tbuckley/cabot-search huggingface dataset:
A Severe Combined Immunodeficient–hu <i>In vivo</i> Mouse Model of Human Primary Mantle Cell Lymphoma
Authors: Michael Wang, Liang Zhang, Xiaohong Han, Jing Yang, Jianfei Qian, Sungyoul Hong, Pei Lin, Yuankai Shi, Jorge Romaguera, Larry W. Kwak, Qing Yi
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To establish a severe combined immunodeficient (SCID)-hu in vivo mouse model of human primary mantle cell lymphoma (MCL) for the study of the biology and novel therapy of human MCL. Experimental Design: Primary MCL cells were isolated from spleen, lymph node, bone marrow aspirates, or peripheral blood of six different patients and injected respectively into human bone chips, which had been s.c. implanted in SCID-hu. Circulating human β2-microglobulin in mouse serum was used to monitor the engraftment and growth of patient's MCL cells. H&amp;E staining and immunohistochemical staining with anti-human CD20 and cyclin D1 antibodies were used to confirm the tumor growth and migration. Results: Increasing levels of circulating human β2-microglobulin in mouse serum indicated that the patient's MCL cells were engrafted successfully into human bone chip of SCID-hu mice. The engraftment and growth of patient's MCL cells were dependent on human bone marrow microenvironment. Immunohistochemical staining with anti-human CD20 and cyclin D1 antibodies confirmed that patient's MCL cells were able to not only survive and propagate in the bone marrow microenvironment of the human fetal bone chips, but also similar to the human disease, migrate to lymph nodes, spleen, bone marrow, and gastrointestinal tract of host mice. Treatment of MCL-bearing SCID-hu mice with atiprimod, a novel antitumor compound against the protection of bone marrow stromal cells, induced tumor regression. Conclusion: This is the first human primary MCL animal model that should be useful for the biological and therapeutic research on MCL.
Long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: review of current data
Authors: M H A Rustin
Journal: British Journal of Dermatology (2012)

Conventional non-biologic systemic agents are regarded as second-line therapy for the treatment of moderate-to-severe plaque psoriasis after topical treatments. However, long-term data have highlighted a number of safety concerns associated with their prolonged use. Biologic agents targeting specific immune mediators have emerged as an alternative treatment option for patients with moderate-to-severe plaque psoriasis who are unresponsive to, or intolerant of, non-biologic systemic agents. Although several biologics have demonstrated good efficacy and tolerability in short-term trials, treatment guidelines recommend them as third-line therapies due to a relative lack of long-term safety data. Here, we have reviewed the long-term (≥ 1 year) safety data from randomized controlled trials, open-label extension studies and meta-analyses of etanercept, infliximab, efalizumab, adalimumab, alefacept and ustekinumab in the treatment of adults with moderate-to-severe plaque psoriasis. With the exception of efalizumab, which has been withdrawn from both the European and U.S. markets due to long-term safety concerns, these biologics are generally well tolerated in long-term studies, and offer a viable alternative to conventional non-biologic agents in patients with moderate-to-severe plaque psoriasis.
Sleep and Circadian Rhythms in Bipolar Disorder: Seeking Synchrony, Harmony, and Regulation
Authors: Allison G. Harvey
Journal: American Journal of Psychiatry (2008)

Despite advances in the treatment of bipolar disorder, a significant proportion of patients experience disabling symptoms between episodes, and relapse rates are high. These circumstances suggest that there is a critical need to achieve a mechanistic understanding of triggers of relapse and to target them with specific, empirically derived treatments. Sleep disturbances are among the most prominent correlates of mood episodes and inadequate recovery, yet sleep has been minimally studied in ways that integrate mechanistic understanding and treatment. In this article, the author seeks to define the limits of current knowledge and to specify preliminary clinical implications. Sleep disturbance is important because it impairs quality of life, contributes to relapse, and has adverse consequences for affective functioning. While sleep disturbance and circadian dysregulation are critical pathophysiological elements in bipolar disorder, many questions about the mechanisms that underpin the association remain. The author presents a model that recognizes a role for genetic vulnerability and suggests that there is a bidirectional relationship between daytime affect regulation and nighttime sleep such that an escalating vicious circle of disturbance in affect regulation during the day interferes with nighttime sleep/circadian functioning, and the effects of sleep deprivation contribute to difficulty in affect regulation the following day.
Tumor Cell Lines Expressing the Proteasome Subunit Isoform LMP7E1 Exhibit Immunoproteasome Deficiency
Authors: Sylvia Heink, Benjamin Fricke, Daniela Ludwig, Peter-M. Kloetzel, Elke Krüger
Journal: Cancer Research (2006)

Abstract The immune system can recognize antigenic peptides derived from tumors by their presentation on MHC class I complexes to CTLs. Immunoproteasomes (i20S) can substantially enhance the MHC class I peptide repertoire, making down-regulation of i20S an important strategy of tumor cells in manipulating immune surveillance. Here, we report that human cancer cells express the nonfunctional immunosubunit-variant LMP7E1, in addition to, or instead of LMP7E2, in response to IFN-γ. This preferential expression of LMP7E1 and the consequent down-regulation of LMP7E2 results in i20S deficiency. The molecular explanation for this phenomenon is the incapacity of LMP7E1 to interact efficiently with the proteasome maturation protein, which regularly recruits LMP7E2 into nascent i20S precursor complexes. In contrast to previous reports, i20S formation in these cancer cells cannot be restored by IFN-γ treatment. However, expression of LMP7E2 in these cells restores the i20S-deficient phenotype. Thus, our data describe a novel mechanism that contributes to the process of oncogenesis. (Cancer Res 2006; 66(2):649-52)
Pulsatile Stretch Remodels Cell-to-Cell Communication in Cultured Myocytes
Authors: Jianping Zhuang, Kathryn A. Yamada, Jeffrey E. Saffitz, André G. Kléber
Journal: Circulation Research (2000)

Abstract —Mechanical stretch is thought to play an important role in remodeling atrial and ventricular myocardium and may produce substrates that promote arrhythmogenesis. In the present work, neonatal rat ventricular myocytes were cultured for 4 days as confluent monolayers on thin silicone membranes and then subjected to linear pulsatile stretch for up to 6 hours. Action potential upstrokes and propagation velocity (Θ) were measured with multisite optical recording of transmembrane voltage of the cells stained with the voltage-sensitive dye RH237. Expression of the gap junction protein connexin43 (Cx43) and the fascia adherens junction protein N-cadherin was measured immunohistochemically in the same preparations. Pulsatile stretch caused dramatic upregulation of intercellular junction proteins after only 1 hour and a further increase after 6 hours (Cx43 signal increased from 0.73 to 1.86 and 2.02% cell area, and N-cadherin signal increased from 1.21 to 2.11 and 2.74% cell area after 1 and 6 hours, respectively). This was paralleled by an increase in Θ from 27 to 35 cm/s after 1 hour and 37 cm/s after 6 hours. No significant change in the upstroke velocity of the action potential or cell size was observed. Increased Θ and protein expression were not reversible after 24 hours of relaxation. Nonpulsatile (static) stretch produced qualitatively similar but significantly smaller changes than pulsatile stretch. Thus, pulsatile linear stretch in vitro causes marked upregulation of proteins that form electrical and mechanical junctions, as well as a concomitant increase in propagation velocity. These changes may contribute to arrhythmogenesis in myocardium exposed to acute stretch.
The toxicity of staphylococcal enterotoxin B in mice is mediated by T cells.
Authors: P Marrack, M Blackman, E Kushnir, J Kappler
Journal: The Journal of Experimental Medicine (1990)

Staphylococcal enterotoxin B (SEB) has been shown in the past to be a potent T cell stimulant in mouse or man. The toxin acts as a superantigen that is, it binds to class II MHC proteins and, as such a complex, stimulates T cells bearing particular V beta s as part of their receptors. The toxin also has several pathological effects, causing, in mice, rapid weight loss, thymus atrophy, immunosuppression, and, at high doses, death. The data in this paper show that at least one of these effects, weight loss, is T cell mediated. Staphylococcal enterotoxin-mediated weight loss is MHC dependent, and is almost absent in animals expressing MHC class II molecules, which, complexed with SEB, are poor T cell stimulants. Also, mice that lack T cell function, genetically or because of cyclosporin A treatment, lose no or less weight than controls in response to SEB. Finally, animals bred such that they express few T cells bearing V beta s with which SEB can interact lose much less weight in response to the toxin than littermate controls that have higher numbers of reactive T cells. It is therefore suggested that the pathological effects of the staphylococcal, T cell-stimulating toxins in mouse and man may be partially or wholly the consequence of massive T cell stimulation.
Hypogonadism in Hemochromatosis: Reversal with Iron Depletion
Authors: THOMAS M KELLY
Journal: Annals of Internal Medicine (1984)

Gonadal function was evaluated in 64 persons homozygous for the HLA-linked hemochromatosis allele. Of 41 men, 10 had reduced libido or impotence and 6 had testicular atrophy. Before treatment, 5 men had below normal testosterone concentrations, 4 of whom also had low gonadotrophin levels. Four hypogonadal men were reevaluated after iron depletion treatment. In 2, 1 with primary and another with secondary hypogonadism, testosterone levels returned to normal after phlebotomy and were accompanied by a return of normal sexual function. None of 23 women with hemochromatosis had loss of libido or had a natural menopause before age 45. Our findings indicate that in some men with hereditary hemochromatosis and hypogonadism of either testicular or central origin, sexual function and sex hormone concentrations can be restored to normal after iron depletion therapy.
The Pathology of Familial Breast Cancer: Predictive Value of Immunohistochemical Markers Estrogen Receptor, Progesterone Receptor, HER-2, and p53 in Patients With Mutations in <i>BRCA1</i> and <i>BRCA2</i>
Authors: Sunil R. Lakhani, Marc J. van de Vijver, Jocelyne Jacquemier, Thomas J. Anderson, Peter P. Osin, Lesley McGuffog, Douglas F. Easton
Journal: Journal of Clinical Oncology (2002)

PURPOSE: The morphologic and molecular phenotype of breast cancers may help identify patients who are likely to carry germline mutations in BRCA1 and BRCA2. This study evaluates the immunohistochemical profiles of tumors arising in patients with mutations in these genes. MATERIALS AND METHODS: Samples of breast cancers obtained from the International Breast Cancer Linkage Consortium were characterized morphologically and immunohistochemically using antibodies to estrogen receptor, progesterone receptor, HER-2 (c-erbB-2 oncogene), and p53 protein. RESULTS: Breast cancers in patients with BRCA1 germline mutations are more often negative for estrogen receptor, progesterone receptor, and HER-2, and are more likely to be positive for p53 protein compared with controls. In contrast, BRCA2 tumors do not show a significant difference in the expression of any of these proteins compared with controls. CONCLUSION: BRCA1 has a distinctive morphology and immunohistochemical phenotype. The combined morphologic and immunohistochemical data can be used to predict the risk of a young patient harboring a germline mutation in BRCA1. The BRCA2 phenotype is currently not well defined.
Budesonide/formoterol vs formoterol, both via Turbuhaler®, in patients with moderate to severe COPD: Phase III study results
Authors: Masakazu Ichinose, Ronnie Samoro, Rustem Fassakhov, Mitsuru Oguri, Jan Ekelund, Lars-Goran Carlsson, Yoshinosuke Fukuchi
Journal: European Respiratory Journal (2012)

Background:  This study evaluated the efficacy and tolerability of budesonide/formoterol (BUD/FORM) vs formoterol (FORM) in patients with moderate to severe COPD.   Methods:  In this randomised, double-blind, parallel-group, phase III study (NCT01069289) patients with moderate to severe COPD for ≥2 years received either BUD/FORM 160/4.5 µg 2 inhalations twice daily via Turbuhaler® or FORM 4.5 µg 2 inhalations twice daily via Turbuhaler® for 12 weeks. Reliever medication: salbutamol 100 μg/actuation via pMDI. Primary outcome variable: change from baseline over the treatment period in predose FEV 1 ; secondary outcome variables included: lung function, time to first exacerbation, tolerability.   Results:  1293 patients were randomised. Both BUD/FORM and FORM improved predose FEV 1  (improvements of 4.6% and 1.5%, respectively); the change from baseline was significantly greater with BUD/FORM vs FORM (BUD/FORM:FORM ratio: 1.032; 95% CI: 1.013–1.052; p=0.0011). Significantly greater improvements in other lung function measures were also observed. BUD/FORM patients had a statistically significantly prolonged time to first exacerbation vs FORM patients (hazard ratio: 0.679; 95% CI: 0.507–0.909; p=0.0094). Both treatments were well tolerated. The incidence and type of adverse events were similar in both groups; most commonly reported adverse events (BUD/FORM vs FORM): COPD (8.0% vs 9.4%), nasopharyngitis (5.5% vs 4.9%) and bronchitis (2.0% vs 2.3%).   Conclusions:  BUD/FORM 160/4.5 µg two inhalations twice daily was more effective than FORM 4.5 µg two inhalations twice daily in patients with moderate to severe COPD. Both treatments were well tolerated.  Funding: AstraZeneca.
Preliminary Observations Regarding Angiographic Pattern of Restenosis After Rapamycin-Eluting Stent Implantation
Authors: Antonio Colombo, Dejan Orlic, Goran Stankovic, Nicola Corvaja, Vassilis Spanos, Matteo Montorfano, Francesco Liistro, Mauro Carlino, Flavio Airoldi, Alaide Chieffo, Carlo Di Mario
Journal: Circulation (2003)

Restenosis after implantation of drug-eluting stents (DES) is a rare phenomenon, occurring more frequently peri-stent.We evaluated the pattern of restenosis occurring after implantation of DES in unselected lesions. From April 15 to December 6, 2002, we treated 368 patients with 735 lesions by using 841 rapamycin-eluting stents (Cypher, Cordis, a Johnson & Johnson Company). Mean baseline lesion length was 17.48+/-12.19 mm, and mean stent length was 27.59+/-14.02 mm. Follow-up ischemia-driven angiography was performed in 24 patients. Eleven patients had angiographic restenosis (> or =50% diameter stenosis) in 14 stented segments (stent and 5 mm proximal and distal to the stent). The pattern of restenosis in all 14 stented segments was focal, and in 6 of them it was multifocal, occurring inside the stents. Mean length of restenotic lesions was 5.62+/-1.90 mm, with a range from 2.54 to 8.44 mm. One multifocal restenosis involved also the distal stent margin. Intravascular ultrasound evaluation at follow-up, performed in 2 patients, showed significant lumen obstruction attributable to in-stent hyperplasia in both cases. Individual cases can be viewed in the Data Supplement.The pattern of restenotic lesions after rapamycin-eluting stent implantation was focal and mostly inside the stent.
Inhibition of Histone Deacetylation Blocks Cardiac Hypertrophy Induced by Angiotensin II Infusion and Aortic Banding
Authors: Hae Jin Kee, Il Suk Sohn, Kwang Il Nam, Jong Eun Park, Yong Ri Qian, Zhan Yin, Youngkeun Ahn, Myung Ho Jeong, Yung-Jue Bang, Nacksung Kim, Jong-Keun Kim, Kyung Keun Kim, Jonathan A. Epstein, Hyun Kook
Journal: Circulation (2005)

A number of distinct stress signaling pathways in myocardium cause cardiac hypertrophy and heart failure. Class II histone deacetylases (HDACs) antagonize several stress-induced pathways and hypertrophy. However, cardiac hypertrophy induced by transgenic overexpression of the homeodomain only protein, HOP, can be prevented by the nonspecific HDAC inhibitors trichostatin A and valproic acid, suggesting that alternate targets that oppose class II HDAC function might exist in myocardium. We tested the effects of several HDAC inhibitors, including a class I HDAC-selective inhibitor, SK-7041, on cardiac hypertrophy induced by angiotensin II (Ang II) treatment or aortic banding (AB).Cardiac hypertrophy was induced by chronic infusion of Ang II or by AB in mice or rats and evaluated by determining the ratio of heart weight to body weight or to tibia length, cross-sectional area, or echocardiogram. Cardiac hypertrophy induced by Ang II or AB for 2 weeks was significantly reduced by simultaneous administration of trichostatin A, valproic acid, or SK-7041. Echocardiogram revealed that exaggerated left ventricular systolic dimensions were relieved by HDAC inhibitors. HDAC inhibitors partially reversed preestablished cardiac hypertrophy and improved survival of AB mice. The expressions of atrial natriuretic factor, alpha-tubulin, beta-myosin heavy chain, and interstitial fibrosis were reduced by HDAC inhibition.These results suggest that the predominant effect of HDAC inhibition, mainly mediated by class I HDACs, is to prevent cardiac hypertrophy in response to a broad range of agonist and stretch stimuli.
Randomized Trial Using Gonadotropin-Releasing Hormone Agonist Triptorelin for the Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer
Authors: Pamela N. Munster, Amy P. Moore, Roohi Ismail-Khan, Charles E. Cox, Mensura Lacevic, Margaret Gross-King, Ping Xu, W. Bradford Carter, Susan E. Minton
Journal: Journal of Clinical Oncology (2012)

Chemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer.Premenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels.Targeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status.When stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.
Maternal age at menarche and atopy among offspring at the age of 31 years
Authors: B. Xu
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Influences of female hormones on the occurrence of allergic disorders have been suggested. Age at menarche may be a marker of endogenous oestrogen levels. Data from a Finnish birth cohort followed to adulthood were analysed to determine whether there is any association between maternal age at menarche and the occurrence of atopy among offspring. <h3>METHODS</h3> The study was conducted in 5188 subjects born in northern Finland for whom data collections were started during pregnancy and a follow up examination was completed at the age of 31 years. Atopy was determined by skin prick tests with cat, birch, grass, and mite extracts, and doctor diagnosed asthma was ascertained by questionnaire at follow up. Maternal age at menarche was obtained from perinatal data. Logistic regression models were used to adjust for maternal age, parity, smoking, season of birth, parental allergy, and measures of adiposity and socioeconomic status. <h3>RESULTS</h3> The prevalence of atopy at the age of 31 years was lower in children whose mothers reached menarche at a later age, especially after age 15. Compared with children whose mothers started menarche at the age of 16 or over, the adjusted odds ratios of being atopic for children whose mothers started menarche younger than or at 12, 13, 14 and 15 years were 1.43 (95% CI 1.12 to 1.83), 1.29 (95% CI 1.03 to 1.60), 1.15 (95% CI 0.93 to 1.42), and 1.19 (95% CI 0.95 to 1.48), respectively. Among girls, the offspring9s own age at menarche was not significantly associated with atopy. <h3>CONCLUSION</h3> Our results encourage further evaluation of the potential effect of maternal age at menarche on the later development of atopy and possible biological mechanisms.
GENERATION OF CYTOTOXIC T LYMPHOCYTES IN VITRO
Authors: Jean-Charles Cerottini, Howard D. Engers, H. Robson MacDonald, K. Theodor Brunner
Journal: The Journal of Experimental Medicine (1974)

Mouse cytotoxic T lymphocytes (CTL) were generated in mixed leukocyte cultures (MLC) using spleen cells as responding cells and irradiated allogeneic spleen cells as stimulating cells. Cytotoxicity was assessed by a quantitative 51Cr assay system and the relative frequency of CTL in individual cell populations was estimated from dose-response curves. Inclusion of 2-mercaptoethanol in the MLC medium resulted in a 20–40-fold increase in the relative number of CTL generated at the peak of the response. Under these culture conditions, cell-mediated cytotoxic activity was detectable in MLC populations as early as 48 h after the onset of the cultures. When spleen cells from mice immunized with allogeneic tumor cells 2–4 mo previously were cultured with irradiated spleen cells of the same alloantigenic specificity (MLC-Imm), it was found that the cell-mediated cytotoxic response was detectable earlier and reached higher levels than that observed in a primary MLC. At the peak of the response, MLC-Imm populations were observed to lyse up to 50% of the target cells within 3 h at a lymphocyte: target cell ratio of 0.3:1. Immunological and physical characterization of the effector cells generated in MLC-Imm indicated that they were medium to large-sized T lymphocytes. Altogether, these studies suggested the existence of an anamnestic cell-mediated cytotoxic response in MLC-Imm.