bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactive access control for autonomic systems
Authors: Koshutanski Hristo , Massacci Fabio
Published: August 2008

Autonomic communication and computing is a new paradigm for dynamic service integration over a network. An autonomic network crosses organizational and management boundaries and is provided by entities that see each other just as partners. For many services no autonomic partner may guess a priori what will be sent by clients nor clients know a priori what credentials are required to access a service.

To address this problem we propose a new
interactive access control
: servers should interact with clients, asking for missing credentials necessary to grant access, whereas clients may supply or decline the requested credentials. Servers evaluate their policies and interact with clients until a decision of grant or deny is taken.

This proposal is grounded in a formal model on policy-based access control. It identifies the formal reasoning services of deduction, abduction and consistency. Based on them, the work proposes a comprehensive access control framework for autonomic systems. An implementation of the interactive model is given followed by system performance evaluation.
Statistical machine translation
Authors: Lopez Adam
Published: August 2008

Statistical machine translation (SMT) treats the translation of natural language as a machine learning problem. By examining many samples of human-produced translation, SMT algorithms automatically learn how to translate. SMT has made tremendous strides in less than two decades, and new ideas are constantly introduced. This survey presents a tutorial overview of the state of the art. We describe the context of the current research and then move to a formal problem description and an overview of the main subproblems: translation modeling, parameter estimation, and decoding. Along the way, we present a taxonomy of some different approaches within these areas. We conclude with an overview of evaluation and a discussion of future directions.
Authorization in trust management
Authors: Chapin Peter C. , Skalka Christian , Wang X. Sean
Published: August 2008

Trust management systems are frameworks for authorization in modern distributed systems, allowing remotely accessible resources to be protected by providers. By allowing providers to specify policy, and access requesters to possess certain access rights, trust management automates the process of determining whether access should be allowed on the basis of policy, rights, and an authorization semantics. In this paper we survey modern state-of-the-art in trust management authorization, focusing on features of policy and rights languages that provide the necessary expressiveness for modern practice. We characterize systems in light of a generic structure that takes into account components of practical implementations. We emphasize systems that have a formal foundation, since security properties of them can be rigorously guaranteed. Underlying formalisms are reviewed to provide necessary background.
Decentralized access control in distributed file systems
Authors: Miltchev Stefan , Smith Jonathan M. , Prevelakis Vassilis , Keromytis Angelos , Ioannidis Sotiris
Published: August 2008

The Internet enables global sharing of data across organizational boundaries. Distributed file systems facilitate data sharing in the form of remote file access. However, traditional access control mechanisms used in distributed file systems are intended for machines under common administrative control, and rely on maintaining a centralized database of user identities. They fail to scale to a large user base distributed across multiple organizations. We provide a survey of decentralized access control mechanisms in distributed file systems intended for large scale, in both administrative domains and users. We identify essential properties of such access control mechanisms. We analyze both popular production and experimental distributed file systems in the context of our survey.
Introducing technology into the Linux kernel
Authors: McKenney Paul E. , Walpole Jonathan
Published: August 2008

There can be no doubt that a great many technologies have been added to Linux™ over the past ten years. What is less well-known is that it is often necessary to introduce a large amount of Linux into a given technology in order to successfully introduce that technology into Linux. This paper illustrates such an introduction of Linux into technology with Read-Copy Update (RCU). The RCU API's evolution over time clearly shows that Linux's extremely diverse set of workloads and platforms has changed RCU to a far greater degree than RCU has changed Linux---and it is reasonable to expect that other technologies that might be proposed for inclusion into Linux would face similar challenges. In addition, this paper presents a summary of lessons learned and an attempt to foresee what additional challenges Linux might present to RCU.
I/O resource management through system call scheduling
Authors: Craciunas Silviu S. , Kirsch Christoph M. , Röck Harald
Published: August 2008

A principal challenge in operating system design is controlling system throughput and responsiveness while maximizing resource utilization. Unlike previous attempts in kernel resource management, which often involve non-trivial changes in kernel subsystems, we focus on the kernel's edge. System calls are usually the default mechanism for user processes to get access to operating system services. System calls can therefore be used to control throughput and responsiveness and thus also affect resource utilization directly. We propose a simple, non-intrusive kernel-space mechanism for explicit, per-process system call scheduling already at kernel entry in order to control the time and rate at which system calls are executed, and, as a result, the per-process utilization of the involved resources. We have developed a high-performance Linux 2.6 kernel patch with SMP support that implements system call scheduling for network- and disk-related I/O calls with policies that resemble traffic shaping in network routers. Our experiments show that already simple and easy-to-use policies provide effective I/O-related process isolation with low overhead, and reduce thrashing in certain overload scenarios. While system call scheduling may still not be able to outperform resource management systems that use specifically tuned kernel subsystems, our experiments indicate that it may sufficiently support relevant soft real-time applications yet using a vastly simpler and more generic approach.
PipesFS
Authors: de Bruijn Willem , Bos Herbert
Published: August 2008

This paper presents PipesFS, an I/O architecture for Linux 2.6 that increases I/O throughput and adds support for heterogeneous parallel processors by (1) collapsing many I/O interfaces onto one: the Unix pipeline, (2) increasing pipe efficiency and (3) exploiting pipeline modularity to spread computation across all available processors.

PipesFS extends the pipeline model to kernel I/O and communicates with applications through a Linux virtual filesystem (VFS), where directory nodes represent operations and pipe nodes export live kernel data. Users can thus interact with kernel I/O through existing calls like mkdir, tools like grep, most languages and even shell scripts. To support performance critical tasks, PipesFS improves pipe throughput through copy, context switch and cache miss avoidance. To integrate heterogeneous processors (e.g., the Cell) it transparently moves operations to the most efficient type of core.
On the design of a new Linux readahead framework
Authors: Fengguang WU , Hongsheng XI , Chenfeng XU
Published: August 2008

As Linux runs an increasing variety of workloads, its in-kernel readahead algorithm has been challenged by many unexpected and subtle problems. To name a few: readahead thrashings arise when readahead pages are evicted prematurely under memory pressure; readahead attempts on already cached pages are undesirable; interrupted-then-retried reads and locally disordered NFS reads that can easily fool the sequential detection logic. In this paper, we present a new Linux readahead framework with flexible and robust heuristics that can cover varied sequential I/O patterns. It also enjoys great simplicity by handling most abnormal cases in an implicit way. We demonstrate its advantages by a host of case studies. Network throughput is 3 times better in the case of thrashing and 1.8 times better for large NFS files. On serving large files with lighttpd, the disk utilization is decreased by 26% while providing 17% more network throughput.
virtio
Authors: Russell Rusty
Published: August 2008

The Linux Kernel currently supports at least 8 distinct virtualization systems: Xen, KVM, VMware's VMI, IBM's System p, IBM's System z, User Mode Linux, lguest and IBM's legacy iSeries. It seems likely that more such systems will appear, and until recently each of these had its own block, network, console and other drivers with varying features and optimizations.

The attempt to address this is virtio: a series of efficient, well-maintained Linux drivers which can be adapted for various different hypervisor implementations using a shim layer. This includes a simple extensible feature mechanism for each driver. We also provide an obvious ring buffer transport implementation called vring, which is currently used by KVM and lguest. This has the subtle effect of providing a path of least resistance for any new hypervisors: supporting this efficient transport mechanism will immediately reduce the amount of work which needs to be done. Finally, we provide an implementation which presents the vring transport and device configuration as a PCI device: this means guest operating systems merely need a new PCI driver, and hypervisors need only add vring support to the virtual devices they implement (currently only KVM does this).

This paper will describe the virtio API layer as implemented in Linux, then the vring implementation, and finally its embodiment in a PCI device for simple adoption on otherwise fully-virtualized guests. We'll wrap up with some of the preliminary work to integrate this I/O mechanism deeper into the Linux host kernel.
Functional impact of high protein intake on healthy elderly people
Authors: Walrand Stephane , Short Kevin R. , Bigelow Maureen L. , Sweatt Andrew J. , Hutson Susan M. , Nair K. Sreekumaran
Published: August 2008

Decline in muscle mass, protein synthesis, and mitochondrial function occurs with age, and amino acids are reported to enhance both muscle protein synthesis and mitochondrial function. It is unclear whether increasing dietary protein intake corrects postabsorptive muscle changes in aging. We determined whether a 10-day diet of high [HP; 3.0 g protein·kg fat-free mass (FFM)−1·day−1] vs. usual protein intake (UP; 1.5 g protein·kg FFM−1·day−1) favorably affects mitochondrial function, protein metabolism, and nitrogen balance or adversely affects insulin sensitivity and glomerular filtration rate (GFR) in 10 healthy younger (24 ± 1 yr) and 9 older (70 ± 2 yr) participants in a randomized crossover study. Net daily nitrogen balance increased equally in young and older participants, but postabsorptive catabolic state also increased, as indicated by higher whole body protein turnover and leucine oxidation with no change in protein synthesis. Maximal muscle mitochondrial ATP production rate was lower in older people, with no change occurring in diet. GFR was lower in older people, and response to HP was significantly different between the two groups, with a significant increase occurring only in younger people, thus widening the differences in GFR between the young and older participants. In conclusion, a short-term high-protein diet increased net daily nitrogen balance but increased the postabsorptive use of protein as a fuel. HP did not enhance protein synthesis or muscle mitochondrial function in either young or older participants. Additionally, widening differences in GFR between young and older patients is a potential cause of concern in using HP diet in older people.
The Na-K-ATPase and Calcium-Signaling Microdomains
Authors: Tian Jiang , Xie Zi-jian
Published: August 2008

The Na-K-ATPase is an energy-transducing ion pump that converts the free energy of ATP into transmembrane ion gradients. It also serves as a functional receptor for cardiotonic steroids such as ouabain and digoxin. Binding of ouabain to the Na-K-ATPase can activate calcium signaling in a cell-specific manner. The exquisite calcium modulation via the Na-K-ATPase is achieved by the ability of the pump to integrate signals from numerous protein and non-protein molecules, including ion transporters, channels, protein kinases/phosphatases, as well as cellular Na+. This review focuses on the unique properties of the Na-K-ATPase and its role in the formation of different calcium-signaling microdomains.
Physiological Dysfunctions Associated with Mutations of the ImprintedGnasLocus
Authors: Krechowec Stefan , Plagge Antonius
Published: August 2008

The ubiquitous Gαs-subunit of the trimeric, stimulatory G-protein plays a central role in receptor-mediated signal transduction, coupling receptor activation with the production of cAMP. The Gαs-encoding locus Gnas is now known to consist of a complex arrangement of several protein-coding and noncoding transcripts. We provide an overview of its genomic organization, its regulation by genomic imprinting, and a summary of the physiological roles of the alternative protein variants Gαsand XLαsas determined from deficient mouse models.
The Combination of Epidermal Growth Factor Receptor Inhibitors with Gemcitabine and Radiation in Pancreatic Cancer
Authors: Morgan Meredith A. , Parsels Leslie A. , Kollar Laura E. , Normolle Daniel P. , Maybaum Jonathan , Lawrence Theodore S.
Published: August 2008

Purpose: Gemcitabine-radiotherapy is a standard treatment for locally advanced pancreatic cancer. Clinical data have shown that gemcitabine plus erlotinib is superior to gemcitabine alone for advanced pancreatic cancer. Therefore, we investigated the effects of the combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation on a pancreatic cancer model.

Experimental Design: EGFR signaling was analyzed by measuring phosphorylated EGFR (pEGFR(Y845), (Y1173)) and AKT (pAKT(S473)) protein levels in pancreatic cancer cell lines and tumors. The effects of scheduling on gemcitabine-mediated cytotoxicity and radiosensitization combined with erlotinib were determined by clonogenic survival. In vivo, the effects of cetuximab or erlotinib in combination with gemcitabine-radiation on the growth of BxPC-3 tumor xenografts were measured.

Results: We found in vitro that gemcitabine induced phosphorylation of EGFR at Y845 and Y1173 that was blocked by erlotinib. Treatment of BxPC-3 cells with gemcitabine before erlotinib enhanced gemcitabine-mediated cytotoxicity without abrogating radiosensitization. In vivo, cetuximab or erlotinib in combination with gemcitabine-radiation inhibited growth compared with gemcitabine-radiation (time to tumor doubling: gemcitabine + radiation, 19 ± 3 days; cetuximab + gemcitabine + radiation, 30 ± 3 days; P < 0.05, erlotinib + gemcitabine + radiation 28 ± 3 days; P < 0.1). Cetuximab or erlotinib in combination with gemcitabine-radiation resulted in significant inhibition of pEGFR(Y1173) and pAKT(S473) early in treatment, and pEGFR(Y845), pEGFR(Y1173), and pAKT(S473) by the end of treatment. This study shows a novel difference pEGFR(Y845) and pEGFR(Y1173) in response to EGFR inhibition.

Conclusions: These results show that the EGFR inhibitors cetuximab and erlotinib increase the efficacy of gemcitabine-radiation. This work supports the integration of EGFR inhibitors with gemcitabine-radiation in clinical trials for pancreatic cancer.
Nuclear and Cytoplasmic Expression of ERβ1, ERβ2, and ERβ5 Identifies Distinct Prognostic Outcome for Breast Cancer Patients
Authors: Shaaban Abeer M. , Green Andrew R. , Karthik Suchita , Alizadeh Yalda , Hughes Thomas A. , Harkins Lynn , Ellis Ian O. , Robertson John F. , Paish Emma C. , Saunders Philippa T.K. , Groome Nigel P. , Speirs Valerie
Published: August 2008

Purpose: Previous conflicting results about the prognostic significance of estrogen receptor (ER)-β in breast cancer may be explained by contribution of isoforms, of which five exist. Our aim was to elucidate the prognostic significance of ERβ1, ERβ2, and ERβ5 by immunohistochemistry in a large cohort of breast carcinomas with long-term follow-up.

Experimental Design: Tissue microarrays were stained with ERβ1, ERβ2, and ERβ5 antibodies and scored as percentage of positive tumor cells and using the Allred system. Nuclear and cytoplasmic staining was evaluated and correlated with histopathologic characteristics, overall survival (OS), and disease-free survival (DFS).

Results: Nuclear ERβ2 and ERβ5, but not ERβ1, significantly correlated with OS (P = 0.006, P = 0.039, and P = 0.099, respectively), and ERβ2 additionally with DFS (P = 0.013). ERβ2 also predicted response to endocrine therapy (P = 0.036); correlated positively with ERα, progesterone receptor, androgen receptor, and BRCA1; and correlated inversely with metastasis and vascular invasion. Tumors coexpressing ERβ2 and ERα had better OS and DFS. Cytoplasmic ERβ2 expression, alone or combined with nuclear staining, predicted significantly worse OS. Notably, patients with only cytoplasmic ERβ2 expression had significantly worse outcome (P = 0.0014).

Conclusions: This is the first study elucidating the prognostic role of ERβ1, ERβ2, and ERβ5 in a large breast cancer series. ERβ2 is a powerful prognostic indicator in breast cancer, but nuclear and cytoplasmic expression differentially affect outcome. Measuring these in clinical breast cancer could provide a more comprehensive picture of patient outcome, complementing ERα.
Clinical and Immunologic Results of a Phase II Trial of Sequential Imiquimod and Photodynamic Therapy for Vulval Intraepithelial Neoplasia
Authors: Winters Ursula , Daayana Sai , Lear John T. , Tomlinson Anne E. , Elkord Eyad , Stern Peter L. , Kitchener Henry C.
Published: August 2008

Purpose: High-risk human papillomavirus (HPV)-associated vulval intraepithelial neoplasia (VIN) is difficult to treat by excision or ablation because of high recurrence rates. Small studies of photodynamic therapy (PDT) and imiquimod treatments have shown some success and function at least in part through stimulation of local immune responses. Indeed, there is evidence that immunosuppressed individuals have higher rates of VIN, suggesting immune control is relevant.

Experimental Design: In the study, 20 women with high-grade VIN were treated with topical imiquimod and the PDT sequentially. Vulval biopsy and blood were taken pretreatment and, after imiquimod and PDT, with follow up for 1 year. Clinical response was assessed by measuring lesion size. Biopsies were analyzed for HPV DNA and tumor-infiltrating lymphocytes including T regulatory cells.

Results: The treatment was well-tolerated. There was an overall response rate of 55% by intention treat and 64% per protocol. The 52-week symptom response was 65% asymptomatic, compared with 5% at baseline. The nonresponders showed a significantly higher level of T regulatory cells in the lesions after imiquimod treatment.

Conclusions: The response rates are clinically relevant, and the treatment regimen was feasible for the majority. Initial nonresponders to imiquimod seem to be relatively refractory, and this may derive from their unfavorable local immune environment, in particular, the increased proportions of T regulatory cells, possibly the limiting action and/or development of any HPV T-cell immunity. The potential benefit of this treatment is its ability to treat multifocal disease.
CTLA-4 Blockade Confers Lymphocyte Resistance to Regulatory T-Cells in Advanced Melanoma: Surrogate Marker of Efficacy of Tremelimumab?
Authors: Ménard Cédric , Ghiringhelli François , Roux Stephan , Chaput Nathalie , Mateus Christine , Grohmann Ursula , Caillat-Zucman Sophie , Zitvogel Laurence , Robert Caroline
Published: August 2008

Purpose: Anti–CTL antigen-4 (CTLA-4) monoclonal antibody (mAb) has led to encouraging antitumor activity associated with immune-related adverse events in patients with heavily pretreated melanoma. However, mechanisms of action and surrogate immunologic markers of efficacy have not been reported thus far.

Experimental Design: We monitored the immune responses of 10 melanoma patients included in a phase II clinical trial, which evaluated the efficacy of a second line of therapy of tremelimumab anti–CTLA-4 mAb in patients with metastatic melanoma. The frequency of blood leukocyte populations in association with T cell and regulatory T cell (Treg) functions were evaluated.

Results: Prior to therapy, patients with advanced melanoma presented with a severe CD4+ and CD8+ T cell lymphopenia associated with blunted T-cell proliferative capacities that could be assigned to Treg. Tremelimumab rapidly restored the effector and memory CD4+ and CD8+ T-cell pool and TCR-dependent T-cell proliferation that became entirely resistant to Treg-mediated suppression. Progression-free survival and overall survival was directly correlated with the acquisition of a biological response defined as the resistance of peripheral lymphocytes to Treg-inhibitory effects (obtained in 7 of 10 patients).

Conclusion: CTLA-4 blockade seems to be a valuable strategy to revive reactive memory T cells anergized in the context of stage IV melanoma, and our work suggests that memory T-cell resistance to Treg resulting from anti–CTLA-4 treatment might be a biological activity marker for tremelimumab in patients with melanoma.
Safety and Immunologic Response of a Viral Vaccine to Prostate-Specific Antigen in Combination with Radiation Therapy when Metronomic-Dose Interleukin 2 Is Used as an Adjuvant
Authors: Lechleider Robert J. , Arlen Philip M. , Tsang Kwong-Yok , Steinberg Seth M. , Yokokawa Junko , Cereda Vittore , Camphausen Kevin , Schlom Jeffrey , Dahut William L. , Gulley James L.
Published: August 2008

Purpose: We have previously reported on the safety and immunologic response of a poxvirus-based vaccine encoding prostate-specific antigen (PSA) used in combination with radiation therapy in patients with localized prostate cancer. We hypothesized that a “metronomic” dose of interleukin 2 (IL-2) as a biological adjuvant would cause less toxicity while maintaining immunologic response.

Experimental Design: Eighteen patients with localized prostate cancer were treated in a single-arm trial using previously established doses of vaccine and radiation therapy. The vaccine used was a recombinant vaccinia virus engineered to encode PSA admixed with a recombinant vaccinia encoding the costimulatory molecule B7.1, followed by booster vaccinations with a recombinant fowlpox vector expressing PSA. Patients received a total of eight planned vaccination cycles, once every 4 weeks, with granulocyte-macrophage colony-stimulating factor given on days 1 to 4 and interleukin 2 (IL-2) at a dose of 0.6 MIU/M2 given from days 8 to 21 after each vaccination. Definitive external beam radiation therapy was initiated after the third vaccination cycle. Patients were evaluated for safety and immunologic response. Toxicity and immunologic activity were compared with the previously reported regimen containing a higher dose of IL-2.

Results: Seventeen of 18 patients received all eight cycles of vaccine with IL-2. Five of eight HLA-A2+ patients evaluated had an increase in PSA-specific T cells of ≥3-fold. Toxicities were generally mild, with only seven vaccination cycles of 140 given resulting in grade 3 toxicities possibly attributable to IL-2.

Conclusions: Metronomic-dose IL-2 in combination with vaccine and radiation therapy is safe, can induce prostate-specific immune responses, and has immunologic activity similar to low-dose IL-2, with markedly reduced toxicities.
Intratumoral Metabolic Heterogeneity of Cervical Cancer
Authors: Kidd Elizabeth A. , Grigsby Perry W.
Published: August 2008

Purpose: Previous research has shown that the intertumoral maximum standardized uptake value (SUVMax) of F-18 fluorodeoxyglucose (FDG)–positron emission tomography (PET) for cervical cancer predicts disease outcome. The purpose of this study was to evaluate the pretreatment intratumoral metabolic heterogeneity of FDG.

Experimental Design: This is a prospective cohort study of 72 patients with International Federation of Gynecology and Obstetrics stages Ib1 to IVa cervical cancer treated with chemoradiation. Three-dimensional FDG-PET threshold tumor volumes were calculated using image segmentation and an adaptive thresholding method for the primary cervix tumor from the pretreatment FDG-PET/computerized tomography. Intratumor heterogeneity was obtained for each patient's cervical tumor by taking the derivative (dV/dT) of the volume-threshold function from 40% to 80%. The association between intratumoral heterogeneity and tumor-specific factors and patient outcomes were determined.

Results: The mean cervix tumor SUVMax was 12.4 (range, 3.0-38.4). The mean differential tumor heterogeneity was −1.074 (range, −0.107 to −5.623). There was no association between dV/dT and SUVMax (R2 = 0.069), but there was a relationship with dV/dT and tumor volume (R2 = 0.881). There was no correlation of dV/dT with tumor histology (P = 0.4905). Heterogeneity was significantly associated with the risk of lymph node metastasis at diagnosis (P = 0.0009), tumor response to radiation as evaluated by FDG-PET obtained 3 months after completing treatment (P = 0.0207), risk of pelvic recurrence (P = 0.0017), and progression-free survival (P = 0.03).

Conclusions: Cervical intratumoral FDG metabolic heterogeneity on the pretreatment FDG-PET predicts risk of lymph node involvement at diagnosis, response to therapy, and risk of pelvic recurrence.
Perifosine Synergistically Enhances TRAIL-Induced Myeloma Cell Apoptosis via Up-Regulation of Death Receptors
Authors: David Ebenezer , Sinha Rajni , Chen Jing , Sun Shi-Yong , Kaufman Jonathan L. , Lonial Sagar
Published: August 2008

Purpose: The aim of this study is to investigate the efficacy of a novel Akt inhibitor, perifosine, in combination with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in human myeloma cells and primary patient samples.

Experimental Design: The activity of perifosine in combination with TRAIL was evaluated with experiments testing the effect of perifosine on DR4/DR5 expression by the use of chimeric blocking antibodies, as well as siRNA.

Results: DR4 and DR5 expression was induced by exposure to single-agent perifosine. After exposure of human myeloma cell lines or primary patient samples to increasing doses of perifosine with exogenous TRAIL, we identified synergistically enhanced apoptosis when compared with the perifosine alone, which was achieved with levels well below clinically achievable concentrations for both agents. Transfection with siRNA against DR4, and DR5 reduced the level of apoptosis induced by the combination but did not result in total abrogation of the combination effect. Overexpression of activated Akt, the proposed target for perifosine, did not inhibit the combination effect. Anti-DR4 and DR5 chimeric proteins blocked the cytotoxicity induced by the combination, and the use of c-FLICE-like interleukin protein (FLIP) siRNA enhanced the efficacy at the combination, further supporting the importance of the DR4/DR5 axis in the effect of perifosine.

Conclusion: Our observation seems to be independent of the effects of perifosine on Akt signaling, and may represent an additional mechanism of action for this agent, and supports future clinical trials combining these two agents.
Multimodality Therapy: Potentiation of High Linear Energy Transfer Radiation with Paclitaxel for the Treatment of Disseminated Peritoneal Disease
Authors: Milenic Diane E. , Garmestani Kayhan , Brady Erik D. , Baidoo Kwamena E. , Albert Paul S. , Wong Karen J. , Flynn Joseph , Brechbiel Martin W.
Published: August 2008

Purpose: Studies herein explore paclitaxel enhancement of the therapeutic efficacy of α-particle-targeted radiation therapy.

Experimental Design: Athymic mice bearing 3 day i.p. LS-174T xenografts were treated with 300 or 600 μg paclitaxel at 24 h before, concurrently, or 24 h after [213Bi] or [212Pb]trastuzumab.

Results: Paclitaxel (300 or 600 μg) followed 24 h later with [213Bi]trastuzumab (500 μCi) provided no therapeutic enhancement. Paclitaxel (300 μg) administered concurrently with [213Bi]trastuzumab or [213Bi]HuIgG resulted in median survival of 93 and 37 days, respectively; no difference was observed with 600 μg paclitaxel. Mice receiving just [213Bi]trastuzumab or [213Bi]HuIgG or left untreated had a median survival of 31, 21, and 15 days, respectively, 23 days for just either paclitaxel dose alone. Paclitaxel (300 or 600 μg) given 24 h after [213Bi]trastuzumab increased median survival to 100 and 135 days, respectively. The greatest improvement in median survival (198 days) was obtained with two weekly doses of paclitaxel (600 μg) followed by [213Bi]trastuzumab. Studies were also conducted investigating paclitaxel administered 24 h before, concurrently, or 24 h after [212Pb]trastuzumab (10 μCi). The 300 μg paclitaxel 24 h before radioimmunotherapy (RIT) failed to provide benefit, whereas 600 μg extended the median survival from 44 to 171 days.

Conclusions: These results suggest that regimens combining chemotherapeutics and high linear energy transfer (LET) RIT may have tremendous potential in the management and treatment of cancer patients. Dose dependency and administration order appear to be critical factors requiring careful investigation.
Gefitinib Induction ofIn vivoDetectable Signals by Bcl-2/Bcl-xL Modulation of Inositol Trisphosphate Receptor Type 3
Authors: Zannetti Antonella , Iommelli Francesca , Fonti Rosa , Papaccioli Angela , Sommella Jvana , Lettieri Anna , Pirozzi Giuseppe , Bianco Roberto , Tortora Giampaolo , Salvatore Marco , Del Vecchio Silvana
Published: August 2008

Purpose: To test whether epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) induce detectable signals in tumor cells and whether such signals may reveal alterations of the apoptotic program.

Experimental Design: Tumor cells were treated with gefitinib or erlotinib and tested for their ability to accumulate 99mTc-Sestamibi, a radiolabeled lipophilic cation that localizes in mitochondria. Then we tested whether Bcl-2 and Bcl-xL alter the pattern of drug-dependent tracer accumulation while reducing tumor cell sensitivity to EGFR TKIs. The mechanism underlying the pattern of tracer accumulation was elucidated. Finally, imaging studies were done in animal models and lung cancer patients before and after treatment with EGFR TKIs using single-photon emission computed tomography and 99mTc-Sestamibi.

Results: Gefitinib increases accumulation of 99mTc-Sestamibi in Bcl-2–overexpressing cells and enhances the physical interaction of phosphorylated Bcl-2 with inositol trisphosphate receptor type 3 (IP3R3). Consequently, a relative increase of cytosolic and mitochondrial calcium levels occurs. Similarly, lung cancer cells showed an increase of tracer uptake and an enhanced interaction of Bcl-xL with IP3R3 on exposure to erlotinib concentrations achievable in plasma. The occurrence of these interactions was associated with an enhanced EGFR TKI–induced apoptosis resistance. Posttreatment imaging studies in nude mice bearing control and Bcl-2–overexpressing breast carcinomas showed a high tumor uptake of the tracer whereas baseline studies failed to visualize tumors. Similarly, an enhancement of tracer uptake could be detected in patients with lung cancer treated with erlotinib.

Conclusion: EGFR TKIs generate detectable signals by Bcl-2/Bcl-xL modulation of IP3R3 in tumor cells.
Phase II Study of Combination Therapy with S-1 and Irinotecan for Advanced Non–Small Cell Lung Cancer: West Japan Thoracic Oncology Group 3505
Authors: Okamoto Isamu , Nishimura Takashi , Miyazaki Masaki , Yoshioka Hiroshige , Kubo Akihito , Takeda Koji , Ebi Noriyuki , Sugawara Shunichi , Katakami Nobuyuki , Fukuoka Masahiro , Nakagawa Kazuhiko
Published: August 2008

Purpose: To evaluate the efficacy and toxicity of combination therapy with the oral fluoropyrimidine formulation S-1 and irinotecan for patients with advanced NSCLC.

Experimental Design: Chemotherapy-naive patients with advanced NSCLC were treated with i.v. irinotecan (150 mg/m2) on day 1 and with oral S-1 (80 mg/m2) on days 1 to 14 every 3 weeks.

Results: Fifty-six patients (median age, 63 years; range, 40-74 years) received a total of 286 treatment cycles (median, 5; range, 1-15). No complete responses and 16 partial responses were observed, giving an overall response rate of 28.6% [95% confidence interval (95% CI), 17.3-42.2%]. Twenty-four patients (42.9%) had stable disease and 12 patients (21.4%) had progressive disease as the best response. The overall disease control rate (complete response + partial response + stable disease) was thus 71.4% (95% CI, 57.8-82.7%). Median progression-free survival was 4.9 months (95% CI, 4.0-6.4 months), whereas median overall survival was 15 months. Hematologic toxicities of grade 3 or 4 included neutropenia (25%), thrombocytopenia (3.6%), and anemia (3.6%), with febrile neutropenia being observed in four patients (7.1%). The most common nonhematologic toxicities of grade 3 or 4 included anorexia (14.3%), fatigue (8.9%), and diarrhea (8.9%). There were no deaths attributed to treatment.

Conclusions: The combination of S-1 and irinotecan is a potential alternative option with a favorable toxicity profile for the treatment of advanced NSCLC. This nonplatinum regimen warrants further evaluation in randomized trials.
Targets of Tumor Immunity After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Ofran Yishay , Ritz Jerome
Published: August 2008

The effectiveness of allogeneic hematopoietic stem cell transplantation for hematologic malignancies results from the donor immunity to antigens expressed in leukemia cells in the recipient. Similar immune responses have now been identified in patients with renal cell cancer with tumor regression after allogeneic hematopoietic stem cell transplantation. Further studies to identify relevant antigens and mechanisms of resistance may improve the effectiveness of this approach in patients with solid tumors.
Nonventilatory Strategies for Prevention and Treatment of Bronchopulmonary Dysplasia – What Is the Evidence?
Authors: Thomas W. , Speer C.P.
Published: August 2008

This review briefly summarizes the evidence for a number of mainly drug-related strategies to prevent or treat bronchopulmonary dysplasia (BPD). Oxygen supplementation is frequently used in neonatal units and oxygen toxicity plays an important role in the pathogenesis of BPD. However, current evidence for an optimal oxygen saturation for extremely premature infants is scarce. This gap in knowledge will hopefully be closed by a number of ongoing or prospective trials addressing this issue. The role of inhalational nitric oxide in the prevention of BPD is still unclear despite existing data from a number of large randomized trials. Early administration of caffeine seems to confer a benefit with regard to BPD. Prophylactic or early application of surfactant may also be beneficial. High intramuscular doses of vitamin A slightly reduce the incidence of the disease. There is currently no evidence supporting other nutritional interventions to prevent BPD. Anti-inflammatory drugs, like α1-proteinase inhibitor, pentoxifylline and azithromycin, and antioxidants, like N-acetylcysteine and superoxide dismutase, have not been proven effective yet. Diuretics can ameliorate lung function, but there is no evidence supporting their long-term use. Ureaplasma urealyticum colonization of airways is associated with an increased risk of BPD. However, there is no proof for an effect of erythromycin on BPD. The potential roles for therapies like bombesin-like peptide-blocking antibodies or Clara cell 10-kDa protein have yet to be defined.
Role of Physical Chemical Properties in Drug Relay into Skin Compartments
Authors: Fortenbach C.R. , Modjtahedi B.S. , Maibach H.I.
Published: August 2008

The ability of a drug to reach the interstitial fluid is an important aspect of drug efficacy – as a possible indicator of skin and cell compartment concentration. This overview addresses the relationship of the physical properties of several antibiotics to their ability to enter the interstitial fluid utilizing a cantharidin blister model. By collecting pharmacokinetic data for 12 antibiotics administered orally and 11 intravenously, we compared the fraction of drug that reaches the interstitial fluid (AUCblister/AUCserum) to partition coefficients. Following data analysis, we found no correlation (p = 0.98 and 0.09, respectively) between hydrophobicity and the ability to reach the interstitium. Both orally and intravenously administered antibiotics display a strong linear correlation (p < 0.001 and p = 0.006, respectively) in the total concentration found in the serum and interstitial fluid indicating that serum concentration may be an important factor in dictating interstitial fluid concentration. This correlation may prove useful in clinical application as a means of determining interstitial fluid concentration by measuring only serum levels.
Pain Therapy in German Neurology
Authors: Gerbershagen Kathrin , Limmroth Volker
Published: August 2008

In order to analyze aspects of pain patient care in neurology, we conducted a survey among German neurology departments that aimed to determine different structural aspects of neurological pain medicine. A 5-page questionnaire was sent to 391 neurological departments, and a return rate of 59.8% was achieved. Some 70% of university-based neurology departments have established their own outpatient clinic, and some 80% of these departments actively take part in interdisciplinary pain services. University hospitals operate an interdisciplinary pain clinic in 94.7%. Almost all neurological departments admit pain patients, especially for further diagnosis and neurological treatment. These fields are accepted as important neurological tasks. The quality of care is reported to be excellent. Routine questioning for pain of all admitted patients is carried out by 85% of all hospitals, and an extensive pain history is taken by almost 90% of departments. Our survey data confirm that the documentation of medical, psychological and psychosocial pain histories and the process of pain patient care are partly fulfilled, yet need improvement. Routine application of validated instruments and regular inquiry of the presence/course of pain may improve the process of care and – as the basis of outcome – pain management in neurology.
Hypoxia and Hypoxia-Inducible Factor in Renal Disease
Authors: Nangaku Masaomi , Inagi Reiko , Miyata Toshio , Fujita Toshiro
Published: August 2008

Abstract
Tissue hypoxia occurs when local metabolism is disturbed by an imbalance between oxygen supply and consumption. In patients with chronic kidney disease, chronic hypoxia in the kidneys is the end result of multiple processes and mechanisms. Once established, however, accumulating evidence points to this chronic hypoxia as the central player and final common pathway to end-stage renal disease. The cellular response to hypoxia is centered on hypoxia-inducible factor, HIF. This factor is composed of two subunits, an oxygen-sensitive HIF-α subunit and a constitutively expressed HIF-β subunit. Intracellular accumulation of HIF induces the coordinated expression of a number of adaptive genes against hypoxic insult.Three isoforms of HIF-α subunits have been identified, HIF-1α, HIF-2α, and HIF-3α, of which HIF-2α is involved in the regulation of erythropoietin as well as oxidative stress. HIF is regulated by prolyl hydroxylation and asparaginyl hydroxylation of the HIF-α subunit at the protein level. Because HIF is activated only to suboptimal levels in various pathogenic states, therapeutic activation holds promise as a novel and effective approach to the future care of end-stage renal disease.
Kleine–Levin Syndrome: History and Brief Review
Authors: Pearce J.M.S.
Published: August 2008

Episodic hypersomnia, compulsive excessive eating and erotic behaviour, with schizophrenic-like mental symptoms are the hallmarks of the rare Kleine–Levin syndrome. This paper traces the origins of its description back to the 18th century and the changing concepts of its complex organic-psychogenic aetiology. The eventual, spontaneous disappearance of the syndrome is unexplained.
Effects of Autoantibodies against M2 Muscarinic Acetylcholine Receptors on Rabbit Atria in vivo
Authors: Hong Chang Ming , Zheng Qiang Sun , Liu Xiong Tao , Shang Fu Jun , Wang Hong Tao , Jiang Wen Rui
Published: August 2008

Background: Evidence has shown that autoantibodies against M2 muscarinic acetylcholine receptors may play a role in the development of atrial fibrillation. The goal of this study was to evaluate the effects of anti-M2 receptor autoantibodies on rabbit atria in vivo. Methods: Rabbits were immunized monthly with a synthetic peptide corresponding to the M2 receptor. The atrial electrophysiology of the isolated perfused rabbit hearts was studied. Western blots and RT-PCR were performed to determine the expression of the atrial muscarinic receptor and the acetylcholine-activated potassium channel. Atrial tissue was stained with Masson’s trichrome stain for fibrosis detection. Results: Autoantibodies were persistently detected in immunized rabbits. M2 rabbits showed a significantly shorter atrial effective refractory period and a longer intra-atrial activation time than control rabbits. Electrical stimuli induced a significantly larger number of repetitive atrial responses in M2 rabbits. The protein levels of the M2 receptor and GIRK4 were upregulated in M2 rabbits. The mRNA levels of GIRK1 and GIRK4 were also upregulated. Histological examination revealed significantly increased diffuse fibrotic deposition in M2 rabbit atria compared with control rabbits. Conclusion: The M2 receptor autoantibody-positive rabbits showed altered atrial electrophysiology, overexpression of the M2 receptor-IK,ACh pathway and atrial fibrosis, which indicates that the autoantibodies against M2 receptors may participate in the induction and perpetuation of atrial fibrillation.
Indirect Comparison of Once Daily Insulin Detemir and Glargine in Reducing Weight Gain and Hypoglycaemic Episodes when Administered in Addition to Conventional Oral Anti-Diabetic Therapy in Patients with Type-2 Diabetes
Authors: Fakhoury Walid , Lockhart Ian , Kotchie Robert W. , Aagren Mark , LeReun Corinne
Published: August 2008

Aims: Basal insulin administered to type-2 diabetic patients with poor glycaemic control when managed with oral anti-diabetics (OADs) alone can lead to an increased risk of weight gain and hypoglycaemia. In the absence of head-to-head trials, an indirect comparison of the once-daily insulin detemir with insulin glargine was conducted on the following outcomes: weight gain, hypoglycaemic episodes, and HbA1c. Methods: Parallel-group randomised controlled trials of at least 20 weeks duration that compared once-daily evening glargine or detemir with a common comparator, neutral protamine Hagedorn insulin (evening), were selected. Trials focused on insulin-naïve, type-2 diabetic patients poorly controlled with OAD. Five open-label trials were identified (n = 2,092 patients; n = 1 detemir and n = 4 glargine trials), with an indirect comparison of glargine (n = 869 patients) and detemir trials (n = 169 patients) carried out using meta-regression to control for covariates. Weight gain was analysed as weighted mean differences (WMD), hypoglycaemic episodes as odds ratios (OR), and HbA1c at the end of study as standardised mean differences (SMD). Results: Patients receiving evening detemir gained significantly less weight (unadjusted WMD –1.22 kg, 95% CI –2.15, –0.29 kg; p = 0.010) and significantly fewer of them experienced hypoglycaemic episodes versus evening glargine (unadjusted OR 0.52, 95% CI 0.28, 0.98; p = 0.044). There was no significant difference between treatments for the mean HbA1c level at study endpoint (unadjusted SMD 0.09, 95% CI –0.16, 0.33; p = 0.480). Conclusions: Once-daily use of insulin detemir resulted in significantly less weight gain and fewer hypoglycaemic episodes than glargine, while maintaining clinically appropriate HbA1c levels in type-2 diabetic patients currently receiving OAD.
Glycated Hemoglobin and Risk of Stroke, Ischemic and Hemorrhagic, in Japanese Men and Women
Authors: Sunaga Kyoko , Miura Katsuyuki , Naruse Yuchi , Sakurai Masaru , Morikawa Yuko , Kurosawa Yutaka , Nakagawa Hideaki
Published: August 2008

Background: The relationship between glycated hemoglobin A1c (HbA1c) and stroke has not been fully elucidated. In addition, there have been few reports from Asia, and few trials have been conducted for each stroke subtype. Methods: A prospective cohort study was performed involving 32,726 participants (9,558 men and 23,168 women) aged 40–79 years at baseline with approximately 6 years of follow-up in a general population of Japan. The end points included the incidence of all, ischemic and hemorrhagic strokes. Multivariate-adjusted hazard ratios by 6 HbA1c categories were calculated using a Cox proportional hazard model. Results: During the follow-up, 393 participants developed a stroke, including 240 ischemic and 139 hemorrhagic stroke cases. The adjusted hazard ratios of all strokes and ischemic stroke showed tendencies to increase with HbA1c level, and the relationships were independent of other confounders. The adjusted hazard ratios of ischemic stroke incidence showed an apparent and graded increase from a relatively mild HbA1c level (≧6.0%); the HRs (95% CI) were 1.79 (1.10–2.93) for HbA1c 6.0–6.4%, 2.20 (1.21–4.00) for HbA1c 6.5–6.9% and 2.91 (1.91–4.44) for HbA1c ≧7.0% compared with the category of HbA1c 5.0–5.4%. For hemorrhagic stroke incidence, no significant increase due to rises in HbA1c level was observed. Conclusions: The relationship of the risk of stroke, especially ischemic stroke, to HbA1c in the general population appears to be graded without any apparent threshold. The ischemic stroke risk would increase from a relatively mild HbA1c level of ≧6.0%.
Rapid Inhibition of ATP-Induced Currents by Corticosterone in Rat Dorsal Root Ganglion Neurons
Authors: Liu Xiao-Hong , Zeng Jun-Wei , Zhao Yan-Dong , Chen Peng-Hui , Xiao Zhi , Ruan Huai-Zhen
Published: August 2008

The effects of corticosterone (CORT), a natural glucocorticoid hormone, on ATP-induced currents in rat dorsal root ganglion (DRG) neurons and the underlying signaling mechanism were studied by using patch-clamp techniques. Three types of currents (fast, slow and mixed) were evoked by ATP in cultured DRG neurons. Pretreatment with CORT (0.01–10 µmol/l) for 30 s could inhibit the fast current and the fast component of the mixed current. In contrast, CORT had no significant effect on the slow current evoked by ATP. The inhibitory effects were concentration dependent, reversible and could be blocked by glucocorticoid receptor antagonist RU38486 (10 µmol/l), but not by GDP-β-S (0.2 mmol/l), a blocker of G protein activation. Membrane-impermeable bovine serum albumin-conjugated corticosterone failed to mimic the effects of CORT. The inhibitory effects of CORT on ATP-induced currents diminished after adding protein kinase A inhibitor H89 (10 µmol/l), but were not influenced by protein kinase C inhibitor chelerythrine chloride (10 µmol/l). These results suggest that glucocorticoid hormones might participate in the control of pain by modulating P2X3 receptor-mediated events in sensory neurons, and the effect is mediated by glucocorticoid receptors and the downstream activation of protein kinase A.