tbuckley/cabot-search huggingface dataset:
Shiftwork and Prostate-Specific Antigen in the National Health and Nutrition Examination Survey
Authors: E. E. Flynn-Evans, L. Mucci, R. G. Stevens, S. W. Lockley
Journal: JNCI Journal of the National Cancer Institute (2013)

Shiftwork has been implicated as a risk factor for prostate cancer. Results from prior studies have been mixed but generally support an association between circadian disruption and prostate cancer. Our aim was to investigate the relationship between shiftwork and prostate-specific antigen (PSA) test obtained as part of the National Health and Nutrition Examination Survey (NHANES) study.We combined three NHANES surveys (2005-2010) to obtain current work schedule among employed men aged 40 to 65 years with no prior history of cancer (except nonmelanoma skin cancer). Men who reported working regular night shifts or rotating shifts were considered shiftworkers. We obtained the total and percentage free PSA test results for these men and dichotomized total PSA into less than 4.0 ng/mL or 4.0 ng/mL or greater and total PSA of 4.0 ng/mL or greater combined with percentage free PSA less than or equal to 25%. Using multivariable logistic regression models, we compared PSA level among current shiftworkers and nonshiftworkers. All statistical tests were two-sided.We found a statistically significant, age-adjusted association between current shiftwork and elevated PSA at the 4.0 ng/mL or greater level (odds ratio = 2.48, 95% confidence interval [CI] = 1.08 to 5.70; P = .03). The confounder-adjusted odds ratio was 2.62 (95% CI = 1.16 to 5.95; P = .02). The confounder-adjusted odds ratio for those with total PSA of 4.0 ng/mL or greater and free PSA less than or equal to 25% was 3.13 (95% CI = 1.38 to 7.09; P = .01).We observed a strong positive association with shiftwork and elevated PSA level. Our data support the notion that sleep or circadian disruption is associated with elevated PSA, indicating that shiftworking men likely have an increased risk of developing prostate cancer.
Donor immune reconstitution after liver–small bowel transplantation for multiple intestinal atresia with immunodeficiency
Authors: Richard K. Gilroy, Peter F. Coccia, James E. Talmadge, Lori I. Hatcher, Samuel J. Pirruccello, Byers W. Shaw, Ronald J. Rubocki, Debra L. Sudan, Alan N. Langnas, Simon P. Horslen
Journal: Blood (2003)
A Signature of Evolutionary Constraint on a Subset of Ectopically Expressed Olfactory Receptor Genes
Authors: O. De la Cruz, R. Blekhman, X. Zhang, D. Nicolae, S. Firestein, Y. Gilad
Journal: Molecular Biology and Evolution (2008)

Olfactory receptor (OR) genes constitute the basis for the sense of smell. It has long been observed that a subset of mammalian OR genes are expressed in nonolfactory tissues, in addition to their expression in the olfactory epithelium. However, it is unknown whether OR genes have alternative functions in the nonolfactory tissues. Using a dedicated microarray, we surveyed OR gene expression in olfactory epithelium as well as a number of nonolfactory tissues, in human and chimpanzee. Our observations suggest that ectopically expressed OR orthologous genes are expressed in the same nonolfactory tissues in human and chimpanzee more often than expected by chance alone. Moreover, we found that the subset of orthologous OR genes with conserved ectopic expression evolve under stronger evolutionary constraint than OR genes expressed exclusively in the olfactory epithelium. Thus, although we cannot provide direct functional data, our observations are consistent with the notion that a subset of ectopically expressed OR genes have additional functions in nonolfactory tissues.
High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology
Authors: Upendra Hegde, Armando Filie, Richard F. Little, John E. Janik, Nicole Grant, Seth M. Steinberg, Kieron Dunleavy, Elaine S. Jaffe, Andrea Abati, Maryalice Stetler-Stevenson, Wyndham H. Wilson
Journal: Blood (2004)
Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter
Authors: Makoto Sugaya, Takahiro Watanabe, Aparche Yang, Matthew F. Starost, Hisataka Kobayashi, April M. Atkins, Debra L. Borris, Elisabeth A. Hanan, Daniel Schimel, Mark A. Bryant, Nicole Roberts, Mihaela Skobe, Katherine A. Staskus, Philipp Kaldis, Andrew Blauvelt
Journal: Blood (2004)
Co-deleting Pten with Rb in retinal progenitor cells in mice results in fully penetrant bilateral retinoblastomas
Authors: Chencheng Xie, Huarui Lu, Alice Nomura, Eric Allan Hanse, Colleen Lynn Forster, Josh Berken Parker, Michael Andrew Linden, Chris Karasch, Timothy Curtis Hallstrom
Journal: Molecular Cancer (2015)

Rb1 is the most frequently mutated gene in the pediatric cancer retinoblastoma, and its loss causes E2F transcription factors to induce proliferation related genes. However, high E2F levels following pRB loss also induce apoptosis-promoting genes as a safeguard mechanism to suppress emergent tumors. Although p53 accumulation and apoptosis induction is believed to be a primary mechanism to eliminate cells with excess E2F activity, p53 deletion doesn't suppress RB/E2F induced apoptosis in vivo in the retina. This prompted us to test the PTEN/PI3K/AKT signaling pathway on RB/E2F apoptosis suppression in vivo, to ascertain if the PI3K pathway may provide a potential avenue for retinoblastoma therapy.We developed a mouse model in which Rb1 and Pten were conditionally deleted from retinal progenitor cells using Chx10-Cre, whereas Rbl1 (p107) was constitutively deleted. Pathway components were also tested individually by in vivo electroporation into newborn retinas for an effect on apoptosis and tumor initiation. Mouse retinal tissues were analyzed by immunohistochemistry (IHC) for proliferation, apoptosis, and pathway activation. ShRNAs were used in vitro to assess effects on apoptosis and gene expression.Co-deleting Pten with Rb1 and Rbl1 in mouse retinal progenitor cells (RPCs) causes fully penetrant bilateral retinoblastomas by 30 days and strongly suppresses Rb/E2F-induced apoptosis. In vivo electroporation of constitutively active (ca)-Pik3ca, ca-Akt, or dominant-negative (dn)-Foxo1 into apoptosis prone newborn murine retina with deleted Rb/p107 eliminate Rb/E2F induced apoptosis and induce retinoblastoma emergence. Retinal deletion of Pten activates p-AKT and p-FOXO1 signaling in incipient retinoblastoma. An unbiased shRNA screen focusing on Akt phosphorylation targets identified FOXOs as critical mediators of Rb/E2F induced apoptosis and expression of Bim and p73 pro-apoptotic genes.These data indicate that we defined a key molecular trigger involving E2F/FOXO functioning to control retinal progenitor cell homeostasis and retinoblastoma tumor initiation. We anticipate that our findings could provide contextual understanding of the proliferation of other progenitor cells, considering the high frequency of co-altered signaling from RB/E2F and PTEN/PI3K/AKT pathways in a wide variety of normal and malignant settings.
Arterial Hypoxemia Following Acute Myocardial Infarction
Authors: A. VALENCIA, J. H. BURGESS
Journal: Circulation (1969)

Arterial hypoxemia was common in 53 patients following acute myocardial infarction. It was most marked in patients with evidence of left ventricular failure. Arterial oxygen tension, however, was reduced in many of the patients who were without evidence of failure. An increase in arterial oxygen tension following three deep breaths suggested maldistribution of ventilation. Right-to-left shunting of blood was demonstrated by 100% oxygen studies. There was a significant correlation between reduced arterial oxygen tension and low pulmonary diffusing capacity, but a poor correlation between the former and a low cardiac index. We suggest that the hypoxemia following acute myocardial infarction is the result of abnormalities in small airways as well as of vascular congestion in the lungs. The patients with the lowest arterial oxygen tension at the time of study subsequently had more marked arrhythmias and a higher mortality rate.
Effect of altitude on oxygen binding by hemoglobin and on organic phosphate levels
Authors: Claude Lenfant, John Torrance, Eugenia English, Clement A. Finch, Cesar Reynafarje, Jose Ramos, Jose Faura
Journal: Journal of Clinical Investigation (1968)

The relationship between oxygen dissociation and 2,3-diphosphoglycerate (2,3-DPG) in the red cell has been studied in subjects moving from low to high altitude and vice versa. Within 24 hr following the change in altitude there was a change in hemoglobin affinity for oxygen; this modification therefore represents an important rapid adaptive mechanism to anoxia. A parallel change occurred in the organic phosphate content of the red cell. While this study does not provide direct evidence of a cause-effect relationship, the data strongly suggest that with anoxia, the observed rise in organic phosphate content of the red cell is responsible for increased availability of oxygen to tissues.
Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease
Authors: J Jasper Deuring, Gwenny M Fuhler, Sergey R Konstantinov, Maikel P Peppelenbosch, Ernst J Kuipers, Colin de Haar, C Janneke van der Woude
Journal: Gut (2013)

<h3>Objective</h3> Although genome wide association studies have partly uncovered the genetic basis of Crohn9s disease (CD), it remains a challenge to link genetic polymorphisms to functional intestinal phenotypes. Paneth cells are specialised antimicrobial epithelial cells localised to the small-intestinal crypt-base. Here, we investigate whether genomic variations in ATG16L1 affect Paneth cell function. <h3>Design</h3> Genomic variation of ATG16L1 (T300A, rs2241880) was determined in DNA from 78 patients with CD and 12 healthy controls. Paraffin-embedded ileal biopsies from patients with genotype AA (n=17), GA (n=38) and patients with the GG allele (n=23) were stained for GRP78, phospho-EIF2α, lysozyme, cleaved-caspase 3, phosphohistone H3, phospho-IκB, p65, phospho-p38MAPK and PHLDA1. Microbial composition of biopsies was assessed by PCR. Disease phenotype was scored. <h3>Results</h3> In patients with quiescent disease but with an ATG16L1 risk allele, the endoplasmic reticulum (ER) stress markers GRP78 and pEIF2α were highly expressed in Paneth cells. Other CD risk gene variations did not correlate with Paneth cell ER stress. Functionally, patients with ER-stressed Paneth cells showed no changes in intestinal epithelial cells proliferation or apoptosis, Paneth cell or stem cell numbers, p65, phospho-IκB and phospho-p38 staining. However, a significantly increased presence of adherent-invasive <i>Escherichia coli</i> was observed in biopsies from patients with ER-stressed Paneth cells. Phenotypically, patients with GRP78 positive Paneth cells have relatively less colonic disease over ileal disease (−21%, p=0.04), more fistulas (+21%, p=0.05) and an increased need for intestinal surgery (+38%, p=0.002). <h3>Conclusions</h3> The ATG16L1 T300A polymorphism defines a specific subtype of patients with CD, characterised by Paneth cell ER stress even during quiescent disease. Paneth cell ER stress correlates with bacterial persistence, and is thus likely to modulate antimicrobial functionality of this cell type in patients with CD.
Toll-like Receptor 3 and Geographic Atrophy in Age-Related Macular Degeneration
Authors: Zhenglin Yang, Charity Stratton, Peter J. Francis, Mark E. Kleinman, Perciliz L. Tan, Daniel Gibbs, Zongzhong Tong, Haoyu Chen, Ryan Constantine, Xian Yang, Yuhong Chen, Jiexi Zeng, Lisa Davey, Xiang Ma, Vincent S. Hau, Chi Wang, Jennifer Harmon, Jeanette Buehler, Erik Pearson, Shrena Patel, Yuuki Kaminoh, Scott Watkins, Ling Luo, Norman A. Zabriskie, Paul S. Bernstein, Wongil Cho, Andrea Schwager, David R. Hinton, Michael L. Klein, Sara C. Hamon, Emily Simmons, Beifeng Yu, Betsy Campochiaro, Janet S. Sunness, Peter Campochiaro, Lynn Jorde, Giovanni Parmigiani, Donald J. Zack, Nicholas Katsanis, Jayakrishna Ambati, Kang Zhang
Journal: New England Journal of Medicine (2008)

Age-related macular degeneration is the most common cause of irreversible visual impairment in the developed world. Advanced age-related macular degeneration consists of geographic atrophy and choroidal neovascularization. The specific genetic variants that predispose patients to geographic atrophy are largely unknown.We tested for an association between the functional toll-like receptor 3 gene (TLR3) variant rs3775291 (involving the substitution of phenylalanine for leucine at amino acid 412) and age-related macular degeneration in Americans of European descent. We also tested for the effect of TLR3 Leu and Phe variants on the viability of human retinal pigment epithelial cells in vitro and on apoptosis of retinal pigment epithelial cells from wild-type mice and Tlr3-knockout (Tlr3(-/-)) mice.The Phe variant (encoded by the T allele at rs3775291) was associated with protection against geographic atrophy (P=0.005). This association was replicated in two independent case-control series of geographic atrophy (P=5.43x10(-4) and P=0.002). No association was found between TLR3 variants and choroidal neovascularization. A prototypic TLR3 ligand induced apoptosis in a greater fraction of human retinal pigment epithelial cells with the Leu-Leu genotype than those with the Leu-Phe genotype and in a greater fraction of wild-type mice than Tlr3(-/-) mice.The TLR3 412Phe variant confers protection against geographic atrophy, probably by suppressing the death of retinal pigment epithelial cells. Since double-stranded RNA (dsRNA) can activate TLR3-mediated apoptosis, our results suggest a role of viral dsRNA in the development of geographic atrophy and point to the potential toxic effects of short-interfering-RNA therapies in the eye.
STUDIES ON THE PATHOGENESIS OF RABIES IN INSECTIVOROUS BATS
Authors: S. Edward Sulkin, Philip H. Krutzsch, Rae Allen, Craig Wallis
Journal: The Journal of Experimental Medicine (1959)

Studies on the pathogenesis of rabies in two species of experimentally infected insectivorous Chiroptera, the Mexican free-tailed bat (Tadarida mexicana), a quasi hibernator, and the little brown bat (Myotis lucifugus), a deep hibernator, provided evidence that brown adipose tissue may serve as an extraneural site for storage and multiplication of rabies virus. Although the Mexican free-tailed bat proved to be relatively insusceptible to experimental rabies infection, virus was demonstrated in the brown fat of 22 per cent of those animals shown to be infected by viral assay in white Swiss mice. Rabies infection in this species was most evident 20 to 40 days after intramuscular inoculation of virus. Rabies virus was found to be widely distributed in the little brown myotis 9 to 26 days following inoculation and virus concentrations in some of the tissues approached the level of the stock mouse brain virus suspension used in inoculating these bats. The shorter incubation period and higher virus titers in the tissues assayed reflect the increased susceptibility of Myotis lucifugus as compared with the Mexican free-tailed bat. Virus was demonstrated in the brown fat of 30 per cent of the experimentally infected Myotis. In the experimentally infected Myotis lucifugus and in the Syrian hamster which is highly susceptible to rabies infection, rabies virus was isolated more frequently from the brown fat than from the salivary gland indicating that in a susceptible host brown adipose tissue may be as frequent a site of viral proliferation as salivary gland. Since rabies virus was found to persist for long periods of time in the brown fat of experimentally infected bats and was occasionally demonstrated in this tissue alone, it is suggested that brown adipose tissue provides a mechanism by which these animals may serve as reservoirs for this agent in nature. The possibility that similar mechanisms may be involved in the maintenance of other viral agents during interepidemic periods is discussed.
The iron chelator deferasirox protects mice from mucormycosis through iron starvation
Authors: Ashraf S. Ibrahim, Teclegiorgis Gebermariam, Yue Fu, Lin Lin,, Mohamed I. Husseiny, Samuel W. French, Julie Schwartz, Christopher D. Skory, John E. Edwards, Brad J. Spellberg
Journal: Journal of Clinical Investigation (2007)

Mucormycosis causes mortality in at least 50% of cases despite current first-line therapies. Clinical and animal data indicate that the presence of elevated available serum iron predisposes the host to mucormycosis. Here we demonstrate that deferasirox, an iron chelator recently approved for use in humans by the US FDA, is a highly effective treatment for mucormycosis. Deferasirox effectively chelated iron from Rhizopus oryzae and demonstrated cidal activity in vitro against 28 of 29 clinical isolates of Mucorales at concentrations well below clinically achievable serum levels. When administered to diabetic ketoacidotic or neutropenic mice with mucormycosis, deferasirox significantly improved survival and decreased tissue fungal burden, with an efficacy similar to that of liposomal amphotericin B. Deferasirox treatment also enhanced the host inflammatory response to mucormycosis. Most importantly, deferasirox synergistically improved survival and reduced tissue fungal burden when combined with liposomal amphotericin B. These data support clinical investigation of adjunctive deferasirox therapy to improve the poor outcomes of mucormycosis with current therapy. As iron availability is integral to the pathogenesis of other infections (e.g., tuberculosis, malaria), broader investigation of deferasirox as an antiinfective treatment is warranted.
Transbronchial Needle Aspiration (TBNA) in Patients Infected with HIV
Authors: TIMOTHY J. HARKIN, CARLO CIOTOLI, DOREEN J. ADDRIZZO-HARRIS, DAVID P. NAIDICH, JAISHREE JAGIRDAR, WILLIAM N. ROM
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Transbronchial needle aspiration (TBNA) of intrathoracic lymph nodes has been shown to be useful in the diagnosis and staging of bronchogenic carcinoma. With the exception of sarcoidosis, the usefulness of TBNA has not been widely investigated in other clinical settings. We investigated the utility of TBNA with a 19-gauge histology needle in HIV-infected patients with mediastinal and hilar adenopathy at Bellevue Hospital Center. We performed 44 procedures in 41 patients. Adequate lymph node sampling was obtained in 35 of 44 (80%), and diagnostic material was obtained in 23 of 44 (52%) procedures. TBNA was the exclusive means of diagnosis in 13 of 41 (32%) patients. Of the 44 procedures, 23 (52%) were performed in patients with mycobacterial disease, with TBNA providing the diagnosis in 20 of 23 (87%). In these patients, positive TBNA specimens included smears of aspirated materials for acid-fast bacilli in 11, mycobacterial culture in 14, and histology in 15. In other diseases, TBNA diagnosed sarcoidosis with noncaseating granulomata in 2 of 4 patients and non-small cell lung cancer in 1 of 2 patients. TBNA was not helpful in other diseases including Pneumocystis carinii pneumonia, infection with Cryptococcus or Nocardia, bacterial pneumonia, viral pneumonia, and Kaposi's sarcoma. No pulmonary diagnosis was established in five patients. No complications of TBNA occurred. We conclude that TBNA through the flexible bronchoscope is safe and effective in the diagnosis of intrathoracic adenopathy in HIV-infected patients, and is particularly efficacious in the diagnosis of mycobacterial disease. Furthermore, TBNA may provide the only diagnostic specimen in almost one-third of HIV-infected patients, thereby sparing these patients more invasive procedures such as mediastinoscopy.
Short-Term Effects of Rapid Pacing on mRNA Level of Voltage-Dependent K <sup>+</sup> Channels in Rat Atrium
Authors: Takeshi Yamashita, Yuji Murakawa, Noriyuki Hayami, Ei-ichi Fukui, Yuji Kasaoka, Masashi Inoue, Masao Omata
Journal: Circulation (2000)

Atrial fibrillation causes electrophysiological changes of the atrium, thereby facilitating its maintenance. Although the expression of ion channels is modulated in chronic atrial fibrillation, it is yet unknown whether paroxysmal atrial fibrillation can also lead to electrical remodeling by affecting gene expression.To examine the short-term effects of rapid pacing on the mRNA level of voltage-dependent K(+) channels, high-rate atrial pacing was performed in Sprague-Dawley rat hearts. Total RNA was prepared from the atrial appendages from 0 to 8 hours after the onset of pacing, and mRNA levels of Kv1.2, Kv1. 4, Kv1.5, Kv2.1, Kv4.2, Kv4.3, erg, KvLQT1, and minK were determined by RNase protection assay. Among these 9 genes, the mRNA level of the Kv1.5 channel immediately and transiently increased, with bimodal peaks at 0.5 and 2 hours after the onset of pacing. Conversely, the pacing gradually and progressively decreased the mRNA levels of the Kv4.2 and Kv4.3 channels. The increase of Kv1.5 and the decrease of Kv4.2 and Kv4.3 mRNA levels were both rate dependent. In correspondence with the changes in the mRNA level, Kv1. 5 channel protein transiently increased in the membrane fraction of the atrium during a 2- to 8-hour pacing period. Electrophysiological findings that the shortening of the action potential produced by 4-hour pacing was almost abolished by a low concentration of 4-aminopyridine implied that the increased Kv1.5 protein was functioning.Even short-term high-rate atrial excitation could differentially alter the mRNA levels of Kv1.5, Kv4.2, and Kv4.3 in a rate-dependent manner. In particular, increased Kv1.5 gene expression, having a transient nature, implied the possible biochemical electrical remodeling unique to paroxysmal tachycardia.
Construction of an rtTA2s-m2/ttskid-Based transcription regulatory switch that displays no basal activity, good inducibility, and high responsiveness to doxycycline in mice and Non-Human primates
Authors: Stefania Lamartina, Luisa Silvi, Giuseppe Roscilli, Danilo Casimiro, Adam J Simon, Mary-Ellen Davies, John W Shiver, Cira Daniela Rinaudo, Immacolata Zampaglione, Elena Fattori, Stefano Colloca, Odalys Gonzalez Paz, Ralph Laufer, Hermann Bujard, Riccardo Cortese, Gennaro Ciliberto, Carlo Toniatti
Journal: Molecular Therapy (2003)

The tetracycline (Tc)-dependent system in its "on" version (rtTA system) displays a baseline activity in the uninduced state, severely limiting its potential applicability in human gene therapy. So far, two different strategies to circumvent this limitation have been described. On one side, co-expression of the tetracycline regulated repressor tTS(kid) has proved capable of substantially reducing the baseline activity of rtTA. On the other, novel versions of the activator, namely rtTA2(s)-S2 and rtTA2(s)-M2, with a lower basal activity have been engineered. We have combined these two approaches by co-expressing TS(kid) with the novel transactivators. Bicistronic vectors were constructed that co-express TS(kid) with rtTA, rtTA2(s)-S2, or rtTA2(s) M2, through an internal ribosome entry site (plasmids IRES-A, IRES-S2, and IRES-M2, respectively). IRES-M2 proved to be the most effective construct EX VIVO: it displayed a negligible basal activity, > 1000 fold inducibility, and high responsiveness to doxycycline (Dox). Upon delivery as plasmid DNA in mouse muscles, IRES-M2 facilitated 1000-fold induction of serum alkaline phosphatase (SEAP) gene expression and long-term, stringent, and strictly Dox-dose-dependent regulation of erythropoietin (Epo) gene expression. Tight regulation of the gene encoding SEAP was demonstrated also in non-human primates. Notably, the system was induced in animals by Dox-dosing regimens comparable to those used in humans.