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Publications in this journal

• Tissue specificities of tumor induction by aromatic amines.

  Authors: Ching Yung Wang, Charles Miller King

  Frontiers in bioscience (Scholar edition). 4:206-15.

  Certain aryl compounds that have nitrogen substitutions on their ring structures are, following metabolic conversion to reactive derivatives, able to elicit toxic responses by virtue of theirCertain aryl compounds that have nitrogen substitutions on their ring structures are, following metabolic conversion to reactive derivatives, able to elicit toxic responses by virtue of their modifications of protein and nucleic acid. This group of compounds is often referred to as aromatic amines (AA), although from a structural perspective, compounds that can be converted metabolically to crucial AA derivatives are also capable of producing the same adverse biological effects. These effects include cellular death, mutagenic events and tumor induction. Importantly, in humans, AA can induce tumors in the urinary tract, and possibly other tissues. This contribution addresses the mechanisms by which AA are likely to produce these carcinogenic consequences.

• Role of histamine H4 receptors in the gastrointestinal tract.

  Authors: Gabriella Coruzzi, Maristella Adami, Cristina Pozzoli

  Frontiers in bioscience (Scholar edition). 4:226-39.

  The location and functional role of histamine H4 receptors (H4Rs) in the gastrointestinal tract (GI) is reviewed, with particular reference to their involvement in the regulation of gastric acidThe location and functional role of histamine H4 receptors (H4Rs) in the gastrointestinal tract (GI) is reviewed, with particular reference to their involvement in the regulation of gastric acid secretion, gastric mucosal defense, intestinal motility and secretion, visceral sensitivity, inflammation, immunity and carcinogenesis. H4Rs have been detected in different cell types of the gut, including immune cells, paracrine cells, endocrine cells and neurons; moreover, H4R expression was reported in human colorectal cancer specimens. Functional studies with selective H4R ligands demonstrated protective effects in several experimental models of gastric mucosal damage and intestinal inflammation, suggesting a potential therapeutic role of drugs targeting this new receptor subtype in GI disorders, such as allergic enteropathy, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and cancer.

• TGF-b signaling in cartilage homeostasis and osteoarthritis.

  Authors: Kenneth W Finnson, Yoon Chi, George Bou-Gharios, Andrew Leask, Anie Philip

  Frontiers in bioscience (Scholar edition). 4:251-68.

  Healthy cartilage is maintained by a delicate balance between the anabolic and catabolic activities of articular chondrocytes. This involves actions of numerous cytokines and growth factors thatHealthy cartilage is maintained by a delicate balance between the anabolic and catabolic activities of articular chondrocytes. This involves actions of numerous cytokines and growth factors that regulate the synthesis and degradation of extracellular matrix components which maintain the functional integrity of the joint. An imbalance between the activities of these anabolic and catabolic factors leads to cartilage degradation resulting in osteoarthritis (OA), a chronic degenerative joint disorder characterized by destruction of articular cartilage, alterations of subchondral bone and synovial fibrosis. Among the cytokines and growth factors that have been studied in the context of cartilage homeostasis and OA, transforming growth factor-beta TGF-beta has emerged as an important molecule that plays a critical role in the development, growth, maintenance and repair of articular cartilage. Deregulation of its signaling and responses has been shown to be involved in OA. Several components of the TGF-beta pathway, including extracellular, cell surface and intracellular molecules, display altered expression or action in OA. In this review, we discuss the regulatory mechanisms of TGF-beta signaling and link these mechanisms to cartilage function, highlighting the important role of TGF-beta in maintaining cartilage function and integrity. We also summarize the alterations in the molecular events of TGF-beta signaling and responses that may contribute to OA progression and discuss the potential of targeting the TGF-beta signaling pathway for the development of novel therapies for OA.

• A better way forward: targeting hedgehog signaling in liver cancer.

  Authors: Roland Kappler, Dietrich von Schweinitz

  Frontiers in bioscience (Scholar edition). 4:277-86.

  Accumulated experimental evidence indicates that Hedgehog (Hh) signaling regulates cell proliferation and specification in a variety of organs during embryonic development. However, abnormalAccumulated experimental evidence indicates that Hedgehog (Hh) signaling regulates cell proliferation and specification in a variety of organs during embryonic development. However, abnormal activation of this pathway in postnatal tissues has been linked to a large number of human cancers. With respect to the liver, it is known that Hh signaling not only influences bipotential precursor cells capable of pancreas and liver development, but is also implicated in the pathogenesis of liver tumors such as hepatoblastoma, hepatocellular and cholangiocellular carcinoma, if aberrantly activated. Blockade of Hh signaling by several specific inhibitors has been proven to successfully inhibit tumor growth of various Hh-associated cancers in vitro and in preclinical mouse models, and recent clinical data suggest that the implementation of novel anticancer therapeutics based on Hh interference into commonly accepted regimens are within reach. Thus, it is highly probable that Hh targeted therapies could be used for the treatment of Hh-dependent liver cancers in the future.

• Operation 'p53 Hunt' to combat cancer: theaflavins in action.

  Authors: Suchismita Mohanty, Arghya Adhikary, Samik Chakrabarty, Gaurisankar Sa, Tanya Das

  Frontiers in bioscience (Scholar edition). 4:300-20.

  With phytochemicals executing a plethora of anti-tumor mechanisms, targeting the 'guardian angel' p53 appears to be a critical strategy to energize the process of cancer therapeutics. Regulation ofWith phytochemicals executing a plethora of anti-tumor mechanisms, targeting the 'guardian angel' p53 appears to be a critical strategy to energize the process of cancer therapeutics. Regulation of anti-tumor p53 functions by dietary plant polyphenols particularly black tea and its active component theaflavins has gained immense recognition from the point of view of both efficacy and safety. This review highlights the complexities of p53 functions, molecular mechanisms of its inactivation in cancer, and therapeutic strategies for rescuing p53 dysfunction in tumors using theaflavins. It describes how theaflavins, by steering a single molecular target - p53, regulate multiple hallmarks of carcinogenesis i.e., tumor glycolysis, angiogenesis, metastasis, apoptosis and drug resistance. Additionally, considering the rising of the current concept of cancer stem cells (CSCs), the sole participant in tumor evolution, the review discusses about the possible role of theaflavin-p53 cross talk in targeting CSCs. Such attempts to target the complexities of p53 functions during neogenesis will be of immense help in developing a "new" strategy for successful cancer prevention and therapy by theaflavins.

• Curcumin: the multi-targeted therapy for cancer regression.

  Authors: Dewan Md Sakib Hossain, Sankar Bhattacharyya, Tanya Das, Gaurisankar Sa

  Frontiers in bioscience (Scholar edition). 4:335-55.

  Tumors are multifaceted; in fact, numerous things happen in synchrony to enable tumor promotion and progression. Any type of cancer is associated with the modification of 300-500 normal genes andTumors are multifaceted; in fact, numerous things happen in synchrony to enable tumor promotion and progression. Any type of cancer is associated with the modification of 300-500 normal genes and characterized by the deregulation of cell signaling pathways at multiple steps leading to cancer phenotype. Thus a proper management of tumorigenesis requires the development of multi-targeted therapies. Several adverse effects associated with present day cancer therapies and the thirsts for multi-targeted safe anticancer drug instigate the use of natural polyphenol, curcumin. It appears to involve a blend of anti-carcinogenic, pro-apoptotic, anti-angiogenic, anti-metastatic, immunomodulatory and antioxidant activities. Also the molecular mechanisms implicated for the pleotropic activities of curcumin are diverse and seem to involve a combination of cell signaling pathways at multiple levels of tumorigenesis. Being a potent scavenger of reactive oxygen species, curcumin also ameliorates systemic toxicity in tumor-bearer. Taken together, by placing particular emphasis on molecular basis of tumor promotion and progression this review summarizes the anti-cancer properties of curcumin that may be exploited for successful clinical cancer prevention.

• New applications of old metal-binding drugs in the treatment of human cancer.

  Authors: Sara M Schmitt, Michael Frezza, Qing Ping Dou

  Frontiers in bioscience (Scholar edition). 4:375-91.

  Significant advances in the use of metal complexes, precipitated by platinum, have fostered a renewed interest in harnessing their rich potential in the treatment of cancer. In addition toSignificant advances in the use of metal complexes, precipitated by platinum, have fostered a renewed interest in harnessing their rich potential in the treatment of cancer. In addition to platinum-based complexes, the anticancer properties of other metals such as ruthenium have been realized, and ruthenium-based compounds are currently being investigated in clinical trials. Since the process of drug development can be expensive and cumbersome, finding new applications of existing drugs may provide effective means to expedite the regulatory process in bringing new drugs to the clinical setting. Encouraging findings from laboratory studies reveal significant anticancer activity from different classes of metal-chelating compounds, such as disulfiram, clioquinol, and dithiocarbamate derivatives that are currently approved for the treatment of various pathological disorders. Their use as coordination complexes with metals such as copper, zinc, and gold that target the ubiquitin-proteasome pathway have shown significant promise as potential anticancer agents. This review discusses the unique role of several selected metals in relation to their anti-cancer properties as well as the new therapeutic potential of several previously approved metal-chelating drugs. In vitro and in vivo experimental evidence along with mechanisms of action (e.g., via targeting the tumor proteasome) will also be discussed with anticipation of strengthening this exciting new concept.

• Targeting endoplasmic reticulum stress for cancer therapy.

  Authors: Axel H Schonthal

  Frontiers in bioscience (Scholar edition). 4:412-31.

  The endoplasmic reticulum (ER) stress response, in combination with autophagy, represents an adaptive mechanism to support cellular survival in response to a great variety of detrimental conditions,The endoplasmic reticulum (ER) stress response, in combination with autophagy, represents an adaptive mechanism to support cellular survival in response to a great variety of detrimental conditions, such as low nutrient levels, hypoxia, calcium imbalance, or accumulation of misfolded proteins. However, when stress conditions become too severe and excessive, this cellular stress response system turns on its pro-apoptotic module, which then gains dominance and triggers cell death. In tumor cells, the cell-protective features of the ER stress response appear to be chronically activated and thus provide support for continuous proliferation and survival even under adverse microenvironmental conditions, which may include chemotherapy. However, persistent activity of these pro-survival pathways primarily in tumor cells may provide a window of opportunity for therapeutic intervention that is principally aimed at these tumor-specific conditions. Appropriate therapeutic regimens would seek to further aggravate this already engaged system in tumor cells in order to exhaust its protective features and instead trigger its pro-apoptotic module. There is accumulating evidence that this can indeed be accomplished, and that tumor-specific ER stress can be exploited by treatment with select pharmacological agents. The principles of this promising new approach to cancer therapy, as well as representative ER stress-aggravating compounds, will be presented in this review.

• Suppression of autophagy by BCR/ABL.

  Authors: Bruno Calabretta, Paolo Salomoni

  Frontiers in bioscience (Scholar edition). 4:453-60.

  Imatinib and second generation BCR/ABL tyrosine kinase inhibitors (TKIs) serve now as standard therapies for patients with chronic myelogenous leukemia (CML); however, CML stem cells areImatinib and second generation BCR/ABL tyrosine kinase inhibitors (TKIs) serve now as standard therapies for patients with chronic myelogenous leukemia (CML); however, CML stem cells are intrinsically insensitive to the cell death-inducing effects of TKIs, allowing the persistence of a "reservoir" of BCR/ABL-expressing CML-initiating cells potentially responsible for disease relapse and progression. Although it is still controversial whether the "insensitivity" of CML stem cells to treatment with TKI is due to BCR/ABL-dependent or independent mechanisms, treatment with IM appears to suppress BCR/ABL-dependent signaling in CML stem cells with no adverse effects on their survival. Recent evidence indicates that BCR/ABL suppresses and treatment of CML cells with IM/TKIs induces autophagy, a genetically-regulated process of adaptation to metabolic stress which could allow tumor cells to become metabolically inert enabling their survival under conditions that may mimic growth factor/nutrients deprivation. Based on this hypothesis, TKI-induced autophagy may "antagonize" TKI-induced cell death and inhibition of autophagy may eliminate this survival mechanism by restoring "sensitivity" of CML stem cells to treatment with IM/TKI. Consistent with this, phenotypically and functionally defined CML-enriched stem cells insensitive to treatment with TKI are efficiently eliminated by the combination of TKI and chloroquine, an inhibitor of late stage autophagy. Thus, inhibition of autophagy may improve the potent and specific effects of TKIs by rendering CML stem cells sensitive to these targeted therapies.

• The contrasting oncogenic and tumor suppressor roles of FES.

  Authors: Peter A Greer, Shigeru Kanda, Thomas E Smithgall

  Frontiers in bioscience (Scholar edition). 4:489-501.

  The FES gene was first discovered as a protein-tyrosine kinase-encoding retroviral oncogene. The ability of v-FES to transform cells in vitro and initiate cancer in vivo has been established by cellThe FES gene was first discovered as a protein-tyrosine kinase-encoding retroviral oncogene. The ability of v-FES to transform cells in vitro and initiate cancer in vivo has been established by cell culture, engraftment and transgenic mouse studies. The corresponding cellular c-FES proto-oncogene encodes a cytoplasmic FES protein-tyrosine kinase with restrained catalytic activity relative to its retrovirally encoded homologs. These observations have stimulated a search for mutations or inappropriate expression of c-FES in human cancers and research aimed at understanding the functions of the FES kinase and its potential involvement in cancer and other diseases. Paradoxically, although first identified as an oncogene, genetic evidence has also implicated c-fes as a potential tumor suppressor. This review will describe observations from basic and translational research which shapes our current understanding of the physiological, cellular and molecular functions of the FES protein-tyrosine kinase and its potential roles in tumorigenesis. We also propose a model to reconcile the conflicting oncogenic and tumor suppressor roles of c-FES in tumorigenesis.

• CARs: driving T-cell specificity to enhance anti-tumor immunity.

  Authors: Partow Kebriaei, Susan S Kelly, Pallavi Manuri, Bipulendu Jena, Rineka Jackson, Elizabeth Shpall, Richard Champlin, Laurence J N Cooper

  Frontiers in bioscience (Scholar edition). 4:520-31.

  Adoptive transfer of antigen-specific T cells is a compelling tool to treat cancer. To overcome issues of immune tolerance which limits the endogenous adaptive immune response to tumor-associatedAdoptive transfer of antigen-specific T cells is a compelling tool to treat cancer. To overcome issues of immune tolerance which limits the endogenous adaptive immune response to tumor-associated antigens, robust systems for the genetic modification and characterization of T cells expressing chimeric antigen receptors (CARs) to redirect specificity have been produced. Refinements with regards to persistence and trafficking of the genetically modified T cells are underway to help improve the potency of genetically modified T cells. Clinical trials utilizing this technology demonstrate feasibility, and increasingly, antitumor activity, paving the way for multi-center trials to establish the efficacy of this novel T-cell therapy.

• Endosomal trafficking in animal cytokinesis.

  Authors: Conor P Horgan, Mary W McCaffrey

  Frontiers in bioscience (Scholar edition). 4:547-55.

  Cytokinesis is the terminal stage of eukaryotic cell division in which the cytoplasm of a dividing cell is partitioned between two daughter cells. In animal cells, this multifaceted cellular processCytokinesis is the terminal stage of eukaryotic cell division in which the cytoplasm of a dividing cell is partitioned between two daughter cells. In animal cells, this multifaceted cellular process is spatially and temporally regulated and requires dramatic remodeling of the cytoskeleton and plasma membrane. Animal cytokinesis proceeds when the acto-myosin contractile-ring, formed at the equatorial cortex of a dividing cell, advances inward like a 'purse string' and is a major driving-force for the separation of the two daughter cells. In this review, we highlight many of the recent advances in our understanding of the function and mechanisms of action of the endocytic protein machinery that control animal cytokinesis. This includes regulation of endosome delivery and targeting by Rab and ARF GTPases, their effectors FIP3, FIP4 and JIP4, the exocyst and centralsplindlin complexes and phosphoinositides. Roles for endosomal SNAREs, BRUCE and the ESCRT pathway in the membrane remodeling processes that lead to abscission are also discussed.

• Molecular mechanisms of the neuroprotective/neurorescue action of multi-target green tea polyphenols.

  Authors: Silvia A Mandel, Orly Weinreb, Tamar Amit, Moussa B H Youdim

  Frontiers in bioscience (Scholar edition). 4:581-98.

  Mounting evidence suggests that lifestyle factors, especially nutrition are essential factor for healthy ageing. However, as a result of the increase in life expectance, neurodegenerative diseasesMounting evidence suggests that lifestyle factors, especially nutrition are essential factor for healthy ageing. However, as a result of the increase in life expectance, neurodegenerative diseases like Alzheimer's and Parkinson's (AD and PD, respectively) are becoming an increasing burden, as aging is their main risk factor. Brain aging and neurodegenerative diseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation. Thus, it is not surprising that a large amount of drugs/agents in therapeutic use for these conditions are antioxidants/metal complexing, bioenergetic and anti-inflammatory agents. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black flavonoids named catechins, may help protecting the aging brain and reduce the incidence of dementia, AD and PD. This review will present salient features of the beneficial multi-pharmacological actions of black and green tea polyphenols in aging and neurodegeneration, and speculate on their potential in drug combination to target distinct pathologies as a therapeutic disease modification approach.

• Optimizing stem cell collection through CXCR4 antagonists.

  Authors: Hemchandra Mahaseth, Jonathan Kaufman

  Frontiers in bioscience (Scholar edition). 4:611-9.

  Currently, nearly all the autologous stem cell transplantation and majority of allogeneic stem cell transplantation are performed using circulating peripheral blood stem cells. At steady conditions,Currently, nearly all the autologous stem cell transplantation and majority of allogeneic stem cell transplantation are performed using circulating peripheral blood stem cells. At steady conditions, less than 0.05 percent of the peripheral white cells are believed to be CD34+, a surrogate marker for stem cells. The content of hematopoietic CD34+ cells in the blood can be increased dramatically following recovery from myelosuppressive chemotherapy and/or the administration of hematopoietic growth factors (GM-CS or G-CSF), and an engrafting dose of stem cells can be collected by large volume apheresis following hematopoietic cytokine treatment. However these strategies fail to result in an adequate number of hematopoietic cells in 5-30 percent of the cases, limiting the ability of patients to receive high dose chemotherapy and stem cell transplantation in the treatment of their cancer. Plerixafor, a CXCR4 antagonist has been found to be a potent stem cell mobilizer and it's superiority used in combination with G-CSF over G-CSF alone has been seen in non-Hodgkin's lymphoma and multiple myeloma in double blind randomized phase III clinical trials, leading to FDA (Food and Drug Administration) approval. This review article describes the development of plerixafor to mobilize stem cells and optimal strategies for stem cell collection from peripheral blood.

• 14-3-3zeta cooperates with phosphorylated Plk1 and is required for correct cytokinesis.

  Authors: Jian Du, Lijian Chen, Xin Luo, Yuxian Shen, Zhen Dou, Jilong Shen, Li Cheng, Ying Chen, Chengjin Li, Hua Wang, Xuebiao Yao

  Frontiers in bioscience (Scholar edition). 4:639-50.

  Proteins of the 14-3-3 family are functionally conserved in eukaryotic kingdom which participates in diversified and critical cellular processes. However, the exact roles of these proteins in mitoticProteins of the 14-3-3 family are functionally conserved in eukaryotic kingdom which participates in diversified and critical cellular processes. However, the exact roles of these proteins in mitotic regulation has remained elusive. Polo-like kinase 1 (Plk1) is a serine/threonine protein kinase that plays multiple critical functions such as centrosome maturation, mitotic chromosome segregation, cytokinesis, and the DNA damage response. Here we show that 14-3-3zeta interacts and cooperates with Plk1 in mitotic progress. 14-3-3zeta is associated with the spindle at metaphase and concentrated in the midbody during cytokinesis. Using yeast two hybrid assay, we found a functional connection between 14-3-3zeta and Plk1. We demonstrate that phosphorylation of Plk1 at S330 and S597 promotes its interaction with 14-3-3zeta. Importantly, 14-3-3zeta cooperates with Plk1 in ensuring successful cytokinesis. We conclude that mitotic phosphorylation of Plk1 promotes interaction with 14-3-3zeta and this interaction is required for faithful cytokinesis. Taken together with the results of previous studies, our results suggest 14-3-3 family emerges as a novel player in mitotic regulation: cooperation with Plk1 to ensure a faithful cytokinesis.

• EGF-receptor signaling and epithelial-mesenchymal transition in human carcinomas.

  Authors: Ala-Eddin Al Moustafa, Amal Achkhar, Amber Yasmeen

  Frontiers in bioscience (Scholar edition). 4:671-84.

  The epidermal growth factor receptor (EGF-R) signaling pathway maintains a balance between cell proliferation, differentiation and apoptosis, and thus it is believed that EGF-R signaling pathwaysThe epidermal growth factor receptor (EGF-R) signaling pathway maintains a balance between cell proliferation, differentiation and apoptosis, and thus it is believed that EGF-R signaling pathways play an important role in the development and progression of several human carcinomas. Epithelial-mesenchymal transition (EMT) describes the dedifferentiation switch between polarized epithelial cancer cells and contractile and motile mesenchymal (invasive) cells during cancer progression and metastasis. Activation of EGF-R signaling regulates EMT-associated invasion and migration in normal and malignant epithelial cells. In contrast, blocking EGF-R and consequently its pathways, by a monoclonal antibody (mAb) or a tyrosine kinase inhibitor (TKI), inhibit cellular migration and invasion, suggesting an essential role for EGF-R inhibitors in the control of cancer metastasis. The purpose of this review is to summarize current information regarding the role of EGF-R signaling on EMT during human cancer progression and metastasis.

• Deciphering the role of Toll-like receptors in humoral responses to Borreliae.

  Authors: Gregory S Dickinson, Kishore R Alugupalli

  Frontiers in bioscience (Scholar edition). 4:699-712.

  The bacteria of the genus Borrelia are arthropod-borne spirochetes that cause relapsing fever and Lyme disease in humans. Like most arthropod-borne pathogens, Borreliae must survive in the peripheryThe bacteria of the genus Borrelia are arthropod-borne spirochetes that cause relapsing fever and Lyme disease in humans. Like most arthropod-borne pathogens, Borreliae must survive in the periphery of their vertebrate hosts to allow for transmission to another arthropod vector. These spatial and temporal restrictions require that Borreliae evade the adaptive immune response. Borreliae have evolved genetic mechanisms that alter their surface protein expression, thereby altering the antigenic target presented to the host. To control Borreliae infection, the host relies on a rapid humoral response. While it is clear that B cell antigen receptor signaling is a critical requirement for the specific antibody responses, growing evidence suggests that additional signaling by innate immune receptors such as Toll-like receptors is necessary for optimal T cell-dependent and T cell-independent antibody responses. This review is focused on the role of Toll-like receptors in B cell responses to relapsing fever and Lyme disease Borreliae.

• TGF-beta antiproliferative effects in tumor suppression.

  Authors: Stephan Christopher Jahn, Mary Elizabeth Law, Patrick Evan Corsino, Brian Keith Law

  Frontiers in bioscience (Scholar edition). 4:749-66.

  The TGF-beta signaling pathway controls multiple functions of cancer cells and the surrounding stromal tissue. Some TGF-beta actions suppress cancer formation, while others contribute to tumorThe TGF-beta signaling pathway controls multiple functions of cancer cells and the surrounding stromal tissue. Some TGF-beta actions suppress cancer formation, while others contribute to tumor progression. Evidence supporting a tumor suppressive role for the TGF-beta/Smad signaling axis is presented here. These data are compiled from cell culture studies, animal models, analyses of human tumors, and investigations of polymorphisms of TGF-beta pathway components and their associated cancer risk. Therapeutic strategies for cancer treatment involving either restoring or potentiating TGF-beta tumor suppressive activities, or blocking TGF-beta tumor promoting functions are considered.

• The role of tumor-associated macrophage in tumor progression.

  Authors: Koji Fukuda, Aya Kobayashi, Kounosuke Watabe

  Frontiers in bioscience (Scholar edition). 4:787-98.

  The tumor progression is not only regulated by metastasis promoting and suppressing genes in cancer cells but it is also strongly influenced by the interaction between cancer cells and the stromalThe tumor progression is not only regulated by metastasis promoting and suppressing genes in cancer cells but it is also strongly influenced by the interaction between cancer cells and the stromal cells. An abundance of inflammatory mediators and leukocytes has been known to promote cancer metastasis, and tumor associated macrophages (TAM) are the key players in the link between inflammation and cancer. TAM are derived from peripheral blood monocytes that are recruited into the tumor by inflammatory chemokines. Upon activation by cancer cells, TAM gain the ability of pro-tumoral functions including expression of various growth factors, promotion of angiogenesis and suppression of adaptive immunity, and many of these factors also play critical roles in cancer metastasis. In this review, we will summarize the recent information about the function of TAM in the inflammatory micro-environment of solid tumors and discuss the potential targets for future therapeutic approaches.

• Roles of microRNAs in cancer stem cells.

  Authors: Nanjiang Zhou, Yin-Yuan Mo

  Frontiers in bioscience (Scholar edition). 4:810-8.

  MicroRNAs are a class of endogenous non-coding RNAs that function as important regulatory molecules via the RNA interference mechanism. Since microRNAs play a fundamental role in regulation of aMicroRNAs are a class of endogenous non-coding RNAs that function as important regulatory molecules via the RNA interference mechanism. Since microRNAs play a fundamental role in regulation of a variety of cellular, physiological, and developmental processes, their aberrant expression can lead to a variety of human diseases including cancer. In particular, microRNAs have been implicated in regulation of stem cells as well as cancer stem cells. Given that cancer stem cells are believed to be responsible for the cancer initiation, metastasis and chemotherapy resistance, a better understanding of how microRNAs mediate gene expression in cancer stem cells will help identify novel cancer biomarkers and therapeutic targets, and as a result, it will aid in the development of better strategy for cancer treatment. In this review, we will update recent advances in microRNAs involved in cancer stem cells and their gene regulations in these cells.

• Modulation of cell cycle regulators by HDACs.

  Authors: Elphine Telles, Edward Seto

  Frontiers in bioscience (Scholar edition). 4:831-9.

  Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues on histones and non-histone proteins. HDACs have been shown to control the functions of key cell cycle proteins. ConsistentHistone deacetylases (HDACs) catalyze the deacetylation of lysine residues on histones and non-histone proteins. HDACs have been shown to control the functions of key cell cycle proteins. Consistent with this, the overexpression of HDACs has been observed in multiple cancers, resulting in deregulation of the cell cycle and uncontrolled proliferation. This review focuses on the impact that HDACs have on cell cycle control through the deacetylation of proteins.

• Integrating structure and function of 'tandem-repeat' galectins.

  Authors: Maria F Troncoso, Maria T Elola, Diego O Croci, Gabriel A Rabinovich

  Frontiers in bioscience (Scholar edition). 4:864-87.

  Galectins (GALs) are evolutionarily-conserved lectins defined by at least one carbohydrate recognition domain (CRD) with affinity for beta-galactosides and conserved sequence motifs. Although theGalectins (GALs) are evolutionarily-conserved lectins defined by at least one carbohydrate recognition domain (CRD) with affinity for beta-galactosides and conserved sequence motifs. Although the biological roles of some members of this family, including the 'proto-type' GAL-1 and the 'chimera-type' GAL-3 have been widely studied, the functions of 'tandem-repeat' galectins are just emerging. The subgroup of 'tandem-repeat' galectins (GAL-4, -6, -8, -9, and -12) contain two distinct CRDs, connected by a linker peptide. Here we integrated and distilled the available information on 'tandem-repeat' galectins, their specific structures, potential ligands and biological activities in inflammatory and neoplastic diseases. While GAL-4 has been implicated in inflammatory bowel diseases, either as a pro-inflammatory or pro-apoptotic mediator, GAL-8 plays roles in autoimmune diseases such as rheumatoid arthritis and lupus erythematosus and modulates tumor progression. GAL-9 controls allergic inflammation and Th1/Th17-mediated autoimmunity and has prognostic value in certain tumor types. Finally, GAL-12 plays important roles in adipocyte physiology. Although this information is just emerging, further studies are needed to dissect the biological roles of 'tandem-repeat' galectins in health and disease.

• Chromosomal mutations involved in antibiotic resistance in Staphylococcus aureus.

  Authors: Bjorn A Espedido, Iain B Gosbell

  Frontiers in bioscience (Scholar edition). 4:900-15.

  Staphylococcus aureus is an important pathogen involved in infections in both the community and hospital setting. Strains that are resistant to multiple classes of antibiotics, particularlyStaphylococcus aureus is an important pathogen involved in infections in both the community and hospital setting. Strains that are resistant to multiple classes of antibiotics, particularly methicillin-resistant strains (MRSA), are prevalent in nosocomial infections and are associated with high morbidity and mortality rates. Such antibiotic-resistant strains limit the therapeutic options and place a burden on the health care system. In the hospital setting, horizontal gene transfer plays an important role in disseminating antibiotic resistant determinants among S. aureus. However, resistance to all known classes of antibiotics have been attributed to genes found within the S. aureus chromosome or to due to mutation as a result of selection pressure. Spontaneous mutations, in particular, are pivotal in the emergence of novel resistances. Consequently, newer drugs with better activity and/or antibacterial agents with novel targets need to be developed to combat and control the further spread of antibiotic resistance.

• Prophylactic vaccines for prevention of prostate cancer.

  Authors: Rajesh K Naz, Briana Shiley

  Frontiers in bioscience (Scholar edition). 4:932-40.

  Prostate cancer is the most prevalent cancer and the second leading cause of cancer death in men. There are various modalities for treatment of prostate cancer. Immunotherapy with several vaccinesProstate cancer is the most prevalent cancer and the second leading cause of cancer death in men. There are various modalities for treatment of prostate cancer. Immunotherapy with several vaccines and antibodies has also been successfully used with positive clinical outcome in prostate cancer patients. The majority of these vaccines are palliative and have been employed when a person is already diagnosed with prostate cancer. The aim of this article is to review various vaccines that have been examined for immunoprophylactic prevention of initiation/development/metastasis of prostate cancer. The Pubmed database and Google Scholar search identified 26 articles on various vaccines that have been investigated for prophylactic prevention of cancer development. These vaccines targeted prostate-specific/restricted antigens (PSA/PSMA/PSCA), oncoproteins (GRP/MUC family, erbB2/HER-2/neu), whole tumor cell antigens, prostate regulating hormones (GnRH/testosterone), and various cytokines and immune modulators. The data indicates that the development of immunoprophylactic vaccines for prostate cancer is an exciting proposition, which can translate into a viable reality for clinical application in humans.

• Hypothalamic Akt/PKB signaling in regulation of food intake.

  Authors: Dong-Hoon Kim, Stephen C Woods, Randy J Seeley

  Frontiers in bioscience (Scholar edition). 4:953-66.

  Recent tremendous advances in our understanding of the regulation of food intake are expected to contribute to the treatment of obesity in the near future. The hypothalamus is a center for regulationRecent tremendous advances in our understanding of the regulation of food intake are expected to contribute to the treatment of obesity in the near future. The hypothalamus is a center for regulation of food intake and NPY/AgRP and POMC neurons are key regulators of food intake in the arcuate nucleus. The level of energy in the body is monitored by energy sensors in the hypothalamus. A variety of signals originating from peripheral organs to sense the status of energy converge on the hypothalamus and diverse neurons in the hypothalamus are involved in determining the output of signal to regulate food intake. Therefore, it is important to understand the signals and energy sensors in the hypothalamus. In this review, we describe the potential role of Akt/PKB signaling as an energy sensor that regulates food intake.

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