tbuckley/cabot-search huggingface dataset:
Captopril-induced Changes in Prostaglandin Production
Authors: Stephen L. Swartz, Gordon H. Williams, Norman K. Hollenberg, Lawrence Levine, Robert G. Dluhy, Thomas J. Moore
Journal: Journal of Clinical Investigation (1980)

Captopril is a potent hypotensive agent whose efficacy has hitherto been attributed to its ability to alter either angiotensin II formation or kinin degradation. Our purpose was to examine captopril's acute effect on prostaglandin production, because changes in neither the renin-angiotensin nor the kallikrein-kinin systems appear adequate to account for the fall in arterial pressure. The plasma levels of angiotensin II, kinins, and prostaglandins were determined in response to increasing doses (5, 12.5, and 25 mg) of captopril and these responses were compared with the change in arterial pressure observed in nine supine normal male subjects studied on both a high (200 meq) and low (10 meq) sodium intake.
Should teaching about non-invasive ventilation be made mandatory to all grades of general medical doctors? An audit of junior doctor knowledge regarding the management of patients on NIV before and after teaching sessions
Authors: Maria Aisha McClintock-Tiongco, Jane Evans, Yee-Ean Ong
Journal: European Respiratory Journal (2012)

Introduction  Patients on non-invasive ventilation (NIV) are usually looked after out of normal working hours by general medical doctors.  Aims and Objectives  We sought to determine the level of knowledge about NIV amongst general medical foundation (F1) doctors, core medical trainees (CMT) and specialist registrars (SpRs) before and after teaching.  Methods  Junior doctors were asked to complete a questionnaire covering knowledge about the criteria for commencing NIV, initial settings and appropriate manipulation of NIV machines according to patient response before and after mandatory teaching for F1 and CMT trainees and a voluntary attendance session for SpRs.  Results  Forty-nine doctors completed the questionnaire pre-teaching and all F1 and CMT doctors attended training but only 5/16 SpRs attended teaching.  Some of the most concerning findings were that all grades were poor at defining type II respiratory failure pre- and post-teaching. Knowledge about initial ventilator settings, alteration of pressure settings and target oxygen saturations on NIV were poor before teaching (although better in SpR group than more junior doctors). Majority would have aimed for pressure settings too low to be effective. However, knowledge improved substantially after teaching amongst those who attended.  Conclusion  Baseline knowledge of all grades of junior doctors about practical NIV care is poor risking ineffective treatment but this can be improved by teaching. However, sessions need to be mandatory to ensure attendance.
Elemental microanalysis of organelles in proximal tubules. II. Effects of oxygen deprivation.
Authors: A J Spencer, A LeFurgey, P Ingram, L J Mandel
Journal: Journal of the American Society of Nephrology (1991)

This communication describes the effects of anoxia on rabbit proximal renal tubule element (ion) content by using high-resolution electron probe x-ray microanalytical imaging to obtain quantitative elemental data from subcellular compartments not previously resolvable with low-resolution imaging. These organelles and regions include the heterochromatin and euchromatin of the nucleus and the microvilli of the apical brush border, in addition to mitochondria, lysosomes, and cytoplasm. Anoxia of 40-min duration caused the expected decrease in K and increase in Na and Cl concentrations in the tubules with the cytoplasmic K:Na ratio declining to 0.13:1. These changes were accompanied by decreases in ATP and total K contents, and an increase in lactate dehydrogenase release. Swelling occurred in some cells as evidenced by ultrastructural changes. No alterations were evident after oxygen deprivation in Ca content of cytoplasm (control, 6.7 +/- 0.6 versus anoxia, 7.6 +/- 0.7 nmol/mg dry wt) or mitochondria (control, 4.0 +/- 0.4 versus anoxia, 4.9 +/- 0.6 nmol/mg dry wt) or in S content of recognizable lysosomes (control, 314 +/- 11 versus anoxia, 325 +/- 12 nmol/mg dry wt). Brush border (microvillus) Ca content was higher than cytoplasmic Ca content during normoxia (10.7 +/- 0.9 nmol/mg dry wt) and increased further during anoxia (17.0 +/- 1.0 nmol of Ca/mg dry wt). The finding of higher Ca content within the brush border region during normoxia is unexpected and novel, because such results suggest that Ca homeostasis in the apical elaboration of the proximal cell may be different from that in the cytoplasm. The results also raise the possibility that an increase in Ca content in the brush border membrane region may be involved in the pathogenesis of renal cell injury.
Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations
Authors: Frank Rolfs, Marcel Huber, Andreas Kuehne, Stefan Kramer, Eric Haertel, Sukalp Muzumdar, Johanna Wagner, Yasmine Tanner, Friederike Böhm, Sigrun Smola, Nicola Zamboni, Mitchell P. Levesque, Reinhard Dummer, Hans-Dietmar Beer, Daniel Hohl, Sabine Werner, Matthias Schäfer
Journal: Cancer Research (2015)

Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis.
In Vitro Reactivity of Macrophages and Lymphocytes From Ultraviolet-Irradiated Mice 2
Authors: Kenneth C. Norbury, Margaret L. Kripke, Marilyn B. Budmen
Journal: JNCI Journal of the National Cancer Institute (1977)

In these experiments we examined the ability of lymphocytes and macrophages from UV-treated mice of the inbred strain C3H/HeN(MTV−) to respond in vitro to nonspecific stimuli. Spleen and lymph node cells from UV-treated mice exhibited blastogenic responses to concanavalin A, phytohemag glutinin, and lipopolysaccharide that were equal to those of lymphoid cells from normal animals. Neither the induction of peritoneal exudate cells by inflammatory agents nor the phagocytic activity of peritoneal macrophages was affected by UV irradiation. Furthermore, no reduction occurred in the in vitro tumoricidal capacity of peritoneal macrophages from UV-treated mice after in vitro activation with xenogeneic lymphokines or endotoxin. We concluded that chronic UV irradiation does not lead to a generalized suppression of the immune system in mice.
Teratomas in the Igbos of Nigeria
Authors: Wilson I. B. Onuigbo
Journal: JNCI Journal of the National Cancer Institute (1976)

A study was made of the site of 86 teratomas occurring in approximately 7,500 surgical specimens received at a central laboratory serving government, mission, and private physicians working among the lgbos of Nigeria. Most teratomas [74 cases (86%] arose in the ovaries. Testicular teratoma was not seen in the series that included three testicular and 37 ovarian primary cancers. Accordingly, gonadal tumors are as uncommon in Igbo males as in other Nigroes.
What is significance?
Authors: P. Sedgwick
Journal: BMJ (2015)

The effects of pelvic floor muscle training on pelvic floor symptoms were investigated using a randomised controlled trial. The intervention consisted of pelvic floor muscle training combined with home exercises. The control intervention consisted of watchful waiting. The length of follow-up was three months. The participants were women recruited from a primary care population, aged 55 years or more, who had symptomatic mild pelvic organ prolapse.1 The primary outcome was the change in bladder, bowel, and pelvic floor symptoms at follow-up from baseline as measured by the Pelvic Floor Distress Inventory-20 (PFDI-20). Higher scores on the inventory indicated a greater severity of symptoms. To calculate the required sample size it was assumed that the watchful waiting group would have a PDFI-20 score of 60 points at baseline with no subsequent change in symptoms at three months. The sample size was based on having 80% power to detect a difference between treatment groups of 15 points (25% reduction) in the PFDI-20 score, with a standard deviation of 36 points at three month follow-up. To achieve this difference using a critical level of significance of 0.05 and two sided alternative hypothesis, 92 women were needed in each treatment arm. To account for an estimated dropout rate of 15%, the required sample size was adjusted to 216. In total, 287 women were recruited and randomised to pelvic floor muscle training (n=145) or watchful waiting (n=142). Overall, 250 (87%) women completed follow-up. At the end of follow-up the intervention group had a significant improvement in symptoms compared with the watchful waiting group, with an average reduction of 9.1 (95% confidence interval 2.8 to 15.4; P=0.005) points on the PFDI-20. Which of the following statements, if any, are true?
Synthesis and biological activity evaluation of 1H-benzimidazoles via mammalian DNA topoisomerase I and cytostaticity assays
Authors: Sevil Zencir, Gunes Coban, Istvan Zupko, Borbala Rethy, H. Semih Gunes, Zeki Topcu
Journal: Clinical Cancer Research (2008)

A16  Benzimidazoles are important compounds because of their antibacterial, antifungal, antimicrobial, antiprotozoal and antihelmintic activities. Some benzimidazole derivatives also interfere with the reactions of DNA topoisomerases, the enzymes functioning at almost all stages of the cell cycle. In this study, nine 1H-benzimidazole derivatives with substituents at positions 2- and 5- were synthesized and the structure of the compounds were elucidated by instrumental methods. The characterized compounds were screened to identify if they interfere with mammalian type I DNA topoisomerase activity via in vitro supercoil relaxation assays. Selected compounds were subjected to cytostatic assays using HeLa (cervix adenocarcinoma), MCF7 (breast adenocarcinoma) and A431 (skin epidermoid carcinoma) cells. Our results showed that 5-chloro-2-(2-hydroxyphenyl)-1H-benzimidazole exerted the most profound topoisomerase I inhibition and cytotoxicity.
The role and prognostic significance of the von Hippel-Lindau (VHL) tumor suppressor gene in renal cancer in a South - Western Irish population
Authors: Michelle J. Nyhan, Sharon L. McKenna, Chris Collins, Colum Dunne, Paul Sweeney, Eamonn Rogers, Gerald C. O Sullivan
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2859 

Renal cell carcinoma is the most common malignancy of the adult kidney. This disease features a lack of early-warning signs, which results in a large proportion of patients with metastases. The von Hippel-Lindau (VHL) tumour suppressor gene is inactivated in a rare inherited cancer syndrome von Hippel-Lindau disease. Recent publications indicate that this gene is also frequently mutated in sporadic clear cell renal cell carcinomas. VHL’s best-characterised function is the regulation of the Hypoxia Inducible Factor (HIF). In the absence of VHL, HIF activates transcription of several genes, including vascular endothelial growth factor (VEGF) and erythropoietin. pVHL is also involved in the formation of the extracellular matrix and regulation of Protein Kinase C. The role of VHL, and the major targets responsible for sporadic renal cell carcinoma have not been established. This study has investigated the incidence of VHL mutations in renal cell carcinoma patients attending the Mercy University Hospital, Cork, Ireland. In addition, we are examining the consequences of mutation for tumour cell dissemination, deregulation of cellular targets and disease progression. A highly sensitive reverse transcription-PCR method has been developed to screen for VHL mutations in renal tumour tissue. This method is also employed to screen for the presence of disseminated tumour cells in pre and post-operative peripheral blood and marrow from renal carcinoma patients. Primers that enable amplification of the entire coding region of VHL mRNA have been designed and optimised. RNA and cDNA have been prepared from 17 Clear Cell Renal Cell Carcinomas, 2 Transitional Cell Carcinomas, 2 Oncocytomas and paired normal tissue. Our data so far has identified VHL mutations in two of eleven patients (18%) diagnosed with clear cell renal cell carcinoma of varying histological grades. This is lower than other reported incidences (ranging from 30 - 65%), and may be due to sample size. Tissue collection is ongoing and further sample analysis will provide information on the incidence of these mutations in the Irish population. In the two patients with mutations, these are located within the HIF binding region of VHL. Western blot analysis has shown a significant up-regulation of HIF-1α expression in the tumour tissue of these two patients compared to their corresponding normal tissue. The results of this study will establish which mutations and downstream targets are potentially the most significant for the development and progression of renal cell carcinoma.
Increased vimentin expression in human primary bronchial epithelium reconstituted in vitro from patients with chronic obstructive pulmonary disease
Authors: Sophie Gohy, Bruno Detry, Caroline Bouzin, Chantal Fregimilika, Charles Pilette
Journal: European Respiratory Journal (2013)

Introduction Chronic obstructive pulmonary disease (COPD) is associated with structural changes notably of the respiratory epithelium. Epithelial-to-mesenchymal transition (EMT), which is mainly induced by TGF-β, has been recently suggested in vitro in the airway epithelium in COPD. The objective is to address aberrant differentiation and EMT in the airway epithelium in COPD. Materials and methods Lung samples from 28 patients undergoing surgery for a solitary nodule or transplantation were collected for primary broncho-epithelial cultures in air-liquid interface (ALI-HBEC). ALI-HBEC were assayed for expression of epithelial (zonula occludens-1 and E-cadherin) and mesenchymal (vimentin) proteins by immunohistochemistry (IHC) and western-blot. The production of TGF-β1 was evaluated by ELISA. Results ALI-HBEC from COPD patients showed a significant increase in vimentin expression in IHC (p= 0.006, severe COPD (40 to 58% of positive area) versus controls (0 to 21%)) and western blot. In contrast, epithelial makers (E-cadherin and ZO-1) were both decreased (p=0.01 and p=0.03 respectively, mild or moderate COPD versus controls. In addition, increased vimentin expression was correlated to FEV1 (r=-0.56, p=0.03) in the COPD population and increased ZO-1 expression correlated also with FEV1 (r=0.46, p= 0.017). Vimentin, Ecadherin and ZO-1 correlated all with the Tiffeneau index (r=-0.48, p=0.09; r=0.487, p=0.09; r=0.519, p=0.006). TGF-β1 release was not significantly different between the groups. Discussion We show that the bronchial epithelium from COPD patients display after in vitro reconstitution, increased vimentin expression and decreased epithelial differentiation. These results suggest that the epithelium from COPD patients retains aberrant programming related to EMT, and that this could be independent from TGF-β.
Predictors of functional exercise capacity allogeneic hematopoietic stem cell transplantation recipients
Authors: Gulsah Bargi, Meral Bosnak Guclu, Zeynep Aribas, Burcu Camcioglu, Muserrefe Nur Karadalli, Zeynep Sahika Aki, Nurdan Köktürk, Müge Aydogdu, Gülsan Türkoz Sucak
Journal: European Respiratory Journal (2013)

Background: Significant declines in functional exercise capacity occur in allogeneic hematopoietic stem cell transplant (HSCT) recipients.

Aim : To investigate the relationship between functional exercise capacity and pulmonary functions, carbon monoxide diffusing capacity (DLCO), serum albumin level, respiratory and peripheral muscle strength, and to find out the best predictor of functional exercise capacity in allogeneic HSCT recipients.

Methods : Thirty-six allogeneic HSCT recipients (>100 days post transplantation, 39.36±12.85 years, 12F, 24M) were included. Albumin levels were recorded, DLCO and pulmonary functions were measured. Functional exercise capacity was evaluated using 6-minute walk test (6MWT), and respiratory muscle strength (MIP, MEP) using mouth pressure device, quadriceps femoris and hand grip muscle strength using a dynamometer.

Results: There was statistically significant correlation between 6MWT distance and pulmonary functions, DLCO, albumin levels, MEP, hand grip muscle strength (p<0.05). Multiple regression analysis, conducted in 36 patients demonstrated that 70% of the variance in the 6MWT distance was explained by hand grip muscle strength (R²=0.45, p<0.001), and the albumin levels (R²=0.25, p=0.002).

Conclusions: Upper extremity muscle strength and albumin levels are factors significantly contributing to impaired functional capacity in allogeneic HSCT recipients. Functional exercise capacity worsens with decreasing diffusion capacity, pulmonary functions, respiratory and peripheral muscle strength. The effects of strengthening exercises and essential amino acid supplementation on functional exercise capacity should be investigated.
Bombesin-like Peptides and Mast Cell Responses
Authors: Meera Subramaniam, Kumiya Sugiyama, David H. Coy, Yanping Kong, York E. Miller, Peter F. Weller, Keiji Wada, Etsuko Wada, Mary E. Sunday
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Bombesin-like peptides (BLPs) are elevated in newborns who later develop bronchopulmonary dysplasia (BPD). In baboon models, anti-BLP blocking antibodies abrogate BPD. We now demonstrate hyperplasia of both neuroendocrine cells and mast cells in lungs of baboons with BPD, compared with non-BPD controls or BLP antibody-treated BPD baboons. To determine whether BLPs are proinflammatory, bombesin was administered intratracheally to mice. Forty-eight hours later, we observed increased numbers of lung mast cells. We analyzed murine mast cells for BLP receptor gene expression, and identified mRNAs encoding bombesin receptor subtype 3 and neuromedin-B receptor (NMB-R), but not gastrin-releasing peptide receptor. Only NMB-R-null mice accumulated fewer lung mast cells after bombesin treatment. Bombesin, gastrin-releasing peptide, NMB, and a bombesin receptor subtype 3-specific ligand induced mast cell proliferation and chemotaxis in vitro. These observations support a role for multiple BLPs in promoting mast cell responses, suggesting a mechanistic link between BLPs and chronic inflammatory lung diseases.
Platelets and protease-activated receptor-4 contribute to acetaminophen-induced liver injury in mice
Authors: Kazuhisa Miyakawa, Nikita Joshi, Bradley P. Sullivan, Ryan Albee, Christina Brandenberger, Hartmut Jaeschke, Mitchell R. McGill, Michael A. Scott, Patricia E. Ganey, James P. Luyendyk, Robert A. Roth
Journal: Blood (2015)
Alterations of the Intestinal Microflora by Diet, Oral Antibiotics, and &lt;italic&gt;Lactobacillus:&lt;/italic&gt; Decreased Production of Free Amines From Aromatic Nitro Compounds, Azo Dyes, and Glucuronides&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: B R Goldin, S L Gorbach
Journal: JNCI Journal of the National Cancer Institute (1984)

F344 rats were fed compounds containing a nitro, azo, or amine-glucuronide group-2-nitronaphthalene (CAS: 581-89-5), 2-nitrofluorene (CAS: 607-57-8; 2-nitro-9H-fluorene), 4-phenylazo-2-naphthol (CAS: 6410-10-2; 1-[(4-nitrophenyl)azo]-2-naphthol), and 2-naphthylamine-N-D-glucuronide--and the formation of free amines was measured in the feces. The effects of diet (mean vs. grain), administration of antibiotic, and the feeding of Lactobacillus acidophilus were evaluated. Meat-fed rats given 2-nitronaphthalene had approximately 4 times higher concentration of free amines in their feces as compared to the concentration in grain-fed rats. In a similar experiment with 2-naphthylamine-N-D-glucuronide, the meat-fed animals had approximately 1.5 times more of the free amines and 50% less of the conjugates in their feces. When meat-fed animals were given L. acidophilus with 2-nitrofluorene or 2-naphthylamine-N-D-glucuronide, they had significantly lower free amines and higher concentrations of conjugates in their feces than did the meat-fed controls. Similarly, erythromycin or tetracycline decreased the fecal amine production in meat-fed animals that had received 2-nitrofluorene or 4-phenylazo-2-naphthol. In another experiment, erythromycin inhibited the production of free amines from 2-naphthylamine-N-D-glucuronide in rats fed a high-fat diet. Studies of fecal enzymes revealed lower levels of beta-D-glucuronidase, nitroreductase, and azoreductase in grain-fed rats and in meat-fed animals also given antibiotics or lactobacilli. These experiments showed that intestinal flora have the ability to convert exogenously administered aromatic nitro and azo compounds and an amine-glucuronide compound to free amines. The rate of these conversions was affected by diet and by oral administration of antibiotics and lactobacilli.
The glomerulopathy of homozygous sickle hemoglobin (SS) disease
Authors: D B Bhathena, J H Sondheimer
Journal: Journal of the American Society of Nephrology (1991)

This morphologic and morphometric study of native-kidney biopsies of six homozygous sickle hemoglobin (SS) nephrotics defines a distinctive glomerulopathy of focal sclerosis developing in maximally hypertrophied glomeruli. In each biopsy, two patterns of segmental glomerulosclerosis were observed: a "collapsing" pattern and an "expansive" pattern. Morphologic analysis comparing group mean glomerular (Bowman's capsular) diameters indicates that glomeruli in SS are routinely markedly enlarged whether nephrotic (group SSN, 233.6 mu +/- SE of 25.3 [N = 6]) or not (control group SSC, 243.5 mu +/- SE of 12.5 [N = 5]). These values are significantly larger when compared with those of matched normal controls (group NC, 158.0 mu +/- SE of 12.7 [N = 6]) or to matched patients with idiopathic focal glomerulosclerosis (group IFS, 188.2 mu +/- SE of 17.9 [N = 6]). Furthermore, based on a previous study, it is most likely that glomerular enlargement in SS represents the maximal hypertrophy attainable in humans. Correlating observations of renal homografts in two sickle hemoglobin patients that developed segmental sclerosis of only the collapsing pattern soon after transplantation, it is proposed that in homozygous sickle hemoglobin nephrotics the collapsing pattern of segmental glomerulosclerosis represents an initial but progressive obliteration of the glomerular capillary bed by red blood cell sickling which cannot be compensated by further glomerular hypertrophy. Hemodynamic glomerular injury then supervenes from the sustained or increasing hyperfiltration in a diminishing capillary bed, manifesting morphologically as the expansive pattern of sclerosis.