tbuckley/cabot-search huggingface dataset:
A Circadian Clock Transcription Model for the Personalization of Cancer Chronotherapy
Authors: Xiao-Mei Li, Ali Mohammad-Djafari, Mircea Dumitru, Sandrine Dulong, Elisabeth Filipski, Sandrine Siffroi-Fernandez, Ali Mteyrek, Francesco Scaglione, Catherine Guettier, Franck Delaunay, Francis Lévi
Journal: Cancer Research (2013)

Circadian timing of anticancer medications has improved treatment tolerability and efficacy several fold, yet with intersubject variability. Using three C57BL/6-based mouse strains of both sexes, we identified three chronotoxicity classes with distinct circadian toxicity patterns of irinotecan, a topoisomerase I inhibitor active against colorectal cancer. Liver and colon circadian 24-hour expression patterns of clock genes Rev-erbα and Bmal1 best discriminated these chronotoxicity classes, among 27 transcriptional 24-hour time series, according to sparse linear discriminant analysis. An 8-hour phase advance was found both for Rev-erbα and Bmal1 mRNA expressions and for irinotecan chronotoxicity in clock-altered Per2(m/m) mice. The application of a maximum-a-posteriori Bayesian inference method identified a linear model based on Rev-erbα and Bmal1 circadian expressions that accurately predicted for optimal irinotecan timing. The assessment of the Rev-erbα and Bmal1 regulatory transcription loop in the molecular clock could critically improve the tolerability of chemotherapy through a mathematical model-based determination of host-specific optimal timing.
Fluoromodule-based reporter/probes designed for in vivo fluorescence imaging
Authors: Ming Zhang, Subhasish K. Chakraborty, Padma Sampath, Juan J. Rojas, Weizhou Hou, Saumya Saurabh, Steve H. Thorne, Marcel P. Bruchez, Alan S. Waggoner
Journal: Journal of Clinical Investigation (2015)

Optical imaging of whole, living animals has proven to be a powerful tool in multiple areas of preclinical research and has allowed noninvasive monitoring of immune responses, tumor and pathogen growth, and treatment responses in longitudinal studies. However, fluorescence-based studies in animals are challenging because tissue absorbs and autofluoresces strongly in the visible light spectrum. These optical properties drive development and use of fluorescent labels that absorb and emit at longer wavelengths. Here, we present a far-red absorbing fluoromodule-based reporter/probe system and show that this system can be used for imaging in living mice. The probe we developed is a fluorogenic dye called SC1 that is dark in solution but highly fluorescent when bound to its cognate reporter, Mars1. The reporter/probe complex, or fluoromodule, produced peak emission near 730 nm. Mars1 was able to bind a variety of structurally similar probes that differ in color and membrane permeability. We demonstrated that a tool kit of multiple probes can be used to label extracellular and intracellular reporter-tagged receptor pools with 2 colors. Imaging studies may benefit from this far-red excited reporter/probe system, which features tight coupling between probe fluorescence and reporter binding and offers the option of using an expandable family of fluorogenic probes with a single reporter gene.
Role of thiopurine metabolite measurement in the management of autoimmune hepatitis
Authors: Safa Al-Shamma, Simon McLaughlin, Raymond McCrudden, Sean Weaver, Earl Williams
Journal: Gut (2012)

We congratulate Gleeson and Heneghan1 on their detailed and comprehensive guidelines on the management of autoimmune hepatitis (AIH). A noteworthy area for comment relates to the use of azathioprine (AZA) in the management of AIH and the utilisation of thiopurine metabolites to detect hepatotoxicity. As general hepatologists we are most familiar and comfortable with the use of AZA compared with other immunosuppressive agents and feel that every effort should be made to maintain our patients on these well-studied and established agents. …
Clinical studies of workers exposed to polyvinylchloride dust.
Authors: C A Soutar, S Gauld
Journal: Thorax (1983)

A previous study showed that exposure of workers to polyvinylchloride (PVC) dust was associated with the presence of small rounded opacities in the chest radiograph, and also with a small average reduction of the forced expiratory volume in one second (FEV1). Studies have now been carried out on selected men to determine the clinical importance of the presence of small rounded opacities and also to identify any clinical or physiological features associated with PVC dust exposure. Among 28 men with small rounded opacities, complaints of persistent bronchial mucous hypersecretion were more common (nine men) than amont 29 men of similar age, smoking habits, and dust exposures (one man, p less than 0.01), and there was a suggestion that the physical sign of late inspiratory crackles was more frequent among men with opacities (seven of 27 men) than the other men (two of 28 men, p less than 0.05). The average lung function of men with opacities was only trivially lower than that of the comparative group and the difference between the groups was not significant. In further studies 13 non-smokers with the highest PVC dust exposure and lowest FEV1 (adjusted for age, height, weight, and dust exposure) were examined. None had an observed FEV1 less than 80% of the predicted value for age and height, and these men did not differ in symptoms, signs, or lung function from non-smokers with low dust exposure and similarly low FEV1. In a similar study of 18 smokers with the highest PVC dust exposures and lowest adjusted FEV1, some men had an observed FEV1 well below 80% of predicted values for non-smokers, but with one exception no clinical or functional differences were found between then and 18 smokers with low dust exposure and similarly low FEV1. The exception was again the presence of end inspiratory crackles on auscultation, which were slightly more frequent among men with the highest dust exposures (seven men) than among those with low exposure (two men, p less than 0.06). We conclude that these findings are consistent with the suggestion that the radiographic abnormalities caused by PVC dust exposure are not associated with important functional effects or clinical illness. Further studies are desirable to examine the eventual outcome of the syndrome.
Transtracheal Open Ventilation in Acute Respiratory Failure Secondary to Severe Chronic Obstructive Pulmonary Disease Exacerbation
Authors: Cesare Gregoretti, Vincenzo Squadrone, Claudio Fogliati, Carlo Olivieri, Paolo Navalesi
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Patients who fail noninvasive ventilation are generally intubated and are then subjected to complications of invasive mechanical ventilation. With transtracheal open ventilation, ventilator support is delivered through an uncuffed small bore minitracheostomy tube, which eliminates pooling of secretions above the cuff and thus reduces the risk of tracheobronchial microbial colonization.To compare transtracheal open ventilation (treatment group) with conventional invasive ventilation (control group) in patients with exacerbation of chronic obstructive pulmonary disease who initially failed noninvasive ventilation.Patients were randomized to receive trans-tracheal open ventilation (n=19) or conventional invasive ventilation (n=20).There was no difference in arterial blood gases after 1 and 30 h between the two groups. Two patients receiving transtracheal open ventilation and 13 undergoing conventional ventilation had complications (p<0.0001). Compared with conventional ventilation, transtracheal open ventilation significantly decreased both the duration of mechanical ventilation (7.6+/-4.7 vs. 18.6+/-10.6 d, p<0.0001) and length of stay in the intensive care unit (10.2+/-4.5 vs. 21.3+/-9.7 d, p<0.0001).Transtracheal open ventilation was as effective as conventional ventilation in maintaining adequate gas exchange and reducing complications, duration of mechanical ventilation, and intensive care unit length of stay.
Erectile Dysfunction Prevalence, Time of Onset and Association with Risk Factors in 300 Consecutive Patients with Acute Chest Pain and Angiographically Documented Coronary Artery Disease
Authors: Francesco Montorsi, Alberto Briganti, Andrea Salonia, Patrizio Rigatti, Alberto Margonato, Andrea Macchi, Stefano Galli, Paolo M Ravagnani, Piero Montorsi
Journal: European Urology (2003)
Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study
Authors: Jean-Michel Molina, Jaime Andrade-Villanueva, Juan Echevarria, Ploenchan Chetchotisakd, Jorge Corral, Neal David, Graeme Moyle, Marco Mancini, Lisa Percival, Rong Yang, Alexandra Thiry, Donnie McGrath
Journal: The Lancet (2008)
Differences in aerodynamic particle size distributions of innovator and generic beclomethasone dipropionate aerosols used with and without a large volume spacer.
Authors: C J Kenyon, N J Dewsbury, S P Newman
Journal: Thorax (1995)

BACKGROUND--The equivalence of generic beclomethasone dipropionate (BDP) formulations with their innovator counterpart must be demonstrated if generic formulations are to be used. This study has examined the aerodynamic particle size distributions of both innovator and generic formulations of BDP and the effect of a large volume spacer (Volumatic) on these distributions. METHODS--Aerosol clouds of three formulations of BDP delivering 250 micrograms per metered dose were characterised using a high precision multistage liquid impinger, and the amount of drug in different particle size bands was determined by spectrophotometric assay. RESULTS--The mean (SD) respirable fractions of Becloforte, Beclazone, and Filair without the spacer (n = 10) were 24.1 (2.1)%, 23.1 (2.7)%, and 23.0 (2.1)% respectively; however, the ratio of deposition on stage 4 of the impinger to that on stage 3 was lower for Beclazone and for Filair than for Becloforte, implying a smaller proportion of fine particles for the generic products. When the three products delivered via the Volumatic spacer device were compared, the respirable fraction for Becloforte (n = 10) was 25.0 (4.0)%, but those of Beclazone (n = 10) and Filair (n = 11) were 16.0 (1.9)% and 14.6 (3.4)%. Repeat testing (n = 5) at a later date showed higher mean respirable fractions for all three products, but a trend towards the highest respirable fraction for Becloforte, and the same rank order for the other two products. CONCLUSIONS--These in vitro findings suggest that the particle size distributions of the two generic formulations of BDP are not equivalent to that of the innovator product. Some differences in particle size distributions might not have been detected by a twin impinger. Clinical testing would be required to assess the therapeutic equivalence of innovator and generic corticosteroid products used with or without spacer devices.
MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib
Authors: Manik Chahal, Yaoxian Xu, David Lesniak, Kathryn Graham, Konrad Famulski, James G. Christensen, Manish Aghi, Amanda Jacques, David Murray, Siham Sabri, Bassam Abdulkarim
Journal: Neuro-Oncology (2010)

Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. In this study, we used the O6-methylguanine methyltransferase (MGMT)-negative GBM cell line U87MG stably transfected with MGMT (U87/MGMT) to assess whether MGMT expression affects the response to sunitinib. We showed that the addition of sunitinib to standard therapy (temozolomide [TMZ] and radiation therapy [RT]) significantly improved the response of MGMT-positive but not of MGMT-negative cells. Gene expression profiling revealed alterations in the angiogenic profile, as well as differential expression of several receptor tyrosine kinases targeted by sunitinib. MGMT-positive cells displayed higher levels of vascular endothelial growth factor receptor 1 (VEGFR-1) compared with U87/EV cells, whereas they displayed decreased levels of VEGFR-2. Depleting MGMT using O6-benzylguanine suggested that the expression of these receptors was directly related to the MGMT status. Also, we showed that MGMT expression was associated with a dramatic increase in the soluble VEGFR-1/VEGFA ratio, thereby suggesting a decrease in bioactive VEGFA and a shift towards an antiangiogenic profile. The reduced angiogenic potential of MGMT-positive cells is supported by: (i) the decreased ability of their secreted factors to induce endothelial tube formation in vitro and (ii) their low tumorigenicity in vivo compared with the MGMT-negative cells. Our study is the first to show a direct link between MGMT expression and decreased angiogenicity and tumorigenicity of GBM cells and suggests the combination of sunitinib and standard therapy as an alternative strategy for GBM patients with MGMT-positive tumors.
Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide
Authors: Nathan R. Martinez, Petra Augstein, Antonis K. Moustakas, George K. Papadopoulos, Silvia Gregori, Luciano Adorini, David C. Jackson, Leonard C. Harrison
Journal: Journal of Clinical Investigation (2003)

Insulin is a major target of the autoimmune response associated with destruction of pancreatic β cells in type 1 diabetes. A peptide that spans the junction of the insulin B chain and the connecting (C) peptide in proinsulin has been reported to stimulate T cells from humans at risk for type 1 diabetes and autoimmune diabetes–prone NOD mice. Here we show that proinsulin B24–C36 peptide binds to I-Ag7, the MHC class II molecule of the NOD mouse, and, after intranasal administration, induces regulatory CD4+ T cells that, in the absence of CD8+ T cells, block the adoptive transfer of diabetes. Curiously, however, intranasal B24–C36 did not inhibit development of spontaneous diabetes in treated mice. We then determined that B24–C36, and its core sequence B25–C34, bind to Kd, the NOD mouse MHC class I molecule, and elicit CD8+ CTLs. When the CD8+ T lymphocyte epitope was truncated at the C34 valine anchor residue for binding to Kd, the residual CD4+ T cell epitope, B24–C32/33, significantly inhibited diabetes development after a single intranasal dose. This study identifies a novel CTL epitope in proinsulin and demonstrates that the therapeutic potential of a "tolerogenic" autoantigen peptide can be compromised by the presence of an integral CTL epitope.
Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies
Authors: Chetan Bettegowda, Mark Sausen, Rebecca J. Leary, Isaac Kinde, Yuxuan Wang, Nishant Agrawal, Bjarne R. Bartlett, Hao Wang, Brandon Luber, Rhoda M. Alani, Emmanuel S. Antonarakis, Nilofer S. Azad, Alberto Bardelli, Henry Brem, John L. Cameron, Clarence C. Lee, Leslie A. Fecher, Gary L. Gallia, Peter Gibbs, Dung Le, Robert L. Giuntoli, Michael Goggins, Michael D. Hogarty, Matthias Holdhoff, Seung-Mo Hong, Yuchen Jiao, Hartmut H. Juhl, Jenny J. Kim, Giulia Siravegna, Daniel A. Laheru, Calogero Lauricella, Michael Lim, Evan J. Lipson, Suely Kazue Nagahashi Marie, George J. Netto, Kelly S. Oliner, Alessandro Olivi, Louise Olsson, Gregory J. Riggins, Andrea Sartore-Bianchi, Kerstin Schmidt, le-Ming Shih, Sueli Mieko Oba-Shinjo, Salvatore Siena, Dan Theodorescu, Jeanne Tie, Timothy T. Harkins, Silvio Veronese, Tian-Li Wang, Jon D. Weingart, Christopher L. Wolfgang, Laura D. Wood, Dongmei Xing, Ralph H. Hruban, Jian Wu, Peter J. Allen, C. Max Schmidt, Michael A. Choti, Victor E. Velculescu, Kenneth W. Kinzler, Bert Vogelstein, Nickolas Papadopoulos, Luis A. Diaz
Journal: Science Translational Medicine (2014)

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
Mechanisms of Cardiac Nerve Sprouting After Myocardial Infarction in Dogs
Authors: Shengmei Zhou, Lan S. Chen, Yasushi Miyauchi, Mizuho Miyauchi, Saibal Kar, Simon Kangavari, Michael C. Fishbein, Behrooz Sharifi, Peng-Sheng Chen
Journal: Circulation Research (2004)

Cardiac nerve sprouting and sympathetic hyperinnervation after myocardial infarction (MI) both contribute to arrhythmogenesis and sudden death. However, the mechanisms responsible for nerve sprouting after MI are unclear. The expression of nerve growth factor (NGF), growth associated protein 43 (GAP43), and other nerve markers were studied at the infarcted site, the noninfarcted left ventricle free wall (LVFW), and the left stellate ganglion (LSG) at several time points (30 minutes to 1 month) after MI. Transcardiac (difference between coronary sinus and aorta) NGF levels were also assayed. Acute MI resulted in the immediate elevation of the transcardiac NGF concentration within 3.5 hours after MI, followed by the upregulation of cardiac NGF and GAP43 expression, which was earlier and more pronounced at the infarcted site than the noninfarcted LVFW. However, cardiac nerve sprouting and sympathetic hyperinnervation were more pronounced in the noninfarcted than the infarcted LVFW site and peaked at 1 week after MI. The NGF and GAP43 protein levels significantly increased in the LSG from 3 days (P<0.01 for all) after MI, without a concomitant increase in mRNA. There was persistent elevation of NGF levels in aorta and coronary sinus within 1 month after MI. We conclude MI results in immediate local NGF release, followed by upregulation of NGF and GAP43 expression at the infarcted site. NGF and GAP43 are transported retrogradely to LSG, which triggers nerve sprouting at the noninfarcted LVFW. A rapid and persistent upregulation of NGF and GAP43 expression at the infarcted site underlies the mechanisms of cardiac nerve sprouting after MI.
Circulating Tumor Cells as Prognostic Factor for Distant Metastases and Survival in Patients with Primary Uveal Melanoma
Authors: Ronny Schuster, Nikolaos E. Bechrakis, Andrea Stroux, Antonia Busse, Alexander Schmittel, Carmen Scheibenbogen, Eckhard Thiel, Michael H. Foerster, Ulrich Keilholz
Journal: Clinical Cancer Research (2007)

The aim of this study was to determine in patients with high-risk primary uveal melanoma whether the detection of circulating tumor cells by quantitative reverse transcription-PCR (RT-PCR) is of prognostic relevance.Blood samples from 110 patients with high-risk nonmetastatic uveal melanoma were collected on the occasion of primary treatment or follow-up visit. mRNA expression of tyrosinase and MelanA/MART1 were analyzed by real-time RT-PCR and compared with clinical data at presentation and follow-up by univariate and multivariate analyses.The RT-PCR assay yielded a positive result in 11 of 110 patients, with five positive findings for tyrosinase and five for MelanA/MART1, and one sample positive for both markers. At a median follow-up of 22 months, 25% of patients had developed metastases and 15% had died. Univariate statistical analysis revealed RT-PCR and the largest tumor diameter as important prognostic factors for the development of metastases and for survival. In a Cox proportional hazard model, RT-PCR result and largest tumor diameter predicted metastases (hazard ratios 7.3 and 2.6, respectively), whereas PCR result, largest tumor diameter, and Karnofsky performance status were significant variables for disease-specific survival (hazard ratios 22.6, 4.7, and 6.0, respectively). Analysis of individual RT-PCR results revealed both tyrosinase and MelanA/MART1 transcripts as independent prognostic factors.The presence of tyrosinase or MelanA/MART1 transcripts is an independent prognostic factor in patients with high-risk primary uveal melanoma for subsequent development of metastases and for survival and can be used to select patients for adjuvant treatment studies.
TRAF4 Is a Critical Molecule for Akt Activation in Lung Cancer
Authors: Wei Li, Cong Peng, Mee-Hyun Lee, DoYoung Lim, Feng Zhu, Yang Fu, Ge Yang, Yuqiao Sheng, Lanbo Xiao, Xin Dong, WeiYa Ma, Ann M. Bode, Ya Cao, Zigang Dong
Journal: Cancer Research (2013)

TRAF4 is an adapter protein overexpressed in certain cancers, but its contributions to tumorigenesis are unclear. In lung cancer cells and primary lung tumors, we found that TRAF4 is overexpressed. RNA interference-mediated attenuation of TRAF4 expression blunted the malignant phenotype in this setting, exerting inhibitory effects on cell proliferation, anchorage-independent growth, and tumor development in a xenograft mouse model. Unexpectedly, we discovered that TRAF4, but not Skp2, was required for activation of the pivotal cell survival kinase Akt through ubiquitination. Furthermore, TRAF4 attenuation impaired glucose metabolism by inhibiting expression of Glut1 and HK2 mediated by the Akt pathway. Overall, our work suggests that TRAF4 offers a candidate molecular target for lung cancer prevention and therapy.
Akt Controls Vascular Smooth Muscle Cell Proliferation In Vitro and In Vivo by Delaying G1/S Exit
Authors: Eugenio Stabile, Yi Fu Zhou, Motoyasu Saji, Marco Castagna, Matie Shou, Timothy D. Kinnaird, Richard Baffour, Matthew D. Ringel, Stephen E. Epstein, Shmuel Fuchs
Journal: Circulation Research (2003)

Constitutive activation of serine/threonine kinase Akt causes uncontrolled cell-cycle progression in different cell types and in malignancy. To investigate how Akt activation modulates cell-cycle progression in vascular smooth muscle cells (SMCs) in vitro and in the intact animal, we inhibited Akt-dependent signaling by adenovirus-mediated transfection of a dominant-negative Akt mutant (AA-Akt). We observed reduced proliferation rate ( P &lt;0.01), DNA synthesis ( P &lt;0.01), and a significant arrest in G1/S exit ( P &lt;0.01) both in vitro in response to serum stimulation and in vivo after vascular injury. In vivo transfection of the balloon-injured vessel with AA-Akt reduced SMC proliferation, resulting in decreased neointima compared with control virus ( P &lt;0.01). These effects were at least in part modulated, both in vitro and in vivo, by increased p21 Cip1 expression, as demonstrated by lack of effect of AA-Akt on cell proliferation in p21 −/− mouse SMCs. In conclusion, this study demonstrates that Akt-dependent signaling enhances cell-cycle progression of nontransformed SMCs in vitro and in response to vascular injury in the intact animal. These results suggest a role for Akt signaling in modulating the response of normal tissues to stress and the response of the arterial wall to acute and possibly repetitive injuries that ultimately contribute to restenosis and atherosclerosis.