Area-Level Attributes and Esophageal Adenocarcinoma in Surveillance,Epidemiology and End Results Registries

Purpose

To examine the associations between area-level socioeconomic attributes and stage of esophageal adenocarcinoma diagnoses in 16 SEER cancer registries during 2000-2007.

Methods

Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression models to assess the relationship between distant-stage esophageal adenocarcinoma and individual, census tract, and county-level attributes.

Results

Among cases with data on birthplace, no significant association was seen between reported birth within versus outside the United States and distant-stage cancer (adjusted OR=1.02, 95% CI: 0.85-1.22). Living in an area with a higher percentage of residents born outside the United States than the national average was associated with distant-stage esophageal adenocarcinoma; census tract level: >11.8%, (OR=1.10, 95% CI:1.01–1.19), county level: >11.8%, (OR=1.14, 95% CI:1.05-1.24). No association was observed between median household income and distant-stage cancer at either census tract or county levels.

Conclusion

The finding of greater odds of distant-stage esophageal adenocarcinoma among cases residing in SEER areas with higher proportion of non-U.S. Natives suggests local areas where esophageal cancer control efforts might be focused. Missing data at the individual level was a limitation of the present study. Furthermore, inconsistent associations with foreign birth at individual- versus area-levels cautions against using area-level attributes as proxies for case attributes.     

Oxidative and Reductive Routes of Glycerol and Glucose Fermentation by Escherichia coli Batch Cultures and Their Regulation by Oxidizing and Reducing Reagents at Different pHs

Glycerol and glucose fermentation redox routes by Escherichia coli and their regulation by oxidizing and reducing reagents were investigated at different pHs. Cell growth was followed by decrease of pH and redox potential (E _h ). During glycerol utilization at pH 7.5 ?pH, the difference between initial and end pH, was lower compared with glucose fermentation. After 8 h growth, during glycerol utilization E _h dropped down to negative values (?150 mV) but during glucose fermentation it was positive (+50 mV). In case of glycerol H₂ was evolved at the middle log phase while during glucose fermentation H₂ was produced during early log phase. Furthermore, upon glycerol utilization, oxidizer potassium ferricyanide (1 mM) inhibited both cell growth and H₂ formation. Reducing reagents dl-dithiothreitol (3 mM) and dithionite (1 mM) inhibited growth but stimulated H₂ production. The findings point out the importance of reductive conditions for glycerol fermentation and H₂ production by E. coli.     

Kinetics of adsorption of extended ligands on DNA at small fillings

In the present work, the adsorption kinetics of extended ligands on DNA duplexes at small fillings when molecules of DNA duplexes are on the underlayer within diffusion layer has been investigated. Both diffusion of ligands in solution (diffusion stage) and adsorption of ligands (kinetic stage) are taken into consideration at adsorption of ligands on DNA duplexes. Nonlinear system of differential equations describing adsorption of ligands where not only diffusion stage but also kinetic stage is taken into account, is obtained, moreover the equations allow localizing duplexes in arbitrary place within diffusion layer. Numeric solution of the equations makes possible to investigate the filling kinetics of DNA duplexes by ligands depending on parameters controlling adsorption process. It has been shown that depending on relation between adsorption parameters different kinetic regimes of adsorption – kinetic, complex, and diffusion regimes may be realized.     

92 Novel interpretation of the isotherms of multimodal ligands binding with DNA

The binding of ligands with DNA is a key moment in a whole range of cellular processes that provide not only the normal cell vital activity but also the development of some pathological processes. Depending on ligand type, structure of DNA adsorption centers, and physical–chemical conditions of the surrounding, the ligand may bind to DNA by several modes [1]. Particularly, adsorption isotherm of multimodal ligands binding to DNA in Scatchard’s coordinates has a concave shape with two brightly expressed linear areas in the region of small fillings. The analysis of such type of adsorption isotherm for determining of important binding parameters such as binding constant and number of adsorption centers (the part of DNA polymer with which one ligand molecule binds) presents difficulties. Practically in all cases, the analysis of such adsorption isotherm is carried out by linear parts of curves. Such analysis mode of experimental points is approximate method, since all registered of experimental points are roughly divided into two groups and they are treated by linear binding isotherm and therefore the binding parameters are determined. In the present work, the non-linear adsorption isotherm in Scatchard‘s coordinates is obtained which allowed, provided, the more precise treatment of all experimental points by unique curve which includes linear regions as well. Such mode of treatment of experimental points makes more precise the determination of not only binding constant and number of adsorption centers that correspond to the one ligand molecule binding, but also additional binding parameter – a proportion of adsorption centers of each binding to DNA type of multimodal ligand.     

Simulation and qualitative analysis of glucose variability,mean glucose,and hypoglycemia after subcutaneous insulin therapy for stress hyperglycemia

Background

The critically ill can have persistent dysglycemia during the “subacute” recovery phase of their illness because of altered gene expression; it is also not uncommon for these patients to receive continuous enteral nutrition during this time. The optimal short-acting subcutaneous insulin therapy that should be used in this clinical scenario, however, is unknown. Our aim was to conduct a qualitative numerical study of the glucose-insulin dynamics within this patient population to answer the above question. This analysis may help clinicians design a relevant clinical trial.

Methods

Eight virtual patients with stress hyperglycemia were simulated by means of a mathematical model. Each virtual patient had a different combination of insulin resistance and insulin deficiency that defined their unique stress hyperglycemia state; the rate of gluconeogenesis was also doubled. The patients received 25 injections of subcutaneous regular or Lispro insulin (0-6 U) with 3 rates of continuous nutrition. The main outcome measurements were the change in mean glucose concentration, the change in glucose variability, and hypoglycemic episodes. These end points were interpreted by how the ultradian oscillations of glucose concentration were affected by each insulin preparation.

Results

Subcutaneous regular insulin lowered both mean glucose concentrations and glucose variability in a linear fashion. No hypoglycemic episodes were noted. Although subcutaneous Lispro insulin lowered mean glucose concentrations, glucose variability increased in a nonlinear fashion. In patients with high insulin resistance and nutrition at goal, “rebound hyperglycemia” was noted after the insulin analog was rapidly metabolized. When the nutritional source was removed, hypoglycemia tended to occur at higher Lispro insulin doses. Finally, patients with severe insulin resistance seemed the most sensitive to insulin concentration changes.

Conclusions

Subcutaneous regular insulin consistently lowered mean glucose concentrations and glucose variability; its linear dose-response curve rendered the preparation better suited for a sliding-scale protocol. The longer duration of action of subcutaneous regular insulin resulted in better glycemic-control metrics for patients who were continuously postprandial. Clinical trials are needed to examine whether these numerical results represent the glucose-insulin dynamics that occur in intensive care units; if present, their clinical effects should be evaluated.

     

TGF-beta mediated Msx2 expression controls occipital somites-derived caudal region of skull development

Craniofacial development involves cranial neural crest (CNC) and mesoderm-derived cells. TGF-beta signaling plays a critical role in instructing CNC cells to form the craniofacial skeleton. However, it is not known how TGF-beta signaling regulates the fate of mesoderm-derived cells during craniofacial development. In this study, we show that occipital somites contribute to the caudal region of mammalian skull development. Conditional inactivation of Tgfbr2 in mesoderm-derived cells results in defects of the supraoccipital bone with meningoencephalocele and discontinuity of the neural arch of the C1 vertebra. At the cellular level, loss of TGF-beta signaling causes decreased chondrocyte proliferation and premature differentiation of cartilage to bone. Expression of Msx2, a critical factor in the formation of the dorsoventral axis, is diminished in the Tgfbr2 mutant. Significantly, overexpression of Msx2 in Myf5-Cre;Tgfbr2flox/flox mice partially rescues supraoccipital bone development. These results suggest that the TGF-beta/Msx2 signaling cascade is critical for development of the caudal region of the skull.     

Inventing the dynamo machine: the evolution of the F-type and V-type ATPases

The rotary proton- and sodium-translocating ATPases are reversible molecular machines present in all cellular life forms that couple ion movement across membranes with ATP hydrolysis or synthesis. Sequence and structural comparisons of F- and V-type ATPases have revealed homology between their catalytic and membrane subunits, but not between the subunits of the central stalk that connects the catalytic and membrane components. Based on this pattern of homology, we propose that these ATPases originated from membrane protein translocases, which, themselves, evolved from RNA translocases. We suggest that in these ancestral translocases, the position of the central stalk was occupied by the translocated polymer.     

Libraries from natural product-like scaffolds

Natural products are an attractive source of varied structures that exhibit potent biological activities, and desirable pharmacological profiles. Since the relatively recent advent of high-throughput organic synthesis in the drug discovery process, several design approaches have been applied to the construction of screening libraries. Libraries of natural-product derivatives, natural-product-like compounds prepared by total synthesis, and libraries derived from natural-products are several types that have been reported.     

Formate increases the F0F1-ATPase activity in Escherichia coli growing on glucose under anaerobic conditions at slightly alkaline pH

Escherichia coli growing on glucose under anaerobic conditions at slightly alkaline pH carries out a mixed-acid fermentation resulting in the production of formate among the other products that can be excreted or further oxidized to H(2) and CO(2). H(2) production is largely dependent on formate dehydrogenase H and hydrogenases 3 and 4 constituting two formate hydrogen lyases, and on the F(0)F(1)-ATPase. In this study, it has been shown that formate markedly increased ATPase activity in membrane vesicles. This activity was significantly (1.8-fold) stimulated by 100mM K(+) and inhibited by N,N(')-dicyclohexylcarbodiimide and sodium azide. The increase in ATPase activity was absent in atp, trkA, and hyf but not in hyc mutants. ATPase activity was also markedly increased by formate when bacteria were fermenting glucose with external formate (30mM) in the growth medium. However this activity was not stimulated by K(+) and absent in atp and hyc but not in hyf mutants. The effects of formate on ATPase activity disappeared when cells were performing anaerobic (nitrate/nitrite) or aerobic respiration. These results suggest that the F(0)F(1)-ATPase activity is dependent on K(+) uptake TrkA system and hydrogenase 4, and on hydrogenase 3 when cells are fermenting glucose in the absence and presence of external formate, respectively.     

Generation of highly selective VPAC2 receptor agonists by high throughput mutagenesis of vasoactive intestinal peptide and pituitary adenylate cyclase-activating peptide

Pituitary adenylate cyclase-activating peptide (PACAP) has a specific receptor PAC1 and shares two receptors VPAC1 and VPAC2 with vasoactive intestinal peptide (VIP). VPAC2 activation enhances glucose-induced insulin release while VPAC1 activation elevates glucose output. To generate a large pool of VPAC2 selective agonists for the treatment of type 2 diabetes, structure-activity relationship studies were performed on PACAP, VIP, and a VPAC2 selective VIP analog. Chemical modifications on this analog that prevent recombinant expression were sequentially removed to show that a recombinant peptide would retain VPAC2 selectivity. An efficient recombinant expression system was then developed to produce and screen hundreds of mutant peptides. The 11 mutations found on the VIP analog were systematically replaced with VIP or PACAP sequences. Three of these mutations, V19A, L27K, and N28K, were sufficient to provide most of the VPAC2 selectivity. C-terminal extension with the KRY sequence from PACAP38 led to potent VPAC2 agonists with improved selectivity (100-1000-fold). Saturation mutagenesis at positions 19, 27, 29, and 30 of VIP and charge-scanning mutagenesis of PACAP27 generated additional VPAC2 selective agonists. We have generated the first set of recombinant VPAC2 selective agonists described, which exhibit activity profiles that suggest therapeutic utility in the treatment of diabetes.