Imaging features of myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of haematological disorders including polycythaemia vera (PV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukaemia (CML). These disorders show large overlap in genetic and clinical presentations, and can have many different imaging manifestations. Unusual thromboses, embolic events throughout the systemic or pulmonary vasculature, or osseous findings can often be clues to the underlying disease. There is limited literature about the imaging features of these disorders, and this may result in under-diagnosis. Multiple treatments are available for symptom control, and the development of multiple new pharmacological inhibitors has significantly improved morbidity and prognosis. Knowledge of these conditions may enable the radiologist to suggest an MPN as a possible underlying cause for certain imaging findings, particularly unexplained splanchnic venous thrombosis, i.e. in the absence of chronic liver disease or pancreatitis. The aim of the present review is to outline using examples the different categories of MPN and illustrate the variety of radiological findings associated with these diseases.

RNA-loaded CD40-activated B cells stimulate antigen-specific T-cell responses in dogs with spontaneous lymphoma.

Cell-based vaccination strategies to induce functional tumor-specific T cells in cancer patients have focused on using autologous dendritic cells. An alternative approach is to use RNA-loaded CD40 activated B cells (CD40-B) that are highly efficient antigen-presenting cells capable of priming naive T cells, boosting memory T-cell responses and breaking tolerance to tumor antigens. The use of tumor RNA as the antigenic payload allows for gene transfer without viruses or vectors and permits major histocompatibility complex (MHC)-independent, multiple-antigen targeting. Here, we use CD40L transfected K562 cells to generate functional CD40-B cells from the peripheral blood of humans and dogs. Testing of RNA-loaded CD40-B cells in dogs allows not only for its development in veterinary medicine but also for determination of its safety and efficacy in a large animal model of spontaneous cancer prior to initiation of human clinical trials. We found that CD40-B cells from healthy humans, healthy dogs and tumor-bearing dogs express increased levels of immune molecules such as MHC and CCR7. Moreover, RNA-loaded CD40-B cells induce functional, antigen-specific T cells from healthy dogs and dogs with lymphoma. These findings pave the way for immunotherapy trials using tumor RNA-loaded CD40-B cells to stimulate antitumor immunity in a large animal model of spontaneous neoplasia.

Bud10p directs axial cell polarization in budding yeast and resembles a transmembrane receptor.

BACKGROUND: The budding yeast Saccharomyces cerevisiae can bud in two spatially programmed patterns: axial or bipolar. In the axial budding pattern, cells polarize and divide adjacent to the previous site of cell separation, in response to a cell-division remnant, which includes Bud3p, Bud4p and septin proteins. This paper investigates the role of an additional component of the cell-division remnant, Bud10p, in axial budding. RESULTS: The sequence of Bud10p predicts a protein that contains a single trans-membrane domain but lacks similarity to known proteins. Subcellular fractionations confirm that Bud10p is associated with membranes. Bud10p accumulates as a patch at the bud site prior to bud formation, and then persists at the mother-bud neck as the bud grows. Towards the end of the cell cycle, the localization of Bud10p refines to a tight double ring which splits at cytokinesis into two single rings, one in each progeny cell. Each single ring remains until a new concentration of Bud10p forms at the developing axial bud site, immediately adjacent to the old ring. Certain aspects of Bud10p localization are dependent upon BUD3, suggesting a close functional interaction between Bud10p and Bud3p. CONCLUSIONS: Bud10p is the first example of a transmembrane protein that controls cell polarization during budding. Because Bud10p contains a large extracellular domain, it is possible that Bud10p functions in a manner analogous to an extracellular matrix receptor. Clusters of Bud10p at the mother-bud neck formed in response to Bud3p (and possibly to an extracellular cue, such as a component of the cell wall), might facilitate the docking of downstream components that direct polarization of the cytoskeleton.

Reduced Intestinal Motility, Mucosal Barrier Function, and Inflammation in Aged Monkeys.

OBJECTIVE: We aimed to examine the general health and intestinal physiology of young and old non-human primates with comparable life histories and dietary environments. DESIGN: Vervet monkeys (Chlorcebus aethiops sabaeus) in stable and comparable social and nutritional environments were selected for evaluation. Health phenotype, circulating cytokines and biomarkers of microbial translocation (MT) were measured (n=26-44). Subsets of monkeys additionally had their intestinal motility, intestinal permeability, and fecal microbiomes characterized. These outcomes document age-related intestinal changes present in the absence of nutritional stressors, which are all known to affect gastrointestinal motility, microbiome, and MT. RESULTS: We found that old monkeys have greater systemic inflammation and poor intestinal barrier function as compared to young monkeys. Old monkeys have dramatically reduced intestinal motility, and all changes in motility and MT are present without large differences in fecal microbiomes. CONCLUSION: We conclude that deteriorating intestinal function is a feature of normal aging and could represent the source of inflammatory burden yet to be explained by disease or diet in normal aging human primate populations. Intestinal changes were seen independent of dietary influences and aging within a consistent environment appears to avoid major microbiome shifts. Our data suggests interventions to promote intestinal motility and mucosal barrier function have the potential to support better health with aging.

Comparative genomic hybridisation of ductal carcinoma in situ of the breast: identification of regions of DNA amplification and deletion in common with invasive breast carcinoma.

Comparative genomic hybridisation has been used to map copy number changes in nine cases of ductal carcinoma in situ of the breast obtained from wax-embedded archive material. A wide variety of abnormalities were detected including gain of regions of 1q, 17q, 19q, 20p and 20q and loss on 13q, 14q, 17p, 16q and 22q. Amplification of areas on 10p, 8q and 20q were also observed. Chromosomal alterations were more frequent in higher grade DCIS and closely resemble those previously detected in invasive breast cancer using the same technique. These data provide strong molecular support for the view that DCIS is a precursor lesion of invasive breast carcinoma.

A previously undescribed mutation within the tetramerisation domain of TP53 in a family with Li-Fraumeni syndrome.

We report details of a family with classic Li-Fraumeni syndrome in which there is a mutation in codon 344 of the tumour suppressor gene TP53. Codon 344 is a key residue within the tetramerisation domain, and the amino acid substitution of a proline for a leucine is predicted to have profound implications for tetramerisation and potentially DNA binding. This is the first report of a mutation at this residue in either sporadic tumours or in the germline and the first report of a germline mutation within the tetramerisation domain. The family does not appear to be remarkable in the spectrum of tumours, and there is loss of the wild-type allele in a leiomyosarcoma from the proband. A cell line has been established from the tumour of the proband and cytogenetic and molecular studies carried out, providing an extensive analysis in this family.

A B cell specific immediate early human gene is located on chromosome band 1q31 and encodes an alpha helical basic phosphoprotein.

We have determined the cDNA sequence of a human B cell specific, immediate early gene, designated 1R20, which is inducible in response to several B cell activation signals. The cDNA sequence predicts a 196 amino acid open reading frame comprising numerous highly basic residues and the predicted structure contains several potential alpha helical domains together with eight consensus protein phosphorylation sites. The 1R20 gene has been localised by fluorescence in situ hybridisation to chromosome band 1q31, a region known to be implicated in the pathogenesis of haemopoietic malignancies.

Comparison of whole blood serotonin and platelet MAO in children with schizophrenia and major depressive disorder.

Whole blood serotonin and platelet monoamine oxidase (MAO) activity in boys with schizophrenia, schizotypal personality disorder, or major depressive disorder was compared with that of boys serving as controls. Boys with schizophrenia and schizotypal personality disorder had significantly higher platelet MAO than boys with major depressive disorder or controls. Boys with major depressive disorder had lower whole blood serotonin than boys with schizophrenia or schizotypal personality disorder.

Structural organisation and chromosomal mapping of the human Id-3 gene.

The helix-loop-helix (HLH) family of transcription factors plays a central role in the regulation of cell growth, differentiation and tumourigenesis. Members of the Id (inhibitor of DNA binding) class of these nuclear proteins are able to heterodimerise with and thereby antagonise the functions of other transcription factors of this family. We report here on the genomic organisation of the human Id3 (HLH 1R21/heir1) gene. Comparison with the two other mammalian Id genes, Id1 and Id2, reveals a highly conserved protein coding gene organisation consistent with evolution from a common, ancestral Id-like gene. In addition, by using a yeast artificial chromosome (YAC) clone of Id3, we have fine-scale mapped the gene to chromosome band 1p36.1 by fluorescence in situ hybridisation (FISH) and, using the same FISH technique, we have detected heterogeneity in tumour-associated 1p36 chromosome translocations.

Biochemical differences in children with conduct disorder socialized and undersocialized.

The authors compared plasma dopamine beta-hydroxylase (DBH), platelet monoamine oxidase (MAO), whole blood serotonin, and RBC catechol O-methyltransferase (COMT) in 25 children with conduct disorder and 20 control children. They found that children diagnosed as having conduct disorder undersocialized had significantly lower DBH activity than children diagnosed as having conduct disorder socialized and the control group. The children with conduct disorder socialized had significantly higher COMT activity than the other two groups. When children with a diagnosis of conduct disorder plus a diagnosis of attention deficit disorder were compared with the control group, no significant biochemical differences were found because of the mixing of the two diagnoses.

A cytogenetic study of male breast cancer.

In a direct preparation from a male breast carcinoma two populations of cells were present, one hypodiploid (range 25-34) and the other hypertriploid (range 56-84). Twenty-two marker chromosomes were recognized. One of these, dic(5:11)(p14:q23) was present in one or two copies in every cell and has not been reported in any other case of breast cancer. There was a consistent monosomy of chromosome 7 and, in the hypertriploid cells, a gain of one to three copies of chromosome 3. The breakpoint 11q23 is a rare, folate-sensitive fragile site but was not expressed in peripheral blood cell lymphocytes from the patient.

The expression of aphidicolin-induced fragile sites in familial breast cancer patients.

The expression frequency of aphidicolin-induced fragile sites was examined in familial breast cancer patients to determine whether this parameter could be used as a marker of genetic susceptibility in at-risk individuals. No difference was found in expression frequency between the breast cancer patients and a group of normal individuals (p = 0.61). This indicates that the expression frequency of aphidicolin-induced fragile sites is not a suitable marker for assessing genetic susceptibility in familial breast cancer.

G2 chromosomal radiosensitivity in fibroblasts of ataxia-telangiectasia heterozygotes and a Li-Fraumeni syndrome patient with radioresistant cells.

PURPOSE: To investigate whether the good discrimination we previously observed between ataxia-telangiectasia (A-T) heterozygotes and normal donors for induction of chromosome aberrations by X-rays in G2 lymphocytes is also seen in G2 fibroblasts. Also to investigate the G2 radiosensitivity of a patient with the cancer-prone Li-Fraumeni syndrome (LFS) whose fibroblasts are resistant to the lethal effects of radiation. MATERIALS AND METHODS: Fibroblasts were exposed to 0.5 Gy X-rays and harvested for metaphase analysis 90 min later. RESULTS: Four A-T heterozygote cell strains were all more sensitive than seven normal controls. The LFS strain with a germline TP53 mutation was twice as sensitive as the mean control value. CONCLUSIONS: Although chromosomal, radiosensitivity is seen in A-T heterozygotes and LFS cells, the former are radiosensitive and the latter radioresistant to cell killing. Repair defects may predominate in A-T heterozygotes, inadequate genome surveillance in LFS cells.

Breast conservation therapy in affiliated county, university, and private hospitals.

BACKGROUND: Breast conservation therapy (BCT) offers equivalent survival to modified radical mastectomy in patients with early-stage (I and IIa) breast cancer, but is utilized in less than 50% of eligible patients. While patient demographics have been linked to BCT rates, we suspected that physician influence was a major factor. The purpose of this study was to compare BCT at three affiliated centers staffed by similarly trained surgeons yet serving widely disparate populations, in order to assess the importance of physician influence on the utilization of BCT. METHODS: Tumor registry data were reviewed from 1993 through 1997 at affiliated city/county (CH), university (UH), and private hospitals (PH). Data were analyzed for clinical stage, treatment, and age of patient. RESULTS: The utilization of BCT for stage I and IIa breast cancer is similar at the three hospitals: 45% of patients at CH, 55% of patient at UH, and 57% of patients at PH (P>0.05). Rates of BCT were similar across all patient age groups at all sites. CONCLUSIONS: Similar BCT utilization rates can be achieved despite widely disparate patient populations. The three affiliated hospitals are staffed by surgeons with similar training, and all offer a multidisciplinary approach to breast cancer care. This suggests that physician influence may override patients' socioeconomic issues in providing optimal breast cancer therapy.

The angiosome concept applied to arteriovenous malformations of the head and neck.

Arteriovenous malformations remain a difficult clinical problem. There is very little understanding of the underlying pathogenesis of these lesions, and therapy frequently involves considerable risks with suboptimal outcomes. Recently, a comprehensive description of the angiosomes of the head and neck was completed in the authors' unit. It was noticed that the location of several clinically observed arteriovenous malformations in the head and neck seemed to correspond to the anatomic location of the choke anastomotic zones linking the angiosomes. Therefore, selective clinical angiograms were compared with those from the authors' previously performed fresh cadaver injection studies, in which they defined the angiosomes of the head and neck. In each patient, the location of the arteriovenous malformation corresponded directly to the choke vessel anastomotic zone linking two or more adjacent angiosomes. Clinical and pathologic ramifications of this observation are discussed.

The occurrence of lampbrush chromosomes in early diplotene oocytes of Xenopus laevis.

Transmission electron microscopy has been used to study the chromosomes found in the early diplotene oocytes of Xenopus laevis. Chromosomes from 40 micron early diplotene oocytes were found to possess a normal lampbrush chromosome morphology. The contour length of the loops found on these chromosomes was measured, the mean value determined and compared with that for lampbrush chromosomes found on 300 micron mid-diplotene (Dumont stage II) oocytes. The mean contour length of the loops from 40 micron oocytes (12.33 +/- 6.5 micron) was longer than that for the 300 micron oocytes (7.897 +/- 5.22 micron). Analysis of variance showed these two values to be significantly different (P less than 0.01). The mean loop density (number of loops per 25 micron chromosome axis) was also determined for the two size classes of oocytes, being 9.33 +/- 2.05 per 25 micron of chromosome axis for the 40 micron size class and 11.2 +/- 2.435 per 25 micron of chromosome axis for the 300 micron size class. Analysis of variance showed these values to be significantly different (P less than 0.01). The results of the present study demonstrate that the lampbrush chromosomes found in 40 micron early diplotene oocytes possess a greater loop contour length and a lower density of loops than those found in 300 micron, mid-diplotene oocytes. Possible reasons for these observations are discussed.

Ring chromosomes in a retroperitoneal lipoma of childhood.

We report here the presence of ring chromosomes in a retroperitoneal lipoma from a 12-year-old male. Ring chromosomes are strongly associated with the pathological subtype "atypical lipoma" in adults. In contrast, however, the tumour described here possesses no atypical features.

Involvement of chromosomes 1 and 17 in a case of neuroblastoma.

We report here the cytogenetic analysis of a neuroblastoma from a 6-month-old male. Both conventional GTG banded analysis and fluorescence in situ hybridization were performed. The tumour was found to have a der(17)t(1;17)(p34;q21).

1p13 is the most frequently involved band in structural chromosomal rearrangements in human breast cancer.

Cytogenetic data on 14 breast carcinomas were examined to determine which chromosome arms and bands are preferentially involved in structural chromosome changes. Chromosome arms 17p, 16q, and 1p and band 1p13 were found to be significantly involved. A review of the world literature confirmed 1p as being the most frequently involved arm in structural chromosome changes in breast cancer and 1p13 as being the band most frequently involved in such changes. The two sets of results were pooled, and the analysis of 113 tumours revealed 229 of 304 bands to be involved, with 1p13 affected in 20% of the tumours.