tbuckley/cabot-search huggingface dataset:
Distant Effects of Experimental Renal Ischemia/Reperfusion Injury
Authors: K. J. Kelly
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Acute renal failure results in significant morbidity and mortality, yet renal failure is not the usual cause of death in the clinical situation. We have previously reported systemic increases in the inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) after renal ischemia in the mouse. In the present study, an animal model of bilateral renal ischemia was used to test the hypothesis that cytokines released with renal ischemia have effects on other organ systems. Increased levels of immunoreactive TNF-α and IL-1 and intercellular adhesion molecule-1 mRNA were found in the heart after renal ischemia in the rat. This was accompanied by increases in myeloperoxidase activity, an index of tissue leukocyte infiltration, in the heart as well as the liver and lung. Functional changes in the heart 48 h after renal ischemia included increases in left ventricular end diastolic diameter, left ventricular end systolic diameter, and decreased fractional shortening by echocardiography. Evidence of apoptosis of cardiac cells was also found 48 h after an abbreviated period of renal ischemia insufficient to induce azotemia but not bilateral nephrectomy (which resulted in significant renal failure), suggesting that renal ischemia but not uremia is necessary for the apoptosis observed. It was also found that blocking the action of TNF-α limited cardiac apoptosis. Renal ischemia results in distant effects and the alterations observed in the heart may be important in the morbidity and mortality observed clinically. E-mail: [email protected]
Outcomes of a population-based series of early breast cancer patients with micrometastases and isolated tumour cells in axillary lymph nodes
Authors: M. van der Heiden-van der Loo, M. Schaapveld, V.K.Y. Ho, S. Siesling, E.J.T. Rutgers, P.H.M. Peeters
Journal: Annals of Oncology (2013)
Impaired Renal Secretion of Substrates for the Multidrug Resistance Protein 2 in Mutant Transport–Deficient (TR−) Rats
Authors: Rosalinde Masereeuw, Sylvia Notenboom, Pascal H. E. Smeets, Alfons C. Wouterse, Frans G. M. Russel
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Previous studies with mutant transport–deficient rats (TR − ), in which the multidrug resistance protein 2 (Mrp2) is lacking, have emphasized the importance of this transport protein in the biliary excretion of a wide variety of glutathione conjugates, glucuronides, and other organic anions. Mrp2 is also present in the luminal membrane of proximal tubule cells of the kidney, but little information is available on its role in the renal excretion of xenobiotics. The authors compared renal transport of the fluorescent Mrp2 substrates calcein, fluo-3, and lucifer yellow (LY) between perfused kidneys isolated from Wistar Hannover (WH) and TR − rats. Isolated rat kidneys were perfused with 100 nM of the nonfluorescent calcein-AM or 500 nM fluo3-AM, which enter the tubular cells by diffusion and are hydrolyzed intracellularly into the fluorescent anion. The urinary excretion rates of calcein and fluo-3 were 3 to 4 times lower in perfused kidneys from TR − rats compared with WH rats. In contrast, the renal excretion of LY (10 μM, free anion) was somewhat delayed but appeared unimpaired in TR − rats. Membrane vesicles from Sf9 cells expressing human MRP2 or human MRP4 indicated that MRP2 exhibits a preferential affinity for calcein and fluo-3, whereas LY is a better substrate for MRP4. We conclude that the renal clearance of the Mrp2 substrates calcein and fluo-3 is significantly reduced in TR − rat; for LY, the absence of the transporter may be compensated for by (an)other organic anion transporter(s). E-mail: R.Masereeuw@ncmls.kun.nl
Disruption of Guanylyl Cyclase-G Protects against Acute Renal Injury
Authors: Heng Lin, Ching-Feng Cheng, Hsin-Han Hou, Wei-Shiung Lian, Ying-Chi Chao, Yi-Yun Ciou, Bambang Djoko, Ming-Tzu Tsai, Chien-Jui Cheng, Ruey-Bing Yang
Journal: Journal of the American Society of Nephrology (2008)

The membrane forms of guanylyl cyclase (GC) serve as cell-surface receptors that synthesize the second messenger cGMP, which mediates diverse cellular processes. Rat kidney contains mRNA for the GC-G isoform, but the role of this receptor in health and disease has not been characterized. It was found that mouse kidney also contains GC-G mRNA, and immunohistochemistry identified GC-G protein in the epithelial cells of the proximal tubule and collecting ducts. Six hours after ischemia-reperfusion (I/R) injury, GC-G mRNA and protein expression increased three-fold and remained upregulated at 24 h. For determination of whether GC-G mediates I/R injury, a mutant mouse with a targeted disruption of the GC-G gene (Gucy2g) was created. At baseline, no histologic abnormalities were observed in GC-G(-/-) mice. After I/R injury, elevations in serum creatinine and urea were attenuated in GC-G(-/-) mice compared with wild-type controls, and this correlated with less tubular disruption, less tubular cell apoptosis, and less caspase-3 activation. Measures of inflammation (number of infiltrating neutrophils, myeloperoxidase activity, and induction of IL-6 and P-selectin) and activation of NF-kappaB were lower in GC-G(-/-) mice compared with wild-type mice. Direct transfer of a GC-G expression plasmid to the kidneys of GC-G(-/-) mice resulted in a dramatically higher mortality after renal I/R injury, further supporting a role for GC-G in mediating injury. In summary, GC-G may act as an early signaling molecule that promotes apoptotic and inflammatory responses in I/R-induced acute renal injury.
4 A cost-effectiveness rationale for the selection of antimicrobial therapy in acne: a randomized controlled trial
Authors: M. Ozolins, E.A. Eady, A. Avery, W.J. Cunliffe, A. Li Wan Po, C. O'Neill, N.B. Simpson, C.E. Walters, E. Carnegie, J.B. Lewis, J. Dada, M. Haynes, K. Williams, H.C. Williams
Journal: British Journal of Dermatology (2002)

Background This NHS/HTA‐funded study aimed to rank five commonly used antimicrobial therapies for acne in order of their clinical effectiveness and cost‐effectiveness. We also wanted to identify which agents are less likely to promote resistance and those which are effective in patients who harbour high numbers of resistant Propionibacterium acnes strains. Methods From surgeries and colleges in the Nottingham and Leeds areas, 649 patients with mild to moderate facial acne were recruited. The two primary outcome measures were patient self‐assessment of improvement in overall acne severity and reduction in inflamed lesion count, measured at 18 weeks. Secondary outcome measures included two acne severity scores, assessors' global estimation of improvement, quality of life and utility scores, enumeration of antibiotic resistant propionibacteria, and the incidence of adverse events. Results and Conclusions The most effective treatments (percentage with at least moderate improvement according to patients, mean change in lesion count) were the topical Benzamycin® b.d. (66%, − 27) and its components given separately (topical erythromycin o.d. + 5% benzoyl peroxide o.d.) (63%, − 26), followed by 5% benzoyl peroxide b.d. (60%, − 23). The least effective were oral oxytetracycline (55%, − 18) and minocycline (54%, − 22). The most cost‐effective treatment was benzoyl peroxide and least cost‐effective was minocycline. In terms of quality of life, benzoyl peroxide moved down the rankings and minocycline moved up. The two topical erythromycin‐containing regimens produced the largest reductions and the oral treatments the smallest in the prevalence and population density of cutaneous propionibacteria. Prior bacterial colonisation did not affect outcome in the topical groups. Efficacy of both oral preparations was influenced by tetracycline resistant P. acnes strains. Disclaimer The views and opinions expressed are those of the authors and do not necessarily reflect those of the Department of Health.
Randomized Phase II Trial of Adjuvant Hepatic Arterial Infusion and Systemic Chemotherapy With or Without Bevacizumab in Patients With Resected Hepatic Metastases From Colorectal Cancer
Authors: Nancy E. Kemeny, William R. Jarnagin, Marinela Capanu, Yuman Fong, Alexandra N. Gewirtz, Ronald P. DeMatteo, Michael I. D'Angelica
Journal: Journal of Clinical Oncology (2010)

Add systemic bevacizumab (Bev) to adjuvant hepatic arterial infusion (HAI) plus systemic therapy after liver resection to increase recurrence-free survival (RFS).
Inhibition of p38 MAPK-dependent bronchial contraction after ozone by corticosteroids
Authors: F. Li, M. Zhang, F. Hussain, K. Triantaphyllopoulos, A.R. Clark, P.K. Bhavsar, X. Zhou, K.F. Chung
Journal: European Respiratory Journal (2010)

We determined the role of p38 mitogen-activated protein kinase (MAPK) in the increased airway smooth muscle (ASM) contractile responses following ozone and modulation by corticosteroids. Mice were exposed to air or ozone (3 ppm for 3 h) and isometric contractile responses of bronchial rings to acetylcholine (ACh) were measured using a myograph in the presence of p38 MAPK inhibitor, SB239063 (10 −6 M) or dexamethasone (10 −6 M). Because MAPK phosphatase (MKP)-1 is a negative regulator of p38 MAPK, we also studied these effects in MKP-1 -/- mice. Bronchial rings from ozone-exposed wild-type and MKP-1 -/- mice showed increased contractile responses, with a leftward shift of the dose–response curve in MKP-1 -/- mice. SB239063 inhibited bronchial contraction equally in air- and ozone-exposed C57/BL6 and MKP-1 -/- mice. Dexamethasone inhibited ACh-induced bronchial contraction in both air- and ozone-exposed C57/BL6 mice, but not in air- or ozone-exposed MKP-1 -/- mice. ACh-stimulated p38 MAPK and heat shock protein (HSP)27 phosphorylation, as measured by Western blotting, and this effect was suppressed by SB239063 in C57/BL6 and MKP-1 -/- mice, but not by dexamethasone in either air- or ozone-exposed MKP-1 -/- mice. p38 MAPK plays a role in maximal ACh-induced isometric contractile responses and increased contractility induced by ozone. Dexamethasone inhibits ACh-induced ASM contraction through phosphorylation of p38 MAPK and HSP27.
Ex-vivo HRMAS of adult brain tumours: metabolite quantification and assignment of tumour biomarkers
Authors: Alan J Wright, Greg A Fellows, John R Griffiths, M Wilson, B Bell, Franklyn A Howe
Journal: Molecular Cancer (2010)

High-resolution magic angle spinning (HRMAS) NMR spectroscopy allows detailed metabolic analysis of whole biopsy samples for investigating tumour biology and tumour classification. Accurate biochemical assignment of small molecule metabolites that are "NMR visible" will improve our interpretation of HRMAS data and the translation of NMR tumour biomarkers to in-vivo studies. 1D and 2D 1H HRMAS NMR was used to determine that 29 small molecule metabolites, along with 8 macromolecule signals, account for the majority of the HRMAS spectrum of the main types of brain tumour (astrocytoma grade II, grade III gliomas, glioblastomas, metastases, meningiomas and also lymphomas). Differences in concentration of 20 of these metabolites were statistically significant between these brain tumour types. During the course of an extended 2D data acquisition the HRMAS technique itself affects sample analysis: glycine, glutathione and glycerophosphocholine all showed small concentration changes; analysis of the sample after HRMAS indicated structural damage that may affect subsequent histopathological analysis. A number of small molecule metabolites have been identified as potential biomarkers of tumour type that may enable development of more selective in-vivo 1H NMR acquisition methods for diagnosis and prognosis of brain tumours.
EXPERIMENTAL HYPERTHYROIDISM AND ITS EFFECT UPON THE MYOCARDIUM IN GUINEA PIGS AND RABBITS
Authors: Geoffrey Rake, Donald McEachern
Journal: The Journal of Experimental Medicine (1931)

A study has been made of the pathological changes in the hearts and other tissues of animals rendered hyperthyroid with thyroxine. Forty-four rabbits and seventeen guinea pigs were given intramuscular injections of thyroxine every other day and sacrificed at varying intervals. Tissues from a series of normal animals (twenty guinea pigs and forty-three rabbits) were examined as a control. The changes in the heart and other tissues of hyperthyroid animals were insignificant and varied but little from changes seen in normal control animals. Of eight thyrotoxic guinea pigs that developed coincidental infection (bronchisepticus) all showed myocardial lesions. Of nine thyrotoxic guinea pigs, free of infection, only one gave evidence of myocardial change. It is pointed out that hyperthyroidism, per se, cannot be held responsible for these lesions, which would appear to have been associated with the infection. It was noted that rigor mortis of the skeletal muscles occurred much sooner in the bodies of hyperthyroid animals than in normal animals.
Selenium Supplementation and Prostate Cancer Mortality
Authors: S. A. Kenfield, E. L. Van Blarigan, N. DuPre, M. J. Stampfer, E. L. Giovannucci, J. M. Chan
Journal: JNCI Journal of the National Cancer Institute (2014)

Few studies have evaluated the relation between selenium supplementation after diagnosis and prostate cancer outcomes. We prospectively followed 4459 men initially diagnosed with nonmetastatic prostate cancer in the Health Professionals Follow-Up Study from 1988 through 2010 and examined whether selenium supplement use (from selenium-specific supplements and multivitamins) after diagnosis was associated with risk of biochemical recurrence, prostate cancer mortality, and, secondarily, cardiovascular disease mortality and overall mortality, using Cox proportional hazards models. All P values were from two-sided tests. We documented 965 deaths, 226 (23.4%) because of prostate cancer and 267 (27.7%) because of cardiovascular disease, during a median follow-up of 8.9 years. In the biochemical recurrence analysis, we documented 762 recurrences during a median follow-up of 7.8 years. Crude rates per 1000 person-years for prostate cancer death were 5.6 among selenium nonusers and 10.5 among men who consumed 140 or more μg/day. Crude rates per 1000 person-years were 28.2 vs 23.5 for all-cause mortality and 28.4 vs 29.3 for biochemical recurrence, for nonuse vs highest-dose categories, respectively. In multivariable analyses, men who consumed 1 to 24 μg/day, 25 to 139 μg/day, and 140 or more μg/day of supplemental selenium had a 1.18 (95% confidence interval [CI] = 0.73 to 1.91), 1.33 (95% CI = 0.77 to 2.30), and 2.60-fold (95% CI = 1.44 to 4.70) greater risk of prostate cancer mortality compared with nonusers, respectively, Ptrend = .001. There was no statistically significant association between selenium supplement use and biochemical recurrence, cardiovascular disease mortality, or overall mortality. Selenium supplementation of 140 or more μg/day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. Caution is warranted regarding usage of such supplements among men with prostate cancer.
Transient Ischemia Reduces Norepinephrine Release During Sustained Ischemia
Authors: Melchior Seyfarth, Gert Richardt, Anna Mizsnyak, Thomas Kurz, Albert Schömig
Journal: Circulation Research (1996)

Endogenous catecholamine release may play a role in ischemic preconditioning either as a trigger or as a target within the process of myocardial preconditioning. Therefore, we investigated the effect of transient ischemia (TI) on norepinephrine release during sustained ischemia in isolated rat hearts. TI was induced by multiple cycles of global ischemia followed by reperfusion with a duration of 5 minutes each, comparable to ischemic preconditioning protocols. After TI, norepinephrine release was evoked by either sustained global ischemia, anoxia, cyanide intoxication, tyramine, or electrical stimulation. During TI, no washout of norepinephrine was observed, and tissue concentrations of norepinephrine were not changed. TI, however, reduced norepinephrine overflow after 20 minutes of sustained ischemia from 239 +/- 26 pmol/g (control) to 79+/-8 pmol/g (67% reduction, P <.01 ). A similar reduction of ischemia-induced norepinephrine release from 192 +/- 22 pmol/g (control) to 90 +/- 15 pmol/g was observed when hearts underwent transient anoxia without glucose (P < .05). When reperfusion between TI and sustained ischemia was prolonged from 5 to 90 minutes, the inhibitory effect of TI on norepinephrine release was gradually lost. Susceptibility to TI was a unique feature of norepinephrine release induced by sustained ischemia, since release of norepinephrine evoked by anoxia, cyanide intoxication, tyramine, or electrical stimulation remained unaffected by TI. We propose a protective effect of TI on neural tissue, which may reduce norepinephrine-induced damage during prolonged myocardial ischemia.
Repression of Sestrin Family Genes Contributes to Oncogenic Ras-Induced Reactive Oxygen Species Up-regulation and Genetic Instability
Authors: Pavel B. Kopnin, Larissa S. Agapova, Boris P. Kopnin, Peter M. Chumakov
Journal: Cancer Research (2007)

Abstract Oncogenic mutations within RAS genes and inactivation of p53 are the most common events in cancer. Earlier, we reported that activated Ras contributes to chromosome instability, especially in p53-deficient cells. Here we show that an increase in intracellular reactive oxygen species (ROS) and oxidative DNA damage represents a major mechanism of Ras-induced mutagenesis. Introduction of oncogenic H- or N-Ras caused elevated intracellular ROS, accumulation of 8-oxo-2′-deoxyguanosine, and increased number of chromosome breaks in mitotic cells, which were prevented by antioxidant N-acetyl-l-cysteine. By using Ras mutants that selectively activate either of the three major targets of Ras (Raf, RalGDS, and phosphatidylinositol-3-kinase) as well as dominant-negative Rac1 and RalA mutants and inhibitors of mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinases kinase-1 and p38 MAPKs, we have shown that several Ras effectors independently mediate ROS up-regulation. Introduction of oncogenic RAS resulted in repression of transcription from sestrin family genes SESN1 and SESN3, which encode antioxidant modulators of peroxiredoxins. Inhibition of mRNAs from these genes in control cells by RNA interference substantially increased ROS levels and mutagenesis. Ectopic expression of SESN1 and SESN3 from lentiviral constructs interfered with Ras-induced ROS increase, suggesting their important contribution to the effect. The stability of Ras-induced increase in ROS was dependent on a p53 function: in the p53-positive cells displaying activation of p53 in response to Ras, only transient (4–7 days) elevation of ROS was observed, whereas in the p53-deficient cells the up-regulation was permanent. The reversion to normal ROS levels in the Ras-expressing p53-positive cells correlated with up-regulation of p53-responsive genes, including reactivation of SESN1 gene. Thus, changes in expression of sestrins can represent an important determinant of genetic instability in neoplastic cells showing simultaneous dysfunctions of Ras and p53. [Cancer Res 2007;67(10):4671–8]
Fatty Acid–Regulated Transcription Factors in the Liver
Authors: Donald B. Jump, Sasmita Tripathy, Christopher M. Depner
Journal: Annual Review of Nutrition (2013)

Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling the expression of transcription factors or the phosphorylation, ubiquitination, or proteolytic cleavage of the transcription factor. Although dietary fatty acids are well-established regulators of hepatic transcription factors, emerging evidence indicates that endogenously generated fatty acids are equally important in controlling transcription factors in the context of glucose and lipid homeostasis. Our first goal in this review is to provide an up-to-date examination of the molecular and metabolic bases of fatty acid regulation of key transcription factors controlling hepatic metabolism. Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population.
Accumulating Evidence for the Effect of Chemotherapy on Cognition
Authors: Gary Rodin, Tim A. Ahles
Journal: Journal of Clinical Oncology (2012)

A strength of meta-analysis is that it provides a technique for examining broad trends in data across studies. However, there is consensus among many investigators associated with the International Cognition and Cancer Task Force that a subgroup of patients may be particularly vulnerable to post-treatment cognitive change. 10 Age and education were not shown to moderate the effects of chemotherapy-induced cognitive change in the present meta-analysis. However, as the authors acknowledge, most studies included relatively young to middle-aged patients who tend to be highly educated. Therefore, there may not have been sufficient numbers of patients who are older or who have lower education levels to yield significant associations. This possibility is illustrated in a recent study that demonstrated that age and cognitive reserve (which is influenced by such factors as education, occupation, and cognitive stimulation) were associated with post-treatment cognitive decline. Those older patients with low levels of pretreatment cognitive reserve who were exposed to chemotherapy were most vulnerable to post-treatment cognitive decline as assessed on measures of processing speed. 4
Usefulness of myeloperoxidase as a biomarker for nanoparticles' toxicity
Authors: Taisuke Tomonaga, Hiroto Izumi, Yukiko Yoshiura, Toshihiko Myojo, Takako Oyabu, Byeong-Woo Lee, Takami Okada, Yasuo Morimoto
Journal: European Respiratory Journal (2014)

Myeloperoxidase (MPO) synthesized in neutrophils is involved in the lung injury, and it has been suggested MPO is involved in inflammation and fibrosis of the lung via the oxidative stress. To investigate MPO as a biomarker for pulmonary toxicities of nanoparticles, we performed an intratracheal instillation study of nanoparticles and measured the concentration of MPO. Nickel oxide nanoparticles (NiO) and two titanium dioxide nanoparticles (TiO 2 ) (Rutile, P90) were used as chemicals with high and low toxicities, respectively. 0.2 mg or 1.0 mg of NiO or two TiO 2  were intratracheally instilled in male rats (about 12 weeks old). MPO in the bronchoalveolar lavage fluid (BALF) were determined using an ELISA kit at 3 days, 1week and 1 month after end of exposure.  Dispersed NiO induced significantly increase of MPO concentration in BALF from 3 days to 1 month, compared with negative control groups. On the other hand, dispersed two TiO 2  induced significantly increase of MPO concentration in BALF at 3 days, however the tendency of decrease of MPO concentration was observed in two TiO 2  exposure groups, and the level was almost the same as in the negative controls. We observed that nanoparticles with high toxicities induced the tendency of persistent increase of MPO concentration, and nanoparticles with low toxicities induced transient increase of MPO concentration. Taken together, it is suggested that MPO is useful as a biomarker for nanoparticles9 toxicity.  This work is partially supported by “Development of innovative methodology for safety assessment of industrial nanomaterials by Ministry of Economy, Trade and Industry (METI) of Japan.