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Biomedical subjects

A Arcangeli

Publications and source records attributed to A Arcangeli.

At least 19 recordsLinked to original sources
PubMed2005

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines.

Recent studies have led to considerable advancement in our understanding of the molecular mechanisms that underlie the relentless cell growth and invasiveness of human gliomas. Partial understanding of these mechanisms has (1) improved the classification for gliomas, by identifying prognostic subgroups, and (2) pointed to novel potential therapeutic targets. Some classes of ion channels have turned out to be involved in the pathogenesis and malignancy of gliomas. We studied the expression and properties of K(+) channels in primary cultures obtained from surgical specimens: human ether a gò-gò related (hERG)1 voltage-dependent K(+) channels, which have been found to be overexpressed in various human cancers, and human ether a gò-gò-like 2 channels, that share many of hERG1's biophysical features. The expression pattern of these two channels was compared to that of the classical inward rectifying K(+) channels, IRK, that are widely expressed in astrocytic cells and classically considered a marker of astrocytic differentiation. In our study, hERG1 was found to be specifically overexpressed in high-grade astrocytomas, that is, glioblastoma multiforme (GBM). In addition, we present evidence that, in GBM cell lines, hERG1 channel activity actively contributes to malignancy by promoting vascular endothelial growth factor secretion, thus stimulating the neoangiogenesis typical of high-grade gliomas. Our data provide important confirmation for studies proposing the hERG1 channel as a molecular marker of tumour progression and a possible target for novel anticancer therapies.

Adult↗
PubMed2005

Interneurons transiently express the ERG K+ channels during development of mouse spinal networks in vitro.

During spinal cord maturation neuronal excitability gradually differentiates to meet different functional demands. Spontaneous activity, appearing early during spinal development, is regulated by the expression pattern of ion channels in individual neurons. While emerging excitability of embryonic motoneurons has been widely investigated, little is known about that of spinal interneurons. Voltage-dependent K+ channels are a heterogeneous class of ion channels that accomplish several functions. Recently voltage-dependent K+ channels encoded by erg subfamily genes (ERG channels) were shown to modulate excitability in immature neurons of mouse and quail. We investigated the expression of ERG channels in immature spinal interneurons, using organotypic embryonic cultures of mouse spinal cord after 1 and 2 weeks of development in vitro. We report here that all the genes of the erg family known so far (erg1a, erg1b, erg2, erg3) are expressed in embryonic spinal cultures. We demonstrate for the first time that three ERG proteins (ERG1A, ERG2 and ERG3) are co-expressed in the same neuronal population, and display a spatio-temporal distribution in the spinal slices. ERG immuno-positive cells, representing mainly GABAergic interneurons, were present in large numbers at early stages of development, while declining later, with a ventral to dorsal gradient. Patch clamp recordings confirmed these data, showing that ventral interneurons expressed functional ERG currents only transiently. Similar expression of the erg genes was observed at comparable ages in vivo. The role of ERG currents in regulating neuronal excitability during the earliest phases of spinal circuitry development will be examined in future studies.

Animals↗
PubMed2004

Physical and functional interaction between integrins and hERG potassium channels.

Integrins are adhesion receptors capable of transmitting intracellular signals that regulate many different cellular functions. Among integrin-mediated signals, the activation of ion channels can be included. We demonstrated that a long-lasting activation of hERG (human ether-a-go-go-related gene) potassium channels occurs in both human neuroblastoma and leukaemia cells after the activation of the beta1 integrin subunit. This activation is apparently a determining factor inducing neurite extension and osteoclastic differentiation in both the cell types. More recently, we provided evidences that beta1 integrins and hERG channels co-precipitate in both the cell types. Preliminary results suggest that a macromolecular signalling complex indeed occurs between integrins and the hERG1 protein and that hERG channel activity can modulate integrin downstream signalling.

Animals↗
PubMed2002

Effects of acid-base abnormalities on blood capacity of transporting CO(2): adverse effect of metabolic acidosis.

OBJECTIVE: To investigate the effects of some acid-base abnormalities on blood capacity of transporting CO(2). DESIGN: Prospective study. SETTING: General and Cardiosurgical ICUs of a University hospital. PATIENTS: Six groups of ten patients characterized by: metabolic alkalosis; respiratory alkalosis; absence of acid-base abnormalities; metabolic acidosis; uncompensated respiratory acidosis; and compensated respiratory acidosis. MEASUREMENTS AND RESULTS: The CO(2) dissociation curve, Haldane effect, and the ratio Ra-v between Ca-vCO(2) and Pa-vCO(2) were calculated from arterial and mixed-venous blood gas analyses. The CO(2) dissociation curve was shifted upwards by metabolic alkalosis and compensated respiratory acidosis and downwards by metabolic acidosis. The slope of the curve was unaffected, but CO(2) transport not due to Haldane effect was significantly lower in respiratory acidosis since the slope was less steep at higher PCO(2) values. In comparison with controls, patients affected by metabolic acidosis showed lower Haldane effect values (0.18+/-0.15 vs 0.59+/-0.26 ml of CO(2) per ml of arterial-mixed venous O(2) content difference; P <.05) and Ra-v values (0.43+/-0.10 vs 0.84+/-0.17 ml of CO(2) transported by 100 ml of blood per Torr of arterial-mixed venous PCO(2) gradient; P <.05). CONCLUSIONS: Our findings suggest that acid-base abnormalities, particularly metabolic acidosis, markedly affect blood capacity of transporting CO(2) and may worsen tissue hypercarbia associated with hypoperfusion. However, because of possible errors due to small measurements and the assumptions of the method, in the future definitive clarification will require the construction of original CO(2) dissociation curves for each acid-base abnormality.

Acidosis↗
PubMed2002

HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitors.

An important target in the understanding of the pathogenesis of acute myeloid leukemias (AML) relies on deciphering the molecular features of normal and leukemic hemopoietic progenitors. In particular, the analysis of the mechanisms involved in the regulation of cell proliferation is decisive for the establishment of new targeted therapies. To gain further insight into this topic we report herein a novel approach by analyzing the role of HERG K(+) channels in the regulation of hemopoietic cell proliferation. These channels, encoded by the human ether-a-gò-gò-related gene (herg), belong to a family of K(+) channels, whose role in oncogenesis has been recently demonstrated. We report here that herg is switched off in normal peripheral blood mononuclear cells (PBMNC) as well as in circulating CD34(+) cells, however, it is rapidly turned on in the latter upon induction of the mitotic cycle. Moreover, hergappears to be constitutively activated in leukemic cell lines as well as in the majority of circulating blasts from primary AML. Evidence is also provided that HERG channel activity regulates cell proliferation in stimulated CD34(+) as well as in blast cells from AML patients. These results open new perspectives on the pathogenetic role of HERG K(+) channels in leukemias.

Acute Disease↗
PubMed2001

Predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study.

CONTEXT: In patients with hypoxemic acute respiratory failure (ARF), randomized studies have shown noninvasive positive pressure ventilation (NPPV) to be associated with lower rates of endotracheal intubation. In these patients, predictors of NPPV failure are not well characterized. OBJECTIVE: To investigate variables predictive of NPPV failure in patients with hypoxemic ARF. DESIGN: Prospective, multicenter cohort study. SETTING: Eight Intensive Care Units (ICU) in Europe and USA. PATIENTS: Of 5,847 patients admitted between October 1996 and December 1998, 2,770 met criteria for hypoxemic ARF. Of these, 2,416 were already intubated and 354 were eligible for the study. RESULTS: NPPV failed in 30% (108/354) of patients. The highest intubation rate was observed in patients with ARDS (51%) or community-acquired pneumonia (50%). The lowest intubation rate was observed in patients with cardiogenic pulmonary edema (10%) and pulmonary contusion (18%). Multivariate analysis identified age > 40 years (OR 1.72, 95% CI 0.92-3.23), a simplified acute physiologic score (SAPS II) > or = 35 (OR 1.81, 95% CI 1.07-3.06), the presence of ARDS or community-acquired pneumonia (OR 3.75, 95% CI 2.25-6.24), and a PaO2:FiO2 < or = 146 after 1 h of NPPV (OR 2.51, 95% CI 1.45-4.35) as factors independently associated with failure of NPPV. Patients requiring intubation had a longer duration of ICU stay ( P < 0.001), higher rates of ventilator-associated pneumonia and septic complications ( P < 0.001), and a higher ICU mortality ( P < 0.001). CONCLUSIONS: In hypoxemic ARF, NPPV can be successful in selected populations. When patients have a higher severity score, an older age, ARDS or pneumonia, or fail to improve after 1 h of treatment, the risk of failure is higher.

Acute Disease↗
PubMed2001

Long-term modulation of HERG channel gating in hypoxia.

Using the patch-clamp technique, we analysed changes in the biophysical properties of HERG potassium channels in neuroblastoma cells long-term exposed to hypoxia. In this condition, HERG channels underwent a profound modulation that consisted of: (i) a slowing in open-close kinetics; (ii) a marked hyperpolarizing shift in voltage dependence of steady-state activation; and (iii) a slowing of the inactivation removal. The overall physiological impact of these changes in neuroblastoma cells is an increase in the HERG window current in the range of the resting potential (V(REST)), which varied between -40 and -30 mV. Such a current modulation is suitable to stabilise the resting potential (V(REST)) in hypoxic environments.

Cation Transport Proteins↗
PubMed2001

Longstanding survival without cancer progression in a patient affected by endometrial carcinoma treated primarily with leuprolide.

We report here a case of a patient affected by endometrial cancer and treated primarily with leuprolide, the surgical approach being unfeasible due to her compromised conditions. The therapy was continued for more than 6 years, and no progression of the disease was observed. During this period, some histological and immunohistochemical evaluations of the tumour (morphology, grading, proliferation and apoptotic index, E-cadherin expression) were performed. Furthermore, the expression of m-RNA for luteinizing-hormone releasing hormone (LHRH) receptors was determined. The results showed a discrepancy between some biological parameters of the tumour and its clinical characteristics. In fact, despite features suggestive of a progression of the cancer (such as the increase of both tumour grading and proliferating capacity (MIB-1), and a fall in the reparative process (appearance of mutated p53, reduced expression of both bcl-2 and c-erb-2) being detected, neither local invasion nor metastatic lesions were clinically observed. This discrepancy might be due to the maintenance of high levels of E-cadhezin. Moreover, since this tumour was shown to express mRNA for LHRH receptors, new evidence is provided about the favourable impact of LHRH analogue treatment in patients affected by endometrial cancer.

Adenocarcinoma↗
PubMed2000

HERG K+ channels activation during beta(1) integrin-mediated adhesion to fibronectin induces an up-regulation of alpha(v)beta(3) integrin in the preosteoclastic leukemia cell line FLG 29.1.

Integrin receptors have been demonstrated to mediate either "inside-to-out" and "outside-to-in" signals, and by this way are capable of regulating many cellular functions, such as cell growth and differentiation, cell migration, and activation. Among the various integrin-centered signaling pathways discovered so far, we demonstrated that the modulation of the electrical potential of the plasma membrane (V(REST)) is an early integrin-mediated signal, which is related to neurite emission in neuroblastoma cells. This modulation is sustained by the activation of HERG K(+) channels, encoded by the ether-à-go-go-related gene (herg). The involvement of integrin-mediated signaling is being discovered in the hemopoietic system: in particular, osteoclasts are generated as well as induced to differentiate by interaction of osteoclast progenitors with the stromal cells, through the involvement of integrin receptors. We studied the effects of cell interaction with the extracellular matrix protein fibronectin (FN) in a human leukemic preosteoclastic cell line (FLG 29.1 cells), which has been demonstrated to express HERG currents. We report here that FLG 29.1 cells indeed adhere to purified FN through integrin receptors, and that this adhesion induces an osteoclast phenotype in these cells, as evidenced by the appearance of tartrate-resistant acid phosphatase, as well as by the increased expression of CD51/alpha(v)beta(3) integrin and calcitonin receptor. An early activation of HERG current (I(HERG)), without any increase in herg RNA or modifications of HERG protein was also observed in FN-adhering cells. This activation is apparently sustained by the beta(1) integrin subunit activation, through the involvement of a pertussis-toxin sensitive G(i) protein, and appears to be a determinant signal for the up-regulation of alpha(v)beta(3) integrin, as well as for the increased expression of calcitonin receptor.

Antibodies, Monoclonal↗
PubMed2000

Hybrid polar compounds produce a positive shift in the surface dipole potential of self-assembled phospholipid monolayers.

Hybrid polar compounds (HPCs) are powerful inducers of terminal differentiation of various types of tumors, including Friend murine erythroleukemia cells (MELCs). They are known to act synergistically with an increase in the extracellular concentration of cations, which causes a positive shift in the negative value of the ionic surface potential. Two HPCs, hexamethylenebisacetamide (HMBA) and suberoylanilide hydroxamic acid (SAHA), were adsorbed on self-assembled phospholipid monolayers supported on a mercury drop and the shift in the surface dipole potential chi of the lipid film due to their adsorption was estimated from charge measurements. At their optimal concentrations for inducing MELC terminal differentiation (5 mM for HMBA and 2.6 microM for SAHA), these HPCs cause a chi shift of about 15-20 mV, positive toward the hydrocarbon tails, both on neutral phosphatidylcholine films and on negatively or positively charged phosphatidylserine films. This strongly suggests that the nonspecific effect of HPCs of different structure in inducing cancer cells to rescue their differentiation program is related to a positive chi shift on the extracellular side of the cell membrane.

Absorption↗
PubMed2000

Inhibitory effect of luteinising hormone-releasing hormone analogues on human endometrial cancer in vitro.

We studied the effects of luteinising hormone-releasing hormone (LHRH) agonist leuproreline (1 microM for 96 h) and LHRH antagonist cetrorelix on the cell growth of primary cultures from nine human endometrial cancers using the sulphorhodamine colorimetric test. Histological examinations and reverse transcription and polymerase chain reaction amplification (RT-PCR) for LHRH receptors were also performed. The endometrial cancers examined had a medium to high degree of proliferative activity and a low degree of apoptotic power; furthermore, they expressed the LHRH receptor RNA variably, detectable in 71% of cases. The addition of leuproreline or cetrorelix to cell cultures inhibited growth in a statistically significant way compared to untreated control cells; nevertheless, the percentage of cell growth inhibition obtained was very variable. These data suggest that LHRH analogues can exert differential inhibitory effects on the growth of endometrial cancer, which seems to be independent of the expression of specific LHRH receptors.

Aged↗
PubMed2000

A transient dephosphorylation of JAK1 and JAK2 characterises the early-phase response of murine erythroleukemia cells to the differentiation inducer hexamethylenebisacetamide.

Although dephosphorylation of tyrosine containing proteins is considered a necessary step in the induction of leukemia cell differentiation by hybrid polar compounds (HPC), the crucial actors in this step remain unknown. We present evidence that tyrosine phosphorylation of JAK1 and JAK2 is down-regulated in murine erythroleukemia cells (MELC) within the first 6 h of their exposure to the prototype of the HPC family, hexamethylenebisacetamide (HMBA), with full recovery at 14 h. Further evidence that the JAKs-centered signalling pathway is switched off early by HMBA was provided by the demonstration that STAT5, a downstream member of this pathway, turned out to be completely dephosphorylated at 6 h in HMBA-treated cells. This JAKs dephosphorylation did not occur in HMBA-resistant clones, suggesting that JAKs are possible targets of the dephosphorylative process required for leukemia cell commitment to differentiation. These results may have impact on leukemia therapy based on JAKs inhibitors.

Acetamides↗
PubMed2000

HERG potassium channels are more frequently expressed in human endometrial cancer as compared to non-cancerous endometrium.

HERG K(+)channels, besides contributing to regulate cardiac and neuronal excitability, are preferentially expressed in tumour cell lines of different histogenesis, where their role in the development and maintenance of the neoplastic phenotype is under study. We show here that both herg gene and HERG protein are expressed with high frequency in primary human endometrial cancers, as compared to normal and hyperplastic endometrium. RT-PCR and immunohistochemistry, using specific anti-HERG antibodies developed in our laboratory, were applied to tissue specimens obtained from 18 endometrial cancers and 11 non-cancerous endometrial tissues. herg RNA and HERG protein are expressed in 67% and 82%, respectively, of cancerous, while in only 18% of non-cancerous tissues. In particular, no expression was found in endometrial hyperplasia. Moreover, electrophysiological experiments confirmed the presence of functioning HERG channels on the plasma membrane of tumour cells. On the whole, these data are the first demonstration of the presence of HERG channels in primary human neoplasias, and could candidate HERG as a potential tool capable of marking cancerous versus hyperplastic endometrial growth.

Aged↗
PubMed2000

Glucose- and arginine-induced insulin secretion by human pancreatic beta-cells: the role of HERG K(+) channels in firing and release.

The human ether-a-go-go-related genes (herg) are expressed in tissues other than heart and brain where the HERG K(+) channels are known to regulate the repolarization of the heart action potential and the neuronal spike-frequency accommodation. We provide evidence that herg1 transcripts are present in human pancreatic islets that were used to study both insulin secretion and electrical activity with radioimmunoassay and single cell perforated patch-clamp techniques, respectively. Glucose- and arginine-induced islets insulin secretion data suggested a net increase of release under perfusion with antiarrhythmic drugs known to selectively block HERG channels. Indeed we could routinely isolate a K(+) current that was recognized as biophysically and pharmacologically similar to the HERG current. An analysis of the glucose- and arginine-induced electrical activity (several applications during 30 min) in terms of firing frequency and putative insulin release was done in control and in the presence of selective blockers of HERG channels: the firing frequency and the release increased by 32% and 77%, respectively. It is concluded that HERG channels have a crucial role in regulating insulin secretion and firing of human beta-cells. This raises the possibility that some genetically characterized hyperinsulinemic diseases of unknown origin might involve mutations in the HERG channels.

ATP-Binding Cassette Transporters↗
PubMed2000

[Non-invasive ventilation in intensive care. Update 2000].

NIV indications and application in critically ill patients have considerably expanded in the last few years: the aim of this paper is to shortly review NIV main indications, on the basis of data from the current scientific literature.

Critical Care↗
PubMed2000

[Home mechanical ventilation: the extra-hospital phase].

Home mechanical ventilation is the choice option, when there are no contraindications of medical or socio-economic order, in all cases of impossible complete weaning from ventilatory support. Easy to use, reliable and size limited positive pressure ventilators lead to a spread diffusion of this technique. In the patient/ventilator interface, tracheostomy is the golden choice for patient with great reduction in spontaneous ventilatory ability. For all other patients, perfectioning of non-invasive access (nasal and oral nasal mask) represent an effective progress. Major limitations in home ventilation are still, up to present, the lack of multidisciplinary structures able to give territorial assistance. Home ventilation therapy in the experience of the Policlinico Universtitario "La Sapienza", Rome is presented.

Home Care Services, Hospital-Based↗