Showing papers by "Medical University of Graz published in 2004"

Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites.

Abstract: Although several recurrent genetic aberrations are known to occur in MALT lymphoma, no comprehensive study on the most prevalent MALT lymphoma-associated genetic aberrations is available. We therefore screened 252 primary MALT lymphomas for translocations t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32), and trisomies 3 and 18. The above-listed translocations occurred mutually exclusively and were detected overall in 13.5, 10.8, and 1.6% of the cases; trisomy 3 and/or 18 occurred in 42.1%. The frequency at which the translocations occurred varied markedly with the primary site of disease. The t(11;18)(q21;q21) was mainly detected in pulmonary and gastric tumors, whereas the t(14;18)(q32;q21) was most commonly found in lesions of the ocular adnexa/orbit, skin, and salivary glands. Trisomies 3 and 18 each occurred most frequently in intestinal and salivary gland MALT lymphomas. Our results demonstrate that the three translocations and trisomies 3 and 18 occur at markedly variable frequencies in MALT lymphoma of different sites.

Vascular structures in skin tumors: a dermoscopy study.

Abstract: Objectives To describe the different vascular structures seen by dermoscopy and to evaluate their association with various melanocytic and nonmelanocytic skin tumors in a large series of cases. Design Digital dermoscopic images of the lesions were evaluated for the presence of various morphologic types of vessels. Setting Specialized university clinic. Patients From a larger database, 531 excised lesions (from 517 patients) dermoscopically showing any type of vascular structures were included. Main Outcome Measures The frequency and positive predictive value of the different vascular structures seen in various tumors were calculated, and the differences were evaluated by the {chi}2 or Fisher exact test. Results Arborizing vessels were seen in 82.1% of basal cell carcinomas, with a 94.1% positive predictive value (P<.001). Dotted vessels were generally predictive for a melanocytic lesion (90.0%, P<.001), and were especially seen in Spitz nevi (77.8% of lesions). In melanoma, linear-irregular, dotted, and polymorphous/atypical vessels were the most frequent vascular structures, whereas milky-red globules/areas were the most predictive ones (77.8%, P = .003). The presence of erythema was most predictive for Clark nevus, whereas comma, glomerular, crown, and hairpin vessels were significantly associated with dermal/congenital nevi, Bowen disease, sebaceous hyperplasia, and seborrheic keratosis, respectively (P<.001 for all). Conclusions Different morphologic types of vessels are associated with different melanocytic or nonmelanocytic skin tumors. Therefore, the recognition of distinctive vascular structures may be helpful for diagnostic purposes, especially when the classic pigmented dermoscopic structures are lacking.

Discrepancies in current practice of pathological evaluation of sentinel lymph nodes in breast cancer. Results of a questionnaire based survey by the European Working Group for Breast Screening Pathology.

Abstract: Aims: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. Methods: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. Results: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. Conclusions: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.

White matter lesion progression A surrogate endpoint for trials in cerebral small-vessel disease

Abstract: There is neuropathologic evidence that confluent MRI white matter lesions in the elderly reflect ischemic brain damage due to microangiopathy. The authors hypothesize that measuring changes in the progression of white matter lesions as shown by MRI may provide a surrogate marker in clinical trials on cerebral small-vessel disease in which the currently used primary outcomes are cognitive impairment and dementia. This hypothesis is based on evidence that confluent white matter lesions progress rapidly as shown in a recent follow-up study in community-dwelling subjects. The mean increase in lesion volume was 5.2 cm 3 after 3 years. Based on these data in a clinical trial, 195 subjects with confluent lesions would be required per treatment arm to demonstrate a 20% reduction in the rate of disease progression over a 3-year period. Like any other MRI metric, the change in white matter lesion volume cannot be considered preferable to clinical outcomes unless it has been demonstrated that it matters to the patient in terms of function.

The keratin cytoskeleton in liver diseases

Abstract: The keratin intermediate filament (IF) cytoskeleton of hepatocytes has continuously gained medical relevance over the last two decades. Originally it was mainly recognized as a differentiation marker for diagnostic purposes in pathology. However, keratin IFs were soon identified as major cellular structures to be affected in a variety of chronic liver diseases, such as alcoholic and non-alcoholic steatohepatitis (ASH, NASH), copper toxicosis, and cholestasis. Based on observations in keratin gene knock-out mice, the insight into the functional role of keratins was extended from a mere structural role providing mechanical stability to hepatocytes, to an additional role as target and modulator of toxic stress and apoptosis. The functional relevance of keratins in human diseases has recently been underlined by the identification of mutations in keratin genes in patients with liver cirrhosis.

Low-Density Lipoprotein Triglycerides Associated With Low-Grade Systemic Inflammation, Adhesion Molecules, and Angiographic Coronary Artery Disease The Ludwigshafen Risk and Cardiovascular Health Study

Abstract: Background— Markers of systemic inflammation and LDL cholesterol (LDL-C) have been considered independent risk factors of coronary artery disease (CAD). We examined whether alterations of LDL metabolism not reflected by LDL-C were associated with low-grade inflammation, vascular injury, and CAD. Methods and Results— We studied 739 subjects with stable angiographic CAD and 570 matched control subjects in which CAD had been ruled out by angiography. The association of LDL triglycerides (LDL-TGs) (odds ratio [OR], 1.30; 95% CI, 1.19 to 1.43; P<0.001) with CAD was stronger than that of LDL-C (OR, 1.10; 95% CI, 1.00 to 1.21; P=0.047). The predictive value of LDL-TG for CAD was independent of LDL-C. “Sensitive” C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin 6, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) increased in parallel to LDL-TG. CRP, ICAM-1, and VCAM-1 were inversely related to LDL-C. To examine whether LDL-TGs were associated with the distrib...

Increased expression of TRPV1 receptor in dorsal root ganglia by acid insult of the rat gastric mucosa.

Abstract: It is still unknown which receptors of peripheral sensory pathways encode and integrate an acid-induced nociceptive event in the gastric mucosa. The transient receptor potential vanilloid receptor 1 (TRPV1) and the acid-sensing ion channel 3 (ASIC3) are two nociception-related receptors. Here we investigated (i) to what extent these receptors are distributed in stomach-innervating neurons of dorsal root and nodose ganglia, using immunohistochemistry and retrograde tracing, and (ii) whether their expression is altered in response to a noxious acid challenge of the stomach. We also explored the presence of TRPV1 in the gastric enteric nervous system because of its possible expression by intrinsic sensory neurons. Most stomach-innervating neurons in nodose ganglia were immunoreactive for TRPV1 (80%) and ASIC3 (75%), these results being similar in the dorsal root ganglia (71 and 82%). RT-PCR and Western blotting were performed up to 6 h after oral application of 0.5 m HCl to conscious rats. TRPV1 protein was increased in dorsal root but not in nodose ganglia whereas TRPV1 and ASIC3 mRNAs remained unchanged. TRPV1 mRNA was detected in longitudinal muscle-myenteric plexus preparations of control stomachs and was not altered by the acid challenge. Combined vagotomy and ganglionectomy abolished expression of TRPV1, indicating that it may derive from an extrinsic source. In summary, noxious acid challenge of the stomach increased TRPV1 protein in spinal but not vagal or intrinsic sensory afferents. The TRPV1 receptor may be a key molecule in the transduction of acid-induced nociception of the gastric mucosa and a mediator of visceral hypersensitivity.

Dermatological manifestations of Lyme borreliosis

Abstract: Lyme borreliosis is a multisystem infectious disease caused by the tick-transmitted spirochete Borrelia burgdorferi sensu lato. About 80% of all Lyme borreliosis cases represent skin manifestations (dermatoborrelioses). The three characteristic dermatoborrelioses are erythema migrans, borrelial lymphocytoma, and acrodermatitis chronica atrophicans, which occur in different stages of the disease. Erythema migrans is the hallmark of early Lyme borreliosis, whereas acrodermatitis chronica atrophicans is the characteristic manifestation of late Lyme borreliosis. Several spirochetal factors (e.g. infection with different genospecies, co-infection with other tick-transmitted pathogens) as well as host factors (e.g. cytokine patterns at the site of infection) influence the course of the disease. Diagnosis in the early stage of Lyme borreliosis relies on the clinical picture, whereas serological, molecular, microbiological, and histopathological findings are important adjuncts in the diagnosis of later stages of the infection. Antibiotic treatment is necessary for all stages and manifestations of Lyme borreliosis. Doxycycline is the antibiotic of choice for most patients with dermatoborrelioses.

Acupuncture using laser needles modulates brain function: first evidence from functional transcranial Doppler sonography and functional magnetic resonance imaging.

Abstract: Acupuncture using laser needles is a new totally painless stimulation method which has been described for the first time. This paper presents an experimental double-blind study in acupuncture research in healthy volunteers using a new optical stimulation method. We investigated 18 healthy volunteers (mean age±SD: 25.4±4.3 years; range: 21–30 years; 11 female, 7 male) in a randomized controlled cross-over trial using functional multidirectional transcranial ultrasound Doppler sonography (fTCD; n=17) and performed functional magnetic resonance imaging (fMRI) in one volunteer. Stimulation of vision-related acupoints resulted in an increase of mean blood flow velocity in the posterior cerebral artery measured by fTCD [before stimulation (mean±SE): 42.2±2.5; during stimulation: 44.2±2.6; after stimulation: 42.3±2.4 cm/s, n.s.]. Mean blood flow velocity in the middle cerebral artery decreased insignificantly. Significant changes (p<0.05) of brain activity were demonstrated in the occipital and frontal gyrus by fMRI. Optical stimulation using properly adjusted laser needles has the advantage that the stimulation cannot be felt by the patient (painless and no tactile stimulation) and the operator may also be unaware of whether the stimulation system is active. Therefore true double-blind studies in acupuncture research can be performed.

The apolipoprotein E polymorphism is associated with circulating C-reactive protein (the Ludwigshafen risk and cardiovascular health study).

Abstract: Background Statins and cholesterol absorption inhibitors lower the concentration of C-reactive protein (CRP). The genetic polymorphism of apolipoprotein (apo) E is a strong endogenous determinant of sterol homeostasis. We therefore examined the relationship of CRP to the apoE polymorphism. Methods and results We studied 739 and 570 subjects with or without stable angiographic coronary artery disease (CAD), respectively. In carriers of apoE2, apoB was lower ( P <0.001) than in apoE3/3 homozygotes; in individuals with apoE3/4 and apoE4/4, it was higher ( P <0.001). Both in the presence and absence of CAD, CRP was higher in carriers of apoE2 ( P =0.002) and apoE3/3 homozygotes ( P =0.032) than in individuals with apoE3/4 or apoE4/4. Fibrinogen and white cell count were not related to the apoE genotype. CRP was associated with CAD. Compared to the lowest tertile, crude odds ratios were 1.87 (95% confidence interval (CI), 1.43–2.45, P <0.001) and 2.24 (95% CI, 1.71–2.94, P <0.001) in the second and third tertile. In carriers of apoE2, the use of tertiles defined in controls with apoE2 only diminished the odds ratios for CAD. In apoE3/4 heterozygotes or apoE4/4 homozygotes, the use of tertiles specific for this group only slightly increased the odds ratios. Conclusions: The concentration of CRP, but not fibrinogen nor white blood cells is associated with the apoE polymorphism. The activity of the mevalonate pathway in the liver may be related to the metabolism of CRP. The predictive value of CRP for CAD may be modified by the apoE polymorphism.

Role of magnetic resonance imaging within diagnostic criteria for multiple sclerosis.

Abstract: The diagnosis of multiple sclerosis (MS) has been improved in recent decades with the incorporation of paraclinical investigations in diagnostic workup. In the last 15 years, magnetic resonance imaging (MRI) has become an especially valuable tool for supporting MS diagnosis, and specific imaging criteria became fundamental to the guidelines for the diagnosis of MS published in 2001 by an international panel (IP). The new IP criteria include MRI evidence of dissemination in space and time, making it possible to diagnose MS after a single clinical episode. This review considers current evidence concerning the reliability of the new IP criteria for the diagnosis of relapsing-onset MS, discusses strengths and weaknesses of the criteria, and outlines areas which may need modification or should be the focus of future research directed toward improving diagnostic accuracy. It also makes practical recommendations when using MRI and the IP criteria in MS diagnosis, especially in patients with clinically isolated syndromes or atypical presentations. The IP criteria are timely and concrete and introduce an important concept to MS diagnosis. Future modifications, based on emerging evidence, should further facilitate their implementation and improve their accuracy.

Body fat distribution of overweight females with a history of weight cycling

Abstract: Weight cycling may cause a redistribution of body fat to the upper body fat compartments. We investigated the distribution of subcutaneous adipose tissue (SAT) in 30 overweight women with a history of weight-cycling and age-matched controls (167 normal weight and 97 overweight subjects). Measurements of SAT were performed using an optical device, the Lipometer. The SAT topography describes the thicknesses of SAT layers at 15 anatomically well-defined body sites from neck to calf. The overweight women with a history of weight cycling had significantly thicker SAT layers on the upper body compared to the overweight controls, but even thinner SAT layers on their legs than the normal weight women. An android fat pattern was attributed to overweight females and, even more pronounced, to the weight cyclers. The majority of normal weight women showed a gynoid fat pattern. Using stepwise discriminant analysis, 89.0% of all weight cyclers and overweight controls could be classified correctly into the two groups. These findings show the importance of normal weight maintenance as a health-promoting factor.

Genital lentigines and melanocytic nevi with superimposed lichen sclerosus: a diagnostic challenge

Abstract: Background Benign pigmented lesions of the genitalia, such as genital lentigines and melanocytic nevi, often show clinical and histopathologic features highly suggestive of malignant melanoma (MM). Superimposed changes of lichen sclerosus (LS) may cause real concern and lead to an erroneous diagnosis of MM. Objective This study was performed to assess clinicopathologic characteristics of genital lentigines and melanocytic nevi with associated LS. Methods We performed a retrospective review of 5 cases. Results Histopathologic sections of the 2 cases of genital lentigines with concurrent changes of LS showed a lichenoid lymphocytic infiltrate and pigment incontinence with melanophages in a fibrosed papillary dermis, features reminiscent of completely regressed MM. The 3 cases of genital melanocytic nevi and superimposed LS were sharply circumscribed, relatively symmetric, but revealed confluent nests varying in size and shape and pagetoid upward spread of melanocytic nests and single melanocytes. Changes of LS extended beyond the melanocytic proliferation. Conclusion Genital lentigines and melanocytic nevi with associated LS may show features that mimic MM.

Hyperglycemic conditions affect shape and Ca2+ homeostasis of mitochondria in endothelial cells.

Abstract: In this study the contribution of alternating architecture and Ca2+ handling of mitochondria to cytosolic Ca2+ homeostasis was elucidated under normoglycemic and hyperglycemic (HGC) conditions in the human endothelial cell line EA.hy926. Exposure of endothelial cells to hyperglycemic medium elevated basal cytosolic free Ca2+ concentration ([Ca2+]cyto), the histamine-initiated cytosolic Ca2+ signaling, and the mitochondrial Ca2+ content after cell stimulation. The latter was possibly due to the prolonged mitochondrial Ca2+ elevation in response to agonists found in HGC-pretreated cells. Moreover, under HGC mitochondrial free radical production was increased and mitochondrial shape changed from a mainly tubular, highly interconnected network toward multiple, isolated singular structures. Such changes could not be correlated with HGC-induced alterations of cytosolic Ca2+ signaling that became normalized with antimycin A, an inhibitor of the respiratory chain. These data suggest that although mitochondrial structure changes considerably during HGC, alterations in cytosolic Ca2+ signaling are more likely due to the enhanced energy status/metabolism of the mitochondria. On the other hand, in normoglycemic cells of unforced fragmentation of mitochondria yielded elevated basal [Ca2+]cyto, while the global Ca2+ signaling in response to histamine remained unchanged. Thus, mitochondrial architecture (ie, tubular versus fragmented structure) per se does not have a detectable impact on agonist-initiated global cytosolic Ca2+ signaling, while this organelle represents an early target in hyperglycemia leading to alterations in cytosolic Ca2+ signaling.

Are heterogenous results of EGFR immunoreactivity in renal cell carcinoma related to non-standardised criteria for staining evaluation?

Abstract: Aims: To assess whether heterogeneity of epidermal growth factor receptor (EGFR) immunoreactivity in renal cell carcinoma (RCC) is related to non-standardised criteria for staining evaluation. Methods: EGFR expression was investigated in 132 primary and 55 metastatic conventional RCCs using a tissue microarray technique. Results: Overall, membranous and/or cytoplasmic EGFR immunostaining was present in 123 of 132 (93%) primary and 49 of 53 (92%) metastatic RCCs, with extensive immunoreactivity (> 50% of tumour cells) in 110 of 132 (83%) primary tumours and 39 of 53 (73%) metastases. Cytoplasmic staining was associated with high tumour stage and high tumour grade. In addition, strong membranous staining (score 3+) prevailed in high grade RCCs. Cytoplasmic immunostaining was associated with an unfavourable prognosis, whereas overall (cytoplasmic and membranous) immunoreactivity and intensity of membranous staining were not. Conclusions: Different methods of immunohistochemical evaluation led to different results, strengthening the need for standardisation, especially against a background of rapidly evolving EGFR targeted cancer treatment strategies.

Influence of Native and Hypochlorite-Modified Low-Density Lipoprotein on Gene Expression in Human Proximal Tubular Epithelium

Abstract: Inflammatory infiltrates can modify (lipo)proteins via hypochlorous acid/hypochlorite (HOCl/OCl−) an oxidant formed by the myeloperoxidase-H2O2-halide system. These oxidatively modified proteins emerge in tubuli in some proteinuric and interstitial diseases. Human proximal tubular cells (HK-2) were used to confirm the hypothesis of detrimental and differential impact of HOCl-modified low density lipoprotein (HOCl-LDL), an in vivo occurring lipoprotein modification exerting proatherogenic and proinflammatory capacity. HOCl-LDL showed dose-dependent antiproliferative effects in HK-2 cells. Small dedicated cDNA macroarrays were used to identify differentially regulated genes. A rapid increase in the expression of genes involved in reactive oxygen species metabolism and cell stress, eg, heme oxygenase-1, thioredoxin reductase, cytochrome b5 reductase, Gadd 153, amino acid transporter E16, and HSP70 was found after HOCl-LDL treatment of HK-2 cells. In parallel, genes involved in tissue remodeling and inflammation eg, CTGF, VCAM-1, IL-1β, MMP7, and VEGF were up-regulated. Quantitative RT-PCR verified differential expression of a subset of these genes in microdissected tubulointerstitia from patients with acute tubular damage, progressive proteinuric renal disease, and membranous glomerulonephritis (with declining renal function), but not in stable patients with proteinuria caused by minimal change disease. The demonstration of selective up-regulation of a subgroup of genes if proteinuria is accompanied by the presence of HOCl-modified (lipo)proteins support the potential pathophysiological role of the myeloperoxidase-H2O2-halide system and HOCl-LDL in renal disease.

G(−30)A Polymorphism in the Pancreatic Promoter of the Glucokinase Gene Associated With Angiographic Coronary Artery Disease and Type 2 Diabetes Mellitus

Abstract: Background— Type 2 diabetes mellitus (T2DM) increases the risk of coronary artery disease (CAD). A G(−30)A polymorphism in the β-cell–specific promoter of glucokinase (GK-30PM) has been implicated in reduced pancreatic β-cell function. Its impact on CAD has not been examined. Methods and Results— The glucokinase G(−30)A variant was determined in 2567 patients with angiographic CAD and in 731 individuals in whom CAD had been ruled out by angiography. In carriers of the A allele, the adjusted OR of CAD was 1.39 (95% CI, 1.15 to 1.70). Corresponding ORs were 1.27 (95% CI, 1.02 to 1.59) and 1.92 (95% CI, 1.26 to 2.93) in individuals without and with T2DM, respectively. The prevalence of the A allele increased in parallel with the Friesinger coronary score. Patients with T2DM were more frequent among carriers of ≥1 A allele (OR, 1.17; 95% CI, 1.00 to 1.28). This association was stronger if CAD patients only were considered. The A allele was associated with higher glucose (fasting, P =0.002; 2 hours after oral glucose, P =0.017) and glycohemoglobin (HbA1c; P =0.002). Furthermore, presence of 1 A allele was negatively related to β-cell function, estimated by β percent ( P =0.012) and by the ratios of proinsulin to insulin ( P =0.025) and proinsulin to C peptide ( P =0.019). Conclusions— The A allele of the pancreatic promoter of glucokinase increases the risk of CAD in individuals with and without T2DM. Furthermore, at least in CAD, it is associated with an augmented prevalence of T2DM.

Gastrointestinal pain in functional bowel disorders: sensory neurons as novel drug targets

Abstract: Functional bowel disorders (FBDs) are defined by symptoms of gastrointestinal (GI) dysfunction, discomfort and pain in the absence of a demonstrable organic cause. Since the prevalence of FBDs, particularly functional dyspepsia and irritable bowel syndrome, can be as high as 20%, FBDs represent a significant burden in terms of direct healthcare and productivity costs. There is emerging evidence that the discomfort and pain experienced by many FBD patients is due to persistent hypersensitivity of primary afferent neurons, which may develop in response to infection, inflammation or other insults. This concept identifies vagal and spinal sensory neurons as important targets for novel therapies of GI hyperalgesia. Sensory neuron-specific targets can be grouped into three categories: receptors and sensors at the peripheral nerve terminals, ion channels relevant to nerve excitability and conduction and transmitter receptors. Particular therapeutic potential is attributed to targets that are selectively expressed by afferent neurons, such as the transient receptor potential channel TRPV1, acid-sensing ion channels and tetrodotoxin-resistant Na + channels.

Wilson disease

Abstract: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. Since daily copper intake exceeds the body’s requirements, effective means of excreting excess copper are essential. These are accomplished by ATP7B, a new member of the cation-transporting p-type ATPase family, which is mainly expressed in the liver and mediates both copper secretion into plasma (coupled with ceruloplasmin synthesis) and its excretion into bile. Thus far, more than 200 mutations of the WD gene have been detected, causing impairment of ATP7B function and, ultimately, copper accumulation. Excess copper, however, induces free-radical reactions and lipid peroxidation. Resultant liver damage leads to steatosis, inflammation, cirrhosis, and, occasionally, fulminant liver failure. The diagnosis of WD is commonly made on the basis of typical clinical and laboratory findings, including low serum ceruloplasmin, increased urinary copper excretion, and increased hepatic copper content. Since liver morphology is non-specific, and copper histochemistry may lead to both false-negative and false-positive results, the pathologist usually only suspects the disease or assists in its confirmation. Although the value of molecular genetic testing is limited due to the high number of possible gene mutations, polymerase chain reaction may be useful for the evaluation of family members of homozygous index patients.

Activity of novel plant extracts against medullary thyroid carcinoma cells.

Abstract: Background:Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing tumor, derived from the parafollicular C-cells of the thyroid. MTC is known to be relatively insensitive to conventional chemotherapy. Materials and Methods: Eight cell lines were established from MTCs; each showed an up-regulation of Bcl-2. We investigated ten agents from plants of the genera Stemona (Stemonaceae), Aglaia (Meliaceae) and Artemisia (Asteraceae) for their effects on proliferation and apoptotic rates. Extracts have been used in traditional Chinese medicine; however, no experience on their effects on medullary thyroid carcinomas has been reported so far. Growth kinetics and viability were examined using the Casy-1-Cell Counter & Analyzer and the WST-1 - based cytotoxicity assay. Apoptosis was studied by DAPI staining, by measurement of caspase-3 activity and Bcl-2 expression. Results: A strong antiproliferative effect was recognized in each Aglaia species and with Artesunate, whereas an enhancement of apoptosis was provoked particularly by Stemona tuberosa Lour. Conclusion: The activity of the novel plant extracts possibly offers a new approach towards successful chemotherapy of the so far chemo-resistant medullary thyroid carcinoma. Medullary thyroid carcinoma (MTC) is a rare calcitonin- producing tumor, derived from the parafollicular C-cells of the thyroid. MTC can be sporadic, familial (FMTC), or part of the inherited cancer syndromes Multiple Endocrine Neoplasia type 2A (MEN2A) and type 2B (MEN2B). (1) MTC is inherited in 25-30% of all cases due to mutation in the RET-proto- oncogene, located on chromosome 10 (10q11.2). Presently the only treatment option is surgery, as MTC is known to be relatively insensitive to chemo- or radiation therapy. Increased expression of the anti-apoptotic protein Bcl-2 is involved in the development and progression of many tumors (2). Bcl-2 localizes to cellular membranes, particularly in mitochondria, where it stabilizes the transmembrane potential and reduces membrane permeability. Bcl-2 seems to contribute to tumor cell survival by enhancing the rate of cell proliferation and by allowing tumor cells to escape destruction by effector cells of the immune system. Caspase-3 is a key protease that is activated during the early stages of apoptosis and, like other members of the caspase family, is synthesized as an inactive proenzyme that is processed in cells undergoing apoptosis by self-proteolysis and/or cleavage by another protease. The aim of this study was to investigate new approaches using plant extracts against chemo-resistant medullary thyroid carcinoma.

Penile clear cell carcinoma: A report of 5 cases of a distinct entity

Abstract: We present a series of 5 penile clear cell carcinomas, which arose in middle-aged men at the inner side of the foreskin. They were large, exophytic, partly ulcerated, and widely invasive tumors with sharp demarcation to the surrounding normal skin/mucosa. Histologically, they were composed of large clear cells with intracytoplasmic PAS/d-PAS-positive material and showed extensive lymphatic and blood vessel invasion. Strong staining with antibodies to Muc-1, EMA, and CEA was typical. All carcinomas harbored HPV16 DNA, although only one carcinoma revealed HPV-related cytologic cell changes. All 5 patients had extensive, partly cystic inguinal lymph node metastases with a striking clear cell differentiation and focal dense sclerotic basement membrane material, either at or within several months after initial diagnosis. Two patients are alive without disease after 7 and 10 years. One patient died after 9 months of widespread disease and 2 patients are presently alive at 7 and 17 months follow-up with widespread lymphatic and hematogenous metastases despite adjuvant chemo- and radiation therapy. In contrast to squamous cell carcinoma, penile clear cell carcinomas show extensive blood and lymph vessel invasion and early metastases to regional lymph nodes. Clear cell carcinomas represent a distinct group of penile cancers that may have a different clinical behavior than usual penile squamous cell carcinomas.

Beyond cholesterol - inflammatory cytokines, the key mediators in atherosclerosis

Abstract: The development of atherosclerotic lesions encompasses a cascade of cellular and molecular responses that can at best be characterized as an inflammatory process, and exhibits striking similarities to autoimmune diseases, such as rheumatoid arthritis. Chemokines, cytokines and their receptors are critically involved in initiation and perpetuation of atherosclerosis, and they play important roles at all levels in the pathogenesis of this disease. In the present article, the currently available information on cytokines and chemokines as key mediators in atherosclerosis is reviewed. Furthermore, based on recent experiences of our own with very early stages of atherosclerosis, possible new ways to make use of these parameters toward improved early detection, prevention and treatment of this disease are indicated.

The biological and clinical significance of MLL abnormalities in haematological malignancies

Abstract: The MLL (Mixed Lineage Leukaemia or Myeloid/Lymphoid Leukaemia) gene on chromosome 11q23 is frequently involved in chromosomal translocations associated with human acute leukaemias. These translocations lead to fusion genes generally resulting in novel chimeric proteins containing the amino terminus of MLL fused in-frame to one of about 30 distinct partner proteins. Abnormalities involving the MLL gene are observed in leukaemias of either lymphoid or myeloid lineage derivation, as well as in poorly differentiated or biphenotypic leukaemias. They are frequently seen in infant patients, and patients with therapy-related secondary AML following treatment with inhibitors of topoisomerase II (epipodophyllotoxins). In the majority of cases, abnormalities involving the MLL gene are associated with a very poor prognostic outcome. In this review, we will discuss some of the recent advances in MLL research resulting from biological as well as clinical studies.

Identification of selective basophil chemoattractants in human nasal polyps as insulin-like growth factor-1 and insulin-like growth factor-2.

Abstract: In a search for novel leukocyte chemoattractants at sites of allergic inflammation, we found basophil-selective chemoattractant activity in extracts of human nasal polyps. The extracts were fractionated by reverse phase HPLC, and the resulting fractions were tested for leukocyte-stimulating activity using sensitive shape change assays. The basophil-selective activity detected was not depleted by a poxvirus CC-chemokine-binding protein affinity column. This activity was further purified by HPLC, and proteins in the bioactive fractions were analyzed by tandem electrospray mass spectrometry. Insulin-like growth factor-2 (IGF-2) was identified in these HPLC fractions, and the basophil-stimulating activity was inhibited by an anti-IGF-2-neutralizing Ab. Recombinant IGF-2 induced a substantial shape change response in basophils, but not eosinophils, neutrophils, or monocytes. IGF-2 stimulated chemokinesis of basophils, but not eosinophils or neutrophils, and synergized with eotaxin-1/CCL11 in basophil chemotaxis. IGF-2 also caused up-regulation of basophil CD11b expression and inhibited apoptosis, but did not stimulate degranulation or Ca2+ flux. Recombinant IGF-1 exhibited similar basophil-selective effects as IGF-2, and both growth factors were detected in nasal polyp extracts by ELISA. This is the first demonstration of chemokinetic factors that increase the motility of basophils, but do not act on other granulocytes or monocytes. IGF-1 and IGF-2 could play a role in the selective recruitment of basophils in vivo.

Analysis of Insulin-Like Growth Factors and Insulin-Like Growth Factor I Receptor Expression in Renal Cell Carcinoma

Abstract: The expression of insulin-like growth factors I (IGF-I) and II (IGF-II) and insulin-like growth factor I receptor (IGF-IR) was studied in 137 clear cell, 23 chromophobe, and 20 papillary renal cell carcinomas (RCCs) using a tissue microarray technique. IGF-I immunoreactivity was detected in 110 (82.1%) of 134 clear cell, 8 (36%) of 22 chromophobe, and 3 (15%) of 20 papillary RCCs (P < .001). IGF-IR immunoreactivity was detected in 39 (29.5%) of 132 clear cell, 9 (41%) of 22 chromophobe, and 19 (95%) of 20 papillary RCCs (P < .001). In contrast, all tumors lacked IGF-II expression. Expression of IGF-I and IGFIR was not related to tumor stage, grade, or prognosis. The IGF system is expressed differentially among different tumor types. The expression of IGF-I together with its receptor, IGF-IR, provides evidence for the existence of an autocrine-paracrine loop of tumor cell stimulation in RCC and makes this type of cancer a candidate for therapeutic strategies aimed to interfere with the IGF pathway. Renal cell carcinoma (RCC) accounts for about 2% of cancers worldwide. It has been increasing in incidence in North America and northern Europe, with rates increasing at about 3% per year in the United States. Survival has improved, with the 5-year relative survival rate increasing from 30% to 40% in the 1960s to between 50% and 60% in the 1990s. 1 As for the majority of cancers, tumor stage at diagnosis and histologic tumor grade are the principal prognostic factors. 2 Prognosis also is related to histologic subtype, because patients with clear cell RCCs have poorer cancer-specific survival than patients with papillary or chromophobe tumors. 3 However, the underlying basis for the unfavorable prognosis