAFF signaling through BR‐3 promotes Tfh cell accumulation. Our findings suggest that the balance between BCMA and BR‐3 signaling in Tfh cells serves as a checkpoint of immune tolerance.
Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract
Authors: Saurabh Mehandru, Michael A. Poles, Klara Tenner-Racz, Amir Horowitz, Arlene Hurley, Christine Hogan, Daniel Boden, Paul Racz, Martin Markowitz
Journal: The Journal of Experimental Medicine (2004)

Given its population of CCR5-expressing, immunologically activated CD4+ T cells, the gastrointestinal (GI) mucosa is uniquely susceptible to human immunodeficiency virus (HIV)-1 infection. We undertook this study to assess whether a preferential depletion of mucosal CD4+ T cells would be observed in HIV-1–infected subjects during the primary infection period, to examine the anatomic subcompartment from which these cells are depleted, and to examine whether suppressive highly active antiretroviral therapy could result in complete immune reconstitution in the mucosal compartment. Our results demonstrate that a significant and preferential depletion of mucosal CD4+ T cells compared with peripheral blood CD4+ T cells is seen during primary HIV-1 infection. CD4+ T cell loss predominated in the effector subcompartment of the GI mucosa, in distinction to the inductive compartment, where HIV-1 RNA was present. Cross-sectional analysis of a cohort of primary HIV-1 infection subjects showed that although chronic suppression of HIV-1 permits near-complete immune recovery of the peripheral blood CD4+ T cell population, a significantly greater CD4+ T cell loss remains in the GI mucosa, despite up to 5 yr of fully suppressive therapy. Given the importance of the mucosal compartment in HIV-1 pathogenesis, further study to elucidate the significance of the changes observed here is critical.
Ultrasound Enhances Reporter Gene Expression After Transfection of Vascular Cells In Vitro
Authors: Allan Lawrie, Axel F. Brisken, Sheila E. Francis, David I. Tayler, Janet Chamberlain, David C. Crossman, David C. Cumberland, Christopher M. Newman
Journal: Circulation (1999)

Background —Restenosis after percutaneous coronary intervention remains a serious clinical problem. Progress in local gene therapy to prevent restenosis has been hindered by concerns over the safety and efficacy of viral vectors and the limited efficiency of nonviral techniques. This study investigates the use of adjunctive ultrasound to enhance nonviral gene delivery. Methods and Results —Cultured porcine vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) were transfected with naked or liposome-complexed luciferase reporter plasmid for 3 hours. Ultrasound exposure (USE) for 60 seconds at 1 MHz, 0.4 W/cm 2 , 30 minutes into this transfection period enhanced luciferase activity 48 hours later by 7.5-fold and 2.4-fold, respectively. Luciferase activity after lipofection of ECs was similarly enhanced 3.3-fold by adjunctive USE. USE had no effect on cell viability, although it inhibited VSMC but not EC proliferation. Conclusions —Adjunctive USE was associated with enhanced transgene expression in VSMCs and ECs and reduced VSMC but not EC proliferation in vitro, which suggests that ultrasound-assisted local gene therapy has potential as an antirestenotic therapy.