HIFs,angiogenesis, and cancer

Tumor hypoxia was first described in the 1950s by radiation oncologists as a frequent cause of failure to radiotherapy in solid tumors. Today, it is evident that tumor hypoxia is a common feature of many cancers and the master regulator of hypoxia, hypoxia‐inducible factor‐1 (HIF‐1), regulates multiple aspects of tumorigenesis, including angiogenesis, proliferation, metabolism, metastasis, differentiation, and response to radiation therapy. Although the tumor hypoxia response mechanism leads to a multitude of downstream effects, it is angiogenesis that is most crucial and also most susceptible to molecular manipulation. The delineation of molecular mechanisms of angiogenesis has revealed a critical role for HIF‐1 in the regulation of angiogenic growth factors. In this article, we review what has been described about HIF‐1: its structure, its regulation, and its implication for cancer therapy and we focus on its role in angiogenesis and cancer. J. Cell. Biochem. 114: 967–974, 2013. © 2012 Wiley Periodicals, Inc.     

Stereocontrolled synthesis of 1-acetylen-2,3-di-o-benzyl-tetrahydrofurans, 1,4-anhydro-arabinitol,and alpha,beta-dihydroxy-gamma-alkyl-butyrolactones

This article describes a concise and efficient synthesis of 1-acetylen-2,3-di-O-benzyl-tetrahydrofurans from tartaric acid esters using as the key step the stereocontrolled cyclization of Co(2)(CO)(6)-complexed propargylic diols. This molecule led to enantiomerically pure 1,4-anhydro-arabinitol and alpha,beta-dihydroxy-gamma-alkyl-butyrolactones. In the latter case, the critical methylene oxidation at the oxygen vicinal position was performed by RuO(4).     

2,2',4-trihydroxybenzophenone: crystal structure, and anti-inflammatory and antioxidant activities

The crystal structure of '2,2',4-trihydroxybenzophenone' (=(2,4-dihydroxyphenyl)(2-hydroxyphenyl)methanone; 1) was determined, and its molecular structure, along with intra- and intermolecular H-bonds, was analyzed. The anti-inflammatory potential of 1, evaluated by means of the rat-paw-edema assay, with carrageenan as inflammation stimulus, was found to be similar high as that of indomethacin. In contrast, benzophenone proper (2) was hardly active in this assay. Our results indicate that these anti-inflammatory effects are related to the action of kinins and prostaglandins. The radical-scavenging properties of 1 towards DPPH were found to be similar as those of typical phenolics, but somewhat lower than that of ascorbic acid. The structure-activity relationship (SAR) of 1 is discussed.     

Kin selection, local competition, and reproductive skew

In a spatially structured population, limited dispersal gives rise to local relatedness, potentially favoring indiscriminate helping behavior. However, it also leads to local competition, which reduces the benefits of helping local kin. This tension has become the focus for a growing body of theoretical work. Existing models, however, have focused chiefly on the net impact of limited dispersal on cooperative or competitive effort in a homogeneous population. Here, I extend existing models of kin selection in a group-structured population to allow for asymmetries in expected fecundity and reproductive success among group members. I explore the consequent impact of limited dispersal on the evolution of helping and harming behavior, and on the degree of reproductive inequality or skew. I show that when individuals in a group differ in their expected fecundity, limited dispersal gives rise to kin selection for harming behavior on the part of more fecund individuals, and for helping behavior on the part of less fecund individuals. As a result, philopatry tends to exaggerate differences in reproductive success, and so promotes greater reproductive skew.     

Standard of Care,Professional Obligations,and Distributive Justice

The problem of standard‐of‐care in clinical research concerns the level of care that investigators ought to provide to research subjects in the control arm of their clinical trials. Commentators differ sharply on whether subjects in trials conducted in lower income countries should be provided with the same level of care as subjects in trials conducted in higher income countries. I consider an argument that commentators have employed on both sides of this debate: professional role arguments. These arguments claim to justify a conclusion to the standard‐of‐care problem solely by appeal to the professional obligations that investigators possess. I argue that prominent versions of professional role arguments cannot justify a solution to the problem of standard‐of‐care that is both determinate and reasonable simply by appeal to the professional obligations of investigators. Instead, to do so, one must also (1) determine the level of care or types of treatment that individuals are entitled to as a matter of distributive justice, and (2) identify which agents possess the duties that correspond to these entitlements. The level of care that investigators owe to subjects in the control arm of their clinical trials is thus in part dependent on the level of care that these subjects are entitled to as a matter of distributive justice, and whether it is the investigators who possess the corresponding distributive obligation to provide them with the care that they are entitled to.     

Female sex pheromone of a nettle caterpillar,Monema flavescens,in China

Monema flavescens Walker (Lepidoptera: Limacodidae) is a multivoltine, generalist moth whose larvae cause serious damage to many types of trees. Pheromone lures prepared according to a study of a Japanese population were found to be ineffective at attracting M. flavescens nettle caterpillars in China, and some studies have shown intraspecific geographical differences in the composition of sex pheromones. We therefore reexamined the sex pheromone composition of M. flavescens in a Chinese population. In this study, the electroantennographically (EAG) active compounds in an extract from Chinese virgin females of M. flavescens were identified as (E)‐8‐decen‐1‐ol (E8‐10:OH), (Z)‐7,9‐decadien‐1‐ol (Z7,9‐10:OH), (Z)‐9,11‐dodecadien‐1‐ol (Z9,11‐12:OH), and (Z)‐9,11‐dodecadienal (Z9,11‐12:Ald) via coupled gas chromatographic‐electroantennographic detection (GC‐EAD) and coupled GC‐mass spectrometry (MS). Pheromone dimorphism might occur in this species, as this mixture of compounds in Chinese females was different from that of E8‐10:OH and E7,9‐10:OH extracted from Japanese females in previous research. In wind tunnel and field tests, the males were significantly attracted to a blend of the pheromone components E8‐10:OH, Z7,9‐10:OH, and Z9,11‐12:OH in a 100:5:4 ratio. The addition of Z9,11‐12:Ald did not change the male response. The optimized three‐component lure blend may provide a useful tool for monitoring and controlling Chinese populations of M. flavescens.     

Wing shape,wing size,and sexual dimorphism in eye‐span in stalk‐eyed flies (Diopsidae)

The eyes of stalk‐eyed flies (Diopsidae) are positioned at the end of rigid peduncles (‘stalks’) protruding laterally from the head. Eye‐stalk length varies within the family and, in some species, varies between males and females. Larger eye‐stalks in males result from sexual selection for longer stalks, a trait that increases male reproductive success. In the present study, we examined whether an increase in eye‐stalk length results in an adjustment of wing size and shape to deal with the burden of bearing an exaggerated ‘ornament’. We compared wing morphology among ten species of stalk‐eyed flies that differ in eye‐span and the degree of sexual dimorphism. Mass‐specific wing length differed between males and females in seven out of the ten species. Nondimensional wing shape parameters differed between the species (P < 0.001), but mostly did not differ between males and females of the same species. Dimorphism in eye‐span closely correlated with dimorphism in wing length (r = 0.89, P < 0.001) and the correlation remained significant (r = 0.81, P = 0.006) after correcting for phylogenetic relationships. Once corrected for phylogenetic relatedness, the mass‐specific wing length of males (but not females) was weakly correlated with mass‐specific eye‐span (r = 0.66, P = 0.042). We propose that the observed proportional increase in wing length associated with increased eye‐span can facilitate aerial manoeuverability, which would otherwise be handicapped by the elevated moment of inertia imposed by the wider head. © 2009 The Linnean Society of London, Biological Journal of the Linnean Society, 2009, 98 , 860–871.     

Crystal-state 3D-structural characterization of novel, Aib-based, turn and helical peptides.

The crystal-state conformations of the hexapeptide amide Pht-(Aib)(6)-NH-C(CH(3))(2)-O-OtBu (7), the hexapeptide Ac-L-aIle-(Aib)(5)-OtBu (6), the pentapeptide Z-(Aib)(3)-L-Glu(OtBu)-Aib-O-(CH(2))(2)-(1)Nap (5), the tetrapeptides Z-(Aib)(2)-L-His(N(tau)-Trt)-Aib-OMe (4 I) and Z-(Aib)(2)-L-Nva-Aib-OtBu (4 II), the tripeptide Pyr-(Aib)(3)-OtBu (3 I), the dipeptide amides Pyr-(Aib)(2)-(4)NH-TEMPO (3 II) and Piv-(Aib)(2)-NH-C(CH(3))(2)-O-OtBu (3 III), and the dipeptides Pht-Aib-betaAc(6)c-OtBu (2 I), Pht-Aib-NH-C(CH(3))(2)-O-OtBu (2 II) and Boc-gGly-mAib-OH (2 III) have been determined by X-ray diffraction analyses. All peptides investigated are characterized by one or more turn/helix forming Aib residues. Except the three short dipeptides, all are folded into C==O...H--N intramolecularly H-bonded 3(10)-helices, or into various types of beta-turns. In the structure of 6, two independent molecules of opposite screw sense were observed in the asymmetric unit, generating diastereomeric 3(10)-helices.     

The N- and C-termini of the human Nogo molecules are intrinsically unstructured: bioinformatics, CD, NMR characterization, and functional implications

RTN4 or Nogo proteins are composed of three alternative splice forms, namely 1192-residue Nogo-A, 373-residue Nogo-B, and 199-residue Nogo-C. Nogo proteins have received intense attentions because they have been implicated in a variety of critical cellular processes including CNS neuronal regeneration, vascular remodeling, apoptosis, interaction with beta-amyloid protein converting enzyme, and generation/maintenance of the tubular network of the endoplasmic reticulum (ER). Despite their significantly-different N-terminal lengths, they share a conserved C-terminal reticulon-homology domain consisting of two transmembrane fragments, a 66-residue extracellular loop Nogo-66 and a 38-residue C-tail carrying ER retention motif. Nogo-A owns the largest N-terminus with 1016 residues while the Nogo-B has an N-terminus almost identical to the first 200 residues of Nogo-A. So far, except for our previous determination of the Nogo-66 solution structure, no structural characterization of the other Nogo regions has been reported. In the present study, we initiated a systematically investigation of structural properties of Nogo molecules by a combined use of bioinformatics, CD, and NMR spectroscopy. The results led to two striking findings: (1) in agreement with bioinformatics prediction, the N- and C-termini of Nogo-B were experimentally demonstrated to be intrinsically unstructured by CD, two-dimensional 1H 15N NMR HSQC, hydrogen exchange, and 15N heteronuclear NOE characterization. (2) Further studies showed that the 1016-residue N-terminus of Nogo-A was again highly disordered. Therefore, it appears that being intrinsically-unstructured allows Nogo molecules to serve as double-faceted functional players, with one set of functions involved in cellular signaling processes essential for CNS neuronal regeneration, vascular remodeling, apoptosis and so forth and with another in generating/maintaining membrane-related structures. We propose that this mechanism may represent a general strategy to place the formation/maintenance of membrane-related structures under the direct regulation of the cellular signaling.     

G-estimation and artificial censoring: problems, challenges, and applications

In principle, G-estimation is an attractive approach for dealing with confounding by variables affected by treatment. It has rarely been applied for estimation of the effects of treatment on failure-time outcomes. Part of this is due to artificial censoring, an analytic device which considers some subjects who actually were observed to fail as if they were censored. Artificial censoring leads to a lack of smoothness in the estimating function, which can pose problems in variance estimation and in optimization. It also can lead to failure to have solutions to the usual estimating functions, which then raises questions about the appropriate criteria for optimization. To improve performance of the optimization procedures, we consider approaches for reducing the amount of artificial censoring, propose the substitution of smooth for indicator functions, and propose the use of estimating functions scaled to a measure of the information in the data; we evaluate performance of these approaches using simulation. We also consider appropriate optimization criteria in the presence of information loss due to artificial censoring. We motivate and illustrate our approaches using observational data on the effect of erythropoietin on mortality among subjects on hemodialysis.     

AL3810, a multi-tyrosine kinase inhibitor, exhibits potent anti-angiogenic and anti-tumour activity via targeting VEGFR, FGFR and PDGFR

Angiogenesis plays an important role in neoplastic transformation and progression as well as in the metastasis process of most human cancers. Herein, we identified AL3810 as a novel and orally bioavailable small molecular inhibitor with potent inhibitory activity against multiple tyrosine kinases involved in the process of angiogenesis. We found that AL3810 substantially inhibited the autophosphorylation of VEGFR2, PDGFRβ and FGFR1 in endothelial cells. Moreover, AL3810 exhibited potent anti-angiogenesis activity, manifested by significant inhibition of microvessel outgrowth of rat arterial ring and chickallantochorion membrane (CAM) in ex vivo angiogenesis models. Daily dosing of AL3810 has shown broad-spectrum anti-tumour activity in human kidney, pancreas, liver cancer xenograft models. Importantly, immunohistochemistry results demonstrated that the anti-tumour activity of AL3810 was closely correlated with its anti-angiogenesis activity, as demonstrated by a decreased microvessel area and reduced microvessel numbers in tumour tissues. The overall pharmacological profiles of AL3810 are superior to sorafenib. The clinical trials of AL3810 will soon be launched in China.     

Effects of the compounds 2-methoxynaphthoquinone, 2-propoxynaphthoquinone, and 2-isopropoxynaphthoquinone on ecdysone 20-monooxygenase activity

The effects of the natural compound 2-methoxy-1,4-naphthoquinone, isolated from the leaves of Impatiens glandulifera and the synthetic compounds 2-propoxy-1,4-naphthoquinone and 2-isopropoxy-1,4-naphthoquinone on ecdysone 20-monooxygenase (E-20-M) activity were examined in three insect species. Homogenates of wandering stage third instar larvae of Drosophila melanogaster, or abdomens from adult female Aedes aegypti, or fat body or midgut from fifth instar larvae of Manduca sexta were incubated with radiolabelled ecdysone and increasing concentrations (from 1 x 10(-8) to 1 x 10(-3) M) of the three compounds. All three compounds were found to inhibit in a dose-dependent fashion the E-20-M activity in the three insect species. The concentration of these compounds required to elicit a 50% inhibition of this steroid hydroxylase activity in the three insect species examined ranged from approximately 3 x 10(-5) to 7 x 10(-4) M.     

Cloning, expression, and localization of a molt-related beta-N-acetylglucosaminidase in the spruce budworm, Choristoneura fumiferana

A beta-N-acetylglucosaminidase cDNA (CfGlcNAcase) was cloned from the spruce budworm, Choristoneura fumiferana. Western blotting analysis of developmental CfGlcNAcase expression revealed high levels of expression of the gene on the last day of the 5th instar larvae and the first day in the 6th instar larvae, followed by a decrease to background levels during the intermolt of the 6th instar. CfGlcNAcase was detected again from the last day of the 6th instar to day 2 of pupal stage. CfGlcNAcase expression was induced by tebufenozide at 24 h post treatment and remained at high levels until 72 h. Immunohistochemical localization analysis of CfGlcNAcase indicated that CfGlcNAcase was present in the molting fluid, epidermis, trachea, and hemolymph in prepupae during the transformation from larva to pupa. CfGlcNAcase cDNA was expressed into a recombinant protein in bacterial and baculovirus systems and the protein expressed in the baculovirus system had a higher chitinolytic activity than in the bacterial system and appeared to be secreted.     

Self-injurious behavior in rhesus monkeys: new insights into its etiology,physiology, and treatment

Self-injurious behavior (SIB) is a significant human health problem frequently associated with profound intellectual disabilities, genetic diseases, and psychiatric conditions. However, it also occurs in subclinical populations and appears to be on the rise in adolescents and young adults. SIB is also seen in a small percentage of nonhuman primates that injure themselves through biting. We have begun to characterize SIB in rhesus monkeys to identify some of the risk factors associated with this disorder, and to determine the parallels with the human condition. In our study population, 14% of individually housed monkeys (the vast majority of which are males) have a veterinary record for self-inflicted wounding. Wounding is rare, but self-directed biting is common. SIB can be elicited during aggressive altercations and may be associated with husbandry events. Some monkeys appear to be more vulnerable to acquiring SIB. This increased vulnerability is associated with certain social experiences in the first 2 years of life and with exposure to a larger number of moderately stressful events as compared to controls. Monkeys with SIB also have a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, indicated by a blunted cortisol response to mild stressors. Our findings suggest that SIB may be a coping strategy to reduce arousal. Biting appears to rapidly lower an escalating heart rate. The potentially reinforcing effects of SIB may account for the failure of some treatment regimens. These findings are compared to studies of SIB in humans, and concordances are identified.