Estrogen-induced microsatellite DNA alterations are associated with Syrian hamster kidney tumorigenesis

Exposure to estrogens is associated with an increase in cancers, including malignancies of the breast and uterus in humans, and of the kidney in hamsters. DNA damage induced by metabolic activation of estrogen has been postulated to result in gene mutations critical for the development of estrogen-induced kidney tumors in hamsters. As part of our examination of the genetic consequences of estrogen-induced DNA damage, we searched for estrogen-induced alterations in microsatellite DNA, a frequent site of mutation in tumors. Genomic DNA isolated from kidney of hamsters treated with estradiol, from estrogen-induced kidney tumors and from untreated age-matched controls, was examined by Southern blot analysis with three multi-locus oligonucleotide probes: (GACA)4, (CAC)6 and (CAG)6. Alterations in DNA fragments containing GACA and CAC tandem repeats were detected in kidney DNA of hamsters treated with hormone for 3 and 4 months, whereas no such effects were seen in control animals. In estrogen-induced tumors, microsatellite alterations were observed in fragments that contain these same two repeat sequences and also CAG repeat sequences. The induction of microsatellite alterations by estradiol in kidney DNA preceding estrogen-induced renal malignancy may play a role in hormone-induced tumorigenesis.      

Low‐dose ultraviolet radiation selectively degrades chromophore‐rich extracellular matrix components

Photoageing of human skin due to chronic exposure to ultraviolet radiation (UVR) is characterized histologically by extensive remodelling of the dermal elastic fibre system. Whilst enzymatic pathways are thought to play a major role in mediating extracellular matrix (ECM) degeneration in UV‐exposed skin, the substrate specificity of UVR‐up‐regulated and activated matrix metalloproteinases (MMPs) is low. It is unclear, therefore, how such cell‐mediated mechanisms alone could be responsible for the reported selective degradation of elastic fibre components such as fibrillin‐1 and fibulin‐5 during the early stages of photoageing. Here we use atomic force microscopy (AFM) and scanning transmission electron microscopy (STEM) to demonstrate that physiologically attainable doses (20–100 mJ/cm²) of direct UV‐B radiation can induce profound, dose‐dependent, changes in the structure of, and mass distribution within, isolated fibrillin microfibrils. Furthermore, using reducing and native PAGE in combination with AFM, we show that, whilst exposure to low‐dose UV‐B radiation significantly alters the macromolecular and quaternary structures of both UV chromophore (Cys, His, Phe, Trp and Tyr)‐rich fibrillin microfibrils (fibrillin‐1, 21.0%) and fibronectin dimers (fibronectin, 12.9%), similar doses have no detectable effect on UV chromophore‐poor type I collagen monomers (2.2%). Analysis of the published primary amino acid sequences of 49 dermal ECM components demonstrates that most elastic fibre‐associated proteins, but crucially neither elastin nor members of the collagen family, are rich in UV chromophores. We suggest, therefore, that the amino acid composition of elastic fibre‐associated proteins [including the fibrillins, fibulins, latent TGFβ binding proteins (LTBPs) and the lysyl oxidase family of enzymes (LOK/LOXLs)] may predispose them to direct degradation by UVR. As a consequence, this selective acellular photochemical pathway may play an important role in initiating and/or exacerbating cell‐mediated ECM remodelling in UVR‐exposed skin. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

胶质母细胞瘤患者低钠血症与患者生存率预测并无相关性（英文）

Glioblastoma is a devastating malignancy with a dismal survival rate.Currently,there are limited prognostic markers of glioblastoma including IDH1,ATRX,MGMT,PTEN,EGFRv Ⅲ,and others.Although these biomarkers for tumor prognosis are available,a surgical biopsy must be performed for these analyses,which has morbidity involved.A non-invasive and readily available biomarker is sought after which provides clinicians prognostic information.Sodium is an electrolyte that is easily and quickly obtained through analysis of a patient's serum.Hyponatremia has been shown to have a predictive and negative prognostic indication in multiple cancer types,but the role of glioblastoma patients' serum sodium at the time of diagnosis in predicting glioblastoma patient survival has not been determined.We assessed whether hyponatremia at the time of glioblastoma diagnosis correlates to patient survival and show that in our cohort of 200 glioblastoma patients,sodium,at any level,did not significantly correlate to glioblastoma survival,unlike what is seen in multiple other cancer types.We further demonstrate that inducing hyponatremia in an orthotopic murine model of glioblastoma has no effects on tumor progression and survival.     

Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor) [see comments]

Transplantation of allogeneic peripheral blood progenitor cells (PBPCs) may have advantages over bone marrow transplantation (BMT) with regards to the speed of hematopoietic and immunologic recovery, which may then shorten the time spent in hospital and decrease costs. The recipient might also profit by an enhanced graft-versus-leukemia reaction exerted by the high number of natural killer cells contained in such grafts. The donor could be spared the discomfort and risks of general anesthesia and marrow harvesting. Primary transplantation of unmanipulated allogeneic PBPCs has not been reported so far because the vast amount of T cells contained in the collection product was thought to cause severe graft-versus-host disease. We present preliminary data on primary transplantation of allogeneic PBPCs in patients who either suffered from advanced leukemia or had a donor unable to undergo general anesthesia. Eight patients with a median age of 42 years suffering from acute myelogenous leukemia (AML) in first remission (n = 3), AML in third remission, AML in relapse (n = 2), acute lymphoblastic leukemia in second remission, or chronic myelogenous leukemia in accelerated phase received myeloablative therapy followed by transplantation of unmanipulated allogeneic PBPCs mobilized with granulocyte colony-stimulating factor (5 to 10 micrograms/kg of body weight of filgrastim administered for 5 to 6 days) in their HLA- identical donors. Hematopoietic reconstitution was achieved in all patients with a median of 15.5 (16.5) days after transplant needed to surpass an absolute neutrophil count of 0.5 (1.0) x 10(9)/L. The median time to an unsupported platelet count greater than 20 (> 50) x 10(9)/L was 19.5 (41) days after grafting. Three patients did not exhibit signs of acute graft-versus-host disease (GVHD), grade I disease was seen in one patient, and three patients experienced grade II disease limited to the skin. The only patient with severe acute GVHD (grade III) refused to take his oral cyclosporin regularly and had ineffective serum levels for most of the time until relapse. Six of eight patients are currently alive without evidence of disease between 61 and 533 days after grafting; two patients grafted for AML in relapse achieved a complete remission after transplantation but relapsed again and died of leukemia on days +48 and +70, respectively. Primary transplantation of unmanipulated allogeneic PBPCs is feasible and results in long-term engraftment without causing detrimental GVHD.     

The first-year costs of establishing an unrelated bone marrow donor registry

The cost of therapies like bone marrow transplantation has been an important consideration for several decades. Bone marrow transplantation is becoming increasingly accepted as an effective treatment for hematologic disorders, including acute nonlymphocytic leukemia. To find suitable donors, bone marrow donor registries are being developed. The first-year costs of establishing an unrelated bone marrow donor registry are reported here. First-year costs are largely due to personnel costs and HLA typing charges. The cost per registrant decreases over time, but further decreases due to economies of scale are limited by the continued fixed requirement for HLA typing. Data are presented by separating costs into six unique categories, thereby allowing other blood centers to estimate start-up costs based on our experience.     

Scalp dermatitis, distinctive hair abnormalities and atopic disease in the ectrodactyly—ectodermal dysplasia—clefting syndrome

Summary We report a 2-year-old girl with a combination of the ectodermal dysplasia, ectrodactyly, cleft lip/ palate (EEC) syndrome, distinctive hair abnormalities, scalp dermatitis and atopic disease. To our knowledge, this is the first report of scalp dermatitis in the EEC syndrome. Distinctive structural hair abnormalities shared by the syndromes of ectodermal dysplasia and clefting are helicotrichia, pili torti et canaliculi, and cuticle defects, all of which were observed in the present case. A high incidence of atopic disease in certain subsets of ectodermal dysplasia has been reported. In our patient this manifested as food-induced exacerbation of atopic dermatitis, associated with positive prick tests and significant levels of circulating specific IgE.     

Anti-melanoma cytotoxic T lymphocytes (CTL) recognize numerous antigenic peptides having 'self' sequences: autoimmune nature of the anti-melanoma CTL response

A line of tumor-infiltrating lymphocytes (660TIL) specifically lysed the autologous HLA-A2+ melanoma (660MEL) and also most A2+ melanoma cell lines. We immunoprecipitated A2 from a large number (>10(12)) of 660MEL cells, extracted naturally processed peptides, fractionated them by HPLC, screened the fractions for recognition by 660TIL, and found a single predominant and a minor peak of activity. Although too little was recovered of the major 660MEL peptide to establish its sequence, HPLC fingerprinting showed that it did not correspond to any of the known A2-associated melanoma peptides recognized by T cells, including peptides from tyrosinase, MART-1/Melan-A, gp100 and MAGE-3. The major 660MEL antigenic peptide appears to be derived from MART-1/Melan-A but is neither AAGIGILTV nor ILTVILGVL nor any other MART-1/Melan-A peptide containing the A2 consensus motif. The multiplicity of melanoma peptides recognized by CD8+ T cells, most of which are non-mutated (including most likely the present 660MEL peptide), suggests the existence of unknown mechanisms, perhaps similar to those operating in autoimmune disorders, whereby T cells that recognize normal 'self' sequences become activated.      

Elevated expression of Bcl-2 and Bcl-x by intestinal intraepithelial lymphocytes: resistance to apoptosis by glucocorticoids and irradiation

Administration of glucocorticoids or exposure to ionizing radiation in vivo results in a rapid cell death of thymocytes. We report that murine small intestinal intraepithelial lymphocytes (IEL) are resistant to both steroid- and radiation-induced deletion. This is due to resistance to apoptosis, as evidenced by the absence of detectable apoptotic IEL nuclei in situ after in vivo glucocorticoid treatment. IEL express normal levels of glucocorticoid receptors and these receptors bind [3H]dexamethasone to equivalent levels as other lymphocyte populations. Thus, their survival is due to post-receptor signaling mechanisms. Many IEL express high levels of Bcl-2 and that of these Bcl-2high IEL are largely TCR gamma delta +. Those IEL that do express high levels of Bcl- 2 are CD8 alpha + beta - CD4-. In addition, IEL express Bcl-x, another protein shown to be involved in the protection of cells from apoptotic signals. IEL represent the first lymphocyte population in vivo shown to have high levels of expression of both molecules, that otherwise occur only in activated lymphocytes in vitro. These data suggest that the Bcl- 2+Bcl-x+ IEL are activated cells and not an effete population of cells necessarily destined to die. Also, the high levels of Bcl-2 and Bcl-x in this in vivo activated population supports the in vitro correlate of protection from activation-induced cell death.