tbuckley/cabot-search huggingface dataset:
Abstract 15426: CSL112 Enhances Cholesterol Efflux Equally in Patients with High and Low High Density Lipoprotein Functionality
Authors: Andreas Gille, Gunter Hartel, Denise D’Andrea, Samuel D Wright
Journal: Circulation (2014)

Introduction: The ability of high-density lipoprotein (HDL) to remove cholesterol from macrophages in atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. CSL112 is a novel formulation of apoA-I purified from human plasma and reconstituted to form HDL particles suitable for infusion. Two phase 1 studies in healthy subjects and one phase 2a study in coronary heart disease (CHD) patients have demonstrated favorable safety, pharmacokinetics and biomarker responses to single or multiple infusions of CSL112. The aim of the current study was to assess the influence of subject-specific HDL functionality, sometimes described as HDL dysfunction, on the pharmacodynamic effects of CSL112. Methods and Results: To assess HDL functionality, we measured the specific cholesterol efflux activity of apoA-I (cholesterol efflux divided by apoA-I) in subjects at baseline. CHD patients (mean ± SD = 7.3 ± 0.3 %efflux per g/L apoA-I (n=43)) had lower activity (p&lt;0.001) than healthy subjects (mean ± SD = 8.8 ± 0.2 % efflux per g/L apoA-I (n=93)), consistent with prior work showing impaired HDL function in CHD patients. Every subject infused with CSL112 responded, showing increased apoA-I plasma levels and serum cholesterol efflux. To assess changes in HDL functionality upon infusion of CSL112, we plotted changes in cholesterol efflux vs changes in apoA-I. To account for variations of these analytes over time and dose, we plotted area under curve (AUC) for 0 to 24 h after infusion of various doses of CSL112. In all three studies, AUC for apoA-I correlated with the AUC for cholesterol efflux, with coincident lines, indicating equal elevation in efflux among healthy and CHD patients. To further examine this relationship, subjects were stratified into tertiles based on specific activity. Infusion of CSL112 elevated efflux similarly in subjects in the highest HDL functionality and lowest HDL functionality tertiles. Conclusion: ApoA-I from CHD patients compared to healthy subjects had lower specific activity in regards to cholesterol efflux. CSL112 causes strong elevation in cholesterol efflux regardless of HDL function and represents a promising candidate to rapidly remove plaque cholesterol and reduce recurrent atherothrombotic events.
Diosgenin induces cell cycle blockade and apoptosis of human breast cancer Hs578T cells with disruption of mitochondrial membrane potential
Authors: Chun-Wen Cheng, Chin-Yi Lin, Tin-Yu Chin, Hsiao-Fong Yeh, Hsiao-Wei Wang, Pei-Ei Wu, Chen-Yang Shen
Journal: Cancer Research (2007)

3222   Diosgenin, a steroidal saponin present in fenugreek, has been reported with many pharmaceutical effects related to anti-cancer and anti-inflammation properties. To elucidate the mechanism of its anti-proliferative capacity, we investigate its effects on cell cycle arrest and apoptosis in human breast cancer Hs578T cells. We observed that diosgenin exerted a dose- and time-dependent inhibitory effect on the viability of Hs578T cell by the MTT assay. Compared with control group, when cells were treated with diosgenin at concentration higher than 25 uM for 48 hrs, the percentage of G2/M fractions was decreased and that of subG1 phase cells was increased ( P  c , caspases 9 and 3 were increased, whereas antiapoptotic Bcl-2 was decreased in Hs578T cells treated with diosgenin, representing a dose-dependent manner. Furthermore, a dramatic increasing of apoptosis was more predominant by the presence of DNA ladder, which was followed by the mitochondrial membrane potential (MMP) depolarization in those cells exposed to diosgenin. In conclusion, diosgenin possesses an anti-cancer effect, inhibiting Hs578T cell proliferation via cell cycle G2/M arrest and subjecting to apoptosis with disruption of MMP and diosgenin may, therefore, be available in the clinical treatment of breast carcinoma.
860. Long-Term Correction of Lysosomal Storage in CNS and Somatic Tissue in Adult MPS II Mice by Intravenous Administration of AAV
Authors: Joseph Muenzer, Jerillyn S. Jennings, Haiyan Fu
Journal: Molecular Therapy (2004)

A major obstacle in developing therapies for the central nervous system (CNS) disease in mucopolysaccharidoses (MPS) is the presence of the blood-brain barrier (BBB). Therapeutic effects of AAV gene delivery on both somatic and the CNS features in adult MPS II mice were studied using IV injection after pretreatment with mannitol, to disrupt the BBB and facilitate the CNS entry of the vector. An AAV serotype 2 vector, AAV2-CMV-hIdS, was used, containing a human iduronate sulfatase cDNA (hIdS) driven by a human cytomegalovirus promoter (CMV). A single dose of AAV2-CMV-hIdS viral vector (2-4×1011 viral particles in 200 μl) was delivered into adult (4-6 week old) MPS II mice (n=20) by tail vein injection 10 minutes after an IV infusion of mannitol (1-2 mg/gm of body weight). Our results demonstrated correction of GAG storage in multiple organs/tissues. A complete correction of GAG accumulation in liver was achieved (P < 0.01) and partial correction in kidney, heart, intestine and muscles was observed (P < 0.05) at 3, 6, 9 and up to 17 months in one animal. No obvious decrease of GAG content was observed in the spleens of the mice after AAV injection. Iduronate sulfatase enzyme activity was detected in the injected mouse liver samples with complete correction of lysosomal storage, at a level of 10-50% of that in the liver of normal mice. Transmission electron microscopy and histopathology study demonstrated clearance of lysosomal storage in liver. In the brain of injected MPS II mice, a decrease of lysosomal storage was shown by histopathology in Purkinje cells and also in the neurons of the hippocampus, thalamus and cerebral cortex. In addition, physical appearances of IV injected MPS II mice, such as facial feature and spinal curvature, were clearly improved, and the life span of IV injected mice was prolonged, compared to that of non-treated MPS II mice. Our results suggest that IV administration of AAV vector following mannitol pretreatment may be a promising approach for treating both somatic and CNS disease in lysosomal storage disorders.
Analysis of the Histocompatibility-2 Locus in the Mouse&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: G. D. Snell, Priscilla Smith, F. Gabrielson
Journal: JNCI Journal of the National Cancer Institute (1953)

Journal Article Analysis of the Histocompatibility-2 Locus in the Mouse Get access G. D. Snell, G. D. Snell Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar Priscilla Smith, Priscilla Smith Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar F. Gabrielson F. Gabrielson Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 14, Issue 3, December 1953, Pages 457–480, https://doi.org/10.1093/jnci/14.3.457 Published: 01 December 1953 Article history Received: 15 June 1953 Published: 01 December 1953
Pathogenesis of chronic friend disease in hybrid bdf1 mice.
Authors: Peter J. Dawson, A. Howard Fieldsteel
Journal: Cancer Research (1969)

Summary  Friend virus induced disease in 93% of BDF 1  hybrid mice inoculated. In these mice, compared with the highly susceptible BALB/c, the disease ran a longer course and showed a period of remission between the 4th and 8th weeks postinoculation. Four phases of disease were recognized histologically; namely, proliferative, regressive, minimal focal, and advanced. Minimal focal disease was found 4 or more weeks after inoculation in apparently healthy mice without significant splenomegaly. Histologically, spleens from these mice showed up to 20 small foci of dividing stem cells in the red pulp. Eventually these progressed to advanced fatal disease. All diseased mice showed typical Friend cells in the peripheral blood although these were very scanty in mice with minimal focal disease. No virus was recovered from the spleens of mice that did not develop disease or in those with minimal focal disease, and only relatively small amounts were recovered from mice with overt disease. Comparison of the titer of neutralizing antibodies in the serum of the mice in the foregoing groups revealed no significant differences.
Structure-activity relationships and cellular effects of novel purine- and pyrimidine-based cyclin dependent kinase inhibitors
Authors: BT Golding, RJ Griffin, CE Arris, AE Gibson, J Bentley, AH Calvert, FT Boyle, NJ Curtin, JA Endicott, S Grant, PJ Jewsbury, LN Johnson, Mem Noble, Newell
Journal: Clinical Cancer Research (2000)
Electrospun Polycaprolactone 3D Nanofibrous Scaffold with Interconnected and Hierarchically Structured Pores for Bone Tissue Engineering
Authors: Tao Xu, Jacob M. Miszuk, Yong Zhao, Hongli Sun, Hao Fong
Journal: Advanced Healthcare Materials (2015)

For the first time, electrospun polycaprolactone (PCL) 3D nanofibrous scaffold has been developed by an innovative and convenient approach (i.e., thermally induced nanofiber self‐agglomeration followed by freeze drying), and the scaffold possesses interconnected and hierarchically structured pores including macropores with sizes up to ≈300 μm. The novel PCL 3D scaffold is soft and elastic with very high porosity of ≈96.4%, thus it is morphologically/structurally similar to natural extracellular matrix and well suited for cell functions and tissue formation. The in vitro studies reveal that the scaffold can lead to high cell viability; more importantly, it is able to promote more potent BMP2‐induced chondrogenic than osteogenic differentiation of mouse bone marrow mesenchymal stem cells. Consistent to the in vitro findings, the in vivo results indicate that the electrospun PCL 3D scaffold acts as a favorable synthetic extracellular matrix for functional bone regeneration through the physiological endochondral ossification process.
Interpretation of the transpulmonary thermodilution curve in the presence of a left-to-right shunt
Authors: Anneliese Nusmeier, Johannes G. van der Hoeven, Joris Lemson
Journal: Intensive Care Medicine (2010)

Dear Editor,

In a recent article by Giraud et al. [1] the effect of a left-to-right shunt on the transpulmonary thermodilution (TPTD) curve and the subsequent calculation of extravascular lung water (EVLW) and intrathoracic blood volume (ITBV) are described. The authors conclude that a left-to-right shunt generates recirculation of thermal indicator, which induces a change in the dilution curve. Although we support their observation their explanation may lead to confusion.

The transpulmonary thermodilution method must fulfill the following conditions: (1) constant blood flow, (2) no or minimal loss of indicator between injection and detection point, (3) complete mixing of the indicator with blood, and (4) the indicator must pass the detection point only once [2]. To satisfy condition 4, the dilution curve is interrupted at the downslope part based upon a specific algorithm to prevent the effects of recirculation [3]. Subsequently the curve is extrapolated from the interrupted point to the baseline in order to calculate the area under the curve [4].

The cases described by Giraud et al. both had a left-to-right shunt (ventricular septal defect (VSD) and aorto-cava fistula (ACF)). The (pulmonary) “recirculation” that occurs in a left-to-right shunt is an extra “short” circuit. The observed TPTD curve is the result of a delay in delivery of the indicator to the systemic circulation and will subsequently show a lower initial peak, followed by a slow re-approximation to the baseline.

Unfortunately the authors do not provide the values of the mean transit time (MTt) and downslope time (DSt), but these numbers are easily deduced from Fig. 1 on page 1,084 [1]. The recalculations are explained in Table 1 and show that the left-to-right shunt induces an increase of both time intervals. The increase of the DSt (51%) is twice the increment of the MTt (25%). Recirculation of the indicator passing the detecting point for a second time is excluded by the fact that true recirculation will not occur before approximately 60 s (≈2 × MTt in the normal situation). This is long after the interruption of the downslope part.



Table 1

Recalculations for case 1



Increment of the DSt and, to a lesser extent, of the MTt can also be observed in the presence of a large volume of lung water. Both situations are the consequence of delayed delivery of indicator to the systemic circulation. In conclusion it can be stated that a left-to-right shunt induces an increase in DSt and, to a lesser extent, MTt as a consequence of delayed delivery of indicator to the systemic circulation because of the presence of an extra circuit. This phenomenon should not be confused with true recirculation.
Abstract 12490: Effects of Muscle Stretching on Endothelium-Dependent Vasodilation and Skeletal Muscle Blood Flow of Aged Rats
Authors: Kazuki Hotta, Bradley J Behnke, Demetra Christou, Payal Ghosh, Patrick Maher, Daniel Kurien, Rahul Verma, Judy M Muller-Delp
Journal: Circulation (2014)

Background: The aim of this study was to determine whether passive muscle stretching enhances endothelium-dependent vasodilation and increases blood flow in skeletal muscle arterioles of aged rats. Methods: Stretching consisted of ankle dorsiflexion splinting, and was performed for 30 min daily for 4 wks in male Fischer 344 rats (n=16, 20 mo old). After splinting, soleus muscle arterioles were isolated, cannulated and pressurized at 70 cm H2O. We assessed vasodilation to acetylcholine (Ach) in the absence and presence of L-NAME, and endothelium-independent vasodilation to Dea-NONOate. We also measured blood flow to the soleus muscle, gastrocnemius muscle, tibialis anterior (TA) muscle, flexor hallicus longus (FHL) muscle, flexor digitorum longus (FDL) muscle and extensor digitorum longus (EDL) muscle with radioactive microspheres during walking at 15 m/min on a treadmill. Vasodilatory responses and skeletal muscle blood flows in the stretched limb were compared with those in the contralateral limb. Result...
β2-Microglobulin Identified as an Apoptosis-Inducing Factor and Its Characterization
Authors: Masaki Mori, Yasuhito Terui, Masayuki Ikeda, Hiroshi Tomizuka, Masaya Uwai, Tadashi Kasahara, Nobuyuki Kubota, Takehito Itoh, Yuji Mishima, Miyuki Douzono-Tanaka, Muneo Yamada, Seiichi Shimamura, Jiro Kikuchi, Yusuke Furukawa, Yukihito Ishizaka, Kazuma Ikeda, Hiroyuki Mano, Keiya Ozawa, Kiyohiko Hatake
Journal: Blood (1999)
Abstract 832: Pre-clinical development of EC1456: A potent Folate targeted Tubulysin SMDC
Authors: Joseph A. Reddy, Alicia Bloomfield, Melissa Nelson, Ryan Dorton, Marilynn Vetzel, Christopher P. Leamon
Journal: Cancer Research (2014)

Abstract Folate targeted small molecule drug conjugates (SMDC) have shown promising results in early stage clinical trials with Vintafolide now being evaluated in a phase 3 trial in FR-positive ovarian cancer patients. We have now developed a new group of folate conjugated Tubulysins, of which EC1456 has emerged as a lead candidate for clinical development. Treatment of nude mice bearing folate receptor (FR) positive human xenografts with EC1456 led to complete remissions (CR's) or cures in 100% of the mice at various doses and schedules. The observed activity was not accompanied by any noticeable weight loss or major organ tissue degeneration. In contrast, no significant anti-tumor activity (0 % CR's) was observed in EC1456-treated animals that were co-dosed with an excess of a benign folate ligand, thus demonstrating EC1456's target-specific activity. The enhanced therapeutic index due to folate conjugation was also evidenced by the fact that the un-targeted free drug (tubulysin B or its hydrazide form) was found to be completely inactive even when administered at highly toxic dose levels. Furthermore, when challenged with larger tumors, EC1456 again displayed remarkable anti-tumor activity with 100% cures in tumors up to 750 mm3. Complete cures were also observed in other FR positive models such as MDA-MB-231 TNBC and M109 lung tumor models. In support of our clinical strategy to treat drug resistant FR-positive cancer patients we have also shown that EC1456 was highly active against FR expressing paclitaxel and cisplatin-resistant cell lines. Taken together, these studies demonstrated that EC1456 has significant anti-tumor growth activity and tolerability, thus lending support to the ongoing Phase 1 clinical evaluation of EC1456 for advanced malignancies. Citation Format: Joseph A. Reddy, Alicia Bloomfield, Melissa Nelson, Ryan Dorton, Marilynn Vetzel, Christopher P. Leamon. Pre-clinical development of EC1456: A potent Folate targeted Tubulysin SMDC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 832. doi:10.1158/1538-7445.AM2014-832
Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial
Authors: Christopher E Brightling, Pascal Chanez, Richard Leigh, Paul M O'Byrne, Stephanie Korn, Dewei She, Richard D May, Katie Streicher, Koustubh Ranade, Edward Piper
Journal: The Lancet Respiratory Medicine (2015)
Is there an association between hyperthyroidism and PAH and, if yes, is pulmonary pressure decreasing after hyperthyroidism treatment?
Authors: Aysar Al Husseini, Shiro Mizuno, Jose Arroyo, Norbert Voelkel, Donatas Kraskauskas, Harm Bogaard
Journal: European Respiratory Journal (2011)

Rationale: About 30-40% of patients of idiopathic pulmonary arterial hypertension (IPAH) have thyroid dysfunction, in particular hypothyroidism. Pulmonary vascular remodeling in PAH is characterized by proliferation of vascular cells and thyroid hormones are known to promote angiogenesis (Mousa et al J Cardiovasc Pharmacol, 2005). We therefore hypothesized that hypothyroidism would improve pulmonary vascular remodeling in a model of angioproliferative pulmonary hypertension (SuHx model).

Objectives: To clarify the effect of thyroid hormone on pulmonary vascular remodeling in SuHx treated rats.

Methods: PAH was induced by the combined exposure of rats to the VEGF receptor blocker SU5416 and hypoxia (SuHx). Hypothyroidism was induced by PTU (10mg/kg, 5times a week), two weeks after the initial SU5416 dose (SuHx) rats. RV function was determined by echocardiography. Right ventricular pressure was measured by direct insertion of a conductance catheter into the heart.

Results: In SuHx rats, pulmonary vascular remodeling and pulmonary hypertension were decreased after PTU treatment and completely suppressed after thyroidectomy.

Conclusions: Thyroid dysfunction may affect the progression of pulmonary vascular cell proliferation in patients with PAH.
Abstract 16273: Ecto-5’-Nucleotidase Suppression of T Cell Trafficking to the Ischemic Brain
Authors: Jessica J Ray, Danica Petrovic-Djergovic, Diane Bouis, Matthew C Hyman, Timothy P Quinn, Anuli C Anyanwu, Natasha N Dolgacheva, David J Pinsky
Journal: Circulation (2011)

Background. Ischemic strokes account for 87% of all strokes in the United States. We studied ecto-5’-nucleotidase (CD73), an ectoenzyme present on brain tissue and leukocytes, which we have shown t...
Excess winter mortality
Authors: D M Fleming
Journal: BMJ (2002)

EDITOR—We challenge the method that Donaldson and Keatinge used to calculate mortality due to influenza.1 Data covering the period 1970-99 were used, but the authors state that the regression analysis started on 1 January 1990. On the basis of the 10 year analysis, they estimate an average of 1265 per million excess winter deaths from all causes, equivalent to 67 000 nationally in England and Wales. They say that 2.4% of this excess (equivalent to a national average of 1620 deaths per year) is attributable to influenza.. This estimate contrasts with those obtained by other groups: Tillett et al estimated an annual average of 12 000 deaths (1968-9 to1977-8)2, Nicholson 13 800 (1975-6 to1989-90)3, and Fleming 12 500 (1989-90 to 1998-9).4 The estimate of 12 500 is equivalent to 19% of the 67 000 total excess winter deaths, rather than 2.4%.

Donaldson and Keatinge estimated total deaths attributable …
Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia
Authors: Xinping Zhao, David Alvarado, Shirley Rainier, Rosemary Lemons, Peter Hedera, Christian H. Weber, Turgut Tukel, Memnune Apak, Terry Heiman-Patterson, Lei Ming, Melanie Bui, John K. Fink
Journal: Nature Genetics (2001)
Establishment and genetic characterization of a novel mixed-phenotype acute leukemia cell line with EP300-ZNF384 fusion
Authors: Nana Ping, Huiying Qiu, Qian Wang, Haiping Dai, Changgeng Ruan, Stefan Ehrentraut, Hans G. Drexler, Roderick A. F. MacLeod, Suning Chen
Journal: Journal of Hematology & Oncology (2015)

Herein, we describe the establishment and characterization of the first mixed-phenotype acute leukemia cell line (JIH-5). The JIH-5 cell line was established from leukemia cells with B lymphoid/myeloid phenotype from a female mixed-phenotype acute leukemia patient. JIH-5 cells exhibit an immunophenotype comprised of myeloid and B lymphoid antigens. Whole-exome sequencing revealed somatic mutations in nine genes in JIH-5 cells. Transcriptional sequencing of JIH-5 cells identified EP300-ZNF384 fusion transcript, which is a recurrent alteration in B cell acute lymphoblastic leukemia. Our results suggest that the JIH-5 cell line may serve as a tool for the study of mixed-phenotype acute leukemia or EP300-ZNF384.
Cellular myosin heavy chain in human leukocytes: isolation of 5' cDNA clones, characterization of the protein, chromosomal localization, and upregulation during myeloid differentiation
Authors: LE Toothaker, DA Gonzalez, N Tung, RS Lemons, MM Le Beau, MA Arnaout, LK Clayton, DG Tenen
Journal: Blood (1991)