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At least 415 records · Page 23Linked to original sources
PubMed1996

Biology of tumor cell invasion: interplay of cell adhesion and matrix degradation.

Invasion of malignant cells requires altered cellular interaction with extracellular matrix. Integrin-type cell adhesion receptors play an important role in this process. Integrin-related cell biological phenomena explain cancer cell migration, and recent developments in the field have made it possible to propose that integrins are also involved in the penetration through basement membranes and other molecular barriers. Finally, malignant melanoma has been used here as an example to speculate on the function of each integrin in light of information from different experimental models.

Animals↗
PubMed2000

Water regulation of actinomycin-D binding to DNA: the interplay among drug affinity, DNA long-range conformation, and hydration.

Actinomycin-D (actD) binds to natural DNA at two different classes of binding sites, weak and strong. The affinity for these sites is highly dependent on DNA sequence and solution conditions, and the interaction appears to be purely entropic driven. Although the entropic character of this reaction has been attributed to the release of water molecules upon drug to DNA complex formation, the mechanism by which hydration regulates actD binding and discrimination between different classes of binding sites on natural DNA is still unknown. In this work, we investigate the role of hydration on this reaction using the osmotic stress method. We show that the decrease of solution water activity, due to the addition of sucrose, glycerol, ethylene glycol, and betaine, favors drug binding to the strong binding sites on DNA by increasing both the apparent binding affinity delta G, and the number of DNA base pairs apparently occupied by the bound drug nbp/actD. These binding parameters vary linearly with the logarithm of the molar fraction of water in solution log(chi w), which indicates the contribution of water binding to the energetic of the reaction. It is demonstrated that the hydration change measured upon binding increases proportionally to the apparent size of the binding site nbp/actD. This indicates that nbp/actD, measured from the Scatchard plot, is a measure of the size of the DNA molecule changing conformation due to ligand binding. We also find that the contribution of DNA deformation, gauged by nbp/actD, to the total free energy of binding delta G, is given by delta G = delta Glocal + nbp/actD x delta GDNA, where delta Glocal = -8020 +/- 51 cal/mol of actD bound and delta GDNA = -24.1 +/- 1.7 cal/mol of base pair at 25 degrees C. We interpret delta Glocal as the energetic contribution due to the direct interactions of actD with the actual tetranucleotide binding site, and nbp/actD x delta GDNA as that due to the change in conformation, induced by binding, of nbp/actD DNA base pairs flanking the local site. This interpretation is supported by the agreement found between the value of delta GDNA and the torsional free energy change measured independently. We conclude suggesting an allosteric model for ligand binding to DNA, such that the increase in binding affinity is achieved by increasing the relaxation of the unfavorable free energy of binding storage at the local site through a larger number of DNA base pairs. The new aspect on this model is that the "size" of the complex is not fixed but determined by solutions conditions, such as water activity, which modulate the energetic barrier to change helix conformation. These results may suggest that long-range allosteric transitions of duplex DNA are involved in the inhibition of RNA synthesis by actD, and more generally, in the regulation of transcription.

Animals↗
PubMed1997

Leukaemogenesis, gene interplay, and the role of the haemopoietic environment.

Malignant initiation, leukaemic transformation, and disease progression in haematological malignancies involves a series of mutational events in genes involved in normal housekeeping functions of the cell. These acquired genetic changes can lead to either increased proliferation or a decreased rate of apoptosis, thus allowing expansion of the malignant clone. Although leukaemia can arise as a de novo disease, it has become increasingly clear that therapies, including the use of irradiation and/or chemotherapy, can give rise to malignancy. Therapy-associated myelodysplasia (t-MDS) and therapy-associated acute myeloid leukaemia (t-AML) account for 10-20% of new cases of these diseases. Although these secondary malignancies have been recognised as a clinical entity for nearly 30 years, molecular studies are now pinpointing various regions of the genome that are susceptible to DNA damage by these chemotherapeutic/radiotherapeutic strategies. The detection of new malignancies (both solid tumours and haematological tumours) following allogeneic bone marrow transplantation (BMT) is also providing us with some clues to the nature of leukaemogenesis, particularly with the observation that leukaemia can occur in donor cells postallogeneic BMT.

Acute Disease↗
PubMed2000

The Melting Point Alternation in alpha,omega-Alkanediols and alpha,omega-Alkanediamines: Interplay between Hydrogen Bonding and Hydrophobic Interactions The Melting Point Alternation in n-Alkanes and Derivatives, Part 2. This work was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie. V.R.T. thanks the Alexander von Humboldt Foundation for a postdoctoral fellowship. Part 1: ref. 6.

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Journal Article↗
PubMed1999

The interplay between T helper subset cytokines and IL-12 in directing human B lymphocyte differentiation.

This study asks how T helper (TH) subset cytokines impact upon IL-12-directed change in B cells engaged in signaling via the B cell receptor and CD40, essential components in the initiation of T-dependent B cell responses. For B cells stimulated in this way, IL-12 promoted a distinct phenotype highlighted by the hyper-expression of CD38: the Th1 cytokine IFN-gamma reproduced the IL-12 effects while neutralizing antibody to IFN-gamma reversed IL-12-dependent change. The divergent pathway of differentiation promoted by the Th2 cytokine IL-4 (characterized by hyper-induction of CD23) was left unchecked by IL-12. IL-10 was found to dampen IL-12 actions by suppressing IL-12-dependent IFN-gamma production but failed to perturb the effects of exogenous IFN-gamma. Thus, IL-12--by invoking autocrine IFN-gamma production--promotes phenotypic deviation in B cells engaging T-dependent signals. The reversal of such Th1 driving of B cells by IL-10 only when the source of IFN-gamma is endogenous and the inability of IL-12 to impact upon IL-4-directed differentiation suggest a progressive and hierarchical commitment of B cells to polarization during a developing T-dependent response dominated at the level of the Th cell rather than that of the dendritic cell.

B-Lymphocytes↗
PubMed1999

The interplay between the duration of TCR and cytokine signaling determines T cell polarization.

Development of Th1 and Th2 effector lymphocytes is driven primarily by IL-12 or IL-4, but is also influenced by the strength of antigenic stimulation. However, the mechanism by which TCR signaling contributes to T cell polarization remains elusive. We show that in the presence of IL-12 a short TCR stimulation can lead to efficient Th1 polarization and IL-12 exerts its effect when present during, as well as after, TCR signaling. In contrast, Th2 polarization requires a prolonged TCR stimulation and IL-4 is effective only when present during the period of TCR triggering. The simultaneous stimulation by TCR and IL-4 is required to induce demethylation of IL-4 and IL-13 genes that accompanies the stochastic generation of Th2 cells producing either or both cytokines. Thus, the duration of TCR stimulation represents a crucial parameter that influences the response to polarizing cytokines and the acquisition of T cell effector functions.

Animals↗
PubMed2000

'Invading edge vs. inner' (edvin) patterns of vascularization: an interplay between angiogenic and vascular survival factors defines the clinical behaviour of non-small cell lung cancer.

Neo-angiogenesis during neoplastic growth involves endothelial mitogenic and migration stimuli produced by cancer or tumour stromal cells. Although this active angiogenesis takes place in the tumour periphery, the process of vessel growth and survival in inner areas and its clinical role remain largely unexplored. The present study compared the microvessel score (MS) as well as the single endothelial cell score (ECS) in the invading edge and in inner areas of non-small cell lung carcinomas (NSCLCs). Three different patterns of vascular growth were distinguished: the edvin (edge vs. inner) type 1, where a low MS was observed in both peripheral and inner tumour areas; the edvin type 2, where a high MS was noted in the invading front but a low MS in inner areas; and the edvin type 3, where both peripheral and inner tumour areas had a high MS. The ECS was high in the invading edge in edvin type 2 and 3 cases and was sharply decreased in both types in inner areas, suggesting that endothelial cell migration is unlikely to contribute to the angiogenic process in areas away from the tumour front. Expression of the vascular endothelial growth factor (VEGF) and of thymidine phosphorylase (TP) was associated with a high MS in the invading edge. VEGF was associated with a high MS in inner areas (edvin 3), while TP expression was associated with edvin type 2, showing that VEGF (and not TP) contributes to the preservation of the inner vasculature. Both edvin type 2 and 3 cases showed an increased incidence of node metastasis, but edvin type 3 cases had a poorer prognosis, even in the N1-stage group. The present study suggests that tumour factors regulating angiogenesis and vascular survival are not identical. A possible method is reported to quantify these two parameters by comparing the MS in the invading edge and inner areas (edvin types). This observation may contribute to the evaluation of the effectiveness of different therapeutic approaches, namely vascular targeting vs. anti-angiogenesis.

Carcinoma, Non-Small-Cell Lung↗
PubMed1990

The interplay of local and distant control in the cure of cervical cancer.

From 1978 to 1986, 183 women with cervical cancer received definitive radiation therapy after extraperitoneal surgical staging. Relapse-free rates were strong functions of pelvic lymph node metastases and cervical size. The recurrence distribution consisted of 4% isolated local, 13% isolated distant, and 17% combined local and distant failures. With the assumption of independent local and distant failure probabilities, Suit et al.'s method was extended to assess potential improvement in cure attainable with perfect local and distant control, yielding local (LSA) and distant (DSA) survival advantages of 17% and 28%. Various subsets of clinical stage, cervical size, pelvic node metastases, periaortic metastases, and peritoneal metastases had LSA from 12% to 27% and DSA from 12% to 71%. For any prognostic group, LSA never exceeded DSA, showing that effective systemic therapy would have a greater impact on improving survival than would advances in local and regional tumor control. Therapeutic implications and limitations of the extended LSA-DSA model are discussed. This form of analysis can be used to guide the intensity of local and distant treatment to maximize the cure of the patient with cancer.

Adult↗
PubMed2000

The interplay of institution and family caregiving: relations between patient hassles, nursing home hassles and caregivers' burnout.

This population-based study investigated the relationship between stresses (hassles) and burnout for 30 family caregivers and their institutionalized demented elderly. The Burnout Measure, the Patient Hassles Scales and the Nursing Home Hassles Scale were used. Hassles included: patient hassles (cognitive, behavior, basic ADL) and nursing home hassles (caregiver - staff, patient - staff, practical/logistical). The caregiver's characteristics are described in relation to burnout and the caregiver's most frequent hassles are discussed. All subscales except basic ADL were correlated to burnout. However, regression analysis showed the nursing home hassles to be the most important stresses explaining variance in burnout among family caregivers.

Aged↗
PubMed2001

Interplay of cubic building blocks in (et6-arene)ruthenium-containing tungsten and molybdenum oxides.

A series of molybdenum and tungsten organometallic oxides containing [Ru(arene)]2+ units (arene =p-cymene, C6Me6) was obtained by condensation of [[Ru(arene)Cl2]2] with oxomolybdates and oxotungstates in aqueous or nonaqueous solvents. The crystal structures of [[Ru(eta6-C6Me6]]4W4O16], [[Ru(eta6-p-MeC6H4iPr]]4W2O10], [[[Ru-(eta6-p-MeC6H4iPr)]2(mu-OH)3]2][[Ru(eta6-p-MeC6H4iPr)]2W8O28(OH)2[Ru(eta6-p-MeC6H4iPr)(H2O)]2], and [[Ru(eta6-C6Me6)]2M5O18[Ru(eta6-C6Me6)(H2O)]] (M = Mo, W) have been determined. While the windmill-type clusters [[Ru(eta6-arene)]4(MO3)4(mu3-O)4] (M = Mo, W; arene =p-MeC6H4iPr, C6Me6), the face-sharing double cubane-type cluster [[Ru(eta6-p-MeC6H4iPr)]4(WO2)2(mu3-O)4(mu4-O)2], and the dimeric cluster [[Ru(eta6-p-MeC6H4iPr)(WO3)3(mu3-O)3(mu3-OH)Ru(eta6-pMeC6H4iPr)(H2O)]2(mu-WO2)2]2- are based on cubane-like units, [(Ru(eta6-C6Me6)]2M5O18[Ru(eta6-C6Me6)(H2O)]] (M = Mo, W) are more properly described as lacunary Lindqvist-type polyoxoanions supporting three ruthenium centers. Precubane clusters [[Ru(eta6-arene)](MO3)2(mu-O)3(mu3-O)]6- are possible intermediates in the formation of these clusters. The cluster structures are retained in solution, except for [[Ru(eta6-p-MeC6H4iPr)]4Mo4O16], which isomerizes to the triple-cubane form.

Journal Article↗
PubMed1999

Photoactivation of rhodopsin: interplay between protein and chromophore.

Data in the literature suggest a finely tuned interaction between ligand (11-cis-retinal) and protein (opsin) in order to allow very efficient photoactivation of the ligand and highly vectorial rhodopsin activation with a huge increase in receptor activity. We have further investigated this interaction using ligand homologues, 13C-ligand labelling or 15N-protein labelling, in combination with Fourier transform infrared (FT-IR) and solid-state magic angle spinning (ss-MAS)-NMR spectroscopy. Using 1D rotational resonance (RR) or double-quantum heteronuclear local field (2Q-HLF) ss-MAS-NMR we report the first structure refinement of the rhodopsin chromophore in situ. These measurements yield a specification of the torsional strain in the for isomerization essential C10-C13 segment of the chromophore. This strain is thought to contribute to the high rate and stereospecificity of the photoisomerization reaction. In agreement with previous data, the C10-C13 segment region reaches a relaxed all-trans configuration at the lumirhodopsin photointermediate. MAS-NMR analysis of [15N]lysine-labelled rhodopsin reveals the presence of a 'soft' counterion, requiring intermediate water molecules for stabilization. FT-IR studies on [2H]tyrosine-labelled rhodopsin demonstrate participation of several tyrosin(at)e residues in receptor activation. One of these, probably Tyr268, is already active at the bathorhodopsin stage. Finally, the effect of ligands with single additional methyl substituents in the C10-C12 region has been investigated. They do not affect the general activation pathway, but perturb the activation kinetics of rhodopsin, suggesting steric interference with protein residues. Possible implications of these results for a structural role of water residues will be discussed, as well.

Animals↗
PubMed2002

Interplay between heredity and environment in the recent explosion of type 1 childhood diabetes mellitus.

The fast increase in the incidence of childhood type 1 diabetes mellitus (T1DM) that cannot be explained by changes in the genetic susceptibility, led us to look for environmental causes. To test the hypothesis that the initiation of the autoimmune process of childhood T1DM in genetically susceptible subjects begins in the perinatal period by a viral infection, we studied the seasonal variations in the month of birth of several cohorts of patients compared to the general population. Population groups with high or low T1DM incidence were analyzed separately by t-test and the Cosinor methods. In areas with populations with a high incidence (Israeli Jews, Sicily, Sardinia, Slovenia, Germany) we found that the children (in Sicily also young adults) who subsequently developed T1DM, have a higher incidence of births in the summer months than in other seasons of the year, a mirror image of the seasonality of the clinical onset of disease. This pattern differed significantly from the seasonality of the total live births in the same populations. In populations with a low T1DM incidence, (China, Japan and Cuba) no seasonality of month of birth was found. Similar findings have been reported, from five counties in the U.K. and the Netherlands. It is hypothesized that mothers who become pregnant during the period of yearly viral epidemics transmit to the fetus, either a virus or antiviral antibodies, which determine whether an autoimmune process against the pancreatic beta is initiated or whether the fetus is protected against that process.

Diabetes Mellitus, Type 1↗
PubMed2026

A Multifaceted Interplay Among Hemophagocytosis, Interleukin-18, and Type I Interferon Distinguishes Still Disease From Other Autoinflammatory Diseases.

OBJECTIVE: The unknown pathophysiology and the lack of specific features for systemic juvenile idiopathic arthritis and adult-onset Still disease (collectively known as Still disease; SD) delay diagnosis and appropriate treatment. The goal of this study was to identify features and mechanisms that distinguish SD from other systemic autoinflammatory diseases (SAID). METHODS: Using the SomaScan assay and RNA sequencing (RNA-Seq), we determined the plasma proteomes and immune cell microRNA (miRNA) and RNA transcriptomes of 372 patients with SAID, respectively. Proteomic findings were validated by enzyme-linked immunosorbent assays. SD (n = 72) and non-SD SAIDs (n = 300) were compared to identify distinguishing features of SD. We performed integrated and unbiased analyses of all data sets using weighted gene correlation network analysis to identify feature modules that characterize SD and stratify patients. RESULTS: Elevated plasma heme oxygenase 1 (HO-1) and interleukin-18 (IL-18) strongly correlate and characterize SD but do not associate with general inflammation. SD was characterized by ferroptosis in plasma, type I interferon (IFN) signaling in monocyte transcriptomes, and elevated natural killer cell miRNA-146a-5p, which is an IL-18 induced miRNA. Finally, we identified feature modules that distinguish SD from other SAIDs and stratified patients with SD into two distinct subgroups not attributable to disease activity or inflammation but hemophagocytosis. CONCLUSION: This unprecedented large omics data set of SAIDs revealed that complex interactions among hemophagocytosis, IL-18, and type I IFN signaling characterize SD. Furthermore, two distinct subgroups in patients with SD were distinguished by the degree of hemophagocytic activity. Finally, the large proteomics and RNA-Seq data sets generated in this study can serve as an invaluable resource for the further investigation of SD and other SAIDs.

Humans↗