tbuckley/cabot-search huggingface dataset:
Evidence for the horizontal acquisition of murine AKR virogenes by recent horizontal infection of the germ line
Authors: SJ O'Brien, JL Moore, MA Martin, JE Womack
Journal: The Journal of Experimental Medicine (1982)

Several recent reports (8, 10, 11, 13) have established the biological and molecular genetic similarity between the endogenous AKV virus of strain AKR, and an N-ecotropic endogenous virus found in the genome of feral Japanese mice, Mus musculus molossinus. The similarities are so striking as to suggest a common origin of these viruses, which are present in some, but not all, inbred mouse strains. The virogenes of AKR mice may have been acquired by either: (a) common descent of AKR (and other AKV(+) strains) from a common ancestor of AKR and molossinus animals, or (b) horizontal germ line infection of the AKR strains by molossinus virus at 1;he strain's inception followed by fixation through inbreeding. The sexual descent model carries with it a prediction of relative consanguinity of the AKR strain and molossinus, whereas the horizontal infection model does not. We have examined the polymorphic allozyme (allelic isozyme) genotype of 51 nonvirus-related loci in 17 strains of mice including AKR, C58, BALB/c, Swiss, and molossinus. By comparing the composite allozyme genotype of different inbred and outbred mouse strains, the "genetic distance" statistic was derived. Genetic distance measures the degree of allelic substitution between populations and increases proportionately with the amount of time the populations have been reproductively isolated. The genetic distance computed between molossinus and AKR is large, nearly 5-10 times the distance between known related populations and strains (e.g., C57L vs. C57BL/6). Molossinus had a similarly large distance from AKV negative strains (Swiss, C57L) as it did from AKV- positive strains. Cellular DNA sequences that flank the integrated AKV provirus were analyzed by restriction enzyme digestion of liver DNA from molossinus, AKR, and additional inbred strains that express ecotropic murine leukemia virus. The integration flanks of three AKR provirus sequences, Akv-1, Akv-2, and a third uncharacterized sequence, were not evident in molossinus cell DNA, which contained at least six different proviral integration fragments. These data effectively exclude the interpretation of consanguinity of AKR and molossinus and support the notion of acquisition of the endogenous virus in AKR by horizontal infection of the molossinus virus.
Association of Plasma Levels of F11 Receptor/Junctional Adhesion Molecule-A (F11R/JAM-A) With Human Atherosclerosis
Authors: Erdal Cavusoglu, Elizabeth Kornecki, Malgorzata B. Sobocka, Anna Babinska, Yigal H. Ehrlich, Vineet Chopra, Sunitha Yanamadala, Cyril Ruwende, Moro O. Salifu, Luther T. Clark, Calvin Eng, David J. Pinsky, Jonathan D. Marmur
Journal: Journal of the American College of Cardiology (2007)
Bortezomib Enhances the Efficacy of Fulvestrant by Amplifying the Aggregation of the Estrogen Receptor, Which Leads to a Proapoptotic Unfolded Protein Response
Authors: Yuki Ishii, Luena Papa, Urvashi Bahadur, Zhenyu Yue, Julio Aguirre-Ghiso, Toshi Shioda, Samuel Waxman, Doris Germain
Journal: Clinical Cancer Research (2011)

Fulvestrant is known to promote the degradation of the estrogen receptor (ER) in the nucleus. However, fulvestrant also promotes the aggregation of the newly synthesized ER in the cytoplasm. Accumulation of protein aggregates leads to cell death but this effect is limited as a result of their elimination by the proteasome. We tested whether combining fulvestrant with the proteasome inhibitor, bortezomib, could enhance the accumulation of ER aggregates and cause apoptotic cell death.The rate of aggregation of the ER was monitored in ER(+) breast cancer cells lines, T47D, ZR-75.1, BT474, MDA-MB-361, MCF-7, fulvestrant resistance MCF-7, and tamoxifen-resistant T47D-cyclin D1 cells. Activation of the unfolded protein response, apoptosis, and metabolic rate were also monitored in these cell lines following treatment with fulvestrant, bortezomib, or bortezomib in combination with fulvestrant.We found that bortezomib enhances the fulvestrant-mediated aggregation of the ER in the cytoplasm without blocking the degradation of the ER in the nucleus. Further, these aggregates activate a sustained unfolded protein response leading to apoptotic cell death. Further, we show that the combination induced tumor regression in a breast cancer mouse model of tamoxifen resistance.Adding bortezomib to fulvestrant enhances its efficacy by taking advantage of the unique ability of fulvestrant to promote cytoplasmic aggregates of the ER. As this effect of fulvestrant is independent of the transcriptional activity of the ER, these results suggest that this novel combination may be effective in breast cancers that are ER(+) but estrogen independent.
Global gene expression analysis of human erythroid progenitors
Authors: Alison T. Merryweather-Clarke, Ann Atzberger, Shamit Soneji, Nicki Gray, Kevin Clark, Craig Waugh, Simon J. McGowan, Stephen Taylor, Asoke K. Nandi, William G. Wood, David J. Roberts, Douglas R. Higgs, Veronica J. Buckle, Kathryn J. H. Robson
Journal: Blood (2011)
Determination of humoral immunoglobulins M and G directed against mycobacterial antigen 60 failed to diagnose primary tuberculosis and mycobacterial adenitis in children.
Authors: M Turneer, E Van Nerom, J Nyabenda, A Waelbroeck, A Duvivier, M Toppet
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

The serodiagnosis of primary tuberculosis (TB) and mycobacterial adenitis in children was tried using the Anda-Tb tests (Anda Biologicals, France) that measure immunoglobulins (Ig) M and G directed against mycobacterial antigen 60 (A60) by enzyme-linked immunosorbent assay. The 188 cases studied included 81 healthy or mycobacteria-unrelated diseased children with no reaction to tuberculin skin test (STN); 9 recent BCG vaccination (BCG); 35 asymptomatic (AsTB), 29 symptomatic (STB) primary TB and 11 adenitis caused by atypical mycobacteria from the group avium-intracellulare-scrofulaceum (MAIS) tested before treatment; and 23 past primary TB tested at different times after completion of specific treatment (past TB). The individual IgM and IgG levels largely overlapped whatever the clinical status of the children. Setting the normal upper limit at the 95th percentile of the STN values, which by definition gives 95% specificity, the highest IgM sensitivity was found in past TB (35%), AsTB showing 23%, STB 17%, and MAIS 18% sensitivity. IgG sensitivity was also the highest in past TB (26%) and was equal to 6, 14, and 9% in AsTB, STB, and MAIS, respectively. Positive and negative predictive values and the test efficiency (63 and 62% for IgM and IgG, respectively) were far too low. Combining positivity for IgM and/or IgG did not improve the results. In our study, the anti-A60 IgM and IgG measurements using the Anda-Tb tests in primary TB and mycobacterial adenitis in children did not prove of any diagnostic help.
Glycoxidation and lipid peroxidation of low-density lipoprotein can synergistically enhance atherogenesis
Authors: N Sakata
Journal: Cardiovascular Research (2001)

Objective: The purpose of this study was to clarify the role of glycoxidation and lipid peroxidation of low-density lipoprotein (LDL) in atherogenesis. Methods and results: We examined the formation of Nϵ-(carboxymethyl) lysine (CML), a glycoxidation product, and malondialdehyde (MDA), a lipid peroxidation product, in vitro and their co-localization in human atherosclerotic lesions. Immunochemical analysis revealed that CML was formed in a time-dependent manner by human LDL incubated with copper ions and glucose, i.e. an in vitro model of glycoxidation of LDL. When LDL was exposed to copper ions alone, a small amount of CML was formed, however this was significantly less in oxidized LDL than glycoxidative LDL. In contrast, MDA formation was observed in both oxidation and glycoxidation of LDL, but not in glycation of LDL. Hexitol-lysine (HL), an Amadori product, was formed by both glycation and glycoxidation of LDL, but not by oxidation of LDL. Immunohistochemical analysis showed that CML and MDA accumulated mainly in macrophage/foam cells, while pyrraline, a non-oxidative product of glycation, and apolipoprotein B were localized in the extracellular matrix in atherosclerotic lesions. Atheromas were positive for CML and MDA, but negative for pyrraline. Macrophage/foam cells in atherosclerotic lesions exhibited co-localization of macrophage scavenger receptor-A with CML and MDA, but not with pyrraline. Conclusion: Our results suggest that glycoxidation and lipid peroxidation of LDL synergistically promote the development of atherosclerotic lesions through interaction with macrophage scavenger receptor-A.
Mechanisms of heteroresistance to isoniazid and rifampin of<i>Mycobacterium tuberculosis</i>in Tashkent, Uzbekistan
Authors: S. Hofmann-Thiel, J. van Ingen, K. Feldmann, L. Turaev, G. T. Uzakova, G. Murmusaeva, D. van Soolingen, H. Hoffmann
Journal: European Respiratory Journal (2008)

Heteroresistance of Mycobacterium tuberculosis (MTB) is defined as the coexistence of susceptible and resistant organisms to anti-tuberculosis (TB) drugs in the same patient. Heteroresistance of MTB is considered a preliminary stage to full resistance. To date, no mechanism causing heteroresistance of MTB has been proven. Clinical specimens and cultures from 35 TB patients from Tashkent, Uzbekistan, were analysed using the Genotype MTBDR assay (Hain Lifescience, Nehren, Germany), which is designed to detect genetic mutations associated with resistance to rifampin and isoniazid. Cases of heteroresistance were further subjected to genotyping using mycobacterial interspersed repetitive unit-variable-number tandem repeat typing, spoligotyping and IS 6110 fingerprinting. Heteroresistance to rifampin and/or isoniazid was found in seven cases (20%). In five of them, heteroresistance was caused by two different strains and in two by a single strain of the Beijing genotype. The latter cases had a history of relapse of their TB. For the first time, two different mechanisms of heteroresistance in tuberculosis have been proven using a stepwise molecular-biological approach: 1) superinfection with two different strains, which is of interest for clinical infection control practitioners; and 2) splitting of a single strain into susceptible and resistant organisms. The latter mechanism is most likely to be related to poor treatment quality and could serve as a quality marker for tuberculosis therapy programmes in the future.
The Relationships between Arterial Oxygen Flow Rate, Oxygen Binding by Hemoglobin, and Oxygen Utilization after Myocardial Infarction
Authors: Marshall A. Lichtman, Jules Cohen, Jerald A. Young, April A. Whitbeck, Marion Murphy
Journal: Journal of Clinical Investigation (1974)

The interrelationships of arterial oxygen flow rate index, oxygen binding by hemoglobin, and oxygen consumption have been examined in patients with acute myocardial infarction. Proportional extraction of oxygen increased in close association with decreasing oxygen flow rate, and hence, whole body oxygen consumption was constant over nearly a three-fold variation in arterial oxygen flow rate. A reduction in hemoglobin-oxygen affinity at in vivo conditions of pH. Pco(2) and temperature also occurred in proportion to the reduction in arterial oxygen flow rate. Therefore, the increased proportional removal of oxygen from arterial blood at low oxygen flow rates, required to maintain oxygen consumption, may have been facilitated by the reduced affinity of hemoglobin for oxygen at in vivo conditions. However, the decrease in affinity did not appear to explain more than 30-40% of the increased extraction. Respiratory alkalosis was a frequent occurrence in these patients and 2,3-diphosphoglycerate was positively associated with blood pH as well as with the time-averaged proportion of deoxyhemoglobin in arterial and venous blood.Hemoglobin-oxygen affinity measured at standard conditions and the mixed venous oxygen saturation were equally good indicators of reduced arterial oxygen flow rate in patients without shock. However, Svo(2) is more easily measured and is a more useful indicator of reduced oxygen flow rate, since its relationship to oxygen flow appears to be independent of affinity changes and time.
An Address on Worthing: Its Climatic and Sanitary Conditions
Authors: W. J. Harris
Journal: BMJ (1886)

pathology of valvular diseases, nor what we know of their clinical his- tory, will allow us to set up absolute.rules of judging what will be their consequences and events in all cases, or how far they can or can- not be postponed.(Op.cit., p. 2319¾) We may also take heed to the wisdom of Stokes as expressed in the following passage: "The practitioner should never forget that local dwieases, theihselves incurable, may co-exist with an excellent state of the health for a period indefinitely long."Inasmuch as we may now fairly claim to approach the study of.eart-valve disease with fuller physiological knowledge, and more exact diagnostic method, than were available either in Latham's or Stokes's time, we may not uDnnaturally expect to begin a new, and, I would submit, a more hopeful chapter of prognostics in relation to it.To all, then, who will aid in this in- quiry, I say " Ausculta et perpende.
Blocking CXCR4-Mediated Cyclic AMP Suppression Inhibits Brain Tumor Growth<i>In vivo</i>
Authors: Lihua Yang, Erin Jackson, B. Mark Woerner, Arie Perry, David Piwnica-Worms, Joshua B. Rubin
Journal: Cancer Research (2007)

Abstract The chemokine CXCL12 and its cognate receptor CXCR4 regulate malignant brain tumor growth and are potential chemotherapeutic targets. However, the molecular basis for CXCL12-induced tumor growth remains unclear, and the optimal approach to inhibiting CXCR4 function in cancer is unknown. To develop such a therapeutic approach, we investigated the signaling pathways critical for CXCL12 function in normal and malignant cells. We discovered that CXCL12-dependent tumor growth is dependent upon sustained inhibition of cyclic AMP (cAMP) production, and that the antitumor activity of the specific CXCR4 antagonist AMD 3465 is associated with blocking cAMP suppression. Consistent with these findings, we show that pharmacologic elevation of cAMP with the phosphodiesterase inhibitor Rolipram suppresses tumor cell growth in vitro and, upon oral administration, inhibits intracranial growth in xenograft models of malignant brain tumors with comparable efficacy to AMD 3465. These data indicate that the clinical evaluation of phosphodiesterase inhibitors in the treatment of patients with brain tumors is warranted. [Cancer Res 2007;67(2):651–8]
Diagnosis of Nonpsychotic Patients in Community Clinics
Authors: M. Katherine Shear, Catherine Greeno, Jasbir Kang, Diane Ludewig, Ellen Frank, Holly A. Swartz, Miyako Hanekamp
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Diagnosis-specific, proven efficacious treatments are a major recent advance in psychiatry. Appropriate use of such treatments presupposes patients who meet the diagnostic criteria and clinicians who have accurately diagnosed the target disorder and comorbid conditions. Since little is known about whether these prerequisites are commonly met, the authors conducted a study at two community treatment sites to determine the frequency of various axis I diagnoses and the concordance between the diagnoses recorded in patient charts and those obtained by a structured interview. Given that a DSM diagnosis may not be sufficient to understand a patient's problems, the authors also obtained ratings of interpersonal functioning. METHOD: The subjects were 164 nonpsychotic patients who were seen at a rural (N=114) or urban (N=50) community treatment facility. Raters trained to reliably use the Structured Clinical Interview for DSM-IV (SCID) conducted diagnostic interviews. Clinical charts were reviewed to obtain clinical diagnoses. Patients completed questionnaires regarding interpersonal functioning. RESULTS: Most (N=145, 88%) of the patients met the SCID criteria for a current axis I diagnosis, and 53% (N=87) met the criteria for two or more disorders. Clinical and SCID diagnoses had poor agreement. Evidence was found for interpersonal dysfunction. CONCLUSIONS: Most patients met the diagnostic criteria for conditions for which there are proven treatments; however, inaccurate diagnosis proved common. This barrier to optimal treatment could be ameliorated with the use of structured interviews for common diagnoses. Scores on social/interpersonal measures support the premise that DSM symptoms provide only part of the relevant information about patients' conditions.
The number of X chromosomes influences protection from cardiac ischaemia/reperfusion injury in mice: one X is better than two
Authors: J. Li, X. Chen, R. McClusky, M. Ruiz-Sundstrom, Y. Itoh, S. Umar, A. P. Arnold, M. Eghbali
Journal: Cardiovascular Research (2014)

Sex differences in coronary heart disease have been attributed to sex hormones, whereas the potential role of the sex chromosomes has been ignored so far. Here, we investigated the role of the sex chromosomes in causing sex differences in myocardial ischaemia/reperfusion (I/R) injury. We used two unique mouse models, the ‘four core genotypes’ [XX mice with ovaries (XXF) or testes (XXM) and XY mice with ovaries (XYF) or testes (XYM)] and XY* (gonadal male or female mice with one or two X chromosomes). All mice were gonadectomized (GDX). In vivo or isolated Langendorff-perfused hearts were subjected to I/R injury. The in vivo infarct size in XY mice was significantly smaller than XX mice regardless of their gonadal type (24.5 ± 4.1% in XYF and 21.8 ± 3.3% in XYM vs. 37.0 ± 3.2% in XXF and 35.5 ± 2.1% in XXM, P < 0.01). Consistent with the results in vivo, the infarct size was markedly smaller and cardiac functional recovery was significantly better in XY mice compared with XX ex vivo. The mitochondrial calcium retention capacity was significantly higher in XY compared with XX mice (nmol/mg protein: XXF = 126 ± 9 and XXM = 192 ± 45 vs. XYF = 250 ± 56 and XYM = 286 ± 51, P < 0.05). In XY* mice, mice with 2X chromosomes had larger infarct size (2X females = 41.4 ± 8.9% and 2X males = 46.3 ± 9.5% vs. 1X females = 23.7 ± 3.9% and 1X males = 26.6 ± 6.9%, P < 0.05) and lower heart functional recovery, compared with those with 1X chromosome. Several X genes that escape X inactivation (Eif2s3x, Kdm6a, and Kdm5c) showed higher expression in XX than in XY hearts. XX mice have higher vulnerability to I/R injury compared with XY mice, which is due to the number of X chromosomes rather than the absence of the Y chromosome.
Gene expression signature for biliary atresia and a role for interleukin-8 in pathogenesis of experimental disease
Authors: Kazuhiko Bessho, Reena Mourya, Pranavkumar Shivakumar, Stephanie Walters, John C. Magee, Marepalli Rao, Anil G. Jegga, Jorge A. Bezerra
Journal: Hepatology (2014)

Biliary atresia (BA) is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to BA. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with BA at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls and seven normal controls, we identified 15 genes uniquely expressed in BA with an accuracy of 92.3%. Among these genes, IL8 and LAMC2 were sufficient to classify subjects with BA distinctly from diseased controls with an area under the curve of 0.934 (95% confidence interval [CI]: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of interleukin (IL)8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in IL8 was relevant to disease pathogenesis, we inactivated the signaling of IL8 homologs by genetic targeting of the Cxcr2 receptor in a murine model of experimental BA. Disruption of Cxcr2 shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice. Conclusion : The hepatic expression of IL8 and LAMC2 has high sensitivity for BA at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental BA. (Hepatology 2014;60:211–223)
Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced pancreatic carcinoma: A University of Chicago phase II consortium study
Authors: S. Mani, J.W. Kugler, D.F. Sciortino, J.C. Garcia, R.H. Ansari, R. Humerickhouse, F. Michelassi, M.C. Posner, K.L. Shulman, R.L. Schilsky, M. List, E.E. Vokes, S. Benner
Journal: Annals of Oncology (1998)

Uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) has broad anti-tumor activity for cancers arising from the gastrointestinal tract. However, there are no published data regarding the efficacy of leucovorin-modulated UFT in patients with pancreatic cancer. The objective of this trial was to determine the activity and evaluate the toxicity of UFT plus oral calcium leucovorin in patients with advanced pancreatic adenocarcinoma.Fourteen patients with advanced measurable adenocarcinoma of the pancreas were enrolled onto the trial. Patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided doses every eight hours for 28 days repeated every 35 days. Objective tumor response was evaluated after two courses of therapy.Fourteen patients were evaluable for response and toxicity. No objective responses were seen. The median (range) time to progression and survival were 14 (1.6-37), and 15 (1.9-62) weeks, respectively. Toxicity was mild with severe (grade 3 or 4) hyperbilirubinemia, pain, diarrhea, transaminitis, venous thrombus, weakness, renal failure, confusion, and edema/ascites seen in three (21%), one (7%), two (14%), one (7%), one (7%), one (7%), one (7%), one (7%), and two (14%) patients, respectively.In the 14 patients evaluable, UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate anti-tumor activity against advanced pancreatic adenocarcinoma; however, this oral regimen was well tolerated and devoid of neutropenia, significant oral mucositis or diarrhea.