tbuckley/cabot-search huggingface dataset:
Directed and Systematic Differentiation of Cardiovascular Cells From Mouse Induced Pluripotent Stem Cells
Authors: Genta Narazaki, Hideki Uosaki, Mizue Teranishi, Keisuke Okita, Bongju Kim, Satoshi Matsuoka, Shinya Yamanaka, Jun K. Yamashita
Journal: Circulation (2008)

Induced pluripotent stem (iPS) cells are a novel stem cell population induced from mouse and human adult somatic cells through reprogramming by transduction of defined transcription factors. However, detailed differentiation properties and the directional differentiation system of iPS cells have not been demonstrated.Previously, we established a novel mouse embryonic stem (ES) cell differentiation system that can reproduce the early differentiation processes of cardiovascular cells. We applied our ES cell system to iPS cells and examined directional differentiation of mouse iPS cells to cardiovascular cells. Flk1 (also designated as vascular endothelial growth factor receptor-2)-expressing mesoderm cells were induced from iPS cells after approximately 4-day culture for differentiation. Purified Flk1(+) cells gave rise to endothelial cells and mural cells by addition of vascular endothelial growth factor and serum. Arterial, venous, and lymphatic endothelial cells were also successfully induced. Self-beating cardiomyocytes could be induced from Flk1(+) cells by culture on OP9 stroma cells. Time course and efficiency of the differentiation were comparable to those of mouse ES cells. Occasionally, reexpression of transgene mRNAs, including c-myc, was observed in long-term differentiation cultures.Various cardiovascular cells can be systematically induced from iPS cells. The differentiation properties of iPS cells are almost completely identical to those of ES cells. This system would greatly contribute to a novel understanding of iPS cell biology and the development of novel cardiovascular regenerative medicine.
Adipose Dipeptidyl Peptidase-4 and Obesity
Authors: Henrike Sell, Matthias Blüher, Nora Klöting, Raphaela Schlich, Miriam Willems, Florian Ruppe, Wolfram Trudo Knoefel, Arne Dietrich, Barbara A. Fielding, Peter Arner, Keith N. Frayn, Jürgen Eckel
Journal: Diabetes Care (2013)

To study expression of the recently identified adipokine dipeptidyl peptidase-4 (DPP4) in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of patients with various BMIs and insulin sensitivities, as well as to assess circulating DPP4 in relation to obesity and insulin sensitivity.DPP4 expression was measured in SAT and VAT from 196 subjects with a wide range of BMIs and insulin sensitivities. DPP4 release was measured ex vivo in paired biopsies from SAT and VAT as well as in vivo from SAT of lean and obese patients. Circulating DPP4 was measured in insulin-sensitive and insulin-resistant BMI-matched obese patients.DPP4 expression was positively correlated with BMI in both SAT and VAT, with VAT consistently displaying higher expression than SAT. Ex vivo release of DPP4 from adipose tissue explants was higher in VAT than in SAT in both lean and obese patients, with obese patients displaying higher DPP4 release than lean controls. Net release of DPP4 from adipose tissue was also demonstrated in vivo with greater release in obese subjects than in lean subjects and in women than in men. Insulin-sensitive obese patients had significantly lower circulating DPP4 than did obesity-matched insulin-resistant patients. In this experiment, DPP4 positively correlated with the amount of VAT, adipocyte size, and adipose tissue inflammation.DPP4, a novel adipokine, has a higher release from VAT that is particularly pronounced in obese and insulin-resistant patients. Our data suggest that DPP4 may be a marker for visceral obesity, insulin resistance, and the metabolic syndrome.
Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer
Authors: Johannes Hofland, Wytske M. van Weerden, Natasja F.J. Dits, Jacobie Steenbergen, Geert J.L.H. van Leenders, Guido Jenster, Fritz H. Schröder, Frank H. de Jong
Journal: Cancer Research (2010)

Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC.
PMO-218 Colonoscopy in patients presenting with melaena and a normal upper gastrointestinal endoscopy: a retrospective review from a single UK centre
Authors: E Russo, L Hicks, J Hoare, H Thomas, J Teare, H Williams, T Orchard
Journal: Gut (2012)

<h3>Introduction</h3> Colonoscopy is frequently performed in patients presenting with melaena who have a negative upper gastrointestinal endoscopy (UGIE). Published literature suggests a diagnostic yield of 8%–30%, the most common pathologies being colonic angiodysplasia and right-sided tumours. However these conditions often give rise to occult haemorrhage and a microcytic profile before patients present with overt bleeding. In patients presenting de novo with melaena a raised urea is known to be predictive of upper GI haemorrhage before any endoscopic assessment. Our aim was to examine the value of colonoscopy in the subgroup of patients with a negative UGIE, and to assess whether the absence of a raised blood urea and/or the presence of a microcytic erythrocyte profile at presentation are predictors of positive colonoscopy. <h3>Methods</h3> Our reporting software was interrogated for the interval November 2007–October 2011. All cases of colonoscopy where melaena was the main indication, and which were preceded by a negative UGIE were analysed. In addition, we collected data on the admission blood urea and mean corpuscular volume (MCV). Patients for whom altered/fresh rectal bleeding were included in the indications in addition to melaena were excluded. <h3>Results</h3> 724 patients had a total of 829 endoscopic evaluations of melena, and of these 62 patients (53% female) with a median age of 69 year (range 27–91) met our inclusion criteria. 6 of 62 (9.6%) had a cause for the melena identified on colonoscopy: cecal angiodysplasia in 2/6, right-sided malignancies in 2/6 and right-sided diverticular bleeds in 2/6. The admission urea was not significantly lower in patients with a positive colonoscopy (median 11.5 mmol/l, range 5.1–14.7) compared to those with a negative colonoscopy (median 7.2 mmol/l, range 1.4–33.6) (p=0.43). Admission MCV however was significantly lower in patients with a colonic haemorrhage (median 77 fL, range 64–89) compared to patients with a negative colonoscopy (median 90 fL, range 66–116) (p=0.012), with 3/6 (50%) having a low MCV compared to 5/56 (8.9%) of those with a negative colonoscopy (normal = 84–99 fL). <h3>Conclusion</h3> The diagnostic yield of colonoscopy in patients with melaena and a non-contributory UGIE in our centre was low (9.6%). A normal/low blood urea on admission did not predict a positive diagnosis for the haemorrhage at colonoscopy in our cohort. However, patients with a colonic source of bleeding had a significantly lower MCV, suggesting a chronic natural history for such right sided colonic haemorrhages. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. Tedesco FJ. <i>Gastrointest Endosc</i> 1981. 2. <b>Ibach MB</b>. <i>Dig Dis Sci</i> 1995. 3. <b>Blatchford O</b>. <i>Lancet</i> 2000.
Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis
Authors: Dominique Thabut, Chittaranjan Routray, Gwen Lomberk, Uday Shergill, Kevin Glaser, Robert Huebert, Leena Patel, Tetyana Masyuk, Boris Blechacz, Andrew Vercnocke, Erik Ritman, Richard Ehman, Raul Urrutia, Vijay Shah
Journal: Hepatology (2011)

Paracrine signaling between hepatic stellate cells (HSCs) and liver endothelial cells (LECs) modulates fibrogenesis, angiogenesis, and portal hypertension. However, mechanisms regulating these processes are not fully defined. Sorafenib is a receptor tyrosine kinase inhibitor that blocks growth factor signaling in tumor cells but also displays important and not yet fully characterized effects on liver nonparenchymal cells including HSCs and LECs. The aim of this study was to test the hypothesis that sorafenib influences paracrine signaling between HSCs and LECs and thereby regulates matrix and vascular changes associated with chronic liver injury. Complementary magnetic resonance elastography, micro-computed tomography, and histochemical analyses indicate that sorafenib attenuates the changes in both matrix and vascular compartments that occur in response to bile duct ligation-induced liver injury in rats. Cell biology studies demonstrate that sorafenib markedly reduces cell-cell apposition and junctional complexes, thus reducing the proximity typically observed between these sinusoidal barrier cells. At the molecular level, sorafenib down-regulates angiopoietin-1 and fibronectin, both released by HSCs in a manner dependent on the transcription factor Kruppel-like factor 6 , suggesting that this pathway underlies both matrix and vascular changes associated with chronic liver disease.Collectively, the results of this study demonstrate that sorafenib inhibits both matrix restructuring and vascular remodeling that accompany chronic liver diseases and characterize cell and molecular mechanisms underlying this effect. These data may help to refine future therapies for advanced gastrointestinal and liver diseases characterized by abundant fibrosis and neovascularization.
Type 1 Diabetes and Coronary Artery Disease
Authors: Trevor J. Orchard, Tina Costacou, Adam Kretowski, Richard W. Nesto
Journal: Diabetes Care (2006)

Although the increased risk of premature heart disease in type 1 diabetes has been recognized for some time, the underlying pathogenesis is still poorly understood. The most likely factor, a priori, to account for this increased risk is hyperglycemia. However, despite recent evidence from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study that prior intensive glycemic control reduces cardiovascular disease (CVD), the epidemiologic association between glycemia and coronary heart disease (CHD) is surprisingly weak. This paradox is a focus of the current review, which also evaluates other major determinants of coronary artery disease (CAD) in type 1 diabetes, including the roles of insulin resistance, cytokines, inflammatory biomarkers, and, briefly, genetic factors. Finally, the clinical implications of this information are discussed.

A high occurrence of, and mortality from, CHD in type 1 diabetes has been documented since the late 1970s (1,2). A 1984 registry reported a 10-fold or greater CHD mortality compared with that expected from U.S. national data (3). This very high relative risk, partly reflecting the extremely low CHD death rate in the general young-adult population, was subsequently confirmed by Joslin investigators (4), who reported that those with type 1 diabetes by 55 years of age experienced a sixfold greater cumulative CHD mortality compared with the rate expected using Framingham Study data. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) also reported a standardized mortality ratio (SMR) from ischemic heart disease of 9.1 (for men) and 13.5 (for women) for those with a diabetes diagnosis before 30 years of age (5).

Two recent prospective epidemiologic studies, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (6) and Eurodiab (7), a multicenter, clinic-based study in Europe, confirmed these earlier reports and reported an incidence of total coronary events (including electrocardiogram [ECG] changes) …
Reduced myocardial cyclic GMP increases myocardial O2 consumption in control but not renal hypertension-induced cardiac hypertrophy
Authors: John D. Sadoff, Peter M. Scholz, James Tse, Harvey R. Weiss
Journal: Cardiovascular Research (1997)

Objectives: We tested the hypothesis that a reduction in myocardial cyclic GMP would increase myocardial O2 consumption and that renal hypertension (One Kidney-One Clip, 1K1C)-induced cardiac hypertrophy would change this relationship. Methods: Either vehicle or LY83583 (10−3 M, a guanylate cyclase inhibitor) was topically applied to the left ventricular surface of control or 1K1C anesthetized open-chest New Zealand white rabbits (N = 38). Coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry) were used to determine subepicardial (EPI) and subendocardial (ENDO) O2 consumption and myocardial cyclic GMP was determined by radioimmunoassay. Results: The heart weight/body weight ratio was greater in the 1K1C rabbits (3.16±0.20) than controls (2.58±0.08 g/kg). Systolic blood pressure was higher in 1K1C rabbits (116±8 mm Hg) than controls (80±6), but topical LY83583 had no significant hemodynamic effects. LY83583 significantly and similarly decreased EPI cyclic GMP in both control (7.9±1.2 to 6.0±1.0 pmol/g) and 1K1C (7.7±1.2 to 5.3±0.9) hearts and control ENDO (8.7±1.7 to 7.2±1.2) but not 1K1C ENDO (6.7±0.5 to 5.7±1.1). Myocardial O2 consumption was significantly increased in control with LY83583 (EPI 6.6±1.1 to 15.6±1.4 and ENDO 7.2±0.9 to 14.2±0.7 ml O2/min/100 g), but not in 1K1C hearts (EPI 12.1±1.0 to 12.9±1.2 or ENDO 11.4±0.7 to 12.9±0.9). Conclusions: Thus myocardial O2 consumption was only increased by LY83583 in control hearts, but LY83583 decreased cyclic GMP similarly in both the control and 1K1C EPI. This indicated, at least in the EPI, a dissociation of the inverse relationship between the myocardial level of cyclic GMP and O2 consumption in the 1K1C rabbit heart.
Inhibition of HSP27 alone or in combination with pAKT inhibition as therapeutic approaches to target SPARC-induced glioma cell survival
Authors: Chad R Schultz, William A Golembieski, Daniel A King, Stephen L Brown, Chaya Brodie, Sandra A Rempel
Journal: Molecular Cancer (2012)

Abstract Background The current treatment regimen for glioma patients is surgery, followed by radiation therapy plus temozolomide (TMZ), followed by 6 months of adjuvant TMZ. Despite this aggressive treatment regimen, the overall survival of all surgically treated GBM patients remains dismal, and additional or different therapies are required. Depending on the cancer type, SPARC has been proposed both as a therapeutic target and as a therapeutic agent. In glioma, SPARC promotes invasion via upregulation of the p38 MAPK/MAPKAPK2/HSP27 signaling pathway, and promotes tumor cell survival by upregulating pAKT. As HSP27 and AKT interact to regulate the activity of each other, we determined whether inhibition of HSP27 was better than targeting SPARC as a therapeutic approach to inhibit both SPARC-induced glioma cell invasion and survival. Results Our studies found the following. 1) SPARC increases the expression of tumor cell pro-survival and pro-death protein signaling in balance, and, as a net result, tumor cell survival remains unchanged. 2) Suppressing SPARC increases tumor cell survival, indicating it is not a good therapeutic target. 3) Suppressing HSP27 decreases tumor cell survival in all gliomas, but is more effective in SPARC-expressing tumor cells due to the removal of HSP27 inhibition of SPARC-induced pro-apoptotic signaling. 4) Suppressing total AKT1/2 paradoxically enhanced tumor cell survival, indicating that AKT1 or 2 are poor therapeutic targets. 5) However, inhibiting pAKT suppresses tumor cell survival. 6) Inhibiting both HSP27 and pAKT synergistically decreases tumor cell survival. 7) There appears to be a complex feedback system between SPARC, HSP27, and AKT. 8) This interaction is likely influenced by PTEN status. With respect to chemosensitization, we found the following. 1) SPARC enhances pro-apoptotic signaling in cells exposed to TMZ. 2) Despite this enhanced signaling, SPARC protects cells against TMZ. 3) This protection can be reduced by inhibiting pAKT. 4) Combined inhibition of HSP27 and pAKT is more effective than TMZ treatment alone. Conclusions We conclude that inhibition of HSP27 alone, or in combination with pAKT inhibitor IV, may be an effective therapeutic approach to inhibit SPARC-induced glioma cell invasion and survival in SPARC-positive/PTEN-wildtype and SPARC-positive/PTEN-null tumors, respectively.
Image-guided Pro-angiogenic Therapy in Diabetic Stroke Mouse Models Using a Multi-modal Nanoprobe
Authors: Ying-Ying Bai, Xihui Gao, Yuan-Cheng Wang, Xin-Gui Peng, Di Chang, Shuyan Zheng, Cong Li, Shenghong Ju
Journal: Theranostics (2014)

Purpose: The efficacy of pro-angiogenic therapy is difficult to evaluate with current diagnostic modalities.The objectives were to develop a non-invasive imaging strategy to define the temporal characteristics of angiogenesis and to evaluate the response to pro-angiogenic therapy in diabetic stroke mouse models.Methods: A home-made α ν β 3 integrin-targeted multi-modal nanoprobe was intravenously injected into mouse models at set time points after photothrombotic stroke.Magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging were carried out at 24 h post-injection.Bone marrow-derived endothelial progenitor cells (EPCs) were infused into the mouse models of ischemic stroke to stimulate angiogenesis.Results: The peak signal intensity in the ischemic-angiogenic area of diabetic and wild-type mouse models was achieved on day 10, with significantly lower signal enhancement observed in the diabetic models.Although the signal intensity was significantly higher after EPC treatment in both models, the enhancement was less pronounced in the diabetic animals compared with the wild-type controls.Histological analysis revealed that the microvessel density and expression of β 3 integrin were correlated with the signal intensity assessed with MRI and NIRF imaging.Conclusions: The non-invasive imaging method could be used for early and accurate evaluation of the response to pro-angiogenic therapy in diabetic stroke models.
Acute cold stress in rheumatoid arthritis inadequately activates stress responses and induces an increase of interleukin 6
Authors: R H Straub, G Pongratz, H Hirvonen, T Pohjolainen, M Mikkelsson, M Leirisalo-Repo
Journal: Annals of the Rheumatic Diseases (2008)

Objective: Acute stress in patients with rheumatoid arthritis (RA) should stimulate a strong stress response. After cryotherapy, we expected to observe an increase of hormones of the adrenal gland and the sympathetic nervous system. Methods: A total of 55 patients with RA were recruited for whole-body cryotherapy at −110°C and −60°C, and local cold therapy between −20°C and −30°C for 7 days. We measured plasma levels of steroid hormones, neuropeptide Y (sympathetic marker), and interleukin (IL)6 daily before and after cryotherapy. Results: In both therapy groups with/without glucocorticoids (GC), hormone and IL6 levels at baseline and 5 h after cold stress did not change over 7 days of cryotherapy. In patients without GC, plasma levels of cortisol and androstenedione were highest after −110°C cold stress followed by −60°C or local cold stress. The opposite was found in patients under GC therapy, in whom, unexpectedly, −110°C cold stress elicited the smallest responses. In patients without GC, adrenal cortisol production increased relative to other adrenal steroids, and again the opposite was seen under GC therapy with a loss of cortisol and an increase of dehydroepiandrosterone. Importantly, there was no sympathetic stress response in both groups. Patients without GC and −110°C cold stress demonstrated higher plasma IL6 compared to the other treatment groups (not observed under GC), but they showed the best clinical response. Conclusions: We detected an inadequate stress response in patients with GC. It is further shown that the sympathetic stress response was inadequate in patients with/without GC. Paradoxically, plasma levels of IL6 increased under strong cold stress in patients without GC. These findings confirm dysfunctional stress axes in RA.
Anti-F(ab')2 antibodies in thrombocytopenic patients at risk for acquired immunodeficiency syndrome.
Authors: J R Yu, E T Lennette, S Karpatkin
Journal: Journal of Clinical Investigation (1986)

22 homosexual or narcotic addict patients at risk for acquired immunodeficiency syndrome (AIDS) or with AIDS, were studied for the presence of antiimmunoglobulin antibodies and circulating immune complexes (20 were thrombocytopenic, 6 had AIDS). Circulating immune complex levels were 10-fold higher than levels in normal subjects. IgG anti-F(ab')2 antibodies were noted in homosexual as well as narcotic addict patients. Of 16 homosexual patients, 7 had IgG anti-F(ab')2 antibody of moderate to marked titer with broad reactivity against autologous, homologous, and control F(ab')2 fragments. Three others demonstrated limited reactivity against one or two F(ab')2 fragments. The remaining six patients were negative. Six of six narcotic addict patients had IgG anti-F(ab')2 antibody, five with limited reactivity, one with broad reactivity. In contrast, neither elevated circulating immune complexes nor anti-F(ab')2 antibodies were detectable in six autoimmune thrombocytopenic patients. Anti-F(ab')2 antibody could be affinity purified from serum or circulating immune complexes. Anti-F(ab')2 reactivity correlated with circulating immune complex levels, r = 0.83, P less than 0.01.
<i>ARTS1</i> polymorphisms are associated with ankylosing spondylitis in Koreans
Authors: Chan-Bum Choi, Tae-Hwan Kim, Jae-Bum Jun, Hye-Soon Lee, Seung Cheol Shim, Bitnara Lee, Angela Pope, Mohammed Uddin, Proton Rahman, Robert D Inman
Journal: Annals of the Rheumatic Diseases (2009)

To test the association between ARTS1 polymorphisms and Koreans with ankylosing spondylitis (AS).All patients and controls were Korean. 872 patients with AS fulfilling the modified New York criteria and 403 healthy controls were genotyped for five single nucleotide polymorphisms (SNPs), rs27044, rs17482078, rs10050860, rs30107 and rs2287987, known to be associated with AS in Caucasians.SNPs rs27044 (p=9.37 x 10(-7)) and rs30187 (p=7.16 x 10(-6)) of ARTS1 were significantly associated with AS in Koreans. There was no significant association for rs17482078, rs10050860 and rs2287987. Two four-marker haplotypes were found to be associated with AS (GCCT: p=4.71 x 10(-7), CCCC: p=8.56 x 10(-6)).This is first confirmation in a non-Caucasian population that genetic polymorphisms in ARTS1 are associated with AS, implicating common pathogenetic mechanisms in Korean and Caucasian patients with AS.