bluuebunny/crossref_metadata_2025 huggingface dataset:
Transformation of Temporal Processing Across Auditory Cortex of Awake Macaques
Authors: Scott Brian H. , Malone Brian J. , Semple Malcolm N.
Published: November 2010

The anatomy and connectivity of the primate auditory cortex has been modeled as a core region receiving direct thalamic input surrounded by a belt of secondary fields. The core contains multiple tonotopic fields (including the primary auditory cortex, AI, and the rostral field, R), but available data only partially address the degree to which those fields are functionally distinct. This report, based on single-unit recordings across four hemispheres in awake macaques, argues that the functional organization of auditory cortex is best understood in terms of temporal processing. Frequency tuning, response threshold, and strength of activation are similar between AI and R, validating their inclusion as a unified core, but the temporal properties of the fields clearly differ. Onset latencies to pure tones are longer in R (median, 33 ms) than in AI (20 ms); moreover, synchronization of spike discharges to dynamic modulations of stimulus amplitude and frequency, similar to those present in macaque and human vocalizations, suggest distinctly different windows of temporal integration in AI (20–30 ms) and R (100 ms). Incorporating data from the adjacent auditory belt reveals that the divergence of temporal properties within the core is in some cases greater than the temporal differences between core and belt.
Defining a relationship between dietary fatty acids and the cytochrome P450 system in a mouse model of fatty liver disease
Authors: Gonzalez Monika , Sealls Whitney , Jesch Elliot D. , Brosnan M. Julia , Ladunga Istvan , Ding Xinxin , Black Paul N. , DiRusso Concetta C.
Published: November 2010

Liver-specific ablation of cytochrome P450 reductase in mice (LCN) results in hepatic steatosis that can progress to steatohepatitis characterized by inflammation and fibrosis. The specific cause of the fatty liver phenotype is poorly understood but is hypothesized to result from elevated expression of genes encoding fatty acid synthetic genes. Since expression of these genes is known to be suppressed by polyunsaturated fatty acids, we performed physiological and genomics studies to evaluate the effects of dietary linoleic and linolenic fatty acids (PUFA) or arachidonic and decosahexaenoic acids (HUFA) on the hepatic phenotypes of control and LCN mice by comparison with a diet enriched in saturated fatty acids. The dietary interventions with HUFA reduced the fatty liver phenotype in livers of LCN mice and altered the gene expression patterns in these livers to more closely resemble those of control mice. Importantly, the expression of genes encoding lipid pathway enzymes were not different between controls and LCN livers, indicating a strong influence of diet over POR genotype. These analyses highlighted the impact of POR ablation on expression of genes encoding P450 enzymes and proteins involved in stress and inflammation. We also found that livers from animals of both genotypes fed diets enriched in PUFA had gene expression patterns more closely resembling those fed diets enriched in saturated fatty acids. These results strongly suggest only HUFA supplied from an exogenous source can suppress hepatic lipogenesis.
On Linear Coding Schemes for Stabilizing LTI Control with Multiple Sensors
Authors: Kim Anna N.
Published: November 2010

We examine the problem of designing the encoding and control policies of a linear stochastic control system, where the communication channel between the plant state observer (sensor) and the controller is a lossy wireless channel that is constrained in terms of transmit power and bandwidth. For a first-order ARMA modeled plant with Gaussian statistics, when there are two sensors observing the plant, nonlinear encoding is shown to result in smaller cost at time instant [Formula: see text] compared to the linear schemes, if transmissions are carried out over parallel Gaussian independent channels. In this paper, optimal linear coding schemes for the case of multiple sensors are examined. They are shown to minimize the control cost at the infinite time horizon, when the wireless channel is accessed using time division multiplexing. Our analysis is carried out for when separation between the state estimation and control is possible, and the optimal steady state control law is certainty equivalent. The distortion lower bound for estimating the plant state is derived, along with the necessary conditions on the transmit power that minimize the steady state control cost. We also propose a linear scheme that reaches the distortion bound asymptotically under relaxed conditions.
Cutaneous Polyarteritis Nodosa in Childhood: A Case Report and Review of the Literature
Authors: Bansal Nina-Karen , Houghton Kristin Michelle
Published: November 2010

Polyarteritis nodosa is a rare vasculitis of childhood. Cutaneous PAN (cPAN) is limited to the skin, muscles, joints, and peripheral nerves. We describe a 7.5-year-old girl with cPAN presenting initially as massive cervical edema who later went on to develop subcutaneous nodules, livedo reticularis, myositis, arthritis, and mononeuritis multiplex. The use of corticosteroids resulted in initial clinical improvement, but symptom recurrence necessitated disease modifying antirheumatic drugs and biologic therapy. We review a further 119 reports of biopsy proven cPAN in the literature. A majority of patients (96.6%) had cutaneous involvement; musculoskeletal involvement was common and included both articular (58.0%) and muscular (42.9%) symptoms, and nervous system involvement was least common (18.5%). Corticosteroids were used in the majority of patients (85.7%), followed by use of disease modifying antirheumatic drugs (33.0%), nonsteroidal anti-inflammatory drugs (10.7%), and intravenous immunoglobulin (9.8%). Therapy of cPAN with biologics has only been reported in 2 patients, and we report the first patient treated with Rituximab. A diagnosis of cPAN should be considered in a child with fever, vasculitic rash, and musculoskeletal symptoms. Most children respond to corticosteroids and have a benign course, but some require disease modifying antirheumatic drugs and biologic therapies.
Kainic Acid‐Induced Neurodegenerative Model: Potentials and Limitations
Authors: Zheng Xiang-Yu , Zhang Hong-Liang , Luo Qi , Zhu Jie
Published: November 2010

Excitotoxicity is considered to be an important mechanism involved in various neurodegenerative diseases in the central nervous system (CNS) such as Alzheimer′s disease (AD). However, the mechanism by which excitotoxicity is implicated in neurodegenerative disorders remains unclear. Kainic acid (KA) is an epileptogenic and neuroexcitotoxic agent by acting on specific kainate receptors (KARs) in the CNS. KA has been extensively used as a specific agonist for ionotrophic glutamate receptors (iGluRs), for example, KARs, to mimic glutamate excitotoxicity in neurodegenerative models as well as to distinguish other iGluRs such as α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptors and N‐methyl‐D‐aspartate receptors. Given the current knowledge of excitotoxicity in neurodegeneration, interventions targeted at modulating excitotoxicity are promising in terms of dealing with neurodegenerative disorders. This paper summarizes the up‐to‐date knowledge of neurodegenerative studies based on KA‐induced animal model, with emphasis on its potentials and limitations.
Photothermal Response of Human and Murine Cancer Cells to Multiwalled Carbon Nanotubes after Laser Irradiation
Authors: Fisher Jessica W. , Sarkar Saugata , Buchanan Cara F. , Szot Christopher S. , Whitney Jon , Hatcher Heather C. , Torti Suzy V. , Rylander Christopher G. , Rylander Marissa Nichole
Published: November 2010

This study demonstrates the capability of multiwalled carbon nanotubes (MWNTs) coupled with laser irradiation to enhance treatment of cancer cells through enhanced and more controlled thermal deposition, increased tumor injury, and diminished heat shock protein (HSP) expression. We also explored the potential promise of MWNTs as drug delivery agents by observing the degree of intracellular uptake of these nanoparticles. To determine the heat generation capability of MWNTs, the absorption spectra and temperature rise during heating were measured. Higher optical absorption was observed for MWNTs in water compared with water alone. For identical laser parameters, MWNT-containing samples produced a significantly greater temperature elevation compared to samples treated with laser alone. Human prostate cancer (PC3) and murine renal carcinoma (RENCA) cells were irradiated with a 1,064-nm laser with an irradiance of 15.3 W/cm2 for 2 heating durations (1.5 and 5 minutes) alone or in combination with MWNT inclusion. Cytotoxicity and HSP expression following laser heating was used to determine the efficacy of laser treatment alone or in combination with MWNTs. No toxicity was observed for MWNTs alone. Inclusion of MWNTs dramatically decreased cell viability and HSP expression when combined with laser irradiation. MWNT cell internalization was measured using fluorescence and transmission electron microscopy following incubation of MWNTs with cells. With increasing incubation duration, a greater number of MWNTs were observed in cellular vacuoles and nuclei. These findings offer an initial proof of concept for the application of MWNTs in cancer therapy. Cancer Res; 70(23); 9855–64. ©2010 AACR.
p21CIP-1/WAF-1 Induction Is Required to Inhibit Prostate Cancer Growth Elicited by Deficient Expression of the Wnt Inhibitor Dickkopf-1
Authors: Hall Christopher L. , Zhang Honglai , Baile Shobun , Ljungman Mats , Kuhstoss Stuart , Keller Evan T.
Published: November 2010

Osteoblastic bone metastases are the most common metastases produced by human prostate cancers (PCa). Deregulated activity of Wnt growth factors resulting from overexpression of the Wnt inhibitor Dickkopf-1 (DKK-1) is known to contribute to formation of the osteoblastic component of PCa skeletal bone metastases. In this study, we report that DKK-1 knockdown in osteolytic human PCa cells unexpectedly delays the development of both soft tissue and osseous lesions. PCa cells deficient in DKK-1 expression did not increase canonical Wnt signaling in target osteoblast cell lines; however, DKK-1 knockdown PCa cells exhibited increased expression of the CDK inhibitor p21CIP1/WAF1 and a 32% increase in G1 arrest compared with control cells. Ablating p21CIP1/WAF1 in PCa cells deficient in DKK-1 was sufficient to rescue tumor growth. Collectively, our findings demonstrate that DKK-1 overexpression supports tumor growth in part by restricting expression of p21CIP1/WAF1 through a mechanism independent of canonical Wnt signaling. Cancer Res; 70(23); 9916–26. ©2010 AACR.
HER2 Silences Tumor Suppression in Breast Cancer Cells by Switching Expression of C/EBPβ Isoforms
Authors: Arnal-Estapé Anna , Tarragona Maria , Morales Mònica , Guiu Marc , Nadal Cristina , Massagué Joan , Gomis Roger R.
Published: November 2010

Tumor progression requires ablation of suppressor functions mediated by transforming growth factor β (TGFβ) signaling and by oncogene-induced senescence (OIS), but how these functions are canceled in specific subtypes of breast cancer remains unknown. In this study, we show that HER2-overexpressing breast cancer cells avert TGFβ- and OIS-mediated tumor suppression by switching expression of 2 functionally distinct isoforms of the transcription factor C/EBPβ, which has been implicated previously in breast cancer development. HER2 signaling activates the translational regulatory factor CUGBP1, which favors the production of the transcriptionally inhibitory isoform LIP over that of the active isoform LAP. LIP overexpression prevents the assembly of LAP/Smad transcriptional repressor complexes on the MYC promoter in response to TGFβ, and interferes with activation of OIS responses. Treatment of HER2-transformed mammary epithelial cells with the HER2 antibody trastuzumab reduces LIP levels, restoring these suppressor responses. Our findings reveal a novel mechanism through which HER2 silences tumor suppression in a concerted manner, contributing to the potency of this oncogene in breast cancer. Cancer Res; 70(23); 9927–36. ©2010 AACR.
Serum microRNA Profiles Serve as Novel Biomarkers for HBV Infection and Diagnosis of HBV-Positive Hepatocarcinoma
Authors: Li Li-Min , Hu Zhi-Bin , Zhou Zhen-Xian , Chen Xi , Liu Fen-Yong , Zhang Jun-Feng , Shen Hong-Bing , Zhang Chen-Yu , Zen Ke
Published: November 2010

Diagnosis of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), particularly HCC independent of cirrhosis etiology, presents a great challenge because of a lack of biomarkers. Here we test the hypothesis that expression profiles of microRNAs (miRNAs) in serum can serve as biomarkers for diagnosis of HBV infection and HBV-positive HCC. We recruited 513 subjects (210 controls and 135 HBV-, 48 hepatitis C virus (HCV)-, and 120 HCC-affected individuals) and employed a strategy of initial screening by Solexa sequencing followed by validation with TaqMan probe-based quantitative reverse transcription-PCR assay. First, because of a close link between chronic hepatitis B and HCC, we compared miRNA expression profiles in HBV serum with that in control serum and successfully obtained 13 miRNAs that were differentially expressed in HBV serum. This 13-miRNA–based biomarker accurately discriminated not only HBV cases from controls and HCV cases, but also HBV-positive HCC cases from control and HBV cases. Second, we directly compared miRNA expressions in HCC serum with those in controls and identified 6 miRNAs that were significantly upregulated in HCC samples. Interestingly, 2 of these miRNAs, miR-375 and miR-92a, were also identified by our first approach as HBV specific. When we employed 3 of these miRNAs (miR-25, miR-375, and let-7f) as biomarkers, we could clearly separate HCC cases from controls, and miR-375 alone had an ROC of 0.96 (specificity: 96%; sensitivity: 100%) in HCC prediction. In conclusion, our study demonstrates for the first time that serum miRNA profiles can serve as novel and noninvasive biomarkers for HBV infection and HBV-positive HCC diagnosis. Cancer Res; 70(23); 9798–807. ©2010 AACR.
Molecular Histopathology by Spectrally Reconstructed Nonlinear Interferometric Vibrational Imaging
Authors: Chowdary Praveen D. , Jiang Zhi , Chaney Eric J. , Benalcazar Wladimir A. , Marks Daniel L. , Gruebele Martin , Boppart Stephen A.
Published: November 2010

Sensitive assays for rapid quantitative analysis of histologic sections, resected tissue specimens, or in situ tissue are highly desired for early disease diagnosis. Stained histopathology is the gold standard but remains a subjective practice on processed tissue taking from hours to days. We describe a microscopy technique that obtains a sensitive and accurate color-coded image from intrinsic molecular markers. Spectrally reconstructed nonlinear interferometric vibrational imaging can differentiate cancer versus normal tissue sections with greater than 99% confidence interval in a preclinical rat breast cancer model and define cancer boundaries to ±100 μm with greater than 99% confidence interval, using fresh unstained tissue sections imaged in less than 5 minutes. By optimizing optical sources and beam delivery, this technique can potentially enable real-time point-of-care optical molecular imaging and diagnosis. Cancer Res; 70(23); 9562–9. ©2010 AACR.
Endothelial Cell-Initiated Signaling Promotes the Survival and Self-Renewal of Cancer Stem Cells
Authors: Krishnamurthy Sudha , Dong Zhihong , Vodopyanov Dmitry , Imai Atsushi , Helman Joseph I. , Prince Mark E. , Wicha Max S. , Nör Jacques E.
Published: November 2010

Recent studies have demonstrated that cancer stem cells play an important role in the pathobiology of head and neck squamous cell carcinomas (HNSCC). However, little is known about functional interactions between head and neck cancer stem-like cells (CSC) and surrounding stromal cells. Here, we used aldehyde dehydrogenase activity and CD44 expression to sort putative stem cells from primary human HNSCC. Implantation of 1,000 CSC (ALDH+CD44+Lin−) led to tumors in 13 (out of 15) mice, whereas 10,000 noncancer stem cells (ALDH−CD44−Lin−) resulted in 2 tumors in 15 mice. These data demonstrated that ALDH and CD44 select a subpopulation of cells that are highly tumorigenic. The ability to self-renew was confirmed by the observation that ALDH+CD44+Lin− cells sorted from human HNSCC formed more spheroids (orospheres) in 3-D agarose matrices or ultra-low attachment plates than controls and were serially passaged in vivo. We observed that approximately 80% of the CSC were located in close proximity (within 100-μm radius) of blood vessels in human tumors, suggesting the existence of perivascular niches in HNSCC. In vitro studies demonstrated that endothelial cell-secreted factors promoted self-renewal of CSC, as demonstrated by the upregulation of Bmi-1 expression and the increase in the number of orospheres as compared with controls. Notably, selective ablation of tumor-associated endothelial cells stably transduced with a caspase-based artificial death switch (iCaspase-9) caused a marked reduction in the fraction of CSC in xenograft tumors. Collectively, these findings indicate that endothelial cell-initiated signaling can enhance the survival and self-renewal of head and neck CSC. Cancer Res; 70(23); 9969–78. ©2010 AACR.
Gadd45a Functions as a Promoter or Suppressor of Breast Cancer Dependent on the Oncogenic Stress
Authors: Tront Jennifer S. , Huang Yajue , Fornace Albert A. , Hoffman Barbara , Liebermann Dan A.
Published: November 2010

Gadd45a plays a pivotal role as a stress sensor that modulates cellular responses to various stress stimuli including oncogenic stress. We reported that the stress sensor Gadd45a gene functions as a tumor suppressor in Ras-driven breast tumorigenesis via increasing JNK-mediated apoptosis and p38-mediated senescence. In contrast, here, we show that Gadd45a promotes Myc-driven breast cancer by negatively regulating MMP10 via GSK3 β/β-catenin signaling, resulting in increased tumor vascularization and growth. These novel findings indicate that Gadd45a functions as either tumor promoter or suppressor, is dependent on the oncogenic stress, and is mediated via distinct signaling pathways. Collectively, these novel findings highlight the significance of the type of oncogenic alteration on how stress response genes function during initiation and progression of tumorigenesis. Because Gadd45a is a target for BRCA1 and p53, these findings have implications regarding BRCA1/p53 tumor suppressor functions. Cancer Res; 70(23); 9671–81. ©2010 AACR.
Combining ATR Suppression with Oncogenic Ras Synergistically Increases Genomic Instability, Causing Synthetic Lethality or Tumorigenesis in a Dosage-Dependent Manner
Authors: Gilad Oren , Nabet Barzin Y. , Ragland Ryan L. , Schoppy David W. , Smith Kevin D. , Durham Amy C. , Brown Eric J.
Published: November 2010

Previous studies indicate that oncogenic stress activates the ATR-Chk1 pathway. Here, we show that ATR-Chk1 pathway engagement is essential for limiting genomic instability following oncogenic Ras transformation. ATR pathway inhibition in combination with oncogenic Ras expression synergistically increased genomic instability, as quantified by chromatid breaks, sister chromatid exchanges, and H2AX phosphorylation. This level of instability was significantly greater than that observed following ATR suppression in untransformed control cells. In addition, consistent with a deficiency in long-term genome maintenance, hypomorphic ATR pathway reduction to 16% of normal levels was synthetic lethal with oncogenic Ras expression in cultured cells. Notably, elevated genomic instability and synthetic lethality following suppression of ATR were not due to accelerated cycling rates in Ras-transformed cells, indicating that these synergistic effects were generated on a per-cell-cycle basis. In contrast to the synthetic lethal effects of hypomorphic ATR suppression, subtle reduction of ATR expression (haploinsufficiency) in combination with endogenous levels of K-rasG12D expression elevated the incidence of lung adenocarcinoma, spindle cell sarcoma, and thymic lymphoma in p53 heterozygous mice. K-rasG12D-induced tumorigenesis in ATR+/−p53+/− mice was associated with intrachromosomal deletions and loss of wild-type p53. These findings indicate that synergistic increases in genomic instability following ATR reduction in oncogenic Ras-transformed cells can produce 2 distinct biological outcomes: synthetic lethality upon significant suppression of ATR expression and tumor promotion in the context of ATR haploinsufficiency. These results highlight the importance of the ATR pathway both as a barrier to malignant progression and as a potential target for cancer treatment. Cancer Res; 70(23); 9693–702. ©2010 AACR.
Homotypic Gap Junctional Communication Associated with Metastasis Suppression Increases with PKA Activity and Is Unaffected by PI3K Inhibition
Authors: Bodenstine Thomas M. , Vaidya Kedar S. , Ismail Aimen , Beck Benjamin H. , Cook Leah M. , Diers Anne R. , Landar Aimee , Welch Danny R.
Published: November 2010

Loss of gap junctional intercellular communication (GJIC) between cancer cells is a common characteristic of malignant transformation. This communication is mediated by connexin proteins that make up the functional units of gap junctions. Connexins are highly regulated at the protein level and phosphorylation events play a key role in their trafficking and degradation. The metastasis suppressor breast cancer metastasis suppressor 1 (BRMS1) upregulates GJIC and decreases phosphoinositide-3-kinase (PI3K) signaling. On the basis of these observations, we set out to determine whether there was a link between PI3K and GJIC in tumorigenic and metastatic cell lines. Treatment of cells with the well-known PI3K inhibitor LY294002, and its structural analogue LY303511, which does not inhibit PI3K, increased homotypic GJIC; however, we found the effect to be independent of PI3K/AKT inhibition. We show in multiple cancer cell lines of varying metastatic capability that GJIC can be restored without enforced expression of a connexin gene. In addition, while levels of connexin 43 remained unchanged, its relocalization from the cytosol to the plasma membrane was observed. Both LY294002 and LY303511 increased the activity of protein kinase A (PKA). Moreover, PKA blockade by the small molecule inhibitor H89 decreased the LY294002/LY303511-mediated increase in GJIC. Collectively, our findings show a connection between PKA activity and GJIC mediated by PI3K-independent mechanisms of LY294002 and LY303511. Manipulation of these signaling pathways could prove useful for antimetastatic therapy. Cancer Res; 70(23); 10002–11. ©2010 AACR.
Tumor Ablation by Gene-Modified T Cells in the Absence of Autoimmunity
Authors: Wang Leanne X.J. , Westwood Jennifer A. , Moeller Maria , Duong Connie P.M. , Wei Wei-Zen , Malaterre Jordane , Trapani Joseph A. , Neeson Paul , Smyth Mark J. , Kershaw Michael H. , Darcy Phillip K.
Published: November 2010

Adoptive immunotherapy involving genetic modification of T cells with antigen-specific, chimeric, single-chain receptors is a promising approach for the treatment of cancer. To determine whether gene-modified T cells could induce antitumor effects without associated autoimmune pathology, we assessed the ability of T cells expressing an anti-Her-2 chimeric receptor to eradicate tumor in Her-2 transgenic mice that express human Her-2 as a self-antigen in brain and mammary tissues. In adoptive transfer studies, we demonstrated significant improvement in the survival of mice bearing Her-2+ 24JK tumor following administration of anti-Her-2 T cells compared with control T cells. The incorporation of a lymphoablative step prior to adoptive transfer of anti-Her-2 T cells and administration of IL-2 were both found to further enhance survival. The reduction in tumor growth was also correlated with localization of transferred T cells at the tumor site. Furthermore, an antigen-specific recall response could be induced in long-term surviving mice following rechallenge with Her-2+ tumor. Importantly, antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen. This study highlights the therapeutic potential of using gene-engineered T cells as a safe and effective treatment of cancer. Cancer Res; 70(23); 9591–8. ©2010 AACR.
Preoperative Circulating Tumor Cell Detection Using the Isolation by Size of Epithelial Tumor Cell Method for Patients with Lung Cancer Is a New Prognostic Biomarker
Authors: Hofman Véronique , Bonnetaud Christelle , Ilie Marius I. , Vielh Philippe , Vignaud Jean Michel , Fléjou Jean François , Lantuejoul Sylvie , Piaton Eric , Mourad Nadine , Butori Catherine , Selva Eric , Poudenx Michel , Sibon Stéphanie , Kelhef Sabrina , Vénissac Nicolas , Jais Jean-Philippe , Mouroux Jérôme , Molina Thierry Jo , Hofman Paul
Published: November 2010

Purpose: Pathologic TNM staging is currently the best prognostic factor for non-small cell lung carcinoma (NSCLC). However, even in early-stage NSCLC, the recurrence rates after surgery range from 25% to 50%. The preoperative detection of circulating tumor cells (CTC) could be useful to tailor new therapeutic strategies in NSCLC. We assessed the presence of CTC in NSCLC patients undergoing surgery, using cytologic analyses, after their isolation by size of epithelial tumor cells (ISET method). The presence and the number of CTCs were considered and correlated with clinicopathologic parameters including patient follow-up.

Experimental Design: Of the 247 blood samples tested, 208 samples were from patients with resectable NSCLC and 39 from healthy subjects. The mean follow-up was 24 months. An image of detected cells with presumably nonhematologic features [initially defined as “circulating nonhematologic cells” (CNHC)] was recorded. The presence of CNHC was assessed blindly and independently by 10 cytopathologists, using cytologic criteria of malignancy on stained filters. The count of detected CNHCs was made for each filter.

Results: One hundred two of 208 (49%) patients showed CNHCs corresponding to CNHC with malignant cytopathologic features in 76 of 208 (36%) cases. CNHCs were not detected in the control group. A level of 50 or more CNHCs corresponding to the third quartile was associated with shorter overall and disease-free-survival, independently of disease staging, and with a high risk of recurrence and death in early-stage I + II-resectable NSCLC.

Conclusion: A high percentage of NSCLC patients show preoperative detection of CNHC by the ISET method. The presence and level of 50 or more CNHCs are associated with worse survival of patients with resectable NSCLC. Clin Cancer Res; 17(3); 505–13. ©2010 AACR.
Nutlin-3a Is a Potential Therapeutic for Ewing Sarcoma
Authors: Pishas Kathleen I. , Al-Ejeh Fares , Zinonos Irene , Kumar Raman , Evdokiou Andreas , Brown Michael P. , Callen David F. , Neilsen Paul M.
Published: November 2010

Purpose: Although mutations in the TP53 gene occur in half of all cancers, approximately 90% of Ewing sarcomas retain a functional wild-type p53. The low frequency of TP53 alterations in Ewing sarcoma makes this tumor type an ideal candidate for p53-targeted therapies. In this study, we have examined the molecular and cellular responses of cultured Ewing sarcoma cell lines following exposure to Nutlin-3a, a recently developed MDM2 antagonist.

Experimental Design: The ability of Nutlin-3a to impart apoptosis or cell cycle arrest in a p53-dependent manner was determined in a comprehensive panel of Ewing sarcoma cell lines. The capacity of Nutlin-3a to augment the antitumor activity of MDM4 antagonists and cytotoxic agents currently used in the clinical treatment of Ewing sarcoma was also investigated.

Results: Apoptosis was the primary response of wild-type p53 expressing Ewing sarcoma cell lines. The cytotoxicity of Nultin-3a was also synergistic with the chemotherapeutic agents, vincristine, actinomycin D, doxorubicin, and etoposide in a concentration-dependent manner. Significant MDM4 protein overexpression was observed in Ewing sarcoma cell lines of wild-type p53 status, providing a mechanism through which Ewing sarcomas can develop in the absence of TP53 alterations. This study provides the first evidence of synergism between targeted inhibition of MDM2 and MDM4.

Conclusion: Our findings suggest that p53-dependent apoptosis is the primary cellular response of Ewing sarcoma cell lines following exposure to Nutlin-3a. Furthermore, Nutlin-3a can synergize with the current Ewing sarcoma chemotherapy protocols, suggesting p53 activation as a novel systemic therapeutic approach for this disease. Clin Cancer Res; 17(3); 494–504. ©2010 AACR.
High-Mobility Group Box Protein 1: A Novel Mediator of Inflammatory-Induced Renal Epithelial-Mesenchymal Transition
Authors: Lynch Julie , Nolan Stephen , Slattery Craig , Feighery Ronan , Ryan Michael P. , McMorrow Tara
Published: November 2010

Background: High-mobility group box protein 1 (HMGB-1) is a chromatin-binding protein that bends DNA, thereby facilitating gene transcription. HMGB-1 has also been observed as an extracellular secreted protein in serum of patients with sepsis and has putative intracellular signalling effects regulating the production of interleukin-1 and tumour necrosis factor in a number of inflammatory conditions. Methods: We established a model of immune-mediated epithelial-mesenchymal transition (EMT) in human proximal tubular epithelial cells (PTECs). PTECs were cultured with conditioned medium containing supernatant from activated peripheral blood mononuclear cells (aPBMCs). The model was characterized using phenotypic and transcriptomic approaches and suppression subtractive hybridisation was performed to identify differentially regulated genes. Results: Activation of PBMCs resulted in increased secretion of HMGB-1. In addition, treatment of PTECs with aPBMC-conditioned medium resulted in significant upregulation of HMGB-1 in PTECs. Direct treatment of PTECs with recombinant human HMGB-1 induced alterations in epithelial morphology consistent with EMT including reduced E-cadherin expression, increased α-smooth muscle actin expression and enhanced cell migration. HMGB-1 effects were mediated at least in part by the receptor for advanced glycation end products and through induction of transforming growth factor-β1 secretion from PTECs. Conclusions: These results suggest that HMGB-1 is a key mediator of immune-mediated EMT of PTECs and a potentially important signalling molecule in the development of renal fibrosis.
Emerging Resistant Gram-Negative Aerobic Bacilli in Hospital-Acquired Infections
Authors: Kunz Anjali N. , Brook Itzhak
Published: November 2010

The increasing emergence of serious multidrug-resistant (MDR) Gram-negative infections has led to a new health-care crisis. These infections predominately include MDR Pseudomonas aeruginosa, extended-spectrum beta-lactamase-producing Enterobacteriaceae and MDR Acinetobacter baumannii. These organisms are present in a variety of clinical settings, but there is a distinct paucity of antibiotics to effectively treat these infections. The increasing use of broad-spectrum antibiotics and lack of good stewardship have contributed to the increase in these MDR organisms. This review focuses on the main MDR Gram-negative infections contributing to the current crisis in health care, their mechanisms of resistance and various treatment options for empiric therapy.
Phase I study of Solulin, a novel recombinant soluble human thrombomodulin analogue
Authors: Iersel Thijs van , Stroissnig Heimo , Giesen Peter , Wemer Johan , Wilhelm-Ogunbiyi Karin
Published: November 2010

Solulin is a novel recombinant soluble derivative of human thrombomodulin. In this first human study of Solulin, the safety, tolerability, pharmacokinetics and pharmacodynamics of Solulin in 30 healthy volunteers in response to single (0.6–30 mg) and 12 healthy volunteers in response to multiple (1 and 10 mg) ascending intravenous bolus doses compared to placebo are described. Solulin was shown to be well tolerated, and demonstrated linear pharmacokinetics over the clinically relevant dose range, with a plasma elimination half-life of 15–30 hours, indicating that a less than daily dose may be required for therapeutic use. Steady-state plasma levels after multiple dosing were reached after 48 hours. Solulin has shown to be able to inhibit thrombin generation without increasing levels of aPC/PCI complexes. Coagulation parameters INR and PT were not changed, aPTT was elevated to about 10% above the upper limit of normal after the highest single dose only. Thrombin clotting time was prolonged after administration of high dose Solulin (10, 30 mg). No effect on in vitro bleeding time has been found. There was no evidence of bleeding risk with Solulin administration. The pharmacodynamic effects correlated with Solulin plasma concentrations. This demonstrates that the antithrombotic effect of Solulin is predictable, suggesting that patient monitoring is not expected. The results of this study provide evidence that Solulin can be expected to be an effective and safe anticoagulant, and further clinical investigation is warranted.
ABO blood group as a potential risk factor for venous thromboembolism in acutely injured patients
Authors: Muellner Sarah , Haut Elliott , Streiff Michael , Holcomb John , Cotton Bryan
Published: November 2010

Venous thromboembolism (VTE) is a major health problem that results in a significant burden on hospitals and patients. VTE screening and prophylaxis protocols in trauma patients vary significantly among hospitals and providers. In addition, many patients develop VTE even in the absence of “high-risk” categories. Therefore, more research is needed to better understand and prevent VTE in these patients. ABO blood group has long been recognised as a risk factor for VTE, but its contribution to VTE risk in the trauma setting is poorly studied. This paper reviews the literature describing the link between ABO blood group and VTE risk and the implications for VTE screening and prophylaxis in trauma patients. The effect of ABO blood groups are genotype-dependent – in most populations the A1 allele and the B allele increase risk while A2, O1, and O2 decrease risk of VTE. ABO group is a major determinant of plasma von Willebrand factor (vWF) and factor VIII levels, thereby (partially) mediating the effects of ABO blood group on VTE susceptibility. In addition, ABH antigens alter plasma levels of vWF via clearance mechanisms, which are in turn mediated by ADAMTS13. ABO blood group is a risk factor for VTE that warrants further investigation in trauma patients.
Clopidogrel withdrawal: Is there a “rebound” phenomenon?
Authors: Sambu Nalyaka , Warner Timothy , Curzen Nick
Published: November 2010

Dual antiplatelet therapy with aspirin and clopidogrel is routinely indicated in patients with acute coronary syndromes and following percutaneous coronary intervention to reduce the risk of cardiovascular mortality and ischaemic events. Although clinical guidelines recommend aspirin lifelong and clopidogrel for between one and 12 months, depending upon the indication, the optimal duration of clopidogrel therapy actually remains contentious. Premature cessation of clopidogrel in patients receiving drug-eluting stents is a clear risk factor for stent thrombosis, but recent clinical studies have also demonstrated a link between “appropriate” cessation of clopidogrel and clustering of adverse clinical events. It has been suggested that this may be due to a “rebound” prothrombotic and/ or proinflammatory response associated with clopidogrel withdrawal. This review will examine the defini- tion and concept of a “rebound” phenomenon associated with clopidogrel cessation as well as the likely mechanisms behind this effect. Within the context of clinical event clustering after clopidogrel cessation, we will also discuss (i) the clinical importance of clopidogrel and the increasing uncertainty surrounding optimal duration of therapy, (ii) the antiplatelet and anti-inflammatory properties of clopidogrel and, in particular, its influence on arachidonic acid pathways traditionally thought to be mediated predominantly by aspirin and (iii) the role of newer, more potent antiplatelet agents and potential changes to anti-platelet therapy prescribing guidelines in the future.
Wnt Signaling and Aging-Related Heart Disorders
Authors: Naito Atsuhiko T. , Shiojima Ichiro , Komuro Issei
Published: November 2010

Aging is associated with various heart diseases, and this may be attributable, in part, to the prolonged exposure of the heart to cardiovascular risk factors. However, aging is also associated with heart disorders such as diastolic dysfunction that are not necessarily linked to the risk factors for cardiovascular diseases. Recent studies have demonstrated a mechanistic link between Wnt signaling and premature aging or aging-related phenotypes. As a part of the review series on Wnt signaling and the cardiovascular system, we discuss here the possible involvement of Wnt signaling in aging-associated heart diseases or heart disorders.
Origins of Cardiac Fibroblasts
Authors: Zeisberg Elisabeth M. , Kalluri Raghu
Published: November 2010

Cardiac fibroblasts play a critical role in maintenance of normal cardiac function. They are indispensable for damage control and tissue remodeling on myocardial injury and principal mediators of pathological cardiac remodeling and fibrosis. Despite their manyfold functions, cardiac fibroblasts remain poorly characterized in molecular terms. Evidence is evolving that cardiac fibroblasts are a heterogeneous population and likely derive from various distinct tissue niches in health and disease. Here, we review our emerging understanding of where cardiac fibroblasts come from, as well as how we can possibly use this knowledge to develop novel therapies for cardiac fibrosis.
Modeling Basal Ganglia for Understanding Parkinsonian Reaching Movements
Authors: Magdoom K. N. , Subramanian D. , Chakravarthy V. S. , Ravindran B. , Amari Shun-ichi , Meenakshisundaram N.
Published: November 2010

We present a computational model that highlights the role of basal ganglia (BG) in generating simple reaching movements. The model is cast within the reinforcement learning (RL) framework with correspondence between RL components and neuroanatomy as follows: dopamine signal of substantia nigra pars compacta as the temporal difference error, striatum as the substrate for the critic, and the motor cortex as the actor. A key feature of this neurobiological interpretation is our hypothesis that the indirect pathway is the explorer. Chaotic activity, originating from the indirect pathway part of the model, drives the wandering, exploratory movements of the arm. Thus, the direct pathway subserves exploitation, while the indirect pathway subserves exploration. The motor cortex becomes more and more independent of the corrective influence of BG as training progresses. Reaching trajectories show diminishing variability with training. Reaching movements associated with Parkinson's disease (PD) are simulated by reducing dopamine and degrading the complexity of indirect pathway dynamics by switching it from chaotic to periodic behavior. Under the simulated PD conditions, the arm exhibits PD motor symptoms like tremor, bradykinesia and undershooting. The model echoes the notion that PD is a dynamical disease.
Conjugate Mixture Models for Clustering Multimodal Data
Authors: Khalidov Vasil , Forbes Florence , Horaud Radu
Published: November 2010

The problem of multimodal clustering arises whenever the data are gathered with several physically different sensors. Observations from different modalities are not necessarily aligned in the sense there there is no obvious way to associate or compare them in some common space. A solution may consist in considering multiple clustering tasks independently for each modality. The main difficulty with such an approach is to guarantee that the unimodal clusterings are mutually consistent. In this letter, we show that multimodal clustering can be addressed within a novel framework: conjugate mixture models. These models exploit the explicit transformations that are often available between an unobserved parameter space (objects) and each of the observation spaces (sensors). We formulate the problem as a likelihood maximization task and derive the associated conjugate expectation-maximization algorithm. The convergence properties of the proposed algorithm are thoroughly investigated. Several local and global optimization techniques are proposed in order to increase its convergence speed. Two initialization strategies are proposed and compared. A consistent model selection criterion is proposed. The algorithm and its variants are tested and evaluated within the task of 3D localization of several speakers using both auditory and visual data.
Least Squares Estimation Without Priors or Supervision
Authors: Raphan Martin , Simoncelli Eero P.
Published: November 2010

Selection of an optimal estimator typically relies on either supervised training samples (pairs of measurements and their associated true values) or a prior probability model for the true values. Here, we consider the problem of obtaining a least squares estimator given a measurement process with known statistics (i.e., a likelihood function) and a set of unsupervised measurements, each arising from a corresponding true value drawn randomly from an unknown distribution. We develop a general expression for a nonparametric empirical Bayes least squares (NEBLS) estimator, which expresses the optimal least squares estimator in terms of the measurement density, with no explicit reference to the unknown (prior) density. We study the conditions under which such estimators exist and derive specific forms for a variety of different measurement processes. We further show that each of these NEBLS estimators may be used to express the mean squared estimation error as an expectation over the measurement density alone, thus generalizing Stein's unbiased risk estimator (SURE), which provides such an expression for the additive gaussian noise case. This error expression may then be optimized over noisy measurement samples, in the absence of supervised training data, yielding a generalized SURE-optimized parametric least squares (SURE2PLS) estimator. In the special case of a linear parameterization (i.e., a sum of nonlinear kernel functions), the objective function is quadratic, and we derive an incremental form for learning this estimator from data. We also show that combining the NEBLS form with its corresponding generalized SURE expression produces a generalization of the score-matching procedure for parametric density estimation. Finally, we have implemented several examples of such estimators, and we show that their performance is comparable to their optimal Bayesian or supervised regression counterparts for moderate to large amounts of data.
Improved Integral Equation Solution for the First Passage Time of Leaky Integrate-and-Fire Neurons
Authors: Dong Yi , Mihalas Stefan , Niebur Ernst
Published: November 2010

An accurate calculation of the first passage time probability density (FPTPD) is essential for computing the likelihood of solutions of the stochastic leaky integrate-and-fire model. The previously proposed numerical calculation of the FPTPD based on the integral equation method discretizes the probability current of the voltage crossing the threshold. While the method is accurate for high noise levels, we show that it results in large numerical errors for small noise. The problem is solved by analytically computing, in each time bin, the mean probability current. Efficiency is further improved by identifying and ignoring time bins with negligible mean probability current.
Building Bensalem at Massachusetts Bay: Francis Bacon and the Wisdom of Eden in Early Modern New England
Authors: Hutchins Zachary Mcleod
Published: November 2010

Francis Bacon's influence on seventeenth-century New England has long passed unnoticed, but his plan for the restoration of prelapsarian intellectual perfections guided John Winthrop's initial colonization efforts, shaped New England's educational policies, and had an impact on civic and religious leaders from John Cotton to Jonathan Edwards.
“Scattered as Christians Are in This Part of Our Country”: Layfolk's Reading, Writing, and Religious Community in New England's Northern Frontier, 1780–1830
Authors: Balik Shelby M.
Published: November 2010

A far-reaching literate culture united northern New England's laity during the early republic and gave rise to a religious public sphere in which distant believers found spiritual sustenance. In a region where religious institutions were fragile, reading and writing supplemented churchgoing and formed a cornerstone of religious life and community.
The Immunity of International Organizations Before Domestic Courts: Recent trends
Authors: Ryngaert Cedric
Published: November 2010

This article addresses the international organizations' immunity defence before domestic courts, and its relationship with the organizations' internal dispute settlement mechanisms. The focus of the article lies primarily on private law disputes between international organizations and individuals, and on (employment) disputes between organizations and their staff in particular. It draws inductively on cases that have recently been decided or made available, and that draw attention to three main issues: 1. the legal nature of the immunity of international organizations, 2. the weighing of the individual's right to a remedy and the organization's immunity and, to a lesser extent, 3. the relationship between the immunity from jurisdiction and the immunity from enforcement.
Immunity of International Organizations in Post-conflict International Administrations
Authors: De Brabandere Eric
Published: November 2010

The role played by international organizations in international law has evolved in the past decades. However, the continued application of an absolute system of immunities to international organizations has often led to a perception of impunity, in particular when organizations are involved in the administrations of foreign territories. Even though absolute immunity has been described as an 'anachronism', this article argues that international organization immunity serves a useful and essential purpose. The grant of privileges and immunities to international organizations is indispensable to allow the organization to effectively and independently carry out its functions. The functional reflections that lie at the basis of the immunities system of international organizations still are extremely pertinent when organizations exercise administrative duties in place of a state. This articles thus claims that there is a need to maintain immunities in order to preserve institutional autonomy, even when the UN or another international organization has taken up administrative duties in a state or territory, and suggests that, instead of proposing a revision or abolition of the system of immunities, the focus should be placed on the establishment of effective alternative mechanisms to assess alleged violations of the international legal obligations of the organization.