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PubMed2000

A possible divergent role for the oestrogen receptor alpha and beta subtypes in clinical breast cancer.

We have examined the relative levels of oestrogen receptor beta (ERbeta) mRNA in 94 breast cancer specimens using a semi-quantitative RT-PCR procedure. We correlated its expression with ERalpha and various clinical, pathological and biochemical features of the disease. The level of ERbeta mRNA expression in these samples was found to be much lower than ERalpha. Although ERalpha mRNA species were found to be most frequently associated with histological grade I and II tumours, displaying tubular differentiation, low grades of nuclear pleomorphism and low mitotic activity, such features were not characteristic of ERbeta positive samples. Indeed, application of the Spearman rank correlation test revealed that there was an inverse association between ERbeta normalised levels and ERalpha protein HScore. Also ERbeta mRNA positive cancers were more frequently EGFR protein positive than their negative counterparts (p = 0.016), a feature normally associated with endocrine-insensitive disease. Our data suggest that although ERbeta levels are most likely lower than ERalpha, they may influence the biological behaviour of breast cancers containing low levels of ERalpha.

Breast Neoplasms↗

PubMed1994

Pathology of the salivary glands: the contribution of electron microscopy.

Electron microscopy has a limited role in the diagnosis of primary salivary gland tumors, although it can be helpful in metastatic lesions of possible salivary gland origin. The diversity of subtypes in salivary gland tumors, as well as the range of histomorphology within any one subtype, is unparalleled in any other human tumor. This and their relative infrequency causes diagnostic problems for pathologists. Ultrastructural techniques have been of major importance in determining the inter-relationship of these tumors for classification purposes, revealing the subtle variations in common cellular differentiation pathways, determining the organization of tumor cells, and displaying the importance of extracellular matrix materials in establishing diagnostic criteria for each of the many subtypes. Electron microscopy has also been valuable in non-neoplastic salivary gland disease and has an increasing role in experimental studies involving tissue from human and animal salivary parenchyma.

Animals↗

PubMed1983

Involvement of fast and slow twitch muscle fibres in avian muscular dystrophy.

The extent of differential fibre type involvement in chicken muscular dystrophy can be assessed quantitatively by the statistical parameters of fibre area, nuclei content and nuclei distribution in the individual fibre types. Two muscles, the posterior latissimus dorsi (PLD) and the serratus metapatagialis (SMP), were found to have similar overall fibre type composition, although the latter contains two subtypes of type I fibres, one of which has not previously been recognised in avian muscle. In both muscles, type IIB fibres are most affected by the progressive pathology. Nuclear proliferation is one of the histopathological features which can be measured, and in the PLD, the mean number of total nuclei in type IIB fibre cross-sections (Nt) is increased from 2.23 in normal chickens to 3.70 in dystrophic chickens, by 60 days. The corresponding values for Nt in type IIB muscle fibres of the SMP at 50 days are 1.74 and 5.10. Likewise, statistical analyses of the distribution of the fibre areas and their variability demonstrate that the incidence of abnormality in chicken dystrophy is greatest in type IIB fibres in both these muscles. Although type I fibres in the PLD are resistant to dystrophic change, it is noteworthy that in the SMP the type I fibres, also, are severely affected from an early stage, by these quantitative criteria. On the other hand, all fibres in a tonic muscle, the metapatagialis latissimus dorsi, are unaffected, as is true of all other tonic muscles previously studied. It is concluded that any twitch fibre type can, in principle, be affected by the actions of the gene concerned, and that this expression can be greatly modified in individual muscles by various physiological features, for example their natural pattern of use or relative disuse.

Adenosine Triphosphatases↗

PubMed1997

B-cell lymphoma accompanying monoclonal macroglobulinemia with features suggesting marginal zone B-cell lymphoma.

Waldenstroem's macroglobulinemia is usually closely related to a histopathologic subtype called lymphoplasmacytoid lymphoma in the Revised European-American Lymphoma (REAL) classification. Here, we report a case of B-cell lymphoma accompanied by monoclonal macroglobulinemia and pathologically compatible with marginal zone B-cell lymphoma (MZBCL) rather than lymphoplasmacytoid lymphoma. The patient was a 74-year-old man with lymphomatous lesions that were recognized as submandibular lymphadenopathy, subcutaneous tumor and bilateral orbital masses, but with no bone marrow involvement. The atypical lymphoid cells that occupied the lymph node were varied such as small cells harboring irregular nuclei, monocytoid B-cells, large cells with vesicular nuclei, and plasma cells. The tumor cells expressed CD19, CD20, IgM and kappa on their cell surfaces and cytoplasmic IgM, but not CD5 or CD10. These findings suggest that the clinical and histopathologic findings of this case are compatible with those of MZBCL rather than lymphoplasmacytoid lymphoma. Serum IgM was elevated up to 4080 mg/dl and M-proteinemia of IgM-kappa type was confirmed by immunoelectrophoresis. Hyperviscosity syndrome caused by monoclonal IgM was not apparent. Immunohistochemical study confirmed that monoclonal IgM-kappa was produced and secreted from the tumor cells of MZBCL. This case suggests a close relationship between MZBCL and lymphoplasmacytoid lymphoma, from the perspective of the cellular origin during B-cell differentiation.

Aged↗

PubMed1986

Diagnostic histopathologic criteria in pediatric tumors: an eclectic review.

Malignant tumors of infants and children, unlike their adult counterparts, are commonly undifferentiated or show minimal evidence of differentiation. Because of this, many of these tumors pose a formidable dilemma to the general pathologist in distinguishing one from another. A broad sampling of the more common malignant neoplasms and of newly recognized histologic subtypes which are restricted more or less to the pediatric age group is presented. The minimal microscopic criteria required to establish a diagnosis are given using widely accepted pathologic classifications and seminal journal references as a guide. Ancillary microscopic features, helpful histochemical stains, immunohistochemistry, and ultrastructural morphology are described for most tumors. Histologic distinction from diagnostic mimickers is discussed. Where appropriate, histologic grading and tumor subclassification are presented and their prognostic relevance is reviewed.

Biopsy↗

PubMedDate not supplied

Telomerase-immortalized lymphatic and blood vessel endothelial cells are functionally stable and retain their lineage specificity.

OBJECTIVE: Microvasculature plays an important role in a variety of physiological and pathological processes. The authors have previously shown that primary cultures of human microvascular endothelial cells consist of 2 distinct populations of blood vascular and lymphatic endothelial cells. These subtypes are ephemeral and lose purity through passaging. To generate reproducible in vitro and in vivo experiments stable blood and lymphatic endothelial cell lines are an essential prerequisite. METHODS: In this study they have used human telomerase gene-immortalized nontransformed human microvascular endothelial cell cloned pure cultures of blood and lymphatic endothelial cell subpopulations. Flow cytometry, immunofluorescence, Northern and Western blotting, microarray gene analysis, as well as basic functional assays were used to characterize these clones. RESULTS AND CONCLUSIONS: Immortalized blood and lymphatic subpopulations are stable and functionally specialized cell lineages that expressed pan-endothelial and cell-type-specific markers. They are excellent candidates for long-term culture studies on microvascular-related diseases.

Biomarkers↗

PubMed2000

The pathologic features and mechanism of traumatic dislocation of the hip.

The term traumatic dislocation of the hip encompasses a heterogenous group of dislocations, and more commonly, fracture-dislocations which have been subclassified. The current study describes the pathologic features in terms of an anatomic description of the displaced parts of the joint and what is known of the associated injured structures in each of the subtypes. The events that lead to traumatic dislocation of the hip are well documented, but understanding of the mechanics of the injury can only be presumptive.

Hip Dislocation↗

PubMedDate not supplied

From the Archives of the AFIP: neoplasms of the urinary bladder: radiologic-pathologic correlation.

In the United States, primary bladder neoplasms account for 2%-6% of all tumors, with bladder cancer ranked as the fourth most common malignancy. Ninety-five percent of bladder neoplasms arise from the epithelium; the most common subtype is urothelial carcinoma, which accounts for 90% of cases. Squamous cell carcinoma accounts for 2%-15%, with rates varying widely according to geographic location. Adenocarcinoma (primary bladder, urachal, or metastatic) represents less than 2%. Bladder cancer typically occurs in men aged 50-70 years and is related to smoking or occupational exposure to carcinogens. Most urothelial neoplasms are low-grade papillary tumors, which tend to be multifocal and recur but have a relatively good prognosis. High-grade invasive tumors are less common and have a much poorer prognosis. Squamous cell carcinoma and adenocarcinoma occur in the setting of chronic bladder infection and irritation. Mesenchymal tumors represent the remaining 5% of bladder tumors, with the most common types being rhabdomyosarcoma, typically seen in children, and leiomyosarcoma, a disease of adults. Rarer mesenchymal tumors include paraganglioma, lymphoma, leiomyoma, and solitary fibrous tumor. Although imaging findings are not specific for these tumors, patterns of growth and tumor characteristics may allow differentiation. For accurate staging, computed tomography and magnetic resonance imaging are the modalities of choice.

Carcinoma↗

PubMed1999

Pharmacological inhibition of the Na(+)/Ca(2+) exchanger enhances depolarizations induced by oxygen/glucose deprivation but not responses to excitatory amino acids in rat striatal neurons.

BACKGROUND AND PURPOSE: Neuronal Na(+)/Ca(2+) exchanger plays a relevant role in maintaining intracellular Ca(2+) and Na(+) levels under physiological and pathological conditions. However, the role of this exchanger in excitotoxicity and ischemia-induced neuronal injury is still controversial and has never been studied in the same neuronal subtypes. METHODS: We investigated the effects of bepridil and 3',4'-dichlorobenzamil (DCB), 2 blockers of the Na(+)/Ca(2+) exchanger, in rat striatal spiny neurons by utilizing intracellular recordings in brain slice preparations to compare the action of these drugs on the membrane potential changes induced either by oxygen and glucose deprivation (OGD) or by excitatory amino acids (EAAs). RESULTS: Bepridil (3 to 100 micromol/L) and DCB (3 to 100 micromol/L) caused a dose-dependent enhancement of the OGD-induced depolarization measured in striatal neurons. The EC(50) values for these effects were 31 micromol/L and 29 micromol/L, respectively. At these concentrations neither bepridil nor DCB altered the resting membrane properties of the recorded cells (membrane potential, input resistance, and current-voltage relationship). The effects of bepridil and DCB on the OGD-induced membrane depolarization persisted in the presence of D-2-amino-5-phosphonovalerate (50 micromol/L) plus 6-cyano-7-nitroquinoxaline-2,3-dione (20 micromol/L), which suggests that they were not mediated by an enhanced release of EAAs. Neither tetrodotoxin (1 micromol/L) nor nifedipine (10 micromol/L) affect the actions of these 2 blockers of the Na(+)/Ca(2+) exchanger, which indicates that voltage-dependent Na(+) channels and L-type Ca(2+) channels were not involved in the enhancement of the OGD-induced depolarization. Conversely, the OGD-induced membrane depolarization was not altered by 5-(N, N-hexamethylene) amiloride (1 to 3 micromol/L), an inhibitor of the Na(+)/H(+) exchanger, which suggests that this antiporter did not play a prominent role in the OGD-induced membrane depolarization recorded from striatal neurons. Bepridil (3 to 100 micromol/L) and DCB (3 to 100 micromol/L) did not modify the amplitude of the excitatory postsynaptic potentials evoked by cortical stimulation. Moreover, these blockers did not affect membrane depolarizations caused by brief applications of glutamate (0.3 to 1 mmol/L), AMPA (0. 3 to 1 micromol/L), and NMDA (10 to 30 micromol/L). CONCLUSIONS: These results provide pharmacological evidence that the activation of the Na(+)/Ca(2+) exchanger exerts a protective role during the early phase of OGD in striatal neurons, although it does not shape the amplitude and the duration of the electrophysiological responses of these cells to EAA.

Amiloride↗

PubMed2026

MYB activity drives emergent enhancer activation and enhancer-promoter interactions in acute lymphoblastic leukemia.

Aberrant enhancer usage is a defining feature of oncogenic transcriptional reprogramming. Therapeutic strategies that disrupt enhancer-driven gene regulation may offer new treatment avenues. MYB is a key hematopoietic transcription factor that is frequently dysregulated in a broad range of cancers and plays a critical role in sustaining malignant cell states, including in aggressive leukemia subtypes such as KMT2A-rearranged leukemias. The molecular mechanisms by which it maintains oncogenic transcription remain incompletely understood. Here, we investigate the role of MYB in directing pathological enhancer activity to drive oncogene expression in leukemia. Using high-resolution Micro Capture-C, we show that upon MYB degradation, highly defined enhancer-promoter interactions at MYB binding sites are lost, correlating with the significant downregulation of target gene expression. When anchored to a gene desert region, the Myb transactivation domain (MybTA) is sufficient and necessary for the nucleation of an enhancer-like region. Critically, long-range chromatin interactions are established up to 400 kb away from where MybTA is anchored. This results in the activation of transcription from distal cryptic elements, which is reduced or abolished in the presence of point mutations that disrupt its interaction with the coactivators P300/CBP. All these results indicate that MYB activity alone is sufficient to generate an enhancer, inducing transcription through precise enhancer-promoter cross talk, and identify the MYB-P300/CBP axis as a therapeutically actionable vulnerability in enhancer-driven malignancies.

Promoter Regions, Genetic↗

PubMed1997

The therapeutic potential of neuropeptide Y in cardiovascular disease.

Neuropeptide Y (NPY), a widely distributed peptide neurotransmitter, is implicated in both the central and peripheral control of the cardiovascular system. Pathological changes in endogenous NPY release and receptor function may contribute to the development and maintenance of hypertension, myocardial ischaemia and cardiac failure. At least six NPY receptor subtypes are known to exist, and the activation of a certain number of these results in complex central and peripheral changes in cardiovascular function. The cloning and sequencing of NPY receptor subtypes has led to the possibility of developing subtype-specific ligands targeted at NPY receptors, and this article will consider their therapeutic potential in cardiovascular disease.

Journal Article↗

PubMed2000

Kidney angiotensin receptors and their role in renal pathophysiology.

A considerable amount of data have implicated angiotensin receptors (AT receptors) in the development and maintenance of essential hypertension and renovascular hypertension as well as in progressive renal pathologies. Inhibition of angiotensin II (Ang II) action by blocking Ang II formation through angiotensin-converting enzyme (ACE) inhibitors, or by blocking AT1 receptors directly using subtype-selective nonpeptide antagonists, has been found to attenuate the proteinuria, microalbuminuria, glomerulosclerosis, and nephrosclerosis in a variety of experimental models and in clinical trials. This review will first broadly discuss AT receptor subtypes in terms of their structure, function, tissue distribution and signaling. Secondly, the mechanistic differences between ACE inhibition and AT1 receptor blockade will be examined because these pharmaceutical agents are widely used tools to investigate the role of AT receptors in renal disease. Lastly, experimental models of essential hypertension, renovascular hypertension and progressive renal disease will be presented, which include the Fawn-hooded rat, the stroke prone spontaneously hypertensive rat, renal mass ablation and the 2K1C and 1K1C animal models. The overall goal of this review is to critically evaluate the data regarding the role of AT receptors in the pathophysiology of renal disease.

Angiotensin II↗

PubMed2003

Bradykinin receptor subtype 1 expression and function in prostate cancer.

Kinins exert multiple pathophysiological functions, including vascular permeability and mitogenesis, by activating their cognate receptors, bradykinin subtype 1 receptor (B1R) and bradykinin subtype 2 receptor (B2R), which belong to the superfamily of G protein-coupled receptors. Tissue-specific expression pattern or contribution of the individual kinin receptors to pathological prostate cell growth is not known. We report here the differential expression of B1R and B2R in human benign and malignant prostate specimens. Whereas B2R is ubiquitously expressed, the B1R is detected only in prostatic intraepithelial neoplasia and malignant lesions and not in benign prostate tissues. Using androgen-insensitive prostate cancer PC3 cells, we show that specific stimulation of endogenous B1R promotes cell growth, migration, and invasion. These findings identify B1R as an early marker for pathological growth of the prostate and suggest its potential utility as a drug target effective for the treatment of prostate cancer.

Biopsy↗

PubMed2005

Adenosine A1 receptor mapping of the human brain by PET with 8-dicyclopropylmethyl-1-11C-methyl-3-propylxanthine.

UNLABELLED: Adenosine is an endogenous modulator of synaptic functions in the central nervous system. To investigate the physiologic and pathologic roles of the adenosine receptors in the human brain, PET is a powerful in vivo technique. In this study, we quantitatively evaluated the distribution of a major subtype A(1) adenosine receptor in the human brain by PET with a newly developed radioligand, 8-dicyclopropylmethyl-1-(11)C-methyl-3-propylxanthine ((11)C-MPDX). METHODS: In 5 healthy volunteers, after PET measurement of the regional cerebral blood flow (rCBF) with (15)O-H(2)O, a 60-min PET scan with (11)C-MPDX was performed. The distribution volume (DV) of (11)C-MPDX was quantitatively evaluated by Logan's graphical analysis. RESULTS: (11)C-MPDX was taken up at a high level, reaching a peak at 2-2.5 min, followed by a rapid decrease. The unchanged form of (11)C-MPDX in plasma was 75% at 60 min after injection. The DV of (11)C-MPDX was large in the striatum and thalamus, moderate in the cerebral cortices and pons, and small in the cerebellum. The distribution pattern of (11)C-MPDX in the brain was coincident with that of adenosine A(1) receptors in vitro, reported previously, but discretely different from that of rCBF. CONCLUSION: (11)C-MPDX PET has the potential for mapping adenosine A(1) receptors in the human brain.

Adult↗

PubMed2002

Radiation hybrid mapping of five muscarinic acetylcholine receptor subtype genes in Rattus norvegicus.

Acetylcholine is the main neurotransmitter of the vestibular efferent system and a wide variety of muscarinic and nicotinic acetylcholine receptors are expressed in the vestibular periphery. The role of these receptors and in particular the role of muscarinic acetylcholine receptors in the physiology of the vestibular neuroepithelium is not understood. Congenic and consomic rats are a convenient way to investigate the involvement of candidate genes in the manifestation of defined traits. To use congenic or consomic rats to elucidate the roles of these receptors in vestibular physiology or pathology the chromosomal location of the genes encoding these receptors has to be determined. Using radiation hybrid (RH) mapping and a rat RH map server (www.rgd.mcw.edu/RHMAP SERVER/), we determined the chromosomal locations of the muscarinic acetylcholine receptor genes in the rat (Rattus norvegicus). The m1-m5 muscarinic subtypes mapped to the following chromosomes: Chrm1, chromosome 1; Chrm2, chromosome 4; Chrm3, chromosome 17; Chrm4, chromosome 3; and Chrm5, chromosome 3. With the chromosomal location for each of these muscarinic subtypes known, it is now possible to develop congenic and consomic strains of rats that can be used to study the functions of each of these subtypes.

Animals↗

PubMed2006

Key issues in handling and reporting radical prostatectomy specimens.

CONTEXT: Patients with prostatic adenocarcinoma commonly undergo radical prostatectomy, and it is often difficult and time consuming to handle the resulting specimens and to report the findings. Pathologic information derived from the radical prostatectomy specimen is used for selecting adjuvant therapy, such as radiotherapy and hormone therapy, and for determining a patient's prognosis. The prostate specimen must be handled in a systematic fashion to derive the appropriate prognostic parameters. OBJECTIVE: To review the prognostic factors of relevance in classifying radical prostatectomy specimens, using the College of American Pathologists categorization system, including a detailed survey of the morphologic-based factors but excluding other factors such as DNA ploidy and novel phenotypic and genotypic markers. CONCLUSIONS: Gleason score, pathologic stage, and margin status are considered category 1 prognostic factors, which are of proven prognostic significance and are useful in patient management. Factors such as tumor volume (intraglandular extent) and tumor subtype are considered category 2 prognostic factors, which show significant promise but require validation in multivariate analysis. Lymphovascular space invasion is a promising category 3 prognostic factor that needs additional study. Perineural invasion is an almost ubiquitous finding in radical prostatectomy specimens and is considered a category 3 prognostic factor. After prognostic factors have been analyzed at the histologic level, it is critical to report the findings in a clear and unambiguous fashion. The synoptic style of reporting is ideal for describing complex cancer resection specimens. A synoptic report based on an evidence-based checklist, such as the one developed by the College of American Pathologists, effectively communicates complex cancer-related data, such as radical prostatectomy specimen findings. This information is used not only for individual case management with respect to treatment and prognostication but also for purposes such as education, research, quality monitoring, and system planning.

Adenocarcinoma↗

PubMed2002

Differences in tau and apolipoprotein E polymorphism frequencies in sporadic frontotemporal lobar degeneration syndromes.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) has different clinical phenotypes and is associated with several pathologic findings, most commonly dementia lacking distinctive histology or Pick disease. We know that the tau H1 haplotype is associated with some clinical and histologic phenotypes, for example, progressive supranuclear palsy and corticobasal degeneration. Furthermore, the apolipoprotein epsilon4 allele (APOE epsilon4) may be associated with Pick disease. OBJECTIVE: To determine if different clinical phenotypes of FTLD are associated with different tau haplotype and APOE allele frequencies. PATIENTS AND METHODS: All patients with FTLD with available DNA specimens (n = 63) seen at the Mayo Clinic, Jacksonville, Fla, were retrospectively classified according to the following clinical phenotypes: frontal dementia (FD); progressive, nonfluent aphasia (PA); or fluent, anomic aphasia (AA). DNA specimens were genotyped for APOEallele and tau haplotype frequencies and were compared with cognitively normal patients (n = 338) and patients with Alzheimer disease (AD) (n = 193). RESULTS: Patients with AA had increased APOE epsilon4 frequency (30.4%) compared with patients with FD (14.8%, P=.04) and cognitively normal patients (11.1%, P<.001). Patients with AA also had increased tau H2 haplotype (37.0%) frequency compared with patients with FD (11.1%,P=.002), patients with AD (21.8%, P=.02), and cognitively normal patients (19.8%, P=.004). The increase in tau H2 haplotype frequency (50.0%) is especially pronounced in patients with AA who are APOE epsilon4 positive compared with patients with FD (18.8%, P=.04), patients with AD (24.8%, P=.005), and cognitively normal patients (15.3%, P<.001).APOE epsilon4 and tau H2 haplotype frequencies are not significantly different in patients with FD and PA compared with healthy patients. CONCLUSIONS: Clinical subtypes of FTLD have different tau and APOE genotype frequencies, suggesting these genes may influence the clinical presentation. Further studies should be performed to confirm this finding and to see if the pathologic phenotypes are also associated with different tau and APOE genotype frequencies.

Adult↗

PubMed1998

The potential role of angiotensin II in the vasculature.

Arterial hypertension is associated with marked changes in the structure of both resistance and large arteries. The renin-angiotensin system is largely involved in these alterations; chronic blockade of the renin-angiotensin system prevents and/or reverses most of the alterations of the vasculature in experimental and clinical hypertension. In this review we have analysed the differential role of AT1 and AT2 receptors in the response of the vessels to arterial hypertension. It emerges that the relative involvement of each receptor depends on cell type, the studied specie, and experimental condition. Several points must be investigated in the near future, and especially: (1) the precise role of angiotensin receptors in different cell types and different stages of differentiation; (2)the transduction pathway used by the AT2 receptor in different cell types; (3) the possible interactions between the two receptor subtypes; and finally, (4) a possible role of (a) new subtype(s) of angiotensin II receptor.

Angiotensin II↗