bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-Neuron Stability during Repeated Reaching in Macaque Premotor Cortex
Authors: Chestek Cynthia A. , Batista Aaron P. , Santhanam Gopal , Yu Byron M. , Afshar Afsheen , Cunningham John P. , Gilja Vikash , Ryu Stephen I. , Churchland Mark M. , Shenoy Krishna V.
Published: October 2007

Some movements that animals and humans make are highly stereotyped, repeated with little variation. The patterns of neural activity associated with repeats of a movement may be highly similar, or the same movement may arise from different patterns of neural activity, if the brain exploits redundancies in the neural projections to muscles. We examined the stability of the relationship between neural activity and behavior. We asked whether the variability in neural activity that we observed during repeated reaching was consistent with a noisy but stable relationship, or with a changing relationship, between neural activity and behavior. Monkeys performed highly similar reaches under tight behavioral control, while many neurons in the dorsal aspect of premotor cortex and the primary motor cortex were simultaneously monitored for several hours. Neural activity was predominantly stable over time in all measured properties: firing rate, directional tuning, and contribution to a decoding model that predicted kinematics from neural activity. The small changes in neural activity that we did observe could be accounted for primarily by subtle changes in behavior. We conclude that the relationship between neural activity and practiced behavior is reasonably stable, at least on timescales of minutes up to 48 h. This finding has significant implications for the design of neural prosthetic systems because it suggests that device recalibration need not be overly frequent, It also has implications for studies of neural plasticity because a stable baseline permits identification of nonstationary shifts.
Modulation of the Receptive Fields of Midbrain Neurons Elicited by Thalamic Electrical Stimulation through Corticofugal Feedback
Authors: Wu Yamin , Yan Jun
Published: October 2007

The ascending and descending projections of the central auditory system form multiple tonotopic loops. This study specifically examines the tonotopic pathway from the auditory thalamus to the auditory cortex and then to the auditory midbrain in mice. We observed the changes of receptive fields in the central nucleus of the inferior colliculus of the midbrain evoked by focal electrical stimulation of the ventral division of the medial geniculate body of the thalamus. The receptive field of an auditory neuron was characterized by five parameters: the best frequency, minimum threshold, bandwidth, size of receptive field, and average spike number. We found that focal thalamic stimulation changed the parametric values characterizing the recorded collicular receptive fields toward those characterizing the stimulated thalamic receptive fields. Cortical inactivation with muscimol prevented the development of the collicular plasticity induced by focal thalamic stimulation. Our data suggest that the intact colliculo-thalamo-cortico-collicular loops are important for the coordination of sound-guided plasticity in the central auditory system.
Preparatory Activity in Occipital Cortex in Early Blind Humans Predicts Auditory Perceptual Performance
Authors: Stevens Alexander A. , Snodgrass Mathew , Schwartz Daniel , Weaver Kurt
Published: October 2007

Early onset blindness leads to a dramatic alteration in the way the world is perceived, a change that is detectable in the organization of the brain. Several studies have confirmed that blindness leads to functional alterations in occipital cortices that normally serve visual functions. These reorganized brain regions respond to a variety of tasks and stimuli, but their specific functions are unclear. In sighted individuals, several studies have reported preparatory activity in retinotopic areas, which enhances perceptual sensitivity. “Baseline shifts,” changes in activity associated with a cue predicting an upcoming event, provides a marker for attentional modulation. Here we demonstrate that, in early blind subjects, medial occipital areas produced significant blood oxygenation level-dependent (BOLD) responses to a cue signaling an auditory discrimination trial but not to a cue indicating a no-trial period. Furthermore, the amplitude of the BOLD response in the anterior calcarine sulcus of early blind subjects correlated with their discrimination performance on the auditory backward masking task. Preparatory BOLD responses also were present in auditory cortices, although they were more robust in blind than sighted control subjects. The pattern of response in visual areas is similar to preparatory effects observed during visual selective attention in sighted subjects and consistent with the hypothesis that the mechanisms implicated in visual attention continue to modulate occipital cortex in the early blind. A possible source of this top-down modulation may be the frontoparietal circuits that retain their connectivity with the reorganized occipital cortex and as a result influence processing of nonvisual stimuli in the blind.
State Dependence of Spike Timing and Neuronal Function in a Motor Pattern Generating Network
Authors: Wu Jin-sheng , Due Michael R. , Sasaki Kosei , Proekt Alex , Jing Jian , Weiss Klaudiusz R.
Published: October 2007

When sustained firing of a neuron is similar in different types of motor programs, its role in the generation of these programs is often similar. We investigated whether this is also the case for neurons involved in phase transition. In theAplysiafeeding central pattern generator (CPG), identified interneuron B64 starts firing at the transition between the protraction and the retraction phases of all types of motor programs, and its firing is sustained during the retraction phase. It was thought that B64 functions as a protraction terminator as it provides strong inhibitory input to protraction interneurons and motoneurons. Furthermore, premature activation of B64 can lead to premature termination of the protraction phase. Indeed, as we show here, B64 can terminate the protraction phase regardless of the type of motor program. However, B64 actually only functions as a protraction terminator in ingestive-like but not in egestive-like programs. This differential role of B64 results from a differential timing of the initiation of B64 spiking in the two types of programs. In turn, this differential timing of the initiation of B64 firing is determined by the internal state of the CPG. Thus, this study indicates the importance of the timing of initiation of firing in determining the functional role of a neuron and demonstrates that this role depends on the activity-dependent state of the network.
Breadth of Tuning and Taste Coding in Mammalian Taste Buds
Authors: Tomchik Seth M. , Berg Stephanie , Kim Joung Woul , Chaudhari Nirupa , Roper Stephen D.
Published: October 2007

A longstanding question in taste research concerns taste coding and, in particular, how broadly are individual taste bud cells tuned to taste qualities (sweet, bitter, umami, salty, and sour). Taste bud cells express G-protein-coupled receptors for sweet, bitter, or umami tastes but not in combination. However, responses to multiple taste qualities have been recorded in individual taste cells. We and others have shown previously there are two classes of taste bud cells directly involved in gustatory signaling: “receptor” (type II) cells that detect and transduce sweet, bitter, and umami compounds, and “presynaptic” (type III) cells. We hypothesize that receptor cells transmit their signals to presynaptic cells. This communication between taste cells could represent a potential convergence of taste information in the taste bud, resulting in taste cells that would respond broadly to multiple taste stimuli. We tested this hypothesis using calcium imaging in a lingual slice preparation. Here, we show that receptor cells are indeed narrowly tuned: 82% responded to only one taste stimulus. In contrast, presynaptic cells are broadly tuned: 83% responded to two or more different taste qualities. Receptor cells responded to bitter, sweet, or umami stimuli but rarely to sour or salty stimuli. Presynaptic cells responded to all taste qualities, including sour and salty. These data further elaborate functional differences between receptor cells and presynaptic cells, provide strong evidence for communication within the taste bud, and resolve the paradox of broad taste cell tuning despite mutually exclusive receptor expression.
Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6
Authors: Smith Stephen E. P. , Li Jennifer , Garbett Krassimira , Mirnics Karoly , Patterson Paul H.
Published: October 2007

Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.
Interactions between Circadian Neurons Control Temperature Synchronization ofDrosophilaBehavior
Authors: Busza Ania , Murad Alejandro , Emery Patrick
Published: October 2007

Most animals rely on circadian clocks to synchronize their physiology and behavior with the day/night cycle. Light and temperature are the major physical variables that can synchronize circadian rhythms. Although the effects of light on circadian behavior have been studied in detail inDrosophila, the neuronal mechanisms underlying temperature synchronization of circadian behavior have received less attention. Here, we show that temperature cycles synchronize and durably affect circadian behavior inDrosophilain the absence of light input. This synchronization depends on the well characterized and functionally coupled circadian neurons controlling the morning and evening activity under light/dark cycles: the M cells and E cells. However, circadian neurons distinct from the M and E cells are implicated in the control of rhythmic behavior specifically under temperature cycles. These additional neurons play a dual role: they promote evening activity and negatively regulate E cell function in the middle of the day. We also demonstrate that, although temperature synchronizes circadian behavior more slowly than light, this synchronization is considerably accelerated when the M cell oscillator is absent or genetically altered. Thus, whereas the E cells show great responsiveness to temperature input, the M cells and their robust self-sustained pacemaker act as a resistance to behavioral synchronization by temperature cycles. In conclusion, the behavioral responses to temperature input are determined by both the individual properties of specific groups of circadian neurons and their organization in a neural network.
Distinct Modes of Neuron Addition in Adult Mouse Neurogenesis
Authors: Ninkovic Jovica , Mori Tetsuji , Götz Magdalena
Published: October 2007

Adult neurogenesis is restricted to two distinct areas of the mammalian brain: the olfactory bulb (OB) and the dentate gyrus (DG). Despite its spatial restriction, adult neurogenesis is of crucial importance for sensory processing and learning and memory. Although it has been shown that tens of thousands of new neurons arrive in the OB and DG every day with about half of them surviving after integration, the total contribution of adult neurogenesis to the pre-existing network remains mostly unknown. This is because of previous approaches labeling only a small proportion of adult-generated neurons. Here, we used genetic fate mapping to follow the majority of adult-generated neurons over long periods. Our data demonstrate two distinct modes of neuron addition to the pre-existing network. In the glomerular layer of the OB, there is a constant net addition of adult-generated neurons reaching a third of the total neuronal population within 9 months. In contrast, adult neurogenesis contributes to only a minor fraction of the entire neuronal network in the granular cell layer of the OB and the DG. Although the fraction of adult generated neurons can be further increased by an enriched environment, it still remains a minority of the neuronal network in the DG. Thus, neuron addition is distinct and tightly regulated in the neuronal networks that incorporate new neurons life long.
Brain-Derived Neurotrophic Factor Rescues Synaptic Plasticity in a Mouse Model of Fragile X Syndrome
Authors: Lauterborn Julie C. , Rex Christopher S. , Kramár Eniko , Chen Lulu Y. , Pandyarajan Vijay , Lynch Gary , Gall Christine M.
Published: October 2007

Mice lacking expression of the fragile X mental retardation 1 (Fmr1) gene have deficits in types of learning that are dependent on the hippocampus. Here, we report that long-term potentiation (LTP) elicited by threshold levels of theta burst afferent stimulation (TBS) is severely impaired in hippocampal field CA1 of young adultFmr1knock-out mice. The deficit was not associated with changes in postsynaptic responses to TBS, NMDA receptor activation, or levels of punctate glutamic acid decarboxylase-65/67 immunoreactivity. TBS-induced actin polymerization within dendritic spines was also normal. The LTP impairment was evident within 5 min of induction and, thus, may not be secondary to defects in activity-initiated protein synthesis. Protein levels for both brain-derived neurotrophic factor (BDNF), a neurotrophin that activates pathways involved in spine cytoskeletal reorganization, and its TrkB receptor were comparable between genotypes. BDNF infusion had no effect on baseline transmission or on postsynaptic responses to theta burst stimulation, but nonetheless fully restored LTP in slices from fragile X mice. These results indicate that the fragile X mutation produces a highly selective impairment to LTP, possibly at a step downstream of actin filament assembly, and suggest a means for overcoming this deficit. The possibility of a pharmacological therapy based on these results is discussed.
Inflammation Activates the Interferon Signaling Pathways in Taste Bud Cells
Authors: Wang Hong , Zhou Minliang , Brand Joseph , Huang Liquan
Published: October 2007

Patients with viral and bacterial infections or other inflammatory illnesses often experience taste dysfunctions. The agents responsible for these taste disorders are thought to be related to infection-induced inflammation, but the mechanisms are not known. As a first step in characterizing the possible role of inflammation in taste disorders, we report here evidence for the presence of interferon (IFN)-mediated signaling pathways in taste bud cells. IFN receptors, particularly the IFN-γ receptor IFNGR1, are coexpressed with the taste cell-type markers neuronal cell adhesion molecule and α-gustducin, suggesting that both the taste receptor cells and synapse-forming cells in the taste bud can be stimulated by IFN. Incubation of taste bud-containing lingual epithelia with recombinant IFN-α and IFN-γ triggered the IFN-mediated signaling cascades, resulting in the phosphorylation of the downstream STAT1 (signal transducer and activator of transcription protein 1) transcription factor. Intraperitoneal injection of lipopolysaccharide or polyinosinic:polycytidylic acid into mice, mimicking bacterial and viral infections, respectively, altered gene expression patterns in taste bud cells. Furthermore, the systemic administration of either IFN-α or IFN-γ significantly increased the number of taste bud cells undergoing programmed cell death. These findings suggest that bacterial and viral infection-induced IFNs can act directly on taste bud cells, affecting their cellular function in taste transduction, and that IFN-induced apoptosis in taste buds may cause abnormal cell turnover and skew the representation of different taste bud cell types, leading to the development of taste disorders. To our knowledge, this is the first study providing direct evidence that inflammation can affect taste buds through cytokine signaling pathways.
Hippocampal α4β2 Nicotinic Acetylcholine Receptor Involvement in the Enhancing Effect of Acute Nicotine on Contextual Fear Conditioning
Authors: Davis Jennifer A. , Kenney Justin W. , Gould Thomas J.
Published: October 2007

Nicotine is known to enhance learning and memory in hippocampus-dependent tasks such as contextual fear conditioning. The present study was designed to directly examine whether the hippocampus plays a role in mediating this enhancement and which nicotinic acetylcholine receptor (nAChR) subtypes localized to the hippocampus are critical for enhanced learning. Contextual fear conditioning consisted of two white noise conditioned stimuli presentations, each coterminating with a 2 s, 0.57 mA footshock separated by a 120 s intertrial interval. Nicotine (0.09, 0.18, and 0.35 μg per side) was bilaterally infused into the dorsal hippocampus before training and testing. Infusions of nicotine into the dorsal hippocampus produced a dose-dependent enhancement of contextual fear conditioning. To determine which nAChRs are critical to the enhancing effect of nicotine, the preferential α4β2 nAChR antagonist, dihydro-β-erythroidine (DHβE) (6.00 and 18.00 μg per side), or the preferential α7 nAChR antagonist, methyllycaconitine (MLA) (13.50 and 27.00 μg per side), was bilaterally infused into the dorsal hippocampus before systemic injections of nicotine (0.09 mg/kg). DHβE infusions dose-dependently blocked the enhancement of contextual fear conditioning by nicotine, whereas MLA infusions yielded an intermediate effect. In addition, neither DHβE nor MLA had an effect on contextual fear conditioning in the absence of systemic nicotine. The present results suggest a critical role for α4β2 nAChRs in the dorsal hippocampus for mediating the enhancing effect of nicotine on contextual fear conditioning.
Two new spaces of vector-valued limit power functions
Authors: Zhang Chuanyi , Meng Chenhui
Published: October 2007

To answer a question in [24], we propose\documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{upgreek} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage{bbm} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} $$\mathcal{U}\mathcal{L}\mathcal{P}(\mathbb{R}^ + ,H)$$ \end{document}, the space of uniform limit power functions and\documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{upgreek} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage{bbm} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} $$\mathcal{L}\mathcal{P}_2$$ \end{document}, the space of limit power functions. We show that\documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{upgreek} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage{bbm} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} $$\mathcal{U}\mathcal{L}\mathcal{P}(\mathbb{R}^ + ,H)$$ \end{document}and\documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{upgreek} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage{bbm} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} $$\mathcal{L}\mathcal{P}_2$$ \end{document}have properties respectively similar to that of\documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{upgreek} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage{bbm} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} $$\mathcal{A}\mathcal{P}(\mathbb{R}^ + ,H)$$ \end{document}, the space of almost periodic functions and to that ofB2, Besicovitch’s space. Finally, we point out that\documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{upgreek} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage{bbm} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} $$\mathcal{L}\mathcal{P}_2$$ \end{document}is the largest among those Hilbert spaces in limit power function set whose members have associated Fourier series (in the sense of a new basis) and satisfy Parseval’s equality.
On constants related to the choice of the local time at 0, and the corresponding Itô measure for Bessel processes with dimension d = 2(1 − α ), 0 < α < 1
Authors: Donati-Martin Catherine , Roynette Bernard , Vallois Pierre , Yor Marc
Published: October 2007

The precise choice of the local time at 0 for a Bessel process with dimensiond∈ ]0,2[ plays some role in explicit computations or limiting results involving excursion theory for these processes. Starting from one specific choice, and deriving the main related formulae, it is shown how the various multiplicative constants corresponding to other choices made in the literature enter into these formulae.
Joint asymptotic behavior of local and occupation times of random walk in higher dimension
Authors: Csáki Endre , Földes Antónia , Révész Pál
Published: October 2007

Considering a simple symmetric random walk in dimension
d
≧ 3, we study the almost sure joint asymptotic behavior of two objects: first the local times of a pair of neighboring points, then the local time of a point and the occupation time of the surface of the unit ball around it.
Zoharitic hints at the historical development of the Sefirot
Authors: Gertel Elliot B
Published: October 2007

Citing references in the Zoharitic literature (compiled in the late thirteenth century) to the historical development of the Kabbalistic doctrine of the Sefirot (Divine Emanations), I argue that these references indicate historical consciousness on the part of the Kabbalists that pre-dates the nineteenth century historians of the Wissenschaft des Judentums. These references may also be indicative of a process of debate and of refinement of that doctrine, as well as an eff ort to shield this process from Jewish and Christian critics by camouflaging it under general discussions of the Shem Hameforash, the Ineffable Divine Name, a term that in and of itself was a lightening rod to some critics, who would have associated it with magic and superstition.
Philosophical Fundamentals of Belief in the Mystical Poetry of Rumi and Donne
Authors: Mannani Manijeh
Published: October 2007

The central focus of my article is a comparative study of the Persian Sufi poet, Jalal al-Din Rumi (1212-1273), and the English Metaphysical poet, John Donne (1572-1631). In this article, I have analyzed the two schools of thought to which these poets belong as well as their individual world-views to elucidate the different dimensions of the shared philosophy governing their poetry. Mine is, in itself, a Metaphysical endeavor, namely to use Dr. Samuel Johnson’s phrase facetiously, “yoking together” two literary monarchs who appear to be culturally, chronologically, and geographically so distant.
My close and comparative study of these two poets has illustrated the basic principles that underlie the metaphysical poems of Rumi and Donne. In a yet more general sense, my article has shed more light on the bonds between the two disciplines of religion/mysticism and literature and has thus examined not only the interdependent issues in the two disciplines but also the invisible and yet highly astonishing closeness that exists in the representative works of the two literary and religious traditions.
Biblical Books and Texts as Self-Contained Sources for the Study of Ancient Israelite History
Authors: Ben Zvi Ehud
Published: October 2007

This article discusses the main value of, or the most significant contributions that the Hebrew Bible or, and much better, the books that were eventually included in that collection make for the critical study of ancient Israelite history. The latter are to be seen in the crucial ways in which these books contribute to the study of the discourses, ideologies, apprehensions and hopes of the communities, or at least the highly literate elites of the communities within which and for which they were written, and at times for social and economic studies of the same communities.
Nikky-Guninder Kaur Singh. The Birth of the Khalsa: A Feminist Re-Memory of Sikh Identity
Authors: Hawley Michael
Published: October 2007

Nikky-Guninder Kaur Singh. The Birth of the Khalsa: A Feminist Re-Memory of Sikh Identity. Albany: State University of New York Press, 2005 xxv + 224 p. pbk ISBN: 0-7914-6583-7. $25.95 US.
Zoledronic Acid and Survival in Breast Cancer Patients with Bone Metastases and Elevated Markers of Osteoclast Activity
Authors: Lipton Allan , Cook Richard J. , Major Pierre , Smith Matthew R. , Coleman Robert E.
Published: October 2007

Learning Objectives

After completing this course, the reader will be able to: Describe the benefits of bisphosphonate treatment in patients with bone metastases from breast cancer.Summarize the association between decreases in elevated urinary NTX levels during the first 3 months of zoledronic acid treatment and clinical outcomes such as survival, time to disease progression, and time to first SRE.Describe the association, if any, between bone marker levels and an impending SRE.

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How to Preserve Fertility in Young Women Exposed to Chemotherapy? The Role of GnRH Agonist Cotreatment in Addition to Cryopreservation of Embrya, Oocytes, or Ovaries
Authors: Blumenfeld Zeev
Published: October 2007

Learning Objectives

After completing this course, the reader will be able to: Discuss the possibilities for preserving fertility in women exposed to chemotherapy.List the possible mechanisms put forward to explain the beneficial effect of GnRH agonists in minimizing the gonadotoxic effect of chemotherapy, in particular that of alkylating agents.Identify the advantages and possible risks and shortcomings of each of the proposed methods for fertility preservation in women exposed to gonadotoxic chemotherapy.Discuss the possibility of combining several methods to maximize the chances of fertility preservation in these patients.Explain the gender differences between male and female patients regarding the methods of fertility preservation.

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Commentary: Oncologic Drugs in Patients with Organ Dysfunction: A Summary
Authors: Superfin Diana , Iannucci Andrea A. , Davies Angela M.
Published: October 2007

Learning Objectives

After completing this course, the reader will be able to: Describe the currently recommended dose adjustments for common chemotherapeutics in oncology patients with organ dysfunction.Explain the rationale for using phase I dose-escalation studies to determine appropriate chemotherapy dosing in patients with organ dysfunction.Discuss the limitations of the currently available studies to guide chemotherapy dose adjustment in patients with organ dysfunction.

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A Mechanistic Perspective of Monoclonal Antibodies in Cancer Therapy Beyond Target-Related Effects
Authors: Strome Scott E. , Sausville Edward A. , Mann Dean
Published: October 2007

Learning Objectives

After completing this course, the reader will be able to: Describe the relationship between antibody structure and effector function, and identify strategies for modifying antibody structure to enhance these functions.Explain how the efficacy of monoclonal antibodies in cancer therapy may occur via antibody- as well as target-related mechanisms.Discuss how the ability of monoclonal antibodies to activate immune-mediated effector functions differs across antibody isotypes.

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Small Cell Lung Cancer: Have We Made Any Progress Over the Last 25 Years?
Authors: Lally Brian E. , Urbanic James J. , Blackstock A. William , Miller Antonius A. , Perry Michael C.
Published: October 2007

Learning Objectives

After completing this course, the reader will be able to: Discuss the currently available SCLC treatment options.Describe the benefits of integrating thoracic radiotherapy into SCLC treatment.Identify the limitations of current SCLC treatment options and explain how future clinical trials are addressing these limitations.

Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Temozolomide for the Treatment of Metastatic Melanoma: A Systematic Review
Authors: Quirt Ian , Verma Shailendra , Petrella Teresa , Bak Kate , Charette Manya
Published: October 2007

Background.

This systematic review examines the role of temozolomide in patients with metastatic melanoma. Outcomes of interest include response rate, progression-free survival, overall survival, quality of life, and adverse effects.

Methods.

The MEDLINE, EMBASE, and Cochrane Library databases were searched from 1980 through to 2005 using variations on the search terms: melanoma, clinical trial, random, temozolomide, temodal, and temodar. The American Society of Clinical Oncology Annual Meeting proceedings were searched from 1996 to 2005. Relevant articles and abstracts were selected and reviewed by two reviewers, and the reference lists from these sources were searched for additional trials.

Results.

Two randomized phase III trials and three randomized phase II trials were located. In addition, 21 phase I or II trials investigating single-agent temozolomide, temozolomide plus interferon-α, and temozolomide plus thalidomide were reviewed. A direct comparison of temozolomide and dacarbazine demonstrated equal efficacy for response rates and overall survival; however, no significant difference was reported. A second phase III study comparing single-agent temozolomide with temozolomide combined with interferon-α indicated a significantly higher response rate for the combination treatment arm, but no difference in overall survival was noted. Further phase III studies are required to confirm whether there is a benefit associated with the combination of temozolomide and interferon-α or thalidomide.

Conclusion.

Our review of the available literature suggests that temozolomide demonstrates comparable activity to the current standard treatment, dacarbazine, with the additional benefit of being a convenient oral treatment that penetrates the blood–brain barrier.
Primary Malignant Sarcomas of the Heart and Great Vessels in Adult Patients — A Single-Center Experience
Authors: Mayer Frank , Aebert Hermann , Rudert Maximilian , Königsrainer Alfred , Horger Marius , Kanz Lothar , Bamberg Michael , Ziemer Gerhard , Hartmann Jörg Thomas
Published: October 2007

Background.

Sarcomas arising in the heart or the great vessels are rare entities. The prognosis of the patients is dismal.

Methods.

Between January 1993 and September 2006, of 1,429 patients registered to the Sarcoma Center, 14 had a primary sarcoma of the heart or large vessels.

Results.

Tumors were located in the left ventricle (n = 3), left/right atrium (n = 2/3), pulmonary artery (n = 2), and ventricular septum, aorta, pericardium, and inferior vena cava (n = 1 each). The most frequently encountered histologic subtypes were leiomyosarcoma and angiosarcoma. Six patients presented with distant metastases to the lungs (n = 5), lymph nodes (n = 2), and liver (n = 1). Eight patients had localized disease. Six of them underwent resection with curative intent. Of those, two developed local recurrence within 2 and 10 months from surgery.

Eleven patients received palliative chemotherapy, seven of those as initial treatment. Eight patients attained a response to treatment, two had disease stabilization for 6 and 12 months. After a median follow-up of 14.5 months (range, 2–156), three patients were alive with no evidence of disease 11, 52, and 156 months after diagnosis. Two patients were alive with disease and nine patients had died.

Conclusions.

Patients with primary sarcomas of the heart and the large vessels were of a young age, and more than half of them presented with advanced disease. Given the promising response to chemotherapy, an optimized treatment approach including neoadjuvant chemo-/radiotherapy in patients with locally advanced disease should be pursued.
Guidelines for Antiemetic Treatment of Chemotherapy-Induced Nausea and Vomiting: Past, Present, and Future Recommendations
Authors: Jordan Karin , Sippel Christoph , Schmoll Hans-Joachim
Published: October 2007

Learning Objectives

After completing this course, the reader will be able to: Explain the optimal antiemetic prophylaxis for patients receiving chemotherapy in regard to the emetogenic potential of the therapy.Describe the difference between acute and delayed emesis.Discuss the properties and optimal use of the different antiemetic drugs.

Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Randomized Crossover Pharmacokinetic Evaluation of Subcutaneous Versus Intravenous Granisetron in Cancer Patients Treated with Platinum-Based Chemotherapy
Authors: Gurpide Alfonso , Sadaba Belen , Martin-Algarra Salvador , Azanza Jose R. , Lopez-Picazo Jose M. , Campanero Miguel A. , Cabello Juan P. , Gil-Aldea Isabel , de la Cruz Susana , Gallego Victor Fernandez , Reyna Carmen , Garate Clara Olier , Blanco-Prieto María J. , Ceballos Jaime , Garcia-Foncillas Jesus , Perez-Gracia Jose L.
Published: October 2007

Background.

5-HT3-receptor antagonists are one of the mainstays of antiemetic treatment, and they are administered either i.v. or orally. Nevertheless, sometimes neither administration route is feasible, such as in patients unable to admit oral intake managed in an outpatient setting. Our objective was to evaluate the bioavailability of s.c. granisetron.

Patients and Methods.

Patients receiving platinum-based chemotherapy were randomized to receive 3 mg of granisetron either s.c. or i.v. in a crossover manner during two cycles. Blood and urine samples were collected after each cycle. Pharmacokinetic parameters observed with each administration route were compared by analysis of variance.

Results.

From May to November 2005, 31 patients were included and 25 were evaluable. Subcutaneous granisetron resulted in a 27% higher area under the concentration–time curve for 0–12 hours (AUC0–12h) and higher levels at 12 hours, with similar values for AUC0–24h. The maximum concentration was lower with the s.c. than with the i.v. route and was observed 30 minutes following s.c. administration.

Conclusion.

Granisetron administered s.c. achieves complete bioavailability. This is the first study that shows that s.c. granisetron might be a valid alternative to i.v. delivery. Further trials to confirm clinical equivalence are warranted. This new route of administration might be especially relevant for outpatient management of emesis in cancer patients.
Gastrointestinal stromal tumors regularly express synaptic vesicle proteins: evidence of a neuroendocrine phenotype
Authors: Bümming Per , Nilsson Ola , Ahlman Håkan , Welbencer Anna , Andersson Mattias K , Sjölund Katarina , Nilsson Bengt
Published: October 2007

Gastrointestinal stromal tumors (GISTs) are thought to originate from the interstitial cells of Cajal, which share many properties with neurons of the gastrointestinal tract. Recently, we demonstrated expression of the hormone ghrelin in GIST. The aim of the present study was therefore to evaluate a possible neuroendocrine phenotype of GIST. Specimens from 41 GISTs were examined for the expression of 12 different synaptic vesicle proteins. Expression of synaptic-like microvesicle proteins, e.g., Synaptic vesicle protein 2 (SV2), synaptobrevin, synapsin 1, and amphiphysin was demonstrated in a majority of GISTs by immunohistochemistry, western blotting, and quantitative reversetranscriptase PCR. One-third of the tumors also expressed the large dense core vesicle protein vesicular monoamine transporter 1. Presence of microvesicles and dense core vesicles in GIST was confirmed by electron microscopy. The expression of synaptic-like microvesicle proteins in GIST was not related to risk profile or to KIT/platelet derived growth factor alpha (PDGFRA) mutational status. Thus, GISTs regularly express a subset of synaptic-like microvesicle proteins necessary for the regulated secretion of neurotransmitters and hormones. Expression of synaptic-like micro-vesicle proteins, ghrelin and peptide hormone receptors in GIST indicate a neuroendocrine phenotype and suggest novel possibilities to treat therapy-resistant GIST.
A multi-gene approach to differentiate papillary thyroid carcinoma from benign lesions: gene selection using support vector machines with bootstrapping
Authors: Fujarewicz Krzysztof , Jarząb Michał , Eszlinger Markus , Krohn Knut , Paschke Ralf , Oczko-Wojciechowska Małgorzata , Wiench Małgorzata , Kukulska Aleksandra , Jarząb Barbara , Swierniak Andrzej
Published: October 2007

Selection of novel molecular markers is an important goal of cancer genomics studies. The aim of our analysis was to apply the multivariate bioinformatical tools to rank the genes – potential markers of papillary thyroid cancer (PTC) according to their diagnostic usefulness. We also assessed the accuracy of benign/malignant classification, based on gene expression profiling, for PTC. We analyzed a 180-array dataset (90 HG-U95A and 90 HG-U133A oligonucleotide arrays), which included a collection of 57 PTCs, 61 benign thyroid tumors, and 62 apparently normal tissues. Gene selection was carried out by the support vector machines method with bootstrapping, which allowed us 1) ranking the genes that were most important for classification quality and appeared most frequently in the classifiers (bootstrap-based feature ranking, BBFR); 2) ranking the samples, and thus detecting cases that were most difficult to classify (bootstrap-based outlier detection). The accuracy of PTC diagnosis was 98.5% for a 20-gene classifier, its 95% confidence interval (CI) was 95.9–100%, with the lower limit of CI exceeding 95% already for five genes. Only 5 of 180 samples (2.8%) were misclassified in more than 10% of bootstrap iterations. We specified 43 genes which are most suitable as molecular markers of PTC, among them some well-known PTC markers (MET, fibronectin 1, dipeptidylpeptidase 4, or adenosine A1 receptor) and potential new ones (UDP-galactose-4-epimerase, cadherin 16, gap junction protein 3, sushi, nidogen, and EGF-like domains 1, inhibitor of DNA binding 3, RUNX1, leiomodin 1, F-box protein 9, and tripartite motif-containing 58). The highest ranking gene, metallophosphoesterase domain-containing protein 2, achieved 96.7% of the maximum BBFR score.
IGF axis gene expression patterns are prognostic of survival in epithelial ovarian cancer
Authors: Spentzos Dimitrios , Cannistra Stephen A , Grall Franck , Levine Douglas A , Pillay Kamana , Libermann Towia A , Mantzoros Christos S
Published: October 2007

The IGF axis has documented growth-promoting effects in various malignancies, but its role in epithelial ovarian cancer (EOC) has not been adequately examined. We studied the expression of the IGF axis genes in relation to outcome in EOC. Microarray expression profiles from 64 patients with advanced-stage EOC were used. Two multi-gene subsets were chosen, one upstream of the IGF receptor (‘IGF family’) and the other downstream of the IGF receptor (‘IGF signaling pathway’), and analyzed in relation to survival. In addition, expression patterns of the two gene subsets were analyzed in relation to favorable and unfavorable prognosis categories identified in a previous study by whole-genome expression profiling. In a gene-by-gene analysis, IGF binding protein 4 and IGF-II receptor gene expression was inversely associated with survival. Using hierarchical clustering, the two multi-gene subsets separated the patient cohort into two groups with different median survival (IGF family: 33 vs 63 months, P=0.02 and IGF signaling pathway: 41 vs 63 months, P=0.05). Furthermore, the two multi-gene subsets were differentially expressed between the previously defined favorable and unfavorable prognosis tumors (Kolmogorov–Smirnov permutation: P=0.0005 and 0.003 for the IGF family and signaling pathway respectively), and individual genes (including IGF-I, IGF-I receptor, and several genes downstream of the receptor) were overexpressed in unfavorable prognosis tumors (permutation P<0.05). The expression patterns of several genes in the IGF axis are associated with survival in EOC, and expression changes of these genes may be underlying previously proposed microarray-derived clinical prognostic models. Future studies are needed to more precisely determine the diagnostic and potential therapeutic significance of these findings.
Body shape throughout life and correlations with IGFs and GH
Authors: Schernhammer Eva S , Tworoger Shelley S , Eliassen A Heather , Missmer Stacey A , Holly Jeff M , Pollak Michael N , Hankinson Susan E
Published: October 2007

Both insulin-like growth factors (IGF) and body size have been linked to premenopausal breast cancer risk. However, observational studies of IGF have not been consistent, and they suggest that perhaps earlier levels of IGF might be more strongly related to breast cancer than those measured at mid-age. We therefore sought to explore associations between several measures of body size throughout life and IGF levels in premenopausal women. We examined cross-sectional associations of birth weight, body shape (or somatotype) at ages 5 and 10, body mass index (BMI) at age 18 and adulthood, bra cup size at age 20, adult waist circumference and waist-to-hip ratio (WHR), and attained height with plasma levels of IGF-I, IGF binding protein 3 (IGFBP-3), IGFBP-1, and GH. Participants were 592 healthy premenopausal women aged 34–52 from the Nurses’ Health Study II. Using multiple linear regression, we computed least-square mean hormone levels across the categories of early life anthropometric factors. We observed consistent and strong inverse associations between body shape at various stages in life and IGF levels. Somatotype at ages 5 and 10 was inversely associated with IGF-I (P for difference, < 0.01) and positively with IGFBP-3 measured later in adulthood. Further, comparing women with a BMI ≥ 25 kg/m2 at age 18 vs < 19 kg/m2, similar associations were observed for IGF-I (P for trend, 0.005) and IGFBP-3 (P for trend, 0.01), which were even stronger for BMI at blood collection (BMI< 20 versus BMI ≥ 30, mean IGF-I 254 ng/ml, 95% CI, 239–271 vs 208 ng/ml, 95% CI, 195–222). Both waist circumference and WHR were strongly and inversely related to IGFBP-1 levels (top versus bottom quartile of waist circumference: 14.5 vs 40.0 ng/ml, P for trend 0.0005; WHR: 18.3 vs 39.4 ng/ml, P for trend 0.002), with similar results for bra cup size at age 20 although they did not reach statistical significance. There was no association between height and IGF or GH levels. Birth weight, on the other hand, was weakly positively associated with both IGF-I and IGFBP-1 levels, and inversely with GH. Our results suggest that childhood and adult body size may affect premenopausal breast cancer risk differently than birth weight, through associations with IGF and GH levels.
Anthropometric measures, plasma adiponectin, and breast cancer risk
Authors: Tian Yu-Feng , Chu Chi-Hong , Wu Mei-Hsuan , Chang Chia-Lin , Yang Tsan , Chou Yu-Ching , Hsu Giu-Cheng , Yu Cheng-Ping , Yu Jyh-Cherng , Sun Chien-An
Published: October 2007

Adiponectin is a peptide hormone secreted exclusively by adipocytes, and obesity is an established risk factor for breast cancer. We have, thus, evaluated the associations of anthropometric measures of adiposity and adiponectin with the development of breast cancer in a case–control study. Questionnaire information, anthropometric measures, and blood samples were taken before treatment from 244 incident cases with breast cancer, including 141 premenopausal and 103 postmenopausal cases, and 244 controls admitted for health examination at the Tri-Service General Hospital, Taipei between 2004 and 2005. Plasma levels of adiponectin were measured by RIA. The relationship between anthropometric measures of adiposity and breast cancer risk was modified by menopausal status, with a significant increase in risk observed in postmenopausal but not premenopausal women. Moreover, a fairly robust inverse association of adiponectin with the risk was observed only in postmenopausal women (adjusted odds ratio (OR), 0.55; 95% confidence interval (CI), 0.23–0.97), but not in premenopausal women. Additionally, the plasma adiponectin levels tended to be inversely associated with estrogen receptor (ER)-positive (adjusted OR, 0.53; 95% CI, 0.27–0.98) but not ER-negative breast tumors. Furthermore, the associations of adiponectin with breast cancer risk overall and by menopausal and ER status remained after adjustment for obesity indices. These results suggest that adiponectin may have an independent role in breast carcinogenesis, particularly in the postmenopausal and ER-positive breast cancer risk.