tbuckley/cabot-search huggingface dataset:
Progressive type of focal nodular hyperplasia characterized by multiple tumors and recurrence
Authors: Daniel C. Sadowski, Samuel S. Lee, Ian R. Wanless, James K. Kelly, E. Jenny Heathcote
Journal: Hepatology (1995)

Focal nodular hyperplasia (FNH) is usually a stable lesion that does not enlarge when studied for long periods of time; recurrence after resection has not been reported. We present a patient with a solitary FNH lesion that enlarged, was resected, and then recurred. A second resection was performed because of abdominal pain and disclosed multiple lesions, two of which were acutely infarcted. Thirty-two months later there was ultrasound evidence of further recurrence. Histology of the lesions showed the usual appearance of FNH with ducts and ductules in the central stalk regions but also some areas with minimal ductular differentiation and scanty connective tissue. Because of the clinical and histological appearance, the lesions in this patient were distinct from the usual type of FNH and merit the name “focal nodular hyperplasia, progressive type.” (HEPATOLOGY 1995; 21:970–975.)
Fecal Occult Blood Screening in the Minnesota Study: Sensitivity of the Screening Test
Authors: T. R. Church, J. S. Mandel, F. Ederer
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: In the Minnesota Colon Cancer Control Study, which used guaiac slides to annually screen stool samples for blood, mortality from colorectal cancer was reduced by 33.4%. The reported sensitivity of this test for colorectal cancer was about 90%. However, results from another study estimated the sensitivity to be 25%–33%; other investigators have reported intermediate values. Given these contradictions, we examined screening sensitivity for colorectal cancer in the Minnesota study by several direct and indirect methods. Methods: In this reanalysis of data from the Minnesota study, we distinguished between sensitivity for colorectal cancer of the screening test (composed of six slides) and of the screening program (a series of such tests). We estimated screen sensitivity by adjusting the crude estimate from the final tests in each screening phase for colorectal cancer incidence in 5 years of followup, by modeling guaiac slide results at each screen as a function of the presence of occult blood, and by incorporating sensitive detection into a modification of a mathematical model developed by Lang and Ransohoff. Program sensitivity was estimated from the fraction of screen-detected cancers among all cancers diagnosed in screened individuals. Results: The crude estimate of program sensitivity was 89.4%, whereas the modified Lang-Ransohoff model estimates screen sensitivities at 94.1%–96.2%, consistent with the estimates from the other methods. Indirect measures, such as the association between the number of positive slides among the six slides in each set and the positive predictivity for colorectal cancer, are consistent with these estimates. Conclusions: The Minnesota study reduced mortality from colorectal cancer through use of a screening test with average screen and program sensitivities of about 90%.
Binding interaction studies of selected receptor subpopulations after partial cross-linking receptor-ligand complexes with a photoactivated heterobifunctional reagent.
Authors: G B Faguet, D Beebe
Journal: Journal of Clinical Investigation (1986)

Certain hormonal and nonhormonal binding systems such as the leukoagglutinin-lymphocyte model exhibit complex receptor-ligand interactions that result in nonlinear Scatchard plots. Such plots are interpreted as indicating either homogeneous negatively interacting binding sites or heterogeneous sites with different and fixed affinity. We assessed the validity of these interpretations in our system by conjugating the ligand to a photoactivated heterobifunctional agent and cross-linking the conjugate to a subset of receptors before studying the binding interactions of non-cross-linked sites. Conjugation did not qualitatively or quantitatively affect the binding properties of the ligand. Cross-linking was specific, efficient, and stable and had no effect on irrelevant surface receptors. Cross-linking of only 3% of the total receptors resulted in 50% decreased ligand binding to high affinity sites consistent with a calculated inactivation of 85% and 2% of high and low affinity sites, respectively. Such preferential inactivation of high affinity sites in an unequivocal demonstration of binding sites heterogeneity in this system and shows a clear rejection of the homogeneous cooperation model.
MSK1 kinase in obliterative bronchiolitis after heterotopic tracheal transplantation
Authors: Simona Nemska, François Daubeuf, Laurent Reber, Nelly Frossard
Journal: European Respiratory Journal (2011)

Introduction: Obliterative bronchiolitis (OB) occurs during chronic allograft rejection of lung transplantation. OB is characterized by airway epithelium degradation, and obstruction of the small airways with inflammatory infiltrate and fibrosis. MSK1 is a nuclear kinase that activates NFκB in inflammation. Our hypothesis proposes MSK1 as an actor in OB via NFκB-induced activation of pro-inflammatory genes like IL-6.

Methods: In the mouse model of heterotopic tracheal transplantation, tracheal MSK1 and IL-6 mRNA was quantified by qPCR. Mice were treated I.P. with compound H89, a MSK1 inhibitor (10mg/kg/day) vs solvent (DMSO 5%). Tracheal sections were stained with hematoxylin-eosin, and epithelium degradation measured. CD3+ cells (SP7 anti-CD3 mAb, Abcam) were counted and dendritic cells (DC, H2-I-A/I-E mAb, M5/114) labeled on fresh tracheas.

Results: MSK1 and IL-6 mRNA levels were increased in allografts by 68±8% and 88±2%, respectively, at D7 as compared to D0 and unmodified in isografts. Progressive epithelium degradation reached 77±4% of the total epithelium at D7 and was inhibited upon H89 treatment of 43±10% (p<0.05). In isografts, epithelium degradation also occurred (18±10%). CD3+ cell recruitment reached 208±82 cells/mm2 at D7 and was inhibited to 16±8 cells/mm2 (p<0.05), compared to isografts (17±9 cells/mm2, NS). DC recruitment also occurred in allografts (525±73 cells/mm2 at D3 and 1065±368 at D7) as compared to D0 (290±17). No effect of H89 was observed on DC recruitment at D3. Inflammatory luminal infiltrate was inhibited at D7 by 44±15%.

Conclusion: Inhibiting MSK1 is therefore a potential strategy to help combat obstruction after lung transplantation in this OB model.
Measuring Quality of Care and Performance from a Population Health Care Perspective
Authors: Stephen F. Derose, Diana B. Petitti
Journal: Annual Review of Public Health (2003)

▪ Abstract Population health care is health information and clinical services provided to individuals of a defined population. From a population health care perspective, quality of care involves the health status of the entire population, and thus issues of access, cost of care, and efficiency matter. In this paper, we describe the definitions of quality health care and the framework for measuring quality, with emphasis on the performance of organizations involved in the delivery and assurance of population health care. We describe quality measurement sets and systems, criteria for the choice of measures, data sources, and how quality measurements are used to improve health care and outcomes from a population health care perspective.
α-MSH Counteracts the Suppressive Effect of Ultraviolet B on Nrf1/2 and Nrf-Dependent Gene Expression in Human Skin
Authors: Agatha Kokot, Dieter Metze, Nicolas Mouchet, Marie-Dominique Galibert, Meinhard Schiller, Thomas A. Luger, Markus Böhm
Journal: Endocrine Reviews (2009)

Human skin is constantly exposed to UV light, the most ubiquitous environmental stressor. Here, we investigated the expression and regulation of Nrf1-3, transcription factors crucially involved in protection against oxidative stress, in human skin cells in vitro, ex vivo and in situ. In particular, we examined whether α-MSH, a UV-induced peptide, is capable of modulating Nrf1/2 and Nrf-dependent gene expression. Both Nrf1 and 2 were found to be expressed in various cutaneous cell types in vitro. Surprisingly, UVB irradiation at physiological doses (10 mJ/cm2) reduced Nrf1/2 and Nrf-dependent gene expression in normal keratinocytes and melanocytes in vitro as well as ex vivo in skin organ cultures. α-MSH alone significantly increased Nrf1/2 as well as Nrf-dependent HO-1, γ-glutamylcysteine-synthetase and glutathione-S-transferase Pi gene expression in both keratinocytes and melanocytes. This effect of α-MSH occurred at physiological doses, was due to transcriptional induction and mimicked by the artificial cAMP inducer forskolin. In silico promoter analysis of Nrf1/2 further identified several putative binding sites for activator protein 1 and cAMP response element binding protein, transcription factors typically activated by α-MSH. Importantly, α-MSH prevented or even over-compensated the UVB-induced suppression of Nrf1/2 and Nrf-dependent genes not only in normal keratinocytes and melanocytes in vitro but also in skin organ cultures. These findings, for the first time, show regulation of Nrf1/2 and Nrf-dependent genes by α-MSH. Our data also highlight a novel facet in the cytoprotective and anti-oxidative effector mechanisms of α-MSH and perhaps of related melanocortin peptides.
A humanized model of experimental autoimmune uveitis in HLA class II transgenic mice
Authors: Giuseppina Pennesi, Mary J. Mattapallil, Shu-Hui Sun, Dody Avichezer, Phyllis B. Silver, Zaruhi Karabekian, Chella S. David, Paul A. Hargrave, J. Hugh McDowell, W. Clay Smith, Barbara Wiggert, Larry A. Donoso, Chi-Chao Chan, Rachel R. Caspi
Journal: Journal of Clinical Investigation (2003)

Experimental autoimmune uveitis (EAU) is a disease of the neural retina induced by immunization with retinal antigens, such as interphotoreceptor retinoid-binding protein (IRBP) and arrestin (retinal soluble antigen, S-Ag). EAU serves as a model for human autoimmune uveitic diseases associated with major histocompatibility complex (HLA) genes, in which patients exhibit immunological responses to retinal antigens. Here we report the development of a humanized EAU model in HLA transgenic (TG) mice. HLA-DR3, -DR4, -DQ6, and -DQ8 TG mice were susceptible to IRBP-induced EAU. Importantly, HLA-DR3 TG mice developed severe EAU with S-Ag, to which wild-type mice are highly resistant. Lymphocyte proliferation was blocked by anti-HLA antibodies, confirming that antigen is functionally presented by the human MHC molecules. Disease could be transferred by immune cells with a Th1-like cytokine profile. Antigen-specific T cell repertoire, as manifested by responses to overlapping peptides derived from S-Ag or IRBP, differed from that of wild-type mice. Interestingly, DR3 TG mice, but not wild-type mice, recognized an immunodominant S-Ag epitope between residues 291 and 310 that overlaps with a region of S-Ag recognized by uveitis patients. Thus, EAU in HLA TG mice offers a new model of uveitis that should represent human disease more faithfully than currently existing models.
Topotecan and Doxorubicin Combination to Treat Recurrent Ovarian Cancer: The Influence of Drug Exposure Time and Delivery Systems to Achieve Optimum Therapeutic Activity
Authors: Nilesh A. Patankar, Julia Pritchard, Mariska van Grinsven, Maryam Osooly, Marcel B. Bally
Journal: Clinical Cancer Research (2013)

To provide proof-of-concept data to support use of Doxil-liposomal topotecan (Topophore C) combinations to treat ovarian cancer.ES-2, OVCAR-3, and SKOV-3 ovarian cancer cell lines were treated with doxorubicin-topotecan combinations by exposing the cells to drugs from 1 to 72 hours. Pharmacokinetic analysis was conducted following administration of liposomal formulations of these drugs alone and in combination. Efficacy assessments were completed in ES-2 and SKOV-3 ovarian cancer models.On the basis of drug doses capable of achieving 50% reduction in cell viability over 72 hours, doxorubicin-topotecan combinations were additive in SKOV-3 but highly synergistic in ES-2 and OVCAR-3 cells. Favorable drug-drug interactions increased with increased drug exposure time. Topophore C pharmacokinetic remained unaffected when co-administered with Doxil. In the ES-2 model, Doxil at maximum tolerated dose (MTD 7.5 mg/kg) in combination with free topotecan (MTD 15 mg/kg) did not enhance median survival time (MST) over that achieved with topotecan alone. In contrast, MST was increased to 52 days with combination of Topophore C (MTD 2.5 mg/kg) and Doxil (7.5 mg/kg) compared with untreated animals (MST 18 days) or those treated with Topophore C alone (MTD 5 mg/kg, MST 40 days). In the SKOV-3 model, combination treatments showed better therapeutic efficacy than the individual drugs.Topotecan-doxorubicin combinations produced additive or synergistic effects which were best achieved when the tumor cells were exposed to drugs over extended time. Doxil-Topophore C combinations are therapeutically superior as judged in two ovarian cancer models. Clin Cancer Res; 19(4); 865-77. ©2012 AACR.
Mineralocorticoids Stimulate the Activity and Expression of Renal H+,K+-ATPases
Authors: Megan M. Greenlee, I. Jeanette Lynch, Michelle L. Gumz, Brian D. Cain, Charles S. Wingo
Journal: Journal of the American Society of Nephrology (2010)

In the renal collecting duct, mineralocorticoids drive Na(+) reabsorption, K(+) secretion, and H(+) secretion through coordinated actions on apical and basolateral transporters. Whether mineralocorticoids act through H(+),K(+)-ATPases to maintain K(+) and acid-base homeostasis is unknown. Here, treatment of mice with the mineralocorticoid desoxycorticosterone pivalate (DOCP) resulted in weight gain, a decrease in blood [K(+)] and [Cl(-)], and an increase in blood [Na(+)] and [HCO(3)(-)]. DOCP treatment increased the rate of H(+),K(+)-ATPase-mediated H(+) secretion in intercalated cells of the inner cortical collecting duct. mRNA expression of the catalytic subunit HKα(1) did not significantly change, whereas HKα(2) mRNA expression dramatically increased in the outer and inner medulla of DOCP-treated mice. A high-K(+) diet abrogated this increase in renal HKα(2) expression, showing that DOCP-mediated stimulation of HKα(2) expression depends on dietary K(+) intake. DOCP treatment of mice lacking HKα(1) (HKα(1)(-/-)) resulted in greater urinary Na(+) retention than observed in either wild-type mice or mice lacking both HKα(1) and HKα(2) (HKα(1,2)(-/-)). DOCP-treated HKα(1,2)(-/-) mice exhibited a lower blood [HCO(3)(-)] and less Na(+) and K(+) retention than either wild-type or HKα(1)(-/-) mice. Taken together, these results indicate that H(+),K(+)-ATPases-especially the HKα(2)-containing H(+),K(+)-ATPases-play an important role in the effects of mineralocorticoids on K(+), acid-base, and Na(+) balance.
Circulating Levels of the Innate and Humoral Immune Regulators CD14 and CD23 Are Associated with Adult Glioma
Authors: Mi Zhou, Joseph L. Wiemels, Paige M. Bracci, Margaret R. Wrensch, Lucie S. Mccoy, Terri Rice, Jennette D. Sison, Joseph S. Patoka, John K. Wiencke
Journal: Cancer Research (2010)

Allergy history has been consistently inversely associated with glioma risk. Two serologic markers, soluble CD23 (sCD23) and soluble CD14 (sCD14), are part of the innate and adaptive humoral immune systems and modulate allergic responses in opposite directions, with sCD23 enhancing and sCD14 blunting inflammatory responses. We measured sCD23 and sCD14 in serum from blood that was drawn at a single time point from 1,079 glioma patients postdiagnosis and 736 healthy controls. Glioma was strongly associated with high sCD14 [highest versus lowest quartile odds ratio (OR), 3.94; 95% confidence interval (95% CI), 2.98-5.21] and low sCD23 (lowest versus highest quartile OR, 2.5; 95% CI, 1.89-3.23). Results were consistent across glioma histologic types and grades, but were strongest for glioblastoma. Whereas temozolomide treatment was not associated with either sCD14 or sCD23 levels among cases, those taking dexamethasone had somewhat lower sCD23 levels than those not taking dexamethasone. However, sCD23 was associated with case status regardless of dexamethasone treatment. These results augment the long-observed association between allergies and glioma and support a role for the innate and adaptive humoral functions of the immune system, in particular immunoregulatory proteins, in gliomagenesis.
Inhibition of cartilage and bone destruction in adjuvant arthritis in the rat by a matrix metalloproteinase inhibitor.
Authors: J G Conway, J A Wakefield, R H Brown, B E Marron, L Sekut, S A Stimpson, A McElroy, J A Menius, J J Jeffreys, R L Clark
Journal: The Journal of Experimental Medicine (1995)

Considerable evidence has associated the expression of matrix metalloproteinases (MMPs) with the degradation of cartilage and bone in chronic conditions such as arthritis. Direct evaluation of MMPs' role in vivo has awaited the development of MMP inhibitors with appropriate pharmacological properties. We have identified butanediamide, N4-hydroxy-2-(2-methylpropyl)-N1-[2-[[2-(morpholinyl)ethyl]-,[S- (R*,S*)] (GI168) as a potent MMP inhibitor with sufficient solubility and stability to permit evaluation in an experimental model of chronic destructive arthritis (adjuvant-induced arthritis) in rats. In this model, pronounced acute and chronic synovial inflammation, distal tibia and metatarsal marrow hyperplasia associated with osteoclasia, severe bone and cartilage destruction, and ectopic new bone growth are well developed by 3 wk after adjuvant injection. Rats were injected with Freund's adjuvant on day 0. GI168 was was administered systemically from days 8 to 21 by osmotic minipumps implanted subcutaneously. GI168 at 6, 12, and 25 mg/kg per d reduced ankle swelling in a dose-related fashion. Radiological and histological ankle joint evaluation on day 22 revealed a profound dose related inhibition of bone and cartilage destruction in treated rats relative to rats receiving vehicle alone. A significant reduction in edema, pannus formation, periosteal new bone growth and the numbers of adherent marrow osteoclasts was also noted. However, no significant decrease in polymorphonuclear and mononuclear leukocyte infiltration of synovium and marrow hematopoietic cellularity was seen. This unique profile of antiarthritic activity indicates that GI168 is osteo- and chondro-protective, and it supports a direct role for MMP in cartilage and bone damage and pannus formation in adjuvant-induced arthritis.
Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth
Authors: Nikolai N. Khodarev, Bernard Roizman, Ralph R. Weichselbaum
Journal: Clinical Cancer Research (2012)

STAT1 is activated by IFNs and other cell signals. Following activation, STAT1 is translocated to the nuclei and activates transcription of IFN-stimulated genes. Although the activation of STAT1 by IFNs is classically associated with antiviral defense and tumor-suppressive functions, emerging data indicate that expression of the STAT1 pathway confers cellular resistance to DNA-damaging agents and mediates aggressive tumor growth. Recent advances in the development of Janus-activated kinase/Stat inhibitors and peptide inhibitors specific for individual Stat proteins may provide new insights into the controversial functions of this pathway.
Villous, hypermucinous mucosa in long standing ulcerative colitis shows high frequency of K-ras mutations
Authors: S N Andersen, T Lovig, O P F Clausen, A Bakka, O Fausa, T O Rognum
Journal: Gut (1999)

<h3>BACKGROUND</h3> K-<i>ras</i>mutation is one of the first genetic alterations in classical colorectal carcinogenesis. <h3>AIMS</h3> To investigate the role of K-<i>ras</i> mutations in carcinogenesis, in long standing ulcerative colitis. <h3>METHODS</h3> A total of 161 microdissected and 100 DNA samples from 13 patients were analysed for K-<i>ras</i> codons 12 and 13 mutations by means of a combination of enriched polymerase chain reaction amplification and temporal temperature gradient electrophoresis. <h3>RESULTS</h3> K-<i>ras</i>mutations were found in 21/161 (13%) microdissected samples in 7/13 large bowels (16 and five in codons 12 and 13, respectively), and in 10/100 (10%) mucosal DNA samples (six and four, respectively). One of four patients with six adenocarcinomas had a K-<i>ras</i> mutation in a carcinoma, as well as one of two patients with large dysplasia associated lesion or mass (DALM). Eight of 13 (61%) areas with villous architecture and large, distended goblet cells, had a K-<i>ras</i>mutation, which was significantly more frequent than in low grade dysplasia (one of 23, 4%) but did not reach significance versus high grade dysplasia (four of 14, 28.5%). K-<i>ras</i>mutations were found in one of 20 (5%) flat lesions indefinite for dysplasia, two of 14 (14%) in non-villous, hypermucinous mucosa, and in one of 57 flat areas negative for dysplasia. <h3>CONCLUSION</h3> The highest K-<i>ras</i> mutation frequency was found in villous, hypermucinous mucosa. We suggest that this entity should be investigated further as a potential risk lesion for cancer development. It may represent a pathway directly from non-classical dysplasia to cancer, not previously described.
Electrophysiological Evidence of Serotonergic Impairment in Long-Term MDMA (“Ecstasy”) Users
Authors: R J Croft, A Klugman, T Baldeweg, J H Gruzelier
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: “Ecstasy,” or 3,4-methylenedioxymethamphetamine (MDMA), causes long-term impairment to the serotonin (5-HT) system in rats, dogs, and nonhuman primates. 5-HT dysfunction has also been observed in human recreational users of the drug, but whether 5-HT dysfunction in humans is caused by MDMA has not been established, since dysfunction may have preceded MDMA exposure. This ambiguity about causation is particularly important in MDMA research, because 5-HT deficiency is a predictor of risky behavior. METHOD: The 5-HT function of 22 long-term MDMA users was compared to that of 20 drug-naive comparison subjects and 19 cannabis users. 5-HT function was assessed with the intensity dependence paradigm, a tool that measures 5-HT-related attenuation of neural response to auditory stimuli (measured with EEG). RESULTS: Long-term MDMA users exhibited 5-HT dysfunction, relative to both cannabis users and drug-naive comparison subjects. This dysfunction was related to total MDMA consumption (after removing the effect of frequency of use) but not to frequency of use (after removing the effect of total consumption). CONCLUSIONS: These data show that 5-HT dysfunction occurs in MDMA users, is related to users’ MDMA consumption, and is independent of cannabis use. The results do not suggest that self-medication explains this relationship, because the deficit was related to total MDMA consumption but not frequency of consumption. The results are thus consistent with the thesis that MDMA consumption causes 5-HT impairment in humans.