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101.
102.
The steroidogenic enzyme 21-hydroxylase (21OH) is the main autoantigen in autoimmune primary adrenal failure (Addison's disease). Autoantibodies against 21OH are immunological markers of an ongoing autoimmune process but are not directly involved in the tissue destruction. Autoreactive T cells are thought to mediate tissue damage, but the T cell antigen(s) has not been identified. To find out whether 21OH contains important immunodominant epitopes for T cells, we first immunized BALB/c and SJL inbred mouse strains with recombinant 21OH and showed that lymph node cells proliferated effectively following in vitro stimulation with recombinant 21OH (stimulation indices (SI) 20-40). We further synthesized a series of peptides based on 21OH with amino acid sequences with propensity to bind to major histocompatibility complex class II molecules. Only a few peptides could trigger lymphocytes of 21OH-primed mice to proliferate. One of these, 21OH (342-361), stimulated effectively 21OH-primed lymph node cells of SJL mice (SI = 4-8) and also, although to a lesser extent, of BALB/c mice (SI = 2.5). When SJL mice were immunized with 21OH (342-361), the immunizing peptide as well as peptide 21OH (346-361) triggered a significant proliferative response (SI = 24). A peptide from another part of 21OH, namely 21OH (191-202), did not stimulate the 21OH (342-361)-primed cells. Moreover, stimulation of lymph node cells of mice immunized with 21OH (342-361) with 21OH resulted in a significant proliferative response. We conclude that 21OH (342-361) is an immunodominant determinant for T cells in SJL and probably BALB/c mice. 21OH (342-361) corresponds to the substrate binding site of the enzyme. The p342-361 region may be involved in the pathogenesis of autoimmune adrenal failure in humans. 相似文献
103.
Genetic variation in putative regulatory loci controlling gene expression in breast cancer
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104.
Per Eystein Lønning 《Current breast cancer reports》2009,1(4):183-189
Hierarchical clustering of gene expression profiles has shown that breast cancers can be separated into subclasses characterized
by distinct gene profiles. It has been known for decades that breast cancer may be classified into estrogen receptor-positive
versus estrogen receptor-negative tumors and, more recently, it was discovered that breast cancer may be classified into tumors
amplified versus not amplified for human epidermal growth factor receptor-2 (HER-2). Now, with the use of gene expression
profiling, estrogen receptor-positive tumors can be separated into luminal A class and B class tumors, revealing different
prognoses and most likely different endocrine sensitivity. Much effort has been focused on characterizing the “triple-negative”
tumors (basal cell-like and normal breast cell-like classes). The finding that these tumors, similar to tumors among BRCA1/BRAC2 mutation carriers, may respond to poly(adenosine diphosphate ribose) polymerase inhibitors has led to a targeted therapy
approach and suggests defects in DNA repair are also a characteristic of basal cell-like tumors in patients harboring wild-type
BRCA1. 相似文献
105.
106.
Løvås K Gebre-Medhin G Trovik TS Fougner KJ Uhlving S Nedrebø BG Myking OL Kämpe O Husebye ES 《The Journal of clinical endocrinology and metabolism》2003,88(3):1112-1118
The physiological role of dehydroepiandrosterone (DHEA) is not well understood, but studies suggest positive effects on subjective health and bone metabolism. We have conducted a clinical trial with DHEA replacement in adrenal failure with the primary aim of evaluating effects on subjective health status and sexuality. Thirty-nine women with adrenal failure were randomized to 9 months of treatment with 25 mg DHEA (n = 19) or placebo (n = 20). Treatment effects were assessed by validated questionnaires of subjective health and sexuality. DHEA replacement yielded a wide variation of effects on the subjective health scales, which were not different from the effects of placebo. Almost all patients receiving DHEA obtained normal androgen levels. Eighty-nine percent of the patients receiving DHEA experienced side-effects, in particular increased sweat odor and scalp itching. DHEA replacement did not significantly change the levels of blood lipids, IGF-I, and markers of bone metabolism. In conclusion, we do not find evidence of beneficial effects of DHEA on subjective health status and sexuality in adrenal failure. However, DHEA may be beneficial for subgroups of patients with adrenal failure, but these remain to be identified. Premenopausal androgen levels can be restored with 25 mg DHEA daily in most female patients, but side-effects are frequent. 相似文献
107.
OBJECTIVE: Many patients with Addison's disease have complaints that might be related to the disease or to its treatment. However, only a few studies have addressed the subjective health status of patients with adrenocortical failure. The aim of the present study was to assess the subjective health status with special emphasis on fatigue among patients with Addison's disease. SUBJECTS, DESIGN AND MEASUREMENT: In a postal survey, 79 patients with confirmed primary adrenal failure (Addison's disease) completed the Short Form 36 (SF-36) and the Fatigue questionnaires. The subjective health status in Addison's disease was compared with normative data from the general population. RESULTS: General health and vitality perception were most consistently impaired in the patients with Addison's disease. The scores on physical functioning and role-physical were low in women. Social functioning and role-emotional scores were also lower than normal in the female patients, but this was confined to the patients with autoimmune polyendocrine syndromes. Patients with autoimmune polyendocrine syndromes tended to have lower scores than patients with solitary Addison's disease. The level of fatigue was higher than normal for both men and women. Working disability at ages 18-67 years was 26%, compared with 10% in the corresponding general Norwegian population. The high working disability increased with age and was higher in subgroups with concomitant endocrine diseases. Most subjective health parameters were lower among the disabled compared to the patients in work. CONCLUSIONS: Patients with Addison's disease under replacement therapy with cortisone acetate and fludrocortisone have reduced general health perception and vitality, and increased fatigue. Female patients reported reduced physical function, which might be due to adrenal androgen depletion. Mental health seems more influenced by concomitant endocrine diseases, but mental fatigue might be a specific feature in adrenal failure. The patient population is heterogeneous, with normal findings in a substantial proportion but markedly reduced subjective health status and working ability in many others. Thus, there might be potential for further refinement of replacement therapy. 相似文献
108.
Refractory myelomatosis treated with mitoxantrone in combination with vincristine and prednisone (NOP-regimen): a phase II study 总被引:1,自引:0,他引:1
Peter Gimsing Ole W. Bjerrum Eystein Brandt Josrgen Ellegaard Stein A. Evensen Mogens Mosrk Hansen Michael Hedenus Erik Hippe Nina Keldsen Ilmari Palva Stig Roudjer Ingebrigt Talstad Jan Westin Finn Wislosff 《British journal of haematology》1991,77(1):73-79
In a phase II study, patients with refractory myelomatosis were treated with a combination chemotherapy (NOP regimen): mitoxantrone (bolus injection of 4 mg/m2 on days 1-4), vincristine (continuous infusion of 0.4 mg/24 h on days 1-4) and prednisone (250 mg/d on days 1-4 and 17-20). The treatment was repeated every 4 weeks. Ninety-two patients were treated after they were found refractory to treatment with melphalan and prednisone (and occasionally vincristine) (n = 50) or more intensive treatment regimens (n = 42) including anthracyclines (n = 18). Response (greater than or equal to 50% reduction of M protein) was obtained in 23 patients and minor response (clinical improvement but less than 50% reduction in M protein) in 22 patients. The median duration of the response was 7.5 months. Equal response rates were observed irrespective of the type of previous treatment. The major toxicity was myelosuppression with severe granulocytopenia and infections. However, the frequency decreased throughout the cycles. The NOP treatment is recommended in refractory myelomatosis, especially in patients refractory to other intensive regimens. Patients in a poor clinical condition or with thrombocytopenia before treatment should have a reduced mitoxantrone dose in the first treatment cycles. 相似文献
109.
Kisand K Link M Wolff AS Meager A Tserel L Org T Murumägi A Uibo R Willcox N Trebusak Podkrajsek K Battelino T Lobell A Kämpe O Lima K Meloni A Ergun-Longmire B Maclaren NK Perheentupa J Krohn KJ Scott HS Husebye ES Peterson P 《Blood》2008,112(7):2657-2666
Neutralizing autoantibodies to type I, but not type II, interferons (IFNs) are found at high titers in almost every patient with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease caused by AIRE gene mutations that lead to defects in thymic T-cell selection. Combining genome-wide expression array with real time RT-PCR assays, we here demonstrate that antibodies against IFN-alpha cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This down-regulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies. Most interestingly, a rare APECED patient with autoantibodies to IFN-omega but not IFN-alpha showed a marked increase in expression of the same interferon-stimulated genes. We also report unexpected increases in serum CXCL10 levels in APECED. Our results argue that the breakdown of tolerance to IFNs in AIRE deficiency is associated with impaired responses to them in thymus, and highlight APECED as another autoimmune disease with associated dysregulation of IFN activity. 相似文献
110.
Sköldberg F Portela-Gomes GM Grimelius L Nilsson G Perheentupa J Betterle C Husebye ES Gustafsson J Rönnblom A Rorsman F Kämpe O 《The Journal of clinical endocrinology and metabolism》2003,88(4):1445-1452
Patients with autoimmune polyendocrine syndrome type 1 often have autoantibodies against neurotransmitter synthesizing enzymes, including the pyridoxal phosphate-dependent enzymes glutamic acid decarboxylase and aromatic L-amino acid decarboxylase. Using a candidate approach, we have identified the histamine-synthesizing enzyme histidine decarboxylase, also pyridoxal phosphate dependent, as an autoantigen in this disorder. Anti-histidine decarboxylase antibodies reacting with in vitro translated antigen were found in 36/97 (37%) of autoimmune polyendocrine syndrome type 1 patients studied. The antibodies also reacted with the native enzyme in HMC-1 cell lysates and did not cross-react with the highly homologous aromatic L-amino acid decarboxylase. Anti-histidine decarboxylase antibodies were associated with a history of intestinal dysfunction (P = 0.017). Gastric and duodenal biopsies from a patient with anti-histidine decarboxylase antibodies were studied by immunohistochemistry. The oxyntic mucosa was found to lack the histamine producing enterochromaffin-like cells, suggestive of an autoimmune destruction. To our knowledge, this is the first report of autoantibodies against histidine decarboxylase and absence of gastric enterochromaffin-like cells. 相似文献