What's new in the field of cancer vaccines?

The observation that in some cases tumors undergo spontaneous regression concomitantly with autoimmune manifestations has been interpreted as an indication of the involvement of the immune system in tumor rejection. This raised the conceptual possibility that the immune system could be used against the tumor. However, since tumor cells are poorly immunogenic by themselves, early attempts to develop immune-based approaches for cancer therapy saw the use of tumor cells transduced with genes coding for cytokines or costimulatory molecules to enhance in vivo immunity. The identification of cytotoxic T lymphocyte (CTL)-defined tumor associated antigens has allowed the development of new strategies for cancer immunotherapy. Novel adjuvants have been identified, and different modes of antigen delivery were devised which aim at inducing efficient CTL responses in patients. This review will discuss some of what is currently considered as relevant aspects of antitumor immunization.Received 19 July 2002; received after revision 11 December 2002; accepted 13 December 2002     

Can online search data improve the forecast accuracy of pork price in China?

Online search data provide us with a new perspective for quantifying public concern about animal diseases, which can be regarded as a major external shock to price fluctuations. We propose a modeling framework for pork price forecasting that incorporates online search data with support vector regression model. This novel framework involves three main steps: that is, formulation of the animal diseases composite indexes (ADCIs) based on online search data; forecast with the original ADCIs; and forecast improvement with the decomposed ADCIs. Considering that there are some noises within the online search data, four decomposition techniques are introduced: that is, wavelet decomposition, empirical mode decomposition, ensemble empirical mode decomposition, and singular spectrum analysis. The experimental study confirms the superiority of the proposed framework, which improves both the level and directional prediction accuracy. With the SSA method, the noise within the online search data can be removed and the performance of the optimal model is further enhanced. Owing to the long-term effect of diseases outbreak on price volatility, these improvements are more prominent in the mid- and long-term forecast horizons.     

β-Lactam resistance in Staphylococcus aureus: the adaptive resistance of a plastic genome

Staphylococci have two mechanisms for resistance to β-lactam antibiotics. One is the production of β-lactamases, enzymes that hydrolytically destroy β-lactams. The other is the expression of penicillin-binding protein 2a (PBP 2a), which is not susceptible to inhibition by β-lactam antibiotics. Strains of S. aureus exhibiting either β-lactamase or PBP 2a-directed resistance (or both) have established a considerable ecological niche among human pathogens. The emergence and subsequent spread of bacterial strains designated as methicillin-resistant S. aureus (MRSA), from the 1960s to the present, has created clinical difficulties for nosocomial treatment on a global scale. The recent variants of MRSA that are resistant to glycopeptide antibiotics (such as vancomycin) have ushered in a new and disconcerting chapter in the evolution of this organism. Received 2 April 2005; received after revision 15 July 2005; accepted 25 July 2005     

Multidrug-resistant cancer cells and cancer stem cells hijack cellular systems to circumvent systemic therapies,can natural products reverse this?

Chemotherapy is one of the most effective and broadly used approaches for cancer management and many modern regimes can eliminate the bulk of the cancer cells. However, recurrence and metastasis still remain a major obstacle leading to the failure of systemic cancer treatments. Therefore, to improve the long-term eradication of cancer, the cellular and molecular pathways that provide targets which play crucial roles in drug resistance should be identified and characterised. Multidrug resistance (MDR) and the existence of tumor-initiating cells, also referred to as cancer stem cells (CSCs), are two major contributors to the failure of chemotherapy. MDR describes cancer cells that become resistant to structurally and functionally unrelated anti-cancer agents. CSCs are a small population of cells within cancer cells with the capacity of self-renewal, tumor metastasis, and cell differentiation. CSCs are also believed to be associated with chemoresistance. Thus, MDR and CSCs are the greatest challenges for cancer chemotherapy. A significant effort has been made to identify agents that specifically target MDR cells and CSCs. Consequently, some agents derived from nature have been developed with a view that they may overcome MDR and/or target CSCs. In this review, natural products-targeting MDR cancer cells and CSCs are summarized and clustered by their targets in different signaling pathways.     

Contributions in the domain of cancer research: Review¶Human papillomaviruses and their role in cervical cancer

Human papillomaviruses (HPVs) have been linked to a variety of human diseases, most notably cancer of the cervix, a disease responsible for at least 200,000 deaths per year worldwide. Over 100 different types of HPV have been identified and these can be divided into two groups. Low-risk HPV types are the causative agent of benign warts. High-risk HPV types are associated with cancer. This review focuses on the role of high-risk HPV types in cervical tumorigenesis. Recent work has uncovered new cellular partners for many of the HPV early proteins and thrown light on many of the pathways and processes in which these viral proteins intervene. At the same time, structural and biochemical studies are revealing the molecular details of viral protein function. Several of these new avenues of research have the potential to lead to new approaches to the treatment and prevention of cervical cancer.     

The role of mammalian target of rapamycin (mTOR) in the regulation of pancreatic β-cell mass: implications in the development of type-2 diabetes

Type-2 diabetes mellitus (T2DM) is a disorder that is characterized by high blood glucose concentration in the context of insulin resistance and/or relative insulin deficiency. It causes metabolic changes that lead to the damage and functional impairment of organs and tissues resulting in increased morbidity and mortality. It is this form of diabetes whose prevalence is increasing at an alarming rate due to the 'obesity epidemic', as obesity is a key risk factor in the development of insulin resistance. However, the majority of individuals who have insulin resistance do not develop diabetes due to a compensatory increase in insulin secretion in response to an increase in insulin demand. This adaptive response is sustained by an increase in both β-cell function and mass. Importantly, there is increasing evidence that the Serine/Threonine kinase mammalian target of rapamycin (mTOR) plays a key role in the regulation of β-cell mass and therefore likely plays a critical role in β-cell adaptation. Therefore, the primary focus of this review is to summarize our current understanding of the role of mTOR in stimulating pancreatic β-cell mass and thus, in the prevention of type-2 diabetes.     

Do professional forecasters believe in the Phillips curve? evidence from the G7 countries

This paper uses monthly survey data for the G7 countries for the time period 1989–2007 to explore the link between expectations on nominal wages, prices and unemployment rates as suggested by the wage and price Phillips curves. Four major findings stand out. First, we find that survey participants trust in both types of Phillips curve relationships. Second, we find evidence in favor of nonlinearities in the price Phillips curve. Third, we take into account a kink in the price Phillips curve to indicate that the slope of the Phillips curve differs during the business cycle. We find strong evidence of this feature in the data which confirms recent theoretical discussions. Fourth, we employ our data to the expectations‐augmented Phillips curve model. The results suggest that professional forecasters adopt this model when forecasting macroeconomic variables. Copyright © 2010 John Wiley & Sons, Ltd.     

Is lysine the source of the pyridine ring in nicotine?

Zusammenfassung Gibt man L(+)-Lysin--¹⁵N oder in allen Stellungen mit¹⁴C markiertes L(+)-Lysin zu keimfreien Kulturen von abgeschnittenen Wurzeln vonNicotiana tabacum, so erzeugen die Wurzeln Nikotin, welches kleine Mengen¹⁵N oder¹⁴C enthält. Ferner enthält das Nikotin mehr¹⁵N oder¹⁴C im Pyrrolidinring als im Pyridinring. Lysin liegt daher nicht auf dem direkten biogenetischen Weg zum Nikotin.

---

---

Research performed under the auspices of the United States Atomic Energy Commission.     

Does the ectodermal proctodaeum participate in the development of the pronephric duct in urodele amphibia?

Zusammenfassung Vom ektodermalen Proctodaeum wächst ein kleiner Divertikel dem Vornierengang entgegen und vereinigt sich mit dessen kaudalem Ende. Einen weiteren Anteil hat das Proctodaeum an der Bildung des Vornierenganges nicht. Zugleich mit dem Proctodaeum invaginiert Material für den Mesonephros, das sich in Zellgruppen entlang dem hinteren Ende des Vornierenganges lagert.     

Cocarcinogens of the diterpene ester type from Croton flavens L. and esophageal cancer in Cura?ao

From the roots of Croton flavens L., 3 highly irritant and tumor promoting Croton factors F1--F3 and the corresponding 3 cryptic Croton factors F'1--F'3 were isolated and characterized as novel esters of 16-hydroxy- and 4-deoxy-16-hydroxyphorbol, respectively. These findings suggest that tumor promoters of the phorbol ester type, ingested through the widespread and frequent use of Croton flavens according to local habits, may be causally related to the well recognized high rate of esophageal cancer on Cura?ao.     

Simvastatin overcomes the resistance to serum withdrawal-induced apoptosis of lymphocytes from Alzheimer’s disease patients

Statins may exert beneficial effects on Alzheimer’s disease (AD) patients. Based on the antineoplastic and apoptotic effects of statins in a number of cell types, we hypothesized that statins may be able to protect neurons by controlling the regulation of cell cycle and/or apoptosis. A growing body of evidence indicates that neurodegeneration involves the cell-cycle activation in postmitotic neurons. Failure of cell-cycle control is not restricted to neurons in AD patients, but occurs in peripheral cells as well. For these reasons, we studied the role of simvastatin (SIM) on cell survival/death in lymphoblasts from AD patients. We report here that SIM induces apoptosis in AD lymphoblasts deprived of serum. SIM interacts with PI3K/Akt and ERK1/2 signaling pathways thereby decreasing the serum withdrawal-enhanced levels of the CDK inhibitor p21^Cip1 (p21) and restoring the vulnerability of AD cells to trophic factor deprivation.     

Implication of the VRK1 chromatin kinase in the signaling responses to DNA damage: a therapeutic target?

DNA damage causes a local distortion of chromatin that triggers the sequential processes that participate in specific DNA repair mechanisms. This initiation of the repair response requires the involvement of a protein whose activity can be regulated by histones. Kinases are candidates to regulate and coordinate the connection between a locally altered chromatin and the response initiating signals that lead to identification of the type of lesion and the sequential steps required in specific DNA damage responses (DDR). This initiating kinase must be located in chromatin, and be activated independently of the type of DNA damage. We review the contribution of the Ser-Thr vaccinia-related kinase 1 (VRK1) chromatin kinase as a new player in the signaling of DNA damage responses, at chromatin and cellular levels, and its potential as a new therapeutic target in oncology. VRK1 is involved in the regulation of histone modifications, such as histone phosphorylation and acetylation, and in the formation of γH2AX, NBS1 and 53BP1 foci induced in DDR. Induction of DNA damage by chemotherapy or radiation is a mainstay of cancer treatment. Therefore, novel treatments can be targeted to proteins implicated in the regulation of DDR, rather than by directly causing DNA damage.     

Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention?

Although the expression of the non-classical HLA class I molecule HLA-G was first reported to be restricted to the fetal–maternal interface on the extravillous cytotrophoblasts, the distribution of HLA-G in normal tissues appears broader than originally described. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. More interestingly, under pathophysiological conditions HLA-G antigens may be expressed on various types of malignant cells suggesting that HLA-G antigen expression is one strategy used by tumor cells to escape immune surveillance. In this article, we will focus on HLA-G expression in cancers of distinct histology and its association with the clinical course of diseases, on the underlying molecular mechanisms of impaired HLA-G expression, on the immune tolerant function of HLA-G in tumors, and on the use of membrane-bound and soluble HLA-G as a diagnostic or prognostic biomarker to identify tumors and to monitor disease stage, as well as on the use of HLA-G as a novel therapeutic target in cancer.     

Was Feyerabend a Popperian? Methodological issues in the History of the Philosophy of Science

For more than three decades, there has been significant debate about the relation between Feyerabend and Popper. The discussion has been nurtured and complicated by the rift that opened up between the two and by the later Feyerabend's controversial portrayal of his earlier self. The first part of the paper provides an overview of the accounts of the relation that have been proposed over the years, disentangles the problems they deal with, and analyses the evidence supporting their conclusions as well as the methodological approaches used to process that evidence. Rather than advancing a further speculative account of the relation based on Feyerabend's philosophical work or autobiographical recollections, the second part of the paper strives to clarify the problems at issue by making use of a wider range of evidence. It outlines a historical reconstruction of the social context within which Feyerabend's intellectual trajectory developed, putting a special emphasis on the interplay between the perceived intellectual identity of Feyerabend, Feyerabend's own intellectual self-concept, and the peculiar features of the evolving Popperian research group.     

Contributions in the domain of cancer research: Review¶Negative regulators of cyclin-dependent kinases and their roles in cancers

In the past decade, the discovery and characterization of cyclin-dependent kinases (CDKs), the engine cores of the cell cycle machinery, have advanced our understanding of the cell cycle. Both positive and negative regulators of CDKs have been characterized, accelerating the important research to unravel the mechanisms of the cell cycle disease--cancer. Cancer can originate from overexpression of positive regulators, such as cyclins, or from underexpression of negative regulators, such as CDK inhibitors (CKIs). CKIs are the focus of much cancer research because they are capable of controlling cell cycle proliferation--the Holy Grail for cancer treatment. CDKs can be inactivated by several mechanisms:, (i) by association with CKIs including p16 (INK4a), p15 (INK4b), p21 (Cip1), p27 (Kip1), and p57 (Kip2), (ii) by disassociation from their cyclin regulatory unit, (iii) by dephosphorylation of a conserved threonine residue in the T-loop, and (iv) by adding inhibitory phosphate. Here we discuss what is known about each mechanism with a hope that these insights will become useful in developing strategies to eliminate cancer in the future.     

A place for pragmatism in the dynamics of reason?

In Dynamics of Reason Michael Friedman proposes a kind of synthesis between the neokantianism of Ernst Cassirer, the logical empiricism of Rudolf Carnap, and the historicism of Thomas Kuhn. Cassirer and Carnap are to take care of the Kantian legacy of modern philosophy of science, encapsulated in the concept of the relativized a priori and the globally rational or continuous evolution of scientific knowledge, while Kuhn’s role is to ensure that the historicist character of scientific knowledge is taken seriously. More precisely, Carnapian linguistic frameworks, guarantee that the evolution of science proceeds in a rational manner locally, while Cassirer’s concept of an internally defined conceptual convergence of empirical theories provides the means to maintain the global continuity of scientific reason. In this paper it is argued that Friedman’s Neokantian account of scientific reason based on the concept of the relativized a priori underestimates the pragmatic aspects of the dynamics of scientific reason. To overcome this shortcoming, I propose to reconsider C.I. Lewis’s account of a pragmatic priori, recently modernized and elaborated by Hasok Chang. This may be considered as a first step to a dynamics of an embodied reason, less theoretical and more concrete than Friedman’s Neokantian proposal.     

Changes in placental permeability to corticosterone and estradiol-17β toward the end of gestation in the rat

Summary Radioactivity in the fetal plasma 1 h after maternal injection of¹⁴C-4-corticosterone or¹⁴C-4-estradiol-17 on day 21 of gestation was markedly higher than that 1 h after injection on day 22. Radioactivity in the maternal plasma was not different on these 2 days. The results suggest that the placental permeability to steroids from the mother to the fetus declines toward the end of gestation in the rat.Acknowledgment. We are indebted to Professor Tatsuo Imori (Department of Veterinary Surgery, College of Agriculture, University of Osaka Prefecture) for his valuable suggestions during the course of this study.     

Defining the role of post-synaptic α-neurotoxins in paralysis due to snake envenoming in humans

Snake venom α-neurotoxins potently inhibit rodent nicotinic acetylcholine receptors (nAChRs), but their activity on human receptors and their role in human paralysis from snakebite remain unclear. We demonstrate that two short-chain α-neurotoxins (SαNTx) functionally inhibit human muscle-type nAChR, but are markedly more reversible than against rat receptors. In contrast, two long-chain α-neurotoxins (LαNTx) show no species differences in potency or reversibility. Mutant studies identified two key residues accounting for this. Proteomic and clinical data suggest that paralysis in human snakebites is not associated with SαNTx, but with LαNTx, such as in cobras. Neuromuscular blockade produced by both subclasses of α-neurotoxins was reversed by antivenom in rat nerve–muscle preparations, supporting its effectiveness in human post-synaptic paralysis.