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PubMed1997

Cellular and molecular basis of cerebral dysgenesis.

Maldevelopment of the cerebral cortex, cortical dysgenesis (CD), may be associated with epilepsy, mental retardation (MR), and focal or widespread neurologic deficits. The histologic hallmark of CD is disrupted cytoarchitecture, including disorganized lamination, malpositioned neurons with respect to their normal radial orientation, abnormal dendritic arborization, and heterotopic neurons within the white matter. Seizures in these patients are particularly difficult to control with conventional anti-epileptic drugs (AEDs) and may require epilepsy surgery to remove these abnormal foci. Focal CD has been reported in up to 30% of epilepsy surgery specimens and are believed to provide the central pathologic substrate responsible for seizures in these patients. How and why CD results in epileptiform activity is unknown. Advances in understanding the pathogenesis of some types of CD have occurred recently with the cloning genes responsible for a few types of X-linked and autosomal CD. This review will outline the major subtypes of CD, the pathologic findings, and the molecular etiologies for a variety of CD. We will also address recent experimental advances in studying the pathogenesis of CD.

Animals↗

PubMed2005

[The application of modified classification of the aortic dissection].

OBJECTIVE: To determine the indication, optimal operative procedures, plan and the estimation of the prognosis depending on the subtype of aortic dissection defined by the extension and extent of dissection. METHODS: The outcome of 708 patients with aortic dissection between January 1994 and December 2004 was analyzed. Among them 477 patients suffered from Stanford type A aortic dissection were treated. Type A dissection can be classified into 3 subtypes based on the pathological change of the aortic root. Type A1 (No pathological change type): 212 patients underwent ascending aorta replacements; Type A2 (mild pathological change type): 63 patients underwent ascending aortic replacement with concomitant aortic valve and valsalva sinus plasty and David procedure was performed in 9 patients; Type A3 (severe pathological change type): 193 patients underwent Bentall procedure. The method of aortic arch repair was determined by the pathological type of distal aorta. Total aortic arch replacement was performed in 78 patients with complex type (type C). There hundred and ninety-nine patients with simple type (type S) underwent partial aortic arch replacement. 231 patients suffered from Stanford type B aortic dissection. Type B dissection can be classified into 3 subtypes based on dilated extension of proximal descending aorta. Type B1 (no dilation was confined in the proximal of thoracic descending aorta): endoluminal stent graft repair was performed in 103 patients. Replacement of the partial proximal thoracic descending aorta and replacement combined with stented elephant trunk procedure were performed in 32 and 12 patients respectively; Type B2 (aneurysm in thoracic descending aorta): 32 patients underwent the part proximal thoracic descending aorta replacement combined with aorta plasty. 21 patients underwent the replacement of entire thoracic descending aorta; Type B3 (aneurysm in thoracic descending and abdominal aorta): thoracoabdominal aortic replacement was operated in 31 patients with deep hypothermia circulatory arrest; Type BC (complex type): 44 patients were performed the operation with the use of deep hypothermia circulatory arrest because their left subclavian arteries or distal aortic arch were affected by the dissection; Type BS (simple type): 103 patients were underwent endoluminal stent graft repair. In the 60 patients, the operations were performed by using the technique which preserved blood was transfused back by pump via the femoral artery. Femoro-femoral bypass was performed in 24 patients. RESULTS: Type A: the operative mortality was 4.6% (27/477), and the hospital morbidity was 14.5% (69/477). Type B: the hospital mortality of endoluminal stent graft repair was 1.9% (2/103). 9.7% (10/103) had mild leakage from proximal communications. The morbidity was 2.9% (3/103) in stent group. The mortality was 3.1% (4/128), and the hospital morbidity was 18.8% (24/128) in the operative group. CONCLUSION: The subtype of aortic dissection is much useful in determining the optimal procedure, operative indication and plan, estimating the prognosis.

Adult↗

PubMed1996

Conventional versus modified morphologic criteria for ganglioneuroblastoma. A review of cases from the Pediatric Oncology Group.

BACKGROUND: Conventional criteria for ganglioneuroblastoma (GNB) do not require the presence of ganglioneuromatous component for pathologic diagnosis. This leads to inclusion of a mixed variety of neuroblastic tumors in the category of GNB. Therefore, GNB diagnosed by conventional criteria includes tumors showing more than 5% ganglion cells but no predominant ganglioneuromatous component, as well as tumors containing predominant ganglioneuromatous component. By previously described modified criteria, the former would be considered differentiating neuroblastoma (NB), and only the latter would be considered GNB. Data on Pediatric Oncology Group cases were analyzed to compare the prognostic subgroups of GNB diagnosed by conventional and modified criteria. The two prognostic subgroups (low risk and high risk) were defined on the basis of previously described prognostic differences between histologic grades of differentiating NBs and subtypes of GNB. METHODS: Pathologic data from cases of neuroblastic tumors registered on Pediatric Oncology Group NB protocols 8104 and 8441 were reviewed. The GNBs diagnosed by conventional and modified criteria were divided into low-risk and high-risk histology subgroups as follows: (1) GNB by conventional criteria: low-risk group, differentiating NB of histologic grades 1 and 2 and GNB of intermixed and borderline subtypes; high-risk group, differentiating NB of histologic grade 3 and GNB of nodular subtype; (2) GNB by modified criteria: low-risk group, GNB of intermixed and borderline subtypes; high-risk group, GNB of nodular subtype. RESULTS: The low- and high-risk subgroups of GNBs diagnosed by conventional (69 cases) and modified (36 cases) criteria showed statistically significant differences in survival (P = .03 and .01, respectively). However, from the histologic point of view, GNBs diagnosed by modified criteria form a more uniform morphologic group, which can be divided into low- and high-risk subgroups by a single set of morphologic criteria. In contrast, GNBs diagnosed by conventional criteria form a heterogeneous group, which requires two sets of criteria (ie, histologic grade and subtypes of GNB) for its classification into low- and high-risk subgroups. CONCLUSIONS: The modified criteria for GNB define a morphologically uniform group of neuroblastic tumors to which a single set of prognostic criteria can be applied. It is recommended that the term GNB should be used both clinically and pathologically to designate a distinctive subgroup of neuroblastic tumors, in contrast to the current use, which designates both NB and GNB.

Ganglioneuroblastoma↗

PubMed2005

Mammary epithelial cell transformation: insights from cell culture and mouse models.

Normal human mammary epithelial cells (HMECs) have a finite life span and do not undergo spontaneous immortalization in culture. Critical to oncogenic transformation is the ability of cells to overcome the senescence checkpoints that define their replicative life span and to multiply indefinitely -- a phenomenon referred to as immortalization. HMECs can be immortalized by exposing them to chemicals or radiation, or by causing them to overexpress certain cellular genes or viral oncogenes. However, the most efficient and reproducible model of HMEC immortalization remains expression of high-risk human papillomavirus (HPV) oncogenes E6 and E7. Cell culture models have defined the role of tumor suppressor proteins (pRb and p53), inhibitors of cyclin-dependent kinases (p16INK4a, p21, p27 and p57), p14ARF, telomerase, and small G proteins Rap, Rho and Ras in immortalization and transformation of HMECs. These cell culture models have also provided evidence that multiple epithelial cell subtypes with distinct patterns of susceptibility to oncogenesis exist in the normal mammary tissue. Coupled with information from distinct molecular portraits of primary breast cancers, these findings suggest that various subtypes of mammary cells may be precursors of different subtypes of breast cancers. Full oncogenic transformation of HMECs in culture requires the expression of multiple gene products, such as SV40 large T and small t, hTERT (catalytic subunit of human telomerase), Raf, phosphatidylinositol 3-kinase, and Ral-GEFs (Ral guanine nucleotide exchange factors). However, when implanted into nude mice these transformed cells typically produce poorly differentiated carcinomas and not adenocarcinomas. On the other hand, transgenic mouse models using ErbB2/neu, Ras, Myc, SV40 T or polyomavirus T develop adenocarcinomas, raising the possibility that the parental normal cell subtype may determine the pathological type of breast tumors. Availability of three-dimensional and mammosphere models has led to the identification of putative stem cells, but more studies are needed to define their biologic role and potential as precursor cells for distinct breast cancers. The combined use of transformation strategies in cell culture and mouse models together with molecular definition of human breast cancer subtypes should help to elucidate the nature of breast cancer diversity and to develop individualized therapies.

Animals↗

PubMedDate not supplied

Incidence, 30-day case-fatality rate, and prognosis of stroke in Iquique, Chile: a 2-year community-based prospective study (PISCIS project).

BACKGROUND: The epidemiology of stroke in Latin-American populations and variation of subtypes between communities are unclear. Our aim was to ascertain prospectively the incidence of first-ever stroke in the predominantly Hispanic-Mestizo population of Iquique, a city in the northern desert region of Chile. METHODS: We prospectively identified all possible cases of stroke and transient ischaemic attacks between July 1, 2000, and June 30, 2002, from several overlapping sources. Patients were rapidly assessed by two field neurologists. Standard definitions for incident cases, stroke, transient ischaemic attack, pathological type, and infarction subtype were used. All cases identified were adjudicated by at least two stroke neurologists and followed up at 6 months. Incidence rates of first-ever strokes were calculated from the population of Iquique (214 526) according to the national census of 2002. FINDINGS: Of 380 cases of stroke identified, 292 were incident. CT scans were done in 267 (91%) patients and the mean time to scan was 2.2 days. The hospital admission rate was 71% (207/292). The overall age-adjusted incidence rate of first-ever stroke was 140.1 per 100,000 (95% CI 124.0-156.2). The incidence rates per 100,000 according to pathological type were: infarcts 87.3, intracerebral haemorrhage 27.6, and subarachnoid haemorrhage 6.2. The 30 day and 6-month case-fatality rates were 23.3% and 33.0%, respectively. INTERPRETATION: Our results show incidence rates of stroke similar to those reported in other community studies. Although the proportion of intracerebral haemorrhages was higher than reported in previous studies, the overall incidence was not, which could indicate a slightly lower incidence of ischaemic strokes in this population than in other countries. The prognosis was similar to that found in other population-based studies.

Adult↗

PubMed2004

Somatostatin receptors and their interest in diagnostic pathology.

Since the discovery of somatostatin (SS) and of its interactions with a family of specific somatostatin receptors (sst), a wide body of evidence has been reported on its biological activities. Those activities include inhibition of hormone secretion, neuromodulatory properties in the central nervous system, cell growth control, and induction of apoptosis. At the same time, the distribution of sst has been analyzed in both normal and pathological tissues and sst subtype selective SS-analogs, able to mimic most SS functions, have been developed. The results have been fundamental insights into sst physiology and potent clinical implications in a variety of neoplastic and non neoplastic diseases. Neuroendocrine tumors have been particular targets of investigation. Alternative methods have been validated and are available to analyze the presence and functionality of sst at the level of either mRNA or protein. These methods include RT-PCR, Northern blot, in situ hybridization, immunohistochemistry, autoradiography, and in vivo scintigraphy. Tissue localization techniques are now accessible to many pathology laboratories worldwide and the role of the pathologist in typing the different sst present in a given sample is becoming more and more crucial. This is particularly, but not exclusively, the case in the field of neuroendocrine oncology, where sst typing may affect the clinical management of patients with sst-positive tumors.

Animals↗

PubMed2002

[Combined thymoma (AB + B)--pathological diagnosis and clinical significance].

OBJECTIVE: To discuss the pathological and biological characteristic and the clinic-pathological relevance of combined thymoma (AB + B). METHODS: According to the WHO Histological Typing of Thymic Tumors, the clinical features and pathological characteristics of AB + B thymomas were analyzed in a series of 141 thymic epithelial tumors (TET) collected in Shanghai Chest Hospital and analyzed statistically with clinical therapy and follow-up data. RESULTS: Seven cases of type A (5.0%), 48 cases of type AB (34.0%), 14 cases of combined thymoma (AB + B) (9.9%), 9 cases of type B1 (6.4%), 22 cases of type B2 (15.6%), 21 cases of type B3 (14.9%) and 20 cases of type C (14.2%) were classified. The overall postoperative survival data showed highly significant differences amongst the histological subtypes. Combined thymoma (AB + B) showed distinctive histopathological characteristics, their prognostic properties were between A, AB and B1-B3, the differences between them being highly significant (log rank: chi(2) = 48.18, P < 0.001). Seventy-three patients (51.8%) were in stage I, 16 (11.3%) were in stage II, 44 (31.2%) were in stage III, and 8 (5.7%) were in stage IV. The association between histological subtype and invasive stage was significant (chi(2) = 71.3, P < 0.001). Combined thymoma (AB + B) was grouped to grade II thymoma. Thymoma grading has a positive relationship with therapy and prognosis (log rank: chi(2) = 57.49, P < 0.001). CONCLUSIONS: It is proposed that combined thymoma (AB + B) may be named as the borderline thymoma. It has a distinctive histopathological definition and criteria and may be grouped as a subtype of thymoma. Its pathological and biological properties are between benign and malignant thymomas, and have significant differences.

Adolescent↗

PubMedDate not supplied

The clinical diagnosis of vascular dementia.

The question was addressed whether the three vascular dementia (VAD) subtypes, multi-infarct dementia (MID), strategic-infarct dementia (SID), and subcortical white matter dementia (SWMD) fulfil the basic criteria for a disease: does a distinct pattern of clinical features match a distinct pathological picture for the various VAD subtypes? No obvious correspondence between structural pathological changes and symptoms or signs was found in the MID and SID subtypes. Therefore, the disease status of these VAD subtypes can be questioned. The VAD subtype SWMD, however, appeared to fulfil the basic criteria for a disease, as the subcortical white matter changes corresponded to the subcortical symptom pattern, with mental slowness, extrapyramidal and bilateral pyramidal deficits.

Brain↗

PubMed1997

The relationship of local and distant failure from endometrial cancer: defining a clinical paradigm.

PURPOSE: Recently, statistical methods have been developed to rigorously assess the relationship between local and distant failures. Such methodology has successfully been applied to a variety of tumors including those arising in the prostate, breast, and cervix. To date, no published data are available to generate a hypothesis to characterize the relationship between local and distant failure for endometrial cancer. The present analysis was undertaken to determine the effect of locoregional control on subsequent metastatic dissemination among women with pathologically staged endometrial cancer treated by hysterectomy followed by adjuvant radiotherapy. METHODS: The series consisted of 394 patients with FIGO stages I-III endometrial cancer who were surgically staged prior to irradiation [median external beam dose 45 Gy +/- brachytherapy (median vaginal surface dose, 30 Gy)]. The duration of follow-up ranged from 2 to 151 months, with a median of 62 months. Multiple factors were evaluated to determine the associations with distant relapse including FIGO pathological stage, grade, histopathologic subtype (adeno vs papillary/papillary-serous/clear cell), depth of myometrial penetration, age, and local disease status. Time-dependent survival models were generated to assess the influence of local failure on distant metastases. RESULTS: For the entire series, the 5-year actuarial rates of local and distant failures were 9 and 20%, respectively. Women who failed locally had nearly a fourfold risk of failing distantly compared to those who remained locally controlled (P = 0.02). Moreover, the earlier a local failure developed (e.g., within 1 year vs within 3 years), the more likely it was to be associated with distant metastases (P < 0. 05). The univariate correlations of other factors with the 5-year rate of freedom from distant relapse also disclosed significant associations for grade, histology (adenoca vs papillary/papillary-serous/clear cell), and FIGO path stage. In multivariate analysis, only local control, low grade (grade 1 and 2), and early pathological stage were independently related to the likelihood of achieving freedom from distant relapse. CONCLUSIONS: Distant dissemination of endometrial cancer may develop secondary to local failure. Optimization of local control is therefore necessary if long-term cure is to be achieved. The limits of the current database cannot establish whether local failure is a cause of distant spread or a high-risk marker for metastases; however, ongoing national cooperative trials may resolve this controversy.

Actuarial Analysis↗

PubMed2004

Influence of breast cancer histology on the relationship between ultrasound and pathology tumor size measurements.

Establishing an accurate primary invasive breast cancer size is crucial for patient management. Although ultrasonographic measurement is reported to correlate reliably with the gold standard pathology measurement, few authors have examined the influence of histologic subtype on ultrasound measurement. The common subtypes of invasive breast carcinoma, ductal and lobular, have different growth patterns, which may influence the ability of ultrasound to predict pathologic size. For this analysis, ultrasound and pathology reports were retrospectively reviewed for 204 women with 210 invasive breast cancers, including 129 ductal, 41 lobular, and 40 mixed pattern ductal and lobular carcinomas. For each tumor, the largest pathology and ultrasound dimensions were compared using Pearson's correlations, linear regression, paired t-tests and Wilcoxon signed ranks tests, stratified by histologic subtype. The Hodges-Lehmann approach was used to obtain 95% confidence intervals (CI) for median difference of the sizes. Ultrasonography consistently underestimated pathologic tumor size; the overall median difference was 3.5 mm (CI: 2.5-4.0 mm) and for subtypes: 2.5 mm (CI: 1.5-3.5 mm) for ductal pattern; 3.0 mm (CI: 1.5-4.5 mm) for mixed pattern; and in contrast, 7.5 mm (CI: 5.0-13.5 mm) for lobular pattern tumors. Significant correlations of similar magnitude, were observed between size measurements for ductal, lobular, and mixed subtypes (r=0.816, 0.811 and 0.672, respectively; all P<0.001); however, linear regression models differed between subtypes. Although practical and widely available, ultrasonography tends to underestimate pathologic tumor size. The size difference may be large for lobular carcinomas, potentially influencing stage; differences are less pronounced for ductal and mixed subtypes. Pathologic tumor size can be estimated from the ultrasonographic measurement, particularly if the histologic tumor subtype is known. The results of this study underscore the continued benefit of pretreatment tumor histology.

Breast Neoplasms↗

PubMed2002

Cytokeratin 20 as a biomarker of gestational trophoblastic disease: diagnostic and prognostic significance.

OBJECTIVES: This study was designed to examine whether cytokeratin 20 (CK20) is expressed in molar pregnancies and may therefore be used in the diagnosis of gestational trophoblastic disease (GTD). The potential of CK20 expression in predicting the evolution and the prognosis of the different subtypes of GTD was also assessed. METHODS: A total of 48 samples were studied for CK20 expression by RT-PCR methodology. Among these, 24 samples were obtained by curettage of the uterine cavity of patients diagnosed with hydatidiform mole (14 complete moles and 10 partial moles), 4 samples were obtained from choriocarcinoma cell lines (2 JAR and 2 JEG), and 20 samples were of normal trophoblast (control group) obtained from patients that underwent elective termination of pregnancy. RESULTS: Expression of CK20 was identified in all the samples of complete mole (CM), all choriocarcinoma cell lines, and 50% of the patients with partial mole (PM). None of the preparations of normal trophoblastic tissue from the control group expressed the CK20. A significant difference (P < 0.00001) was found in CK20 expression between samples of patients with GTD and control samples. Comparison between CK20 expression in CMs and PMs revealed a significantly more frequent expression of CK20 in CMs (P = 0.006). More than 50% of the patients with PMs that were positive for CK20 had an invasive evolution. CONCLUSIONS: In our opinion, CK20 may assist in distinguishing between molar and normal trophoblastic tissue and may be considered a marker of GTD. In cases in which pathological classification of different subtypes of GTD is in doubt, CK20-positive expression is suggestive for a CM whereas CK20-negative is more indicative for PM.

Biomarkers, Tumor↗

PubMed2004

Causes of death within 1 year of resection for lung cancer. Early mortality after resection.

OBJECTIVES: Some of the lung cancer patients who are treated surgically with curative intent ultimately die in the early postoperative period. The aim of this study is to analyze the causes of death within 1 year of resection for lung cancer in our patients. METHODS: Six hundred and twenty patients, who underwent resection for lung cancer with a curative intent were reviewed retrospectively. Eighteen patients (2.9%) died due to postoperative complications or within the first month and 51 (8.4%) patients (group 1) died within the first year after operation. Fifty-one patients (group 1) were compared with the survivors (group 2) in terms of age, gender, preoperative FEV 1, pathological tumor node metastasis (TNM), histopathological subtypes, type of resection, completeness of the resection, preoperative Karnofsky performance status and application of postoperative radiotherapy. RESULTS: Pathological TNM (P<0.001) type of resection (P<0.01) histopathological subtype (P<0.001) completeness of the resection (P<0.05) and postoperative radiotherapy (P<0.001) were determined to be significant factors in mortality within 1 year after resection for lung cancer. CONCLUSIONS: The patients with pathological stage 3 disease, with large cell histology or who had undergone pneumonectomy have a higher risk of mortality within 1 year. These patients require detailed preoperative work up in terms of metastatic disease and cardiopulmonary physiological status.

Adult↗

PubMed1998

Correlation between methylation status of the p16/CDKN2 gene and the expression of p16 and Rb proteins in primary non-small cell lung cancers.

In order to clarify the frequency of p16 gene inactivation and its relationship with Rb expression, immunohistochemical analysis of p16 and Rb proteins was carried out on 82 paraffin-embedded sections of primary non-small cell lung cancers (NSCLCs). From immunohistochemical results, abnormal p16 expression was observed in 66% of NSCLCs, 80% in squamous cell carcinomas and 46% in adenocarcinomas. An inverse correlation between p16 and Rb expressions was noted. Moreover, the methylation status of the p16 gene was investigated by the methylation-specific polymerase chain reaction (MS-PCR) using 29 frozen samples of NSCLCs. MS-PCR revealed the methylation of the p16 gene in 10(34%)of 29 NSCLCs. All NSCLCs exhibiting methylation exhibited abnormal p16 expression and were positive for Rb. In NSCLCs, no difference in methylation status was observed with respect to clinico-pathological characteristics including histological subtype and tumor stage. Our results demonstrate that abnormality of p16 expression is frequent in primary NSCLCs and methylation of the promoter of the p16 gene occurs in 34% of primary NSCLCs, which might play a significant role in the inactivation of the p16 gene.

Adenocarcinoma↗

PubMed2006

Histologic subtypes as determinants of outcome in esophageal carcinoma patients with pathologic complete response after preoperative chemoradiotherapy.

BACKGROUND: The current study tested the hypothesis that the clinical outcome of patients with localized esophageal carcinoma after preoperative chemoradiotherapy (CTRT) depends on histology. METHODS: The authors stratified patients by adenocarcinoma (ACA) or squamous cell carcinoma (SCC) and compared the overall survival (OS) and patterns of failure among patients achieving pathologic complete response (pathCR) and or=0.05). In the ACA group, a greater portion of <pathCR patients (32%) than pathCR patients (16%) had distant metastases (P=0.02) and the distant metastases-free survival of pathCR patients was longer than that of <pathCR patients (P=0.0012). In the SCC group, the proportion or time to distant-metastases did not differ significantly. Pretreatment clinical stage did not correlate with pathologic response for either histology. CONCLUSIONS: The results of the current study suggest that the clinical biology of SCC and ACA is different after CTRT. An investigation of molecular and patient genetics is needed to improve therapy.

Adenocarcinoma↗

PubMedDate not supplied

Heterogeneity of response and survival in diffuse histiocytic lymphoma after BACOP therapy (bleomycin, doxorubicin, cyclophosphamide, vincristine, prednisone).

Diffuse 'histiocytic' lymphoma (DHL) is heterogeneous pathologically, consisting of four subtypes within Lukes-Collins; large-cleaved (LC), large non-cleaved (LNC), immunoblastic sarcoma of B cells (B-IBS), and immunoblastic sarcoma of T-cells (T-IBS). This heterogeneity is also recognized in the Cooperative Working Formulation on non-Hodgkin's lymphoma. Prior studies have suggested clinical heterogeneity of DHL as well, although conclusions were hampered by small numbers, and lack of therapeutic uniformity. We treated 57 patients with advanced DHL, using BACOP: 22 LNC, 16 T-IBS, 13 B-IBS, six LC. Complete remission rate for LNC was 64 per cent (14/22); B-IBS was 54 per cent (7/13); LC was 33 per cent (2/6); T-IBS was 25 per cent (4/16). (p = 0.10). Median survival for LNC was 27.8 months, B-IBS was 25.9, LC was 14, T-IBS was 12.0. The survival was significantly shorter for T-IBS patients when compared to the others (p = 0.01). By multi-variate analysis, histologic subtype (p = 0.02), age (p = 0.03), and stage (p = 0.06) were significant and independent prognostic variables in predicting survival. We conclude that LNC may respond the most favourably to BACOP, whereas alternative regimens appear necessary for patients with T-IBS.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1994

Atrial natriuretic factor as a volume regulator.

Atrial natriuretic factor, originally isolated from the atrium of the heart, has been found to consist of three major groups: atrial natriuretic peptide (ANP), B-form natriuretic peptide (BNP), and C-form natriuretic peptide (CNP). In addition, ANP exists in its precursor form, pro-ANP, an active ANP with a longer peptide chain (urodilatin) and an antiparallel dimer of active ANP. Sites and production of these diverse forms of the peptides are also diverse, depending on pathologic states. Three major subtypes of ANP receptors exist; these include a clearance receptor and two types of a transmembrane receptor with guanylyl cyclase structures in their intracellular domain. The latter exists at least in two forms, one of which is found mainly in the brain. All the actions of ANP mediated by the transmembrane form of ANP receptors are mediated by cGMP generated by the guanylyl cyclase in the cytosolic domain of the receptor. Among the numerous effects of ANP, its major effects are stimulation of natriuresis and diuresis by the kidney through its hemodynamic and tubular effects. In addition, ANP causes vasodilatation and fluid volume reduction by direct actions on vascular smooth muscle cells, and inhibition of secretion of hormones, such as aldosterone, from adrenal cortex and norepinephrine from peripheral adrenergic neurons. Centrally mediated effects on the regulation of the fluid volume may also be important.

Atrial Natriuretic Factor↗

PubMed2004

Anaplastic lymphoma kinase proteins in growth control and cancer.

The normal functions of full-length anaplastic lymphoma kinase (ALK) remain to be completely elucidated. Although considered to be important in neural development, recent studies in Drosophila also highlight a role for ALK in gut muscle differentiation. Indeed, the Drosophila model offers a future arena for the study of ALK, its ligands and signalling cascades. The discovery of activated fusion forms of the ALK tyrosine kinase in anaplastic large cell lymphoma (ALCL) has dramatically improved our understanding of the pathogenesis of these lymphomas and enhanced the pathological diagnosis of this subtype of non-Hodgkin's lymphoma (NHL). Likewise, the realisation that a high percentage of inflammatory myofibroblastic tumours express activated-ALK fusion proteins has clarified the causation of these mesenchymal neoplasms and provided for their easier discrimination from other mesenchymal-derived inflammatory myofibroblastic tumour (IMT) mimics. Recent reports of ALK expression in a range of carcinoma-derived cell lines together with its apparent role as a receptor for PTN and MK, both of which have been implicated in tumourigenesis, raise the possibility that ALK-mediated signalling could play a role in the development and/or progression of a number of common solid tumours. The therapeutic targeting of ALK may prove to have efficacy in the treatment of many of these neoplasms.

Anaplastic Lymphoma Kinase↗

PubMed2001

Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice.

The recent cloning of two GABA(B) receptor subunits, GABA(B1) and GABA(B2), has raised the possibility that differences in GABA(B) receptor subunit composition may give rise to pharmacologically or functionally distinct receptors. If present, such molecular diversity could permit the selective targeting of GABA(B) receptor subtypes specifically involved in pathologies such as drug addiction, spasticity, pain, and epilepsy. To address these issues we have developed a GABA(B1) subunit knockout mouse using gene targeting techniques. In the brains of GABA(B1) null mice, all pre- and postsynaptic GABA(B) receptor function was absent demonstrating that the GABA(B1) subunit is essential for all GABA(B) receptor-mediated mechanisms. Despite this, GABA(B1) null mice appeared normal at birth, although by postnatal week four their growth was retarded and they developed a generalized epilepsy that resulted in premature death. In addition, GABA(B1) heterozygote animals showed enhanced prepulse inhibition responses compared to littermate controls, suggesting that GABA(B1) deficient mice exhibit increased sensorimotor gating mechanisms. These data suggest that GABA(B) receptor antagonists may be of benefit in the treatment of psychiatric and neurological disorders in which attentional processing is impaired.

Action Potentials↗