tbuckley/cabot-search huggingface dataset:
Gene expression profiling of cholangiocarcinoma-derived fibroblast reveals alterations related to tumor progression and indicates periostin as a poor prognostic marker
Authors: Kusumawadee Utispan, Peti Thuwajit, Yoshimitsu Abiko, Komgrid Charngkaew, Anucha Paupairoj, Siri Chau-in, Chanitra Thuwajit
Journal: Molecular Cancer (2010)

Abstract Background Fibroblasts play important roles in several cancers. It was hypothesized that cholangiocarcinoma (CCA)-associated fibroblasts (Cfs) differ from non-tumorigenic liver fibroblasts (Lfs) in their gene expression profiles resulting in the capability to promote cancer. Periostin (PN) is a multi-functional protein and has emerged as a promising marker for tumor progression. The role of PN in CCA, however, has not yet been explored. Results In this study, the gene expression profile of Cfs in comparison to Lfs was performed using oligonucleotide microarrays. The common- and unique-expressed genes in Cfs and the promising roles in cancer promotion and progression were determined. PN was markedly over-expressed in Cfs confirmed by real time RT-PCR and western blot analysis. Immunohistochemistry examination of a number of patients with intrahepatic CCA showed the expression of PN solely in stromal fibroblasts, but was expressed neither in cancer cells nor immune cells. Low to no expression of PN was observed in tissues of benign liver disease and hepatocellular carcinoma. CCA patients with high levels of PN had significantly shorter survival time than those with low levels ( P = 0.026). Multivariate analysis revealed high levels of PN ( P = 0.045) and presence of lymph node metastasis ( P = 0.002) as independent poor prognostic factors. The in vitro study revealed that recombinant PN induced CCA cell proliferation and invasion. Interestingly, interference RNA against integrin α 5 significantly reduced the cellular response to PN-stimulated proliferation and invasion. Conclusion The gene expression profile of fibroblasts in CCA is apparently explored for the first time and has determined the genes involving in induction of this cancer progression. High PN can be used to distinguish CCA from other related liver diseases and is proposed as a prognostic factor of poor survival. Regulation of fibroblast-derived PN in CCA proliferation and invasion may be considered as an alternative therapeutic approach.
Ph<sup>1</sup>‐chromosome positive acute lymphoblastic leukemia: Is t(9;22) the initial abnormality?
Authors: Igor Aurer, Robert S. Sparkes, Gary Schiller, Robert Peter Gale
Journal: American Journal of Hematology (1993)

Abstract We report a case of pre‐B‐cell acute lymphoblastic leukemia (ALL) with the Ph 1 ‐chromosome, t(9;22) translocation and P190 associated BCR/ABL rearrangement. One cell with the Ph 1 ‐chromosome and t(9;22) also had del(5q). Interestingly, another diploid cell with iso(17q) lacked the Ph 1 ‐chromosome and t(9;22). This finding, similar to one reported in chronic myelogenous leukemia, is consistent with the possibility that abnormality manifest as chromosome instability antedates the Ph 1 ‐chromosome and t(9;22) in some cases of Ph 1 ‐chromosome positive acute leukemia.
Cytoplasmic Irradiation Results in Mitochondrial Dysfunction and DRP1-Dependent Mitochondrial Fission
Authors: Bo Zhang, Mercy M. Davidson, Hongning Zhou, Chunxin Wang, Winsome F. Walker, Tom K. Hei
Journal: Cancer Research (2013)

Abstract Direct DNA damage is often considered the primary cause of cancer in patients exposed to ionizing radiation or environmental carcinogens. Although mitochondria are known to play an important role in radiation-induced cellular response, the mechanisms by which cytoplasmic stimuli modulate mitochondrial dynamics and functions are largely unknown. In the present study, we examined changes in mitochondrial dynamics and functions triggered by α particle damage to the mitochondria in human small airway epithelial cells, using a precision microbeam irradiator with a beam width of 1 μm. Targeted cytoplasmic irradiation using this device resulted in mitochondrial fragmentation and a reduction of cytochrome c oxidase and succinate dehydrogenase activity, when compared with nonirradiated controls, suggesting a reduction in respiratory chain function. In addition, mitochondrial fragmentation or fission was associated with increased expression of the dynamin-like protein DRP1, which promotes mitochondrial fission. DRP1 inhibition by the drug mdivi-1 prevented radiation-induced mitochondrial fission, but respiratory chain function in mitochondria inhibited by radiation persisted for 12 hours. Irradiated cells also showed an increase in mitochondria-derived superoxide that could be quenched by dimethyl sulfoxide. Taken together, our results provide a mechanistic explanation for the extranuclear, nontargeted effects of ionizing radiation. Cancer Res; 73(22); 6700–10. ©2013 AACR.
Spontaneous bacterial peritonitis: recent guidelines and beyond
Authors: R Wiest, A Krag, A Gerbes
Journal: Gut (2011)

<h3>Background</h3> Patients with primary intracerebral haemorrhage (ICH) are at increased long-term risks of recurrent stroke and other comorbidities. However, available estimates come predominantly from hospital-based studies with relatively short follow-up. Moreover, there are also uncertainties about the influence of ICH location on risks of recurrent stroke, disability, dementia and quality of life. <h3>Methods</h3> In a population-based study (Oxford Vascular Study/2002–2018) of patients with a first ICH with follow-up to 10 years, we determined the long-term risks of recurrent stroke, disability, quality of life, dementia and hospital care costs stratified by haematoma location. <h3>Results</h3> Of 255 cases with primary ICH (mean/SD age 75.5/13.1), 109 (42.7%) had lobar ICH, 144 (56.5%) non-lobar ICH and 2 (0.8%) had uncertain location. Annual rates of recurrent ICH were higher after lobar versus non-lobar ICH (lobar=4.0%, 2.7–7.2 vs 1.1%, 0.3–2.8; p=0.02). Moreover, cumulative rate of dementia was also higher for lobar versus non-lobar ICH (n/% lobar=20/36.4% vs 16/20.8%, p=0.047), and there was a higher proportion of disability at 5 years in survivors (15/60.0% vs 9/31.0%, p=0.03). The 10-year quality-adjusted life years (QALYs) were also lower after lobar versus non-lobar ICH (2.9 vs 3.8 for non-lobar, p=0.04). Overall, the mean 10-year censor-adjusted costs were £19 292, with over 80% of costs due to inpatient hospital admission costs, which did not vary by haematoma location (p=0.90). <h3>Conclusion</h3> Compared with non-lobar ICH, the substantially higher 10-year risks of recurrent stroke, dementia and lower QALYs after lobar ICH highlight the need for more effective prevention for this patient group.
Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity
Authors: Pascal Descargues, Céline Deraison, Chrystelle Bonnart, Maaike Kreft, Mari Kishibe, Akemi Ishida-Yamamoto, Peter Elias, Yann Barrandon, Giovanna Zambruno, Arnoud Sonnenberg, Alain Hovnanian
Journal: Nature Genetics (2004)
Phase III Study of Gemcitabine in Combination With Fluorouracil Versus Gemcitabine Alone in Patients With Advanced Pancreatic Carcinoma: Eastern Cooperative Oncology Group Trial E2297
Authors: Jordan D. Berlin, Paul Catalano, James P. Thomas, John W. Kugler, Daniel G. Haller, Al Bowen Benson
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Gemcitabine is generally considered to constitute first-line therapy for pancreatic cancer. To determine whether the addition of fluorouracil (5-FU) improves on the results from single-agent gemcitabine, the Eastern Cooperative Oncology Group (ECOG) compared gemcitabine plus bolus 5-FU with gemcitabine alone for patients with advanced pancreatic carcinoma. PATIENTS AND METHODS: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients were randomized to receive either gemcitabine alone (1,000 mg/m 2 /wk) weekly for 3 weeks of every 4 or to receive gemcitabine (1,000 mg/m 2 /wk) followed by 5-FU (600 mg/m 2 /wk) weekly on the same schedule. The primary end point of the trial was survival, with secondary end points of time to progression and response rate. RESULTS: Of 327 patients enrolled over 18 months, 322 were eligible. Overall, the median survival was 5.4 months for gemcitabine alone and 6.7 months for gemcitabine plus 5-FU (P = .09). Progression-free survival for gemcitabine alone was 2.2 months, compared with 3.4 months for gemcitabine plus 5-FU (P = .022). Objective responses were uncommon and were observed in only 5.6% of patients treated with gemcitabine and 6.9% of patients treated with gemcitabine plus 5-FU. Most toxicities were hematologic or gastrointestinal; no significant differences were noted between the two treatment arms. CONCLUSION: 5-FU, administered in conjunction with gemcitabine, did not improve the median survival of patients with advanced pancreatic carcinoma compared with single-agent gemcitabine. Further studies with other combinations of gemcitabine and 5-FU are not compelling, and clinical trial resources should address other combinations and novel agents.
Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis
Authors: Maddalena Frau, Francesco Feo, Rosa M. Pascale
Journal: Journal of Hepatology (2013)

Downregulation of liver-specific MAT1A gene, encoding S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, and upregulation of widely expressed MAT2A, encoding MATII isozyme, known as MAT1A:MAT2A switch, occurs in hepatocellular carcinoma (HCC). Being inhibited by its reaction product, MATII isoform upregulation cannot compensate for MATI/III decrease. Therefore, MAT1A:MAT2A switch contributes to decrease in SAM level in rodent and human hepatocarcinogenesis. SAM administration to carcinogen-treated rats prevents hepatocarcinogenesis, whereas MAT1A-KO mice, characterized by chronic SAM deficiency, exhibit macrovesicular steatosis, mononuclear cell infiltration in periportal areas, and HCC development. This review focuses upon the pleiotropic changes, induced by MAT1A/MAT2A switch, associated with HCC development. Epigenetic control of MATs expression occurs at transcriptional and post-transcriptional levels. In HCC cells, MAT1A/MAT2A switch is associated with global DNA hypomethylation, decrease in DNA repair, genomic instability, and signaling deregulation including c-MYC overexpression, rise in polyamine synthesis, upregulation of RAS/ERK, IKK/NF-kB, PI3K/AKT, and LKB1/AMPK axis. Furthermore, decrease in MAT1A expression and SAM levels results in increased HCC cell proliferation, cell survival, and microvascularization. All of these changes are reversed by SAM treatment in vivo or forced MAT1A overexpression or MAT2A inhibition in cultured HCC cells. In human HCC, MAT1A:MAT2A and MATI/III:MATII ratios correlate negatively with cell proliferation and genomic instability, and positively with apoptosis and global DNA methylation. This suggests that SAM decrease and MATs deregulation represent potential therapeutic targets for HCC. Finally, MATI/III:MATII ratio strongly predicts patients' survival length suggesting that MAT1A:MAT2A expression ratio is a putative prognostic marker for human HCC.
ACTIVATION OF QUIESCENT MUCORMYCOTIC GRANULOMATA IN RABBITS BY INDUCTION OF ACUTE ALLOXAN DIABETES
Authors: Walter H. Sheldon, Heinz Bauer
Journal: The Journal of Experimental Medicine (1958)

In normal rabbits subcutaneous granulomata produced by the injection of a spore suspension of Rhizopus oryzae remained confined to the site of inoculation, showed no fungus proliferation, no longer yielded the agent on culture 10 weeks after inoculation, and eventually healed. Similar well established granulomata in rabbits with acute alloxan diabetes induced 8, 10, and 15 days after injection of the fungus uniformly showed activation of the infection. This occurred only in animals showing acetonuria. In these animals the skin lesions showed proliferation of the fungus frequently associated with invasion and early necrosis of the granuloma wall. In some instances, spread of the infection to adjacent tissues with invasion of blood vessels had occurred. These experiments illustrate that changes in host metabolism can activate a preexisting quiescent infection.
Mixed Response to New PSA Screening Study
Authors: Pat Phillips
Journal: JAMA (1998)

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Effect of Graded Testicular Doses of Radiotherapy in Patients Treated for Carcinoma-In-Situ in the Testis
Authors: Peter Meidahl Petersen, Aleksander Giwercman, Gedske Daugaard, Mikael Rørth, Jørgen Holm Petersen, Niels E. Skakkebæk, Steen W. Hansen, Hans von der Maase
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine the effect of radiotherapy in doses 14 to 20 Gy on eradication of carcinoma-in-situ (CIS) testis and on the Leydig cell function. PATIENTS AND METHODS: Forty-eight patients presented with unilateral testicular germ cell cancer and CIS of the contralateral testis. The CIS-bearing testis was treated with daily irradiation doses of 2 Gy, 5 days a week, to a cumulative dose of 20 Gy (21 patients), 18 Gy (three patients), 16 Gy (10 patients), and 14 Gy (14 patients). RESULTS: All patients treated at dose levels 20 Gy to 16 Gy achieved histologically verified complete remission without signs of recurrence of CIS after an observation period of more than 5 years. One of 14 patients treated at dose level 14 Gy had a relapse of CIS 20 months after irradiation. Leydig cell function was examined before and regularly after radiotherapy in 44 of 48 patients. The levels of testosterone were lower after radiotherapy than before. Testosterone showed a stable decrease for more than 5 years after treatment (3.6% per year) without dose dependency. The levels of luteinizing hormone and follicle-stimulating hormone were increased after radiotherapy. The need of androgen substitution therapy was similar at all dose levels. CONCLUSION: Testicular irradiation is a safe treatment at dose level 20 Gy (10 × 2 Gy). Decrease of dose to 14 Gy (7 × 2 Gy) might lead to risk of relapse of CIS. Impairment of hormone production without clinically significant dose dependency is seen in the dose range 14 to 20 Gy.
Modulation of the bronchial inflammation in sensitized guinea-pigs by FK506, nedocromil sodium and dexamethasone
Authors: e Lapa Silva, C Ruffie, BB Vargaftig, M Pretolani
Journal: European Respiratory Journal (1995)

Guinea-pigs sensitized by a subcutaneous injection of ovalbumin in Al(OH)3 and boosted 2 weeks later exhibit marked bronchial hyperresponsiveness to various agonists and intense bronchial wall infiltration by CD4+ T-lymphocytes and eosinophils. We have compared the effect of FK506, a novel immunosuppressive agent, on the mucosal infiltration by T-cells and eosinophils with the well established drugs, nedocromil sodium and dexamethasone. Sensitized Hartley guinea-pigs were treated subcutaneously for 5 days with FK506 (100 micrograms.kg-1 daily), nedocromil sodium (30 micrograms.kg-1 daily), or dexamethasone (200 micrograms.kg-1 daily). On the day of the experiment, i.e. one week after the booster injection of antigen, the animals were killed, the lungs dissected, frozen and cryostat sections stained by immunohistochemical methods using monoclonal antibodies specific for total T-lymphocytes, CD4+ and CD8+ T-cells. Cyanide-resistant eosinophil peroxidase activity was used to stain the eosinophils. Sections were coded and positive cells enumerated in the lamina propria and adventitia of the bronchi. Sensitized and antigen-stimulated vehicle-treated guinea-pigs showed marked infiltration of the bronchial wall by CD4+ T-lymphocytes and eosinophils compared with sensitized, non-antigen stimulated animals. As compared to vehicle, FK506 or dexamethasone abolished the T-cell/eosinophil invasion in the bronchial wall, whereas nedocromil sodium was ineffective in protecting the lungs from T-lymphocyte or eosinophil infiltration. We conclude that both FK506 and dexamethasone are effective in curtailing bronchial inflammation in allergic guinea-pigs, whereas nedocromil sodium did not resolve the inflammation associated with T-lymphocytes or eosinophils.
Imatinib Plasma Levels Are Correlated With Clinical Benefit in Patients With Unresectable/Metastatic Gastrointestinal Stromal Tumors
Authors: George D. Demetri, Yanfeng Wang, Elisabeth Wehrle, Amy Racine, Zariana Nikolova, Charles D. Blanke, Heikki Joensuu, Margaret von Mehren
Journal: Journal of Clinical Oncology (2009)

PURPOSE To study the pharmacokinetics (PK) of imatinib (IM) in patients with advanced GI stromal tumors (GISTs) treated in a randomized phase II study and to explore the potential relationship between IM plasma levels and long-term clinical outcomes. PATIENTS AND METHODS Patients were randomly assigned to receive IM at 400 mg versus 600 mg daily. IM plasma levels were analyzed in a subset of patients (n = 73) for whom PK data on day 1 and at steady-state (SS, day 29) were available. IM PK was evaluated using a population PK approach. The relationship between IM plasma exposure and clinical outcome was explored by grouping patients into quartiles according to IM trough concentration (C(min)). The clinical outcome parameters evaluated include overall objective benefit rate (OOBR; complete response plus partial response plus stable disease) time to progression (TTP), and KIT genotyping. Results IM PK exposure showed a high inter-patient variability, and clinical outcomes were correlated with IM trough levels at SS. The median TTP was 11.3 months for patients in the lowest C(min) quartile (Q1, < 1,110 ng/mL) compared with more than 30 months for Q2 to Q4 (P = .0029). OOBR was also inferior in Q1 patients. In patients with GIST with KIT exon 11 mutations (n = 39), the OOBR was 67% for Q1 patients versus 100% for all others (P = .001). CONCLUSION In patients with advanced GIST, IM trough levels at SS were associated with clinical benefit. Patients with IM C(min) below 1,100 ng/mL showed a shorter TTP and lower rate of clinical benefit (OOBR). Further studies are justified to test whether monitoring IM plasma levels might optimize clinical outcomes for patients with GIST.
Long-Term Effects of Irbesartan Treatment and Smoking on Nucleic Acid Oxidation in Patients With Type 2 Diabetes and Microalbuminuria
Authors: Kasper Broedbaek, Trine Henriksen, Allan Weimann, Morten Petersen, Jon T. Andersen, Shoaib Afzal, Espen Jimenez-Solem, Frederik Persson, Hans-Henrik Parving, Peter Rossing, Henrik E. Poulsen
Journal: Diabetes Care (2011)

OBJECTIVE We tested whether long-term treatment with the angiotensin II receptor antagonist irbesartan reduces nucleic acid oxidation in patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS The Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA 2) study was a 2-year multicenter randomized double-blind trial comparing irbesartan (150 and 300 mg once daily) with placebo. We studied a subgroup of 50 patients where urine samples were available for analysis of albumin and the oxidatively modified guanine nucleosides 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo). RESULTS During the 2-year trial, no significant differences in 8-oxodG and 8-oxoGuo excretions between placebo and irbesartan treatment were seen. 8-oxodG and albumin excretion decreased with time (P = 0.0004 and P &amp;lt; 0.0001, respectively), whereas treatment-related differences were shown for albumin excretion (P = 0.0008) only, as previously reported. Important secondary findings were significant associations between changes in 8-oxodG excretion and changes in albumin excretion and glycated hemoglobin (HbA1c). During the study period, 8-oxodG excretion decreased by 3 and 26% in smokers and nonsmokers, respectively (P = 0.015), and urinary albumin excretion decreased 22% in smokers and 58% in nonsmokers (P = 0.011). CONCLUSIONS Irbesartan treatment was not significantly more effective than placebo in reducing nucleic acid oxidation. The results indicate that DNA oxidation in diabetes patients is reduced by various components in the treatment of diabetes where glycemic control seems to be important and addition of angiotensin II receptor antagonists does not lead to any substantial additional reduction. Furthermore, the reductions in DNA oxidation and albumin excretion seem to be counteracted by smoking.
Effects of Androgen Treatment on the Male Rat Aorta
Authors: Harvey Wolinsky
Journal: Journal of Clinical Investigation (1972)

Androgen was given to male rats to determine if it exerted effects on the aortic wall distinct from those of estrogen deficit. Although a general anabolic effect was avoided, significant vascular effects were observed. The amounts of mural fibrous proteins, elastin and collagen, were significantly increased in treated animals; noncollagenous, alkali-soluble protein, thought to reflect the cellular component, was unchanged with treatment. These effects were not detectable on microscopic examination and measurement of the vessel wall despite attempts to duplicate closely in vivo wall dimensions before study. These findings of distinct and marked effects of androgen on vascular metabolism extend the growing evidence for an important role of sex hormones in vessel wall structure and function.