tbuckley/cabot-search huggingface dataset:
AAV Vectors Containing rDNA Homology Display Increased Chromosomal Integration and Transgene Persistence
Authors: Zhongya Wang, Leszek Lisowski, Milton J Finegold, Hiroyuki Nakai, Mark A Kay, Markus Grompe
Journal: Molecular Therapy (2012)

Although recombinant adeno-associated viral (rAAV) vectors are promising tools for gene therapy of genetic disorders, they remain mostly episomal and hence are lost during cell replication. For this reason, rAAV vectors capable of chromosomal integration would be desirable. Ribosomal DNA (rDNA) repeat sequences are overrepresented during random integration of rAAV. We therefore sought to enhance AAV integration frequency by including 28S rDNA homology arms into our vector design. A vector containing ~1 kb of homology on each side of a cDNA expression cassette for human fumarylacetoacetate hydrolase (FAH) was constructed. rAAV of serotypes 2 and 8 were injected into Fah-deficient mice, a model for human tyrosinemia type 1. Integrated FAH transgenes are positively selected in this model and rDNA-containing AAV vectors had a ~30× higher integration frequency than controls. Integration by homologous recombination (HR) into the 28S rDNA locus was seen in multiple tissues. Furthermore, rDNA-containing AAV vectors for human factor IX (hFIX) demonstrated increased transgene persistence after liver regeneration. We conclude that rDNA containing AAV vectors may be superior to conventional vector design for the treatment of genetic diseases, especially those associated with increased hepatocyte replication. Although recombinant adeno-associated viral (rAAV) vectors are promising tools for gene therapy of genetic disorders, they remain mostly episomal and hence are lost during cell replication. For this reason, rAAV vectors capable of chromosomal integration would be desirable. Ribosomal DNA (rDNA) repeat sequences are overrepresented during random integration of rAAV. We therefore sought to enhance AAV integration frequency by including 28S rDNA homology arms into our vector design. A vector containing ~1 kb of homology on each side of a cDNA expression cassette for human fumarylacetoacetate hydrolase (FAH) was constructed. rAAV of serotypes 2 and 8 were injected into Fah-deficient mice, a model for human tyrosinemia type 1. Integrated FAH transgenes are positively selected in this model and rDNA-containing AAV vectors had a ~30× higher integration frequency than controls. Integration by homologous recombination (HR) into the 28S rDNA locus was seen in multiple tissues. Furthermore, rDNA-containing AAV vectors for human factor IX (hFIX) demonstrated increased transgene persistence after liver regeneration. We conclude that rDNA containing AAV vectors may be superior to conventional vector design for the treatment of genetic diseases, especially those associated with increased hepatocyte replication.
Islet cell cytoplasmic autoantibody reactivity to glutamate decarboxylase in insulin-dependent diabetes.
Authors: M A Atkinson, D L Kaufman, D Newman, A J Tobin, N K Maclaren
Journal: Journal of Clinical Investigation (1993)

Individuals with or at risk for insulin-dependent diabetes (IDD) frequently have autoantibodies against an islet cell cytoplasmic (ICA) antigen thought to be a sialoglycolipid. However, we now report that preabsorption of ICA-positive sera with recombinant glutamate decarboxylase (human GAD 65 and/or GAD 67) reduced or blocked the ICA reactivity of 5/18 (27%) new-onset IDD patients and 7/18 (39%) prediabetics. Interestingly, nondiabetic subjects with ICA of > or = 5 yr in duration had GAD-reactive ICA significantly more often (16/24, 67%, P < 0.04) than the diabetic groups. ICA reactivity to GAD was not related to serum ICA titer nor the age of the individual, and in all cases tested was blocked by GAD 65 or GAD 67 with equivalent efficiency. The ICA observed in 21/25 (84%) IDD patients with ICA long after clinical onset of disease (9-42 yr) was reactive to GAD. A natural history analysis of three individuals showed conversions from ICA which was reactive to GAD to a non-GAD-reactive ICA nearer to their clinical onsets of IDD. This study further defines the autoantigens reactive to ICA, and suggests that, whereas ICA that are not reactive to GAD may identify an advanced and more prognostic lesion, GAD-reactive ICA may typify the early or inductive lesion that may or may not progress to clinically significant beta cell injury.
Update on rupatadine in the management of allergic disorders
Authors: J. Mullol, J. Bousquet, C. Bachert, G. W. Canonica, A. Giménez‐Arnau, M. L. Kowalski, F. E. R. Simons, M. Maurer, D. Ryan, G. Scadding
Journal: Allergy (2014)

In a review of rupatadine published in 2008, the primary focus was on its role as an antihistamine, with a thorough evaluation of its pharmacology and interaction with histamine H1 -receptors. At the time, however, evidence was already emerging of a broader mechanism of action for rupatadine involving other mediators implicated in the inflammatory cascade. Over the past few years, the role of platelet-activating factor (PAF) as a potent mediator involved in the hypersensitivity-type allergic reaction has gained greater recognition. Rupatadine has dual affinity for histamine H1 -receptors and PAF receptors. In view of the Allergic Rhinitis and its Impact on Asthma group's call for oral antihistamines to exhibit additive anti-allergic/anti-inflammatory properties, further exploration of rupatadine's anti-PAF effects was a logical step forward. New studies have demonstrated that rupatadine inhibits PAF effects in nasal airways and produces a greater reduction in nasal symptoms than levocetirizine. A meta-analysis involving more than 2500 patients has consolidated the clinical evidence for rupatadine in allergic rhinoconjunctivitis in adults and children (level of evidence Ia, recommendation A). Other recent advances include observational studies of rupatadine in everyday clinical practice situations and approval of a new formulation (1 mg/ml oral solution) for use in children. In this reappraisal, we revisit some key properties and pivotal clinical studies of rupatadine and examine new clinical data in more detail including studies that measured health-related quality of life and studies that investigated the efficacy and safety of rupatadine in other indications such as acquired cold urticaria, mosquito bite allergy and mastocytosis.
Black cat in a dark room: the absence of a directly oncogenic virus does not eliminate the role of an infectious agent in cutaneous T-cell lymphoma pathogenesis
Authors: B. O. Dulmage, H. Feng, E. Mirvish, L. Geskin
Journal: British Journal of Dermatology (2014)

Journal Article Black cat in a dark room: the absence of a directly oncogenic virus does not eliminate the role of an infectious agent in cutaneous T‐cell lymphoma pathogenesis Get access B. O. Dulmage, B. O. Dulmage Department of Dermatology University of Pittsburgh Pittsburgh PA U.S.A Search for other works by this author on: Oxford Academic Google Scholar H. Feng, H. Feng Cancer Virology Program University of Pittsburgh Cancer Institute Pittsburgh PA U.S.A Search for other works by this author on: Oxford Academic Google Scholar E. Mirvish, E. Mirvish Department of Dermatology University of Pittsburgh Pittsburgh PA U.S.A Search for other works by this author on: Oxford Academic Google Scholar L. Geskin L. Geskin Department of Dermatology Columbia University 161 Fort Washington Avenue, 12th Floor New York NY 10032 U.S.A Correspondence: Larisa J. Geskin. E‐mail: ljg2145@columbia.edu Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 172, Issue 5, 1 May 2015, Pages 1449–1451, https://doi.org/10.1111/bjd.13519 Published: 01 May 2015
Blood doping--a literature review.
Authors: M Jones, D S Tunstall Pedoe
Journal: British Journal of Sports Medicine (1989)

There is increasing evidence that the technique of reinfusing an athlete's stored blood prior to competition to improve performance has been used on many occasions. Although early experimental results were controversial and the precise mechanism by which the technique improves performance is still debated, there is now strong evidence that if the blood doping produces a sufficient rise in total red cell mass there are significant improvements in physiological variables such as maximum oxygen uptake, lactate buffering and thermoregulation. These physiological changes are matched by improvements in endurance performance. These may persist in diminishing degree for several weeks, but have to be weighed against the detraining effect produced by the repeated venesection required to obtain an adequate amount of stored blood for autologous reinfusion. Experimental evidence suggests that the transient increase in blood volume and cardiac output following reinfusion is too short lived to be of any real importance and the major effect is related to the increase in total red blood cell mass and haemoglobin enabling an increased transport of oxygen and therefore a potentially greater reserve of blood which can be diverted to non-exercising tissues to improve thermoregulation. The increased red cell mass also improves lactate buffering. Although these benefits have been shown in several studies the increases in performance and measured physiological parameters do not bear a direct relationship to the changes in haematological variables. Blood doping is of considerable importance, not only as an abuse of fair competition, but also because of the light it throws on the physiological limits to endurance performance. It has reawakened controversy as to whether oxygen transport is the limiting factor in endurance.
Early menopause is an independent predictor of rheumatoid arthritis
Authors: Mitra Pikwer, Ulf Bergström, Jan-Åke Nilsson, Lennart Jacobsson, Carl Turesson
Journal: Annals of the Rheumatic Diseases (2011)

Background As rheumatoid arthritis (RA) occurs more often in women than in men, it has been suggested that reproductive hormones may play an important role in the pathogenesis. Methods Between 1991 and 1996, 30 447 subjects (18 326 women) were included in a community-based health survey. Information on female hormonal changes and stress-related factors was obtained using a self-administered questionnaire. This population was linked to four different local and national RA registers. The medical records for patients with a diagnosis of RA were subjected to a structured review and all women with incident RA according to the 1987 American College of Rheumatology criteria after inclusion in the health survey were included in a nested case–control study. Matched controls (1:4) were selected from the health survey population. Results Early age at menopause (≤45 years) was associated with the subsequent development of RA (OR 2.42, 95% CI 1.32 to 4.45). The effect of early menopause remained significant after adjusting for smoking, level of education and length of breastfeeding (OR 1.92, 95% CI 1.02 to 3.64) Conclusion RA was predicted by an early age at menopause. This implicates an influence of hormonal changes during the fertile period on the development of RA in postmenopausal women.
Blood cysts of the cardiac valves of calves and cattle
Authors: R. B. Smith, I. M. Taylor
Journal: Cardiovascular Research (1971)

The incidence of blood-filled cysts in the valvular cusps of a large series of calf and cattle hearts has been investigated and the results have been compared with previous reports. Two distinct types of cyst were discovered. One variety is common, being small, often multiple, unilocular, and situated at the closing edge of the valves. The other type is comparatively rare and is large and solitary. It lies near the base of the valve and is multilocular. The possible aetiology of these different lesions is evaluated.
Abstract P216: The Association Between Reduction in Inflammation and Changes in Lipoprotein Levels and HDL Cholesterol Efflux Capacity in Rheumatoid Arthritis
Authors: Katherine Liao, Martin Playford, Michelle Frits, Jonathan Coblyn, Christine Iannaccone, Michael Weinblatt, Nancy Shadick, Nehal Mehta
Journal: Circulation (2015)

Background: Potent anti-inflammatory RA treatments are associated with reduced cardiovascular (CV) risk as well as increases in low density lipoprotein (LDL). This apparent paradox may be explained by favorable changes in other lipid measurements. The objective of this study was to determine the longitudinal association between changes in inflammation with advanced lipoprotein measurements and HDL cholesterol efflux capacity. Methods and Results: We conducted this study in a longitudinal RA cohort from a large academic center. We included subjects with hsCRP reduction ≥10mg/L at two time points one year apart. Subjects on statins during the study period or 6 months prior were excluded. We measured total cholesterol (TC), LDL, high density lipoprotein (HDL), apolipoprotein B (apoB), apoA1, and HDL cholesterol efflux capacity at baseline and one year follow-up. We determined the correlations between reduction in hsCRP and change in lipid parameters using the Pearson test. We studied 90 RA subjects, mean age 57 years, 89% female, all subjects were on disease modifying anti-rheumatic drugs; median baseline hsCRP was 28.6mg/L and follow-up 4.3 mg/L (reduction of 85%, p&lt;0.0001). We observed significant correlations between a reduction in hsCRP with increases in LDL (r=0.25,p=0.02, Figure 1a), HDL (r=0.23, p=0.03), apoA1 (r=0.27, p=0.01 and HDL cholesterol efflux capacity (r=0.24, p=0.02), an overall improvement of efflux capacity of 5.7% (p=5x10 -4 , Figure 1b). Conclusion: Reduction in inflammation was associated increased LDL levels, and concomitant increases in HDL, ApoA1, and improvements in HDL cholesterol efflux capacity. These findings provide further insight into lipid modulation and the beneficial effect of reduction in inflammation on lipids in vivo.
The role of T helper 17 cell subsets in Sjögren's syndrome: similarities and differences between mouse model and humans
Authors: Alessia Alunno, Francesco Carubbi, Sara Caterbi, Onelia Bistoni, Elena Bartoloni, Roberto Giacomelli, Roberto Gerli
Journal: Annals of the Rheumatic Diseases (2014)

We read with great interest the article by Lin et al that provided the clue for a pathogenic role of T helper (h) 17 cells in the development of experimental Sjogren's syndrome (SS).1 In particular, interleukin (IL)-17 knockout C57BL/6 mouse immunised with salivary glands (SGs) proteins does not display clinical, histological and serological features of SS as the wild type counterpart.1 Previous studies reported that the infusion of adenovirus vectors expressing IL-17 into SGs, via retrograde cannulation, was able to induce clinical, serological and histological features of SS in non-susceptible mice, thereby suggesting a pathogenic role of this cytokine in the induction of glandular damage in SS.2 To date, it is still a matter of …
Adjuvant Management of Rectal Cancer: The More We Learn, the Less We Know
Authors: Bruce D. Minsky
Journal: Journal of Clinical Oncology (2007)

Two decades ago, the adjuvant management of rectal cancer was less complex and far less controversial. Patients in the United States underwent surgery, commonly by blunt dissection, and if there was pT3 and/or pN1-2 disease, they received 6 months of postoperative fluouracil (FU)-based chemotherapy with pelvic radiation during months 3 and 4 (combined-modality therapy). Subsequent randomized and nonrandomized trials have taught us manynewlessons.Amongthesearetotalmesorectalexcisionasthe preferred surgical technique 1 ; at least 12 examined nodes to accurately determine the nodal stage 2 ; the relationship of local failure notonlytostagebutalsotothelocationofthetumorintherectum and the presence of a positive circumferential margin 3 ; and the subsets of patients with pT3N0 of pT1-2N1 disease who may not require postoperative radiation. 4 Furthermore, for patients with cT3 and or N disease, the German trial confirmed that preoperative combined-modality therapy has significantly improved local control, caused less acute short and long-term toxicity, and increased sphincter preservation compared with postoperative combined-modality therapy. 5
Exhaled nitric oxide, nitrite/nitrate levels, allergy, rhinitis and asthma in the EGEA study
Authors: Rachel Nadif, Marta Rava, Brigitte Decoster, Hélène Huyvaert, Nicole Le Moual, Jean Bousquet, Valérie Siroux, Raphaëlle Varraso, Isabelle Pin, Farid Zerimech, Régis Matran
Journal: European Respiratory Journal (2014)

Although interest in biomarkers in the nitrate–nitrite–NO pathway has recently increased, associations between nitrite (NO 2 − ) and nitrate (NO 3 − ), and asthma, allergic sensitisation and rhinitis remain unclear. The study aimed to evaluate the associations between NO 2 − /NO 3 − and exhaled fraction of nitric oxide ( F eNO ) levels with asthma, allergic sensitisation and rhinitis. Plasma and exhaled breath condensate (EBC) NO 2 − /NO 3 − and F eNO levels were measured in 523 adults of the French Epidemiological study on Genetics and Environment of Asthma. Allergic sensitisation was defined by a positive skin prick test for at least one aeroallergen. Subjects were classified as non-sensitised, sensitised and as having allergic rhinitis. Plasma NO 2 − /NO 3 − level was unrelated to any disease phenotypes. EBC NO 2 − /NO 3 − level was unrelated to any asthma phenotypes. EBC NO 2 − /NO 3 − and F eNO levels were correlated in sensitised subjects only (r=0.21±0.10, p=0.01). EBC NO 2 − /NO 3 − and F eNO levels were higher in sensitised than in non-sensitised subjects (adjusted geometric mean (95% CI): 2.36 (1.96–2.84) versus 1.72 (1.38–2.14) μmol per mg proteins, p=0.008; and 18.3 (16.7–20.0) versus 14.8 (13.3–16.5) ppb, p=0.0006, respectively), with gradual relationships from sensitised subjects to those with allergic rhinitis (p&lt;0.0001). Results suggest that EBC NO 2 − /NO 3 − and F eNO levels may be considered as biological markers of intensity of allergic sensitisation and rhinitis.
Relative survival of patients with supratentorial low-grade gliomas
Authors: N. R. Smoll, O. P. Gautschi, B. Schatlo, K. Schaller, D. C. Weber
Journal: Neuro-Oncology (2012)

We sought to assess the population-based estimates of age-standardized survival among patients with low-grade gliomas (LGG) and to determine the impact of age and time on relative survival (RS). Data from the Surveillance, Epidemiology, and End Results (SEER) program of NCI from 1973 through 2006 were analyzed to assess survival among 5037 patients. Relationships were modeled using Dickman's piecewise constant hazards RS model. The 3- and 10-year age-standardized RS were 67% and 37%, respectively. When analyzed by age group, the 10-year overall survival (OS) and RS for children (age, <16 years), young adults (age, 16–39 years), adults (age, 40–64 years), and older patients (age, ≥65 years) were 86% and 86%, 61% and 62%, 40% and 43%, and 10% and 14%, respectively. The observed difference between OS and RS was larger among older patients (4%) and smallest among children (<1%). Older patients were 30.5 times (excess hazard ratio [eHR]; 95% confidence interval [CI], 20.3–50.0) as likely as young adults to die during the first year and 18.2 times as likely to die during the second year. Adults were 5.3 (eHR; 95% CI, 3.5–8.1) times as likely to die during their first year as young adults. In the remaining years, the observed survival differences were substantially decreased, and the presence of an age-by-follow-up interaction was observed. Survival among older patients with LGG was substantially different from the one computed for young adults and children. Despite the hazards across age groups not being proportional, RS does not provide additional information, compared with OS, in patients with LGG.
ANTIPLATELET AND ANTICOAGULANT USE FOR ACUTE MYOCARDIAL INFARCTION IN EMERGENCY DEPARTMENT: “A CASE FOR QUALITY IMPROVEMENT” – AN ANALYSIS FROM NATIONAL HOSPITAL AMBULATORY MEDICAL CARE SURVEY 2002-2010
Authors: Ankur Sethi, Rohit R. Arora, Sandeep Khosla
Journal: Journal of the American College of Cardiology (2014)
STUDIES ON THE ANTIGENIC STRUCTURE OF SOME MAMMALIAN SPERMATOZOA
Authors: Werner Henle, Gertrude Henle, Leslie A. Chambers
Journal: The Journal of Experimental Medicine (1938)

1. A method has been described for separation of heads and tails of mammalian spermatozoa. 2. By means of absorption technique applied to homologous spermatozoal sera, head-specific and tail-specific antigens could be demonstrated. Both are heat-labile. 3. A heat-stable antigen was found to be common to both heads and tails. This substance is species-specific. 4. Antibodies against the head- and tail-specific antigens led to two different types of agglutination as shown by the slide method. 5. Using heterologous antisera against spermatozoa three different cross-reacting antigens could be observed, two in the heads, one in the tails. 6. One of the head-antigens is not active in the native cell; it comes to action only after breaking the cell. Antibodies against this substance were not found in antisera against native bull spermatozoa but were formed when vibrated spermatozoa or heads were injected into rabbits. 7. The cross-reactions can be removed from an antiserum leaving the head- as well as the tail-specific reaction intact.
Host and tumor derived MMP13 regulate extravasation and establishment of colorectal metastases in the liver
Authors: Alisha M Mendonsa, Michael N VanSaun, Alessandro Ustione, David W Piston, Barbara M Fingleton, David Lee Gorden
Journal: Molecular Cancer (2015)

Non alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the United States and worldwide. Our studies have previously shown an increase in metastatic burden in steatotic vs. normal livers using a mouse model of diet induced steatosis. In the present study we aim to identify and evaluate the molecular factors responsible for this increase in tumor burden. We assessed changes in expression of a panel of matrix metalloproteinases (MMPs) using qRT-PCR between normal and steatotic livers and validated them with western blot analysis of protein levels. To evaluate the role of MMP13 on tumor development, we utilized a splenic injection model of liver metastasis in Wildtype and Mmp13 deficient mice, using either parental or stable Mmp13 knockdown cell lines. Further, to evaluate changes in the ability of tumor cells to extravasate we utilized whole organ confocal microscopy to identify individual tumor cells relative to the vasculature. MTT, migration and invasion assays were performed to evaluate the role of tumor derived MMP13 on hallmarks of cancer in vitro. We found that MMP13 was significantly upregulated in the steatotic liver both in mice as well as human patients with NAFLD. We showed a decrease in metastatic tumor burden in Mmp13−/− mice compared to wildtype mice, explained in part by a reduction in the number of tumor cells extravasating from the hepatic vasculature in the Mmp13−/− mice compared to wildtype mice. Additionally, loss of tumor derived MMP13 through stable knockdown in tumor cell lines lead to decreased migratory and invasive properties in vitro and metastatic burden in vivo. This study demonstrates that stromal as well as tumor derived MMP13 contribute to tumor cell extravasation and establishment of metastases in the liver microenvironment.