Gender and cystectomy for bladder cancer: A high-volume tertiary urologic care center experience.

BACKGROUND: Differences have often been reported in the outcomes of bladder cancer (BC) patients according to gender. OBJECTIVE: This study aims to provide data on patients undergoing radical cystectomy (RC) in a high-volume tertiary urologic center and to assess whether gender discrepancies do exist in terms of surgical options and clinical outcomes. MATERIALS AND METHODS: Consecutive BC patients treated between 2016 and 2020 at a single center (Careggi University Hospital, Florence, Italy) were included in the study. The impact of gender on disease stage at diagnosis, overall survival (OS), and type of surgery was analyzed. RESULTS: The study series comprised 447 patients (85 females and 362 males). At a median follow-up of 28.3 months (IQR: 33.5), OS was 52.6% and cancer-specific survival was 67.6%. Significant differences in OS emerged for age, acute myocardial infarction (AMI), Charlson Comorbidity Index (CCI), pT, and pN. OS rates were higher in patients undergoing robot-assisted surgery and in those receiving open orthotopic neobladder (ONB) (p = 0.0001). No statistically significant differences were found between male and female patients regarding surgical offer in any age group, surgical time, early postoperative complications, pathologic stage, and OS. CONCLUSIONS: After adjustment for pathologic tumor stage and treatment modalities, female and male patients showed similar oncologic outcomes. Further studies should be undertaken to evaluate functional results in women subjected to RC.

[Heparin-induced thrombocytopenia: Update]. / La thrombopénie induite par héparine : mise au point.

Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy. It is due to the synthesis of antibodies most often directed against platelet factor 4 (FP4) modified by heparin (H). HIT is manifested by a platelet count fall, associated with a high risk of venous or arterial thrombosis. The diagnosis of HIT is based on the assessment of clinical probability (4Ts score or change in platelet count after cardiac surgery) and the demonstration of heparin-modified anti-FP4 antibodies (FP4/H). If the immunological tests are positive, functional tests should be performed. In case of suspicion of HIT, it is necessary to urgently stop heparin therapy, to perform a doppler ultrasound of the lower limbs, and to prescribe an alternative anticoagulation agent at a curative dose. Currently, danaparoid sodium and argatroban are authorized. The diagnosis and management of HIT remain complex and requires multidisciplinary collaboration.

Increase of renal resistive index and mineral metabolism disorder in patients with acute coronary syndrome with preserved renal function.

OBJECTIVE: Coronary artery disease is one of the first causes of death in the Western world; for this reason, it is essential to identify new, systemic, non-invasive and low-cost cardiovascular risk markers. The acute coronary syndrome includes ST-Elevation Myocardial Infarction (STEMI) and Non-ST-Elevation Myocardial Infarction (NSTEMI), based on ECG findings. We aimed to evaluate Renal Resistive Index (RRI) as a marker of cardiovascular risk and assess the associations with other cardiovascular risk factors (metabolic indexes, mineral metabolism disorders and endothelial dysfunction and atherosclerosis markers) in STEMI and NSTEMI patients. PATIENTS AND METHODS: Clinical, laboratory and instrumental examinations as metabolic and inflammation indexes, markers of atherosclerosis and endothelial dysfunction (renal function, mineral metabolism disorders, inflammation indexes, Intima Media Thickness (IMT), Ankle Brachial Pressure Index, Left Ventricular Mass Index, Relative Wall Thickness) were performed. RESULTS: Eighty-one patients with STEMI and NSTEMI were enrolled. We showed a significant positive correlation between RRI and age (p<0.01), intact parathyroid hormone (p<0.01) and IMT (p<0.01), as well as a significant negative correlation between RRI and body surface area (BSA) (p=0.02), estimated Glomerular Filtration Rate (eGFR) (p<0.01), serum calcium (p<0.01) and 25-hydroxy-vitamin D (p=0.03). Moreover, we found a significant correlation between RRI and male patients (p<0.01), coronary artery disease history (CAD) (p=0.049), hypertension (p=0.025) and left ventricular eccentric hypertrophy (LVEH) (p=0.047). CONCLUSIONS: Our study showed an association between RRI and the main traditional and non-traditional cardiovascular risk factors involved in atherosclerosis pathogenesis, such as age, BSA, hypertension, male sex, CAD history, mineral metabolism disorders and LVEH, in patients with preserved renal function. Moreover, we found a significant correlation between RRI and eGFR, suggesting that RRI could be useful in the evaluation of both renal function and progression of renal damage, even in an early stage with a conserved or only slightly reduced kidney function. We also showed a significant correlation with some markers of systemic atherosclerosis such as IMT and LVEH. For a more precise assessment of prognosis and cardiovascular risk in patients with high cardiovascular mortality, we suggest performing a systematic RRI evaluation, considering the non-invasive nature of the procedure, its reproducibility, easy execution, and low costs.

Preservation of root cementum: a comparative evaluation of power-driven versus hand instruments.

OBJECTIVES: The purpose of this study was to evaluate the effects of three distinct periodontal treatment methods in comparison with hand instrumentation on residual cementum of periodontal diseased teeth. Cementum can influence the activities of periodontal cells and may play an important regulatory role in periodontal treatment. The ideal method for periodontal therapy involves removal of biofilm, calculus and endotoxin while preserving root cementum. MATERIAL AND METHODS: Forty-eight caries free, single-rooted teeth in patients diagnosed with severe chronic periodontitis were treated using four different methods prior to extraction. The teeth were instrumented subgingivally at one approximal site either by hand curettes (HC), piezoelectric ultrasonic scalers (U), piezoelectric ultrasonic scalers following air polishing (U + AP) or air polishing (AP) alone. Following extraction of teeth, instrumented and non-instrumented sites were analysed with a dissecting microscope and SEM for measurement of the amount of and surface characteristics of residual cementum. RESULTS: The percentage of coronal cementum remaining following subgingival instrumentation was 84% for U, 80% for U + AP, 94% for AP and 65% for HC. Although subgingival instrumentation of apical portions of the cementum demonstrated 6% less retained cementum in comparison with coronal portions, the amount of retained cementum with AP was still significantly greater than with HC. SEM results found the smoothest root surfaces were produced by the HC followed by the AP, while root surfaces instrumented by U or U + AP presented grooves and scratches. CONCLUSIONS: This study demonstrated that AP was superior to U devices in preserving cementum, whereas HC were the most effective instruments in removing cementum.

Culture of human cell lines by a pathogen-inactivated human platelet lysate.

Alternatives to the use of fetal bovine serum (FBS) have been investigated to ensure xeno-free growth condition. In this study we evaluated the efficacy of human platelet lysate (PL) as a substitute of FBS for the in vitro culture of some human cell lines. PL was obtained by pools of pathogen inactivated human donor platelet (PLT) concentrates. Human leukemia cell lines (KG-1, K562, JURKAT, HL-60) and epithelial tumor cell lines (HeLa and MCF-7) were cultured with either FBS or PL. Changes in cell proliferation, viability, morphology, surface markers and cell cycle were evaluated for each cell line. Functional characteristics were analysed by drug sensitivity test and cytotoxicity assay. Our results demonstrated that PL can support growth and expansion of all cell lines, although the cells cultured in presence of PL experienced a less massive proliferation compared to those grown with FBS. We found a comparable percentage of viable specific marker-expressing cells in both conditions, confirming lineage fidelity in all cultures. Functionality assays showed that cells in both FBS- and PL-supported cultures maintained their normal responsiveness to adriamycin and NK cell-mediated lysis. Our findings indicate that PL is a feasible serum substitute for supporting growth and propagation of haematopoietic and epithelial cell lines with many advantages from a perspective of process standardization, ethicality and product safety.

Autoimmune polyglandular syndrome in a woman of 51 years.

INTRODUCTION: Autoimmune polyglandular syndromes (APS) are constellations of symptoms and signs of multiple glandular insufficiencies. We report a rare case of type III APS in a female patient. CASE REPORT: A 51-year-old woman was treated with radiotherapy because of thymus hyperplasia when she was two years old; she was diagnosed with celiac disease and autoimmune hypothyroidism at 41 years old and with sicca syndrome and myasthenia gravis seronegative a few years later. CONCLUSIONS: Our patient demonstrates a previous constellation of diseases of APS, which may be a random association but may also indicate a common immunological and genetic disturbance. The APS is an expression of a system impairment of immune tolerance to autoreactive clones, and this is necessary because the phenomena can become aggressive and expressed clinically. We suppose that the development of thymic hyperplasia or its radiotherapy in childhood may have compromise the patient's immune system.

Uricemia and homocysteinemia: nontraditional risk factors in the early stages of chronic kidney disease--preliminary data.

BACKGROUND: Patients with chronic kidney disease (CKD) show a risk of cardiovascular death, which is 10-100 times higher than that in the general population. This increase is not completely explained by the traditional cardiovascular risk factors. Hyperuricemia and hyperhomocysteinemia are highly prevalent in CKD. Patients suffering from these complications present accelerated atherosclerosis, determined mainly from the endothelial dysfunction that carries out a central role in the pathogenesis of cardiovascular diseases. AIM: The hypothesis was that brachial artery flow mediated dilation (FMD) and carotid intima-media thickness (cIMT) evaluation can be considered as early and systemic markers of atherosclerosis and that nontraditional risk factors, such as hyperhomocysteinemia and hyperuricemia, are associated with early endothelial dysfunction and vascular damage in patients suffering from first- and second-stage CKD. PATIENTS AND METHODS: The study comprised 50 patients, 10 for each CKD stage, and 15 age- and sex-matched healthy controls. We compared the traditional and nontraditional factors for cardiovascular diseases with alterations of vascular reactivity, such as cIMT, and brachial artery FMD, in patients affected by CKD with those in the control group. RESULTS: In our study, hyperuricemia was significantly and independently associated with brachial artery FMD reduction (p = 0.007), while hyperhomocysteinemia was significantly and independently associated with carotid intima-media thickening (p = 0.021) in patients at Stage I and II KDOQI (Kidney Disease Outcomes Quality Initiative). CONCLUSIONS: In our study, we found a progressive increase in the inflammatory indices and endothelial dysfunction at the early stages of CKD. Hyperuricemia and hyperhomocysteinemia were associated with IMT and FMD at Stage I-III KDOQI, and can be used as markers of subclinical atherosclerosis, especially in nephropathic patients with high cardiovascular risk.

MFG-E8/lactadherin regulates cyclins D1/D3 expression and enhances the tumorigenic potential of mammary epithelial cells.

Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein highly expressed in breast cancer that contributes to tumor progression through largely undefined mechanisms. By analyzing publicly available gene expression profiles of breast carcinomas, we found that MFG-E8 is highly expressed in primary and metastatic breast carcinomas, associated with absent estrogen receptor expression. Immunohistochemistry analysis of breast cancer biopsies revealed that MFG-E8 is expressed on the cell membrane as well as in the cytoplasm and nucleus. We also show that increased expression of MFG-E8 in mammary carcinoma cells increases their tumorigenicity in immunodeficient mice, and conversely, its downregulation reduces their in vivo growth. Moreover, expression of MFG-E8 in immortalized mammary epithelial cells promotes their growth and branching in three-dimensional collagen matrices and induces the expression of cyclins D1/D3 and N-cadherin. A mutant protein unable to bind integrins can in part exert these effects, indicating that MFG-E8 function is only partially dependent on integrin activation. We conclude that MFG-E8-dependent signaling stimulates cell proliferation and the acquisition of mesenchymal properties and contributes to mammary carcinoma development.

Functional infrared imaging of paroxysmal ischemic events in patients with Raynaud's phenomenon.

The use of thermal infrared (IR) imaging together with the study of the thermal recovery from a controlled cold challenge has been proposed in the diagnosis and follow-up of therapeutic response of Raynaud's Phenomenon (RP) and Systemic Sclerosis (SSc). The controlled cold challenge test usually performed during IR investigations may induce a RP in patients with the latter condition. In our Institution we routinely perform capillaroscopy and thermal IR to follow-up SSc patients. In this paper, we describe the thermal recovery patterns shown by two SSc patients (a 40 year-old male with diffuse variant of SSc and a 71 year-old female with a limited variant of SSc) who presented ischemic and paroxysmal RP attack while recovering from the routine controlled cold challenge test. During RP attack, the cutaneous temperature of some fingers continued to decrease for some minutes even after the cessation of the cold stress. To the best of our knowledge, to date, no literature report has documented the thermal behaviour of SSc patients' fingers which occasionally present ischemic and paroxysmal response. Triggering of ischemic RP attack appears to not rely only on morphological and structural finger impairment, but also upon other aspects, like the emotional attitude of the subject and the possible discomfort experienced with the proceeding of the functional cold stress test.

A clonal cell line (BME-UV1) as a possible model to study bovine mammary epithelial metabolism: metabolism and cytotoxicity of aflatoxin B1.

Despite the toxicological risks to which humans and animals are exposed due to the transfer of toxic xenobiotic metabolites into milk of domestic animals, studies on the metabolizing mechanisms occurring in ruminant mammary gland are totally lacking. To investigate the possible biotransformation capabilities of a bovine mammary epithelial cell line (BME-UV1), monolayers were exposed to aflatoxin B1 (AFB1--1.0-8.0 microM). Starting from 4 h of exposure, the hydroxylate metabolite aflatoxin M1 (AFM1) was detected in media by high performance liquid chromatography. AFM1 concentration increased linearly with time for 36-48 h and the percent biotransformation of AFB1 (2-4 microM) at 48 h was about 12-14%. Parallel cytotoxicity assays (neutral red uptake-NRU and MTT assays) were performed to investigate the possible interference of AFB1 cytotoxicity with cellular metabolism. MTT assay (from 24 h of cell exposure) and NRU assay (from 16 h of cell exposure) showed time-dependent and time/concentration-dependent decrease of cell viability, respectively, and the former assay being more successful at revealing cytotoxic effects (NRU: CC50 at 48 h = 12.00 +/- 2.66 microM; MTT: CC50 at 72 h = 20.42 +/- 7.30 microM). The results suggest that BME-UV1 cells express metabolizing enzymes having catalytic activity, thus representing a potential in vitro model for studying biotransformation in bovine mammary gland.

Ageing processes and soil microbial community effects on the biodegradation of soil (13)C-2,4-D nonextractable residues.

The biodegradation of nonextractable residues (NER) of pesticides in soil is still poorly understood. The aim of this study was to evaluate the influence of NER ageing and fresh soil addition on the microbial communities responsible for their mineralisation. Soil containing either 15 or 90-day-old NER of (13)C-2,4-D (NER15 and NER90, respectively) was incubated for 90 days with or without fresh soil. The addition of fresh soil had no effect on the mineralisation of NER90 or of SOM, but increased the extent and rate of NER15 mineralisation. The analyses of (13)C-enriched FAME (fatty acids methyl esters) profiles showed that the fresh soil amendment only influenced the amount and structure of microbial populations responsible for the biodegradation of NER15. By coupling biological and chemical analyses, we gained some insight into the nature and the biodegradability of pesticide NER.

Expression of CD133-1 and CD133-2 in ovarian cancer.

Cancer stem cells have been isolated from several solid tumors including prostate, colon, liver, breast, and ovarian cancer. Stem cells isolated from nervous system and prostate express CD133 antigen, which is widely used to isolate hematopoietic stem and progenitor cells. The aims of this study were to investigate the expression of the CD133-1 and CD133-2 epitopes in primary ovarian tumors and to biologically characterize CD133(+) ovarian cancer cells, also according to clinicopathologic parameters. Tissue specimens were obtained at primary surgery from 41 ovarian carcinomas; eight normal ovaries and five benign ovarian tumors were also collected. Flow cytometry with monoclonal antibodies against CD133-1 and CD133-2 epitopes was employed. FACS (fluorescence activated cell sorting) analysis enabled the selection of CD133(+) cells, whose epithelial origin was confirmed by immunofluorescence analysis with monoclonal anti-cytokeratin 7. CD133(+) cells gave rise to a 4.7 +/- 0.9-fold larger number of colonies than that documented in CD133(-) population (P < 0.001). Moreover, CD133(+) cells showed an enhanced proliferative potential compared to CD133(-) cells. The percentages of CD133-1- and CD133-2-expressing cells were significantly lower in normal ovaries/benign tumors with respect to those in ovarian carcinoma. Both the percentages of CD133-1- and CD133-2-expressing cells were significantly lower in omental metastases than in primary ovarian cancer (P = 0.009 and 0.007 for CD133-1- and CD133-2-expressing cells, respectively). There seems not to be any difference in the distribution of the percentage of CD133-1- and CD133-2-expressing cells according to clinicopathologic parameters and response to primary chemotherapy. CD133-1 and CD133-2 may be useful in order to select and enrich the population of CD133(+) ovarian tumor cells, which are characterized by a higher clonogenic efficiency and proliferative potential.

Tracing 2,4-D metabolism in Cupriavidus necator JMP134 with 13C-labelling technique and fatty acid profiling.

The use of stable isotope probing of fatty acid methyl esters (FAME-SIP) is a powerful tool to study the microorganisms involved in xenobiotic biodegradation in soil. Nevertheless, it is important to determine how representative these molecules are of microorganisms both qualitatively and quantitatively. Using Cupriavidus necator JMP134 as a simple experimental model, we showed that the (13)C-labelling technique can be used both at a global (here defined as cellular, medium and CO(2)) and molecular level to study the metabolism of 2,4-Dichlorophenoxyacetic acid (2,4-D). Although isotopic fractionation among substrate, biomass and FAME were observed, this technique could be used when using a highly (13)C-labelled substrate. Global (13)C analyses gave similar results to those obtained with traditional (14)C-labelling methods. After 10 days of incubation 59% of ring-C was mineralized and about 30% remained in the liquid medium. A maximum of 11% was incorporated into the biomass after 3 days. The assimilation yield of chain-C into the biomass was about half that of ring-C, suggesting a preferential use of chain-C for energy acquisition. Molecular analysis of the lipid fraction evidenced that the incorporation of the labelled 2,4-D did not correspond to a bioaccumulation of pesticide residues but to the metabolism of the 2,4-D carbons for FAME synthesis. Provided the labelling is located on the benzenic ring, the assessment of (13)C-FAME is a robust method to quantify the incorporation of (13)C into the whole microbial biomass. However, the variability of the (13)C incorporation among FAME due to physiological processes has to be considered in complex biological systems. The coupling of bulk and molecular studies with a simple model as C. necator JMP134 is a good approach for testing FAME-SIP.

A human umbilical cord stem cell rescue therapy in a murine model of toxic liver injury.

BACKGROUND: Several studies have demonstrated that bone marrow contains a subpopulation of stem cells capable of participating in the hepatic regenerative process, even if some reports indicate quite a low level of liver repopulation by human stem cells in the normal and transiently injured liver. AIMS: In order to overcome the low engraftment levels seen in previous models, we tried the direct intraperitoneal administration of human cord blood stem cells, using a model of hepatic damage induced by allyl alcohol in NOD/SCID mice. METHODS: We designed a protocol based on stem cell infusion following liver damage in the absence of irradiation. Flow cytometry, histology, immunohistochemistry and RT-PCR for human hepatic markers were performed to monitor human cell engraftment. RESULTS: Human stem cells were able to transdifferentiate into hepatocytes, to improve liver regeneration after damage and to reduce the mortality rate both in both protocols, even if with qualitative and quantitative differences in the transdifferentiation process. CONCLUSIONS: We demonstrated for the first time that the intraperitoneal administration of stem cells can guarantee a rapid liver engraftment. Moreover, the new protocol based on stem cell infusion following liver damage in the absence of irradiation may represent a step forward for the clinical application of stem cell transplantation.

Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesis.

New blood vessel formation, a process referred to as angiogenesis, is essential for embryonic development and for many physiological and pathological processes during postnatal life, including cancer progression. Endothelial cell adhesion molecules of the integrin family have emerged as critical mediators and regulators of angiogenesis and vascular homeostasis. Integrins provide the physical interaction with the extracellular matrix necessary for cell adhesion, migration and positioning, and induction of signaling events essential for cell survival, proliferation and differentiation. Antagonists of integrin alpha V beta 3 suppress angiogenesis in many experimental models and are currently tested in clinical trials for their therapeutic efficacy against angiogenesis-dependent diseases, including cancer. Furthermore, interfering with signaling pathways downstream of integrins results in suppression of angiogenesis and may have relevant therapeutic implications. In this article we review the role of integrins in endothelial cell function and angiogenesis. In the light of recent advances in the field, we will discuss their relevance as a therapeutic target to suppress tumor angiogenesis.

Influence of hyperbranched multi-methacrylates for dental neat resins on proliferation of human gingival fibroblasts.

We have previously shown that hyperbranched multi-methacrylate (H-MMA)-modified dental resins have VLC activities, lower polymerization shrinkage, and improved mechanical properties, compared to the 2,2-bis[4-(2-hydroxy-3-methacryloyolxypropoxy)phenyl]propane/triethyleneglycol dimethacrylate (BisGMA/TEGDMA) neat resin. The results are due to the unique molecular structure and high molecular weight of H-MMA intermediates. The purpose of this study was to evaluate the biocompatibility of H-MMA-modified dental neat resins. The cell proliferation of three human gingival fibroblast strains on either H-MMA, BisGMA/TEGDMA, or a polystyrene disk was examined. Following 10 days of cell proliferation, there was no statistical difference in cell number between H-MMA-modified and unmodified resin disks. H-MMA-modified resins had less free monomer leaching than the unmodified resin but showed similar properties in water sorption and contact angle values. All these results suggest that the biocompatibility of H-MMA-modified dental neat resins is as good as that of commercially used BisGMA/TEGDMA resin and H-MMA has potential applications in dental composites.

Immune reconstitution after autologous peripheral blood progenitor cell transplantation: effect of interleukin-15 on T-cell survival and effector functions.

OBJECTIVE: The aim of this study was to evaluate the occurrence of T-cell spontaneous apoptosis (A(spont)) and its modulation in vitro by the interleukin-2 receptor (IL-2R) gamma-chain (gammac)-signaling cytokine IL-15 in patients transplanted with autologous peripheral blood progenitor cells (PBPC) for hematologic malignancies. MATERIALS AND METHODS: Patients were examined on days 30-60, 60-90, and 90-120 after PBPC infusion. Dissipation of mitochondrial transmembrane potential, a hallmark of T-cell apoptosis, has been detected using the fluorescent probe 3,3'-dihexyloxacarbocyanine iodide, after short-term T-cell culture in the absence or presence of exogenous cytokines. Expression of Bcl-2 family members has been studied by flow cytometry and reverse transcriptase polymerase chain reaction. T-cell proliferative responses to recall antigens have been estimated in autologous mixed leukocyte cultures. RESULTS: A(spont) was seen in 45% +/- 6% of CD4(+) and 55% +/- 6% of CD8(+) T cells cultured in the absence of cytokines. Of interest, IL-15 and, to a lesser extent, its structural cousin IL-2 counteracted T-cell A(spont) by inhibiting the processing of caspase-3 and up-regulating Bcl-2 mRNA and protein levels. Cell division tracking confirmed that IL-15 did not rescue T cells from A(spont) by promoting proliferation but rather acted as a genuine survival factor. Addition of a gammac-blocking antibody to cytokine-conditioned cultures abrogated both apoptosis inhibition and Bcl-2 induction by IL-15, suggesting involvement of the IL-2Rgammac signal transduction pathway. Whereas cytokine-unprimed posttransplant T cells mounted inadequate responses to recall antigens, T cells conditioned with IL-15 expanded vigorously, indicating restoration of antigen-specific proliferation. CONCLUSIONS: T cells recovering after autologous PBPC transplantation are highly susceptible to spontaneous apoptosis in vitro. This phenomenon can be counteracted by the gammac-signaling cytokine IL-15. These findings suggest that IL-15 might be a promising immunomodulating agent to improve postgrafting T-cell function.

EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion.

We have examined the mechanism and functional significance of hemidesmosome disassembly during normal epithelial cell migration and squamous carcinoma invasion. Our findings indicate that a fraction of EGF receptor (EGF-R) combines with the hemidesmosomal integrin alpha6beta4 in both normal and neoplastic keratinocytes. Activation of the EGF-R causes tyrosine phosphorylation of the beta4 cytoplasmic domain and disruption of hemidesmosomes. The Src family kinase inhibitors PP1 and PP2 prevent tyrosine phosphorylation of beta4 and disassembly of hemidesmosomes without interfering with the activation of EGF-R. Coimmunoprecipitation experiments indicate that Fyn and, to a lesser extent, Yes combine with alpha6beta4. By contrast, Src and Lck do not associate with alpha6beta4 to a significant extent. A dominant negative form of Fyn, but not Src, prevents tyrosine phosphorylation of beta4 and disassembly of hemidesmosomes. These observations suggest that the EGF-R causes disassembly of hemidesmosomes by activating Fyn, which in turn phosphorylates the beta4 cytoplasmic domain. Neoplastic cells expressing dominant negative Fyn display increased hemidesmosomes and migrate poorly in vitro in response to EGF. Furthermore, dominant negative Fyn decreases the ability of squamous carcinoma cells to invade through Matrigel in vitro and to form lung metastases following intravenous injection in nude mice. These results suggest that disruption of hemidesmosomes mediated by Fyn is a prerequisite for normal keratinocyte migration and squamous carcinoma invasion.

Assessment of the contaminant concentration variability among Lake Geneva Arctic char using stable isotopic composition (delta15N and delta13C).

Measurements of organochlorine [polychlorinated biphenyls (PCBs) and dichloro-diphenyl-dichloroethylene (DDE)] and Hg concentrations and nitrogen and carbon stable isotopic compositions (delta15N and delta13C) were performed on 63 Arctic char (Salvelinus alpinus) from Lake Geneva. Fish exhibited a high interindividual variablity in pollutant concentrations. Since the accumulation of such persistent contaminants is obtained from food, the co-occurrence of dietary differentiation leading to the contaminant interindividual variability was suspected. delta15N and delta13C were used for assessing trophic position and food source differences among Arctic char. The low ranges of delta15N and delta13C could not explain the interindividual variability in pollutant concentrations. The lack of relation between delta15N and contaminant concentration did not suggest a trophic level biomagnification of PCB, DDE, and Hg. Lake Geneva spatial variability in pollutants may be an important factor of variability within the Arctic char population. The bioaccumulation pattern occurring for Hg was not apparent for PCB and DDE. Organochlorines are hydrophobic contaminants, and their bioaccumulation pattern may be masked by seasonal variations in fish lipid content.