tbuckley/cabot-search huggingface dataset:
Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion
Authors: Ana P. Bastos, Klaus Piontek, Ana M. Silva, Dino Martini, Luis F. Menezes, Jonathan M. Fonseca, Ivone I. Fonseca, Gregory G. Germino, Luiz F. Onuchic
Journal: Journal of the American Society of Nephrology (2009)

Mutations in PKD1 cause the majority of cases of autosomal dominant polycystic kidney disease (ADPKD). Because polycystin 1 modulates cell proliferation, cell differentiation, and apoptosis, its lower biologic activity observed in ADPKD might influence the degree of injury after renal ischemia/reperfusion. We induced renal ischemia/reperfusion in 10- to 12-wk-old male noncystic Pkd1(+/-) and wild-type mice. Compared with wild-type mice, heterozygous mice had higher fractional excretions of sodium and potassium and higher serum creatinine after 48 h. In addition, in heterozygous mice, also cortical damage, rates of apoptosis, and inflammatory infiltration into the interstitium at time points out to 14 d after injury all increased, as well as cell proliferation at 48 h and 7 d. The mRNA and protein expression of p21 was lower in heterozygous mice than wild-type mice at 48 h. After 6 wk, we observed dilated tubules, microcysts, and increased renal fibrosis in heterozygotes. The early mortality of heterozygotes was significantly higher than that of wild-type mice when we extended the duration of ischemia from 32 to 35 min. In conclusion, ischemia/reperfusion induces a more severe injury in kidneys of Pkd1-haploinsufficient mice, a process that apparently depends on a relative deficiency of p21 activity, tubular dilation, and microcyst formation. These data suggest the possibility that humans with ADPKD from PKD1 mutations may be at greater risk for damage from renal ischemia/reperfusion injury.
HCMV infection of human vascular smooth muscle cells leads to enhanced expression of functionally intact PDGF β-receptor
Authors: B REINHARDT, T MERTENS, U MAYRBEYRLE, H FRANK, A LUSKE, K SCHIERLING, J WALTENBERGER
Journal: Cardiovascular Research (2005)

Background: Cytomegaloviruses have been shown to promote atherogenesis in animal models. In humans, several epidemiological and clinical studies suggest involvement of the human cytomegalovirus (HCMV) in the development of atherosclerosis. HCMV is suspected to be associated with an enhanced restenosis rate and the occurrence of vasculopathies after solid organ transplantation. However, knowledge about the cellular and molecular bases of these findings is very limited. Methods and results: Human coronary artery smooth muscle cells (HCASMC) were successfully infected with HCMV in vitro. Infection of HCASMC with all HCMV strains analyzed resulted in a substantial upregulation of the β-receptor of platelet-derived growth factor (PDGFR-β) expression as demonstrated by immunohistochemistry, immunofluorescence, FACS, and Western blot analysis. The amount of PDGFR-β protein present in HCASMC rapidly increased after 12 h of infection and this difference persisted for 72 h post-infection. We showed by quantitative FACS analysis that the extent of PDGFR-β upregulation differed significantly between the HCMV strains TB40E, Toledo, and AD169. The expression of insulin-like growth factor receptors as well as hepatocyte growth factor receptors, however, was downmodulated in HCMV-infected HCASMC. Most importantly, the HCMV-associated upregulation of PDGFR-β protein resulted in functionally intact receptors. A significantly higher increase of proliferative activity following stimulation with PDGF-BB was observed in HCMV-infected HCASMC compared to the uninfected control. Conclusions: Our data suggest that HCMV directly activates the PDGF system, which could promote atherogenesis and restenosis by activation of smooth muscle cell proliferation and neointima formation.
Evolving Concepts in the Pathophysiology, Diagnosis, and Treatment of Pheochromocytoma
Authors: EMMANUEL L. BRAVO
Journal: Endocrine Reviews (1994)

THE very first known successful operation for removal of a pheochromocytoma was performed by Cesar Roux in February 1926 in Lausanne, Switzerland (1). C. H. Mayo performed the first successful removal of a pheochromocytoma in North America in October of the same year (2). Since these first successful operations, considerable progress has been made in the diagnosis and treatment of pheochromocytoma. The availability of sensitive and specific immunoassay procedures, the development of simplified diagnostic testing, and the introduction of sensitive imaging techniques have enhanced the clinician's ability to make the diagnosis with greater certainty. In addition, a better understanding of catecholamine action and the pathophysiology of pheochromocytoma and an appreciation of the wide range of clinical manifestations associated with it have led not only to earlier recognition of the disease but also to a more rational approach to its diagnosis and management. Nevertheless, there are still uncertainties regarding the pathophysiology of hypertension, about optimal screening methods, the sensitivity and specificity of the various diagnostic tests, the diagnostic process, and the approach to treatment.
Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours
Authors: D.S. Boss, G.K. Schwartz, M.R. Middleton, D.D. Amakye, H. Swaisland, R.S. Midgley, M. Ranson, S. Danson, H. Calvert, R. Plummer, C. Morris, R.D. Carvajal, L.R. Chirieac, J.H.M. Schellens, G.I. Shapiro
Journal: Annals of Oncology (2009)
p16/Cyclin-Dependent Kinase Inhibitor 2A Deficiency in Human Melanocyte Senescence, Apoptosis, and Immortalization: Possible Implications for Melanoma Progression
Authors: E. V. Sviderskaya, V. C. Gray-Schopfer, S. P. Hill, N. P. Smit, T. J. Evans-Whipp, J. Bond, L. Hill, V. Bataille, G. Peters, D. Kipling, D. Wynford-Thomas, D. C. Bennett
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: The melanoma susceptibility locus cyclin-dependent kinase inhibitor 2A encodes two unrelated cell growth inhibitors, p16 and alternative reading frame (ARF). In fibroblasts, both proteins are implicated in cellular senescence, a key barrier to tumor development. The p16 coding sequence is more often mutated in melanoma families than is the ARF sequence. To investigate the role of p16 in melanocytes, we assessed aspects of growth, apoptosis, and immortalization in melanocytes cultured from two melanoma patients, both of whom had two inactive p16 alleles but functional ARF. Methods: Growth and senescence were evaluated by cumulative population-doubling curves, and apoptosis by terminal deoxytransferase labeling. Expression of p53 and p21, which are associated with fibroblast senescence, was assessed by immunoblotting. Amphotropic retroviruses were used to transfer exogenous gene sequences into the melanocytes. Results: Both melanocyte cultures showed high rates of apoptosis, which were reduced when the cells were grown in the presence of keratinocyte feeder cells or human stem cell factor plus endothelin 1. With these growth factors, both cultures proliferated for 45–55 net population doublings, markedly longer than the maximum of 10 net population doublings of normal adult human melanocytes in similar media, indicating impaired senescence. One of the cultures developed chromosomal aberrations, with numerous dicentric chromosomes at senescence, consistent with telomere dysfunction. p53 and p21 levels were not elevated in senescent normal melanocytes but were elevated in senescent p16-deficient melanocytes. Interference with p53 function by transfer of human papillomavirus 16-E6 further extended the lifespan of p16-deficient melanocytes. Human telomerase reverse transcriptase was sufficient to immortalize both these cell strains but not normal melanocytes. Conclusion: Normal senescence in human melanocytes requires p16 activity. p53 contributes to a delayed form of senescence that requires telomere shortening, in p16-deficient melanocytes. These findings provide some basis for the role of p16 in melanoma susceptibility.
Ligandinemia in primary liver cell cancer in rat and man
Authors: Naohito Ohmi, Irwin M. Arias
Journal: Hepatology (1981)

Ligandin was quantitated by radioimmunoassay in serum and, when possible, in tumors from patients with primary hepatocellular carcinoma, massive hepatic metastasis or nonhepatic primary neoplasms, and in rats and athymic (nu/nu) mice bearing transplantable ligandin-containing or nonligandin-containing rat hepatocellular carcinomas. Following transplantation of a ligandin-containing rat hepatocellular carcinoma in rats or athymic (nu/nu) mice, mean serum ligandin concentrations progressively increased and, within 4 months, exceeded normal serum ligandin concentrations by 10-fold. In 11 of 15 HBsAg negative patients with primary hepatocellular carcinoma, serum ligandin concentrations ranged from 82 to 551 (mean: 298) ng per ml; the mean ligandin concentration in the hepatic neoplasm was 32% of the ligandin concentration in normal liver. In 19 of 22 patients with extensive hepatic metastasis and in each of 20 patients with primary carcinomas without hepatic metastasis, serum ligandin concentrations were normal (7.0 +/- 4.0 ng per ml).
c-Myc dependent expression of pro-apoptotic Bim renders HER2-overexpressing breast cancer cells dependent on anti-apoptotic Mcl-1
Authors: Mario Campone, Bélinda Noël, Cécile Couriaud, Morgan Grau, Yannis Guillemin, Fabien Gautier, Wilfried Gouraud, Catherine Charbonnel, Loïc Campion, Pascal Jézéquel, Frédérique Braun, Benjamin Barré, Olivier Coqueret, Sophie Barillé-Nion, Philippe Juin
Journal: Molecular Cancer (2011)

Abstract Background Anti-apoptotic signals induced downstream of HER2 are known to contribute to the resistance to current treatments of breast cancer cells that overexpress this member of the EGFR family. Whether or not some of these signals are also involved in tumor maintenance by counteracting constitutive death signals is much less understood. To address this, we investigated what role anti- and pro-apoptotic Bcl-2 family members, key regulators of cancer cell survival, might play in the viability of HER2 overexpressing breast cancer cells. Methods We used cell lines as an in vitro model of HER2-overexpressing cells in order to evaluate how anti-apoptotic Bcl-2, Bcl-xL and Mcl-1, and pro-apoptotic Puma and Bim impact on their survival, and to investigate how the constitutive expression of these proteins is regulated. Expression of the proteins of interest was confirmed using lysates from HER2-overexpressing tumors and through analysis of publicly available RNA expression data. Results We show that the depletion of Mcl-1 is sufficient to induce apoptosis in HER2-overexpressing breast cancer cells. This Mcl-1 dependence is due to Bim expression and it directly results from oncogenic signaling, as depletion of the oncoprotein c-Myc, which occupies regions of the Bim promoter as evaluated in ChIP assays, decreases Bim levels and mitigates Mcl-1 dependence. Consistently, a reduction of c-Myc expression by inhibition of mTORC1 activity abrogates occupancy of the Bim promoter by c-Myc, decreases Bim expression and promotes tolerance to Mcl-1 depletion. Western blot analysis confirms that naïve HER2-overexpressing tumors constitutively express detectable levels of Mcl-1 and Bim, while expression data hint on enrichment for Mcl-1 transcripts in these tumors. Conclusions This work establishes that, in HER2-overexpressing tumors, it is necessary, and maybe sufficient, to therapeutically impact on the Mcl-1/Bim balance for efficient induction of cancer cell death.
Minimally modified low density lipoprotein-induced inflammatory responses in endothelial cells are mediated by cyclic adenosine monophosphate.
Authors: F Parhami, Z T Fang, A M Fogelman, A Andalibi, M C Territo, J A Berliner
Journal: Journal of Clinical Investigation (1993)

We have previously shown that minimally oxidized LDL (MM-LDL) activated endothelial cells to increase their interaction with monocytes but not neutrophils, inducing monocyte but not neutrophil binding and synthesis of monocyte chemotactic protein-1 and monocyte colony-stimulating factor (M-CSF). In the present studies we have examined the signaling pathways by which this monocyte-specific response is induced. Both induction of monocyte binding and mRNA levels for M-CSF by MM-LDL were not inhibited in protein kinase C-depleted endothelial cells. A number of our studies indicate that cAMP is the second messenger for the effects of MM-LDL cited above. Incubation of endothelial cells with MM-LDL caused a 173% increase in intracellular cAMP levels. Agents which increased cAMP levels, including cholera toxin, pertussis toxin, dibutyryl cAMP, and isoproterenol mimicked the actions of MM-LDL. Agents which elevated cAMP were also shown to activate NF kappa B, suggesting a role for this transcription factor in activation of monocyte-endothelial interactions. Although endothelial leukocyte adhesion molecule (ELAM) mRNA synthesis can be regulated by NF kappa B, ELAM was not expressed and ELAM mRNA was only slightly elevated in response to MM-LDL. We present evidence that induction of neutrophil binding by LPS is actually suppressed by agents that elevated cAMP levels.
Isotretinoin therapy and the incidence of acne relapse: a nested case–control study
Authors: L. Azoulay, D. Oraichi, A. Bérard
Journal: British Journal of Dermatology (2007)

Journal Article Isotretinoin therapy and the incidence of acne relapse: a nested case–control study Get access L. Azoulay, L. Azoulay Faculty of Pharmacy, University of Montreal, Montreal, Quebec, CanadaResearch Center, CHU Sainte‐Justine, Centre de Recherché, 3175, Chemin de la Côte‐Ste‐Catherine, Montreal, Quebec, Canada H3T 1C5 Search for other works by this author on: Oxford Academic Google Scholar D. Oraichi, D. Oraichi Research Center, CHU Sainte‐Justine, Centre de Recherché, 3175, Chemin de la Côte‐Ste‐Catherine, Montreal, Quebec, Canada H3T 1C5 Search for other works by this author on: Oxford Academic Google Scholar A. Bérard A. Bérard Faculty of Pharmacy, University of Montreal, Montreal, Quebec, CanadaResearch Center, CHU Sainte‐Justine, Centre de Recherché, 3175, Chemin de la Côte‐Ste‐Catherine, Montreal, Quebec, Canada H3T 1C5 Correspondence: Anick Bérard. E‐mail: anick.berard@umontreal.ca Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 157, Issue 6, 1 December 2007, Pages 1240–1248, https://doi.org/10.1111/j.1365-2133.2007.08250.x Published: 01 December 2007
Pressure Overload Induces Cardiac Dysfunction and Dilation in Signal Transducer and Activator of Transcription 6–Deficient Mice
Authors: Shungo Hikoso, Osamu Yamaguchi, Yoshiharu Higuchi, Shinichi Hirotani, Toshihiro Takeda, Kazunori Kashiwase, Tetsuya Watanabe, Masayuki Taniike, Ikuko Tsujimoto, Michio Asahi, Yasushi Matsumura, Kazuhiko Nishida, Hiroshi Nakajima, Shizuo Akira, Masatsugu Hori, Kinya Otsu
Journal: Circulation (2004)

Background— Signal transducer and activator of transcription (STAT) proteins constitute a family of transcription factors that mediate many cytokine-induced responses. STAT6 is activated by angiotensin II and in rat hypertrophied hearts and in human hearts with dilated cardiomyopathy. This suggests that STAT6 may be involved in the pathogenesis of cardiac hypertrophy and heart failure. For this study we used STAT6-deficient (STAT6 −/− ) mice to examine the in vivo role of STAT6. Methods and Results— STAT6 −/− hearts showed no morphological, histological, or functional defects. We examined left ventricular structural and functional remodeling 1 week after thoracic transverse aortic constriction (TAC). Western blot and immunohistochemical analyses showed increased STAT6 activity after TAC in the heart of wild-type mice. STAT6 −/− mice showed a significant increase in end-diastolic left ventricular internal dimension accompanied by impaired contractility compared with wild-type mice but no differences in hypertrophic parameters. The number of terminal deoxynucleotidyl transferase–mediated biotin dUTP nick-end labeling–positive myocytes after TAC had increased in STAT6 −/− compared with wild-type mice. Prolonged induction of tumor necrosis factor-α (TNF-α) mRNA was observed in STAT6 −/− hearts, whereas TNF-α mRNA was only transiently induced in wild-type mice. Tristetraprolin was induced after TAC in wild-type mice but not in STAT6 −/− mice. Tristetraprolin reporter assay with the use of isolated neonatal cardiomyocyte indicated that the promoter was significantly activated by endothelin-1 in wild-type but not in STAT6 −/− cardiomyocytes. The lack of promoter activation by endothelin-1 in STAT6 −/− cardiomyocytes was rescued by forced expression of STAT6. Conclusions— STAT6 plays a protective role against hemodynamic stress in hearts.
Mammary Gland Development After Hypophysial Isografts in Intact Mice of High and Low Mammary Cancer Strains&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: C. Wayne Bardin, Annabel G. Liebelt, Robert A. Liebelt
Journal: JNCI Journal of the National Cancer Institute (1966)

A single hypophysial isograft in intact mice induced pseudo-pregnancy-like vaginal cycles and mammary gland development in females of the C57BL, A, CE, C3H, CBA, and RIII strains of mice and in (CBA × RIII), (RIII × CBA), and (RIII × A)F1 hybrids. Mammary gland development was also observed in male (RIII × CBA) and (RIII × A)F1 hybrids bearing hypophysial grafts. There was a marked strain difference in the extent of mammary gland development in the hypophysial grafted mice. A slight difference was noted in the mammary glands of controls from the various strains. Morphological correlation could not be made between the extent of mammary gland development in control or hypophysial grafted mice and the spontaneous incidence of mammary cancer in the various strains. Hypophysial grafts in (RIII × CBA)F1 females became neoplastic after 240 days. Mammary carcinoma was noted in male (RIII × CBA)F1 hybrids after long-term exposure to hypophysial graft stimulation.
A patchy consolidation at the apical segment of the left lower lobe associated with productive cough
Authors: Y-L Chang, C-T Wu, Y-C Lee
Journal: Thorax (2008)

A 65-year-old female non-smoker had a 3-month history of productive cough and intermittent haemoptysis for 1 month. Plain chest radiography showed a mass-like shadow at the medial side of the left lower …
Multispectral Near-Infrared Fluorescence Molecular Imaging of Matrix Metalloproteinases in a Human Carotid Plaque Using a Matrix-Degrading Metalloproteinase–Sensitive Activatable Fluorescent Probe
Authors: Bastiaan M. Wallis de Vries, Jan-Luuk Hillebrands, Gooitzen M. van Dam, René A. Tio, Johannes S. de Jong, Riemer H.J.A. Slart, Clark J. Zeebregts
Journal: Circulation (2009)
Postabsorptive and Insulin-Stimulated Energy Homeostasis and Leucine Turnover in Offspring of Type 2 Diabetic Patients
Authors: Guido Lattuada, Lucia Piceni Sereni, Dora Ruggieri, Antonella Scollo, Stefano Benedini, Francesca Ragogna, Federica Costantino, Alberto Battezzati, Livio Luzi, Gianluca Perseghin
Journal: Diabetes Care (2004)

OBJECTIVE—This study was performed to ascertain whether insulin resistance with respect to protein metabolism is an additional primary metabolic abnormality affecting insulin-resistant offspring of type 2 diabetic parents, along with insulin resistance with respect to glucose and lipid metabolism. RESEARCH DESIGN AND METHODS—We studied 18 young, nonobese offspring of type 2 diabetic parents and 27 healthy matched (by means of dual-energy X-ray absorption) individuals with the bolus plus continuous infusion of [6,6-2H2]glucose and [1-13C]leucine in combination with the insulin clamp (40 mU · m–2 · min−1). RESULTS—Fasting plasma leucine, phenylalanine, alanine, and glutamine concentrations, as well as the glucose and leucine turnover (reciprocal pool model: 155 ± 10 vs. 165 ± 5 μmol · kg lean body mass–1 · h−1 in offspring of type 2 diabetic patients and healthy matched individuals, respectively), were also not different. During the clamp, glucose turnover rates were significantly reduced in offspring of type 2 diabetic patients (7.1 ± 0.5) in comparison with healthy matched individuals (9.9 ± 0.6 mg · kg lean body mass–1 · min−1; P &amp;lt; 0.01). Also, the suppression of leucine turnover was impaired in offspring of type 2 diabetic patients (12 ± 1%) in comparison with healthy matched individuals (17 ± 1%; P = 0.04) and correlated with the degree of the impairment of insulin-stimulated glucose metabolism (R2 = 0.13; P = 0.02). CONCLUSIONS—Nonobese, nondiabetic, insulin-resistant offspring of type 2 diabetic patients were characterized by an impairment of insulin-dependent suppression of protein breakdown, which was proportional to the impairment of glucose metabolism. These results demonstrate that in humans, a primary in vivo impairment of insulin action affects glucose and fatty acid metabolism as previously shown and also protein/amino acid metabolism.
External Financial Aid to Blood Transfusion Services in Sub-Saharan Africa: A Need for Reflection
Authors: Fereydoun Ala, Jean-Pierre Allain, Imelda Bates, Kamel Boukef, Frank Boulton, James Brandful, Elizabeth M. Dax, Magdy El Ekiaby, Albert Farrugia, Jed Gorlin, Oliver Hassall, Helen Lee, André Loua, Kathryn Maitland, Dora Mbanya, Zainab Mukhtar, William Murphy, Ohene Opare-Sem, Shirley Owusu-Ofori, Henk Reesink, David Roberts, Oscar Torres, Grace Totoe, Henrik Ullum, Silvano Wendel
Journal: PLoS Medicine (2012)

Jean-Pierre Allain and colleagues argue that, while unintended, the foreign aid provided for blood transfusion services in sub-Saharan Africa has resulted in serious negative outcomes, which requires reflection and rethinking.
Disruption in the Balance Between Goal-Directed Behavior and Habit Learning in Obsessive-Compulsive Disorder
Authors: Claire M. Gillan, Martina Papmeyer, Sharon Morein-Zamir, Barbara J. Sahakian, Naomi A. Fineberg, Trevor W. Robbins, Sanne de Wit
Journal: American Journal of Psychiatry (2011)

Obsessive-compulsive disorder (OCD) is characterized by repetitive, ritualistic behaviors and thought patterns. Although patients with OCD report that these compulsive behaviors are unproductive and often senseless, they are unable to desist. This study investigated whether the urge to perform compulsive acts is mediated by a disruption in the balance between flexible, goal-directed action control and habitual behavior.A total of 21 patients with OCD and 30 healthy comparison subjects participated in a set of tasks designed to assess relative goal-directed versus habitual behavioral control. In the training stage, participants were asked to respond to different pictured stimuli in order to gain rewarding outcomes. In the subsequent (instructed) outcome devaluation test and in a novel "slips-of-action" test, the authors assessed whether participants were able to flexibly adjust their behavior to changes in the desirability of the outcomes. The authors also used a questionnaire to test explicit knowledge of the relationships between stimuli, responses, and outcomes.Patients with OCD showed no deficit in their ability to use feedback to respond appropriately to stimuli in the training stage. However, their knowledge of the outcomes of these responses was impaired relative to healthy comparison subjects, and patients were more prone to slips of action, indicating a deficit in goal-directed control and an overreliance on habits.This study provides the first experimental evidence for selective impairment in flexible and goal-directed behavioral control in patients with OCD. The impairment forces patients with OCD to rely instead on habits that can be triggered by stimuli regardless of the desirability of the consequences. Goal-directed actions are supported by orbitofronto-striatal circuitry, and the study findings are thus in line with findings from research that implicate dysfunction in this circuitry in the neuropathology of OCD.