tbuckley/cabot-search huggingface dataset:
Oral Delivery of Anticoagulant Doses of Heparin
Authors: Robert A. Baughman, Shiv C. Kapoor, Rajesh K. Agarwal, James Kisicki, Francesca Catella-Lawson, Garret A. FitzGerald
Journal: Circulation (1998)

Background —Parenteral heparin is the anticoagulant of choice in hospitalized patients. Continued anticoagulation is achieved by subcutaneous administration of low-molecular-weight heparin or with an orally active anticoagulant such as warfarin. An oral heparin formulation would avoid the inconvenience of subcutaneous injection and the unfavorable drug interactions and adverse events associated with warfarin. A candidate delivery agent, sodium N -[8(-2-hydroxybenzoyl)amino]caprylate (SNAC), was evaluated with escalating oral heparin doses in a randomized, double-blind, controlled clinical study for safety, tolerability, and effects on indexes of anticoagulation. Methods and Results —Increases in activated partial thromboplastin time (aPTT), anti-factors IIa and Xa, and tissue factor pathway inhibitor (TFPI) concentrations were detected when normal volunteers were dosed with 10.5 g SNAC/20 000 IU heparin by gavage in some subjects. For the entire group, 30 000 IU SNAC and heparin elevated TFPI from 74.9±7.6 to 254.2±12.3 mg/mL ( P &lt;0.001) 1 hour after dosing ( P &lt;0.001). Similar changes occurred in anti-factor IIa and anti-factor Xa. aPTT rose from 28±0.5 to 42.2±6.3 seconds 2 hours after dosing ( P &lt;0.01). No significant changes in vital signs, physical examination, ECGs, or clinical laboratory values were observed. Neither 30 000 IU heparin alone nor 10.5 g SNAC alone altered the hemostatic parameters. Emesis was associated with 10.5 g SNAC. A taste-masked preparation of SNAC 2.25 g was administered orally with heparin 30 000 to 150 000 IU. Both aPTT and anti-factor Xa increased with escalating doses of heparin. This preparation was well tolerated. Conclusions —Heparin, administered orally in combination with the delivery agent SNAC, produces significant elevations in 4 indexes of anticoagulant effect in healthy human volunteers. These results establish the feasibility of oral delivery of anticoagulant doses of heparin in humans and may have broader implications for the absorption of macromolecules.
New Approaches to the Immunotherapy of Cancer Using Interleukin-2
Authors: STEVEN A. ROSENBERG
Journal: Annals of Internal Medicine (1988)

Experimental studies in animals have shown that therapy with high-dose interleukin-2 either alone or in combination with lymphokine-activated killer cells can reduce established pulmonary and hepatic metastases. Based on these experiments, recent clinical trials have shown that therapy with high-dose interleukin-2 alone or in combination with lymphokine-activated killer cells can mediate the regression of established metastatic disease in selected patients with advanced malignancy. Of 221 patients with advanced cancer treated with this immunotherapy, 16 have had a complete regression of all metastatic cancer, and an additional 26 have had a partial regression (greater than 50% reduction) of cancer. Toxicity from treatment was primarily due to increased capillary permeability, which led to fluid extravasation and organ dysfunction. Based on these findings, new approaches are being explored, including the use of tumor-infiltrating lymphocytes and combinations of lymphokines. These studies show that the regression of established growing cancer can be mediated by manipulating the immune system.
Nonendocytic Delivery of Lipoplex Nanoparticles into Living Cells Using Nanochannel Electroporation
Authors: Pouyan E. Boukany, Yun Wu, Xi Zhao, Kwang J. Kwak, Piotr J. Glazer, Kam Leong, L. James Lee
Journal: Advanced Healthcare Materials (2013)

The delivery of biomolecules, including siRNAs (≈21 bp) and large plasmids (≈10 kbp), into living cells holds a great promise for therapeutic and research applications. Lipoplex nanoparticles are popular nanocarriers for gene delivery. In conventional transfection methods, the cellular uptake of lipoplex nanoparticels occurs through the endocytosis process. The entrapment of lipoplex nanoparticles into endocytic vesicle is a major barrier in achieving efficient gene silencing and expression. Here, a novel nanochannel electroporation (NEP) method is employed to facilitate the cellular uptake and release of siRNAs/DNAs from lipoplexes. First, it is demonstrated that in a NEP device, lipoplex nanoparticles can be injected directly into the cell cytoplasm within several seconds. Specifically, it is found that lipoplexes containing MCL‐1 siRNA delivered by NEP can more efficiently down‐regulate the expression of MCL‐1 mRNA in A549 cancer cells than conventional transfection. Quantum dot‐mediated Förster resonance energy transfer (QD‐FRET) reveals that lipoplexes delivered via NEP can directly release siRNA in the cytoplasm without going through the endocytosis route, which unravels the responsible mechanism for efficient gene delivery. Furthermore, the advantage of combining NEP with lipoplex nanoparticles by the successful delivery of large plasmids (pCAG2LMKOSimO, 13 kbp) into CHO cells is demonstrated.
The size of duplication does not add to the prognostic significance of FLT3 internal tandem duplication in acute myeloid leukemia patients
Authors: V Ponziani, G Gianfaldoni, F Mannelli, F Leoni, S Ciolli, P Guglielmelli, E Antonioli, G Longo, A Bosi, A M Vannucchi
Journal: Leukemia (2006)
N-ethyl-N-nitrosourea (ENU) mutagenesis and male fertility research
Authors: C.L. Kennedy, M.K. O’Bryan
Journal: Human Reproduction Update (2006)

Male infertility affects about 1 in 25 men in the western world. Conversely, there is an urgent requirement for additional male-based contraceptives, yet progress in both areas has been severely hampered by a lack of knowledge of the biochemistry and physiology of male reproductive function. It is only through a thorough knowledge of these processes that we can hope to insightfully regulate male reproductive function. Without doubt, mouse models will form an important foundation in any future process. In recent years, the chemical mutagen N-ethyl-N-nitrosourea (ENU) has been used widely to identify genes essential for a range of biological systems including male infertility. These studies have shown random mutagenesis is an attractive means of identifying key genes for male fertility. This technique has distinct, but complementary advantages compared to knockout technologies. Specifically, it allows the removal of researcher bias whereby only pre-conceived genes are tested for function; it produces mice with a guaranteed phenotype and allows for the production of allelic series of mice to dissect all aspects of gene function. ENU mouse mutagenesis programs will enable advances in the diagnosis and treatment of human male infertility and ultimately aid in the development of novel male-based contraceptives.
Predictors of Early Death Risk in Older Patients Treated With First-Line Chemotherapy for Cancer
Authors: Pierre Soubeyran, Marianne Fonck, Christèle Blanc-Bisson, Jean-Frédéric Blanc, Joël Ceccaldi, Cécile Mertens, Yves Imbert, Laurent Cany, Luc Vogt, Jerôme Dauba, Francis Andriamampionona, Nadine Houédé, Anne Floquet, Francois Chomy, Véronique Brouste, Alain Ravaud, Carine Bellera, Muriel Rainfray
Journal: Journal of Clinical Oncology (2012)

Objective factors for making choices about the treatment of elderly patients with cancer are lacking. This investigation aimed to help physicians select appropriate treatments through the identification of factors that predict early death (< 6 months) after initiation of chemotherapy treatment.Previously untreated patients greater than 70 years of age who were scheduled for first-line chemotherapy for various types of cancer were included. Baseline abbreviated comprehensive geriatric assessment (aCGA), including the Mini-Mental State Exam, Timed Get Up and Go (GUG), Activities of Daily Living (ADL), Instrumental Activities in Daily Living (IADL), Mini Nutritional Assessment (MNA), Geriatric Depression Scale (GDS15), and comorbidities index (Cumulative Index Rating Scale-Geriatric), was carried out. Prognostic factors of early death were sought from aCGA results and traditional oncology measures.A total of 348 patients were included across 12 centers in Southwest France (median age, 77.45 years; ratio of men to women, 1.47; advanced disease, 65%). Abnormal aCGA scores were observed for 18.1% of patients on the ADL, 73.0% of patients on the IADL, 24.1% of patients on the GUG, 19.0% of patients on the MMS, 44.0% of patients on the GDS15, and 64.9% of patients on the MNA. Advanced disease (odds ratio [OR], 3.9; 95% CI, [1.58 to 9.73]), a low MNA score (OR 2.77; 95% CI, [1.24 to 6.18]), male sex (OR, 2.40; 95% CI, [1.2 to 4.82]), and long GUG (OR, 2.55; 95% CI, [1.32 to 4.94] were associated with higher risk of early death.In patients greater than 70 years of age with cancer, advanced disease, a low MNA score, and poor mobility predicted early death. We recommend that the MNA and GUG, performed by a trained nurse, be maintained as part of routine pretreatment workup in these patients to identify at-risk patients and to inform the decision-making process for chemotherapy.
Origin of serum hepatitis B virus in acute exacerbation: Comparison with HBV in the liver and from other exacerbation
Authors: Chun-Jen Liu, Jia-Horng Kao, Hurng-Yi Wang, Ming-Yang Lai, Ting-Chih Chen, Pei-Jer Chen, Ding-Shinn Chen
Journal: Hepatology (2004)

Acute exacerbation (AE) of chronic hepatitis B is usually preceded by reemergence or increase of hepatitis B virus (HBV) in the serum. To investigate the origin of the reemergence or increase, we compared the identity of the serum viral genome to that in the liver and in previous AE by full-length sequencing. The full-length viral genome and extent of quasispecies were obtained from serum and liver biopsy specimens at the same time from 9 subjects with hepatitis B exacerbation (group I). Composition of viral quasispecies was compared by the genetic diversity and the average number of nucleotide substitutions within and between different viral sources. Another 2 patients with repeated AEs (group II) were also enrolled, and their serial serum alanine aminotransferase, HBV DNA levels and full-length sequences were determined. In all group I patients, serum viral genome was identical to that in the liver. The genetic diversity and the average number of nucleotide difference were also comparable between serum and liver tissue. In 2 group II patients, the viral variant that emerged after previous AE was not identical to that caused by the subsequent AE. Dominant viral strains for serial AEs in a single patient did not show a sequential evolution, but presented as a horizontal selection of a minor population from the original viral pool. In conclusion, the findings suggest that viral strain in serum reflects the intrahepatic strain of the AE. Random reactivation of the original HBV pool, rather than a sequential evolution of one strain, also contributes to the onset of repeated AE. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
Inference of Natural Selection from Interspersed Genomic Elements Based on Polymorphism and Divergence
Authors: Ilan Gronau, Leonardo Arbiza, Jaaved Mohammed, Adam Siepel
Journal: Molecular Biology and Evolution (2013)

Complete genome sequences contain valuable information about natural selection, but extracting this information for short, widely scattered noncoding elements remains a challenging problem. Here we introduce a new computational method for addressing this problem called Inference of Natural Selection from Interspersed Genomically coHerent elemenTs (INSIGHT). INSIGHT uses a generative probabilistic model to contrast patterns of polymorphism and divergence in the elements of interest with those in flanking neutral sites, pooling weak information from many short elements in a manner that accounts for variation among loci in mutation rates and genealogical backgrounds. The method is able to disentangle the contributions of weak negative, strong negative, and positive selection based on their distinct effects on patterns of polymorphism and divergence. Information about divergence is obtained from multiple outgroup genomes using a full phylogenetic model. The model is efficiently fitted to genome-wide data by decomposing the maximum likelihood estimation procedure into three straightforward stages. The key selection-related parameters are estimated by expectation maximization. Using simulations, we show that INSIGHT can accurately estimate several parameters of interest even in complex demographic scenarios. We apply our methods to noncoding RNAs, promoter regions, and transcription factor binding sites in the human genome, and find clear evidence of natural selection. We also present a detailed analysis of particular nucleotide positions within GATA2 binding sites and primary micro-RNA transcripts.
Evaluation of a method for assessing respiratory mechanics during noninvasive ventilation
Authors: D. Navajas, J. Alcaraz, R. Peslin, J Roca, R Farré
Journal: European Respiratory Journal (2000)

Noninvasive assessment of respiratory resistance (Rrs) and elastance (Ers), which is not easy with conventional methods, could be useful in the optimization of pressure support ventilation. The aim of this study was to evaluate a simple noninvasive method (Delta-inst) of measuring Rrs during nasal pressure support ventilation. Rrs and Ers (Delta-inst) were computed from inspiratory mask pressure, flow and volume recorded during pressure support ventilation. The Delta-inst method was compared with the forced oscillation technique (FOT) in seven patients with chronic obstructive pulmonary disease (COPD) and in eight healthy subjects without and with added resistance (3.1 cmH2O x s x L(-1)). Rrs measured by Delta-inst (5.2+/-1.7, 7.2+/-0.5 and 6.9+/-1.2 cmH2O x s x L(-1)) and by FOT (5.0+/-0.7, 7.6+/-0.9 and 8.1+/-2.7 cmH2O x s x L(-1)) in healthy subjects without and with added resistance and COPD, respectively, were not significantly different (p>0.05). Rrs measured by both techniques showed a significant coefficient of linear correlation (r=0.70 s) (p<0.01). In the COPD patients, the variability of Delta-inst Rrs (30%) was greater than that of FOT Rrs (21%). The agreement between Ers obtained by Delta-inst and by FOT was less than that found for Rrs. Delta-inst is a noninvasive and simple method for reliably assessing resistance. Therefore, it is useful for monitoring airway obstruction and is potentially helpful in adapting the settings for pressure support ventilation in accordance with patient mechanics.
MYD88 L265P mutation in Waldenstrom macroglobulinemia
Authors: Stéphanie Poulain, Christophe Roumier, Audrey Decambron, Aline Renneville, Charles Herbaux, Elisabeth Bertrand, Sabine Tricot, Agnès Daudignon, Sylvie Galiègue-Zouitina, Valerie Soenen, Olivier Theisen, Nathalie Grardel, Olivier Nibourel, Catherine Roche-Lestienne, Bruno Quesnel, Patrick Duthilleul, Claude Preudhomme, Xavier Leleu
Journal: Blood (2013)
Studies on Human Thyroxine-Binding Globulin
Authors: James S. Marshall, Jack Pensky, Allan M. Green
Journal: Journal of Clinical Investigation (1972)

A model system utilizing a highly purified partially desialylated thyroxine-(T(4)) binding protein (STBG) was studied. STBG was prepared by the same affinity chromatographic method we have reported for preparation of highly purified T(4)-binding globulin (TBG). The necessary prerequisite for preparation of STBG was the use of T(4)-substituted Sepharose which had been repeatedly exposed to large volumes of serum for purification of TBG. STBG moved more slowly on cellulose acetate electrophoresis than TBG but had the same molecular weight and antigenic determinants as TBG. It bound T(4) with a 1: 1 molar ratio but its affinity for T(4) was about 10 times less than that of TB. STBG had about onefourth the sialic acid content of TBG and the electrophoretic mobility of this protein was similar to that of a T(4)-binding protein with a mobility slower than that of TBG which has been seen in the electrophoretic patterns of some normal human serums and in serums of patients with hepatic cirrhosis and which does not appear to be an artifact caused by storage and freezing of serum. This fourth slowly migrating T(4)-binding region in electrophoretograms of cirrhotic serums is completely abolished by prior incubation with rabbit antiserum to TBG. The in vitro production of partially desialylated TBG from T(4)-Sepharose which had been previously exposed to large volumes of serum may be due to adsorption of neuraminidases to the Sepharose either directly from serum or as the result of bacterial contamination. Partial desialylation of TBG in vivo may be an early step in the catabolism of this protein.
Dermoscopic criteria associated with <i> <scp>BRAF</scp> </i> and <i> <scp>NRAS</scp> </i> mutation status in primary cutaneous melanoma
Authors: F.C. Pozzobon, J.A. Puig‐Butillé, T. González‐Alvarez, C. Carrera, P. Aguilera, L. Alos, C. Badenas, J.M. Grichnik, J. Malvehy, S. Puig
Journal: British Journal of Dermatology (2014)

The identification of BRAF mutations in melanoma led to the development and implementation of new and effective therapies. Few clinical and histological features have been associated with this mutational status.The main objective of this study was to investigate clinical, histopathological and dermoscopic characteristics of primary melanomas according to BRAF or NRAS mutational status.An observational retrospective study including melanoma dermoscopy images assessed for somatic mutations in BRAF and NRAS.Seventy-two patients were included, 30 women (42%) and 42 men (58%), mean age was 59 ± 15.51 years. BRAF-mutated melanomas were more frequently located on the trunk (n = 18, 64% for BRAF-mutated vs. n = 11, 29% for wild-type melanomas, P = 0.013). Histological ulceration was associated with the presence of BRAF mutations [odds ratio (OR) 3.141; 95% confidence interval (CI) 1.289-7.655; P = 0.002]. The Breslow index tended to be thicker in BRAF-mutated compared with wild-type (P = 0.086). BRAF mutations were present in 28 (39%) patients and only four cases were positive for NRAS mutations (6%), BRAF and NRAS mutations being mutually exclusive. The presence of dermoscopic peppering was associated with MAPK mutations (BRAF and NRAS) (OR 1.68; 95% CI 1.089-2.581; P = 0.015). Dermoscopic ulceration was also associated with BRAF mutations excluding acral and facial melanomas (OR 2.64; 95% CI 1.032-6.754).This study showed a correlation between BRAF and NRAS status and dermoscopic findings of 'peppering' as an expression of regression and melanophages in the dermis, suggesting a morphological consequence of immune behaviour in BRAF-mutated melanomas.
Purine enzymes in rheumatoid arthritis: possible association with response to azathioprine. A pilot study.
Authors: P J Kerstens, J N Stolk, A M Boerbooms, L H Lambooy, R de Graaf, R A De Abreu, L B van de Putte
Journal: Annals of the Rheumatic Diseases (1994)

OBJECTIVE--To study the possible association of purine enzyme activities with response to azathioprine (AZA) treatment in rheumatoid arthritis (RA) and their correlation with parameters of disease activity. PATIENTS AND METHODS--Lymphocyte activities of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT), adenine phosphoribosyltransferase (APRT), purine nucleoside phosphorylase (PNP) and 59-nucleotidase (5NT), and erythrocyte activities of thiopurine methyltransferase (TPMT) were measured in 14 healthy controls and 36 patients with RA. Eight patients had not previously been treated with AZA. Response to AZA therapy in 28 patients, determined in a prospective trial, was considered good in nine (group 1), insufficient in seven (group 2). In 12 patients AZA was withdrawn because of adverse reactions (group 3). Disease activity parameters were obtained simultaneously with purine enzyme measurements. Purine enzyme levels in the different groups were compared. RESULTS--Levels of 5NT activity were significantly lower in patients with RA than in healthy controls. PNP activity was higher in patients with RA not using prednisone compared with those who did and healthy controls. No clear correlation between purine enzyme levels and disease activity parameters was found. 5NT activities were significantly higher in group one than in group three (p = 0.012; alpha = 0.017), and almost significantly higher than in group two (p = 0.03; alpha = 0.017). CONCLUSIONS--The results indicate that purine enzyme activities in patients with RA differ from healthy controls, are associated with the outcome of AZA treatment and seem not to be associated with disease activity. Our findings may offer a clue to predict the response to AZA therapy in RA.
Utility of bronchoalveolar lavage in the determination of lung asbestos burden in Barcelona, Spain
Authors: Patricia Chang-Macchiu, Daniel Alvarez, Maria Jesús Cruz, Cecilia Perez, Victor Curull, Maria Guadalupe Silveira, Lara Pijuan, Albert Sanchez-Font, Javier De Gracia, Jaume Ferrer
Journal: European Respiratory Journal (2013)

Objectives: To evaluate the utility of bronchoalveolar lavage (BAL) as an indicator of lung asbestos content in lung cancer patients in our laboratory.  Methods: Patients with lung cancer underwent a diagnostic bronchoscopy and subsequently lung resection (lobectomy or pneumonectomy). BAL was performed in the lingula or the middle lobe contralateral to the lesion. After surgery, 2 cm3 of pulmonary tissue were collected at an equal or greater distance than 5 cm from the tumor. Samples of 10 ml of BAL and 0.5 g of lung tissue were chemically digested with sodium hypochlorite and filtered with cellulose filters. Asbestos bodies (AB) were detected and counted by optical microscopy at 500x. Values were expressed as AB/ml of LBA or AB/g of dried lung, respectively. Correlations between AB counting in BAL and lung tissue were calculated with the Spearman’s rank correlation coefficient.  Results: We included 26 patients (24 men, mean age 66 ± 9.9 years). Nine patients had been previously exposed to asbestos. The most common type of lung tumor was adenocarcinoma (58%). Median values for AB in BAL and lung tissue were 0.20 (0-19.4) AB/ml and 160 (0-7499) AB/g of tissue, respectively. Five patients (19%) had values above 1 AB/ml in BAL, although two reported no previous exposure. Four patients (15%) had values above 1,000 AB/g of tissue (one naive). The Spearman’s rank correlation coefficient between levels of AB/ml of BAL and AB/g tissue was 0.59 (p = 0.003).  Conclusions: There was an acceptable correlation between the number of asbestos bodies in BAL and lung tissue, so we believe that BAL may be a reliable measure reflecting the lung asbestos content in our laboratory.