tbuckley/cabot-search huggingface dataset:
Randomized trial of high-dose adjuvant chemotherapy with autologous hematopoietic stem-cell support versus standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: overall survival after 6 years of follow-up
Authors: A.R. Zander, C. Schmoor, N. Kröger, W. Krüger, V. Möbus, N. Frickhofen, B. Metzner, W.E. Berdel, M. Koenigsmann, E. Thiel, H. Wandt, K. Possinger, R. Kreienberg, M. Schumacher, W. Jonat
Journal: Annals of Oncology (2008)
Prospective Study of Gefitinib in Epidermal Growth Factor Receptor Fluorescence In Situ Hybridization–Positive/Phospho-Akt–Positive or Never Smoker Patients With Advanced Non–Small-Cell Lung Cancer: The ONCOBELL Trial
Authors: Federico Cappuzzo, Claudia Ligorio, Pasi A. Jänne, Luca Toschi, Elisa Rossi, Rocco Trisolini, Daniela Paioli, Alison J. Holmes, Elisabetta Magrini, Giovanna Finocchiaro, Stefania Bartolini, Alessandra Cancellieri, Fortunato Ciardiello, Marco Patelli, Lucio Crino, Marileila Varella-Garcia
Journal: Journal of Clinical Oncology (2007)

Purpose In non–small-cell lung cancer (NSCLC), clinical and biologic predictors for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor sensitivity have been identified in retrospective studies, and there is urgent need to validate these results in prospective trials. The ONCOBELL trial is a prospective phase II study evaluating gefitinib sensitivity in NSCLC patients who never smoked or have increased EGFR gene copy number or activation of the antiapoptotic protein Akt. Patients and Methods EGFR gene copy number was evaluated using fluorescence in situ hybridization (FISH), and presence of phospho-Akt was evaluated using immunohistochemistry. Additional tests included immunohistochemistry analysis of EGFR, FISH analysis of HER2, and mutation analysis of EGFR, HER2, and K-ras. Results From November 2004 to February 2006, 183 patients were screened, and 42 patients were enrolled onto the trial. We observed one complete and 19 partial responses, for an overall response rate (RR) of 47.6% (95% CI, 32.5% to 62.7%). Median duration of response was 6.1 months, median time to progression (TTP) was 6.4 months, 1-year survival rate was 64.3%, and median survival time was not reached. EGFR FISH–positive patients, compared with negative patients, had higher RR (68.0% v 9.1%, respectively; P &lt; .001), longer TTP (7.6 v 2.7 months, respectively; P = .02), and a trend for longer survival (median survival not reached v 7.4 months, respectively; P = .3). Therapy was well tolerated, and there were no drug-related deaths. Median follow-up time was too short for significance tests of differences in survival outcomes. Conclusion Gefitinib is active and well tolerated in patients with trial characteristics, and EGFR FISH analysis is an accurate predictor for such therapy.
Role for Mismatch Repair Proteins Msh2, Mlh1, and Pms2 in Immunoglobulin Class Switching Shown by Sequence Analysis of Recombination Junctions
Authors: Carol E. Schrader, Joycelyn Vardo, Janet Stavnezer
Journal: The Journal of Experimental Medicine (2002)

B cells from mice deficient in mismatch repair (MMR) proteins show decreased ability to undergo class switch recombination in vitro and in vivo. The deficit is not accompanied by any reduction in cell viability or alterations in the cell cycle in B cells cultured in vitro. To assess the role of MMR in switching we examined the nucleotide sequences of Sμ-Sγ3 recombination junctions in splenic B cells induced in culture to switch to IgG3. The data demonstrate clear differences in the sequences of switch junctions in wild-type B cells in comparison with Msh2-, Mlh1-, and Pms2-deficient B cells. Sequences of switch junctions from Msh2-deficient cells showed decreased lengths of microhomology between Sμ and Sγ3 relative to junctions from wild-type cells and an increase in insertions, i.e., nucleotides which do not appear to be derived from either the Sμ or Sγ3 parental sequence. By contrast, 23% of junctions from Mlh1- and Pms2-deficient cells occurred at unusually long stretches of microhomology. The data indicate that MMR proteins are directly involved in class switching and that the role of Msh2 differs from that of Mlh1 and Pms2.
Serum immunoglobulins and the risk of rheumatoid arthritis
Authors: K Aho, M Heliovaara, P Knekt, A Reunanen, A Aromaa, A Leino, P Kurki, R Heikkila, T Palosuo
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVE</h3> Rheumatoid arthritis (RA) is associated with several autoantibodies that can precede the clinical disease. The immunoglobulin concentrations in serum samples before illness were studied to learn more about the immunological process before RA. <h3>METHODS</h3> A case-control study was nested within a Finnish cohort of 19 072 adults who had neither arthritis nor a history of it at the baseline examination during 1973–1977. By late 1989, 124 had developed RA, of which 89 were positive for rheumatoid factor (RF). Three controls per each incident case were individually matched for sex, age, and municipality. The concentrations of IgG, IgA, and IgM were measured from stored serum samples. <h3>RESULTS</h3> Serum IgG before illness was found to be directly proportional to the risk of RF positive RA, and a non-linear association was present between serum IgA and the risk of RF positive RA. These associations were constant between men and women and other subgroups of the study population and not confounded by serum orosomucoid concentration, level of education, smoking, alcohol intake or body mass index. As adjusted for these factors, the odds ratios (95% confidence intervals) of RF positive RA in the lowest, mid, and highest tertiles of IgG distribution were 1.00, 1.55 (0.81, 2.97), and 2.22 (1.16, 4.26), and in the tertiles of IgA 1.00, 2.23 (1.14, 4.36), and 1.78 (0.89, 3.57), respectively. The associations persisted throughout the entire observation period but were most distinct when the period to the onset of clinical RA was ≥ 10 years. IgM carried no predictive significance. None of the serum immunoglobulins predicted the development of RF negative RA. <h3>CONCLUSIONS</h3> Increased IgG levels may reflect some, at present unknown process in the early events leading to the development of RA, typically occurring ≥ 10 years before the onset of clinical disease.
The modulation of lymphocyte functions by molecules secreted by macrophages. II. Conditions leading to increased secretion.
Authors: E R Unanue, J M Kiely, J Calderon
Journal: The Journal of Experimental Medicine (1976)

Cultures of peritoneal exudate cells rich in macrophages were studied for the secretion of lymphostimulatory molecules. Two conditions produced increased secretion: (a) addition to the cultures of various agents that readily interacted with macrophages, such as latex particles, antibody-coated red cells, endotoxin, Listeria organisms, or Be salt; or (b) addition of activated lymphocytes. In the first case the increased activity was found during the first 24 or 48 h after uptake of the stimuli. Increased activity was found in normal or peptone-stimulated macrophages but not in macrophages after injection of endotoxin or thioglycollate. The addition of T lymphocytes from Listeria-infected mice to macrophage cultures increased greatly the activities. This increase was also produced by addition to antigen-primed T cells together with antigen. The lymphocytes by themselves did not secrete active factors. The lymphostimulatory activities were tested on thymocyte DNA synthesis and on antibody formation in vitro. The latter assay was done on spleen cells from immunized mice where one striking effect was the stimulation of differentiation to antibody-secreting cells. Some dissociation of both activities (thymocyte DNA synthesis and B-cell differentiation) was observed with selected culture fluids.
Lung Function Growth in Children with Long-Term Exposure to Air Pollutants in Mexico City
Authors: Rosalba Rojas-Martinez, Rogelio Perez-Padilla, Gustavo Olaiz-Fernandez, Laura Mendoza-Alvarado, Hortensia Moreno-Macias, Teresa Fortoul, William McDonnell, Dana Loomis, Isabelle Romieu
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Although short-term exposure to air pollution has been associated with acute, reversible lung function decrements, the impact of long-term exposure has not been well established.To evaluate the association between long-term exposure to ozone (O(3)), particulate matter less than 10 mum in diameter (PM(10)), and nitrogen dioxide (NO(2)) and lung function growth in Mexico City schoolchildren.A dynamic cohort of 3,170 children aged 8 years at baseline was followed from April 23, 1996, through May 19, 1999. The children attended 39 randomly selected elementary schools located near 10 air quality monitoring stations and were visited every 6 months. Statistical analyses were performed using general linear mixed models.After adjusting for acute exposure and other potential confounding factors, deficits in FVC and FEV(1) growth over the 3-year follow-up period were significantly associated with exposure to O(3), PM(10), and NO(2). In multipollutant models, an interquartile range (IQR) increase in mean O(3) concentration (IQR, 11.3 ppb) was associated with an annual deficit in FEV(1) of 12 ml in girls and 4 ml in boys, an IQR range (IQR, 36.4 microg/m(3)) increase in PM(10) with an annual deficit in FEV(1) of 11 ml in girls and 15 ml in boys, and an IQR range (IQR, 12.0 ppb) increase in NO(2) with an annual deficit in FEV(1) of 30 ml in girls and 25 ml in boys.We conclude that long-term exposure to O(3), PM(10), and NO(2) is associated with a deficit in FVC and FEV(1) growth among schoolchildren living in Mexico City.
Vitamin C Inactivates the Proteasome Inhibitor PS-341 in Human Cancer Cells
Authors: Wei Zou, Ping Yue, Na Lin, Min He, Zhongmei Zhou, Sagal Lonial, Fadlo R. Khuri, Binghe Wang, Shi-Yong Sun
Journal: Clinical Cancer Research (2006)

Abstract Purpose: PS-341 (bortezomib, Velcade), the first proteasome inhibitor approved by the Food and Drug Administration for the treatment of patients with relapsed multiple myeloma, induces apoptosis in human cancer cell lines. Vitamin C (ascorbic acid) is an essential water-soluble vitamin required for many normal physiologic functions and has to be obtained through diet or supplemental tablets in humans. Here we studied the potential effect of vitamin C on the anticancer activity of PS-341 in human cancer cell lines. Experimental Design: The effects of vitamin C on apoptosis induction by PS-341 alone and by PS-341 combined with tumor necrosis factor–related apoptosis-inducing ligand were studied. In addition, the effects of vitamin C and other antioxidants on PS-341-mediated proteasome inhibition were also examined. Finally, the direct chemical interaction between vitamin C and PS-341 was determined. Results: Vitamin C abrogated the ability of PS-341 to induce apoptosis in various human cancer cell lines, to induce G2-M arrest, and to augment apoptosis induced by tumor necrosis factor–related apoptosis-inducing ligand. Moreover, vitamin C suppressed PS-341-mediated inhibition of proteasome activity. PS-341 itself did not induce generation of intracellular reactive oxygen species whereas other antioxidants failed to abrogate its biological activity. Importantly, we detected a direct chemical interaction between vitamin C and PS-341. Conclusion: Vitamin C directly binds to PS-431, thus inactivating PS-341 independent of its antioxidant activity. Our findings suggest that vitamin C may have a negative effect on PS-341-mediated anticancer activity.
T cell receptor-zeta and granzyme B expression in mononuclear cell infiltrates in normal colon mucosa and colon carcinoma.
Authors: W M Mulder, E Bloemena, M J Stukart, J A Kummer, J Wagstaff, R J Scheper
Journal: Gut (1997)

BACKGROUND: Whereas the presence of a lymphoid infiltrate has been associated with a favourable prognosis in colorectal carcinoma, the proliferative and cytotoxic responses of freshly isolated tumour infiltrating lymphocytes are frequently impaired. In mice, tumour induced immune suppression has been associated with a decreased expression of the zeta-chain of the T cell receptor (TCR)-CD3 complex, and loss of mRNA for granzyme B. AIM: To compare the expression of TCR-zeta and granzyme B in lymphocytes infiltrating normal colonic mucosa and Duke9s A and D colorectal carcinomas. SPECIMENS: Paraffin wax embedded normal (n = 10) and malignant colonic mucosa (seven Dukes9s A, nine Dukes9s D). METHOD: Immunohistochemistry. RESULTS: The numbers of TCR-zeta + lymphocytes decreased from normal mucosa to Dukes9s D carcinomas. In contrast, granzyme B+ lymphocytes were more frequent in Dukes9s A carcinomas than in normal mucosa, but disappeared from advanced stage tumours. Granzyme B expressing cells were mainly CD3- (natural killer/lymphokine activated killer cells) in normal mucosa, but CD3+ in tumours, indicating the presence of activated cytotoxic T lymphocytes. In vitro culture of tumour infiltrating lymphocytes rapidly restored the expression of both molecules. CONCLUSION: The frequency of TCR-zeta + and granzyme B+ lymphocytes is decreased in advanced stage colorectal carcinomas. The restoration of expression during in vitro stimulation suggests the presence of tumour derived suppressive factors in situ.
miR-21: a central regulator of fibrosis not only in the broken heart: EXPERT'S PERSPECTIVE
Authors: J. Bauersachs
Journal: Cardiovascular Research (2012)

This editorial refers to an article by S. Roy et al . [5][1] published in Cardiovascular Research in 2009. It is accompanied by a retrospective editorial by two of the authors of that original article, C.K. Sen and S. Roy, pp. 230–233, this issue, as part of this Spotlight on Landmark Papers in Cardiovascular Research . 

Adverse remodelling of the heart associated with hypertension, valve disease, or myocardial infarction includes diverse functional, structural, and metabolic abnormalities, such as sarcomere disorganization, cardiomyocyte loss, and interstitial and perivascular fibrosis, ultimately leading to left ventricular hypertrophy, dilatation, and failure.1,2

MicroRNAs, endogenous single-stranded molecules consisting of ∼22 non-coding nucleotides, are important regulators of cardiovascular (patho)physiology.2–4 The work by the group of C.K. Sen appearing in Cardiovascular Research early in 20095 was among the first (i) to recognize the importance of microRNAs for ischaemic injury of the heart, (ii) to characterize the expression of a specific microRNA, miR-21, in a time-dependent and cell-specific manner, and (iii) to define a specific target gene and pathophysiological response.

Reactive myocardial fibrosis is associated with reduced microvascular network and disruption of normal myocardial structures, and results from an excessive deposition of extracellular matrix by fibroblasts. While reactive fibrosis accompanying hypertrophy in response to pressure overload …

 [1]: #ref-5
Diabetes Risk Perception and Intention to Adopt Healthy Lifest yles Among Primary Care Patients
Authors: Marie-France Hivert, Ana Sofia Warner, Peter Shrader, Richard W. Grant, James B. Meigs
Journal: Diabetes Care (2009)

OBJECTIVE To examine perceived risk of developing diabetes in primary care patients. RESEARCH DESIGN AND METHODS We recruited 150 nondiabetic primary care patients. We made standard clinical measurements, collected fasting blood samples, and used the validated Risk Perception Survey for Developing Diabetes questionnaire. RESULTS Patients with high perceived risk were more likely than those with low perceived risk to have a family history of diabetes (68 vs. 18%; P &amp;lt; 0.0001) and to have metabolic syndrome (53 vs. 35%; P = 0.04). However, patients with high perceived risk were not more likely to have intentions to adopt healthier lifestyle in the coming year (high 26.0% vs. low 29.2%; P = 0.69). CONCLUSIONS Primary care patients with higher perceived risk of diabetes were at higher actual risk but did not express greater intention to adopt healthier lifestyles. Aspects of health behavior theory other than perceived risk need to be explored to help target efforts in the primary prevention of diabetes.
INTERACTION OF HUMAN THYMUS-DERIVED AND NON-THYMUS-DERIVED LYMPHOCYTES IN VITRO
Authors: Raif S. Geha, Eveline Schneeberger, Fred S. Rosen, Ezio Merler
Journal: The Journal of Experimental Medicine (1973)

Relatively pure populations of human T and B lymphocytes were obtained from blood and tonsils using density gradient centrifugation in bovine serum albumin. Antigen alone was incapable of triggering the B lymphocyte into blast transformation or to secrete antibody. However, supernatants from tetanus toxoid-stimulated T cells obtained from immune donors contained a factor mitogenic for B lymphocytes. 50-60% of B cells responded to this lymphocyte mitogenic factor (LMF) by proliferation, loss of C3 reactivity, and change to a secretory state. LMF-stimulated B cells exhibited a three- to fivefold increase in protein secretion and a six- to eightfold increase in gamma G globulin secretion. De novo secreted IgG had specificity directed to the tetanus toxoid present in the LMF containing T-cell supernatants. This was confirmed by an increase in the number of indirect plaque-forming cells to tetanus toxoid-coated sheep red blood cells after stimulation of B cells with LMF. It is proposed that in the course of the response to a previously encountered protein antigen, sensitized human T cells emit a signal in the form of a soluble product that, together with antigen, triggers B cells into division and antibody secretion. The experimental model utilized can be adapted to study human T-B cell cooperation under various conditions in normal individuals and in individuals with immunodeficiency diseases.
Clonal analysis of a human antibody response. Quantitation of precursors of antibody-producing cells and generation and characterization of monoclonal IgM, IgG, and IgA to rabies virus.
Authors: Y Ueki, I S Goldfarb, N Harindranath, M Gore, H Koprowski, A L Notkins, P Casali
Journal: The Journal of Experimental Medicine (1990)

We quantitated and characterized the changes in the human B cell repertoire, at the clonal level, before and after immunization with rabies virus. Moreover, we generated 10 monoclonal cell lines producing IgM, IgG, and IgA antibodies to the virus. We found that in healthy subjects, not previously exposed to the virus, nearly 2% of the circulating B lymphocytes were committed to the production of antibodies that bound the virus. These B cells expressed the surface CD5 molecule. The antibodies they produced were polyreactive IgM that displayed a relatively low affinity for the virus components (Kd, 1.0-2.4 x 10(-6) g/microliters). After immunization, different anti-virus (IgG and IgA) antibody-producing cells consistently appeared in the circulation and increased from less than 0.005% to greater than 10% of the total B cells committed to the production of IgG and IgA, respectively. Most of such B cells do not express CD5 and produce monoreactive antibodies of high affinity for rabies virus (Kd, 6.5 x 10(-9) to 1.2 x 10(-10) g/microliters). One of these IgG mAbs efficiently neutralized rabies virus in vitro and in vivo, as detailed elsewhere (Dietzschold, B., P. Casali, Y. Ueki, M. Gore, C. E. Rupprecht, A. L. Notkins, and H. Koprowski, manuscript submitted for publication). Hybridization experiments using probes specific for the different human V gene segment families revealed that cell precursors producing low affinity IgM binding to rabies virus utilized a restricted number of VH gene segments (i.e., only members of the VHIIIb subfamily), whereas cell precursors producing high affinity IgG and IgA to rabies virus utilized an assortment of different VH gene segments (i.e., members of the VHI, VHIII, VHIV, and VHVI families and VHIIIb subfamily). In conclusion, our studies show that EBV transformation in conjunction with limiting dilution technology and somatic cell hybridization techniques are useful methods for quantitating, at the B cell clonal level, the human antibody response to foreign Ags and for generating human mAbs of predetermined specificity and high affinity.
Peripheral Expression of Jak3 Is Required to Maintain T Lymphocyte Function
Authors: Daniel C. Thomis, Leslie J. Berg
Journal: The Journal of Experimental Medicine (1997)

The Jak family tyrosine kinase, Jak3, is involved in signaling through cytokine receptors that utilize the common γ chain (γc), such as those for IL-2, IL-4, IL-7, IL-9, and IL-15. Recent studies of Jak3-deficient mice and humans have demonstrated that Jak3 plays a critical role in B and T lymphocyte maturation and function. The T lymphocyte defects in Jak3-deficient mice include a small thymus, a decrease in peripheral CD8+ cells, an increase in the surface expression of activation markers, and a severe reduction in proliferative and cytokine secretion responses to mitogenic stimuli. To determine whether the peripheral T lymphocyte defects result from aberrant maturation in the thymus or from the absence of Jak3 protein in peripheral T cells, we generated reconstituted mice that express normal levels of Jak3 protein in the thymus but lose Jak3 expression in peripheral T cells. Jak3 expression in the thymus restores normal T cell development, including CD8+, γδ, and natural killer cells. However, the loss of Jak3 protein in peripheral T cells leads to the Jak3−/− phenotype, demonstrating that Jak3 is constitutively required to maintain T cell function.
Certain Histological and Chemical Responses of the Vascular Interface to Acutely Induced Mechanical Stress in the Aorta of the Dog
Authors: DONALD L. FRY
Journal: Circulation Research (1969)

The purpose of this study is to quantify certain histologic and chemical responses of the intimal tissues in vivo to acutely induced mechanical stresses. Evans blue dye was given to tag serum albumin and an artificial fat emulsion was infused so that altered fluxes of either serum proteins or the artificial chylomicrons across the vascular interface into the intimal region could be detected. Special histologic and photodensimetric techniques were developed to estimate these fluxes as well as the architectural changes in the endothelial cell population. Architectural changes were quantified by doing endothelial cell counts to quantify the "normal" and "abnormal" endothelial cell population density as a function of stress exposure. The stress corresponding to the greatest rate of change of normal to abnormal cell forms is defined as the acute critical yield stress (τ c ) and was found to average &lt; 420 dynes/cm 2 . Similarly the stress at which the greatest number of cells are being eroded is defined as the erosion stress (τ e ). The flux of Evans blue dye into the intima increased with pressure or wall strain, with shearing stress, and with increased turbulence. The flux of artificial chylomicrons into the intimal region never occurred in the presence of a normal endothelial cell population and was found to be most heavy in areas of total cellular erosion.