tbuckley/cabot-search huggingface dataset:
Differential antitumor immunity mediated by NKT cell subsets in vivo
Authors: Nadine Y. Crowe, Jonathan M. Coquet, Stuart P. Berzins, Konstantinos Kyparissoudis, Rachael Keating, Daniel G. Pellicci, Yoshihiro Hayakawa, Dale I. Godfrey, Mark J. Smyth
Journal: The Journal of Experimental Medicine (2005)

We showed previously that NKT cell-deficient TCR Jalpha18(-/-) mice are more susceptible to methylcholanthrene (MCA)-induced sarcomas, and that normal tumor surveillance can be restored by adoptive transfer of WT liver-derived NKT cells. Liver-derived NKT cells were used in these studies because of their relative abundance in this organ, and it was assumed that they were representative of NKT cells from other sites. We compared NKT cells from liver, thymus, and spleen for their ability to mediate rejection of the sarcoma cell line (MCA-1) in vivo, and found that this was a specialized function of liver-derived NKT cells. Furthermore, when CD4(+) and CD4(-) liver-derived NKT cells were administered separately, MCA-1 rejection was mediated primarily by the CD4(-) fraction. Very similar results were achieved using the B16F10 melanoma metastasis model, which requires NKT cell stimulation with alpha-galactosylceramide. The impaired ability of thymus-derived NKT cells was due, in part, to their production of IL-4, because tumor immunity was clearly enhanced after transfer of IL-4-deficient thymus-derived NKT cells. This is the first study to demonstrate the existence of functionally distinct NKT cell subsets in vivo and may shed light on the long-appreciated paradox that NKT cells function as immunosuppressive cells in some disease models, whereas they promote cell-mediated immunity in others.
Loss of Cables, a Cyclin-Dependent Kinase Regulatory Protein, Is Associated with the Development of Endometrial Hyperplasia and Endometrial Cancer
Authors: Lawrence R. Zukerberg, Robert L. DeBernardo, Sandra D. Kirley, Massimo D’Apuzzo, Maureen P. Lynch, Ramey D. Littell, Linda R. Duska, Landin Boring, Bo R. Rueda
Journal: Cancer Research (2004)

Abstract Endometrial cancer is the most common gynecological cancer in Western industrialized countries. Cables, a cyclin-dependent kinase binding protein, plays a role in proliferation and/or differentiation. Cables mutant mice are viable, but develop endometrial hyperplasia and carcinoma in situ at a young age. Exposure to chronic low levels of estrogen results in development of endometrial cancer, similar to that observed in the postmenopausal female. In vitro and in vivo studies demonstrate that levels of Cables mRNA in benign human endometrial epithelium are up-regulated by progesterone and down-regulated by estrogen. Furthermore, nuclear immunostaining for Cables is lost in a high percentage of cases of human endometrial hyperplasia and adenocarcinoma, which are likely the product of unopposed estrogen. The loss of Cables immunostaining in the human endometrial cancer samples correlates with a marked decrease in Cables mRNA. Ectopic expression of Cables in human endometrial cells dramatically slows cell proliferation. Collectively, these data provide evidence that Cables is hormonally regulated and is involved in regulating endometrial cell proliferation. In addition, loss or suppression of Cables may be an early step in the development of endometrial cancer.
Identification of the Source of Androgen Excess in Hyperandrogenic Type 1 Diabetic Patients
Authors: Belén Roldán, Héctor F. Escobar-Morreale, Raquel Barrio, Hermenegildo de la Calle, Milagros Alonso, Rafael García-Robles, José Sancho
Journal: Diabetes Care (2001)

We recently reported that the prevalence of hyperandrogenic disorders is markedly increased in women with type 1 diabetes (1). The polycystic ovary syndrome (PCOS) defined by endocrine criteria was found in 18.8% of the type 1 diabetic women who followed-up in our hospital (1), as compared with the 6.5% prevalence in nondiabetic women from similar ethnic and genetic backgrounds (2). The prevalence of hirsutism in type 1 diabetic women was 30.6% (1), which is markedly higher than the 7.1% prevalence of hirsutism found in nondiabetic women (2).

In the present study, we evaluated the adrenal and ovarian steroidogenic profiles of hyperandrogenic and nonhyperandrogenic type 1 diabetic women and compared them with those of nondiabetic hyperandrogenic women and healthy control subjects.

A total of 24 women with type 1 diabetes were recruited for the study (1). Fourteen diabetic patients (age [mean ± SD] 20.6 ± 4.0 years, BMI 24.8 ± 2.9 kg/m2) were considered to have hyperandrogenism. The other 10 women with type 1 diabetes (age 19.0 ± 3.0 years, BMI 23.3 ± 2.6 kg/m2) had no evidence of clinical or biochemical hyperandrogenism and had regular menstrual cycles. Both groups of type 1 diabetic patients had similar HbA1c levels (7.4 ± 1.2 vs 7.8 ± 1.2% in nonhyperandrogenic and hyperandrogenic diabetic patients, respectively, F = 0.591, P = 0.450), and there were no differences in the mean daily insulin dose used for their treatment (0.82 ± 0.27 vs. 0.66 ± 0.28 U · kg−1 body wt · day−1 in nonhyperandrogenic and hyperandrogenic diabetic patients, F = 1.875, P = 0.185).

A total of 86 nondiabetic women were included as control subjects. Nondiabetic women were matched for BMI and age with the diabetic patients to avoid any influence of age and obesity on the results. Thirteen …
Prediction of LDL cholesterol response to statin using transcriptomic and genetic variation
Authors: Kyungpil Kim, Eugene Bolotin, Elizabeth Theusch, Haiyan Huang, Marisa W Medina, Ronald M Krauss
Journal: Genome biology (2014)

Abstract Background Statins are widely prescribed for lowering LDL-cholesterol (LDLC) levels and risk of cardiovascular disease. There is, however, substantial inter-individual variation in the magnitude of statin-induced LDLC reduction. To date, analysis of individual DNA sequence variants has explained only a small proportion of this variability. The present study was aimed at assessing whether transcriptomic analyses could be used to identify additional genetic contributions to inter-individual differences in statin efficacy. Results Using expression array data from immortalized lymphoblastoid cell lines derived from 372 participants of the Cholesterol and Pharmacogenetics clinical trial, we identify 100 signature genes differentiating high versus low statin responders. A radial-basis support vector machine prediction model of these signature genes explains 12.3% of the variance in statin-mediated LDLC change. Addition of SNPs either associated with expression levels of the signature genes (eQTLs) or previously reported to be associated with statin response in genome-wide association studies results in a combined model that predicts 15.0% of the variance. Notably, a model of the signature gene associated eQTLs alone explains up to 17.2% of the variance in the tails of a separate subset of the Cholesterol and Pharmacogenetics population. Furthermore, using a support vector machine classification model, we classify the most extreme 15% of high and low responders with high accuracy. Conclusions These results demonstrate that transcriptomic information can explain a substantial proportion of the variance in LDLC response to statin treatment, and suggest that this may provide a framework for identifying novel pathways that influence cholesterol metabolism.
Follow-up of the Finnish Asthma Programme 2000–2010: reduction of hospital burden needs risk group rethinking
Authors: Paula Kauppi, Miika Linna, Jaana Martikainen, Mika J Mäkelä, Tari Haahtela
Journal: Thorax (2012)

The Finnish Asthma Programme 1994–2004 focused on early intervention and disease control, thereby resulting in a significant reduction of asthma morbidity. During the follow-up period from 2000 to 2010, the number of hospital days continued to fall by 54%. Patients ≥65 years, especially women, accounted for 39% of the hospital days, and they need attention if the hospital burden is to be reduced further.
Response to: ‘Is there a direct relationship between serum level of methotrexate and clinical efficacy and tolerability?’ by Fleishman and Yazici
Authors: Michael H Schiff, Jonathan S Jaffe, Bruce Freundlich
Journal: Annals of the Rheumatic Diseases (2014)

Drs Fleishman and Yazici pose several worthwhile questions.1 It is important to appreciate that this was not a clinical trial, but rather a classic pharmacokinetic study. Unlike previous studies, ours compared commonly used doses of two different formulations of methotrexate (MTX), subcutaneous (SC) and oral. The key concept demonstrated is that the absorption of oral MTX is both variable and saturable. Because there is extensive overlap in the …
Comparison of tuberculosis surveillance systems in low-incidence industrialised countries
Authors: Z. Mor, G. B. Migliori, S. P. Althomsons, R. Loddenkemper, L. Trnka, M. F. Iademarco
Journal: European Respiratory Journal (2008)

The comparative analysis of National Tuberculosis Control Programmes (NTPs) in industrialised, low-tuberculosis-incidence countries is limited. Analysis of applied methods, function and accumulated experience contributes to improving global tuberculosis control. A questionnaire addressing NTP surveillance infrastructure and characteristics was completed in 19 industrialised countries, with populations of &gt;3 million and annual notified tuberculosis incidence rates of &lt;16 cases per 100,000 population (2003 data). All European countries surveyed adopted World Health Organization Collaborating Centre for the Surveillance of Tuberculosis in Europe (EuroTB) definitions. Surveillance information, which usually includes names, was transferred electronically to the national level in 17 out of the 19 countries. Surveillance systems capture process and social determinants. Case notification to the central level occurred within a median period of 7 days, independent of mandatory notification requirements. The mean completeness of tuberculosis case-reporting was estimated to be 93.5% (range 65–100%). Integration between HIV and tuberculosis registries was performed in two countries, and, in seven others, both databases were cross-matched periodically. National Tuberculosis Control Programme function in industrialised low-incidence countries utilises well-established infrastructure and relies upon centralised operations. Approaches are consistent with current World Health Organization surveillance recommendations. The present study lays collaborative groundwork for additional multinational analyses for the enhancement of global tuberculosis surveillance, which may assist policy-makers in countries moving from medium to low rates of incidence.
Transient and Steady-State Effects of Shear Stress on Endothelial Cell Adherens Junctions
Authors: Sabrena Noria, Douglas B. Cowan, Avrum I. Gotlieb, B. Lowell Langille
Journal: Circulation Research (1999)

Abstract —Endothelial cells exhibit profound changes in cell shape in response to altered shear stress that may require disassembly/reassembly of adherens junction protein complexes that mediate cell-cell adhesion. To test this hypothesis, we exposed confluent porcine aortic endothelial cells to 15 dyne/cm 2 of shear stress for 0, 8.5, 24, or 48 hours, using a parallel plate flow chamber. Cells were fixed and stained with antibodies to vascular endothelial (VE) cadherin, α-catenin, β-catenin, or plakoglobin. Under static conditions, staining for all proteins was intense and peripheral, forming a nearly continuous band around the cells at cell-cell junctions. After 8.5 hours of shear stress, staining was punctate and occurred only at sites of continuous cell attachment. After 24 or 48 hours of shear, staining for VE-cadherin, α-catenin, and β-catenin was intense and peripheral, forming a band of “dashes” (adherens plaques) that colocalized with the ends of stress fibers that inserted along the lateral membranes of cells. Staining for plakoglobin was not observed after 24 hours of shear stress, but returned after 48 hours. Western blot analysis indicated that protein levels of VE-cadherin, α-catenin, and plakoglobin decreased, whereas β-catenin levels increased after 8.5 hours of shear stress. As cell shape change reached completion (24 to 48 hours), all protein levels were upregulated except for plakoglobin, which remained below control levels. The partial disassembly of adherens junctions we have observed during shear induced changes in endothelial cell shape may have important implications for control of the endothelial permeability barrier and other aspects of endothelial cell function.
A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2
Authors: Honglin Song, Susan J Ramus, Jonathan Tyrer, Kelly L Bolton, Aleksandra Gentry-Maharaj, Eva Wozniak, Hoda Anton-Culver, Jenny Chang-Claude, Daniel W Cramer, Richard DiCioccio, Thilo Dörk, Ellen L Goode, Marc T Goodman, Joellen M Schildkraut, Thomas Sellers, Laura Baglietto, Matthias W Beckmann, Jonathan Beesley, Jan Blaakaer, Michael E Carney, Stephen Chanock, Zhihua Chen, Julie M Cunningham, Ed Dicks, Jennifer A Doherty, Matthias Dürst, Arif B Ekici, David Fenstermacher, Brooke L Fridley, Graham Giles, Martin E Gore, Immaculata De Vivo, Peter Hillemanns, Claus Hogdall, Estrid Hogdall, Edwin S Iversen, Ian J Jacobs, Anna Jakubowska, Dong Li, Jolanta Lissowska, Jan Lubiński, Galina Lurie, Valerie McGuire, John McLaughlin, Krzysztof Mędrek, Patricia G Moorman, Kirsten Moysich, Steven Narod, Catherine Phelan, Carole Pye, Harvey Risch, Ingo B Runnebaum, Gianluca Severi, Melissa Southey, Daniel O Stram, Falk C Thiel, Kathryn L Terry, Ya-Yu Tsai, Shelley S Tworoger, David J Van Den Berg, Robert A Vierkant, Shan Wang-Gohrke, Penelope M Webb, Lynne R Wilkens, Anna H Wu, Hannah Yang, Wendy Brewster, Argyrios Ziogas, Richard Houlston, Ian Tomlinson, Alice S Whittemore, Mary Anne Rossing, Bruce A J Ponder, Celeste Leigh Pearce, Roberta B Ness, Usha Menon, Susanne Krüger Kjaer, Jacek Gronwald, Montserrat Garcia-Closas, Peter A Fasching, Douglas F Easton, Georgia Chenevix-Trench, Andrew Berchuck, Paul D P Pharoah, Simon A Gayther
Journal: Nature Genetics (2009)
Ipilimumab: An Anti-CTLA-4 Antibody for Metastatic Melanoma
Authors: Evan J. Lipson, Charles G. Drake
Journal: Clinical Cancer Research (2011)

Ipilimumab (MDX-010, Yervoy; Bristol-Myers Squibb), a fully human monoclonal antibody against CTL antigen 4 (CTLA-4), was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma. In both early- and late-phase trials, ipilimumab has shown consistent activity against melanoma. For example, in a randomized phase III trial that enrolled patients with previously treated metastatic disease, ipilimumab, with or without a peptide vaccine, improved overall survival: Median overall survival was 10.1 and 10.0 months in the ipilimumab and ipilimumab plus vaccine arms, respectively, versus 6.4 months in the vaccine-alone group (hazard ratio, 0.68; P ≤ 0.003). Serious (grade 3-5) immune-related adverse events occurred in 10% to 15% of patients. Thus, although it provides a clear survival benefit, ipilimumab administration requires careful patient monitoring and sometimes necessitates treatment with immune-suppressive therapy. Here, we review the mechanism of action, preclinical data, and multiple clinical trials that led to FDA approval of ipilimumab for metastatic melanoma.
RB acute loss induces centrosome amplification and aneuploidy in murine primary fibroblasts
Authors: Flora Iovino, Laura Lentini, Angela Amato, Aldo Di Leonardo
Journal: Molecular Cancer (2006)

Abstract Background Incorrect segregation of whole chromosomes or parts of chromosome leads to aneuploidy commonly observed in cancer. The correct centrosome duplication, assuring assembly of a bipolar mitotic spindle, is essential for chromosome segregation fidelity and preventing aneuploidy. Alteration of p53 and pRb functions by expression of HPV16-E6 and E7 oncoproteins has been associated with centrosome amplification. However, these last findings could be the result of targeting cellular proteins in addition to pRb by HPV16-E7 oncoprotein. To get a more detailed picture on the role of pRb in chromosomal instability and centrosome amplification, we analyzed the effects of the acute loss of retinoblastoma gene function in primary conditional Rb deficient mouse embryonic fibroblasts (MEFs). Moreover, since pRb is a transcriptional repressor, microarray analysis was done on pRb-competent and pRb-deficient MEFs to evaluate changes in expression of genes for centrosome homeostasis and for correct mitosis. Results Acute loss of pRb induces centrosome amplification and aneuploidy in the vast majority of cells analyzed. A time course analysis shows a decrease of cells with amplified centrosomes after 40 days from the adenoviral infection. At this time only 12% of cells still show amplified centrosomes. Interestingly, cells with pRb constitutive loss show a similar percentage of cells with amplified centrosomes. DNA-Chip analyses in MEFs wt (mock infected) and pRb depleted (Ad-Cre infected) cells reveal differential expression of genes controlling both centrosome duplication and mitotic progression. Conclusion Our findings suggest a direct link between pRb status, centrosome amplification and chromosomal instability, and define specific mitotic genes as targets whose gene expression has to be altered to achieve or maintain aneuploidy.
Bedside methods<i>versus</i>dual energy X‐ray absorptiometry for body composition measurement in COPD
Authors: M.C. Steiner, R.L. Barton, S.J. Singh, M.D.L. Morgan
Journal: European Respiratory Journal (2002)

The measurement of body composition is of value in the nutritional assessment of patients with chronic obstructive pulmonary disease (COPD). The purpose of the present study was to compare two bedside methods for the measurement of body composition using dual energy X‐ray absorptiometry (DEXA) as a reference method. Fat-free mass (FFM) was measured using DEXA, bioelectric impedance analysis (BIA) and skinfold anthropometry (SFA) in a cohort of 85 COPD patients accepted for pulmonary rehabilitation. Patients whose body mass index was &gt;30 were excluded. Relative to DEXA, BIA underestimated FFM, whereas it was overestimated by SFA. There was a systematic increase in bias with mean FFM for both DEXA versus BIA and DEXA versus SFA, but this was almost eliminated when results were expressed as FFM index. Significant sex differences in the bias of BIA and SFA measurements of FFM were found. Forty-two (49.4%) patients were identified as nutritionally depleted using DEXA. Compared to DEXA, the sensitivity for detecting nutritional depletion was 86 and 74% for BIA and SFA, respectively, and the specificity 88 and 98%, respectively. There are significant intermethod differences in the measurement of body composition in chronic obstructive pulmonary disease patients. The choice of measurement method will have implications for nutritional assessment in chronic obstructive pulmonary disease.
Sphingosine-1-phosphate effects on guinea pig atrial myocytes: Alterations in action potentials and K+ currents
Authors: R OCHI, Y MOMOSE, K OYAMA, W GILES
Journal: Cardiovascular Research (2006)

Sphingosine-1-phosphate (S-1-P), a potent lysophospholipid mediator which is released from platelets during clotting, activates a G-protein-gated inwardly rectifying K+ current (GIRK) in atrial and sino-atrial node myocytes. We denote this current I(K(S-1-P).) A similar GIRK, which is activated by acetylcholine (ACh) and denoted I(K(ACh)), is expressed in atrium. It shortens the action potential duration (APD) and reduces the effective refractory period (ERP). We have examined the effect of S-1-P on APD in guinea pig atrial myocytes by characterizing the rectification properties of I(K(S-1-P)) and evaluating whether I(K(S-1-P)) and I(K(ACh)) exhibit convergence/occlusion.Membrane potential and K+ currents were recorded from guinea pig atrial myocytes. Inwardly rectifying K+ currents were recorded using a ramp voltage clamp waveform between +30 to -130 mV from a holding potential of -7 mV. Agonist-induced current changes were obtained by subtracting the control current.S-1-P (1 and 10 nM) altered both passive and active properties of atrial myocytes. S-1-P increased the threshold current for excitation and decreased the time constant of the subthreshold electrotonic potentials. In addition, both APD50 and APD90 were decreased substantially. Voltage clamp analysis showed that the outward conductance of I(K(IR)) (G(K(IR)out)) was 134.8+/-11.3 pS pF(-1) (n = 19) in S-1-P (100 nM), and 207.0+/-19.6 pS pF(-1) (n = 18) in ACh (10 microM). The ratio of G(K(IR)out):G(K(IR)in) was about 0.7 for both S-1-P and ACh. The EC50 values for the activation of G(K(IR)out) and G(K(IR)in) by S-1-P were 1.6 and 1.3 nM, respectively. Addition of S-1-P (100 nM) after the effect of ACh (10 microM) had developed fully caused very little additional change.I(K(S-1-P)) is carried by weakly inwardly-rectifying K+ channels that are the same as those activated by ACh. This K+ current can markedly shorten APD in guinea pig atrial myocytes. This effect would be expected to increase the incidence of atrial rhythm disturbances.
Sarcoidosis: social predictors of severity at presentation
Authors: D.L. Rabin, B. Thompson, K.M. Brown, M.A. Judson, X. Huang, D.T. Lackland, G.L. Knatterud, H. Yeager, C. Rose, J. Steimel
Journal: European Respiratory Journal (2004)

To determine relationships among social predictors and sarcoidosis severity at presentation, demographic characteristics, socioeconomic status, and barriers to care, A Case-Control Etiologic Study of Sarcoidosis (ACCESS) was set up. Patients self-reported themselves to be Black or White and were tissue-confirmed incident cases aged ≥l8-yrs-old (n=696) who had received uniform assessment procedures within one of 10 medical centres and were studied using standardised questionnaires and physical, radiographical, and pulmonary function tests. Severity was measured by objective disease indicators, subjective measures of dyspnoea and short form-36 subindices. The results of the study showed that lower income, the absence of private or Medicare health insurance, and other barriers to care were associated with sarcoidosis severity at presentation, as were race, sex, and age. Blacks were more likely to have severe disease by objective measures, while women were more likely than males to report subjective measures of severity. Older individuals were more likely to have severe disease by both measures. In conclusion, it was found that low income and other financial barriers to care are significantly associated with sarcoidosis severity at presentation even after adjusting for demographic characteristics of race, sex, and age.