tbuckley/cabot-search huggingface dataset:
Professionals Assess the Acceptability of Preimplantation Genetic Diagnosis and Prenatal Diagnosis for Managing Inherited Predisposition to Cancer
Authors: Claire Julian-Reynier, Françoise Chabal, Thierry Frebourg, Didier Lemery, Catherine Noguès, Francis Puech, Dominique Stoppa-Lyonnet
Journal: Journal of Clinical Oncology (2009)

Preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND) practices for inherited predisposition to cancer are heterogeneous in industrialized countries. In France, permission to perform PGD/PND must be obtained from registered Multidisciplinary Prenatal Diagnosis Teams (MPDTs). The aim of this study was to determine French professionals' attitudes about the acceptability of PGD and PND for inherited predisposition to cancer.A cross-sectional survey was performed, involving self-administered questionnaires mailed to all registered cancer geneticists (CGs; n = 123) and MPDTs (n = 47) in France.The response rates of CGs and MPDTs were 62% and 64%, respectively; 59% and 50% of the CGs had at least discussed PGD and PND, respectively, with their consultees during the previous year. When severe cancer is liable to occur in childhood with a high penetrance and no effective methods of prevention/treatment exist, high rates of acceptability of PGD/PND were recorded (> 80%). When cancer is liable to occur before the age of 50 years but not in childhood and some form of prevention/treatment is available that preserves quality of life, PGD was rated as acceptable by one MPDT (3.3%) and 10 CGs (13.2%), and PND was rated acceptable by nine CGs (11.8%). Most respondents agreed that the acceptability of PND/PGD depends on patients' family history of cancer and their reproductive history.With the most severe forms of inherited cancer, no differences were observed between the acceptability to practitioners of PND and PGD, but with late-onset syndromes, there is still much uncertainty. Guidelines would help to standardize the practices of professionals handling these reproductive issues.
A 4-weekly course of rituximab is safe and improves tumor control for patients with minimal residual disease persisting 3 months after autologous hematopoietic stem-cell transplantation: results of a prospective multicenter phase II study in patients with follicular lymphoma
Authors: F. Morschhauser, C. Recher, N. Milpied, R. Gressin, G. Salles, P. Brice, N. Vey, C. Haioun, P. Colombat, J.F. Rossi, E. Deconinck, F. Lazreg, L. Bergougnoux, G. Delsol, M. Attal
Journal: Annals of Oncology (2012)
Clinical Recovery From End-Stage Heart Failure Using Left-Ventricular Assist Device and Pharmacological Therapy Correlates With Increased Sarcoplasmic Reticulum Calcium Content but Not With Regression of Cellular Hypertrophy
Authors: C.M.N. Terracciano, J. Hardy, E.J. Birks, A. Khaghani, N.R. Banner, M.H. Yacoub
Journal: Circulation (2004)

Background— Left ventricular assist device (LVAD) treatment is known to lead to structural and functional cellular modifications in the heart. The relevance of these changes for clinical recovery is unknown. Methods and Results— We compared properties of cardiomyocytes obtained from tissue taken at explantation of the LVAD in patients with clinical recovery with those obtained from hearts of patients who did not show clinical recovery, thus requiring transplantation. Compared with myocytes taken at implantation, both the recovery and nonrecovery groups showed ≈50% reduction in cell capacitance, an index of cell size. However, action potential duration shortened, L-type Ca 2+ current fast inactivation was more rapid, and sarcoplasmic reticulum Ca 2+ content was increased in the recovery compared with the nonrecovery group. Conclusions— These results show that specific changes in excitation-contraction coupling, and not regression of cellular hypertrophy, are specifically associated with clinical recovery after LVAD and further identify sarcoplasmic reticulum Ca 2+ handling as a key functional determinant in patients with heart failure.
Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells.
Authors: E Roosnek, A Lanzavecchia
Journal: The Journal of Experimental Medicine (1991)

Using Epstein-Barr virus B cell clones and antigen-specific T cell clones, we asked how antigen-antibody complexes are handled by B cells. We found that the only B cells capable of efficient presentation of antigen-antibody complexes are those that bind the complexes via membrane immunoglobulin, i.e., rheumatoid factor-producing B cells and, to a lower extent, antigen-specific B cells. On the contrary, nonspecific B cells, although capable of binding antigen-antibody complexes, fail to present them to T cells. Thus, rheumatoid factor B cells can present any antigen in the context of an immune complex and be triggered by T cells specific for a variety of foreign antigens. These results demonstrate a mechanism of intermolecular help that may be responsible for the production of rheumatoid factor and possibly of other types of autoantibodies.
AntiCD3Fv fused to human interleukin-3 deletion variant redirected T cells against human acute myeloid leukemic stem cells
Authors: Dongmei Fan, Zhenzhen Li, Xiaolong Zhang, Yuqi Yang, Xiangfei Yuan, Xiuli Zhang, Ming Yang, Yizhi Zhang, Dongsheng Xiong
Journal: Journal of Hematology & Oncology (2015)

Leukemic stem cells (LSCs) are frequently seen as a cause of treatment failure and relapse in patients with acute myeloid leukemia (AML). Thus, successful new therapeutic strategies for the treatment of AML should aim at eradicating LSCs. The identification of targets on the cell surface of LSCs is getting more and more attention. Among these, CD123, also known as the interleukin-3 (IL3)-receptor α chain, has been identified as a potential immunotherapeutic target due to its overexpression on LSCs in AML as well as on AML blasts, rather than normal hematopoietic stem cells. We constructed a CD123-targeted fusion protein antiCD3Fv-⊿IL3, with one binding site for T cell antigen receptor (TCRCD3) and the other for CD123, by recombinant gene-engineering technology. Cysteine residues were introduced into the V domains of the antiCD3Fv segment to enhance its stability by locking the two chains of Fv together with disulfide covalent bonds. The stability and cytotoxicity of the two fusion proteins were detected in vitro and in vivo. Both fusion proteins were produced and purified from Escherichia coli 16C9 cells with excellent yields in fully active forms. High-binding capability was observed between these two fusion proteins and human IL3R, leading to the specific lysis of CD123-expressing cell lines KG1a; also, mononuclear cells from primary AML patients were inhibited in a colony forming assay in vitro, presumably by redirecting T lymphocytes in vitro. In addition, they displayed an antileukemic activity against KG1a xenografts in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice, especially disulfide-stabilized (ds)-antiCD3Fv-⊿IL3 for its improved stability. These results suggest that both fusion proteins display the antileukemic activity against CD123-expressing cell lines as well as leukemic progenitors in vitro and in vivo, especially ds-antiCD3Fv-⊿IL3. They could be the promising candidates for future immunotherapy of AML.
Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: Case study
Authors: Amy B. Heimberger, Wei Sun, S. Farzana Hussain, Mahua Dey, Lamonne Crutcher, Ken Aldape, Mark Gilbert, Samuel J. Hassenbusch, Raymond Sawaya, Bob Schmittling, Gary E. Archer, Duane A. Mitchell, Darell D. Bigner, John H. Sampson
Journal: Neuro-Oncology (2007)

Cytotoxic chemotherapy that induces lymphopenia is predicted to ablate the benefits of active antitumor immunization. Temozolomide is an effective chemotherapeutic agent for patients with glioblastoma multiforme, but it induces significant lymphopenia. Although there is monthly fluctuation of the white blood cell count, specifically the CD4 and CD8 counts, there was no cumulative decline in the patient described in this case report. Depriving patients of this agent, in order to treat with immunotherapy, is controversial. Despite conventional dogma, we demonstrated that chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. In fact, the temozolomide-induced lymphopenia may prove to be synergistic with a peptide vaccine secondary to inhibition of regulatory T cells or their delayed recovery.
Genetic and Structural Evidence for Antigen Selection of Anti-DNA Antibodies
Authors: M Z Radic, M Weigert
Journal: Annual Review of Immunology (1994)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
Molecular cloning of gene sequences from rat heart rapidly responsive to pressure overload.
Authors: I Komuro, Y Shibazaki, M Kurabayashi, F Takaku, Y Yazaki
Journal: Circulation Research (1990)

Although pressure overload induces cardiac hypertrophy and reexpression of contractile protein isogenes, the molecular mechanism of both is not well understood. We demonstrated the early change in the translational activity of specific cardiac messenger RNA by two-dimensional gel electrophoresis of in vitro translational products. A total of over 400 translational products were detected by fluorography, and the relative predominance of eight species was increased by pressure overload whereas that of two translational products was decreased. We cloned four pressure-overload-responsive complementary DNA clones, pPO-1, -4, -5, and -6, by differential dot blot hybridization. Two clones were increased from the early period after the imposition of pressure overload; the other two were decreased. The expression pattern of each complementary DNA clone in the pressure-overloaded hearts was similar to that in fetal hearts. Pressure overload also induced the additional messenger RNA, which hybridized with pPO-4. This mRNA was also recognized in fetal, neonatal, and adult spontaneously hypertensive rat hearts. The induction of this transcript by pressure overload was not suppressed but, rather, stimulated by cycloheximide. These results suggest that there are some genes that rapidly respond to pressure overload and that may play some role in the development of cardiac hypertrophy.
Na Transport in Autosomal Recessive Polycystic Kidney Disease (ARPKD) Cyst Lining Epithelial Cells
Authors: Rajeev Rohatgi, Andrew Greenberg, Christopher R. Burrow, Patricia D. Wilson, Lisa M. Satlin
Journal: Journal of the American Society of Nephrology (2003)

<h3>Summary</h3> Globally 149 million children under five are estimated to be stunted (length more than 2 standard deviations below international growth standards). Stunting, a form of linear growth faltering, increases risk of illness, impaired cognitive development, and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering— a key consideration for defining critical windows to deliver preventive interventions. We performed the largest pooled analysis of longitudinal studies in low- and middle-income countries to date (n=32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of linear growth faltering onset and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to age 3 months. From 0 to 15 months, less than 5% of children per month reversed their stunting status, and among those who did, stunting relapse was common. Early timing and low reversal rates emphasize the importance of preventive intervention delivery within the prenatal and early postnatal phases coupled with continued delivery of postnatal interventions through the first 1000 days of life.
The Future of Antiplatelet Therapy in Cardiovascular Disease
Authors: Carlo Patrono, Bianca Rocca
Journal: Annual Review of Medicine (2010)

Mechanisms of platelet inhibition are reviewed with emphasis on the pharmacokinetic and pharmacodynamic determinants of clinical efficacy and safety of antiplatelet drugs. Current developments in antiplatelet therapy are discussed in relation to both primary and secondary prevention of atherothrombotic complications. Interindividual variability in response to antiplatelet agents and new drug targets are outlined within the context of optimizing the balance between the cardiovascular benefits and bleeding risks of antiplatelet therapy. Recent advances in the pharmacogenetics of thienopyridines open the realistic prospect of a personalized choice of the most appropriate antiplatelet agent and tailored dose adjustment for an individual patient.
MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs
Authors: Giovanni Sitia, Masanori Isogawa, Matteo Iannacone, Iain L. Campbell, Francis V. Chisari, Luca G. Guidotti
Journal: Journal of Clinical Investigation (2004)

We recently showed that antigen-nonspecific inflammatory cells are recruited into the liver when hepatitis B virus (HBV)-specific CTLs are injected into HBV transgenic mice, and that this process amplifies the severity of liver disease. We also showed that the severity of CTL-induced liver disease is ameliorated by the depletion of Gr-1(+) cells (Gr-1 is an antigen highly expressed by neutrophils), which, secondarily, abolishes the intrahepatic recruitment of all antigen-nonspecific Gr-1(-) mononuclear cells (NK and NKT cells, T and B lymphocytes, monocytes, macrophages, dendritic cells) despite the strong induction of chemokine gene expression. Those results suggested that in addition to chemokine expression, CTL-induced functions are necessary for mononuclear cell recruitment to occur. We now report that MMPs known to be produced by Gr-1(+) cells are rapidly induced in the livers of CTL-injected mice. The inhibition of MMP activity reduced the intrahepatic recruitment of antigen-nonspecific mononuclear cells and much of the attending liver disease without affecting the migration or antiviral potential of antigen-specific CTLs. The notion that the inhibition of MMP activity is associated with maintenance of antiviral effects but diminished tissue damage may be significant for the development of immunotherapeutic approaches for the treatment of chronic HBV infection.
Late Cardiac Complications of Chronic, Severe, Refractory Anemia with Hemochromatosis
Authors: MARY ALLEN ENGLE, MARION ERLANDSON, CARL H. SMITH
Journal: Circulation (1964)

Four fifths of 49 patients with chronic, severe anemia from birth have manifested, usually during the second decade, signs of hemochromatosis with cardiac involvement. Nineteen patients had 33 attacks of pericarditis. Congestive cardiac failure with arrhythmias developed in 26 patients, and all but one died with this complication. Four others died of sepsis before heart failure was evidenced. Postmortem examination showed hemochromatosis with severe myocardial involvement.
New mechanism for foam cell generation in atherosclerotic lesions.
Authors: L K Curtiss, A S Black, Y Takagi, E F Plow
Journal: Journal of Clinical Investigation (1987)

Because of a close association between platelets and macrophages in early fatty streak lesions, the hypothesis was tested that platelets contribute to lesion progression by directly enhancing macrophage cholesteryl ester (CE) accumulation. Both the rate of cholesterol esterification and the accumulation of CE were increased within 24 h of the co-culture of adherent macrophages with platelets. Maximum increases in esterification and CE accumulation were observed within 3 to 4 d of culture and were greater than 10-fold over controls. Optimum accumulation of CE by 5 X 10(5) was obtained with 5 X 10(8) autologous platelets. When similar amounts of free cholesterol were supplied with platelets, red blood cells (RBC), RBC ghosts, or sonicated RBC, only platelets enhanced macrophage CE accumulation, which indicates specificity for platelets. Products released from platelets 30 min after thrombin stimulation were active as well. The results suggest that platelets and/or substances shed by activated platelets are potent mediators of macrophage CE accumulation.
Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously.
Authors: S R Kupfer, L E Underwood, R C Baxter, D R Clemmons
Journal: Journal of Clinical Investigation (1993)

The use of growth hormone (GH) as an anabolic agent is limited by its tendency to cause hyperglycemia and by its inability to reverse nitrogen wasting in some catabolic conditions. In a previous study comparing the anabolic actions of GH and IGF-I (insulin-like growth factor I), we observed that intravenous infusions of IGF-I (12 micrograms/kg ideal body wt [IBW]/h) attenuated nitrogen wasting to a degree comparable to GH given subcutaneously at a standard dose of 0.05 mg/kg IBW per d. IGF-I, however, had a tendency to cause hypoglycemia. In the present study, we treated seven calorically restricted (20 kcal/kg IBW per d) normal volunteers with a combination of GH and IGF-I (using the same doses as in the previous study) and compared its effects on anabolism and carbohydrate metabolism to treatment with IGF-I alone. The GH/IGF-I combination caused significantly greater nitrogen retention (262 +/- 43 mmol/d, mean +/- SD) compared to IGF-I alone (108 +/- 29 mmol/d; P < 0.001). GH/IGF-I treatment resulted in substantial urinary potassium conservation (34 +/- 3 mmol/d, mean +/- SE; P < 0.001), suggesting that most protein accretion occurred in muscle and connective tissue. GH attenuated the hypoglycemia induced by IGF-I as indicated by fewer hypoglycemic episodes and higher capillary blood glucose concentrations on GH/IGF-I (4.3 +/- 1.0 mmol/liter, mean +/- SD) compared to IGF-I alone (3.8 +/- 0.8 mmol/liter; P < 0.001). IGF-I caused a marked decline in C-peptide (1,165 +/- 341 pmol/liter; mean +/- SD) compared to the GH/IGF-I combination (2,280 +/- 612 pmol/liter; P < 0.001), suggesting maintenance of normal carbohydrate metabolism with the latter regimen. GH/IGF-I produced higher serum IGF-I concentrations (1,854 +/- 708 micrograms/liter; mean +/- SD) compared to IGF-I only treatment (1,092 +/- 503 micrograms/liter; P < 0.001). This observation was associated with increased concentrations of IGF binding protein 3 and acid-labile subunit on GH/IGF-I treatment and decreased concentrations on IGF-I alone. These results suggest that the combination of GH and IGF-I treatment is substantially more anabolic than either IGF-I or GH alone. GH/IGF-I treatment also attenuates the hypoglycemia caused by IGF-I alone. GH/IGF-I treatment could have important applications in diseases associated with catabolism.
Optimal Glycemic Control, Pre-eclampsia, and Gestational Hypertension in Women With Type 1 Diabetes in the Diabetes and Pre-eclampsia Intervention Trial
Authors: Valerie A. Holmes, Ian S. Young, Christopher C. Patterson, Donald W.M. Pearson, James D. Walker, Michael J.A. Maresh, David R. McCance
Journal: Diabetes Care (2011)

To assess the relationship between glycemic control, pre-eclampsia, and gestational hypertension in women with type 1 diabetes.Pregnancy outcome (pre-eclampsia or gestational hypertension) was assessed prospectively in 749 women from the randomized controlled Diabetes and Pre-eclampsia Intervention Trial (DAPIT). HbA(1c) (A1C) values were available up to 6 months before pregnancy (n = 542), at the first antenatal visit (median 9 weeks) (n = 721), at 26 weeks' gestation (n = 592), and at 34 weeks' gestation (n = 519) and were categorized as optimal (<6.1%: referent), good (6.1-6.9%), moderate (7.0-7.9%), and poor (≥8.0%) glycemic control, respectively.Pre-eclampsia and gestational hypertension developed in 17 and 11% of pregnancies, respectively. Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy compared with women who did not develop pre-eclampsia (P < 0.05, respectively). In early pregnancy, A1C ≥ 8.0% was associated with a significantly increased risk of pre-eclampsia (odds ratio 3.68 [95% CI 1.17-11.6]) compared with optimal control. At 26 weeks' gestation, A1C values ≥ 6.1% (good: 2.09 [1.03-4.21]; moderate: 3.20 [1.47-7.00]; and poor: 3.81 [1.30-11.1]) and at 34 weeks' gestation A1C values ≥ 7.0% (moderate: 3.27 [1.31-8.20] and poor: 8.01 [2.04-31.5]) significantly increased the risk of pre-eclampsia compared with optimal control. The adjusted odds ratios for pre-eclampsia for each 1% decrement in A1C before pregnancy, at the first antenatal visit, at 26 weeks' gestation, and at 34 weeks' gestation were 0.88 (0.75-1.03), 0.75 (0.64-0.88), 0.57 (0.42-0.78), and 0.47 (0.31-0.70), respectively. Glycemic control was not significantly associated with gestational hypertension.Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy. These data suggest that optimal glycemic control both early and throughout pregnancy may reduce the risk of pre-eclampsia in women with type 1 diabetes.
Lung-marginated Monocytes Modulate Pulmonary Microvascular Injury during Early Endotoxemia
Authors: Kieran P. O'Dea, Arnold J. Young, Hirotoshi Yamamoto, James L. Robotham, Fionula M. Brennan, Masao Takata
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: The role of monocytes in acute endotoxemia has been ascribed to systemic release of mediators within the central circulation. Little is known about the potential role of "marginated" monocytes in regulating microvascular inflammatory signaling. Objectives: To investigate whether lung-marginated monocytes can locally activate pulmonary endothelial cells through cell contact–dependent interactions in early endotoxemia. Methods: Mice were challenged with LPS to produce acute endotoxemia and pulmonary vascular injury. Adoptive transfer of ex vivo LPS-stimulated donor leukocytes to recipient mice was also performed to evaluate cell-associated inflammatory signaling between monocytes and endothelial cells within the lung. Cell suspensions from excised lungs were analyzed by flow cytometry for expression of tumor necrosis factor α (TNF-α) on monocytes and cell adhesion molecules on endothelial cells. Results: Substantial numbers of monocytes rapidly marginated to the lungs after endotoxin challenge in mice, and lung-marginated monocytes expressed significantly higher levels of membrane TNF than circulating monocytes, due to higher TNF production by the marginated cells. Injection of activated wild-type donor leukocytes to wild-type or TNF receptor double knockout recipients demonstrated that lung-marginated monocytes can induce TNF-dependent upregulation of adhesion molecules on pulmonary endothelial cells. Injection of activated donor leukocytes from TNF knock-in mice that express uncleavable mutant membrane TNF also induced adhesion molecule upregulation in wild-type recipients without a systemic soluble TNF release. Conclusions: These results reveal a previously unacknowledged role for lung-marginated monocytes in early endotoxemia, exerting local, cell-associated TNF signaling within the pulmonary microcirculation, contributing to the evolution of pulmonary vascular injury.