tbuckley/cabot-search huggingface dataset:
Antiangiogenic Therapy with Mammalian Target of Rapamycin Inhibitor RAD001 (Everolimus) Increases Radiosensitivity in Solid Cancer
Authors: Philipp C. Manegold, Carmen Paringer, Ulrike Kulka, Klaus Krimmel, Martin E. Eichhorn, Ralf Wilkowski, Karl-Walter Jauch, Markus Guba, Christiane J. Bruns
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Radiotherapy exerts direct antivascular effects in tumors and also induces a proangiogenic stress response in tumor cells via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. Therefore, the combination of radiotherapy and antiangiogenic therapy with mTOR inhibitor RAD001 (Everolimus) might exert additive/synergistic effects on tumor growth. Experimental Design: Effects of radiation combined with mTOR inhibitor RAD001 were studied on proliferation of murine colon cancer CT-26, human pancreatic cancer L3.6pl, and human umbilical vascular endothelial cells in vitro. In vivo tumor growth of subcutaneous colon cancer CT 26 and orthotopic pancreatic cancer L3.6pl was assessed after fractionated radiotherapy (5 × 2 or 5 × 4 Gy) with or without the addition of the mTOR inhibitor RAD001. RAD001 (1.5 mg/kg/d) was administered until the end of experiments beginning before or after radiotherapy. Results: A single dose of 2 Gy reduced in vitro proliferation of L3.6pl (−16%), CT-26 (−70%), and human umbilical vascular endothelial cells (HUVEC; −72%). The mTOR inhibitor RAD001 (10 ng/mL) suppressed proliferation of HUVEC (−83%), L3.6pl (−8%), and CT-26 (−82%). Combination of even low concentrations of 0.01 ng/mL RAD001 and 0.25 Gy radiation significantly reduced proliferation of HUVECs (−57%), whereas additive effects of RAD001 and radiation on tumor cells were seen only at the highest concentrations tested. In vivo, RAD001 introduced before radiotherapy (5 × 2 Gy) improved tumor growth control in mice (L3.6pl: 326 mm3 versus 1144 mm3; CT-26: 210 mm3 versus 636 mm3; P &amp;lt; 0.05 versus control). RAD001 turned out to possess a dose-modifying effect on radiotherapy. Conclusion: Endothelial cells seem to be most sensitive to combination of mTOR inhibition and radiotherapy. Additive tumor growth delay using the mTOR inhibitor RAD001 and radiotherapy in vivo therefore might rely on combined antiangiogenic and antivascular effects.
THE OPHTHALMOLOGIST'S PLACE IN THE PREVENTION OF TRAFFIC ACCIDENTS
Authors: LOWELL S. SELLING
Journal: JAMA (1942)

The annual loss of life as the result of war casualties during the year of blitz in England was scarcely more than the equivalent loss of life in traffic in that country. Here in the United States the situation still remains serious in spite of rationing, voluntary limitation of the use of cars and the removal of a certain number of drivers from the civilian community. There is a clarion call which has already been recognized by the ophthalmologist that everybody in the community should take part in a continuous crusade for the prevention of traffic injury and death. Through the subcommittee of the Section on Ophthalmology of the American Medical Association, standards have been set up which have been absorbed into the field of the examination of the driver. Many individual members of the section must have been called on to express an opinion about visual acuity standards in
Protein Kinase C–Dependent Increase in Reactive Oxygen Species (ROS) Production in Vascular Tissues of Diabetes
Authors: Toyoshi Inoguchi, Toshiyo Sonta, Hirotaka Tsubouchi, Takashi Etoh, Maiko Kakimoto, Noriyuki Sonoda, Naoichi Sato, Naotaka Sekiguchi, Kunihisa Kobayashi, Hideki Sumimoto, Hideo Utsumi, Hajime Nawata
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Hyperglycemia seems to be an important causative factor in the development of micro- and macrovascular complications in patients with diabetes. Several hypotheses have been proposed to explain the adverse effects of hyperglycemia on vascular cells. Both protein kinase C (PKC) activation and oxidative stress theories have increasingly received attention in recent years. This article shows a PKC-dependent increase in oxidative stress in diabetic vascular tissues. High glucose level stimulated reactive oxygen species (ROS) production via a PKC-dependent activation of NAD(P)H oxidase in cultured aortic endothelial cells, smooth muscle cells, and renal mesangial cells. In addition, expression of NAD(P)H oxidase components were shown to be upregulated in vascular tissues and kidney from animal models of diabetes. Furthermore, several agents that were expected to block the mechanism of a PKC-dependent activation of NAD(P)H oxidase clearly inhibited the increased oxidative stress in diabetic animals, as assessed by in vivo electron spin resonance method. Taken together, these findings strongly suggest that the PKC-dependent activation of NAD(P)H oxidase may be an essential mechanism responsible for increased oxidative stress in diabetes. E-mail: [email protected]
Effect of pulmonary exacerbations on long-term lung function decline in cystic fibrosis
Authors: Valerie Waters, Sanja Stanojevic, Eshetu G. Atenafu, Annie Lu, Yvonne Yau, Elizabeth Tullis, Felix Ratjen
Journal: European Respiratory Journal (2011)

It is unknown what proportion of long-term lung function decline in cystic fibrosis (CF) is explained by pulmonary exacerbations. The aim of this study was to determine how exacerbations requiring hospitalisation contribute to the course of CF lung disease. This was a retrospective cohort study. The primary outcome was the rate of decline of forced expiratory volume in 1 s (FEV(1)) % predicted. Out of 851 subjects, 415 (48.8%) subjects had ≥ 1 exacerbation. After adjustment for confounders, the annual rate of FEV(1) decline in those without an exacerbation was 1.2% per yr (95% CI 1.0-1.5), compared with 2.5% per yr (95% CI 2.1-2.8) in those with an exacerbation. The proportion of overall FEV(1) decline associated with ≥ 1 exacerbation was 52% (95% CI 35.0-68.9). For a given number of exacerbations, the annual rate of FEV(1) decline was greatest in subjects with ≤ 6 months between exacerbations. Half of FEV(1) decline seen in CF patients was associated with pulmonary exacerbations. Time between exacerbations, specifically ≤ 6 months between exacerbations, plays an important contribution to overall lung function decline. These findings support using time to next exacerbation as a clinical end-point for CF trials.
Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial
Authors: Eric L Chang, Jeffrey S Wefel, Kenneth R Hess, Pamela K Allen, Frederick F Lang, David G Kornguth, Rebecca B Arbuckle, J Michael Swint, Almon S Shiu, Moshe H Maor, Christina A Meyers
Journal: The Lancet Oncology (2009)
Reverse Evolution in RH1 for Adaptation of Cichlids to Water Depth in Lake Tanganyika
Authors: H. Nagai, Y. Terai, T. Sugawara, H. Imai, H. Nishihara, M. Hori, N. Okada
Journal: Molecular Biology and Evolution (2010)

Reverse evolution is a widespread phenomenon in biology, but the genetic mechanism for the reversal of a genetic change for adaptation to the ancestral state is not known. Here, we report the first case of complete reverse evolution of two amino acids, serine and alanine, at a single position in RH1 opsin pigment for adaptation to water depth. We determined RH1 sequences of cichlid fishes from four tribes of Lake Tanganyika with different habitat depths. Most of the species were divided into two types: RH1 with 292A for species in shallow water or 292S for species in deep water. Both types were adapted to their ambient light environments as indicated by the absorption spectra of the RH1 pigments. Based on the RH1 locus tree and ecological data, we inferred the ancestral amino acids at position 292 and the distribution of the depth ranges (shallow or deep) of ancestral species of each tribe. According to these estimates, we identified two distinct parallel adaptive evolutions: The replacement A292S occurred at least four times for adaptation from shallow to deep water, and the opposite replacement S292A occurred three times for adaptation from deep to shallow water. The latter parallelism represents the complete reverse evolution from the derived to the ancestral state, following back adaptive mutation with reversal of the RH1 pigment function accompanied by reversal of the species habitat shift.
A randomized controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients
Authors: G. Dragieva, B.M. Prinz, J. Hafner, R. Dummer, G. Burg, U. Binswanger, W. Kempf
Journal: British Journal of Dermatology (2004)

Background Transplant recipients have an increased propensity to develop multiple actinic keratoses, which demonstrate an increased transformation rate into invasive squamous cell carcinoma. Objective To evaluate the efficacy and tolerability of topical photodynamic therapy with the new highly tumour-selective photosensitizer methyl aminolaevulinate vs. placebo in the treatment of actinic keratoses in transplant recipients. Methods Seventeen transplant recipients with a total number of 129 mild to moderate actinic keratoses were enrolled in a prospective, randomized, double-blind, placebo-controlled study. Two lesional areas within a patient were randomized for two consecutive treatments of topical photodynamic therapy 1 week apart using either methyl aminolaevulinate or placebo cream. Sites were illuminated with 75 J cm−2 of visible light delivered at 80 mW cm−2 by a noncoherent light source. Complete resolution and reduction in the number or size of actinic keratoses within the lesional area relative to the initial findings were evaluated at weeks 4, 8 and 16 after treatment. Results The lesional areas treated with methyl aminolaevulinate were clinically cleared in 13 of 17 patients at 16 weeks. A partial response was recorded in a further three. No reduction in the size or number of actinic keratoses was observed in one area treated with methyl aminolaevulinate and in all placebo-treated areas. Adverse events, such as erythema, oedema and crust formation, were mild to moderate, and treatment was well tolerated by all patients. Conclusion Photodynamic therapy using methyl aminolaevulinate is a safe and effective treatment for actinic keratoses in transplant recipients. It may also reduce the risk of transformation of actinic keratoses to invasive, potentially fatal, squamous cell carcinoma.
RAGE mediates oxidized LDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice
Authors: L. Sun, T. Ishida, T. Yasuda, Y. Kojima, T. Honjo, Y. Yamamoto, H. Yamamoto, S. Ishibashi, K.-i. Hirata, Y. Hayashi
Journal: Cardiovascular Research (2008)

Receptor for advanced glycation end products (RAGE) plays a pivotal role in the genesis of diabetic vascular diseases. To further explore the mechanisms underlying atherosclerosis under non-diabetic conditions, we examined the effect of RAGE deficiency on atherosclerosis in hyperlipidaemic mice. RAGE−/− mice were crossed with low-density lipoprotein receptor-deficient (LDLr−/−) mice to generate the double knockout (DKO) mice. After feeding with high-fat diet for 12 weeks, aortic atherosclerotic lesions were analysed histologically in these mice. Although there were no differences in serum levels of glucose and known RAGE ligands between DKO and LDLr−/− mice, DKO mice exhibited a significant decrease in the size and macrophage content in atherosclerotic lesions compared with LDLr−/− mice. Expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the aorta was lower in DKO mice than in LDLr−/− mice. Fluorescence-based assays revealed that oxidative stress in the vessel wall was attenuated in DKO mice than in LDLr−/− mice. Cell culture experiments revealed that RAGE mediated oxidative LDL-induced activation of p42/44 mitogen-activated protein kinases and oxidative stress in macrophages. Oxidative LDL may be a ligand of RAGE in the hyperlipidaemic state. RAGE inactivation inhibits the atherosclerosis through reducing oxLDL-induced pro-inflammatory responses and oxidative stress in hyperlipidaemia.
Frequent Truncating Mutation of <i>TFAM</i> Induces Mitochondrial DNA Depletion and Apoptotic Resistance in Microsatellite-Unstable Colorectal Cancer
Authors: Jianhui Guo, Li Zheng, Wenyong Liu, Xianshu Wang, Zemin Wang, Zehua Wang, Amy J. French, Dongchon Kang, Lin Chen, Stephen N. Thibodeau, Wanguo Liu
Journal: Cancer Research (2011)

The mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA (mtDNA) replication and transcription. Disruption of TFAM results in heart failure and premature aging in mice. But very little is known about the role of TFAM in cancer development. Here, we report the identification of frequent frameshift mutations in the coding mononucleotide repeat of TFAM in sporadic colorectal cancer (CRC) cell lines and in primary tumors with microsatellite instability (MSI), but not in microsatellite stable (MSS) CRC cell lines and tumors. The presence of the TFAM truncating mutation, in CRC cells with MSI, reduced the TFAM protein level in vivo and in vitro and correlated with mtDNA depletion. Furthermore, forced overexpression of wild-type TFAM in RKO cells carrying a TFAM truncating mutation suppressed cell proliferation and inhibited RKO cell-induced xenograft tumor growth. Moreover, these cells showed more susceptibility to cisplatin-induced apoptosis due to an increase of cytochrome b (Cyt b) expression and its release from mitochondria. An interaction assay between TFAM and the heavy-strand promoter (HSP) of mitochondria revealed that mutant TFAM exhibited reduced binding to HSP, leading to reduction in Cyt b transcription. Collectively, these data provide evidence that a high incidence of TFAM truncating mutations leads to mitochondrial copy number reduction and mitochondrial instability, distinguishing most CRC with MSI from MSS CRC. These mutations may play an important role in tumorigenesis and cisplatin-induced apoptotic resistance of most microsatellite-unstable CRCs.
Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease
Authors: P M A Calverley
Journal: Thorax (2003)

<b>Background:</b> In chronic obstructive pulmonary disease (COPD), the degree of circadian variation in forced expiratory volume in 1 second (FEV<sub>1</sub>) and the influence of anticholinergic blockade is not known. Tiotropium is a long acting inhaled anticholinergic bronchodilator that increases daytime FEV<sub>1</sub> in COPD. We hypothesised that tiotropium would modify the overnight change in FEV<sub>1</sub>, and this would be unaffected by the timing of drug administration. <b>Methods:</b> A double blind, randomised, placebo controlled trial was conducted with tiotropium 18 mg once daily in the morning (09.00 hours), evening (21.00 hours), or an identical placebo. Patients with stable COPD (n=121, FEV<sub>1</sub>=41% predicted) underwent spirometric tests every 3 hours for 24 hours at baseline and after 6 weeks of treatment. <b>Results:</b> There were no significant differences at baseline between the groups. Tiotropium improved mean (SE) FEV<sub>1</sub> (over 24 hours) in the morning (1.11 (0.03) l) and evening (1.06 (0.03) l) groups compared with placebo (0.90 (0.03) l), and nocturnal FEV<sub>1</sub> (mean of 03.00 and 06.00 hours) in the morning (1.03 (0.03) l) and evening (1.04 (0.03) l) groups compared with placebo (0.82 (0.03) l) at the 6 week visit (p&lt;0.01). FEV<sub>1</sub> before morning or evening dosing was similar, while the peak FEV<sub>1</sub> moved later in the day with active treatment. The mean percentage change in FEV<sub>1</sub> from 09.00 hours to 03.00 hours (the nocturnal decline in FEV<sub>1</sub>) was −2.8% in the morning group, −1.0% in the evening group, and −12.8% in the placebo group. The magnitude of the peak to trough change in FEV<sub>1</sub> was not statistically different. <b>Conclusions:</b> Tiotropium produced sustained bronchodilation throughout the 24 hour day without necessarily abolishing circadian variation in airway calibre.
Residual Symptoms and Impairment in Major Depression in the Community
Authors: Ramin Mojtabai
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Studies of patients with major depression in treatment settings have found significant residual symptoms and impairment after resolution of the depressive episode. However, only a small proportion of individuals with major depression seek treatment, and little is known about the residual symptoms and impairment associated with major depression in the community. This study used data from the National Comorbidity Survey, which included a nationally representative household sample of respondents in the United States, to assess the course of residual symptoms and impairment after resolution of major depressive episodes in the community. METHOD: National Comorbidity Survey respondents with lifetime major depression who were currently experiencing a major depressive episode and respondents whose last episode had ended more than 1 to 6 months, more than 6 to 12 months, or more than 12 months ago were compared with those without a history of major depression with regard to depressive symptoms and days of impairment in work functioning or other activities in the past 30 days. RESULTS: Respondents whose last episode of major depression had resolved even more than a year ago were still more symptomatic than those without a history of major depression, whereas the number of days of impairment returned to a level indistinguishable from that of respondents without a history of major depression after >6 tο 12 months of resolution of the last episode. CONCLUSIONS: Major depression in the community, as in treatment settings, is associated with residual symptoms and impairment. In the community, however, residual impairment may resolve more quickly than residual symptoms.
Baseline Predictors of Visual Acuity and Retinal Thickness Outcomes in Patients with Retinal Vein Occlusion: Standard Care versus COrticosteroid for REtinal Vein Occlusion Study Report 10
Authors: Ingrid U. Scott, Paul C. VanVeldhuisen, Neal L. Oden, Michael S. Ip, Barbara A. Blodi, Mary Elizabeth Hartnett, Geoff Cohen
Journal: Ophthalmology (2010)
Multicenter Randomized Phase II Clinical Trial Comparing Neoadjuvant Oxaliplatin, Capecitabine, and Preoperative Radiotherapy With or Without Cetuximab Followed by Total Mesorectal Excision in Patients With High-Risk Rectal Cancer (EXPERT-C)
Authors: Alice Dewdney, David Cunningham, Josep Tabernero, Jaume Capdevila, Bengt Glimelius, Andres Cervantes, Diana Tait, Gina Brown, Andrew Wotherspoon, David Gonzalez de Castro, Yu Jo Chua, Rachel Wong, Yolanda Barbachano, Jacqueline Oates, Ian Chau
Journal: Journal of Clinical Oncology (2012)

Purpose To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. Patients and Methods Patients with operable magnetic resonance imaging–defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. Results One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. Conclusion Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.
Effects of a Topically Applied Bioadhesive Berry Gel on Loss of Heterozygosity Indices in Premalignant Oral Lesions
Authors: Brian S. Shumway, Laura A. Kresty, Peter E. Larsen, Jared C. Zwick, Bo Lu, Henry W. Fields, Russell J. Mumper, Gary D. Stoner, Susan R. Mallery
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The aim of this study was to assess the effects of topical application of a 10% (w/w) freeze-dried black raspberry (FBR) gel on oral intraepithelial neoplasia (IEN) variables that included histologic diagnoses and loss of heterozygosity (LOH) indices. Microsatellite instability and/or LOH at tumor suppressor gene–associated chromosomal loci have been associated with a higher risk for oral IEN progression to oral squamous cell carcinoma. Previously, our laboratories have shown that FBRs are well tolerated and possess potent antioxidant, apoptotic, and differentiation-inducing properties. Experimental Design: Each participant with IEN served as their own internal control. Before treatment, all lesions were photographed, and lesional tissue was hemisected to obtain a pretreatment diagnosis and baseline biochemical and molecular variables. Gel dosing (0.5 g applied four times daily for 6 weeks) was initiated 1 week after the initial biopsy. Genomic DNA was isolated from laser-captured basilar and suprabasilar surface epithelial cells followed by PCR amplification using primer sets that targeted known and presumed tumor suppressor gene loci associated with INK4a/ARF, p53, and FHIT. Allelic imbalance was determined by sequence analysis using normal participant tissues to establish microsatellite marker peak patterns and allele sizes. Results: Confirming earlier phase I data, none of the 27 participants developed FBR gel–associated toxicities. Furthermore, our results show histologic regression in a subset of patients as well as statistically significant reduction in LOH at tumor suppressor gene–associated loci. Conclusions: These preliminary data suggest that further evaluation of berry gels for oral IEN chemoprevention is warranted.
Performance of Self-Collected Cervical Samples in Screening for Future Precancer Using Human Papillomavirus DNA Testing
Authors: C. Porras, A. Hildesheim, P. Gonzalez, M. Schiffman, A. C. Rodriguez, S. Wacholder, S. Jimenez, W. Quint, D. Guillen, A. R. Kreimer, R. Herrero
Journal: JNCI Journal of the National Cancer Institute (2014)

Background:Self-collected human papillomavirus (HPV) testing could reduce barriers to cervical cancer screening, with performance comparable to clinician-collected specimens. The ability of self-collected specimens to cross-sectionally and prospectively detect precursor lesions was investigated in an HPV vaccine randomized trial in Costa Rica.