Prominent Subtype Research Articles

Candidate biomarkers in renal cell carcinoma

Although the human genome has been decoded, the knowledge about the pathogenesis of diseases including cancer is still limited. By focusing on renal cell carcinoma (RCC) we here summarize the data of various research groups analyzing the protein/peptide expression profiles of tumor lesions/cell lines or serum obtained from patients and respective controls. Different powerful approaches such as 2-DE, PROTEOMEX/SERPA/SPEARS, and T cell epitope discovery upon elution of MHC class I-bound peptides in combination with MS/LC-MS/MS revealed 500 differentially expressed proteins. The overlap in target recognition limits the pool to 299 unique protein identities, but only few thereof (12%) have been validated. The management, analysis, and interpretation of the distinct data sets derived from 27 publications required bioinformatic restructuring of the results. However, the comprehensive analysis of the results expands the knowledge about the pathophysiology of RCC in particular of the most prominent clear cell subtype by providing information on the differentially expressed proteins, their regulation status in RCC compared to normal kidney epithelium next to additional information on MHC-presented T cell epitopes and on serological targets. Despite the low number of validated differentially expressed proteins some of them might serve as candidate biomarkers for the diagnosis and/or as therapeutic targets.

Rainfall Types in the West African Sudanian Zone during the Summer Monsoon 2002

Abstract Enhanced surface and upper-air observations from the field campaign of the Integrated Approach to the Efficient Management of Scarce Water Resources in West Africa (IMPETUS) project are used to partition rainfall amounts over the West African Sudanian zone during the 2002 summer monsoon season into several characteristic types and subtypes of precipitating systems. The most prominent rainfall subtype was fast-moving, long-lived, and extensive cloud clusters that often developed far upstream over the central Nigerian highlands in the afternoon hours and arrived at the Upper Ouémé Valley (UOV) after midnight. These organized convective systems (advective OCSs, subtype Ia) accounted for 50% of the total rain amount in the UOV catchment in Benin. Subtypes Ia and IIa (i.e., locally developing OCSs) were found to pass by or organize when a highly sheared environment with deep and dry midtropospheric layers was present over the UOV. These systems were most frequent outside the peak of the monsoon season. The second major type of organized convection, termed mesoscale convective systems (subtypes Ib, IIb, and IIIb) in the present study, contributed 26% to the annual UOV precipitation. They occurred in a less-sheared and moister tropospheric environment mainly around the height of the rainy season. A third distinct class of rainfall events occurred during an unusual synoptic situation in which a cyclonic vortex to the north of the UOV led to deep westerly flow. During these periods, the African easterly jet was lacking. The so-called vortex-type rainfalls (subtypes IIIa, IIIb, and IIIc) contributed about 9% to the annual rainfall totals.

Colocalization of somatostatin receptors and epidermal growth factor receptors in breast cancer cells.

BackgroundSomatostatin receptor (SSTR) expression is positively correlated with tumor size and inversely correlated with epidermal growth factor receptor (ErbB) levels and tumor differentiation. In the present study, we compared SSTR1-5 and ErbB1-4 mRNA and protein expression in two breast cancer cell lines: MCF-7 (ER+) and MDA-MB-231 (ERα-).ResultsAll five SSTRs and four ErbBs were variably expressed as both cell surface and cytoplasmic proteins. In both cell lines, SSTR4 and SSTR1 were highly expressed, followed by SSTR2 and SSTR5 with SSTR3 being the least expressed subtype, at the protein level. ErbBs were variably expressed with ErbB1 as the predominant subtype in both cell lines. ErbB1 is followed by ErbB3, ErbB2 and ErbB4 in MCF-7 at both the protein and mRNA levels. In MDA-MB-231 cells, ErbB1 is followed by ErbB2, ErbB4 and ErbB3. Our results indicate significant correlations at the level of mRNA and protein expression in a cell and receptor-specific manner. Using indirect immunofluorescence, we found that, in MCF-7 cells, SSTR5 was the most prominent subtype coexpressed with ErbBs followed by SSTR3, SSTR4, SSTR1 and SSTR2, respectively. In MDA-MB-231 cells, SSTR1 colocalized strongly with ErbBs followed by SSTR5, SSTR4, SSTR3 and SSTR2. ErbBs displayed higher levels of colocalization amongst themselves in MCF-7 cells than in MDA-MB-231 cells.ConclusionThese findings may explain the poor response to endocrine therapy in ER-cancer. Differential distribution of SSTR subtypes with ErbBs in breast cancer cells in a receptor-specific manner may be considered as a novel diagnosis for breast tumors.

Clinical and morphological features of paediatric myelodysplastic syndromes: a review of 34 cases.

The clinical and morphological spectrum of myelodysplastic syndromes (MDS) during childhood has not yet been completely documented. We herein present the clinical features and morphological data from peripheral blood (PB), bone marrow aspirates (BMA) and bone marrow biopsies (BMB) of a series of paediatric MDS patients, with particular emphasis on their specific morphological characteristics and their diverse underlying genetic background. Thirty-four patients with MDS (median age 8.45 y) were consecutively diagnosed and treated during a period of 15 y (1988-2002). Diagnosis was based on clinical manifestations, morphology of PB, BMA and BMB, and cytogenetic analysis of BM cells. Clonogenic methylcellulose cell cultures were performed in 23/34 patients. Patients were categorized into group A [26 primary/de novo MDS, i.e. refractory anaemia (RA) 18, RA with excess of blasts (RAEB) 2, RAEB in transformation (RAEB-t) 6] and group B (8 secondary MDS, i.e. RA 4, RAEB 1, RAEB-t 3). Treatment options varied according to protocols active during the period of the study and the availability of a suitable BM donor. Survival probabilities were estimated using the Kaplan-Meier method. Dysplastic features of the erythroid, myeloid and megakaryocytic lineage were detected at BMA in 85%, 50% and 90% of the patients, respectively, while decreased cellularity was found at BMB in 21/34 patients (60%). RA patients of group A presented at BMB significant hypocellularity (14/18) as a prominent finding due to decrease of the myeloid (13/18 patients) and/or the megakaryocytic (14/18 patients) lineage. Hypocellularity in RA was accompanied by dysplasia of the erythroid (17/18 patients) and megakaryocytic (16/18 patients) lineage, the presence of abnormal localization of immature precursors (ALIP, 8/18 patients), fibrosis (5/18) and stromal changes (11/18). Chromosomal aberrations were revealed in 17/34 patients, of which monosomy 7 was present in seven. Cell cultures demonstrated abnormal myeloid and/or erythroid in vitro clonal growth pattern in all the examined patients. An associated disorder or inherited disease, was identified in 14/26 patients (54%) with primary MDS. Cumulative survival of group A patients was 44.2% (RA 66.6%, RAEB/RAEBt 14.6%; p = 0.001), and of the whole group 42.4%, at 14 y. Hypocellularity of significant degree is a constant and prominent feature among paediatric MDS, especially those with RA. A large variety of associated disorders underlies the clinical appearance of paediatric MDS, reflecting their marked heterogeneity. RA represents the prominent subtype during childhood (69% in this study), and it appears to have the best prognosis, while prognosis of RAEB/RAEBt remains extremely poor.

Intracellular pathways involved in upregulation of vascular endothelin type B receptors in cerebral arteries of the rat.

Previous studies have shown that contractile endothelin type B (ETB) receptors are upregulated in cerebral arteries after experimental focal cerebral ischemia. The aim of this study was to examine the upregulation of contractile ETB receptors in cerebral arteries after organ culture and to elucidate the intracellular pathways involved. Rat middle cerebral arteries (MCAs) were incubated with or without inhibitors. The vessels were mounted in myographs, and the contractile responses to endothelin-1 (ET-1) (ETA and ETB receptor agonist) and sarafotoxin 6c (ETB receptor agonist) were measured. Levels of ETB receptor mRNA were measured with real-time polymerase chain reaction. In fresh MCA, sarafotoxin 6c had no contractile effect. However, after organ culture, a strong concentration-dependent contraction was induced. ET-1 produced a strong contraction, in which the Emax was unaffected by organ culture but the EC50 was decreased with time. The sarafotoxin 6c-induced contraction after 24 hours of organ culture was attenuated by the transcriptional inhibitor actinomycin D and the translational inhibitor cycloheximide as well as the protein kinase C inhibitor Ro-31-8220. Real-time polymerase chain reaction revealed that the mRNA levels of the ETB receptor were increased after organ culture compared with fresh vessels. Actinomycin D and Ro-31-8220 diminished the enhanced mRNA levels considerably. The results suggest that, in fresh MCA, the ETA receptor is the most prominent subtype, while after organ culture ETB receptors also contribute to the contraction. This upregulation is due to de novo transcription of receptors. Protein kinase C is involved in the upregulation as Ro-31-8220 attenuates the contraction and the mRNA increase.

On the role of somatostatin in seizure control: clues from the hippocampus.

The role of the hippocampal somatostatin (somatotropin release-inhibiting factor, SRIF) system in the control of partial complex seizures is discussed in this review. The SRIF system plays a role in the inhibitory modulation of hippocampal circuitries under normal conditions: 1) SRIF neurons in the dentate gyrus are part of a negative feedback circuit modulating the firing rate of granule cells; 2) SRIF released in CA3 interacts both with presynaptic receptors located on associational/commissural terminals and with postsynaptic receptors located on pyramidal cell dendrites, reducing excitability of pyramidal neurons; 3) in CA1, SRIF exerts a feedback inhibition and reduces the excitatory drive on pyramidal neurons. Significant changes in the hippocampal SRIF system have been documented in experimental models of temporal lobe epilepsy (TLE), in particular in the kindling and in the kainate models. SRIF biosynthesis and release are increased in the kindled hippocampus, especially in the dentate gyrus. This hyper-function may be instrumental to control the latent hyperexcitability of the kindled brain, preventing excessive discharge of the principal neurons and the occurrence of spontaneous seizures. In contrast, the hippocampal SRIF system undergoes damage in the dentate gyrus following kainate-induced status epilepticus. Although surviving SRIF neurons appear to hyperfunction, the loss of hilar SRIF interneurons may compromise inhibitory mechanisms in the dentate gyrus, facilitating the occurrence of spontaneous seizures. In keeping with these data, pharmacological activation of SRIF1 (sst2) receptors, i.e. of the prominent receptor subtype on granule cells, exerts antiseizure effects. Taken together, the data presented suggest that the hippocampal SRIF system plays a role in the control of partial complex seizures and, therefore, that it may be proposed as a therapeutic target for TLE.

Regulation of the kinin receptors after induction of myocardial infarction: a mini-review.

It is well known that the responses to vasoactive kinin peptides are mediated through the activation of two receptors termed bradykinin receptor B1 (B1R) and B2 (B2R). The physiologically prominent B2R subtype has certainly been the subject of more intensive efforts in structure-function studies and physiological investigations. However, the B1R activated by a class of kinin metabolites has emerged as an important subject of investigation within the study of the kallikrein-kinin system (KKS). Its inducible character under stress and tissue injury is therefore a field of major interest. Although the KKS has been associated with cardiovascular regulation since its discovery at the beginning of the last century, less is known about the B1R and B2R regulation in cardiovascular diseases like hypertension, myocardial infarction (MI) and their complications. This mini-review will summarize our findings on B1R and B2R regulation after induction of MI using a rat model. We will develop the hypothesis that differences in the expression of these receptors may be associated with a dual pathway of the KKS in the complex mechanisms of myocardial remodeling.

Panic disorder subtypes: differential responses to CO2 challenge.

The purpose of this study was to investigate the possibility of a differential sensitivity to CO2 in patients diagnosed with panic disorder subtypes that were defined by the presence of prominent respiratory symptoms. The authors used a 35% CO2 and 65% O2 mixture as a challenge agent. Fifty-one unmedicated subjects with DSM-III-R panic disorder, who were divided into respiratory (N = 28) and nonrespiratory (N = 23) subtypes by their symptom profiles, underwent a CO2 challenge procedure. Patients in the two groups were compared with regard to physiological and psychological measures, pulmonary function tests, panic rates, and smoking habits. The patients in the respiratory group were significantly more sensitive to CO2 than were the patients in the nonrespiratory group. The respiratory group also had higher scores on the Panic and Agoraphobia Scale and had a longer duration of illness; both of these factors can be indicators of illness severity. In addition, the respiratory group's higher cigarette consumption (mean = 12.46 package-years, SD = 2.49) may have been a contributory factor not only for illness severity but also for the pathogenesis of panic disorder. The CO2 challenge procedure appears to be a good dissection tool in the understanding of different subtypes of panic disorder. Moreover, there may be a more specific association with prominent respiratory symptom subtype and CO2 hypersensitivity.

Distribution of glutamate transporter subtypes during human brain development.

In the mature brain, removal of glutamate from the synaptic cleft plays an important role in the maintenance of subtoxic levels of glutamate. This requirement is handled by a family of glutamate transporters, EAAT1, EAAT2, EAAT3, and EAAT4. Due to the involvement of glutamate also in neuronal development, it is believed that glutamate transport plays a role in developmental processes as well. Therefore, we have used immunohistochemical and immunoblot analysis to determine the distribution of the four glutamate transporters during human brain development using human pre- and postnatal brain tissue. Regional analysis showed that each transporter subtype has a unique distribution during development. EAAT2 was the most prominent glutamate transporter subtype and was highly enriched in cortex, basal ganglia, cerebellum, and thalamus in all ages examined. EAAT1 immunoreactivity was lower than that of EAAT2, with predominant localization in cortex, basal ganglia, hippocampus, and periventricular region. EAAT3 was located mainly in cortex, basal ganglia, and hippocampus, and EAAT4 was found only in cortex, hippocampus, and cerebellar cortex. The distinct regional distribution of various EAAT subtypes and also the transient expression of specific EAAT subtypes during development suggest multiple functional roles for glutamate transporters in the developing brain.

Inhibition by ketamine of muscarinic acetylcholine receptor function.

Although ketamine's primary site of action appears to be the phencyclidine receptor on the N-methyl-D-aspartate (NMDA) receptor complex, additional activity on opiate and quisqualate receptors is suggested. Some phencyclidines have been shown to interact with muscarinic receptors, but this has not been determined for ketamine. We studied the interaction between ketamine and the m1 muscarinic receptor, the most prominent subtype in cortex and hippocampus. Receptors were expressed recombinantly in Xenopus oocytes, and intracellular Ca2+ release in response to the agonist acetyl-beta-methylcholine (MCh, 10(-6)M) was assessed by measuring charge movement through Ca(2+)-activated Cl- channels. Average responses to MCh were 4.1 +/- 0.7 microC. Ketamine inhibited responses to MCh, with complete inhibition at approximately 200 microM ketamine. The IC50 was 5.7 microM, (1.56 micrograms/mL), well within the clinically relevant concentration range. To demonstrate that intracellular signaling pathways and the Ca2+ activated Cl- channel were not affected by ketamine, we tested the effect of ketamine (365 microM) on currents induced by angiotensin II (10(-6) M) in oocytes expressing the AT1A angiotensin receptor. No inhibitory effect was noted. In summary, ketamine profoundly inhibits muscarinic signaling. This effect might explain some of the anticholinergic clinical effects of ketamine, both central (effects on memory and consciousness) and peripheral (prominent sympathetic tone, bronchodilation, mydriasis).

Some sensory neurons express neuropeptide Y receptors: potential paracrine inhibition of primary afferent nociceptors following peripheral nerve injury

Neuropeptide Y (NPY) has been suggested to exert antinociceptive actions by inhibiting the release of neurotransmitters from trigeminal and dorsal root ganglia (DRG) neurons, but the site of direct NPY action in vivo and the NPY receptor subtype mediating these effects are unknown. 125I-peptide YY (PYY) was used to localize and characterize NPY receptor binding sites in trigeminal ganglia, DRG, and spinal cord of the rat, rabbit, and monkey. In the rat, rabbit, and monkey, 5-20% of trigeminal ganglia and DRG neurons express NPY binding sites. Unilateral cuff-induced neuropathy or transection of the rat sciatic nerve did not significantly alter the density or number of DRG neurons expressing NPY receptors. A unimodal size distribution for L4 and L5 DRG neurons expressing NPY binding sites in the rat was determined, with a mean cross-sectional area of 947 microns 2. In the spinal cord the highest concentration of NPY receptors is found in laminae I, II, V, X, and Onuf's nucleus. Pharmacological experiments using selective Y1 and Y2 receptor antagonists suggest that Y2 is the prominent NPY receptor subtype expressed in trigeminal ganglia neurons, DRG neurons, and spinal cord. Previous studies have demonstrated that a population of large-diameter, presumably myelinated primary afferents express NPY after peripheral nerve injury. NPY released from these injured large-diameter DRG neurons may act in a paracrine fashion to block the transmission of nociceptive information from the small- and medium-diameter DRG neurons that constitutively express NPY receptors. NPY receptors are therefore uniquely positioned to inhibit primary afferent nociceptors directly, especially after peripheral nerve injury.

Trigeminal and dorsal root ganglion neurons express CCK receptor binding sites in the rat, rabbit, and monkey: possible site of opiate- CCK analgesic interactions

125I-Bolton-Hunter sulfated cholecystokinin-8 was used to localize and characterize cholecystokinin (CCK) receptor binding sites in trigeminal and dorsal root ganglia, and in the spinal cord of the rat, rabbit, and monkey. In the rabbit and monkey, a substantial number, 90 +/- 21% and 24 +/- 8%, respectively, of trigeminal and dorsal root ganglion neurons express CCK binding sites. In the spinal cord, the highest concentration of CCK receptors is found in laminae I and II, which is the major termination site of dorsal root ganglia neurons expressing CCK receptor binding sites. Neonatal capsaicin treatment of the rat results in a 70% decline in CCK receptor binding sites in laminae I and II of the spinal cord, indicating that dorsal root ganglia neurons are a major source of CCK receptors in the spinal cord. Pharmacological experiments using selective CCK-A and CCK-B receptor antagonists demonstrate that CCK-B is the prominent CCK receptor subtype in trigeminal and dorsal root ganglia neurons in the rat, rabbit, and monkey. In the rat and rabbit spinal cord, CCK-B binding sites are the prominent subtype, whereas in the monkey cord, CCK-A is the prominent receptor subtype. These results demonstrate that CCK-B receptors are expressed by a substantial percentage of dorsal root ganglion neurons at all spinal levels, and that CCK may antagonize opiate analgesia at the level of the primary afferent neuron itself.

Black-white differences in Hodgkin's disease incidence in the United States by age, sex, histology subtype and time.

Black-white differences in Hodgkin's disease (HD) occurrence have been reported in older US mortality statistics and in limited international data, suggesting either genetic or socioeconomic determinants of susceptibility. However, there has been no evaluation with reliable data of the interracial incidence patterns by age, sex, and histologic subtype, that are prerequisite to understanding the causes of such variation. This project utilized 15 years of recent, high quality, incidence data from well-defined black and white US populations to calculate age-, sex-, and histology-specific rates of HD by race over time. Rates were somewhat lower for blacks (N = 593) than whites (N = 8,541) of both sexes, except among young boys. For blacks, age-specific incidence curves were slightly bimodal, although less than for whites; the male excess of HD was larger; and rates among women were low at all ages. For each histology subtype, blacks had lower incidence than whites; however, for the first time, nodular sclerosis was found to be the most common variant for both races. Between 1969-74 and 1980-84, HD rates declined in whites over age 55 but increased in white young adult women; among blacks, rates decreased slightly for boys and young adult men, the latter likely due to improving population enumeration. These findings confirm some interracial differences noted previously in HD. For blacks, they also reveal an incipiently bimodal age incidence and more prominent nodular sclerosis subtype occurrence that support a strong role for environmental factors in racial variation of this lymphoma.

5-HT1c receptor is a prominent serotonin receptor subtype in the central nervous system.

Neurons in rat central nervous system (CNS) that express 5-HT1c receptor mRNA have been localized by in situ hybridization histochemistry. The 5-HT1c receptor is expressed in a wide variety of cortical and subcortical neurons including hippocampal pyramidal neurons, neurons within most of the central monoaminergic cell groups, neurons in thalamic sensory relay nuclei, and neurons involved in the central processing and regulation of nociceptive transmission. Therefore, the 5-HT1c receptor is a prominent but poorly characterized central subclass of serotonin (5-HT) receptor. The distribution of the 5-HT1c receptor within the CNS is considerably more widespread than that of the structurally and functionally related 5-HT2 receptor.

Do positive symptom and negative symptom subtypes of schizophrenia show qualitative differences in language production?

The present study examined a prominent symptom subtype conception of the psychopathology of schizophrenia. It analysed the presumed dichotomy between hallucinations, delusions and formal thought disorder as positive symptoms and flattening of affect and poverty of speech as negative symptoms, and tested predictions concerning the nature of the mediating processes of positive and negative symptoms. Four different analyses were applied to the transcripts of speech produced by 9 normals, 10 chronic schizophrenics with only positive symptoms of whom 7 had incoherence of speech, and 9 chronic schizophrenics with only negative symptoms of whom 4 had poverty of speech. The conception of the nature of the mediating processes of positive and negative symptoms was not supported by the results. Further, a clear dichotomy between positive and negative symptom groups was not shown to exist, because positive speech disorder and negative speech disorder did not follow the presupposed dichotomy. Thus, contrary to existing conceptions of speech disorder in schizophrenia, both positive and negative speech disorder are marked by poverty of thought, as measured by the production of fewer and shorter ideas and lower speech variability.