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PubMed2004

Histidine-proline rich glycoprotein (HPRG) binds and transduces anti-angiogenic signals through cell surface tropomyosin on endothelial cells.

The anti-angiogenic properties of the histidine-proline-rich (H/P) domain of HPRG have recently been described (Juarez JC, et al. Cancer Research 2002; 62: 5344-50). However, the binding site that mediates these properties is unknown. HPRG is evolutionarily, functionally and structurally related to cleaved high molecular weight kininogen (HKa), an anti-angiogenic polypeptide that stimulates apoptosis of proliferating endothelial cells through binding to cell-surface tropomyosin (Zhang J-C, et al. Proc Natl Acad Sci USA 2002; 99: 12224-9). In this study, we demonstrate that HPRG binds with high affinity to FGF-2-stimulated human umbilical vein endothelial cells (HUVEC) and immobilized tropomyosin in a Zn2+ or pH-dependent manner, and that this interaction is mediated by the H/P domain of HPRG. At least two binding sites for HPRG, tropomyosin and heparan sulfate proteoglycans (HSPs), were identified on the surface of FGF-2-activated endothelial cells. Translocation of tropomyosin to the surface of HUVEC occurred in response to FGF-2, and the anti-angiogenic activity of HPRG in a Matrigel plug model was partially inhibited by soluble tropomyosin. These results suggest that HPRG binds to endothelial cell surface tropomyosin which at least partially mediates the antiangiogenic effects of HPRG.

Angiogenesis Inhibitors↗

PubMed2003

Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is defined by recurrent pregnancy loss and thrombosis in the presence of antiphospholipid (aPL) Ab's. Currently, therapy for pregnant women with APS is focused on preventing thrombosis, but anticoagulation is only partially successful in averting miscarriage. We hypothesized that complement activation is a central mechanism of pregnancy loss in APS and tested this in a model in which pregnant mice receive human IgG containing aPL Ab's. Here we identify complement component C5 (and particularly its cleavage product C5a) and neutrophils as key mediators of fetal injury, and we show that Ab's or peptides that block C5a-C5a receptor interactions prevent pregnancy complications. The fact that F(ab)'2 fragments of aPL Ab's do not mediate fetal injury and that C4-deficient mice are protected from fetal injury suggests that activation of the complement cascade is initiated via the classical pathway. Studies in factor B-deficient mice, however, indicate that alternative pathway activation is required and amplifies complement activation. In contrast, activating Fc gamma Rs do not play an important role in mediating aPL Ab-induced fetal injury. Our findings identify the key innate immune effectors engaged by pathogenic autoantibodies that mediate poor pregnancy outcomes in APS and provide novel and important targets for prevention of pregnancy loss in APS.

Abortion, Spontaneous↗

PubMed1990

Experimental tibial fractures in rabbits simulating proximal tibial metaphyseal fractures in children.

The etiology of valgus deformity after a seemingly innocuous fracture of the proximal tibial metaphysis in children is unknown. The purpose of this work was to identify the etiology of this deformity using a rabbit model. Twenty-two eight-week-old rabbits were divided into two groups. In Group I, the medial periosteum was excised from the left proximal tibial metaphysis. A partial osteotomy was created 5 mm distal to the epiphyseal plate, involving the medial one-half of the tibial metaphysis. Two 0.7-mm Kirschner wires were placed as markers on each side of the osteotomy. In Group II, the identical procedure was performed from the lateral side. Standard roentgenograms were obtained postoperatively and weekly until death by sodium pentobarbital overdose at six weeks. The angular deformity, medial growth, and lateral growth were calculated from the markers on the roentgenograms. All tibias were decalcified and analyzed under light microscopy. In Group I, all 11 rabbits developed valgus deformity averaging 12.2 degrees; asymmetric growth was statistically significant. In Group II, ten of 11 rabbits developed varus deformity averaging 9.8 degrees; asymmetric growth was not statistically significant. Despite obvious asymmetric growth in both groups, light microscopy failed to reveal any asymmetry of the physis. Valgus and varus deformities are secondary to asymmetric growth, which is not demonstrable by light microscopy.

Animals↗

PubMed1981

Protection against pneumococcal bacteremia by partial splenectomy.

An animal model of partial splenectomy and its effect upon subsequent challenge with pneumococcus were evaluated. Results of these studies support the contention that partial splenectomy protects the host against pneumococcal bacteremia. The data show that small splenic remnant attached to identifiable blood vessels afford protection against sepsis. Thus, partial splenectomy may be used in massive splenic fractures if hemostasis can be achieved, even if less than 25 per cent of the spleen remains in continuity with its vascular supply. The conclusion that the filtering effect of the spleen is paramount in protecting against sepsis appears justified.

Animals↗

PubMed1999

Comparison of direct hospital costs and length of stay for radical nephrectomy versus nephron-sparing surgery in the management of localized renal cell carcinoma.

OBJECTIVES: Recent work has demonstrated comparable surgical results and 5-year cancer-specific survival rates between radical nephrectomy and nephron-sparing surgery (NSS) in the treatment of patients with small (4 cm or smaller) solitary renal cell carcinomas (RCCs). However, differences exist in the intraoperative management and postoperative care of patients undergoing NSS versus radical nephrectomy, and we sought to compare direct hospital costs and length of stay (LOS) between these two groups to determine whether either treatment imparts a specific cost advantage. METHODS: Data were retrieved from medical records and administrative data sets containing billing encounters for all costs incurred during hospitalization at the Cleveland Clinic Foundation. Individual costs were grouped together using nine cost center categories encompassing every aspect of direct hospital care, including anesthesiology, laboratory, radiology, nursing, pharmaceutical, and emergency services, and medical care, surgical care, and miscellaneous costs. Each cost center was further subdivided, and a total of 52 cost subcategories were assessed. The total direct costs of hospitalization were compared using a multivariate regression model in which patient demographics and tumor characteristics, type and year of surgery, LOS, and cost center categories were assessed as single and interactive factors. Postoperative complication and cancer-specific survival rates were also compared to identify any potential therapeutic differences between the two groups. RESULTS: Between 1991 and 1995, 80 patients underwent surgery at the Cleveland Clinic Foundation for solitary RCCs 4 cm or smaller, including 52 partial and 28 radical nephrectomies. We found no difference in the postoperative complication rate or cancer-specific survival rate between the two surgical groups. Total direct hospital costs and LOS were not statistically different between the NSS and radical nephrectomy groups (P >0.05). This was further supported by our multivariate model, which accounted for 61% of the observed variance in the total costs (F = 12.11, P = 0.0001). The type of surgery was not associated with total cost when controlling for all other factors, including age, sex, year of surgery, tumor size, grade, and stage, and postoperative complications (P = 0.7). There was no significant interaction between the type of surgery and the LOS (P = 0.5). CONCLUSIONS: This study demonstrated that elective NSS can be performed with equivalent direct hospital costs and LOS when compared with patients undergoing radical nephrectomy for small solitary RCCs. These data have significant economic implications for the comparison of competing surgical treatment strategies for localized RCC.

Aged↗

PubMed2004

Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease.

Inhibition of polyglutamine-induced protein aggregation could provide treatment options for polyglutamine diseases such as Huntington disease. Here we showed through in vitro screening studies that various disaccharides can inhibit polyglutamine-mediated protein aggregation. We also found that various disaccharides reduced polyglutamine aggregates and increased survival in a cellular model of Huntington disease. Oral administration of trehalose, the most effective of these disaccharides, decreased polyglutamine aggregates in cerebrum and liver, improved motor dysfunction and extended lifespan in a transgenic mouse model of Huntington disease. We suggest that these beneficial effects are the result of trehalose binding to expanded polyglutamines and stabilizing the partially unfolded polyglutamine-containing protein. Lack of toxicity and high solubility, coupled with efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases. The saccharide-polyglutamine interaction identified here thus provides a new therapeutic strategy for polyglutamine diseases.

Animals↗

PubMed2004

Basal prostate epithelial cells stimulate the migration of prostate cancer cells.

Carcinoma cells in PIN are situated above a layer of basal epithelial cells, which shield the tumor cells from stimulation by factors from the prostate stroma. During progression to invasive carcinoma, the basal cell layer becomes disrupted and tumor cells adhere to the basement membrane. The close proximity of basal epithelial cells to tumor cells in the early stages of prostate oncogenesis raises the possibility that basal epithelial cells participate in tumor cell invasion. Here, we investigated the migration-promoting activity of secreted factors from basal epithelial cells on BPH-1 cells, which we used as an in vitro model of preinvasive prostate cancer cells. We showed that the conditioned medium of basal epithelial cells (PEC-CM) contains adhesion proteins and chemotactic factors that stimulate adhesion, planar polarization, migration, and phosphorylation of Akt and that LY294002 and Wortmannin partially inhibit PEC-CM-triggered migration. We identified laminin-5 as a major migration-stimulating protein for BPH-1 cells in PEC-CM. Laminin-5 induced migration is completely inhibited by LY294002 or Wortmannin. In addition, antibody-depletion of laminin-5 from PEC-CM significantly diminishes the migration of BPH-1 cells. These results demonstrated, that laminin-5 is secreted by basal prostate epithelial cells in vivo and in vitro and stimulates migration of BPH-1 cells through a PI3-kinase dependent mechanism. Altogether, the possibility that basal epithelial cells assist in the invasion of in situ carcinoma cells is supported by the results from our in vitro system.

Cell Adhesion↗

PubMed2006

CpG-C ISS-ODN activation of blood-derived B cells from healthy and chronic immunodeficiency virus-infected macaques.

Cytosine-phosphate-guanine class C (CpG-C) immunostimulatory sequence oligodeoxynucleotides (ISS-ODNs) activate human B cells and dendritic cells (DCs), properties that suggest potential use as a novel adjuvant to enhance vaccine efficacy. After demonstrating that the CpG-C ISS-ODN C274 activates macaque DCs, we examined in vitro activation of macaque B cells by C274 as a prelude to evaluation of this molecule as an adjuvant in the testing of candidate human immunodeficiency virus vaccines in the rhesus macaque-simian immunodeficiency virus (SIV) model. C274 induced macaque CD20(+) B cells to proliferate more strongly than CD40 ligand or CpG-B ISS-ODN. C274 enhanced B cell survival; increased viability was most evident after 3-7 days of culture. Increased expression of CD40, CD80, and CD86 by B cells was apparent within 24 h of exposure to C274 and persisted for up to 1 week. C274-stimulated, B cell-enriched and peripheral blood mononuclear cell suspensions from naïve and immunodeficiency virus-infected monkeys secreted several cytokines [e.g., interleukin (IL)-3, IL-6, IL-12, interferon-alpha] and chemokines [e.g., monocyte chemoattractant protein-1/CC chemokine ligand 2 (CCL2), macrophage-inflammatory protein-1alpha/CCL3, IL-8/CXC chemokine ligand 8]. In comparison, exposure of macaque B cells to SIV had minimal impact on surface phenotype, despite inducing cytokine and chemokine production in cells from infected and uninfected animals. These observations emphasize the need to identify strategies to optimally boost immune function, as immunodeficiency viruses themselves only partially activate B cells and DCs. The ability of C274 to stimulate B cells and DCs in healthy and infected monkeys suggests its possible use as a broad-acting adjuvant to be applied in the rhesus macaque model for the development of preventative and therapeutic vaccines.

AIDS Vaccines↗

PubMed1990

In vivo 31P NMR spectroscopic changes during liver regeneration.

Liver regeneration following partial hepatectomy involves rapid cell division 24 to 72 hr postresection. This cell division would necessarily involve changes in intracellular energy stores and cell membrane phospholipid precursors. In tumor models 31P nuclear magnetic resonance (NMR) has been shown to identify intracellular substrate changes associated with cell growth. The ability to monitor early changes in adenosine triphosphate (ATP), inorganic orthophosphate (Pi), phosphomonoesters (PME), or phosphodiesters (PDE) after liver resection could indicate the intracellular changes necessary for hepatocellular regeneration. In vivo 31P NMR scans of the liver were performed in both normal rats and in rats at 24, 48, 72, and 120 hr after 70% hepatectomy. At 48 hr, total ATP fell to 18.9% (P less than 0.05) and both Pi/beta-ATP and PME/beta-ATP were significantly elevated (P less than 0.01) from controls. These changes correlate with the known mitotic peak in the rat following hepatectomy. We conclude that in vivo 31P NMR is a potentially valuable tool for studying hepatic regeneration. The data also suggest that hepatocellular regeneration may be critically dependent on cellular ATP stores.

Adenosine Triphosphate↗

PubMed2026

Climate and soil shape Daqu wheat quality and seed microbiome via rhizosphere taxa and microbial assembly.

The grain quality and seed microbiome of Daqu wheat are fundamental determinants of Daqu fermentation performance; however, the mechanisms by which cultivation environments influence these traits via rhizosphere microbial communities remain unclear. Bacterial and fungal communities across the bulk soil-rhizosphere-seed continuum of three wheat cultivars grown in four ecoregions were characterized using absolute quantitative amplicon sequencing. The rhizosphere microbiome was treated as a central intermediary, while the response variables were seed microbial diversity and grain-quality traits, including starch content, protein content, and grain hardness. Twelve physicochemical properties of soil and 11 climatic factors were integrated into a multidimensional association framework. Environmental conditions exerted stronger influences on both seed quality traits and microbial diversity than cultivar identity. Distinct regional signatures were also evident in rhizosphere microbiomes, with environmental gradients explaining community variation more effectively than geographic distance. Bacterial communities exhibited greater sensitivity to environmental fluctuations than fungi. Mantel analyses identified available nitrogen, precipitation, and atmospheric pressure as significant drivers of core rhizosphere taxa (P < 0.05). iCAMP revealed that stochastic processes predominantly governed rhizosphere bacterial assembly, whereas stochastic and deterministic mechanisms jointly shaped fungal assembly. Partial least squares path modeling further uncovered a rhizosphere-mediated environment-seed cascade, wherein sunlight intensity and duration, atmospheric pressure, and soil nitrogen directly or indirectly affected seed wet gluten content, grain hardness, and seed microbial diversity through their influences on rhizosphere microbiota. Rhizosphere bacterial diversity was negatively associated with seed bacterial diversity (path coefficient = -0.118, P < 0.05), indicating that rhizosphere communities may shape seed endophytic bacterial assemblages via environmental filtering and competitive interactions. Collectively, these findings elucidate how environments shape the quality and seed microbiomes of Daqu wheat, providing scientific guidance for optimal site selection and the standardized production of high-quality brewing wheat for industrial Baijiu.

Triticum↗

PubMed2005

The efficiency of multi-target drugs: the network approach might help drug design.

Despite considerable progress in genome- and proteome-based high-throughput screening methods and rational drug design, the number of successful single-target drugs did not increase appreciably during the past decade. Network models suggest that partial inhibition of a surprisingly small number of targets can be more efficient than the complete inhibition of a single target. This and the success stories of multi-target drugs and combinatorial therapies led us to suggest that systematic drug-design strategies should be directed against multiple targets. We propose that the final effect of partial, but multiple, drug actions might often surpass that of complete drug action at a single target. The future success of this novel drug-design paradigm will depend not only on a new generation of computer models to identify the correct multiple targets and their multi-fitting, low-affinity drug candidates but also on more-efficient in vivo testing.

Computational Biology↗

PubMed2003

Age of menarche: the role of some psychosocial factors.

BACKGROUND: The goal of this study was to determine associations between the age of first menstrual period (menarche) and adverse childhood experiences in a random community sample of New Zealand women. Previous reports have linked early menarche to absence of a live-in father figure and to family conflict, as well as genetic determination of early puberty and adiposity. METHOD: Two groups of women randomly selected from the community on their responses to a mailed screening questionnaire on childhood sexual abuse (CSA) were interviewed in detail. Data about their childhood experiences, including age of menarche, were collected on two occasions, 6 years apart. Early menarche was defined as first menstruation occurring before the age of 12 years. RESULTS: Univariate analyses identified a number of adverse childhood experiences preceded early menarche, which was reported by 20.3% of this sample. These included low family socio-economic status, absence of father, a number of variables showing family conflict, poor relationships between the girl and either/both parents, a self-rated childhood personality style as a loner, childhood physical and sexual abuse. Sequential modelling showed parental rows, being a loner and the duration of CSA to be most important, although lack of a father and any CSA were each also independently associated with early menarche. No variables survived the modelling exercise as predictors of early menarche for those women who did not report childhood sexual abuse. CONCLUSIONS: The identified variables statistically interacted with each other in a highly complex manner. The attempt to rank their importance was only partially successful, for methodological reasons (half the sample reporting CSA). Chronic or protracted CSA needs to be added to the list of factors associated with early menarche in future studies.

Adult↗

PubMed1997

Magnetic resonance spectroscopy of isoflurane kinetics in humans. Part II: Functional localization.

We describe the first experiments to relate the cerebral kinetics of isoflurane (determined by fluorine magnetic resonance spectroscopy) to cerebral function. Using a surface receive coil we found two-compartment kinetics within the head with equilibrium half-times of 3.5 min and approximately 1 h with respect to expired isoflurane concentrations. Using critical fusion flicker frequency as an objective measure of the cerebral effect of isoflurane, we found evidence to identify the fast component as the brain. Responsiveness to command was lost at a brain partial pressure of 0.3% isoflurane. We conclude that the measured cerebral kinetics of isoflurane exactly matched the predictions of the classical perfusion-limited model.

Anesthetics, Inhalation↗

PubMed2002

Nuclear import of Upf3p is mediated by importin-alpha/-beta and export to the cytoplasm is required for a functional nonsense-mediated mRNA decay pathway in yeast.

Upf3p, which is required for nonsense-mediated mRNA decay (NMD) in yeast, is primarily cytoplasmic but accumulates inside the nucleus when UPF3 is overexpressed or when upf3 mutations prevent nuclear export. Upf3p physically interacts with Srp1p (importin-alpha). Upf3p fails to be imported into the nucleus in a temperature-sensitive srp1-31 strain, indicating that nuclear import is mediated by the importin-alpha/beta heterodimer. Nuclear export of Upf3p is mediated by a leucine-rich nuclear export sequence (NES-A), but export is not dependent on the Crm1p exportin. Mutations identified in NES-A prevent nuclear export and confer an Nmd(-) phenotype. The addition of a functional NES element to an export-defective upf(-) allele restores export and partially restores an Nmd(+) phenotype. Our findings support a model in which the movement of Upf3p between the nucleus and the cytoplasm is required for a fully functional NMD pathway. We also found that overexpression of Upf2p suppresses the Nmd(-) phenotype in mutant strains carrying nes-A alleles but has no effect on the localization of Upf3p. To explain these results, we suggest that the mutations in NES-A that impair nuclear export cause additional defects in the function of Upf3p that are not rectified by restoration of export alone.

Adaptor Proteins, Signal Transducing↗

PubMed2000

From tonus to tonicity: physiology of CLC chloride channels.

Chloride channels are involved in a multitude of physiologic processes ranging from basal cellular functions such as cell volume regulation and acidification of intracellular vesicles to more specialized mechanisms such as vectorial transepithelial transport and regulation of cellular excitability. This plethora of functions is accomplished by numerous functionally highly diverse chloride channels that are only partially identified at the molecular level. The CLC family of chloride channels comprises at present nine members in mammals that differ with respect to biophysical properties, cellular compartmentalization, and tissue distribution. Their common structural features include a predicted topology model with 10 to 12 transmembrane regions together with two C-terminal CBS domains. Loss of function mutations affecting three different members of the CLC channel family lead to three human inherited diseases : myotonia congenita, Dent's disease, and Bartter's syndrome. These diseases, together with the diabetes insipidus symptoms of a knockout mouse model, emphasize the physiologic relevance of this ion channel family.

Animals↗

PubMed2005

[PPARs as molecular targets for drug discovery].

Peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors. PPARs form the heterodimers with retinoid X receptors (RXRs), and modulate specific gene expressions related to the lipid and carbohydrate metabolism. Since fibrate-type lipid-lowering agents and thiazolidinedione (TZD)-type antidiabetic agents are identified as PPARalpha and gamma agonists, respectively, a number of ligands for PPARs have been developed, including PPAR subtype-selective and dual agonists. Recent report that RXR antagonist exhibited antidiabetic and antiobestic activities in animal model experiments, PPARs partial agonists, antagonists, and RXR antagonists have been also synthesized and their function in vivo are under investigations. In this paper, recent studies on the ligands for the PPAR-RXR heterodimers are reviewed.

Drug Design↗

PubMedDate not supplied

Parameter-free structure-property correlation via progressive reaction posets for substituted benzenes.

Progressive reaction networks as frequently arise in chemistry are naturally identifiable as "partially ordered sets" (or posets). Here the direction of the reaction identifies the partial ordering of the set of molecular species. The possibility that different properties are similarly ordered is a further natural consideration and is here investigated for a suite of over 30 properties for (methyl and chloro) substituted benzenes. Such a posetic correlation is favorably demonstrated for these substituted benzenes, and it is illustrated how suitable properties may be simply predicted in an interpolative parameter-free (albeit not model-free) fashion through the use of the reaction poset. Some numerical model-quality indicators are identified, and the simple approach is deemed quite reasonable.

Journal Article↗

PubMed2001

Caries incidence following restoration of shortened lower dental arches in a randomized controlled trial.

CONTEXT: Removable partial dentures used to restore the shortened lower dental arch may adversely affect the remaining natural teeth and are associated with a low prevalence of use. OBJECTIVE: To report the findings for caries incidence 2 years after restoration of lower shortened arches with bilateral cantilever resin-bonded bridges (RBBs) and conventional partial dentures (RPDs). DESIGN: Randomised controlled trial. SETTING: Secondary care PATIENTS: 25 male and 35 female subjects of median age 67 years. were randomly allocated to 'bridge' and 'denture' treatment groups of 30 patients each matched for age and sex. Caries incidence was recorded during dental examinations 3 months, 1 and 2 years after insertion of new lower prostheses. INTERVENTIONS: Cantilever RBBs and conventional RPDs with cast metal frameworks. RESULTS: There was a highly significant difference in the frequency of new caries lesions, 11 and 51 in the bridge and denture groups respectively (P < 0.01). 20 out of 27 bridge patients and 9 of 23 denture patients had no caries experience. Multivariate modeling identified treatment group as the only significant predictor of caries occurrence. CONCLUSIONS: Two years after restoration of lower shortened arches for an elderly sample of patients, there was a significantly greater incidence of new and recurrent caries lesions in subjects restored with RPDs compared with cantilever RBBs.

Adult↗