tbuckley/cabot-search huggingface dataset:
Glycosaminoglycan Therapy Prevents TGF-β1 Overexpression and Pathologic Changes in Renal Tissue of Long-Term Diabetic Rats
Authors: MONICA CEOL, GIOVANNI GAMBARO, ULRICH SAUER, BRUNO BAGGIO, FRANCA ANGLANI, MONICA FORINO, SONIA FACCHIN, LUCIANA BORDIN, CORA WEIGERT, ANDREAS NERLICH, ERWIN D. SCHLEICHER
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Chronic induction of the prosclerotic cytokine transforming growth factor β (TGF-β) has been implicated in the pathogenesis of diabetic nephropathy. In a rat model of diabetes mellitus-induced glomerulosclerosis, daily administration of a modified heparin (mH) glycosaminoglycan (GAG) preparation with low anticoagulant activity prevented glomerular and tubular matrix accumulation, as well as overexpression of TGF-β1 mRNA and albuminuria, without obvious side effects. To elucidate the molecular mechanisms of GAG/mH inhibitory actions on TGF-β1, studies using cultured mesangial cells were also performed. In these cells, high glucose-induced, dose-dependent increases in TGF-β1 mRNA and bioactive TGF-β protein expression were inhibited by GAG/mH treatment, whereas basal TGF-β1 expression was not affected. Both the heparin-derived GAG and dermatan sulfate were effective, indicating that the heparin chemical structure is not necessary for inhibitory activity. Coincubation of GAG with active TGF-β1 demonstrated no inhibitory effect on TGF-β1 bioactivity, excluding a neutralizing effect of GAG on TGF-β1 at the protein level. Furthermore, it was demonstrated that GAG inhibited phorbol myristate acetate-induced translocation of protein kinase C-α (PKC-α) and -β1 and activation of PKC-α, as well as high glucose-induced activation of PKC-α. These results suggest that GAG inhibit TGF-β1 overexpression at the transcriptional level, possibly via inhibition of high glucose-activated PKC. The findings indicate the potential of GAG therapy for the prevention of diabetic glomerulosclerosis by the inhibition of chronic disease-induced TGF-β1 mRNA overexpression.
Pulmonary Blood Flow Heterogeneity during Hypoxia and High-Altitude Pulmonary Edema
Authors: Susan R. Hopkins, Joy Garg, Divya S. Bolar, Jamal Balouch, David L. Levin
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Uneven hypoxic pulmonary vasoconstriction has been proposed to expose parts of the pulmonary capillary bed to high pressure and vascular injury in high-altitude pulmonary edema (HAPE). We hypothesized that subjects with a history of HAPE would demonstrate increased heterogeneity of pulmonary blood flow during hypoxia. A functional magnetic resonance imaging technique (arterial spin labeling) was used to quantify spatial pulmonary blood flow heterogeneity in three subject groups: (1) HAPE-susceptible (n = 5), individuals with a history of physician-documented HAPE; (2) HAPE-resistant (n = 6), individuals with repeated high-altitude exposure without illness; and (3) unselected (n = 6), individuals with a minimal history of altitude exposure. Data were collected in normoxia and after 5, 10, 20, and 30 minutes of normobaric hypoxia FI(O(2)) = 0.125. Relative dispersion (SD/mean) of the signal intensity was used as an index of perfusion heterogeneity. Oxygen saturation was not different between groups during hypoxia. Relative dispersion was not different between groups (HAPE-susceptible 0.94 +/- 0.05, HAPE-resistant 0.94 +/- 0.05, unselected 0.87 +/- 0.06; means +/- SEM) during normoxia, but it was increased by hypoxia in HAPE-susceptible (to 1.10 +/- 0.05 after 30 minutes, p < 0.0001) but not in HAPE-resistant (0.91 +/- 0.05) or unselected subjects (0.87 +/- 0.05). HAPE-susceptible individuals have increased pulmonary blood flow heterogeneity in acute hypoxia, consistent with uneven hypoxic pulmonary vasoconstriction.
Stereotactic Body Radiation Therapy for Prostate Cancer: The Need to Assess Patient-Reported Outcomes
Authors: Dirk Vordermark
Journal: Journal of Clinical Oncology (2014)

TO THE EDITOR: In their recent contribution to Journal of Clinical Oncology, Yu et al reported on toxicity profiles of stereotactic body radiation therapy in 1,335 patients with early-stage prostate cancer, as compared with a matched cohort of 2,670 patients treated with intensity-modulated radiotherapy. The authors used procedural and diagnostic codes from a Medicare database as indicators of specific genitourinary and GI complications. This approach deviates from the standard procedure to objectively rate organ-related toxicity after cancer treatment, that is, describing adverse events according to a well-defined classification, such as the Common Terminology Criteria for Adverse Events (CTCAE). Toxicity-related codes in the Medicare database could, however, serve as a surrogate of objective toxicity, especially considering some of the definitions in the CTCAE. For instance, “intervention indicated” or “operative intervention indicated” are among the criteria used to define grade 2 or grade 3 urinary toxicities such as incontinence or noninfective cystitis in the CTCAE system. Therefore, documented use of specific medical services after a cancer treatment is a potentially useful indicator of treatment tolerance and of toxicity. However, none of these approaches describes the true burden of adverse events for individual patients with prostate cancer. Especially in prostate cancer, for which different treatment strategies such as prostatectomy and radiotherapy have been shown to have similar disease-related outcomes (eg, biochemical control), self-assessment of patient-reported outcomes, such as symptoms and quality of life, using validated questionnaires has been highly informative regarding patterns of symptom development and resolution after specific treatments. Smaller studies also comparatively evaluated the profiles of competing radiotherapy techniques, such as 3D-conformal radiotherapy versus high-dose-rate brachtherapy boost in prostate cancer. In the absence of data from randomized clinical trials comparing stereotactic body radiotherapy of prostate cancer with intensity-modulated radiotherapy, a cross-sectional quality-of-life study in comparable cohorts of patients treated with these techniques could be a next step to test the hypothesis that stereotactic body radiotherapy results in increased chronic genitourinary toxicity.
Out-of-Pocket Costs in the Year After Early Breast Cancer Among Canadian Women and Spouses
Authors: Sophie Lauzier, Pascale Lévesque, Myrto Mondor, Mélanie Drolet, Douglas Coyle, Jacques Brisson, Benoît Mâsse, Louise Provencher, André Robidoux, Elizabeth Maunsell
Journal: JNCI Journal of the National Cancer Institute (2013)

We lack comprehensive information about the extent of out-of-pocket costs after diagnosis of early breast cancer and their effects on the family's financial situation.This longitudinal study assessed out-of-pocket costs and wage losses during the first year after diagnosis of early breast cancer among Canadian women and spouses. Out-of-pocket costs for treatments and follow-up, consultations with other practitioners, home help, clothing, and natural health products were estimated, with information collected from telephone interviews. Generalized linear models were used to identify women at risk of having higher costs and the effects of out-of-pocket costs on perceptions of the family's financial situation.Overall, 829 women (participation, 86.2%) and 391 spouses participated. Women's median net out-of-pocket costs during the year after diagnosis were $1002 (2003 Canadian dollars; mean = $1365; SD = $1238), and 74.4% of these costs resulted from treatments and follow-up. Spouses' median costs were $111 (mean = $234; SD = $320), or 9% of couples' total expenses. In multivariable analyses, the percentage of women with out-of-pocket costs of $1773 or more (upper quartile) was statistically significantly associated with higher education, working at diagnosis, living more than 50 km from the hospital where surgery was performed, and having two and three different types of adjuvant treatment (all 2-sided P values ≤ .01). However, when considered simultaneously with wage losses, out-of-pocket costs were not associated with perceived deterioration in the family's financial situation; rather, wage losses were the driving factor.Overall, out-of-pocket costs from breast cancer for the year after diagnosis are probably not unmanageable for most women. However, some women were at higher risk of experiencing financial burden resulting from these costs.
Metabolism of purines in macrophages. Effect of functional state of the cells.
Authors: R J Soberman, M L Karnovsky
Journal: The Journal of Experimental Medicine (1980)

Ecto-5'-nucleotidase is known to be diminished markedly in activated compared to control mouse macrophages. The level of three purine nucleoside metabolizing enzymes, adenosine deaminase (EC 3.5.4.4), purine nucleoside phosphorylase (EC 2.4.2.1), and adenine phosphoribosyltransferase (EC 2.4.2.7) were measured in the sonicates of different populations of mouse peritoneal macrophages. Levels of adenine phosphoribosyltransferase and purine nucleoside phosphorylase in macrophages that were elicited with sodium caseinate or activated in vivo by prior intravenous injection of Listeria monocytogenes were eight times higher than those in resident cells. Levels of adenosine deaminase also tended to increase and were two times higher in elicited cells than in resident cells. The Km of each enzyme was the same in each cell population. The findings suggest that the levels of the ecto-5'-nucleotidase and of the intracellular enzymes are coordinated.
Reduction in Atherosclerotic Lesion Size in Pigs by αVβ3 Inhibitors Is Associated With Inhibition of Insulin-Like Growth Factor-I–Mediated Signaling
Authors: Timothy C. Nichols, Tracey du Laney, Bo Zheng, Dwight A. Bellinger, G. Allen Nickols, Wayne Engleman, David R. Clemmons
Journal: Circulation Research (1999)

Abstract —Insulin-like growth factor-I (IGF-I) is a potent stimulant of smooth muscle cell (SMC) migration and proliferation and has been implicated in the development of experimental atherosclerotic lesions. Because optimal stimulation of SMC in vitro by IGF-I requires ligand occupancy of αVβ3, these studies were conducted to determine whether αVβ3 antagonists would result in a change in lesion size and whether they could alter IGF-I-mediated actions. Clamps were placed on the carotid and femoral arteries of normal pigs that had been fed a high-cholesterol diet for 4 weeks. αVβ3 inhibitors (SC-69000, SC-65811) (10 −6 mol/L) or saline were infused for 2 weeks into the peristenotic area. Lesion area, the number of SMC layers, and proliferating cell nuclear antigen positive cells were determined in a 1.2-mm segment of each artery. Lesion areas were 304 788±113 453 μ 2 (saline), compared with 149 799±35 456 μ 2 (SC-69000) ( P &lt;0.01). Lesion areas in arteries treated with SC-64258, a compound that does not bind to αVβ3, were 310 284±160 467 μ 2 , P =not significant. In a second experiment, lesion areas were 110 391±17 347 μ 2 (saline) and 59 533±17 568 μ 2 (SC-65811, P &lt;0.001). Neointimal SMC layers were reduced by SC-65811 from 7.4±4.5 to 3.0±0.4 ( P &lt;0.001). To determine whether IGF-I action was altered, IGF binding protein-5, which is synthesized in response to IGF-I, was analyzed. IGF-I binding protein-5 mRNA abundance was reduced by 67±8% in the 6 lesions treated with SRL-69000 compared with saline controls ( P &lt;0.001). We conclude that αVβ3 antagonists block the development of lesions in pigs that have been induced by a high-cholesterol diet and stenosis, and the effect of these compounds is associated with their ability to inhibit IGF-I–mediated signaling.
Histone Deacetylase Inhibitors Decrease DNA Methyltransferase-3B Messenger RNA Stability and Down-regulate <i>De novo</i> DNA Methyltransferase Activity in Human Endometrial Cells
Authors: Yuning Xiong, Sean C. Dowdy, Karl C. Podratz, Fan Jin, John R. Attewell, Norman L. Eberhardt, Shi-Wen Jiang
Journal: Cancer Research (2005)

Abstract It is well known that the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) acts synergistically with the DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (ADC) to reactivate DNA methylation-silenced genes. Moreover, in several studies, TSA was capable of inducing DNA demethylation even in the absence of ADC. Here we describe a mechanism by which HDAC inhibitors affect DNA methylation through their regulation on DNMT3B, a methyltransferase responsible for de novo DNA methylation. Using quantitative real-time PCR and Western blot analysis, we show that TSA down-regulates DNMT3B mRNA and protein expression in human endometrial cancer cells. This decrease in DNMT3B mRNA results in a significant reduction in de novo methylation activities. Further experiments indicated that TSA decreases DNMT3B mRNA stability and reduces its half-life from ∼4 to 2.5 hours. We established that protein synthesis is required for posttranscriptional regulation, suggesting the involvement of an RNase and/or key mRNA stabilization factor(s) controlling the DNMT3B mRNA stability. Therefore, TSA may not only modify histone acetylation, but also potentially alter DNA methylation. Since the HDAC inhibitors are frequently used in epigenetic studies and are considered to be promising anticancer drugs, these new findings will have implications in both laboratory and clinical settings.
Emergence of Polyclonal FLT3 Tyrosine Kinase Domain Mutations during Sequential Therapy with Sorafenib and Sunitinib in FLT3-ITD–Positive Acute Myeloid Leukemia
Authors: Sharyn D. Baker, Eric I. Zimmerman, Yong-Dong Wang, Shelley Orwick, Douglas S. Zatechka, Jassada Buaboonnam, Geoffrey A. Neale, Scott R. Olsen, Eric J. Enemark, Sheila Shurtleff, Jeffrey E. Rubnitz, Charles G. Mullighan, Hiroto Inaba
Journal: Clinical Cancer Research (2013)

Abstract Purpose: To evaluate the clinical activity of sequential therapy with sorafenib and sunitinib in FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myelogenous leukemia (AML) and monitor the emergence of secondary FLT3 tyrosine kinase domain (TKD) mutations during treatment. Experimental Design: Six children with relapsed/refractory AML were treated with sorafenib in combination with clofarabine and cytarabine, followed by single-agent sorafenib if not a candidate for transplantation. Sunitinib was initiated after sorafenib relapse. Bone marrow samples were obtained for assessment of FLT3 TKD mutations by deep amplicon sequencing. The phase of secondary mutations with ITD alleles was assessed by cloning and sequencing of FLT3 exons 14 through 20. Identified mutations were modeled in Ba/F3 cells, and the effect of kinase inhibitors on FLT3 signaling and cell viability was assessed. Results: Four patients achieved complete remission, but 3 receiving maintenance therapy with sorafenib relapsed after 14 to 37 weeks. Sunitinib reduced circulating blasts in two patients and marrow blasts in one. Two patients did not respond to sorafenib combination therapy or sunitinib. FLT3 mutations at residues D835 and F691 were observed in sorafenib resistance samples on both ITD-positive and -negative alleles. Deep sequencing revealed low-level mutations and their evolution during sorafenib treatment. Sunitinib suppressed leukemic clones with D835H and F691L mutations, but not D835Y. Cells expressing sorafenib-resistant FLT3 mutations were sensitive to sunitinib in vitro. Conclusions: Sunitinib has activity in patients that are resistant to sorafenib and harbor secondary FLT3 TKD mutations. The use of sensitive methods to monitor FLT3 mutations during therapy may allow individualized treatment with the currently available kinase inhibitors. Clin Cancer Res; 19(20); 5758–68. ©2013 AACR.
Identification of Galanin and Its Receptor GalR1 as Novel Determinants of Resistance to Chemotherapy and Potential Biomarkers in Colorectal Cancer
Authors: Leanne Stevenson, Wendy L. Allen, Richard Turkington, Puthen V. Jithesh, Irina Proutski, Gail Stewart, Heinz-Josef Lenz, Sandra Van Schaeybroeck, Daniel B. Longley, Patrick G. Johnston
Journal: Clinical Cancer Research (2012)

A major factor limiting the effective clinical management of colorectal cancer (CRC) is resistance to chemotherapy. Therefore, the identification of novel, therapeutically targetable mediators of resistance is vital.
Environmental tobacco smoke, indoor allergens, and childhood asthma.
Authors: D R Gold
Journal: Environmental Health Perspectives (2000)

Both environmental tobacco smoke and indoor allergens can exacerbate already established childhood albeit primarily through quite disparate mechanisms. In infancy and childhood, environmental tobacco smoke (ETS) exposure is associated with measures of decreased flow in the airways, bronchial hyperresponsiveness, and increased respiratory infections, but the relationship between ETS and allergy is poorly understood. Indoor allergens from dust mite, cockroach, and cat can be associated with asthma exacerbation in children sensitized to the specific allergens. The precise role of either ETS or indoor allergens in the development of asthma is less well understood. The strong and consistent association between ETS and asthma development in young children may relate to both prenatal and postnatal influences on airway caliber or bronchial responsiveness. Dust mite allergen levels predict asthma in children sensitized to dust mite. The tendency to develop specific IgE antibodies to allergens (sensitization) is associated with and may be preceded by the development of a T-helper (Th)2 profile of cytokine release. The importance of either ETS or indoor allergens in the differentiation of T cells into a Th2-type profile of cytokine release or in the localization of immediate-type allergic responses to the lung is unknown. This article evaluates the strength of the evidence that ETS or indoor allergens influence asthma exacerbation and asthma development in children. We also selectively review data for the effectiveness of allergen reduction in reducing asthma symptoms and present a potential research agenda regarding these two broad areas of environmental exposure and their relationship to childhood asthma.
Nineteenth Century Seeds Reveal the Population Genetics of Landrace Barley (Hordeum vulgare)
Authors: M. W. Leino, J. Hagenblad
Journal: Molecular Biology and Evolution (2009)

Barley (Hordeum vulgare) is a major crop, grown worldwide and in a wide range of climatic conditions. Despite its importance as a crop species, little is known about the population genetics of barley and the effects of bottlenecks, adaptation, and gene flow on genetic diversity within and between landrace populations. In areas with highly developed agriculture, such as Northern Europe, these types of genetic studies are hampered by lack of landraces preserved in situ or ex situ. Here, we report a genetic study of Swedish landrace barley using 113-year-old seed samples. The results demonstrate differing levels of variation with some latitudinal effect. We also detect clear population differentiation and population structure within Sweden into a southern and a northern cluster. These results possibly reflect different introduction routes of barley into Sweden. We thus show that the study of historic material can be an important alternative for regions where no or little extant landrace material is available.
A histometric analysis of chronically rejected human liver allografts: Insights into the mechanisms of bile duct loss: Direct immunologic and ischemic factors
Authors: Shiro Oguma, Steven Belle, Thomas E. Starzl, Jake A. Demetris
Journal: Hepatology (1989)

Conspicuous pathologic features of chronic liver allograft rejection include bile duct loss and chronic obliterative arteriopathy. A quantitative histometric analysis was performed to document the extent of bile duct loss, the size of the "vanished" ducts and the extent of chronic obliterative arteriopathy and to determine whether there was any relationship between chronic obliterative arteriopathy and bile duct loss. All failed liver allograft specimens with chronic rejection were reviewed and categorized according to the degree of chronic obliterative arteriopathy, assessed by the degree of luminal narrowing of hilar hepatic artery branches. Histometric analysis of the grafts revealed: (i) there was a loss of small portal arterioles (less than 35 microns); (ii) bile ducts which should accompany arteries less than 35, 35 to 54 or 55 to 74 microns in diameter were missing, with the greatest decrease occurring among the smallest ducts; (iii) bile duct loss was seen in the absence of significant large vessel chronic obliterative arteriopathy, and (iv) the severity of arteriole and bile duct loss, as well as the size of the vanished ducts, was directly proportional to the degree of chronic obliterative arteriopathy. Furthermore, the size of the "vanished" bile ducts in liver allografts appeared to differ from the size of ducts destroyed in primary biliary cirrhosis. These studies offer indirect, but suggestive proof that two mechanisms are operative in the bile duct loss seen in chronic rejection: direct lymphocytotoxicity and ischemic damage.
Lung Cancer Susceptibility in <i>Fhit</i>-Deficient Mice Is Increased by <i>Vhl</i> Haploinsufficiency
Authors: Nicola Zanesi, Rita Mancini, Cinzia Sevignani, Andrea Vecchione, Mohamed Kaou, Mauro Valtieri, George A. Calin, Yuri Pekarsky, James R. Gnarra, Carlo M. Croce, Kay Huebner
Journal: Cancer Research (2005)

Abstract The FHIT gene plays important roles in cancer development, including lung cancers, in which the Fhit protein is frequently lost. To determine if Fhit-deficient mice exhibit increased susceptibility to carcinogen-induced lung cancer, mice were treated with the pulmonary carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone. Wild-type and Fhit-deficient animals did not exhibit significantly different frequencies of lung lesions, but Fhit−/− mice showed significantly increased average tumor volume (1.62 mm3) and multiplicity in tumor-bearing mice, compared with wild-type mice (0.70 mm3). Tumors of Fhit−/− mice were all carcinomas, whereas Fhit+/+ mice did not develop carcinomas. To determine if Fhit absence, in combination with deficiency of an additional 3p tumor suppressor, would affect the frequency of tumor induction, we examined the spontaneous and dimethylnitrosamine-induced tumor phenotype of Fhit−/−Vhl+/− mice. Whereas no spontaneous lung tumors were observed in Fhit−/− or Vhl+/− mice, 44% of Fhit−/−Vhl+/− mice developed adenocarcinomas by 2 years of age. Dimethylnitrosamine (6 mg/kg body weight) induced lung tumors (adenomas and carcinomas) in 100% of Fhit−/−Vhl+/− mice and adenomas in 40% of Fhit−/− mice by 20 months of age. Thus, double deficiency in murine homologues of 3p suppressor genes, including haploinsufficiency of Vhl, predisposes to spontaneous and induced lung cancers, showing that Fhit-deficient mice will be useful, in combination with other 3p tumor suppressors, in recapitulating a pattern of lung cancer development similar to the human pattern; such double- or triple-deficient mice will be excellent lung cancer prevention and therapy models.