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PubMed2002

The CD154-CD40 costimulatory pathway in transplantation.

The CD154-CD40 pathway is one of the critical costimulatory pathways that are required for full activation of T cells during alloimmune responses. Blockade of this pathway with anti-CD154 antibodies has been reported to prolong allograft survival in experimental transplantation models and to induce tolerance in some instances. However, anti-CD154 monotherapy cannot induce tolerance in "stringent" models such as skin and islet transplantation and is not sufficient to prevent chronic graft vasculopathy in vascularized organ transplantation. Therefore, combined therapies of anti-CD154 antibodies plus donor-specific transfusion, bone marrow infusion, or B7 blockade by CTLA4-Ig have been tried, and synergistic effects for tolerance induction have been reported. Furthermore, the efficacy of CD154 blockade in primate models has been confirmed for islet and kidney transplantation. The mechanisms of CD154 blockade in vivo include CTLA4-dependent anergy or regulation, T-cell apoptosis, and induction of regulatory cells. Finally, anti-CD154 antibody therapy has been reported to result in unexpected thromboembolic complications in both primates and humans, although the etiology of these conditions remains unclear. In addition, not all antibodies cause this side effect. Clinical trials with humanized anti-CD154 monoclonal antibodies are underway in severe autoimmune diseases, but its development in transplantation is unclear at this time.

Animals↗

PubMed2006

Critical nodes in signalling pathways: insights into insulin action.

Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique role using insulin signalling as a model system.

Animals↗

PubMed2002

Critical involvement of the phosphatidylinositol 3-kinase/Akt pathway in anchorage-independent growth and hematogeneous intrahepatic metastasis of liver cancer.

In the multistep process of metastasis, "anchorage-independent growth," where cancer cells need to survive without cell-substratum interaction, is supposed to be important. In this study, we found that anchorage-independent growth analyzed using the soft agar colony formation assay correlated with hematogeneous intrahepatic metastasis of liver cancer cell lines and also Akt activation status. Two highly metastatic liver cancer cell lines showed high Akt activity and formed many colonies in soft agar, whereas three nonmetastatic cell lines showed less Akt activity and formed fewer colonies. Inhibition of Akt activation in the highly metastatic cell line Li7 by transfection with kinase-dead Akt or the phosphatidylinositol 3-kinase inhibitor, LY294002, resulted in formation of fewer colonies in soft agar than was the case with control cells. Moreover, in orthotopic implantation model, this inhibition resulted in a reduced rate of hematogeneous intrahepatic metastasis. These findings indicated that anchorage-independent growth regulated by phosphatidylinositol 3-kinase/Akt pathway plays a critical role in metastasis, and that this could be a potential therapeutic target to combat metastasis.

Animals↗

PubMed2001

Three-dimensional distribution of bipolar atrial electrogram voltages in patients with congenital heart disease.

Voltage differences might be used to distinguish normal atrial tissue from abnormal atrial tissue. This study was aimed at identifying lowest voltage areas in patients with atrial tachycardia after surgical correction of congenital heart disease and to evaluate if identification of these areas in diseased hearts facilitates selection of critical conduction pathways in reentrant circuits as target sites for catheter ablation. Ten patients (four men, age 39 +/- 15 years) with normal sized atria and atrioventricular reciprocating tachycardia (control group) and ten patients (5 men, 32 +/- 7 years) with congenital heart disease and postoperative atrial tachycardia (CL 281 +/- 79 ms) referred for radiofrequency catheter ablation were studied. Mapping and ablation was guided by a three-dimensional electroanatomic mapping system (CARTO) in all patients. In the control group, voltage maps were constructed during sinus rhythm and during tachycardia to evaluate the voltage distribution. The amplitude of bipolar signals was 1.90 +/- 1.45 mV (0.11-8.12 mV, n = 660) during sinus rhythm and 1.45 +/- 1.66 mV (0.12-5.83 mV, n = 440, P < 0.05) during atrioventricular reciprocating tachycardia. In the study group, the amplitude of 1,962 bipolar signals during tachycardia was 1.01 +/- 1.19 mV (0.04-9.40 mV), which differed significantly from the control group during tachycardia (P < 0.0001). No significant difference in the tachycardia cycle length was found (P < 0.05) between the control and study groups. As the lowest voltage measured in normal hearts was 0.1 mV, this value was used as the upper limit of the lowest voltage areas in the patients with congenital heart disease. These areas were identified by detailed voltage mapping and represented by a gray color. Activation and propagation maps were then used to select critical conduction pathways as target sites for ablation. These sites were characterized by fragmented signals in all patients. Ablation resulted in termination of the tachycardia in eight (80%) of ten patients. Complications were not observed. Identification of the lowest voltage areas using a cut-off value of 0.1 mV in congenital heart disease patients with postoperative atrial reentrant tachycardia facilitated the selection of critical conduction pathways as target sites for ablation.

Adult↗

PubMed2003

Peroxisome proliferator-activated receptors: a critical review on endogenous pathways for ligand generation.

Lipid mediators can exert their effects by interactions with well-characterised cell surface G-protein-linked receptors. Recently, a group of intracellular receptors have been identified that are activated by a large variety of lipid-derived mediators. Amongst these novel targets, the peroxisome proliferator-activated receptors (PPARs), a family of three (PPARalpha, beta/delta and gamma) nuclear receptor/transcription factors have become a major area for investigation. PPARs are found throughout the body, where they have diverse roles regulating lipid homeostasis, cellular differentiation, proliferation and the immune response. There is a great interest, therefore, in the roles of PPARs in a variety of pathological conditions, including diabetes, atherosclerosis, cancer and chronic inflammation. Although, a number of naturally occurring compounds can activate PPARs, it has been difficult, as yet, to characterise any of these mediators as truly endogenous ligands. These findings have lead to the suggestion that PPARs may act just as general lipid sensors. Acting as lipid sensors, PPARs may take changes in lipid/fatty acid balance in the diet or local metabolism and translate them to tissue-specific ligands, exerting tissue-specific effects. Using classical pharmacological criteria for endogenous mediator classification we will critically discuss the variety of pathways for putative ligand generation.

Cytochrome P-450 Enzyme System↗

PubMed1999

Inhibition of mammalian cell proliferation by genetically selected peptide aptamers that functionally antagonize E2F activity.

The p16-cyclin D-pRB-E2F pathway is frequently deregulated in human tumors. This critical regulatory pathway controls the G1/S transition of the mammalian cell cycle by positive and negative regulation of E2F-responsive genes required for DNA replication. To assess the value of the transcription factors E2Fs as targets for antiproliferative strategies, we have initiated a program aiming to develop inhibitors targeting specifically these proteins in vitro and in vivo. The cellular activity of E2F is the result of the heterodimeric association of two families of proteins, E2Fs and DPs, which then bind DNA. Here, we use a two hybrid approach to isolate from combinatorial libraries peptide aptamers that specifically interact with E2Fs DNA binding and dimerization domains. One of these is a potent inhibitor of E2F binding activity in vitro and in mammalian fibroblasts, blocks cells in G1, and the free variable region from this aptamer has the same effect. Our experiments argue that the variable region of this aptamer is structured, and that it functions by binding E2F with a motif that resembles a DP heterodimerization region, and blocking E2F's association with DP. These results show that cell proliferation can be inhibited using genetically-selected synthetic peptides that specifically target protein-protein interaction motifs within cell cycle regulators. These results also emphasize the critical role of the E2F pathway for cell proliferation and might allow the design of novel antiproliferative agents targeting the cyclin/CDK-pRB-E2F pathway.

Amino Acid Sequence↗

PubMed2000

Frequent association of beta-catenin and WT1 mutations in Wilms tumors.

The etiology of Wilms tumor, an embryonic kidney tumor, is genetically heterogeneous. One Wilms tumor gene, WT1, which encodes a zinc finger transcription factor, is mutated in 10-20% of Wilms tumors, but it is still not clear what critical cellular pathway(s) is affected by these mutations. Recently beta-catenin mutations have been reported in 6 of 40 (15%) of Wilms tumors. Beta-catenin is the central effector in the Wnt signal transduction pathway, and deregulation of beta-catenin signaling is critical in the development of a number of malignancies. The observation of beta-catenin mutations in Wilms tumors suggests that abrogation of the Wnt signaling pathway also plays a role in some Wilms tumors. To assess the relationship of WT1 mutations vis-à-vis beta-catenin mutations in Wilms tumor, we analyzed 153 primary tumors, and 21 of 153 (14%) carried beta-catenin mutations. Surprisingly, we observed a highly significant (P = 3.6 x 10(-13)) association between WT1 and beta-catenin mutations; 19 of 20 beta-catenin-mutant tumors had also sustained WT1 mutations. By analogy to the patterns of concordant and discordant gene mutations observed in other tumors, our data suggest that mutation of WT1 and beta-catenin affects two different cellular pathways, both of which are critically altered in at least a subset of Wilms tumors.

Adolescent↗

PubMed1997

Radical hysterectomy: current management guidelines.

Over the past 11 years (January 1985 through December 1996) the senior authors (B.F.H. and H.B.K.) have performed 205 radical hysterectomies. The most notable trend observed was a marked decrease in length of stay from 12.8 days to 3.5 days. Contributing factors include use of the Maylard incision, placement of suprapubic Foley catheters, discontinuation of drains, early oral feeding, admission to the hospital on the day of surgery, and initiation of a critical care pathway. All criteria for short-stay radical hysterectomy were established by 1994. With continued modification of surgical technique and use of the critical care pathway, short stay has become our standard of care for radical hysterectomy. Complications are minimal, with neither long-term morbidity nor mortality associated with the short stay. In addition, significant cost savings occur, which benefits the patient, hospital, and the health care system.

Adult↗

PubMed2005

Inhibition of EGFR signaling in human prostate cancer PC-3 cells by combination treatment with beta-phenylethyl isothiocyanate and curcumin.

Many naturally occurring compounds, including beta-phenylethyl isothiocyanate (PEITC) and curcumin, exhibit significant anti-cancer chemopreventive effects. In this study, we investigated the combined effects of PEITC and curcumin in PC-3 human prostate cancer cells and in PC-3 cells that were stably transfected with an NF-kappaB luciferase plasmid (PC-3 C4). We found an additive effect of PEITC and curcumin for the induction of apoptosis. To elucidate the potential mechanisms of this effect, we studied several critical cellular signaling pathways, including the critical NF-kappaB cell survival signal that is hyper-activated in PC-3 cells and many other cancers. PEITC and curcumin additively inhibited NF-kappaB luciferase activity. Furthermore, the combined treatment significantly increased the activity of poly(ADP-Ribose) polymerase and cleavage of caspase-3 in correlation with apoptotic cell death. Studying upstream signaling events, we found that the phosphorylations of IkappaBalpha and Akt (Ser473, Thr308) were significantly attenuated by the combination of PEITC and curcumin. As these events can be downstream of the activation of epidermal growth factor receptor (EGFR), we pretreated PC-3 cells with PEITC and curcumin and then stimulated them with EGF. EGFR phosphorylations (Y845 and Y1068) were dramatically suppressed by PEITC or curcumin, and more so by the combination. Importantly, the degree of Akt and PI3K phosphorylations induced by EGF were also significantly suppressed. We conclude that the simultaneous targeting of EGFR, Akt and NF-kappaB signaling pathways by PEITC and curcumin could be the molecular targets by which PEITC and curcumin exert their additive inhibitory effects on cell proliferation and ultimately lead to programmed cell death of tumor cells.

Anticarcinogenic Agents↗

PubMed2005

Emerging role of protein kinase B/Akt signaling in pancreatic beta-cell mass and function.

The serine-threonine kinase Akt also known as protein kinase B is one of the most studied molecules. In addition to the important role in carcinogenesis, Akt is a major regulator of carbohydrate metabolism. Akt mediates insulin-dependent glucose uptake in insulin-sensitive tissues. Recent evidence underscores the importance of Akt for regulation of beta-cell mass and function. This review summarizes current findings concerning the molecular mechanisms, downstream signaling pathways, and critical components involved in regulation of beta-cell mass and function by Akt. The results of these observations suggest that elucidation of critical downstream effectors of this signaling pathway could generate promising molecules as a potential target to induce proliferation and survival of beta-cells.

Animals↗

PubMed2001