tbuckley/cabot-search huggingface dataset:
Cellular and Molecular Pharmacology of Antiestrogen Action and Resistance
Authors: Robert Clarke, Fabio Leonessa, James N. Welch, Todd C. Skaar
Journal: Pharmacological Reviews (2001)

Antiestrogen therapy remains one of the most widely used and effective treatments for the management of endocrine responsive breast cancers. This reflects the ability of antiestrogens to compete with estrogens for binding to estrogen receptors. Whereas response rates of up to 70% are reported in patients with tumors expressing estrogen and progesterone receptors, most responsive tumors will eventually acquire resistance. The most important factor in de novo resistance is lack of expression of these receptors. However, the mechanisms driving resistance in tumors that express estrogen and/or progesterone receptors are unclear. A tamoxifen-stimulated phenotype has been described, but seems to occur only in a minority of patients. Most tumors (>80%) may become resistant through other, less well defined, resistance mechanisms. These may be multifactorial, including changes in immunity, host endocrinology, and drug pharmacokinetics. Significant changes within the tumor cells may also occur, including alterations in the ratio of the estrogen receptor alpha:beta forms and/or other changes in estrogen receptor-driven transcription complex function. These may lead to perturbations in the gene network signaling downstream of estrogen receptors. Cells may also alter paracrine and autocrine growth factor interactions, potentially producing a ligand-independent activation of estrogen receptors by mitogen-activated protein kinases. Antiestrogens can affect the function of intracellular proteins and signaling that may, or may not, involve estrogen receptor-mediated events. These include changes in oxidative stress responses, specific protein kinase C isoform activation, calmodulin function, and cell membrane structure/function.
Notch Activation Induces Akt Signaling via an Autocrine Loop to Prevent Apoptosis in Breast Epithelial Cells
Authors: Olivier Meurette, Spyros Stylianou, Rebecca Rock, Giovanna M. Collu, Andrew P. Gilmore, Keith Brennan
Journal: Cancer Research (2009)

The Notch pathway is aberrantly activated in a wide range of cancers, including breast carcinoma, and is required to maintain the transformed phenotype of many of these tumors. Notch signaling contributes to the transformed phenotype, in part, by preventing apoptosis in response to many different stimuli. However, it is unclear how Notch activation can lead to a general suppression of apoptosis. We show here that Notch signaling induced an autocrine signaling loop that activates Akt in breast epithelial cells. This activation of Akt was necessary for Notch-induced protection against apoptosis in the nontransformed breast epithelial cell line MCF10A. Moreover, inhibiting Notch signaling in breast cancer cells induced a decrease in Akt activity and an increase in sensitivity to apoptosis. Finally, the inhibition of ASK1 by Akt was responsible for the protection from apoptosis induced by DNA damage, as it prevented c-Jun NH(2)-terminal kinase-mediated phosphorylation and activation of p53.
Randomized Trial of Breast Self-Examination in Shanghai: Final Results
Authors: D. B. Thomas, D. L. Gao, R. M. Ray, W. W. Wang, C. J. Allison, F. L. Chen, P. Porter, Y. W. Hu, G. L. Zhao, L. D. Pan, W. Li, C. Wu, Z. Coriaty, I. Evans, M. G. Lin, H. Stalsberg, S. G. Self
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Among women who practice breast self-examination (BSE), breast cancers may be detected when they are at an earlier stage and are smaller than in women who do not practice BSE. However, the efficacy of breast self-examination for decreasing breast cancer mortality is unproven. This study was conducted to determine whether an intensive program of BSE instruction will reduce the number of women dying of breast cancer. Methods: From October 1989 through October 1991, 266 064 women associated with 519 factories in Shanghai were randomly assigned to a BSE instruction group (132 979 women) or a control group (133 085 women). Initial instruction in BSE was followed by reinforcement sessions 1 and 3 years later, by BSE practice under medical supervision at least every 6 months for 5 years, and by ongoing reminders to practice BSE monthly. The women were followed through December 2000 for mortality from breast cancer. Cumulative risk ratios of dying from breast cancer were estimated using Cox proportional hazards models. All statistical tests were two-sided. Results: There were 135 (0.10%) breast cancer deaths in the instruction group and 131 (0.10%) in the control group. The cumulative breast cancer mortality rates through 10 to 11 years of follow-up were similar (cumulative risk ratio for women in the instruction group relative to that in the control group = 1.04, 95% confidence interval = 0.82 to 1.33; P = .72). However, more benign breast lesions were diagnosed in the instruction group than in the control group. Conclusions: Intensive instruction in BSE did not reduce mortality from breast cancer. Programs to encourage BSE in the absence of mammography would be unlikely to reduce mortality from breast cancer. Women who choose to practice BSE should be informed that its efficacy is unproven and that it may increase their chances of having a benign breast biopsy.
IL-7 Contributes to the Progression of Human T-cell Acute Lymphoblastic Leukemias
Authors: Ana Silva, Angelo B.A. Laranjeira, Leila R. Martins, Bruno A. Cardoso, Jocelyne Demengeot, J. Andrés Yunes, Benedict Seddon, João T. Barata
Journal: Cancer Research (2011)

The importance of microenvironmental factors for driving progression in leukemia has been debated. Previous evidence has pointed to interleukin-7 (IL-7), a fundamental cytokine to normal T-cell development and homeostasis, as an important determinant of the viability and proliferation of T-cell acute lymphoblastic leukemia (T-ALL) cells in vitro. In this study, we report that IL-7 is also a critical determinant of T-ALL progression. T-ALL cell lines and primary T-ALL samples initiated leukemia more slowly when engrafted to immunocompromised Rag2(-/-)IL2rg(-/-) mice lacking IL-7. This effect was not related to reduced engraftment or homing of transplanted cells to the bone marrow. Instead, IL-7 deficiency diminished expansion of leukemia cells in the bone marrow and delayed leukemia-associated death of transplanted mice. Moreover, infiltration of different organs by T-ALL cells, which characterizes patients with advanced disease, was more heterogeneous and generally less efficient in IL-7-deficient mice. Leukemia progression was associated with increased Bcl-2 expression and cell viability, reduced p27(Kip1) expression, and decreased cell-cycle progression. Clinical measurements of IL-7 plasma levels and IL-7 receptor (IL-7R) expression in T-ALL patients versus healthy controls confirmed that IL-7 stimulates human leukemia cells. Our results establish that IL-7 contributes to the progression of human T-cell leukemia, and they offer preclinical validation of the concept that targeting IL-7/IL-7R signaling in the tumor microenvironment could elicit therapeutic effects in T-ALL.
ETIOLOGY OF YELLOW FEVER
Authors: Hideyo Noguchi
Journal: The Journal of Experimental Medicine (1920)

The use ot a polyvalent immune serum ot nign potency in tne treatment of an experimental infection of guinea pigs with Leptospira icteroides was found to be of definite advantage in checking the progress of the infection. When administered during the period of incubation the serum was found capable of completely preventing the development of the disease, although on subsequent examination hemorrhagic lesions of greater or less number and extent were found in the lungs of the guinea pigs which survived. Moreover, the serum modified the course of the disease and when used in the early stages of infection prevented a fatal outcome. Employed at a later stage, however, when jaundice and nephritis had been present for several days and the animal was near collapse, the serum had no perceptible beneficial effect. This was, of course, to be expected in view of the incidence of various pathological phases of this disease-nephritis, hepatitis, and other toxic symptoms in succession. In man the clinical manifestations are more gradual and distinct than in the guinea pig, yet the yellow fever patient whose temperature is sub-normal, and who has reached the stage of hemorrhages from the gums, nose, stomach, and intestines, and of uremia and cholemia, would seem to have little or no chance of deriving benefit from the use of a specific immune serum. This latter assumption would probably hold irrespective of the relation which Leptospira icteroides proves to have to the etiology of yellow fever.
Rheumatic Complaints in a Rural Population
Authors: J. M. Bremner
Journal: Annals of the Rheumatic Diseases (1961)

The geographic distribution of disease is a subject in which increasing interest has been shown in recent years. Cobb and Lawrence (1957) summarized the findings in nine surveys of the prevalence of rheumatoid arthritis in different countries and discussed some of the factors which might contribute to the varying results reported. The prevalence of rheumatic complaints other than rheumatoid arthritis has received less attention. Kellgren, Lawrence, and Aitken-Swan (1953), in a study of rheumatic complaints in Leigh in Lancashire, included accounts of the prevalence of osteo-arthrosis, disk lesions, and other conditions. De Blecourt (1954) included osteo-arthrosis, ankylosing spondylitis, and rheumatism of the soft tissues in his report from Holland. The present study was undertaken to investigate the prevalence of rheumatic complaints in an isolated rural community in England, in which the majority of the population were born in the district and had lived and worked there all their lives, and amongst whose ancestors there had been much inter-marriage. It was thought that such a study might offer a useful comparison with others of populations with different genetic, environmental, and occupational backgrounds. This paper reports the prevalence of rheumatic complaints in two groups of people, those born in the district and those coming into it from other parts of the country, and discusses some features of inflammatory polyarthritis found in these groups.
MECHANISMS OF MHC CLASS I–RESTRICTED ANTIGEN PROCESSING
Authors: Eric Pamer, Peter Cresswell
Journal: Annual Review of Immunology (1998)

▪ Abstract Classical class I molecules assemble in the endoplasmic reticulum (ER) with peptides mostly generated from cytosolic proteins by the proteasome. The activity of the proteasome can be modulated by a variety of accessory protein complexes. A subset of the proteasome β-subunits (LMP2, LMP7, and MECL-1) and one of the accessory complexes, PA28, are upregulated by γ-interferon and affect the generation of peptides to promote more efficient antigen recognition. The peptides are translocated into the ER by the transporter associated with antigen processing (TAP). A transient complex containing a class I heavy chain–β 2 microglobulin (β 2 m) dimer is assembled onto the TAP molecule by successive interactions with the ER chaperones calnexin and calreticulin and a specialized molecule, tapasin. Peptide binding releases the class I–β 2 m dimer for transport to the cell surface, while lack of binding results in proteasome-mediated degradation. The products of certain nonclassical MHC-linked class I genes bind peptides in a similar way. A homologous set of β 2 m-associated membrane glycoproteins, the CD1 molecules, appears to bind lipid-based ligands within the endocytic pathway.
Ovariectomy enhances and estrogen replacement inhibits the activity of bone marrow factors that stimulate prostaglandin production in cultured mouse calvariae.
Authors: H Kawaguchi, C C Pilbeam, S J Vargas, E E Morse, J A Lorenzo, L G Raisz
Journal: Journal of Clinical Investigation (1995)

To examine PG production in estrogen deficiency, we studied effects on cultured neonatal mouse calvariae of bone marrow supernatants (MSup) from sham-operated (SHAM), ovariectomized (OVX), or 17 beta-estradiol (OVX+E)-treated mice. MSups were obtained 3 wk after OVX when bone density had decreased significantly. 10-60% MSup increased medium PGE2 and levels of mRNA for inducible and constitutive prostaglandin G/H synthase (PGHS-2 and PGHS-1) and cytosolic phospholipase A2 in calvarial cultures. OVX MSups had twofold greater effects on PGHS-2 and medium PGE2 than other MSups. IL-1 receptor antagonist and anti-IL-1 alpha neutralizing antibody decreased MSup-stimulated PGHS-2 mRNA and PGE2 levels and diminished differences among OVX, sham-operated, and OVX+E groups. In contrast, antibodies to IL-1 beta, IL-6, IL-11, and TNF alpha had little effect. There were no significant differences in IL-1 alpha concentrations or IL-1 alpha mRNA levels in MSups or marrow cells. PGHS-2 mRNA in freshly isolated tibiae from OVX mice was slightly greater than from sham-operated. We conclude that bone marrow factors can increase PG production through stimulation of PGHS-2; that OVX increases and estrogen decreases activity of these factors; and that IL-1 alpha activity, together with additional unknown factors, mediates the differential MSup effects.
Single Injection of P-Selectin or P-Selectin Glycoprotein Ligand-1 Monoclonal Antibody Blocks Neointima Formation After Arterial Injury in Apolipoprotein E-Deficient Mice
Authors: J. William Phillips, Kurt G. Barringhaus, John M. Sanders, Sean E. Hesselbacher, Ann C. Czarnik, David Manka, Dietmar Vestweber, Klaus Ley, Ian J. Sarembock
Journal: Circulation (2003)

Background— Emerging data suggest that P-selectin, by controlling adhesion of white blood cells, may be important in limiting the response to vascular injury. Methods and Results— We tested the hypothesis that transient inhibition of P-selectin with either anti-P-selectin monoclonal antibody (mAb) or anti-P-selectin glycoprotein ligand-1 (PSGL-1) mAb would reduce neointima formation in the setting of carotid denudation injury in atherosclerosis-prone apolipoprotein E −/− mice. Neointima formation at 28 days was reduced significantly, by 50% or 80%, by a single injection on the day of injury of 100 or 200 μg P-selectin mAb RB 40.34 and by 55% by a single injection of 100 μg PSGL-1 mAb 4RA10 ( P ≤0.005). In addition, there was a significant reduction in neointimal macrophage content. Conclusions— These findings demonstrate that transient P-selectin or PSGL-1 blockade at the time of arterial injury significantly limits plaque macrophage content and neointima formation in a dose-dependent manner after carotid denudation injury in apolipoprotein E −/− mice.
Estrogen Receptor-α Mediates the Protective Effects of Estrogen Against Vascular Injury
Authors: Gary Pare, Andrée Krust, Richard H. Karas, Sonia Dupont, Mark Aronovitz, Pierre Chambon, Michael E. Mendelsohn
Journal: Circulation Research (2002)

Blood vessel cells express the 2 known estrogen receptors, α and β (ERα, ERβ), which are thought to mediate estrogen inhibition of vascular injury and atherosclerosis, but the relative role of ERα and ERβ in these events is controversial. Estrogen inhibits the vascular injury response to the same extent in ovariectomized female wild-type mice and in the original single gene knockout mice for ERα (ERαKO Chapel Hill [ERαKO CH ]) and ERβ (ERβKO Chapel Hill [ERβKO CH ]). In double gene knockout mice generated by crossing these animals (ERα,βKO CH ), estrogen no longer inhibits medial thickening after vascular injury, but still inhibits vascular smooth muscle cell proliferation and increases uterine weight. The partial retention of estrogen responsiveness in ERα,βKO CH mice could be due either to the presence of a novel, unidentified estrogen receptor or to functional expression of an estrogen receptor-α splice variant in the parental ERαKO CH mice. To distinguish between these possibilities, we studied recently generated mice fully null for estrogen receptor α (ERαKO Strasbourg [ERαKO St ]) and examined the effect of estrogen on the response to vascular injury. In the present study, we show that after vascular injury in ovariectomized ERαKO St mice, estrogen has no detectable effect on any measure of vascular injury, including medial area, proteoglycan deposition, or smooth muscle cell proliferation. These data demonstrate that estrogen receptor-α mediates the protective effects of estrogen on the response to vascular injury.
Huntington's Disease
Authors: I Shoulson, T N Chase
Journal: Annual Review of Medicine (1975)

Huntington'S disease (HD) is an autosomal dominant disorder associated with neuronal degeneration especially involving the basal ganglia and cerebral cortex. The cardinal signs of dementia and involuntary movements usually appear in middle life. Although the pathogenesis of this disease remains unknown, its course progres­ sive, and the efficacy of available treatments limited, a recent surge of investigative interest has yielded significant information about HD and related central degenera­ tive disorders.
Decisions to limit or continue life-sustaining treatment by critical care physicians in the United States: conflicts between physicians' practices and patients' wishes.
Authors: D A Asch, J Hansen-Flaschen, P N Lanken
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

We surveyed a national sample of 879 physicians practicing in adult intensive care units in the United States, in order to determine their practices with regard to limiting life-sustaining medical treatment, and particularly their decisions to continue or forgo life support without the consent or against the wishes of patients or surrogates. Virtually all of the respondents (96%) have withheld and withdrawn life-sustaining medical treatment on the expectation of a patient's death, and most do so frequently in the course of a year. Many physicians continue life-sustaining treatment despite patient or surrogate wishes that it be discontinued (34%), and many unilaterally withhold (83%) or withdraw (82%) life-sustaining treatment that they judge to be futile. Some of these decisions are made without the knowledge or consent of patients or their surrogates, and some are made over their objections. We conclude that physicians do not reflexively accept requests by patients or surrogates to limit or continue life-sustaining treatment, but place these requests alongside a collection of other factors, including assessments of prognosis and perceptions of other ethical, legal, and policy guidelines. While debate continues about the ethical and legal foundations of medical futility, our results suggest that most critical care physicians are incorporating some concept of medical futility into decision making at the bedside.
Sequential Transcription Factor Targeting for Diffuse Large B-Cell Lymphomas
Authors: Leandro C. Cerchietti, Jose M. Polo, Gustavo F. Da Silva, Pedro Farinha, Rita Shaknovich, Randy D. Gascoyne, Steven F. Dowdy, Ari Melnick
Journal: Cancer Research (2008)

Abstract Transcription factors play a central role in malignant transformation by activating or repressing waves of downstream target genes. Therapeutic targeting of transcription factors can reprogram cancer cells to lose their advantages in growth and survival. The BCL6 transcriptional repressor plays a central role in the pathogenesis of diffuse large B-cell lymphomas (DLBCL) and controls downstream checkpoints, including the p53 tumor suppressor gene. We report that a specific inhibitor of BCL6 called BPI can trigger a p53 response in DLBCL cells. This was partially due to induction of p53 activity and partially due to relief of direct repression by BCL6 of p53 target genes. BPI could thus induce a p53-like response even in the presence of mutant p53. Moreover, sequential BCL6 peptide inhibitors followed by p53 peptide or small-molecule activators provided a more powerful antilymphoma effect than either treatment alone by maximally restoring p53 target gene expression. Therefore, tandem targeting of the overlapping BCL6 and p53 transcriptional programs can correct aberrant survival pathways in DLBCL and might provide an effective therapeutic approach to lymphoma therapy. [Cancer Res 2008;68(9):3361–9]
Effects of alpha interferon induction plus ribavirin with or without amantadine in the treatment of interferon non-responsive chronic hepatitis C: a randomised trial
Authors: L E Adinolfi
Journal: Gut (2003)

<b>Background:</b> Fifty per cent of chronic hepatitis C patients are non-responders to interferon. At present, there are no recommended therapeutic options for non-responders. <b>Aims:</b> The safety and long term effect of alpha interferon induction plus ribavirin with or without amantadine in the treatment of interferon non-responsive chronic hepatitis C was evaluated. <b>Patients and methods:</b> A total of 114 consecutive patients were randomly divided into three groups with a final 2:2:1 ratio: group A (44 patients) received interferon alfa 2b, 3 million units (MU), three times a week, and oral ribavirin (1000 mg/day); group B (46 patients) received interferon 3 MU daily for the first four weeks and subsequently 3 MU three times a week, and ribavirin as in regimen A; and group C (24 patients) received interferon and ribavirin as in regimen B, plus oral amantadine hydrochloride (200 mg/day). The duration of treatment was 12 months. <b>Results:</b> The end of treatment response for groups A and B was 25% and 29%, respectively, and for group C, 68% (p&lt;0.005). At the end of one year of follow up, a sustained response was observed for six (25%) patients in group C, one (2%) patient in group A, and two (4%) patients in group B (p&lt;0.002). The triple regimen was well tolerated and did not increase the frequency or severity of side effects. <b>Conclusions:</b> The study demonstrates that for the treatment of interferon non-responder hepatitis C patients, the association of interferon-ribavirin has a negligible long term effect whereas a triple regimen including interferon, ribavirin, and amantadine can be an effective and safe treatment.