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Supplementary Fig. S3 from Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor

Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species. [Mol Cancer Ther 2008;7(7):1880–9]

Supplementary Table 1 from PF00299804, an Irreversible Pan-ERBB Inhibitor, Is Effective in Lung Cancer Models with EGFR and ERBB2 Mutations that Are Resistant to Gefitinib

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective treatments for a subset of non–small cell lung cancers. In particular, cancers with specific EGFR-activating mutations seem to be the most sensitive to these agents. However, despite their initial response, such cancers almost invariably develop resistance. In 50% of such cancers, a secondary EGFR mutation, T790M, has been identified that renders gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity. Thus, there is a clinical need to develop novel EGFR inhibitors that can effectively inactivate T790M-containing EGFR proteins. In this study, we evaluate the effectiveness of a novel compound, PF00299804, an irreversible pan-ERBB inhibitor. The results from these studies show that PF00299804 is a potent inhibitor of EGFR-activating mutations as well as the EGFR T790M resistance mutation both in vitro and in vivo. Additionally, PF00299804 is a highly effective inhibitor of both the wild-type ERBB2 and the gefitinib-resistant oncogenic ERBB2 mutation identified in lung cancers. These preclinical evaluations support further clinical development of PF00299804 for cancers with mutations and/or amplifications of ERBB family members. [Cancer Res 2007;67(24):11924–32]

The fields of positive psychology (PP) and the psychology of religion/spirituality (PRS) have much in common, both in terms of their areas of interest and the presuppositions they bring to their work. For example, PP and PRS are both rooted in the philosophies of positivism (which assumes all knowledge must be empirically verified using the scientific method) and naturalism (which assumes there are no realities beyond the natural, material world). Both PP and PRS have much to offer society and the scientific community, but their historic roots in positivistic naturalism currently limit this potential, both in terms of concepts and methods. In this chapter, we argue that for PP and the PRS to coevolve and flourish, they must transcend their perhaps often unaware—but staunch—commitment to positivistic naturalism. In particular, the fields of PP and PRS need to draw inclusively and meaningfully from the methodological, conceptual, and experiential insights of philosophical and religious traditions. Doing so will help PP and PRS broaden the scope of what they each consider meaningful, possible, desirable, and transformative. Ironically, a greater appreciation of the past will enable both fields to have greater scientific, societal, and practical impact in the future.

I use the Fama and French (2015) five-factor model to reexamine the seemingly anomalous result of Nelson, Moffitt, and Affleck-Graves (2005), who document significant positive abnormal returns for firms that hedge. Contrary to their results, using the five-factor model on a new sample of U.S. firms from 2013 – 2021, I observe significant negative monthly abnormal returns of -0.190% (-2.26% annually) for firms using derivative securities (hedgers). My result is consistent with poorly diversified managers engaging in costly hedging behavior that benefits management at the cost of shareholders. When I divide the sample by size (total assets), I find that the significant negative abnormal returns are confined only to large firms, offering no support for the economies of scale or managerial sophistication hypotheses.

Purpose Prior research suggests that institutional investors prefer higher priced stock, while individual investors prefer lower priced stock. The purpose of this paper is to examine whether the IPO filing price reflects firm characteristics that are commonly associated with quality, including size, age, earnings, underwriter reputation and venture capital backing. Design/methodology/approach The authors used t-tests, Wilcoxon rank sum tests, logistic and ordinary least squares regressions to test the hypotheses. Findings The authors find that IPO filing prices are positively related to measures of quality, except venture backing, which impacts prices non-linearly. Ceteris paribus, small (large) venture backed firms’ filing prices are set significantly lower (higher). Research limitations/implications Firm managers set IPO filing prices high when they believe the firm is likely to attract institutional investors due to its size, quality and certification, and will set prices low otherwise. Practical implications Individual investors should be wary of IPO firms with lower prices. Managers should be cognizant of the positive relationship between IPO quality and price. Originality/value This study provides evidence that IPO prices reflect firm quality and may be set deliberately to attract individual investors when institutional investor demand is expected to be low. It also provides evidence that venture backing affects IPO prices non-linearly, consistent with the grandstanding hypothesis.

Polyphosphazenes form one of the most diverse classes of macromolecules. They have a backbone of alternating phosphorus and nitrogen atoms and bear two organic or organometallic side groups linked to each phosphorus. Most of the known examples are prepared via the replacement of chlorine atoms in the macromolecular intermediate (NPCl2)n by the use of organic or organometallic nucleophiles. The different polymers generated by the introduction of various side groups span the range of properties from elastomers to glasses, and from hydrogels to bioerodible polymers. Uses are being developed in biomedicine, aerospace technology, fire-resistance, fuel cell membranes, and in solid polymer electrolyte batteries. However, until recently, the only access route to (NPCl2)n was via the thermal ring-opening polymerization of the cyclic trimer, (NPCl2)3, which yields polymers with broad molecular weight distributions, and little or no means for molecular weight control or access to block copolymers. A new method for the synthesis of polyphosphazenes is described here. It involves the room-temperature, living cationic condensation polymerization of Me3SiN=PCl3 catalyzed by PCl5, which gives (NPCl2)n with precise molecular weight control and access via living mechanisms to block copolymers, stars, and telechelic systems. The recent synthesis of phosphazene-organic block copolymers by these methods is a major advance toward the commercialization of polyphosphazenes. The impact of these developments on the properties and uses of polyphosphazenes is also mentioned.

An enduring feature of Christian religious life has been the experience of the demonic. This experience can be found in the New Testament, most obviously in reported encounters with demons, but more centrally in the language of spiritual warfare that pervades much of the Pauline literature. In the Patristic period, these ideas were cemented in the Christian tradition in the writings of the Desert Fathers. A phenomenological understanding of experience holds that percepts have qualities that are inherently given as part of the experience, and that these qualities can be observed through the use of phenomenological concepts. An examination of the writings of the Desert Fathers suggests that one inherent quality of some religious experiences is their externality. Thoughts or feelings within the person are perceived as having an external source, and external threats can take on an embodied quality in perception, as in visions of demonic beings. These experiences have their initial constitution in an Otherness centered in the body. On reflection, it is not surprising that we would find a quality of externality in religious experience. Religion and spirituality deal with our relationship to the broader world around us. Recent phenomenological writings by Levinas and Marion have begun to recover the importance of externality, however, they neglect aspects of demonic experiences such as their negative valence. Critics of the demonic have tried hard to expel the idea from Western consciousness, pointing to tragic experiences in early modern history and the apparent need to posit the existence of immaterial entities. However, a careful phenomenological and historical analysis casts serious doubt on this modernist picture. The abandonment of the demonic in much of Christian religious thought and practice carries negative consequences, as it invalidates the external quality of many difficult religious experiences. A recovery of the concept of the demonic would help us better understand the phenomenology of religious life.

Positive psychology offers two visions for human life: a hedonic path that focuses on the seeking of pleasure and happiness, and a eudaimonic journey that involves the development of virtues conducive to a good life. Early Christian thought offers a sophisticated critique of the strengths and weaknesses of these visions because it responded to similar ideas that were present in classical philosophical systems like Stoicism. Early Christian writers rejected hedonic understandings of human flourishing (as did most people in the classical period) and approved of a focus on virtue as necessary to a good life. They also would join with positive psychologists and criticize a narrowly medical model view of mental health. However, there are also important differences between early Christian thought and eudaimonic positive psychology. Early Christian authors had a different understanding of virtue as holistic and relational, in contrast to the more fragmented and individualistic picture of virtue and healt...

The poly(ferrocenylethylene)s [Fe(η-C5H3RCH2)2](n) 5a and 5b (a: R = H, b: R = Me) have been prepared by thermal ring-opening polymerization of the corresponding strained hydrocarbon-bridged [2]ferrocenophanes [Fe(η-C5-H3RCH2)2] (4a and 4b). An X-ray diffraction study of 4a indicated significant strain. Polymer 5a was crystalline and insoluble in common organic solvents and was characterized by solid-state 13C NMR. Polymer 5b, which was soluble in organic solvents, was characterized by 1H and 13C NMR. UV/visible spectroscopy and elemental analysis. Its molecular weight distribution was bimodal (gel permeation chromatography: M(w) = 9.6 x 104, M(n) = 8.6 x 104 for the high molecular weight fraction. M(w) = 4.8 x 103, M(n) = 3.5 x 103 for the oligomeric fraction), suggesting two polymerization mechanisms. The UV/visible spectrum implied a localized structure for the polymer backbone. Cyclic voltammetry revealed that 5b undergoes two reversible oxidations in CH2Cl2 solution at -0.25 and -0.16 V. The redox coupling is indicative of only a small degree of interaction between the iron centres. Thermogravimetric analysis indicated that 5a and 5b are thermally stable to ca. 300-350°C under N2. At higher temperatures they yield ferromagnetic iron carbide ceramics 6a and 6b (ca. 50% and 32%, respectively, at 600°C) together with molecular depolymerization products. The reaction of 5b with tetracyanoethylene (TCNE) yielded insoluble and soluble oxidized products 11 and 12, which differed in the degree of oligomerization of the TCNE(x)/(y-) counterions. These products were characterized by IR, elemental analysis, ESR spectroscopy, and magnetic susceptibility measurements. The last revealed the presence of significant antiferromagnetic interactions in 12.

In contemporary scholarship, the psychology of religion involves the scientific study of religious life. Traditionally, psychologists have pursued a strikingly individualistic approach to their study of the topic, which seems at odds with the emphasis on groups or society in most definitions of religion. What would happen if we took this relational aspect of religion seriously? The paper investigates the question by asking (1) how might the underlying philosophy of science for the field differ if we took a more relational approach to the topic, and (2) how might our altered assumptions affect the scientific study of religion in psychology. The result is a modest proposal for a community-oriented psychology of religion that embraces a greater diversity of methods and a sharper emphasis on goals that will be directly beneficial to the people we study.

The study of religion in Western psychology has an interesting history that provides many lessons for future attempts to understand the spiritual aspects of human experience. In the past, psychologists have typically operated from one of three paradigms in their study of religion: (1) hermeneutic–phenomenological, (2) positivistic naturalism, and (3) religious integration. Each of these paradigms has a number of important theoretical assumptions and a preferred set of methodologies that offer significant advantages and disadvantages. The paradigm of positivistic naturalism, with its emphasis on quantitative questionnaire methodology, has been the most influential but also the least helpful in generating new ideas for the psychological understanding of religion, particularly as it is practiced in non-Western contexts. A historical survey of the other competing paradigms offers many insights and practical suggestions about how research in the psychology of religion might proceed in the twenty-first century.

History is a central part of any academic discipline, as how scholars write and think about the history of their field helps define its identity. This paper presents an overview of the key issues involved in writing histories of the psychology of religion, particularly as these issues appear in the Chinese context. Attention to these issues will help Chinese scholars write rich histories of their field that acknowledge their connection to Western research while appreciating the powerful distinctive characteristics of the Chinese situation. The paper provides a number of practical suggestions that may help Chinese researchers in this process.

In the Middle Ages, studies of the natural world, human behavior and theology were part of an interwoven body of knowledge. However, in modern times an increasing divide has separated science and religion. A careful review suggests that currents and accidents in intellectual and social history have served to unnecessarily foreclose lines of thought that might lead to rapprochement of religion with science, including psychology. Developments in Western views of epistemology and the philosophy of science have been a major factor in this estrangement. In the early modern period, flexible views of science (e.g. Bacon) were replaced by doctrinaire formulations emphasizing quantitative methodologies. Especially important was the development of positivism, which opened the door to a reductionistic naturalism that intended not only to reduce dialogue with religion but also to replace it with science. Within psychology, Freud and other early psychologists were eager to establish psychology as a "real" science and enthusiastically embraced the positivist perspective and rejected possible alternatives. Although this positivist approach is philosophically untenable, it continues to dominate psychology and obstruct dialogue between science and religion as well as progress in psychology as a whole. A return to a broader and more modest conception of science is warranted. ********** For many years, a number of scientific fields including psychology have taken an ambivalent or even hostile stance toward religion, especially Christianity. Recently, however, there has been at least a superficial change in this position. The past few years have seen an explosion in literature related to religion and science (e.g. Barbour, 1997; Russell, 2003;), As Reber (this issue) has noted, psychology has an especially pressing need for dialogue with religion, and contemporary work by theologians suggests that they also see a need to converse (e.g. Loder, 1998; Pannenberg, 1985; Ulanov, 2001). Yet there remains a hesitancy that is partly driven by professional concerns that religion and science are incompatible (Drees, 1999, p. 2). Conversations between disciplines can proceed in different ways, the most substantive of which is integration. Gorsuch (2002a) defines integration as "when two or more disciplines are jointly brought to bear on the same issue so that decisions about that issue reflect the contributions of both disciplines" (p. 6). Integration requires two things: a positive attitude between two disciplines, and the identification of particular problems for conversation (Gorsuch, 2002a, p. 19). In this view, since psychology and religion share many interests, difficulties about integration must lie in the attitudes of each towards the other--in other words, the issue is a problem of mutual understanding. For Richardson (this issue), hermeneutic dialogue may provide the most fruitful model for overcoming these barriers and providing a non-assimilative approach to integration (Nelson & Slife, this issue). From a historical perspective, negative attitudes between science and religion are a relatively recent development. This article will argue that negative attitudes are not inevitable, but are partly a product of outdated ways of thinking that continue to influence us. CONCEPTUAL STRUCTURES The history of science and religion is largely a history of ideas, so we need to begin by looking at some key philosophical presuppositions that have affected their relationship. In modern science and psychology, these typically include ontological assumptions of materialism and naturalism, which in turn are related to epistemological attitudes toward science and non-science inquiry that can lead to the problem of scientism. Materialism Materialism is an old ontological category, going back to pre-Socratic philosophers like Democritus who saw the world as consisting exclusively of material entities. …

In this short essay it will be my privilege to extend the dialogue of this issue by responding to the comments of Siang Yang Tan (this issue), and then reflecting on some implications of his article and those of the other contributors. Comments on Babies and Bathwater Tan's essay is a statement by a scholar who is committed to the very best standards of scientific inquiry and thus represents a view from "inside" the scientific study of psychology and religion. Given the position from which he speaks, it is highly significant that he adds his voice to the authors of this special issue who express concerns about the presuppositions of modern psychological science and the effect they may have on the integration enterprise. He obviously recognizes the presence of logical positivism, scientism and a reductionistic naturalism in much of what goes on in our field. Tan raises two important criticisms of the articles in this special issue. First, he makes the excellent point that new ways of doing things should not lead us to "throw out the baby with the bathwater," as current quantitative methodologies have much to contribute. This is a good point not sufficiently emphasized in the articles. While the exclusive use of quantitative methods is to be avoided (Nelson, this issue), they are ideal for testing the role of specific variables in limited contexts across many individuals. Fortunately as Tan notes, the hermeneutic approach advanced by Richardson (this issue) allows for the inclusion of the helpful aspects of current practice while broadening our methods beyond the positivist approach. Second, Tan argues that authors such as Slife and Whoolery overstate their case and don't sufficiently acknowledge that some work is informed by religious ideas or values. In essence, Tan is pointing out that some investigators already make conscious, intentional use of their personal religious preunder-standings and thus are operating within the interpretive, dialogical, hermeneutic framework advocated by the authors of this special issue. This is undeniably true and a very positive development. However, it is also the case that these individuals don't represent the mainstream of thought and method within the field of psychology, or even perhaps with the psychology of religion community. For instance, the work by Murphy (e.g. 2002) on nonreductive physicalism presents a highly interesting alternative to a reductive materialist position, but it is not widely accepted. In most of the academy, reductive materialism continues to reign as a mostly unexamined assumption (Nelson, this issue; Slife, this issue). Overall, it would seem that Tan and I are in agreement. A new methodological paradigm needs to be widely applied, one that employs qualitative and other methodologies along with the traditional quantitative methods we have applied to questions in the field (Nelson, Klein & Sexton, 2005). Problems and Solutions At this point, however, some key problems come up. First, why should psychologists--including those interested in religion--do things differently? The move to a more open, dialogical model has obvious advantages for religious communities, who gain an equal voice in the conversation with psychology. What's in it for psychologists, though? This is a crucial question, because change is unlikely unless researchers see that it is to their advantage to reexamine their presuppositions and consider different approaches to problems. Second, how might a dialogical model address the relationship between science and ethics, which has been problematic since the time of Bacon (Nelson, this issue)? Third, how might we find a way to follow the suggestion of Slife and Whoolery (this issue) and do a kind of integration that would allow us to embrace theistic ideas and values? Fourth, can our integration paradigm find a role for the voice of religious communities as Tan (this issue) has urged? …

I examine two anomalies where the Fama and French three-factor model fails to adequately explain monthly industry and index returns. Both anomalies are consistent with a bad model problem where the book-to-market factor introduces a negative bias in the intercepts. I propose the intangibles model as an alternative where the three-factor model is known to have difficulty. This alternative model, which replaces the book-to-market factor with zero investment portfolio returns based on prior investments in intangible assets, is well specified in random samples, has comparable power, and fully explains both anomalies.

Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of alkynamide analogues of quinazoline- and pyrido[3,4-d]pyrimidine-based compounds. The compounds were prepared by coupling the appropriate 6-aminoquinazolines or 6-aminopyrido[3,4-d]pyrimidines with alkynoic acids, using EDCI.HCl in pyridine. The compounds showed pan-erbB enzyme inhibition but were on average about 10-fold more potent against erbB1 than against erbB2 and erbB4. For cellular inhibition, the nature of the alkylating side chains was an important determinant, with 5-dialkylamino-2-pentynamide type Michael acceptors providing the highest potency. This is suggested to be due to an improved ability of the amine to participate in an autocatalysis of the Michael reaction with enzyme cysteine residues. Pyrido[3,4-d]pyrimidine analogue 39 was selected for in vivo evaluation and achieved tumor regressions at 10 mg/kg in the A431 human epidermoid carcinoma and at 40 mg/kg for the SF767 human glioblastoma and the SKOV3 human ovarian carcinoma. Complete stasis was observed at 40 mg/kg in the BXPC3 human pancreatic carcinoma as well as in the H125 human non-small-cell lung carcinoma.

Smith [Smith, M., 1996. Shareholder activism by institutional investors: evidence from CALPERS. Journal of Finance 51, 227-252] and Wahal [Wahal, S., 1996. Public pension fund activism and firm performance. Journal of Financial and Quantitative Analysis 31, 1-23] identify significant positive abnormal returns surrounding the announcement of performance targetings by the California Public Employees Retirement System (CalPERS), dubbed the “CalPERS effect.” More recent studies suggest that this “CalPERS effect” continues in later samples. While I confirm the early period results, I find the results reported in studies examining later periods are driven by the inclusion of early 1992–1993 targetings and from a significant bias in the market model parameters caused by estimation during periods of known under-performance. Additionally, these results are partially driven by the failure to control for contaminating events and the use unnecessarily long event windows. Contrary to previous studies, after addressing these methodological concerns, I find no evidence to support the continued existence of a “CalPERS effect”.

The California Public Employee Retirement System (CalPERS) asserts ‘Our activism creates significant value for our members and all shareholders’. As evidence for this claim, CalPERS cites Anson et al. (‘The Shareholder Wealth Effects of CalPERS' Focus List’, Journal of Applied Corporate Finance, 15, 8–17, 2003), who show that positive excess (abnormal) returns from focus list firms average about 12 per cent for the 90 days following targetings between 1992 and 2001. In a follow-up study, Anson et al. (‘Good Corporate Governance Works: More Evidence from CalPERS’, Journal of Asset Management, 5, 149–56, 2004) show excess returns of 59 per cent for the 365 trading days following CalPERS' targeting. This study finds that their results are driven by a significant bias in their market model alphas caused by estimation during periods of known underperformance and compounded over unnecessarily long event windows. When their analysis is repeated using parameters estimated post-event, no evidence of significant abnormal returns attributable to CalPERS activism is found. When shorter event windows immediately surrounding the announcement of the CalPERS focus lists are examined, no evidence that the market values CalPERS activism is found. Contrary to the results of Anson et al. (2003, 2004), after addressing various methodological concerns, this study finds no evidence of any shareholder wealth effects attributable to CalPERS activism.

We examine the annual stock performance of firms that disclose the use of derivatives to hedge over the period 1995 to 1999. We find that only 21.6% of publicly traded U.S. corporations in our sample hedged with derivative instruments over this period and their use is concentrated in the larger companies. Similar to other studies we find that when derivatives are used, interest rate and currency securities are used much more frequently than commodity products. Our sample of 1308 companies that hedge outperforms other securities by 4.3% per year on average over our sample period. This result is robust to several alternative methods of estimating abnormal returns. When we segment performance by the type of hedge used, however, we find that the over-performance is due entirely to larger firms that hedge currency. We find no abnormal returns for firms hedging either interest rates or commodities. The abnormal returns in firms hedging currency is robust to alternative models that seek to control for exchange rate fluctuations and global equity returns; however, we find no significant abnormal returns to currency hedgers when using an augmented model that controls for the role of intangible assets.

The ErbB receptor family is implicated in the malignant transformation of several tumor types and is overexpressed frequently in breast, ovarian, and other tumors. The mechanism by which CI-1033 and gemcitabine, either singly or in combination, kill tumor cells was examined in two breast lines, MDA-MB-453 and BT474; both overexpress the ErbB-2 receptor. CI-1033, a potent inhibitor of the ErbB family of receptor tyrosine kinases, reduced levels of activated Akt in MDA-MB-453 cells. This effect alone, however, did not induce apoptosis in these cells. Gemcitabine treatment resulted in a moderate increase in the percentage of apoptotic cells that was accompanied by activation of p38 and MAPK (ERK1/2). CI-1033 given 24 h after gemcitabine produced a significant increase in the apoptotic fraction over treatment with either drug alone. During the combined treatment p38 remained activated, whereas Akt and activated MAPK were suppressed. Substitution of CI-1033 with the phosphatidylinositol 3-kinase inhibitor LY294002 and the MAPK/ERK kinase inhibitor PD 098059 in combination with gemcitabine produced the same results as the combination of CI-1033 and gemcitabine. p38 suppression by SB203580 prevented the enhanced cell kill by CI-1033. In contrast to MDA-MB-453, BT474 cells exhibited activated p38 under unstressed conditions as well as activated Akt and MAPK. Treatment of BT474 cells with CI-1033 inhibited both the phosphorylation of Akt and MAPK and resulted in a 47% apoptotic fraction. Gemcitabine did not cause apoptosis in the BT474 cells. These data indicate that suppression of Akt and MAPK in the presence of activated p38 results in cell death and a possible mechanism for the enhanced apoptosis produced by the combination of CI-1033 and gemcitabine in MDA-MB-453 cells. Furthermore, tumors that depend on ErbB receptor signaling for survival and exhibit activated p38 in the basal state may be susceptible to apoptosis by CI-1033 as a single agent.

4-Anilinoquinazoline- and 4-anilinopyrido[3,4-d]pyrimidine-6-acrylamides are potent pan-erbB tyrosine kinase inactivators, and one example (CI-1033) is in clinical trial. A series of analogues with a variety of Michael acceptor units at the 6-position were prepared to define the structural requirements for irreversible inhibition. A particular goal was to determine whether additional functions to increase solubility could be appended to the Michael acceptor. Substituted acrylamides were prepared by direct acylation of the corresponding 6-amines with the requisite acid or acid chloride. Vinylsulfonamide derivatives were obtained by acylation of the amines with chloroethylsulfonyl chloride followed by base-promoted elimination. Vinylsulfone and vinylsulfine derivatives were prepared by oxidation and base elimination of a hydroxyethylthio intermediate. The compounds were evaluated for their inhibition of phosphorylation of the isolated EGFR enzyme and for inhibition of EGF-stimulated autophosphorylation of EGFR in A431 cells and of heregulin-stimulated autophosphorylation of erbB2 in MDA-MB 453 cells. Substitution at the nitrogen of the acrylamide was tolerated only with a methyl group; larger substituents were dystherapeutic, and no substitution at all was tolerated at the acrylamide alpha-carbon. In contrast, while electron-donating groups at the acrylamide beta-carbon were not useful, even quite large electron-withdrawing groups (which increase its electrophilicity) were tolerated. A series of derivatives with solubility-enhancing substituents linked to the acrylamide beta-carbon via amides were potent irreversible inhibitors of isolated EGFR (IC50s = 0.4-1.1 nM), with weakly basic morpholine and imidazole derivatives being the best. Vinylsulfonamides were also potent and irreversible inhibitors, but vinylsulfones and vinylsulfines were reversible and only poorly active. Two compounds were evaluated against A431, H125, and MCF-7 xenografts in nude mice but were inferior in these assays to the clinical trial compound CI-1033.

A novel catalytic dehydrocoupling route for the synthesis of linear, cyclic, and polymeric phosphinoboranes has been developed. The dehydrocoupling of neat Ph2PH·BH3, which is otherwise very slow below 170 °C, is catalyzed by [{Rh(μ-Cl)(1,5-cod)}2] or [Rh(1,5-cod)2][OTf] (0.5−1 mol % Rh) to give the linear compound Ph2PH−BH2−PPh2−BH3 (1) at 90 °C, and a mixture of the cyclic trimer [Ph2P−BH2]3 (2a) and tetramer [Ph2P−BH2]4 (2b) at 120 °C. In addition, the catalytic potential of other (e.g., Ti, Ru, Rh, Ir, Pd, Pt) complexes toward the dehydrocoupling of Ph2PH·BH3 was investigated and was in many cases demonstrated. The molecular structures of 1 and 2b, and of the primary phosphine−borane adduct PhPH2·BH3, were determined by single-crystal X-ray analysis. The dehydrogenative coupling of PhPH2·BH3 gave low-molecular-weight poly(phenylphosphinoborane) [PhPH−BH2]n (3) when performed in toluene (110 °C) with ca. 0.5 mol % [Rh(1,5-cod)2][OTf] as catalyst. The absolute weight-average molecular weight was determi...

An advanced process for the synthesis of polyphosphazenes with controlled architectures has been investigated. By this method, a wide range of well-defined phosphazene di- and triblock copolymers with controlled molecular weights and narrow polydispersities have been synthesized (Mn up to 4.8 × 104 with polydispersities of 1.06−1.39). The diblock copolymers, {[NPCl2]n[NPR(R‘)]m}, were synthesized by the cationic condensation polymerization of the phosphoranimines, PhCl2PNSiMe3, Me(Et)ClPNSiMe3, Me2ClPNSiMe3, Ph2ClPNSiMe3, and PhF2PNSiMe3, at 35 °C initiated from the “living” end unit of poly(dichlorophosphazene), [Cl−(PCl2N)n-PCl3+PCl6-] which was itself formed by the polymerization of Cl3PNSiMe3 with small amounts of PCl5 initiator in CH2Cl2 at 25 °C. Halogen replacement reactions through the use of NaOCH2CF3 and/or NaOCH2CH2OCH2CH2OCH3 on the diblock copolymers yielded fully organo-substituted macromolecules. In addition, the diblock copolymer {[NPMe(Et)]n[NPMe(Ph)]m} was formed by the block copolymeriz...

A new polyphosphazene, [N=PPh(CF 3 )] n , has been prepared via the PCl 5 -induced cationic polymerization of Me 3 SiN=P(CF 3 )(Ph)Br. In addition, the cationic route has been used to produce [N= PPh(Me)] n with controlled molecular weights and narrow polydispersities. By contrast, the new monomer Me 3 SiN=P(t-Bu)(Ph)F failed to polymerize under any conditions but was used as an initiator and terminator to prepare both mono- and ditelechelic polymers. This monomer was also used to prepare [F(Ph)(t-Bu)P=N(PCl 2 =N)P(t-Bu)(Ph)F] + , which was used as a substrate for reactions with alkoxy and aryloxy groups to yield the hydrolytically stable materials, [R(Ph)(t-Bu)P=N(PR 2 =N)P(t-Bu)(Ph)R 2 ].

Three types of polyphosphazenes with different architectures have been synthesized and characterized. The influence of the polymer architecture on solid ionic conductivity was of particular interest. The first type includes linear oligo- and polyphosphazenes with the general formula [NP(OCH2CH2OCH2CH2OCH3)2]n (MEEP) with different chain lengths. The second type consists of a series of triarmed star-branched polyphosphazenes with the general formula N{CH2CH2NH(CF3CH2O)2P[NP(OCH2CH2OCH2CH2OCH3)2]n}3 with different arm lengths. These were synthesized via the reaction of the tridentate initiator [N{CH2CH2NH(CF3CH2O)2PN−PCl3+}3][PCl6-]3 with the phosphoranimine Cl3PNSiMe3 in CH2Cl2 followed by halogen replacement with sodium (methoxyethoxy)ethoxide. The molecular weights in this system were carefully controlled by variation of the monomer-to-initiator ratios, and the effect of polymer molecular weight on solid ionic conductivity was examined. The third polymer system was designed to examine the effect of compl...

A class of high-affinity inhibitors is disclosed that selectively target and irreversibly inactivate the epidermal growth factor receptor tyrosine kinase through specific, covalent modification of a cysteine residue present in the ATP binding pocket. A series of experiments employing MS, molecular modeling, site-directed mutagenesis, and 14 C-labeling studies in viable cells unequivocally demonstrate that these compounds selectively bind to the catalytic domain of the epidermal growth factor receptor with a 1:1 stoichiometry and alkylate Cys-773. While the compounds are essentially nonreactive in solution, they are subject to rapid nucleophilic attack by this particular amino acid when bound in the ATP pocket. The molecular orientation and positioning of the acrylamide group in these inhibitors in relation to Cys-773 entirely support these results as determined from docking experiments in a homology-built molecular model of the ATP site. Evidence is also presented to indicate that the compounds interact in an analogous fashion with erbB2 but have no activity against the other receptor tyrosine kinases or intracellular tyrosine kinases that were tested in this study. Finally, a direct comparison between 6-acrylamido-4-anilinoquinazoline and an equally potent but reversible analog shows that the irreversible inhibitor has far superior in vivo antitumor activity in a human epidermoid carcinoma xenograft model with no overt toxicity at therapeutically active doses. The activity profile for this compound is prototypical of a generation of tyrosine kinase inhibitors with great promise for therapeutic significance in the treatment of proliferative disease.

As we look back over the articles, comments, and replies of this special issue, we are struck by two themes that appear to garner the most agreement among the various authors and involve the most important implications for the psychology of religion. The first theme is the need to respect the unique worldviews of today's religions and treat them as equal partners in dialogue. Too often, we believe, the naturalism and scientism of psychology are viewed as neutral discourses and given a higher status. The second theme follows from the first-the need for a pluralism of methods to help level the research playing field and formalize the respect of religious worldviews. Some pluralism is already occurring with the advent of qualitative methods, but we envision an even broader pluralism that is open to theism. Space limitations allow only a brief description of each theme here. Respecting a Religious Worldview We should clarify at the outset that we believe that few, if any, researchers intend to disrespect a religious worldview. Although some border on this in our view, depicting religious worldviews as "folk beliefs" and "counterintuitive ideas" (Boyer, 2001; Churchland, 1995), we believe the most problematic issues are the more subtle, method-related issues. For many cultural and historical reasons, psychological practices have long been centered on methods (Nelson, this issue; Reber, this issue). Research questions are framed in ways that the method can handle; theoretical constructs are measured in ways that the method can use; and results are interpreted in ways that are "close" to the method-generated data. This method-centeredness would not be a problem if the methods were themselves devoid of values and assumptions. Without values, this centering would exert no particular bias and permit no taint of the ultimate outcome of empirical studies or research programs (Reber, this issue). However, this common understanding of psychological methods is a myth (Slife, this issue). The traditional methods of psychology do have assumptions and values that influence how research questions are posed, constructs are measured, and data are interpreted. More importantly for this special journal issue, these assumptions and values are not the assumptions and values of most world religions. The articles of this special issue make clear that the assumptions and values of psychological science include a slew of "isms"--materialism, reductionism, objectivism, scientism, positivism, and determinism. These assumptions are often wrapped together in the term "naturalism" (e.g., Griffin, 2000), but they point to radically different understandings of the world from most religions. Psychologists who study religious claims and experiences with naturalistic methods could overlook these differences or assume the superiority of a "scientific understanding" and impose a naturalistic rendering on both the research process and outcome. The authors of the first four articles focus primarily on theistic religions in this regard, such as Christianity, Islam, and Judaism. However, the assumptions and values of psychological science are problematic for a host of nontheistic religions. For instance, the reductive materialism implicit or explicit in much of psychology (Nelson, this issue; Slife, this issue) marginalizes or explains away the type of consciousness needed for many schools of Hinduism, such as Sankhya and Ayurveda, where the Brahma underlies the generation of matter. Consider also traditional Buddhist Abhidhamma philosophy where the importance of consciousness is emphasized over the obvious material world. In all these situations, philosophical positions are adopted in modern psychology that foreclose the possibility of real dialogue by denying assumptions that are fundamental to religious points of view. Perhaps the primary implication, in this sense, is that researchers should allow themselves to consider other research questions, construct measurements, and data interpretations than those associated with naturalism. …

The tyrosine kinase inhibitors PD 69896, 153717, and 158780, which belong to the chemical class 4-[ar(alk)ylamino]pyridopyrimidines, have been characterized with respect to enzymology, target specificity, and antiproliferative effects in tumor cells. These compounds were competitive inhibitors with respect to ATP against purified epidermal growth factor (EGF) receptor tyrosine kinase and inhibited EGF receptor autophosphorylation in A431 human epidermoid carcinoma with IC50 values of 2085, 110, and 13 nM, respectively. Onset of inhibition was immediate once cells were exposed to these compounds, whereas recovery of receptor autophosphorylation activity after the cells were washed free of the compound was dependent on inhibitory potency. Thus, full activity returned immediately after removal of PD 69896 but required 8 hr after exposure to PD 158780. PD 158780 was highly specific for the EGF receptor in Swiss 3T3 fibroblasts, inhibiting EGF-dependent receptor autophosphorylation and thymidine incorporation at low nanomolar concentrations while requiring micromolar levels for platelet-derived growth factor- and basic fibroblast growth factor-dependent processes. PD 158780 inhibited heregulin-stimulated phosphorylation in the SK-BR-3 and MDA-MB-453 breast carcinomas with IC50 values of 49 and 52 nM, respectively, suggesting that the compound was active against other members of the EGF receptor family. The antiproliferative effects of this series of compounds against A431 cells correlated precisely with the inhibitory potency against EGF receptor autophosphorylation. PD 158780 reduced clone formation in soft agar of fibroblasts transformed by EGF, EGF receptor, or the neu oncogene but not ras or raf, further demonstrating its high degree of specificity. Finally, this compound was active against clone formation in several breast tumors having different expression patterns of the erbB family, indicating an anticancer utility in tumors expressing these receptors.

The epidermal growth factor (EGF) receptor is well known as a mediator of mitogenic signaling and its tyrosine kinase activity has been suggested as a viable target in cancer chemotherapy. To explore the consequences of abolishing the kinase activity of this receptor, we have utilized a potent and specific inhibitor of the enzyme, PD 153035, to sustain a long-term suppression of its activity. This compound inhibits EGF receptor autophosphorylation in cells with an IC50 in the low nanomolar range and does not block PDGF or FGF receptor kinase until concentrations are greater than 10 microM. [1] Human epidermoid carcinoma A431 cells were grown in the presence of PD 153035 and were passed weekly until cells grew in the presence of 1 microM inhibitor. These cells, referred to as A431R, showed a remarkable change in morphology, becoming flattened and spread out. A comparison of the sensitivity of EGF receptor autophosphorylation to PD 153035 between A431 and A431R showed a similar dose response, indicating that the cells had not developed any defect in the kinase which might make it resistant to the inhibitor. Likewise, EGF receptor autophosphorylation in response to exogenously added EGF, as well as receptor internalization, was similar between the two cell lines. Furthermore, analysis of A431R cells by flow cytometry showed no significant change in DNA content or percentage of cells in any one phase of the cell cycle compared to the parent line. 125I-labeled EGF/receptor binding studies showed that receptor number in the A431R cells was equivalent to that of the parent line; however, the Scatchard plot was linear, in contrast to the typical biphasic plot obtained with the parent cells, implying a loss of high-affinity receptors. Cytoskeletal preparations from both cell lines indicated that the A431R had fourfold less EGF receptor associated with the cytoskeleton than A431. This was accompanied by a remarkable increase in polymerized actin stress fibers throughout the A431R cells, which most likely accounts for their flattened morphology. The A431R cells also exhibited a twofold increase in the expression of focal adhesion kinase, which is consistent with a greater contact area for their cell surface and increase in focal adhesions. Finally, although the A431R cells have a doubling time of 24 h, similar to that of the parent line, these cells stop growing as the monolayer approaches confluence, reminiscent of the contact inhibition seen in nontransformed cells. These data indicate that long-term suppression of the EGF receptor tyrosine kinase activity in A431 human epidermoid carcinoma results in certain cellular properties which are more consistent with a differentiated and nontransformed phenotype.

A new, ambient-temperature method for the direct synthesis of organo-substituted polyphosphazenes is described. It involves the initiation of a series of organophosphoranimines R(R‘)XPNSiMe3 (3, R = Ph, R‘ = X = Cl; 5, R = R‘ = Ph, X = Cl; 7, R = Me, R‘ = Et, X = Cl; 9, R = R‘ = CF3CH2O, X = Br) with catalytic amounts of PCl5 in CH2Cl2 to yield (after treatment with NaOCH2CF3 in the case of 3) the corresponding polyphosphazene species (NPRR‘)n (4, R = Ph, R‘ = OCH2CF3; 6, R = R‘ = Ph; 8, R = Me, R‘ = Et; 10, R = R‘ = OCH2CF3) with narrow polydispersities. The molecular weights of the polyphosphazenes were controlled by altering the ratio of monomer to initiator. The polymer chains were found to be active after chain propagation since further addition of monomer resulted in the formation of higher molecular weight polymer. For monomers 7 and 9 optimum polymerization behavior was found to occur at 35 °C in the absence of solvent in the presence of catalytic quantities of PCl5. These reactions proceeded to 1...

A new method for the synthesis of poly(dichlorophosphazene) at ambient temperatures is described. It involves the initiation of Cl3PNSiMe3 with small amounts of PCl5 in CH2Cl2 to yield poly(dichlorophosphazene), (NPCl2)n, with narrow polydispersities. The molecular weight of poly(dichlorophosphazene) was controlled by altering the ratio of monomer to initiator. The polymer chains were found to be active after chain propagation since further addition of monomer resulted in the formation of higher molecular weight polymer. Integration of 1H and 31P NMR spectra of these reactions revealed that the polymerization follows first-order reaction kinetics with respect to monomer concentration. Active polymer chains may be quenched or end-capped by the addition of trace quantities of Me2(CF3CH2O)PNSiMe3 or (CF3CH2O)3PNSiMe3. Furthermore, PBr5, SbCl5, and Ph3C[PF6] were also found to be effective initiators in CH2Cl2 at room temperature.

The psychology of religion and spirituality (PRS) involves applying the methods and procedures of psychological science to the study of religion and spirituality. Since PRS is a scientific endeavor, best practices in the field will always involve a thorough understanding of the scientific process, such as that provided by contemporary philosophers of science. One of the most important things to be learned from these writers is that all science—including inquiry in PRS—involves methodological, epistemological, ethical, and ontological assumptions that greatly affect the conduct of scientific work. A brief review of these assumptions in PRS suggests that current scientific practices in the field fall short in a number of ways, making it difficult for investigators to truly increase our understanding of the important psychological processes involved in religious activities and spiritual experience. We explore the nature of these assumptions and their problems, and offer a possible alternative framework that will help advance the science of PRS.

The twenty-third volume of RSSSR includes a landmark collection of papers on Theism and Non-Theism in Psychological Science, as well as papers on other key areas in the study of religion such as spirituality and social capital.

A tetramethylethylene bridged ferrocene 1 and cobaltocene 3 are synthesised in two steps from 2-tert-butyl-6,6-dimethylfluvene. Both can be oxidised to the corresponding cations, 2 and 4, the single-crystal X-ray structures of which have been determined.