tbuckley/cabot-search huggingface dataset:
Elevated levels of the pro-carcinogenic adduct, O6-methylguanine, in normal DNA from the cancer prone regions of the large bowel
Authors: A C Povey
Journal: Gut (2000)

<h3>BACKGROUND</h3> The pro-mutagenic lesion<i>O</i><sup>6</sup>-methyldeoxyguanosine (<i>O</i><sup>6</sup>-MedG), a marker of exposure to many <i>N</i>-nitroso compounds (NOC), can be detected in normal and tumour DNA isolated from colorectal tissue. The biological significance of this exposure is, as yet, unknown but in situ NOC formation is bacterially catalysed suggesting that NOC formation and potentially DNA alkylation will vary throughout the large bowel. <h3>AIMS</h3> To determine if<i>O</i><sup>6</sup>-MedG levels in colorectal DNA vary within the large bowel. <h3>PATIENTS</h3> We studied 62 men and women undergoing surgery for colorectal tumours in the north west of England. <h3>METHODS</h3> <i>O</i><sup>6</sup>-MedG levels were measured in paired normal and tumour DNA samples. DNA was digested to nucleosides, fractionated by HPLC, and purified <i>O</i><sup>6</sup>-MedG quantified by a radioimmunoassay. <h3>RESULTS</h3> <i>O</i><sup>6</sup>-MedG was detected in 27 out of a total of 62 (43%) normal DNA samples and in 30 of 58 (52%) tumour DNA samples: it was present at concentrations of &lt;0.01–0.94 and &lt;0.01–0.151 μmol<i>O</i><sup>6</sup>-MedG/mol deoxyguanosine for normal and tumour DNA, respectively. Levels of<i>O</i><sup>6</sup>-MedG in normal, but not tumour, DNA from the proximal colon were lower than those found in DNA from either the sigmoid colon (p=0.03) or rectum (p=0.05). When the analysis was restricted to samples that contained<i>O</i><sup>6</sup>-MedG, similar results were obtained in that <i>O</i><sup>6</sup>-MedG levels in normal DNA were lower in the proximal colon than in the sigmoid colon (p=0.04) or rectum (p=0.03). <h3>CONCLUSIONS</h3> DNA alkylation varied within the large bowel possibly due to in situ NOC formation and was highest in areas of the colon and rectum where the highest incidence of large bowel tumours occurs, suggesting that DNA alkylation may play a role in the aetiology of colorectal cancer.
Evaluation of out-in skin transparency using a colorimeter and food dye in patients with atopic dermatitis
Authors: H. Mochizuki, H. Tadaki, S. Takami, R. Muramatsu, S. Hagiwara, T. Mizuno, H. Arakawa
Journal: British Journal of Dermatology (2009)

Atopic dermatitis is a disease of skin barrier dysfunction and outside stimuli can cross the skin barrier.To examine a new method for evaluating the outside to inside skin transparency with a colorimeter and yellow dyes.In study 1, a total of 28 volunteer subjects (24 normal and four with atopic dermatitis) participated. After provocation with yellow dye, the skin colour of all the subjects was measured using a colorimeter. The skin transparency index was calculated by the changes of the skin colour to yellow. Other variables of skin function, including transepidermal water loss (TEWL) and stratum corneum hydration, were also measured. In study 2, the skin transparency index was evaluated for a cohort of 38 patients with atopic dermatitis, 27 subjects with dry skin and 29 healthy controls.In study 1, the measurement of skin colour (b*) using tartrazine showed good results. There was a significant relationship between the skin transparency index with tartrazine and the atopic dermatitis score (P = 0.014). No other measurements of skin function, including the TEWL, were correlated. In study 2, the skin transparency index score obtained with tartrazine in the patients with atopic dermatitis was significantly higher than that of the controls and those with dry skin (P < 0.001 and P = 0.022, respectively). However, the TEWL in patients with atopic dermatitis was not significantly higher than that of patients with dry skin and the TEWL in subjects with dry skin was not higher than that of the controls.This method, which used a colorimeter and food dye, is noninvasive, safe and reliable for the evaluation of out-in skin transparency and can demonstrate the characteristic dysfunction in the skin barrier in patients with atopic dermatitis.
Young Adults With Acute Lymphoblastic Leukemia Have an Excellent Outcome With Chemotherapy Alone and Benefit From Intensive Postinduction Treatment: A Report From the Children's Oncology Group
Authors: James B. Nachman, Mei K. La, Stephen P. Hunger, Nyla A. Heerema, Paul S. Gaynon, Caroline Hastings, Leonard A. Mattano, Harland Sather, Meenakshi Devidas, David R. Freyer, Peter G. Steinherz, Nita L. Seibel
Journal: Journal of Clinical Oncology (2009)

Patients 16 to 21 years of age with acute lymphoblastic leukemia (ALL) have an inferior outcome compared with younger children, leading some medical oncologists to advocate allogeneic stem-cell transplantation in first remission for these patients. We examined outcome for young adults with ALL enrolled onto the Children's Cancer Group (CCG) 1961 study between 1996 and 2002.CCG 1961 entered patients with ALL 1 to 21 years of age with initial WBC count > or = 50,000/microL and/or age > or = 10 years. Randomly assigned therapies evaluated the impact of postinduction treatment intensification on outcome. We examined outcome and prognostic factors for 262 young adults with ALL.Five-year event-free and overall survival rates for young adult patients are 71.5% (SE, 3.6%) and 77.5% (SE, 3.3%), respectively. Rapid responder patients (< 25% bone marrow blasts on day 7) randomly assigned to augmented therapy had 5-year event-free survival of 81.8% (SE, 7%), as compared with 66.8% (SE, 6.7%) for patients receiving standard therapy (P = .07). One versus two interim maintenance and delayed intensification courses had no significant impact on event-free survival. WBC count more than 50,000/microL was an adverse prognostic factor.Young adult patients with ALL showing a rapid response to induction chemotherapy benefit from early intensive postinduction therapy but do not benefit from a second interim maintenance and delayed intensification phase. Given the excellent outcome with this chemotherapy, there seems to be no role for the routine use of allogeneic stem-cell transplantation in first remission for young adults with ALL.
Glycine-Extended Gastrin Promotes the Growth of Lung Cancer
Authors: Theodore J. Koh, John K. Field, Andrea Varro, Triantafillos Liloglou, Pat Fielding, Guanglin Cui, JeanMarie Houghton, Graham J. Dockray, Timothy C. Wang
Journal: Cancer Research (2004)

Abstract The less processed forms of gastrin have recently been shown to act as trophic factors for both normal and malignant colonic cells. Although incompletely processed forms of gastrin such as glycine-extended gastrin and progastrin are also expressed in human lung cancers, the clinical significance of this expression has not been addressed. Consequently, we investigated the effects of overexpression of glycine-extended gastrin in a mouse strain that is prone to developing lung cancer and also examined the expression of incompletely processed gastrins in primary human lung cancers. We found that transgenic overexpression of glycine-extended gastrin in FVB/N mice resulted in a significant increase in the prevalence and growth of bronchoalveolar carcinoma. In addition, a substantial subset of human lung cancers was found to express progastrin and/or glycine-extended gastrin. Overexpression of glycine-extended gastrin by human lung cancers was associated with a significantly decreased survival. Taken together, these results suggest that glycine-extended gastrin may play a role in the growth and progression of some human lung cancers.
MiR-378 Controls Cardiac Hypertrophy by Combined Repression of Mitogen-Activated Protein Kinase Pathway Factors
Authors: Jayavarshni Ganesan, Deepak Ramanujam, Yassine Sassi, Andrea Ahles, Claudia Jentzsch, Stanislas Werfel, Simon Leierseder, Xavier Loyer, Mauro Giacca, Lorena Zentilin, Thomas Thum, Bernhard Laggerbauer, Stefan Engelhardt
Journal: Circulation (2013)

Background— Several microRNAs (miRs) have been shown to regulate gene expression in the heart, and dysregulation of their expression has been linked to cardiac disease. miR-378 is strongly expressed in the mammalian heart but so far has been studied predominantly in cancer, in which it regulates cell survival and tumor growth. Methods and Results— Here, we report tight control of cardiomyocyte hypertrophy through miR-378. In isolated primary cardiomyocytes, miR-378 was found to be both necessary and sufficient to repress cardiomyocyte hypertrophy. Bioinformatic prediction suggested that factors of the mitogen-activated protein kinase (MAPK) pathway are enriched among miR-378 targets. Using mRNA and protein expression analysis along with luciferase assays, we validated 4 key components of the MAPK pathway as targets of miR-378: MAPK1 itself, insulin-like growth factor receptor 1, growth factor receptor-bound protein 2, and kinase suppressor of ras 1. RNA interference with these targets prevented the prohypertrophic effect of antimiR-378, suggesting their functional relation with miR-378. Because miR-378 significantly decreases in cardiac disease, we sought to compensate for its loss through adeno-associated virus–mediated, cardiomyocyte-targeted expression of miR-378 in an in vivo model of cardiac hypertrophy (pressure overload by thoracic aortic constriction). Restoration of miR-378 levels significantly attenuated thoracic aortic constriction–induced cardiac hypertrophy and improved cardiac function. Conclusions— Our data identify miR-378 as a regulator of cardiomyocyte hypertrophy, which exerts its activity by suppressing the MAPK signaling pathway on several distinct levels. Restoration of disease-associated loss of miR-378 through cardiomyocyte-targeted adeno-associated virus–miR-378 may prove to be an effective therapeutic strategy in myocardial disease.
Maximal and Partial Expiratory Flow Rates in a Population Sample of 10- to 11-yr-old Schoolchildren
Authors: GEORGE T. O'CONNOR, DAVID SPARROW, DEBORAH DEMOLLES, DOUGLAS DOCKERY, MARK RAIZENNE, MARTHA FAY, ROLAND H. INGRAM, FRANK E. SPEIZER
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The effect of volume history on forced expiratory flow rates has been reported to differ between patients with asthma and healthy persons, and it has been hypothesized that the peripheral airway inflammation of patients with asthma may underlie this difference. There are no published data, however, on the distribution of such volume history effects or the relation of these effects to airways disease in children. We obtained combined partial and maximal forced expiratory flow–volume curves on 1,834 children, age 10–11 yr, in eight communities in the United States and Canada. The effect of a deep inhalation on forced expiratory flow rates at low lung volumes was quantitated by the ratio of V˙ 30 during a maximal expiratory maneuver (V˙ 30M) to V˙ 30 during a partial expiratory maneuver (V˙ 30P). The V˙ 30M/V˙ 30P ratio was slightly higher among girls than boys (1.26 versus 1.18, p = 0.0001) indicating that a deep inhalation increased V˙ 30 slightly more among girls than among boys. The V˙ 30M/V˙ 30P ratio was related to neither history of asthma nor to maternal smoking. In contrast, most spirometric indices from either the maximal or the partial expiratory flow–volume curve were lower in association with a history of asthma or a report of maternal smoking. The ratio of FEF25–75/FVC was particularly consistent as a measurement that discriminated both of these effects in boys and girls. These results suggest that the measurement of volume history effects offers no benefits for epidemiological studies of childhood respiratory disease whereas spirometric indices such as the FEF25–75/FVC ratio are quite sensitive to the effects of asthma and environmental tobacco smoke exposure on the airways.
Effect of Docetaxel in Patients With Hormone-Dependent Prostate-Specific Antigen Progression After Local Therapy for Prostate Cancer
Authors: Susan Goodin, Patrick Medina, Terry Capanna, Weichung J. Shih, Sybil Abraham, Jessica Winnie, Susan Doyle-Lindrud, Mary Todd, Robert S. DiPaola
Journal: Journal of Clinical Oncology (2005)

Purpose To evaluate docetaxel in the treatment of patients with early-stage prostate cancer with prostate-specific antigen (PSA) progression after local therapy without androgen ablation therapy. Patients and Methods Twenty-five patients with adenocarcinoma of the prostate with PSA progression despite local therapy were treated with 70 mg/m 2 docetaxel every 21 days. Treatment was planned for eight cycles. Patients were followed up for effects on PSA, testosterone, and toxicity. Results Twenty-three of 25 patients completed at least one full cycle of therapy. Ten (43%) of 23 patients demonstrated a decrease in PSA by ≥ 50% for at least 4 weeks. The nadir decrease in PSA occurred beyond 150 days of therapy in most patients. Therapy was well tolerated. Grade 4 neutropenia with fever occurred in only six cycles (4.5%). Two patients required 25% dose reductions, both occurring with cycle 6, secondary to increased transaminases in one patient, and grade 3 lacrimation in the other patient. Two patients were removed after the first cycle of therapy due to toxicity (deep venous thrombosis, chest palpitations). Mean testosterone levels were not reduced in 17 patients assessed before and during therapy (P = .12). Conclusion This study demonstrated the activity of docetaxel alone, without androgen ablation, in patients with PSA progression after completion of local therapy. Treatment with docetaxel in this population with early disease progression was well tolerated, biochemically active, and was not androgen ablative. Accrual to national phase III studies in early disease is now critical and should be strongly encouraged to determine the ability of early chemotherapy to improve survival.
Relative Abundance of <i>EGFR</i> Mutations Predicts Benefit From Gefitinib Treatment for Advanced Non–Small-Cell Lung Cancer
Authors: Qing Zhou, Xu-Chao Zhang, Zhi-Hong Chen, Xiao-Lu Yin, Jin-Ji Yang, Chong-Rui Xu, Hong-Hong Yan, Hua-Jun Chen, Jian Su, Wen-Zhao Zhong, Xue-Ning Yang, She-Juan An, Bin-Chao Wang, Yi-Sheng Huang, Zhen Wang, Yi-Long Wu
Journal: Journal of Clinical Oncology (2011)

Purpose Our aim was to determine whether abundance of epidermal growth factor receptor (EGFR) mutations in tumors predicts benefit from treatment with EGFR–tyrosine kinase inhibitors (TKIs) for advanced non–small-cell lung cancer (NSCLC). Patients and Methods We detected EGFR mutations in 100 lung cancer samples using direct DNA sequencing and amplification refractory mutation system (ARMS). Mutation-positive tumors by both methods carried high abundance of EGFR mutations. Tumors that were mutation positive by ARMS but mutation negative by direct DNA sequencing harbored low abundance of EGFR mutations. Mutation-negative tumors by both methods carried wild-type EGFR. All patients received gefitinib treatment. The correlation between EGFR mutation abundance and clinical benefit from gefitinib treatment was analyzed. Results Of 100 samples, 51 and 18 harbored high and low abundances of EGFR mutations, respectively; 31 carried wild-type EGFR. Median progression-free survival (PFS) was 11.3 (95% CI, 7.4 to 15.2) and 6.9 months (95% CI, 5.5 to 8.4) in patients with high and low abundances of EGFR mutations, respectively (P = .014). Median PFS of patients with low abundance of EGFR mutations was significantly longer than that of those with wild-type tumors (2.1 months; 95% CI, 1.0 to 3.2; P = .010). Objective response rates (ORRs) were 62.7%, 44.4%, and 16.1%, and overall survival (OS) rates were 15.9 (95% CI, 13.4 to 18.3), 10.9 (95% CI, 2.7 to 19.1), and 8.7 months (95% CI, 4.6 to 12.7) for patients with high abundance of EGFR mutations, low abundance of EGFR mutations, and wild-type EGFR, respectively. The difference between patients with high and low abundances of EGFR mutations was not significant regarding ORR and OS. Conclusion The relative EGFR mutation abundance could predict benefit from EGFR-TKI treatment for advanced NSCLC.
Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-beta-muricholic Acid, a Naturally Occurring FXR Antagonist
Authors: Sama I. Sayin, Annika Wahlström, Jenny Felin, Sirkku Jäntti, Hanns-Ulrich Marschall, Krister Bamberg, Bo Angelin, Tuulia Hyötyläinen, Matej Orešič, Fredrik Bäckhed
Journal: Cell Metabolism (2013)
Doxazosin Induces Apoptosis of Benign and Malignant Prostate Cells via a Death Receptor–Mediated Pathway
Authors: Jason B. Garrison, Natasha Kyprianou
Journal: Cancer Research (2006)

Abstract Quinazoline-based α1-adrenoceptor antagonists such as doxazosin and terazosin have been previously shown to induce apoptosis in prostate cancer cells via an α1-adrenoceptor–independent pathway, involving activation of transforming growth factor-β1 (TGF-β1) signaling. In this study, the molecular events initiating this apoptotic effect were further investigated in vitro using the human androgen-independent prostate cancer cells PC-3 and the human benign prostate epithelial cells BPH-1. Quantitative microarray assays were done in PC-3 and BPH-1 cells after treatment with doxazosin (25 μmol/L, 6 and 24 hours) to identify the early gene changes. Transient changes in the expression of several apoptosis regulators were identified, including up-regulation of Bax and Fas/CD95 and down-regulation of Bcl-xL and TRAMP/Apo3. Moreover, there were significant changes in the expression pattern of signaling components of the extracellular matrix such as integrins α2, αV, β1, and β8. Western blot analysis revealed activation of caspase-8 and caspase-3 within the first 6 to 12 hours of treatment with doxazosin in both PC-3 and BPH-1 cells. Doxazosin-induced apoptosis was blocked by specific caspase-8 inhibitors, supporting the functional involvement of caspase-8 in doxazosin-induced apoptosis. The effect of doxazosin on recruitment of Fas-associated death domain (FADD) and procaspase-8 to the Fas receptor was examined via analysis of death-inducing signaling complex formation. Doxazosin increased FADD recruitment and subsequent caspase-8 activation, implicating Fas-mediated apoptosis as the underlying mechanism of the effect of doxazosin in prostate cells. These results show that doxazosin exerts its apoptotic effects against benign and malignant prostate cells via a death receptor–mediated mechanism with a potential integrin contribution towards cell survival outcomes. (Cancer Res 2006; 66(1): 464-72)
Respiratory-related pharyngeal constrictor muscle activity in normal human adults.
Authors: S T Kuna, J S Smickley, C R Vanoye
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Electromyographic activity of the superior, middle, and inferior pharyngeal constrictor (PC) muscles was examined in 10 normal adult humans during wakefulness and sleep. Wire electrodes were inserted close to the midline of the posterior pharyngeal wall at the level of the soft palate (superior PC), tip of the epiglottis (middle PC), and corniculate tubercle (inferior PC). In general, the three PC muscles exhibited similar patterns of activation. The PCs were activated during swallows, repetitive "pa" sounds, changes in head position, and the last portions of slow inspiratory and expiratory vital capacity maneuvers. Respiratory-related PC activity was infrequent during quiet breathing during wakefulness; variable and inconsistent phasic activation in expiration in one or more of the PCs was present in seven of the 10 subjects, particularly after a swallow. Progressive hyperoxic hypercapnia and progressive isocapnic hypoxia were associated with recruitment of phasic PC activity, which was predominantly expiratory; however, variable discharge patterns were observed within a given muscle and a given subject. When phasic PC activity was present, preactivation during late inspiration was frequently observed. PC activity was absent in NREM sleep and exhibited sporadic, nonrespiratory-related bursts of activity during REM sleep. Passively induced hypocapnic hyperventilation in NREM sleep was not associated with PC activation. The results indicate that the PCs have very similar patterns of activation and exhibit phasic expiratory activity during relatively high ventilatory output states in wakefulness.
Frequency of B lymphocytes responsive to anti-immunoglobulin.
Authors: A L Defranco, E S Raveche, R Asofsky, W E Paul
Journal: The Journal of Experimental Medicine (1982)

The frequency of murine B lymphocytes that respond to antibodies directed against membrane IgM was measured. These anti-mu antibodies induced all, or almost all, resting B cells to enlarge over the first 24 h of stimulation. This probably represents the transition from the resting state (G0) to active transit through the cell cycle. In contrast, only a fraction of these cells, approximately 60% for BDF1 mice, continued through the cell cycle into S phase. This is consistent with previous experiments that had suggested there were some types of B cells that did not proliferate in response to anti-mu. The results presented here demonstrate that many, perhaps all, of these nonresponding B cells, both from normal mice and from mice with the xid defect, actually do respond to the presence of anti-mu by going through early parts of the cell cycle. These cells appear to become blocked at some point before the beginning of S phase, perhaps requiring a signal from a T cell or a macrophage to continue through the cell cycle. Thus, the role of antigen may be to prepare all B cells for proliferation. Different subpopulations of B cells may then require different regulatory signals before actually proliferating or before differentiating into antibody-secreting cells.
Rett's syndrome in the west of Scotland.
Authors: A M Kerr, J B Stephenson
Journal: BMJ (1985)

Nineteen girls with characteristic features of Rett's syndrome, including normal initial development, regression at about 12 months of age, repetitive hand movements, and severe mental handicap were studied. This represents an estimated incidence of one in 30 000 live births (one in 15 000 girls) in the west of Scotland. Although the children were often initially considered to be autistic, they did not conform to this diagnosis as they made good personal contact within the limits of their mental development. The developmental regression was sometimes falsely attributed to vaccination. Each child showed striking involuntary movements and abnormality of tone, varying from hypotonia, which was found only in the youngest, to rigidity, which was common in older girls; this permitted classification into three clinical subtypes. The abnormalities were highly suggestive of an extrapyramidal disorder, and this has implications for further research and possible treatment.