tbuckley/cabot-search huggingface dataset:
Young Adult Bone Marrow–Derived Endothelial Precursor Cells Restore Aging-Impaired Cardiac Angiogenic Function
Authors: Jay M. Edelberg, Lilong Tang, Koichi Hattori, David Lyden, Shahin Rafii
Journal: Circulation Research (2002)

Delivery of young bone marrow–derived stem cells offers a novel approach for restoring the impaired senescent cardiac angiogenic function that may underlie the increased morbidity and mortality associated with ischemic heart disease in older individuals. Recently, we reported that alterations in endothelial cells of the aging heart lead to a dysregulation in the cardiac myocyte platelet-derived growth factor (PDGF)-B–induced paracrine pathway, which contributes to impaired cardiac angiogenic function. Based on these results, we hypothesized that cellular restoration of the PDGF pathway by bone marrow–derived endothelial precursor cells (EPCs) could reverse the aging-associated decline in angiogenic activity. In vitro studies revealed that young murine (3-month-old) bone marrow–derived EPCs recapitulated the cardiac myocyte–induced expression of PDGF-B, whereas EPCs from the bone marrow of aging mice (18-month-old) did not express PDGF-B when cultured in the presence of cardiac myocytes. Transplantation of young, but not old, genetically marked syngeneic bone marrow cells into intact, unirradiated aging mice that populated the endogenous senescent murine bone marrow incorporated into the neovasculature of subsequently transplanted syngeneic neonatal myocardium. Moreover, the young bone marrow–derived EPCs restored the senescent host angiogenic PDGF-B induction pathway and cardiac angiogenesis, with graft survival and myocardial activity in the aging murine host (cardiac allograft viability: 3-month-old controls, 8/8; 18-month-old controls, 1/8; 18-month-old donors receiving bone marrow from 3-month-old mice, 15/16; or 18-month-old mice, 0/6; P &lt;0.05). These results may offer a foundation for the development of novel therapies for the prevention and treatment of cardiovascular disease associated with aging. The full text of this article is available at http://www.circresaha.org.
National prevalence and risk factors for food allergy and relationship to asthma: Results from the National Health and Nutrition Examination Survey 2005-2006
Authors: Andrew H. Liu, Renee Jaramillo, Scott H. Sicherer, Robert A. Wood, S. Allan Bock, A. Wesley Burks, Mark Massing, Richard D. Cohn, Darryl C. Zeldin
Journal: Journal of Allergy and Clinical Immunology (2010)
Discoidin Domain Receptor 1 Controls Growth and Adhesion of Mesangial Cells
Authors: Cyrile A. Curat, Wolfgang F. Vogel
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Various types of collagen are known as modulators of mesangial cell proliferation. Here the function of the collagen-binding tyrosine kinase receptor discoidin domain receptor 1 (DDR1) in mesangial cells is investigated. The expression of DDR1 in the mouse kidney is confirmed by Northern analysis. In primary mesangial cells isolated from wild-type and DDR1-null mice, tyrosine phosphorylation in response to collagen-stimulation, adhesion to collagen, and cellular proliferation were measured. DDR1 phosphorylation was induced after overnight incubation of cells with type I collagen. Compared with wild-type cells, the adhesion of DDR1-null cells was drastically reduced. In contrast, DDR1-knockout cells showed significantly enhanced proliferation compared with wild-type cells. Both effects were largely independent of the collagen-binding α1/β1 integrin function. This study found that the increased proliferation rate of DDR1-null cells is caused by a constitutive upregulation of p42/p44 and p38 mitogen-activated protein kinases (MAPK) activity. This is the first evidence indicating that DDR1 could be involved in the proliferative stage of renal disorders.
Renal tubular effects of chronic phosphate depletion.
Authors: S Goldfarb, G R Westby, M Goldberg, Z S Agus
Journal: Journal of Clinical Investigation (1977)

The effects of chronic phosphate depletion on renal tubular function were evaluated by micropuncture and free water clearance studies in the dog. Proximal tubular punctures demonstrated that chronic hypophosphatemia led to a reduction in ratio of tubular fluid to plasma inulin in late superficial tubular from 1.59+/-0.08 in control animals to 1.29+/-0.06 in phosphate-depleted dogs, with proportional inhibition of calcium and sodium reabsorption. The chronic decrease in proximal tubular fluid reabsorption was confirmed by the analysis of sustained water diuresis in conscious, phosphate-depleted dogs, before and after repletion of body PO4 stores, and in control animals. Urine flow rate/100 ml glomerular filtration rate (V/GFR) was significantly higher in PO4 DEPLETION THAN CONTROL (15.8+/-1.1 VS. 10.7+/-0.82). In addition, acetazolamide infusion did not increase V/GFR in phosphate-depleted dogs (15.8+/-1.1 vs. 17.16+/-0.9), supporting the conclusion that inhibition of proximal tubular fluid reabsorption was responsible for the elevated urine flow rate. PO4 repletion over 5 days reduced V/GFR to 9.2+/-0.7 despite no change in urine osmolality and no change in GFR, further suggesting a specific reversible alteration in proximal tubular reabsorption in phosphate depletion. Although hypercalciuria was a constant finding in phosphate depletion (fractional excretion of calcium of 2.04+/-0.4% vs. 0.47+/-0.13% in controls), the enhanced distal delivery of calcium was not a crucial factor; acute phosphate infusion reduced urinary calcium excretion to control values without affecting the reduced proximal tubular reabsorption in either intact or thyroparathyroidectomized phosphate-depleted dogs the change in distal nephron calcium reabsorption was independent of parathyroid hormone (PTH) levels since infusion of PTH failed to alter urinary calcium excretion. We conclude that chronic phosphate depletion leads to a reversible, sustained inhibition in proximal tubular reabsorptive fuction as well as a specific decrease in distal nephron calcium reabsorption. This latter reabsorptive defect is sensitive to phosplate infusion but not corrected by PTH.
Cost-Sharing: A Blunt Instrument
Authors: Dahlia K. Remler, Jessica Greene
Journal: Annual Review of Public Health (2008)

Cost-sharing is a health care cost-containment technique in which health care services are partially paid for by patients out of pocket. Cost-sharing can reduce non-cost-effective care, but it can also undermine the financial protection and access values of health insurance. We review the empirical evidence published since the mid-1980s about cost-sharing's effect on utilization, expenditures, health, and adverse consequences, including how the effects vary by form of care, by health status, and by sociodemographic characteristics. Some cost-sharing, such as emergency department copayments, reduces utilization without any harmful effects, whereas other cost-sharing reduces valuable care such as maintenance drug use among the chronically ill. Cost-sharing should be used judiciously, with attention taken not to reduce highly cost-effective care.
Important Roles for Macrophage Colony-stimulating Factor, CC Chemokine Ligand 2, and Mononuclear Phagocytes in the Pathogenesis of Pulmonary Fibrosis
Authors: Christopher P. Baran, Judy M. Opalek, Sara McMaken, Christie A. Newland, James M. O'Brien, Melissa G. Hunter, Benjamin D. Bringardner, Martha M. Monick, David R. Brigstock, Paul C. Stromberg, Gary W. Hunninghake, Clay B. Marsh
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: An increase in the number of mononuclear phagocytes in lung biopsies from patients with idiopathic pulmonary fibrosis (IPF) worsens prognosis. Chemokines that recruit mononuclear phagocytes, such as CC chemokine ligand 2 (CCL2), are elevated in bronchoalveolar lavage (BAL) fluid (BALF) from patients with IPF. However, little attention is given to the role of the mononuclear phagocyte survival and recruitment factor, macrophage colony-stimulating factor (M-CSF), in pulmonary fibrosis.Objectives: To investigate the role of mononuclear phagocytes and M-CSF in pulmonary fibrosis.Methods: Wild-type, M-CSF−/−, or CCL2−/− mice received intraperitoneal bleomycin. Lung inflammation and fibrosis were measured by immunohistochemistry, ELISA, collagen assay, BAL differentials, real-time polymerase chain reaction, and Western blot analysis. Human and mouse macrophages were stimulated with M-CSF for CCL2 expression. BALF from patients with IPF was examined for M-CSF and CCL2.Measurements and Main Results: M-CSF−/− and CCL2−/− mice had less lung fibrosis, mononuclear phagocyte recruitment, collagen deposition, and connective tissue growth factor (CTGF) expression after bleomycin administration than wild-type littermates. Human and mouse macrophages stimulated with M-CSF had increased CCL2 production, and intratracheal administration of M-CSF in mice induced CCL2 production in BALF. Finally, BALF from patients with IPF contained significantly more M-CSF and CCL2 than BALF from normal volunteers. Elevated levels of M-CSF were associated with elevated CCL2 in BALF and the diagnosis of IPF.Conclusions: These data suggest that M-CSF contributes to the pathogenesis of pulmonary fibrosis in mice and in patients with IPF through the involvement of mononuclear phagocytes and CCL2 production.
18-Hydroxy-Deoxycorticosterone Secretion in Experimental Hypertension in Rats
Authors: J. P. RAPP, L. K. DAHL
Journal: Circulation Research (1971)

Adrenal steroidogenesis was studied in vitro and in vivo in rats which have been specifically bred for susceptibility (S strain) or resistance (R strain) to the hypertensive effects of salt. A marked quantitative difference was found between S and R rats in the adrenal biosynthetic pathways which are subsequent to deoxycorticosterone (DOC). There was a twofold difference in the ability to 18-hydroxylate DOC to form 18-hydroxy-deoxycorticosterone (18OH-DOC) with the greater activity in the S rats. This increment in 18-hydroxylation of DOC in S over R rats was offset by an equal decrement in 11β-hydroxylation of DOC to form corticosterone (B) in S compared with R rats. These alterations in metabolic pathways gave rise to characteristic 18OH-DOC/B ratios for S and R animals that were obvious both in vitro and in vivo.  The data suggest, therefore, that in selectively breeding rats on the basis of blood pressure response to salt, a gene (or genes) which affects the 18OH-DOC/B ratio has been segregated in the S and R strains. Although this segregation is in itself good evidence for an effect of 18OH-DOC (or 18OH-DOC/B ratio) on blood pressure in rats, it was also emphasized that there is evidence for more than one gene affecting blood pressure in rats. Thus, the steroid difference described is likely to be controlled by only one of several genes affecting the quantitative character of blood pressure. Comparison of 18OH-DOC/B ratios in S and R strains with other strains of rats showed that the high ratio in S rats was quite common, but that the low ratio in R rats was rather unique. Thus, it seems that the low 18OH-DOC/B ratio of R animals connotes resistance to salt, while the higher ratio in S and unselected strains probably only connotes normal susceptibility to salt. The extreme sensitivity of S rats to salt must therefore be accounted for by other genes.
A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice
Authors: Jo Waaler, Ondrej Machon, Lucie Tumova, Huyen Dinh, Vladimir Korinek, Steven Ray Wilson, Jan Erik Paulsen, Nina Marie Pedersen, Tor J. Eide, Olga Machonova, Dietmar Gradl, Andrey Voronkov, Jens Peter von Kries, Stefan Krauss
Journal: Cancer Research (2012)

Increased nuclear accumulation of β-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/β-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the β-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the β-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl)ation activity by JW55 led to stabilization of AXIN2, a member of the β-catenin destruction complex, followed by increased degradation of β-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of β-catenin. In addition, JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen-induced polyposis formation in conditional APC mutant mice. Together, our findings provide a novel chemotype for targeting canonical Wnt/β-catenin signaling through inhibiting the PARP domain of TNKS1/2.
Different Differentiation Kinetics of Vascular Progenitor Cells in Primate and Mouse Embryonic Stem Cells
Authors: Masakatsu Sone, Hiroshi Itoh, Jun Yamashita, Takami Yurugi-Kobayashi, Yutaka Suzuki, Yasushi Kondo, Akane Nonoguchi, Naoki Sawada, Kenichi Yamahara, Kazutoshi Miyashita, Kwijun Park, Masabumi Shibuya, Shinji Nito, Shin-Ichi Nishikawa, Kazuwa Nakao
Journal: Circulation (2003)

We demonstrated that vascular endothelial growth factor receptor 2 (VEGF-R2)-positive cells derived from mouse embryonic stem (ES) cells can differentiate into both endothelial cells and mural cells to suffice as vascular progenitor cells (VPCs). Here we examined whether VPCs occur in primate ES cells and investigated the differences in VPC differentiation kinetics between primate and mouse ES cells.In contrast to mouse ES cells, undifferentiated monkey ES cells expressed VEGF-R2. By culturing these undifferentiated ES cells for 4 days on OP9 feeder layer, VEGF-R2 expression disappeared, and then reappeared after 8 days of differentiation. We then isolated these VEGF-R2-positive and vascular endothelial cadherin (VEcadherin)-negative cells by flow cytometry sorting. Additional 5-day reculture of these VEGF-R2+ VEcadherin- cells on OP9 feeder layer resulted in the appearance of platelet endothelial cell adhesion molecule-1 (PECAM1)-positive, VEcadherin-positive, endothelial nitric oxide synthase (eNOS)-positive endothelial cells. On a collagen IV-coated dish in the presence of serum, these cells differentiated into smooth muscle actin (SMA)-positive and calponin-positive mural cells (pericytes or vascular smooth muscle cells). Addition of 50 ng/mL VEGF to the culture on a collagen IV-coated dish resulted in the appearance of PECAM1+ cells surrounded by SMA+ cells. In addition, these differentiated VEGF-R2+ cells can form tube-like structures in a 3-dimensional culture.Our findings indicate that differentiation kinetics of VPCs derived from primate and mouse ES cells were different. Differentiated VEGF-R2+ VEcadherin- cells can act as VPCs in primates. To seek the clinical potential of VPCs for vascular regeneration, investigations of primate ES cells are indispensable.
Is there a common upstream link for autophagic and apoptotic cell death in human high-grade gliomas?
Authors: L. Emdad, Z. A. Qadeer, L. B. Bederson, H. P. Kothari, M. Uzzaman, I. M. Germano
Journal: Neuro-Oncology (2011)

The prognosis of patients with human high-grade gliomas (HGGs) remains dismal despite major advances in their management, due mainly to the high resistance of these infiltrative tumor cells to programmed cell death (PCD). Most therapeutic strategies for HGGs are aimed to maximize PCD type I, apoptosis or type II, autophagy. These are predominantly distinctive processes, but many studies suggest a cross-talk between the two. A better understanding of the link between PCD types I and II might allow development of more effective therapies for HGGs. In this study, we examined whether there is a common upstream signaling event responsible for both apoptotic and autophagic PCD using 3 chemotherapeutic agents in human HGG cells. Our study shows that each agent caused a significant decrease in cell viability in each of the HGG cell lines tested. The increase rate of apoptosis and autophagy varied among cell lines and chemotherapeutic agents used. Increased expression of cytidine-cytidine-adenosine-adenosine-thymidine (C)/enhancer binding protein (EBP) homologous transcription factor C/EBP homologous protein (CHOP)/growth arrest and DNA damage-inducible gene 153 (GADD153) was documented after use of either pro-autophagic or pro-apoptotic agents. The involvement of CHOP/GADD153 in both type I and type II PCD was confirmed by overexpression and gene-silencing studies. Gene silencing by small-interfering RNA-mediated CHOP/GADD153 resulted in increased cell viability, decreased upregulation of microtubule-associated protein light-chain 3' type II (LC3II) and cleaved caspase-3, and inhibition of apoptosis and autophagy. Exogenous expression of CHOP/GADD153 triggered apoptosis and autophagy in the absence of other stimuli. The clinical significance of these findings was supported by the evidence that celecoxib, a nonsteroidal anti-inflammatory drug known to induce GADD153-mediated apoptosis, strongly increases both type I and type II PCD in HGG cells when combined with another inducer of GADD153. These data suggest that CHOP/GADD153 should be investigated as a novel targetable signaling step to improve therapies for HGGs.
Severe serum sickness–like syndrome after omalizumab therapy for asthma
Authors: Charles Pilette, Nathalie Coppens, Frédéric A. Houssiau, Daniel O. Rodenstein
Journal: Journal of Allergy and Clinical Immunology (2007)

In conclusion, using a nationwide database on prescriptions filled, we found a disconnect between the guideline recommendations on the use of a combination of ICS 1 LABA for treatment of asthma in school children with an excessive use of this combination therapy and particularly its use in approximately half of all children starting firsttime ICS therapy.The prescription pattern varies significantly among regions of this small country, illustrating the inefficient penetrance of evidence-based guidelines.Because this prescription pattern is at odds with the general agreement among international and national guidelines, this raises the question: what drives prescription patterns?It is possible that real-life experience is better than the evidence provided in controlled clinical trials, but this seems unlikely.Another possibility is that the disease severity is increasing, though the rapidly increased use after introduction of the fixed combination products suggests that other factors are more important.The pharmaceutical industry has been pushing the new combination products since their introduction to the market because the patent has expired on the mono-ICS products, which is the more probable contributor to this development.Finally, the data might suggest an inefficient dissemination of current guidelines and encourage a stronger emphasis on their implementation.
Endomyocardial Biopsies
Authors: H. Thomas Aretz
Journal: JAMA (1997)

Short-term survival of cardiac allografts has increased markedly because of surveillance by protocol endomyocardial biopsies and improvements in immunosuppression, which have largely prevented graft loss from acute rejection. Currently, 85% of allograft recipients survive for 1 year, and 70% can expect to survive 5 years.<sup>1</sup>Despite this progress, chronic cardiac allograft arteriopathy (also known as chronic rejection, graft vascular disease, or accelerated atherosclerosis) remains a substantial and intractable obstacle to long-term survival, accounting for 21% to 30% of deaths.<sup>2,3</sup>The other major complications relate to the immunosuppression treatment itself (malignancy, infections). See also p 1169. Although graft atherosclerotic disease shares certain aspects with native coronary atherosclerosis, including dysfunctional endothelium with subsequent endothelial—inflammatory cell interaction, there are significant differences in the morphology, distribution, and most certainly pathogenesis.<sup>4</sup>The introduction of intravascular ultrasound has also shown that the process is much more prevalent and occurs earlier than had been
Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma1
Authors: Rajeev Vibhakar, Greg Foltz, Jae-geun Yoon, Lorie Field, Hwahyung Lee, Gi-yung Ryu, Jessica Pierson, Beverly Davidson, Anup Madan
Journal: Neuro-Oncology (2007)

Neuro-oN cologyMedulloblastoma is a heterogeneous pediatric brain tumor with significant therapy-related morbidity, its five-year survival rates ranging from 30% to 70%.Improvement in diagnosis and therapy requires better understanding of medulloblastoma pathology.We used whole-genome microarray analysis to identify putative tumor suppressor genes silenced by epigenetic mechanisms in medulloblastoma.This analysis yielded 714 upregulated genes in immortalized medulloblastoma cell line D283 on treatment with histone deacetylase (HDAC) inhibitor trichostatin A (TSA).Dickkopf-1 (DKK1), a Wnt antagonist, was found to be up-regulated on HDAC inhibition.We examined DKK1 expression in primary medulloblastoma cells and patient samples by reverse transcriptase PCR and found it to be significantly downregulated relative to normal cerebellum.Transfection of a DKK1 gene construct into D283 cell lines suppressed medulloblastoma tumor growth in colony focus assays
Actual Status of Distribution and Prognostic Impact of Extramural Discontinuous Cancer Spread in Colorectal Cancer
Authors: Hideki Ueno, Hidetaka Mochizuki, Kazuo Shirouzu, Takaya Kusumi, Kazutaka Yamada, Masahiro Ikegami, Hiroshi Kawachi, Shingo Kameoka, Yasuo Ohkura, Tadahiko Masaki, Ryoji Kushima, Keiichi Takahashi, Yoichi Ajioka, Kazuo Hase, Atsushi Ochiai, Ryo Wada, Keiichi Iwaya, Takahiro Nakamura, Kenichi Sugihara
Journal: Journal of Clinical Oncology (2011)

To clarify the prognostic impact of tumor nodules without residual lymph node (LN) structure (ND) in colorectal cancer and to determine optimal categorization of ND in tumor staging.A multicenter, retrospective pathologic review was performed for 1716 patients with stages I to III curatively resected colorectal cancer treated at 11 institutions between 1994 and 1998. An additional 2242 patients from nine institutions were enrolled between 1999 and 2003 as a second cohort to validate the results.LN metastasis (LNM) and ND were observed in 33.7% and 16.0% (smooth-contour nodule [S-ND], 8.2%; irregular-contour nodule [I-ND], 10.7%) of patients in the first cohort. S-ND and I-ND were similarly distributed in the regional area. There was no considerable difference in the impact on survival between S-ND (hazard ratio [HR], 2.7; 95% CI, 1.9 to 3.8) and I-ND (HR, 4.3; 95% CI, 3.3 to 5.8) or between LNM (HR, 4.5; 95% CI, 3.4 to 6.0) and ND (HR, 4.0; 95% CI, 3.1 to 5.3). LNM and ND were similarly associated with the mode of recurrence. Tumor nodules ≥ 5 mm growing with venous/perineural invasion (ND [v/pni+]), judged with 0.61 κ value among 11 observers, had an independent prognostic value for 5-year survival of 42%; similar results were observed in the second cohort.These results do not support the TNM system in which S-ND is treated differently from I-ND in tumor staging; LNM and ND should be considered together in the same category. The presence of ND (v/pni+) has a considerable adverse prognostic effect.