tbuckley/cabot-search huggingface dataset:
Clinical relevance of right ventricular diastolic stiffness in pulmonary hypertension
Authors: Pia Trip, Silvia Rain, M. Louis Handoko, Cathelijne van der Bruggen, Harm J. Bogaard, J. Tim Marcus, Anco Boonstra, Nico Westerhof, Anton Vonk-Noordegraaf, Frances S. de Man
Journal: European Respiratory Journal (2015)

Right ventricular (RV) diastolic stiffness is increased in pulmonary arterial hypertension (PAH) patients. We investigated whether RV diastolic stiffness is associated with clinical progression and assessed the contribution of RV wall thickness to RV systolic and diastolic stiffness. Using single-beat pressure–volume analyses, we determined RV end-systolic elastance ( E es ), arterial elastance ( E a ), RV­–arterial coupling ( E es / E a ), and RV end-diastolic elastance (stiffness, E ed ) in controls (n=15), baseline PAH patients (n=63) and treated PAH patients (survival &gt;5 years n=22 and survival &lt;5 years n=23). We observed an association between E ed and clinical progression, with baseline E ed &gt;0.53 mmHg·mL -1 associated with worse prognosis (age-corrected hazard ratio 0.27, p=0.02). In treated patients, E ed was higher in patients with survival &lt;5 years than in patients with survival &gt;5 years (0.91±0.50 versus 0.53±0.33 mmHg·mL -1 , p&lt;0.01). Wall-thickness-corrected E ed values in PAH patients with survival &gt;5 years were not different from control values (0.76±0.47 versus 0.60±0.41 mmHg·mL -1 , respectively, not significant), whereas in patients with survival &lt;5 years, values were significantly higher (1.52±0.91 mmHg·mL -1 , p&lt;0.05 versus controls). RV diastolic stiffness is related to clinical progression in both baseline and treated PAH patients. RV diastolic stiffness is explained by the increased wall thickness in patients with &gt;5 years survival, but not in those surviving &lt;5 years. This suggests that intrinsic myocardial changes play a distinctive role in explaining RV diastolic stiffness at different stages of PAH.
Importance of group X–secreted phospholipase A2 in allergen-induced airway inflammation and remodeling in a mouse asthma model
Authors: William R. Henderson, Emil Y. Chi, James G. Bollinger, Ying-tzang Tien, Xin Ye, Luca Castelli, Yuri P. Rubtsov, Alan G. Singer, Gertrude K.S. Chiang, Timo Nevalainen, Alexander Y. Rudensky, Michael H. Gelb
Journal: The Journal of Experimental Medicine (2007)

Arachidonic acid metabolites, the eicosanoids, are key mediators of allergen-induced airway inflammation and remodeling in asthma. The availability of free arachidonate in cells for subsequent eicosanoid biosynthesis is controlled by phospholipase A(2)s (PLA(2)s), most notably cytosolic PLA(2)-alpha. 10 secreted PLA(2)s (sPLA(2)s) have also been identified, but their function in eicosanoid generation is poorly understood. We investigated the role of group X sPLA(2) (sPLA(2)-X), the sPLA(2) with the highest in vitro cellular phospholipolysis activity, in acute and chronic mouse asthma models in vivo. The lungs of sPLA(2)-X(-/-) mice, compared with those of sPLA(2)-X(+/+) littermates, had significant reduction in ovalbumin-induced infiltration by CD4(+) and CD8(+) T cells and eosinophils, goblet cell metaplasia, smooth muscle cell layer thickening, subepithelial fibrosis, and levels of T helper type 2 cell cytokines and eicosanoids. These data direct attention to sPLA(2)-X as a novel therapeutic target for asthma.
Additive Glucose-Lowering Effects of Glucagon-Like Peptide-1 and Metformin in Type 2 Diabetes
Authors: Mette Zander, Mustafa Taskiran, Mai-Britt Toft-Nielsen, Sten Madsbad, Jens Juul Holst
Journal: Diabetes Care (2001)

OBJECTIVE—The incretin hormone glucagon-like peptide-1 (GLP-1) reduces plasma glucose in type 2 diabetic patients by stimulating insulin secretion and inhibiting glucagon secretion. The biguanide metformin is believed to lower plasma glucose without affecting insulin secretion. We conducted this study to investigate the effect of a combination therapy with GLP-1 and metformin, which could theoretically be additive, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—In a semiblinded randomized crossover study, seven patients received treatment with metformin (1,500 mg daily orally) alternating with GLP-1 (continuous subcutaneous infusion of 2.4 pmol · kg–1 · min–1) alternating with a combination of metformin and GLP-1 for 48 h. Under fixed energy intake, we examined the effects on plasma glucose, insulin, C-peptide, glucagon, and appetite. RESULTS—Fasting plasma glucose (day 2) decreased from 13.9 ± 1 (no treatment) to 11.2 ± 0.4 (metformin) and 11.5 ± 0.5 (GLP-1) and further decreased to 9.4 ± 0.7 (combination therapy) (P = 0.0005, no difference between monotherapy with GLP-1 and metformin). The 24-h mean plasma glucose (day 2) decreased from 11.8 ± 0.5 (metformin) and 11.7 ± 0.8 (GLP-1) to 9.8 ± 0.5 (combination) (P = 0.02, no difference between GLP-1 and metformin). Insulin levels were similar between the three regimens, but glucagon levels were significantly reduced with GLP-1 compared with metformin (P = 0.0003). Combination therapy had no additional effect on appetite scores. CONCLUSIONS—Monotherapy with GLP-1 and metformin have equal effects on plasma glucose and additive effects upon combination.
SPLUNC1: link between acidity and dehydration of the airway surface liquid in CF
Authors: James P Garnett
Journal: Thorax (2013)

SPLUNC1: link between acidity and dehydration of the airway surface liquid in CF Short palate lung and nasal epithelial clone 1 (SPLUNC1) is the most abundant secreted protein in the airways and helps maintain a normal airway surface liquid (ASL) volume through its regulation of the epithelial Na + channel (ENaC).In cystic fibrosis (CF), it has been proposed that increased Na + absorption by ENaC contributes to ASL depletion, despite the presence of SPLUNC1.The study by Garland et al showed the pH of nasal secretions from CF subjects (pH∼6.5)was more acidic than non-CF subjects ( pH∼7.2), consistent with previous studies of CF ASL.Re-creating such conditions in vitro, the investigators found that alkalinising the ASL across CF airway epithelial cultures prevented fluid hyperabsorption, an effect absent in SPLUNC1-depleted cultures.SPLUNC1 binding to the cell surface, which was dependent on ENaC expression, was reduced under acidic conditions.The authors reasoned the acidity of the CF airways may alter the ability of SPLUNC1 to bind to ENaC, explaining why it is unable to limit ENaC activity in CF.This hypothesis was supported by demonstrating that deletion of two pH-sensitive salt bridges in the SPLUNC1 protein rendered SPLUNC1 binding at the cell surface pH-insensitive, restoring normal ENaC regulation and ASL volume under acidic conditions.In addition to identifying the pH-dependent activity of SPLUNC1 as an important link between the acidity of the CF airways and the dysregulation of ENaC, the study may also provide evidence of how the cystic fibrosis transmembrane conductance regulator (CFTR) indirectly regulates ENaC activity, since aberrant CFTR-dependent HCO 3 -secretion is proposed to contribute to the acidity of the CF ASL.Raising CF ASL pH could restore normal mucosal hydration, as well as other vital pH-dependent processes such as bacterial killing by antimicrobials, and thus warrants further investigation as a potential avenue for CF therapy.
Estimating the Basic Reproductive Number from Viral Sequence Data
Authors: Tanja Stadler, Roger Kouyos, Viktor von Wyl, Sabine Yerly, Jürg Böni, Philippe Bürgisser, Thomas Klimkait, Beda Joos, Philip Rieder, Dong Xie, Huldrych F. Günthard, Alexei J. Drummond, Sebastian Bonhoeffer
Journal: Molecular Biology and Evolution (2011)

Epidemiological processes leave a fingerprint in the pattern of genetic structure of virus populations. Here, we provide a new method to infer epidemiological parameters directly from viral sequence data. The method is based on phylogenetic analysis using a birth-death model (BDM) rather than the commonly used coalescent as the model for the epidemiological transmission of the pathogen. Using the BDM has the advantage that transmission and death rates are estimated independently and therefore enables for the first time the estimation of the basic reproductive number of the pathogen using only sequence data, without further assumptions like the average duration of infection. We apply the method to genetic data of the HIV-1 epidemic in Switzerland.
Parathyroid Hormone-Related Protein (107-139) Stimulates Interleukin-6 Expression in Human Osteoblastic Cells
Authors: FERNANDO DE MIGUEL, PILAR MARTINEZ-FERNANDEZ, CARLOS GUILLEN, ALVARO VALIN, ANA RODRIGO, MARIA EUGENIA MARTINEZ, PEDRO ESBRIT
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The N-terminal region of both parathyroid hormone (PTH) and PTH-related protein (PTHrP) binds to the same PTH/PTHrP receptor in osteoblasts. However, C-terminal PTHrP (107-139) inhibits growth and various functions of osteoblasts and osteoclasts apparently through PTHrP-specific receptors. PTH (1-34) and PTHrP (1-34) rapidly induce interleukin-6 (IL-6) expression by osteoblasts. The aim of the present study was to assess the effects of PTHrP (107-139) on IL-6 gene expression and secretion by osteoblastic cells from human trabecular bone (hOB). Using reverse transcription followed by PCR, it was found that IL-6 mRNA was twofold maximally increased by either PTHrP (1-34) or PTHrP (107-139), at 10 nM, over basal within 1 to 2 h in hOB cells. This effect of PTHrP (107-139), and that of PTHrP (1-34), were abolished by the transcription inhibitor actinomycin D. Meanwhile, puromycin, a protein synthesis inhibitor, superinduced IL-6 expression in the presence or absence of each PTHrP peptide. Both PTHrP (1-34) and PTHrP (107-139), but not PTHrP (38-64), stimulated IL-6 secretion to the hOB cell-conditioned medium at 24 h, dose dependently. In addition, this maximal stimulatory effect (twofold over basal) was similar with each PTHrP peptide alone, and not additive when added together. PTHrP (107-139) stimulation of mRNA and protein in hOB cells was abolished by bisindolylmaleimide I, a protein kinase C inhibitor, but not by either adenosine 3′,5′-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS), or N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H89), two protein kinase A inhibitors. These results indicate that C-terminal PTHrP, like its N-terminal domain, induces IL-6 production by human osteoblastic cells. This effect of both PTHrP regions could provide a mechanism to modulate bone turnover.
Response to Comment on: Lin et al. Long-Term Changes in Adiposity and Glycemic Control Are Associated With Past Adenovirus Infection. Diabetes Care 2013;36:701–707
Authors: Wan-Yu Lin, Olga Dubuisson, Rohina Rubicz, Nianjun Liu, David B. Allison, Joanne E. Curran, Anthony G. Comuzzie, John Blangero, Charles T. Leach, Harald Göring, Nikhil V. Dhurandhar
Journal: Diabetes Care (2013)

We would like to thank Yamada et al. (1) for their comments about our article (2) and for their interest in our work. They state that the association of Ad36 infection with better glycemic control that we reported does not correspond with their previous meta-analysis (3). Although there may be a number of possibilities to explain the difference, it should be noted that the meta-analysis by Yamada et al. (3) included 2,870 subjects for BMI analyses but only 1,083 subjects for determining the association of Ad36 with glucose levels. However, data are now available for additional 3,037 subjects that show an association of various components of glycemic control with Ad36 seropositivity in humans. These additional data are …
Imaging Three-Dimensional Cardiac Function
Authors: W. G. O'Dell, A. D. McCulloch
Journal: Annual Review of Biomedical Engineering (2000)

▪ Abstract The three-dimensional (3-D) nature of myocardial deformations is dependent on ventricular geometry, muscle fiber architecture, wall stresses, and myocardial-material properties. The imaging modalities of X-ray angiography, echocardiography, computed tomography, and magnetic resonance (MR) imaging (MRI) are described in the context of visualizing and quantifying cardiac mechanical function. The quantification of ventricular anatomy and cavity volumes is then reviewed, and surface reconstructions in three dimensions are demonstrated. The imaging of myocardial wall motion is discussed, with an emphasis on current MRI and tissue Doppler imaging techniques and their potential clinical applications. Calculation of 3-D regional strains from motion maps is reviewed and illustrated with clinical MRI tagging results. We conclude by presenting a promising technique to assess myocardial-fiber architecture, and we outline its potential applications, in conjunction with quantification of anatomy and regional strains, for the determination of myocardial stress and work distributions. The quantification of multiple components of 3-D cardiac function has potential for both fundamental-science and clinical applications.
Extracellular Matrix Metabolism in Diabetic Nephropathy
Authors: Roger M. Mason, Nadia Abdel Wahab
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Diabetic nephropathy is characterized by excessive deposition of extracellular matrix proteins in the mesangium and basement membrane of the glomerulus and in the renal tubulointerstitium. This review summarizes the main changes in protein composition of the glomerular mesangium and basement membrane and the evidence that, in the mesangium, these are initiated by changes in glucose metabolism and the formation of advanced glycation end products. Both processes generate reactive oxygen species (ROS). The review includes discussion of how ROS may activate intracellular signaling pathways leading to the activation of redox-sensitive transcription factors. This in turn leads to change in the expression of genes encoding extracellular matrix proteins and the protease systems responsible for their turnover. E-mail: [email protected]
A case of vancomycin-associated linear IgA bullous dermatosis and IgA antibodies to the α3 subunit of laminin-332
Authors: Y. Zenke, T. Nakano, H. Eto, H. Koga, T. Hashimoto
Journal: British Journal of Dermatology (2013)

Journal Article A case of vancomycin‐associated linear IgA bullous dermatosis and IgA antibodies to the α3 subunit of laminin‐332 Get access Y. Zenke, Y. Zenke Department of Dermatology St Luke's International Hospital 9‐1 Akashi‐cho Chuo‐ku Tokyo 104‐8560 Japan Correspondence Yukari Zenke. E‐mail: yukazen@luke.or.jp Search for other works by this author on: Oxford Academic Google Scholar T. Nakano, T. Nakano Department of Dermatology St Luke's International Hospital 9‐1 Akashi‐cho Chuo‐ku Tokyo 104‐8560 Japan Search for other works by this author on: Oxford Academic Google Scholar H. Eto, H. Eto Department of Dermatology St Luke's International Hospital 9‐1 Akashi‐cho Chuo‐ku Tokyo 104‐8560 Japan Search for other works by this author on: Oxford Academic Google Scholar H. Koga, H. Koga Department of Dermatology Kurume University School of Medicine and Institute of Cutaneous Cell Biology Kurume Fukuoka Japan Search for other works by this author on: Oxford Academic Google Scholar T. Hashimoto T. Hashimoto Department of Dermatology Kurume University School of Medicine and Institute of Cutaneous Cell Biology Kurume Fukuoka Japan Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 170, Issue 4, 1 April 2014, Pages 965–969, https://doi.org/10.1111/bjd.12720 Published: 01 April 2014
Sleep Apnea and Heart Failure
Authors: T. Douglas Bradley, John S. Floras
Journal: Circulation (2003)

I n the first part of this 2-part review, we provided a synopsis of the cardiovascular effects of normal sleep and an overview of the diagnostic, pathophysiological, and therapeutic implications of obstructive sleep apnea (OSA) in the setting of heart failure (HF).In this second part, we turn our attention to central sleep apnea (CSA), commonly referred to as Cheyne-Stokes respiration.This breathing disorder has a strikingly higher prevalence in patients with HF as compared with the general population with normal left ventricular function, and when present appears to have adverse prognostic implications.Our objective in Part II of this review is to provide a broad perspective of the pathophysiological and clinical significance of CSA in HF.
Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study
Authors: Wieneke A Buikhuisen, Jacobus A Burgers, Andrew D Vincent, Catharina M Korse, Rob J van Klaveren, Franz MNH Schramel, Nick Pavlakis, Anna K Nowak, Frank LJ Custers, J Hugo Schouwink, Steven JM Gans, Harry JM Groen, Wim FM Strankinga, Paul Baas
Journal: The Lancet Oncology (2013)
Abstract 4380: Cadmium-induced toxicity in human liver carcinoma (HepG2) cells: Involvement of oxidative stress, phosphatidylserine externalization, and nucleosomal DNA fragmentation
Authors: Anthony C. Skipper, Clement Yedjou, Kenneth Ndebele, Paul B. Tchounwou
Journal: Cancer Research (2010)

Abstract Human liver carcinoma (HepG2) cells were used as a test model to evaluate the in vitro cytotoxicity of cadmium and to determine whether oxidative stress plays a key role in cadmium induced apoptosis. To achieve this goal, we performed the MTT assay to measure cell viability and lipid peroxidation to determine the level of oxidative cell/tissue damage. The annexin V assay and DNA fragmentation analysis were performed for early and late apoptosis, respectively. The results of MTT assay indicated that cadmium chloride induces toxicity to HepG2 cells in a dose-dependent manner, showing a 24 h-LD50 of 3.6 µg/mL. We detected a significant increase in lipid peroxidation (malondialdehyde) concentrations in cadmium chloride-treated HepG2 cells compared to the control. Similarly, a strong dose-response relationship (p &amp;lt; 0.05) was obtained in connection with cadmium chloride-induced apoptosis. Cadmium chloride-induced apoptosis was characterized by a significant increase in the percentage of annexin-V positive cells (apoptotic cells), as well by the occurrence of nucleosomal DNA fragmentation. In summary, this study indicated cadmium chloride is highly cytotoxic to HepG2 cells. This cytotoxic effect may be mediated at least in part through oxidative cell/tissue damage, phosphatidylserine externalization and occurrence of nucleosomal DNA fragmentation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4380.
Intratumoral Administration of TLR4 Agonist Absorbed into a Cellular Vector Improves Antitumor Responses
Authors: Meghan B. Davis, David Vasquez-Dunddel, Juan Fu, Emilia Albesiano, Drew Pardoll, Young J. Kim
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Because toll-like receptor (TLR) agonists have been well characterized as dendritic cell (DC) activators, we hypothesized that the admixture of TLR4 agonist into a cellular vector could improve the antitumor response in vivo. Experimental Design: Granulocyte macrophage colony stimulating factor secreting whole cell tumor cell vector (GVAX) was formulated with lipopolysaccharide (LPS), a TLR4 agonist, and its intratumoral therapeutic efficacy was tested in three different murine models. We utilized immunohistochemistry, fluorescence-activated cell sorting, enzyme-linked immunosorbent spot (ELISPOT), and in vivo CTL analysis to assess both local innate immune responses within the tumor tissue as well as the downstream generation of antitumor T-cell responses. Results: Intratumoral treatment of LPS-absorbed GVAX showed efficacy in improving an antitumor response in vivo in comparison with GVAX alone. Improved antitumor efficacy of this novel admixture was not present in TLR4 signaling impaired mice. In the CT26 model, 40% to 60% of the mice showed regression of the transplanted tumor. When rechallenged with CT26 tumor cells, these mice proved to be immunized against the tumor. Tumors treated with TLR4 agonist–absorbed GVAX showed increased infiltrating CD4 and CD8 T cells as well as increased numbers of CD86+ cells in the tumor tissue. Draining lymph nodes from the treated mice had enhanced number of activated CD86+, MHCII+, and CD80+ DCs in comparison with GVAX alone and mock-treated groups. ELISPOT assay and in vivo CTL assay showed increased numbers of CTLs specific for the AH1 tumor antigen in mice treated with LPS-absorbed GVAX. Conclusion: TLR4 on antigen-presenting cells in the tumor microenvironment may be targeted by using cell-based vectors for improved antitumor response in vivo. Clin Cancer Res; 17(12); 3984–92. ©2011 AACR.
Pertuzumab in Combination with Trastuzumab Shows Significantly Enhanced Antitumor Activity in HER2-Positive Human Gastric Cancer Xenograft Models
Authors: Yoriko Yamashita-Kashima, Shigeyuki Iijima, Keigo Yorozu, Koh Furugaki, Mitsue Kurasawa, Masateru Ohta, Kaori Fujimoto-Ouchi
Journal: Clinical Cancer Research (2011)

We investigated the antitumor activity of the combination of two different humanized monoclonal human epidermal growth factor receptor (HER) 2 antibodies, pertuzumab and trastuzumab, for gastric cancer.Tumor mouse xenograft models were used to examine antitumor activity. Cell proliferation was examined using crystal violet staining. HER family proteins' expression was analyzed by ELISA and immunohistochemistry. Phosphorylated proteins and heterodimers were detected by Western blotting and in situ proximity ligation assay (PLA), respectively. Apoptosis activity was examined by caspase 3/7 activity. Antibody-dependent cellular cytotoxicity (ADCC) activity was detected by xCELLigence. Microvessel density was examined by CD31 staining.Pertuzumab in combination with trastuzumab showed significant antitumor activity compared with each monotherapy in NCI-N87, an HER2-positive human gastric cancer xenograft model. The efficacy was stronger than that of the maximum effective dose with each monotherapy. Similar antitumor activity was shown in 4-1ST, another HER2-positive gastric cancer model, but not in MKN-28, an HER2-negative model. Combining pertuzumab with trastuzumab enhanced cell growth inhibition and apoptosis activity by inhibiting EGFR-HER2 heterodimerization and the phosphorylation of these receptors and their downstream factors. This effect was also seen in HER2-HER3 signaling. Furthermore, pertuzumab in combination with trastuzumab potentiated the ADCC activity of those antibodies and reduced tumor microvessel density.We showed the significantly enhanced efficacy of pertuzumab combining with trastuzumab for HER2 overexpressing gastric cancer through the potentiation of cell growth inhibition, apoptosis activity, cell killing activity by ADCC, and antiangiogenic activity. This study suggests the clinical benefit of combination therapy with pertuzumab and trastuzumab for patients with HER2-positive gastric cancers.