The small blood vessels in areas of lymphocytic infiltration around malignant neoplasms.

LYMPHOCYTIC INFILTRATES have been described in association with many different human non-lymphoid malignant neoplasms (Underwood, 1974) and in a few, such as medullary carcinoma of the breast, are characteristic of the tumour. Many investigators have reported an association between improved prognosis and lymphocyte infiltration (Bloom et al., 1970

Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: an in situ zymographic and gene therapy study

Data implicate IL-1 in the altered matrix biology that characterizes human intervertebral disc (IVD) degeneration. In the current study we investigated the enzymic mechanism by which IL-1 induces matrix degradation in degeneration of the human IVD, and whether the IL-1 inhibitor IL-1 receptor antagonist (IL-1Ra) will inhibit degradation. A combination of in situ zymography (ISZ) and immunohistochemistry was used to examine the effects of IL-1 and IL-1Ra on matrix degradation and metal-dependent protease (MDP) expression in explants of non-degenerate and degenerate human IVDs. ISZ employed three substrates (gelatin, collagen, casein) and different challenges (IL-1β, IL-1Ra and enzyme inhibitors). Immunohistochemistry was undertaken for MDPs. In addition, IL-1Ra was introduced into degenerate IVD explants using genetically engineered constructs. The novel findings from this study are: IL-1Ra delivered directly onto explants of degenerate IVDs eliminates matrix degradation as assessed by multi-substrate ISZ; there is a direct relationship between matrix degradation assessed by ISZ and MDP expression defined by immunohistochemistry; single injections of IVD cells engineered to over-express IL-1Ra significantly inhibit MDP expression for two weeks. Our findings show that IL-1 is a key cytokine driving matrix degradation in the degenerate IVD. Furthermore, IL-1Ra delivered directly or by gene therapy inhibits IVD matrix degradation. IL-1Ra could be used therapeutically to inhibit degeneration of the IVD

Sarcomas in north west England: II. Incidence.

Incidence data on a population-based series of bone, soft tissue and visceral sarcomas from the North West of England are presented. The data are derived mainly from a total of 429 cases registered with the North Western Regional Cancer Registry and diagnosed during the period 1982-84, 76% of which were confirmed as sarcomas by a panel of five pathologists. Overall incidence of confirmed sarcomas per million person years was slightly higher in females (26.81) than in males (24.71) but there was no sex difference when 38 non-reviewed cases were taken into consideration (females 29.07, males (28.83). After exclusion of tumours of female genital tract, incidence of soft tissue tumours was very similar in both sexes (females 18.25, males 18.70). Bone tumours were almost twice as frequent in males (6.01) as in females (3.55)

Multiple primary tumours in a population-based series of patients with histopathologically peer-reviewed sarcomas.

Multiple primary tumours occurring in a three-year population-based series of patients with histopathologically peer-reviewed sarcomas from North West England were ascertained in order to look at the patterns of neoplasms seen. A total of 30 out of the 310 patients entered in the study had additional primary tumours. Very few patients were aged under 60 years at diagnosis of both their malignancies. The youngest was a known case of neurofibromatosis and, although seven patients were diagnosed with a sarcoma and carcinoma of the breast--a combination of cancers characteristic of the Li-Fraumeni cancer family syndrome--no other patients could directly be identified as suffering from any other cancer predisposition syndrome

Sarcomas in north west England: III. Survival.

Survival data on a population-based series of bone, soft tissue and visceral sarcomas diagnosed in the North West of England between 1982-84 and subjected to histopathological peer review are presented. Five-year crude survival for all cases was 34%. Survival in males and females did not differ significantly (P = 0.6, 5-year survival 32% vs 36%) but was markedly worse for patients diagnosed over the median age of 60 years, even when allowance was made for underlying mortality (P = 0.03, 34% vs 44%). Five-year survival rates for the major site groups were: bone 44%; soft tissues of head, neck and trunk 36%; soft tissues of extremities 35%; female genital tract 35%; retroperitoneum 15%; gastro-intestinal tract 13%. Analysis by the major histological types revealed the following survival rates: leiomyosarcoma--female genital tract 25%, gastro-intestinal tract 14%, non-visceral soft tissue 21%; malignant fibrous histiocytoma of soft tissue 29%; liposarcoma 52%; osteosarcoma of bone 46%; and chondrosarcoma of bone 50%

Sarcomas in north west England: I. Histopathological peer review.

A total of 468 cases of bone, soft tissue and visceral sarcomas (and certain other tumours) diagnosed during the years 1982-84 in North West England were entered in a study of histopathological peer review, incidence and survival. This paper describes the effects of peer review. Material was reviewed by a panel of five pathologists for 413 of the 450 cases originally registered as sarcomas with the Regional Cancer Registry. The diagnosis of sarcomas was confirmed in 76% cases and and there was agreement on sub-type for 53% cases. Measures of agreement were lowest for the two sub-types most commonly diagnosed i.e. malignant fibrous histiocytoma and leiomyosarcoma. Degree of agreement between individual pathologists and final panel diagnosis was also very variable but never less than 65%. It is concluded that second opinion is essential in cases of presumed sarcomas for studies of incidence and aetiology and to ensure that appropriate treatment is selected

The Transcriptional Regulator CBP Has Defined Spatial Associations within Interphase Nuclei

It is becoming increasingly clear that nuclear macromolecules and macromolecular complexes are compartmentalized through binding interactions into an apparent three-dimensionally ordered structure. This ordering, however, does not appear to be deterministic to the extent that chromatin and nonchromatin structures maintain a strict 3-D arrangement. Rather, spatial ordering within the cell nucleus appears to conform to stochastic rather than deterministic spatial relationships. The stochastic nature of organization becomes particularly problematic when any attempt is made to describe the spatial relationship between proteins involved in the regulation of the genome. The CREB–binding protein (CBP) is one such transcriptional regulator that, when visualised by confocal microscopy, reveals a highly punctate staining pattern comprising several hundred individual foci distributed within the nuclear volume. Markers for euchromatic sequences have similar patterns. Surprisingly, in most cases, the predicted one-to-one relationship between transcription factor and chromatin sequence is not observed. Consequently, to understand whether spatial relationships that are not coincident are nonrandom and potentially biologically important, it is necessary to develop statistical approaches. In this study, we report on the development of such an approach and apply it to understanding the role of CBP in mediating chromatin modification and transcriptional regulation. We have used nearest-neighbor distance measurements and probability analyses to study the spatial relationship between CBP and other nuclear subcompartments enriched in transcription factors, chromatin, and splicing factors. Our results demonstrate that CBP has an order of spatial association with other nuclear subcompartments. We observe closer associations between CBP and RNA polymerase II–enriched foci and SC35 speckles than nascent RNA or specific acetylated histones. Furthermore, we find that CBP has a significantly higher probability of being close to its known in vivo substrate histone H4 lysine 5 compared with the closely related H4 lysine 12. This study demonstrates that complex relationships not described by colocalization exist in the interphase nucleus and can be characterized and quantified. The subnuclear distribution of CBP is difficult to reconcile with a model where chromatin organization is the sole determinant of the nuclear organization of proteins that regulate transcription but is consistent with a close link between spatial associations and nuclear functions

Down-regulation of human osteoblast PTH/PTHrP receptor mRNA in end-stage renal failure

Down-regulation of human osteoblast PTH/PTHrP receptor mRNA in end-stage renal failure.BackgroundResistance to the action of parathyroid hormone (PTH) has been demonstrated in end-stage renal failure and is considered to be important in the pathogenesis of secondary hyperparathyroidism. The mechanism of resistance is unknown. However, altered regulation of cellular PTH/PTH-related protein (PTH/PTHrP) receptor (PTH1R) has been assumed to be important.MethodsWe have used in situ hybridization to examine PTH1R mRNA expression by osteoblasts in human bone and have compared the expression in high- and low-turnover renal bone disease, high-turnover nonrenal bone disease (healing fracture callus and Pagetic bone), and normal bone. Bone biopsies were formalin fixed, ethylenediaminetetraacetic acid decalcified, and paraffin wax embedded. A 1.8kb PTH1R cDNA probe, labeled with 35S, was used, and the hybridization signal was revealed by autoradiography. The density of signal over osteoblasts was quantitated using a semiautomated Leica™ image analysis software package.ResultsThe mean density of PTH1R mRNA signal over osteoblasts in renal high-turnover bone was only 36% of that found in nonrenal high-turnover bone (P < 0.05) and 51% of that found in normal bone (P < 0.05). Osteoblast PTH1R mRNA signal in adynamic bone from individuals with diabetes mellitus was 28% of normal bone (P < 0.05) and 54% of that found in renal high-turnover bone (P < 0.05).ConclusionsThese results demonstrate a down-regulation of osteoblast PTH1R mRNA in end-stage renal failure in comparison to normal and high-turnover bone from otherwise healthy individuals, and provide an insight into the mechanisms of “skeletal resistance” to the actions of PTH