bluuebunny/crossref_metadata_2025 huggingface dataset:
Adult Neurogenesis Supports Short-Term Olfactory Memory
Authors: Arenkiel Benjamin R.
Published: April 2010

Adult neurogenesis has captivated neuroscientists for decades, with hopes that understanding the programs underlying this phenomenon may provide unique insight toward avenues for brain repair. Interestingly, however, despite intense molecular and cellular investigation, the evolutionary roles and biological functions for ongoing neurogenesis have remained elusive. Here I review recent work published in the Journal of Neuroscience that reveals a functional role for continued neurogenesis toward forming short-term olfactory memories.
Transcriptional profiling of hypothalamus during development of adiposity in genetically selected fat and lean chickens
Authors: Byerly Mardi S. , Simon Jean , Cogburn Larry A. , Le Bihan-Duval Elisabeth , Duclos Michel J. , Aggrey Samuel E. , Porter Tom E.
Published: April 2010

The hypothalamus integrates peripheral signals to regulate food intake, energy metabolism, and ultimately growth rate and body composition in vertebrates. Deviations in hypothalamic regulatory controls can lead to accumulation of excess body fat. Many regulatory genes involved in this process remain unidentified, and comparative studies may be helpful to unravel evolutionarily conserved mechanisms controlling body weight and food intake. In the present study, divergently selected fat (FL) and lean (LL) lines of chickens were used to characterize differences in hypothalamic gene expression in these unique genetic lines that develop differences in adiposity without differences in food intake or body weight. Hypothalamic transcriptional profiles were defined with cDNA microarrays before and during divergence of adiposity between the two lines. Six differentially expressed genes identified in chickens are related to genes associated with control of body fat in transgenic or knockout mice, supporting the importance of these genes across species. We identified differences in expression of nine genes involved in glucose metabolism, suggesting that alterations in hypothalamic glycolysis might contribute to differences in levels of body fat between genotypes. Expression of the sweet taste receptor ( TAS1R1), which in mammals is involved in glucose sensing and energy uptake, was also higher in FL chickens, suggesting that early differences in glucose sensing might alter the set point for subsequent body composition. Differences in expression of genes associated with tumor necrosis factor (TNF) signaling were also noted. In summary, we identified alterations in transcriptional and metabolic processes within the hypothalamus that could contribute to excessive accumulation of body fat in FL chickens in the absence of differences in food intake, thereby contributing to the genetic basis for obesity in this avian model.
Long-Term Histologic Changes in Nasal Mucosa after Total Laryngectomy
Authors: Karaca Çiğdem Tepe , Gültekin Erdoğan , Yelken M. Kürşat , İğdem Ayşenur Akyıldız , Külekçi Mehmet
Published: April 2010

Objective. To determine the long-term histopathologic changes in nasal mucosa and the relationship between progression of the histopathologic changes and the duration without air current stimulation.Material and Method. Biopsies were taken from the inferior turbinates of 11 laryngeal cancer patients after total laryngectomy. Specimens were stained with hematoksilen-eosin and several histopathologic parameters were examined under light microscopy.Results. All of the patients demonstrated at least one histopathologic abnormality (100%,n=11). Goblet destruction and stromal fibrosis were the most common findings (81%,n=9), followed by focal epithelial atrophy and subepithelial seromusinous gland destruction (45%,n=5), neovascularization and congestion (36%,n=4), complete epithelial atrophy and mixoid degeneration (27%,n=3). According to the duration between laryngectomy and biopsy, patients were grouped in to three: group 1; less than 12 months (36%,n=4), group 2; 12–36 months (18%,n=2), and group 3; more than 36 months (45%,n=5). Only congestion was found to be decreased as the duration increased (P<.005).Conclusion. In laryngeal cancer patients histopathologic changes occur in nasal mucosa eventuate due to the cessation of air current stimulation, however there was no relation between progression of the histopathologic findings and the duration of cessation.
Computational Laser Spectroscopy in a Biological Tissue
Authors: Gantri M. , Trabelsi H. , Sediki E. , Ben Salah R.
Published: April 2010

We present a numerical spectroscopic study of visible and infrared laser radiation in a biological tissue. We derive a solution of a general two-dimensional time dependent radiative transfer equation in a tissue-like medium. The used model is suitable for many situations especially when the external source is time-dependent or continuous. We use a control volume-discrete ordinate method associated with an implicit three-level second-order time differencing scheme. We consider a very thin rectangular biological-tissue-like medium submitted to a visible or a near infrared light sources. The RTE is solved for a set of different wavelength source. All sources are assumed to be monochromatic and collimated. The energetic fluence rate is computed at a set of detector points on the boundaries. According to the source type, we investigate either the steady-state or transient response of the medium. The used model is validated in the case of a heterogeneous tissue-like medium using referencing experimental results from the literature. Also, the developed model is used to study changes on transmitted light in a rat-liver tissue-like medium. Optical properties depend on the source wavelength and they are taken from the literature. In particular, light-transmission in the medium is studied for continuous wave and for short pulse.
The Role of the Lactadherin in Promoting Intestinal DCs Development In Vivo and Vitro
Authors: Zhou Yi-Jun , Gao Juan , Yang Hua-Mei , Yuan Xiang-Liang , Chen Tong-Xin , He Zhen-Juan
Published: April 2010

Lactadherin, as one of the immune components in the breast milk, might play a role in the intestinal immune system of newborn. Therefore, we investigated the effect of lactadherin‐feeding in early time on the development of intestinal immune system compared with naturally rearing and artificially rearing (non‐lactadherin). In the present study, we observed that the Peyer′s Patches (PP) from the pups of artificially reared group with lactadherin added were characterized by an excess of OX62+CD4+SIRP+ DC cells and a higher expression of CD3+CD4+CD25+T cells. Additionally, this study also demonstrated that IL‐10 production was dramatically increased when lactadherin was present in culture medium compared with lactadherin‐absent culture. These results suggested that lactadherin could adjust intestinal DCs activity, induce CD3+CD4+CD25+T cell differentiation, and enhance IL‐10 production.
Differential Subordination Defined by New Generalised Derivative Operator for Analytic Functions
Authors: Harayzeh Al-Abbadi Ma′moun , Darus Maslina
Published: April 2010

A new generalised derivative operator is introduced. This operator generalised many well‐known operators studied earlier by many authors. Using the technique of differential subordination, we will study some of the properties of differential subordination. In addition we investigate several interesting properties of the new generalised derivative operator.
Retrosternal Percutaneous Tracheostomy: An Approach for Predictably Impossible Classic Tracheostomy
Authors: Biderman Philippe , Weinbroum Avi A. , Rafaeli Yael , Raz Eyal , Porat Eyal , Wiesel Ory , Szold Oded
Published: April 2010

Percutaneous tracheostomy is a routine procedure in intensive care units. In cases of very low position of the larynx, cervical spine deformation, morbid obesity, or neck tumor, performance of the classic tracheostomy is inapplicable. Retrosternal approach to tracheostomy in such 20 patients is herein reported. After preoperative neck computerized tomography to define the neck anatomy, a small suprasternal incision followed by a short retrosternal tissue dissection to expose the trachea was done; the trachea was then catheterized at the level of the 2nd ring in the usual tracheostomy manner. The immediate and late (6 months) outcomes were similar to that of the standard tracheostomy. Thus, percutaneous retrosternal tracheostomy is safe in patients with abnormal positioning of the trachea or neck constitution. It is a bedside applicable technique, that, however, requires caution to avoid hazardous vascular complications.
Bacterial Adaptor Membrane Fusion Proteins and the Structurally Dissimilar Outer Membrane Auxiliary Proteins Have Exchanged Central Domains inα-Proteobacteria
Authors: Xiao Anthony Y. , Wang Jing , Saier Milton H.
Published: April 2010

Transport systems frequently include auxiliary proteins that perform subfunctions within the transporter protein complex. Two such proteins found in Gram-negative bacteria are the Membrane Fusion Proteins (MFPs) and the Outer Membrane Auxiliary (OMA) proteins. We here demonstrate that OMAs present inα-proteobacteria (but not in other bacterial types) contain a longα-helical region that is homologous to corresponding regions in the MFPs. The results suggest that during their evolution, OMAs, specifically fromα-proteobacteria, exchanged their ownα-helical domain for one derived from an MFP. The structural and functional implications of these findings are discussed.
Performance of Surgical Stress Index during Sevoflurane-Fentanyl and Isoflurane-Fentanyl Anesthesia
Authors: Mustola S. , Parkkari T. , Uutela K. , Huiku M. , Kymäläinen M. , Toivonen J.
Published: April 2010

The performance of recently introduced Surgical Stress Index (SSI), based on heart rate and photoplethysmography, was estimated during sevoflurane-fentanyl and isoflurane-fentanyl anesthesia during surgical procedures. Forty ASA I–III patients were enrolled. Anesthesia was induced with fentanyl 2 μg kg−1and thiopentone 3–5 mg kg−1. Tracheal intubation was performed 5 minutes after fentanyl bolus. Patients were randomly allocated to receive sevoflurane (n=20) or isoflurane (n=20) in 30% oxygen/air. State entropy was kept at 40–60, target being 50. During surgery, fentanyl boluses 1.5 μg kg−1were given at 30–40-minute intervals. SSI increased significantly after intubation. During surgery, the decrease of SSI after fentanyl boluses was similar in sevoflurane and isoflurane groups but SSI values were higher in sevoflurane than in isoflurane group. Tracheal intubation, skin incision, and surgical stimuli increased SSI from baseline, indicating that nociceptive stimuli increase SSI. Fentanyl boluses during surgery decreased SSI, indicating that increasing analgesia decreases SSI.
The REM Observing Software
Authors: Stefanon Mauro , Covino Stefano , Fugazza Dino , Molinari Emilio , D′Alessio Francesco , Malaspina Giuseppe , Nicastro Luciano , Testa Vincenzo , Tosti Gino , Vitali Fabrizio
Published: April 2010

The Rapid Eye Mount (REM) is a 60 cm robotic telescope located at La Silla, Chile. Its Observing Software (REMOS) is constituted by a set of distributed intercommunicating processes organized around a central manager.
Together they grant the system safety, automatically schedule and perform observations with two simultaneous cameras of user‐defined targets, and drive fast reaction to satellite alerts. Subsequent data reduction is left to pipelines managed by each camera.
Crosstalk between Mast Cells and Pancreatic Cancer Cells Contributes to Pancreatic Tumor Progression
Authors: Strouch Matthew J. , Cheon Eric C. , Salabat Mohammad R. , Krantz Seth B. , Gounaris Elias , Melstrom Laleh G. , Dangi-Garimella Surabhi , Wang Edward , Munshi Hidayatullah G. , Khazaie Khashayarsha , Bentrem David J.
Published: April 2010

Purpose: To assess the clinical and pathologic significance of mast cell infiltration in human pancreatic cancer and evaluate crosstalk between mast cells and cancer cells in vitro.

Experimental Design: Immunohistochemistry for tryptase was done on 53 pancreatic cancer specimens. Mast cell counts were correlated with clinical variables and survival. Serum tryptase activity from patients with cancer was compared with patients with benign pancreatic disease. In vitro, the effect of pancreatic cancer–conditioned medium on mast cell migration was assessed. The effect of conditioned medium from the human mast cell line, LAD-2, on cancer and normal ductal cell proliferation was assessed by thymidine incorporation. Matrigel invasion assays were used to evaluate the effect of mast cell–conditioned medium on cancer cell invasion in the presence and absence of a matrix metalloproteinase inhibitor, GM6001.

Results: Mast cell infiltration was significantly increased in pancreatic cancer compared with normal pancreatic tissue (11.4 ± 6.7 versus 2.0 ± 1.4, P < 0.001). Increased infiltrating mast cells correlated with higher grade tumors (P < 0.0001) and worse survival. Patients with pancreatic cancer had elevated serum tryptase activity (P < 0.05). In vitro, AsPC1 and PANC-1 cells induced mast cell migration. Mast cell–conditioned medium induced pancreatic cancer cell migration, proliferation, and invasion but had no effect on normal ductal cells. Furthermore, the effect of mast cells on cancer cell invasion was, in large part, matrix metalloproteinase–dependent.

Conclusions: Tumor-infiltrating mast cells are associated with worse prognosis in pancreatic cancer. In vitro, the interaction between mast cells and pancreatic cancer cells promotes tumor growth and invasion. Clin Cancer Res; 16(8); 2257–65. ©2010 AACR.
The EPHB6 Receptor Tyrosine Kinase Is a Metastasis Suppressor That Is Frequently Silenced by Promoter DNA Hypermethylation in Non–Small Cell Lung Cancer
Authors: Yu Jun , Bulk Etmar , Ji Ping , Hascher Antje , Tang Moying , Metzger Ralf , Marra Alessandro , Serve Hubert , Berdel Wolfgang E. , Wiewroth Rainer , Koschmieder Steffen , Müller-Tidow Carsten
Published: April 2010

Purpose: Loss of EPHB6 receptor tyrosine kinase expression in early-stage non–small cell lung carcinoma (NSCLC) is associated with the subsequent development of distant metastasis. Here, we analyzed the regulation and function of EPHB6 in lung cancer metastasis.

Experimental Design: The expression levels of EPHB6 were compared among normal lung tissue (n = 9), NSCLC without metastasis (n = 39), and NSCLC with metastasis (n = 39) according to the history of the patients. In addition, EPHB6 expression levels of matched tumor-normal pairs from 24 NSCLC patients were analyzed. The promoter DNA methylation status and its association with the expression levels of EPHB6 were determined among 14 pairs of tumor-normal samples. Metastatic potential of EPHB6 was assessed in vitro and in vivo in a metastasis mouse model. Overexpression and RNA interference (RNAi) approaches were used for analysis of the biological functions of EPHB6.

Results: EPHB6 mRNA and protein levels were significantly reduced in NSCLC tumors compared with matched normal lung tissue. Decreased EPHB6 expression levels were associated with an increased risk for metastasis development in NSCLC patients. Loss of expression correlated with EPHB6 hypermethylation. EPHB6 expression was induced by 5-aza-2'-deoxycytidine treatment in an NSCLC cell line. Restoration of EPHB6 expression in lung adenocarcinoma cells increased adhesion and decreased migration. Reexpression of EPHB6 in lung cancer cells almost entirely abolished metastasis formation in non obese diabetic (NOD)/severe combined immunodeficient mice.

Conclusions: Taken together, these analyses show that EPHB6 is a metastasis inhibitory gene that is frequently silenced by hypermethylation of its promoter in NSCLC. Clin Cancer Res; 16(8); 2275–83. ©2010 AACR.
Histone Deacetylase Inhibitors and 15-Deoxy-Δ12,14-Prostaglandin J2 Synergistically Induce Apoptosis
Authors: Koyama Makoto , Izutani Yasuyuki , Goda Ahmed E. , Matsui Taka-aki , Horinaka Mano , Tomosugi Mitsuhiro , Fujiwara Jun , Nakamura Yoshitaka , Wakada Miki , Yogosawa Shingo , Sowa Yoshihiro , Sakai Toshiyuki
Published: April 2010

Purpose: The clinically relevant histone deacetylase inhibitors (HDI) valproic acid (VPA) and suberoylanilide hydroxamic acid exert variable antitumor activities but increase therapeutic efficacy when combined with other agents. The natural endogenous ligand of peroxisome proliferator–activated receptor γ 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a potent antineoplastic agent. Therefore, we investigated whether these HDIs in combination with 15d-PGJ2 could show synergistic antitumor activity in colon cancer DLD-1 cells.

Experimental Design: Cell viability was determined using a Cell Counting Kit-8 assay. Apoptosis and reactive oxygen species (ROS) generation were determined using flow cytometry analysis. Western blotting and real-time reverse transcription-PCR analysis were carried out to investigate the expression of apoptosis-related molecules. Mice bearing DLD-1 xenograft were divided into four groups (n = 5) and injected everyday (i.p.) with diluent, VPA (100 mg/kg), 15d-PGJ2 (5 mg/kg), or a combination for 25 days.

Results: HDI/15d-PGJ2 cotreatments synergistically induced cell death through caspase-dependent apoptosis in DLD-1 cells. Moreover, HDIs/15d-PGJ2 caused histone deacetylase inhibition, leading to subsequent ROS generation and endoplasmic reticulum stress to decrease the expression of antiapoptotic molecules Bcl-XL and XIAP and to increase that of proapoptotic molecules CAAT/enhancer binding protein homologous protein and death receptor 5. Additionally, VPA/15d-PGJ2 cotreatment induced ROS-dependent apoptosis in other malignant tumor cells and was more effective than a VPA or 15d-PGJ2 monotherapy in vivo.

Conclusions: Cotreatments with the clinically relevant HDIs and the endogenous peroxisome proliferator–activated receptor γ ligand 15d-PGJ2 are promising for the treatment of a broad spectrum of malignant tumors. Clin Cancer Res; 16(8); 2320–32. ©2010 AACR.
Synergistic Antitumor Effect of the Activated PPARγ and Retinoid Receptors on Human Osteosarcoma
Authors: He Bai-Cheng , Chen Liang , Zuo Guo-Wei , Zhang Wenli , Bi Yang , Huang Jiayi , Wang Yi , Jiang Wei , Luo Qing , Shi Qiong , Zhang Bing-Qiang , Liu Bo , Lei Xia , Luo Jinyong , Luo Xiaoji , Wagner Eric R. , Kim Stephanie H. , He Connie J. , Hu Yawen , Shen Jikun , Zhou Qixin , Rastegar Farbod , Deng Zhong-Liang , Luu Hue H. , He Tong-Chuan , Haydon Rex C.
Published: April 2010

Purpose: Osteosarcoma is the most common primary malignancy of bone. The long-term survival of osteosarcoma patients hinges on our ability to prevent and/or treat recurrent and metastatic lesions. Here, we investigated the activation of peroxisome proliferator-activated receptor γ (PPARγ) and retinoid receptors as a means of differentiation therapy for human osteosarcoma.

Experimental Design: We examined the endogenous expression of PPARγ and retinoid receptors in a panel of osteosarcoma cells. Ligands or adenovirus-mediated overexpression of these receptors were tested to inhibit proliferation and induce apoptosis of osteosarcoma cells. Osteosarcoma cells overexpressing the receptors were introduced into an orthotopic tumor model. The effect of these ligands on osteoblastic differentiation was further investigated.

Results: Endogenous expression of PPARγ and isotypes of retinoic acid receptor (RAR) and retinoid X receptor (RXR) is detected in most osteosarcoma cells. Troglitazone, 9-cis retinoic acid (RA), and all-trans RA, as well as overexpression of PPARγ, RARα, and RXRα, inhibit osteosarcoma cell proliferation and induce apoptosis. A synergistic inhibitory effect on osteosarcoma cell proliferation is observed between troglitazone and retinoids, as well as with the overexpression pairs of PPARγ/RARα, or PPARγ/RXRα. Overexpression of PPARγ, RARα, RXRα, or in combinations inhibits osteosarcoma tumor growth and cell proliferation in vivo. Retinoids (and to a lesser extent, troglitazone) are shown to promote osteogenic differentiation of osteosarcoma cells and mesenchymal stem cells.

Conclusions: Activation of PPARγ, RARα, and RXRα may act synergistically on inhibiting osteosarcoma cell proliferation and tumor growth, which is at least partially mediated by promoting osteoblastic differentiation of osteosarcoma cells. Clin Cancer Res; 16(8); 2235–45. ©2010 AACR.
CK2 Modulation of NF-κB, TP53, and the Malignant Phenotype in Head and Neck Cancer by Anti-CK2 OligonucleotidesIn vitroorIn vivovia Sub–50-nm Nanocapsules
Authors: Brown Matthew S. , Diallo Oumou T. , Hu Michael , Ehsanian Reza , Yang Xinping , Arun Pattatheyil , Lu Hai , Korman Vicci , Unger Gretchen , Ahmed Khalil , Van Waes Carter , Chen Zhong
Published: April 2010

Purpose: The aim of this study is to investigate the expression of CK2 subunits and CK2 effects on NF-κB–mediated and TP53-mediated signal activation and gene expression, the malignant phenotype, and chemosensitivity in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo.

Experimental Design: Protein expression of CK2 subunits was investigated by Western blot and immunohistochemistry. CK2 subunits were knocked down by small interfering RNA, and NF-κB activation was examined using DNA binding, Western blot, and luciferase reporter assays. Gene expression was measured by quantitative reverse transcription–PCR. Cell growth, survival, motility, and sensitivity to cisplatin were measured by MTT, flow cytometry, and migration assays. In vivo targeting of CK2α/α′ in HNSCC xenograft models was achieved using anti-CK2α/α′ oligodeoxynucleotide encapsulated in sub–50-nm tenfibgen nanocapsules.

Results: CK2 subunit proteins were overexpressed in HNSCC lines and tissues. Knockdown of CK2 subunits differentially inhibited IκBα degradation, NF-κB nuclear localization, phosphorylation, DNA binding, and reporter activity. CK2 subunits modulated gene expression and the malignant phenotype involved in cell cycle and migration, whereas CK2α is critical to promote proliferation, antiapoptosis, and cisplatin resistance in vitro. Furthermore, in vivo delivery of anti-CK2α/α′ oligodeoxynucleotide nanocapsules significantly suppressed tumor growth in HNSCC xenograft models, in association with modulation of CK2 and NF-κB regulated molecules, TP53 family proteins, and induction of apoptosis.

Conclusions: Our study reveals a novel role of CK2 in coregulating NF-κB activation, TP53/p63 expression, and downstream gene expression. Downregulation of CK2 in HNSCC models in vitro and in vivo shows antitumor effects as well as sensitization to cisplatin. Clin Cancer Res; 16(8); 2295–307. ©2010 AACR.
A Phase I Study of Weekly R1507, A Human Monoclonal Antibody Insulin-like Growth Factor-I Receptor Antagonist, in Patients with Advanced Solid Tumors
Authors: Kurzrock Razelle , Patnaik Amita , Aisner Joseph , Warren Terri , Leong Stephen , Benjamin Robert , Eckhardt S. Gail , Eid Joseph E. , Greig Gerard , Habben Kai , McCarthy Cinara D. , Gore Lia
Published: April 2010

Purpose: A phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of R1507—a fully human IgG1 type monoclonal antibody directed against the human insulin-like growth factor-I receptor.

Experimental design: Patients with advanced solid tumors were assigned to receive i.v. R1507 weekly (qW), starting with 1 mg/kg. Subsequent cohorts were dosed at 3 and then 9 mg/kg. An additional 12 patients received 9 mg/kg R1507 qW. Patients remained on the study until the development of a dose-limiting toxicity or progressive disease.

Results: In total, 37 patients were treated with R1507 qW. No dose-limiting toxicities were identified and the maximum tolerated dose was not reached. The pharmacokinetics of R1507 were characterized by a slow clearance and limited volume of distribution, with an estimated elimination half-life justifying weekly administration. Serum IGF-I ligand levels increased proportionally to dose during the first 72 hours in all cohorts. R1507 was well tolerated. Two patients diagnosed with Ewing's sarcoma had partial responses of 11.5 and >26 months (ongoing at time of submission); 13 patients had stable disease; and 16 had progressive disease as best response by the Response Evaluation Criteria in Solid Tumors.

Conclusion: R1507 is well tolerated and shows antitumor activity in patients with solid neoplasms, in particular Ewing's sarcoma. The recommended dose for the weekly schedule is 9 mg/kg qW. Clin Cancer Res; 16(8); 2458–65. ©2010 AACR.
Serial Monitoring of Circulating Tumor Cells Predicts Outcome of Induction Biochemotherapy plus Maintenance Biotherapy for Metastatic Melanoma
Authors: Koyanagi Kazuo , O'Day Steven J. , Boasberg Peter , Atkins Michael B. , Wang He-Jing , Gonzalez Rene , Lewis Karl , Thompson John A. , Anderson Clay M. , Lutzky Jose , Amatruda Thomas T. , Hersh Evan , Richards Jon , Weber Jeffrey S. , Hoon Dave S.B.
Published: April 2010

Purpose: Molecular biomarkers in blood are promising for assessment of tumor progression and treatment response. We hypothesized that serial monitoring of circulating tumor cells (CTC) with the use of multimarker quantitative real-time reverse transcriptase-PCR assays could be a surrogate predictor of outcome for melanoma patients enrolled in a multicenter phase II clinical trial of biochemotherapy (BCT) combined with maintenance biotherapy (mBT).

Experimental Design: Blood specimens were collected from 87 patients before and during induction BCT and mBT for stage IV melanoma. Expression of five melanoma-associated CTC biomarkers (MART-1, GalNAc-T, PAX-3, MAGE-A3, and Mitf) was assessed by quantitative real-time reverse transcriptase-PCR, and correlated with treatment response and disease outcome.

Results: The number of positive CTC biomarkers decreased overall during induction BCT (P < 0.0001). CTC biomarker detection after two cycles of BCT was correlated with treatment response (P = 0.005) and overall survival (P = 0.001): an increase in the number of CTC biomarkers was associated with poor response (P = 0.006) and overall survival (P < 0.0001). Multivariate analyses with the use of a Cox proportional hazards model identified the change in CTC biomarkers after two cycles of BCT as an independent prognostic factor for disease progression (risk ratio, 12.6; 95% confidence interval, 4.78-33.4; P < 0.0001) and overall survival (risk ratio, 6.11; 95% confidence interval, 2.37-15.7; P = 0.0005).

Conclusion: Serial monitoring of CTC during induction BCT may be useful for predicting therapeutic efficacy and disease outcome in patients receiving BCT and mBT for stage IV melanoma. Clin Cancer Res; 16(8); 2402–8. ©2010 AACR.
Dual Inhibition of Akt/Mammalian Target of Rapamycin Pathway by Nanoparticle Albumin-Bound–Rapamycin and Perifosine Induces Antitumor Activity in Multiple Myeloma
Authors: Cirstea Diana , Hideshima Teru , Rodig Scott , Santo Loredana , Pozzi Samantha , Vallet Sonia , Ikeda Hiroshi , Perrone Giulia , Gorgun Gullu , Patel Kishan , Desai Neil , Sportelli Peter , Kapoor Shweta , Vali Shireen , Mukherjee Siddhartha , Munshi Nikhil C. , Anderson Kenneth C. , Raje Noopur
Published: April 2010

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway mediates multiple myeloma (MM) cell proliferation, survival, and development of drug resistance, underscoring the role of mTOR inhibitors, such as rapamycin, with potential anti-MM activity. However, recent data show a positive feedback loop from mTOR/S6K1 to Akt, whereby Akt activation confers resistance to mTOR inhibitors. We confirmed that suppression of mTOR signaling in MM cells by rapamycin was associated with upregulation of Akt phosphorylation. We hypothesized that inhibiting this positive feedback by a potent Akt inhibitor perifosine would augment rapamycin-induced cytotoxicity in MM cells. Perifosine inhibited rapamycin-induced phosphorylated Akt, resulting in enhanced cytotoxicity in MM.1S cells even in the presence of interleukin-6, insulin-like growth factor-I, or bone marrow stromal cells. Moreover, rapamycin-induced autophagy in MM.1S MM cells, as evidenced by electron microscopy and immunocytochemistry, was augmented by perifosine. Combination therapy increased apoptosis detected by Annexin V/propidium iodide analysis and caspase/poly(ADP-ribose) polymerase cleavage. Importantly, in vivo antitumor activity and prolongation of survival in a MM mouse xenograft model after treatment was enhanced with combination of nanoparticle albumin-bound–rapamycin and perifosine. Utilizing the in silico predictive analysis, we confirmed our experimental findings of this drug combination on PI3K, Akt, mTOR kinases, and the caspases. Our data suggest that mutual suppression of the PI3K/Akt/mTOR pathway by rapamycin and perifosine combination induces synergistic MM cell cytotoxicity, providing the rationale for clinical trials in patients with relapsed/refractory MM. Mol Cancer Ther; 9(4); 963–75. ©2010 AACR.
Gene Expression Signatures as a Guide to Treatment Strategies for In-Transit Metastatic Melanoma
Authors: Augustine Christina K. , Jung Sin-Ho , Sohn Insuk , Yoo Jin Soo , Yoshimoto Yasunori , Olson John A. , Friedman Henry S. , Ali-Osman Francis , Tyler Douglas S.
Published: April 2010

In-transit metastatic melanoma, which typically presents as multifocal lesions, provides a unique setting to evaluate the utility of gene signatures for defining optimal regional therapeutic strategies and assessing the efficacy of treatment. The goal of this study was to determine whether a single multifocal lesion is representative of residual tumor burden in terms of gene expression signatures predictive of response to therapy. Using microarray-based gene expression profiling, we examined 55 in-transit melanoma lesions across 29 patients with multifocal disease. Principal component analysis, unsupervised hierarchical clustering, one-way ANOVA, binary regression analysis, and gene signatures predictive of oncogenic pathway activation were used to compare patterns of gene expression across all multifocal lesions from a patient. Patterns of gene expression were highly similar (P < 0.006; average r = 0.979) across pretreatment lesions from a single patient compared with the significantly different patterns observed across patients (P < 0.05). The findings presented in this study show that individual melanoma tumor nodules in patients with multifocal disease harbor similar patterns of gene expression and a single lesion can be used to predict response to chemotherapy, evaluate the activation status of oncogenic signaling pathways, and characterize other aspects of the biology of an individual patient's disease. These results will facilitate the use of gene expression profiling in melanoma regional therapy clinical trials to not only select optimal regional chemotherapeutic agents but to also allow for a more rational identification of candidates for specific targeted therapies and evaluation of their therapeutic efficacy. Mol Cancer Ther; 9(4); 779–90. ©2010 AACR.
Sorafenib Induces Growth Arrest and Apoptosis of Human Glioblastoma Cells through the Dephosphorylation of Signal Transducers and Activators of Transcription 3
Authors: Yang Fan , Brown Christine , Buettner Ralf , Hedvat Michael , Starr Renate , Scuto Anna , Schroeder Anne , Jensen Michael , Jove Richard
Published: April 2010

Glioblastoma is the most common type of primary brain tumor and is rapidly progressive with few treatment options. Here, we report that sorafenib (≤10 μmol/L) inhibited cell proliferation and induced apoptosis in two established cell lines (U87 and U251) and two primary cultures (PBT015 and PBT022) from human glioblastomas. The effects of sorafenib on these tumor cells were associated with inhibiting phosphorylated signal transducers and activators of transcription 3 (STAT3; Tyr705). Expression of a constitutively activated STAT3 mutant partially blocked the effects of sorafenib, consistent with a role for STAT3 inhibition in the response to sorafenib. Phosphorylated Janus-activated kinase (JAK)1 was inhibited in U87 and U251 cells, whereas phosphorylated JAK2 was inhibited in primary cultures. Sodium vanadate, a general inhibitor of protein tyrosine phosphatases, blocked the inhibition of phosphorylation of STAT3 (Tyr705) induced by sorafenib. These data indicate that the inhibition of STAT3 activity by sorafenib involves both the inhibition of upstream kinases (JAK1 and JAK2) of STAT3 and increased phosphatase activity. Phosphorylation of AKT was also reduced by sorafenib. In contrast, mitogen-activated protein kinases were not consistently inhibited by sorafenib in these cells. Two key cyclins (D and E) and the antiapoptotic protein Mcl-1 were downregulated by sorafenib in both cell lines and primary cultures. Our data suggest that inhibition of STAT3 signaling by sorafenib contributes to growth arrest and induction of apoptosis in glioblastoma cells. These findings provide a rationale for potential treatment of malignant gliomas with sorafenib. Mol Cancer Ther; 9(4); 953–62. ©2010 AACR.
ZD6474, a Multitargeted Inhibitor for Receptor Tyrosine Kinases, Suppresses Growth of Gliomas Expressing an Epidermal Growth Factor Receptor Mutant, EGFRvIII, in the Brain
Authors: Yiin Jia-Jean , Hu Bo , Schornack Paul A. , Sengar Raghvendra S. , Liu Kun-wei , Feng Haizhong , Lieberman Frank S. , Chiou Shih-Hwa , Sarkaria Jann N. , Wiener Erik C. , Ma Hsin-I , Cheng Shi-Yuan
Published: April 2010

Epidermal growth factor receptor (EGFR) vIII is a mutated EGFR that is frequently overexpressed in glioblastomas and implicated in response to receptor tyrosine kinase inhibitors. In this study, we investigate the effect of ZD6474 (ZACTIMA, vandetanib), a dual inhibitor for vascular endothelial growth factor receptor 2 and EGFR on growth and angiogenesis of gliomas expressing EGFRvIII. We used two glioma xenograft models, U87MG cells overexpressing EGFRvIII and short-term cultured primary glioma GBM8 cells with EGFRvIII. ZD6474 inhibited tumor growth and angiogenesis and induced cell apoptosis in various brain gliomas. Moreover, significant inhibition of EGFRvIII-expressing U87MG and GBM8 gliomas was observed compared with their controls. Magnetic resonance imaging analysis using the apparent diffusion coefficient and three-dimensional T2*weighed measurements validated ZD6474 inhibition on tumor growth and angiogenesis in EGFRvIII-expressing GBM8 gliomas. Mechanistically, ZD6474 shows better inhibition of cell growth and survival of U87MG/EGFRvIII, GBM6, and GBM8 cells that express EGFRvIII than U87MG or GBM14 cells that have nondetectable EGFRvIII through attenuation of activated phosphorylation of signal transducer and activator of transcription 3, Akt, and Bcl-XL expression. Albeit in lesser extent, ZD6474 also displays suppressions of U87MG/EGFR and GBM12 cells that overexpress wild-type EGFR. Additionally, ZD6474 inhibits activation of extracellular signal-regulated kinase 1/2 in both types of cells, and expression of a constitutively active phosphoinositide 3-kinases partially rescued ZD6474 inhibition in U87MG/EGFRvIII cells. Taken together, these data show that ZD6474 significantly inhibited growth and angiogenesis of gliomas expressing EGFRvIII by specifically blocking EGFRvIII-activated signaling mediators, suggesting a potential application of ZD6474 in treatments for glioblastomas that overexpress EGFRvIII. Mol Cancer Ther; 9(4); 929–41. ©2010 AACR.
Bridging the Gap between Cytotoxic and Biologic Therapy with Metronomic Topotecan and Pazopanib in Ovarian Cancer
Authors: Merritt William M. , Nick Alpa M. , Carroll Amy R. , Lu Chunhua , Matsuo Koji , Dumble Melissa , Jennings Nicholas , Zhang ShuYun , Lin Yvonne G. , Spannuth Whitney A. , Kamat Aparna A. , Stone Rebecca L. , Shahzad Mian M.K. , Coleman Robert L. , Kumar Rakesh , Sood Anil K.
Published: April 2010

This study aimed to investigate the antitumor and antiangiogenic effects utilizing a novel therapy regimen of metronomic topotecan and pazopanib, a multireceptor tyrosine kinase inhibitor. In vitro (Western blot) and in vivo dose-finding experiments were done following pazopanib therapy in ovarian cancer models. Pazopanib and metronomic (daily) oral topotecan therapy was examined in an orthotopic model of ovarian cancer. Tumor weights, survival, and markers of the tumor microenvironment [angiogenesis (CD31 and pericyte coverage), proliferation (Ki-67), and apoptosis (terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling)] were analyzed by immunostaining following therapy. Pazopanib therapy reduced vascular endothelial growth factor receptor 2 (VEGFR-2) activity in vitro and vivo in a dose-dependent manner. Compared with control mice, pazopanib reduced tumor weight by 28% to 82% (P < 0.01 in the SKOV3ip1 model) and metronomic topotecan reduced tumor weight by 40% to 59% in the HeyA8 (P = 0.13) and SKOV3ip1 (P = 0.07) models. Combination therapy had the greatest effect with 79% to 84% reduction (P < 0.01 for both models). In the SKOV3ip1 and A2780 models, mouse survival was significantly longer (P < 0.001 versus controls) with pazopanib and metronomic topotecan therapy. Pazopanib therapy reduced murine endothelial cell migration in vitro in a dose-dependent manner following VEGF stimulation and decreased tumor microvessel density and pericyte coverage when given in combination with metronomic topotecan. Tumor cell proliferation decreased in all treatment arms compared with controls (P < 0.01 for combination groups) and increased tumor cell apoptosis by 4-fold with combination therapy. Pazopanib therapy in combination with metronomic topotecan therapy showed significant antitumor and antiangiogenic properties in preclinical ovarian cancer models and warrants further investigation as a novel therapeutic regimen in clinical trials. Mol Cancer Ther; 9(4); 985–95. ©2010 AACR.
RelB-Dependent Differential Radiosensitization Effect of STI571 on Prostate Cancer Cells
Authors: Xu Yong , Fang Fang , Sun Yulan , St. Clair Daret K. , St. Clair William H.
Published: April 2010

Radiation therapy is an effective treatment for localized prostate cancer. However, when high-risk factors are present, such as increased prostate-specific antigen, elevated Gleason scores and advanced T stage, undetected spreading of the cancer, and development of radiation-resistant cancer cells are concerns. Thus, additional therapeutic agents that can selectively sensitize advanced prostate cancer to radiation therapy are needed. Imatinib mesylate (Gleevec, STI571), a tyrosine kinase inhibitor, was evaluated for its potential to enhance the efficacy of ionizing radiation (IR) against aggressive prostate cancer cells. STI571 significantly enhances the IR-induced cytotoxicity of androgen-independent prostate cancer cells but not of androgen-responsive prostate cancer cells. The differential cytotoxic effects due to STI571 are associated with the nuclear level of RelB in prostate cancer cells. STI571 inhibits IR-induced RelB nuclear translocation, leading to increased radiosensitivity in aggressive androgen-independent PC-3 and DU-145 cells. In contrast, STI571 enhances RelB nuclear translocation in androgen-responsive LNCaP cells. The different effects of STI571 on RelB nuclear translocation are consistent with RelB DNA binding activity and related target gene expression. STI571 inhibits the phosphoinositide 3-kinase-AKT-IκB kinase-α pathway in PC-3 cells by decreasing the phosphorylation levels of phosphoinositide 3-kinase (Tyr458) and AKT (Ser473), whereas STI571 increases NF-κB inducible kinase (Thr559) phosphorylation, leading to activation of IκB kinase-α in LNCaP cells. These results reveal that STI571 exhibits differential effects on the upstream kinases leading to different downstream effects on the NF-κB alternative pathway in prostate cancer cells and suggest that STI571 is effective for the treatment of androgen-independent prostate cancer in the context of high constitutive levels of RelB. Mol Cancer Ther; 9(4); 803–12. ©2010 AACR.
Vinblastine Induces Acute, Cell Cycle Phase–Independent Apoptosis in Some Leukemias and Lymphomas and Can Induce Acute Apoptosis in Others when Mcl-1 Is Suppressed
Authors: Salerni Bethany L. , Bates Darcy J. , Albershardt Tina C. , Lowrey Christopher H. , Eastman Alan
Published: April 2010

Chemotherapeutic agents modify intracellular signaling that culminates in the inhibition of Bcl-2 family members and initiates apoptosis. Inhibition of the extracellular signal-regulated kinase by PD98059 dramatically accelerates vinblastine-mediated apoptosis in ML-1 leukemia with cells dying in 4 hours from all phases of the cell cycle. Inhibition of protein synthesis by cycloheximide also markedly accelerated vinblastine-induced apoptosis, showing that the proteins required for this acute apoptosis are constitutively expressed. Vinblastine induced the rapid induction of Mcl-1 that was inhibited by PD98059 and cycloheximide. No change in Bcl-2 or Bcl-X was observed. We hypothesize that ML-1 cells use Mcl-1 for protection from the rapid vinblastine-induced apoptosis. This was confirmed by targeting Mcl-1 with short hairpin RNA. We also investigated the response of 13 other leukemia and lymphoma cell lines and cells from seven chronic lymphocytic leukemia patients. Four cell lines and all chronic lymphocytic leukemia cells were killed in 6 hours by vinblastine alone. Two additional cell lines were sensitized to vinblastine by PD98059, which suppressed Mcl-1. This acute apoptosis either alone or in combination with PD98059 required vinblastine-mediated activation of c-Jun-NH2-terminal kinase. PD98059 did not suppress Mcl-1 in other cell lines whereas sorafenib did, but this did not sensitize the cells to vinblastine, suggesting that the acute apoptosis varies depending on which Bcl-2 protein mediates protection. Most of the cell lines were sensitized to vinblastine by cycloheximide, suggesting that inhibition of a short-lived protein in addition to Mcl-1 can acutely sensitize cells. These results suggest several clinical strategies that might provide an effective therapy for selected patients. Mol Cancer Ther; 9(4); 791–802. ©2010 AACR.
Transition of Distinctive Symptoms of Semantic Dementia during Longitudinal Clinical Observation
Authors: Kashibayashi Tetsuo , Ikeda Manabu , Komori Kenjiro , Shinagawa Shunichiro , Shimizu Hideaki , Toyota Yasutaka , Mori Takaaki , Ishikawa Tomohisa , Fukuhara Ryuji , Ueno Shu-ichi , Tanimukai Satoshi
Published: April 2010

Background/Aims: The aim of this study is to examine the clinical symptoms in a number of semantic dementia (SD) patients and to reveal the longitudinal progression and clinical course of these distinctive symptoms of SD. Methods: 19 consecutive SD patients were examined. Symptoms were classified into 23 distinct categories: behavioral symptoms, language and cognitive symptoms and symptoms concerning the impairment of activities of daily living (ADL). We divided patients into two subgroups, left- and right-dominant SD, and compared the onset of each symptom. Results: Language impairments occurred as the initial symptom in 16 cases. At the first examination, all cases showed both anomia and impairment of word comprehension. By around 3 years after onset, almost all language impairments were observed. Approximately 3–5 years after onset, prosopagnosia and behavioral symptoms appeared. Around the period when the loss of the language faculty and apathy became remarkable, impairment of ADL appeared. Patients spent all day in bed at this stage. Moreover, prosopagnosia appeared significantly earlier in right-dominant SD. Conclusion: Our findings clarify the progression of distinctive symptoms of SD patients. It is necessary to create a treatment strategy for SD patients with such a disease-specific course of SD.
In vivo Evidence of γ-Tocotrienol as a Chemosensitizer in the Treatment of Hormone-Refractory Prostate Cancer
Authors: Yap W.N. , Zaiden N. , Luk S.Y. , Lee D.T.W. , Ling M.T. , Wong Y.C. , Yap Y.L.
Published: April 2010

γ-Tocotrienol (γT3) is known to selectively kill prostate cancer (PCa) cells and to sensitize the cells to docetaxel (DTX)-induced apoptosis. In the present study, the pharmacokinetics of γT3 and the in vivo cytotoxic response of androgen-independent prostate cancer (AIPCa) tumor following γT3 treatment were investigated. Here, we investigated these antitumor effects for PCa tumors in vivo. The pharmacokinetic and tissue distribution of γT3 after exogenous γT3 supplementation were examined. Meanwhile, the response of the tumor to γT3 alone or in combination with DTX were studied by real-time in vivo bioluminescent imaging and by examination of biomarkers associated with cell proliferation and apoptosis. After intraperitoneal injection, γT3 rapidly disappeared from the serum and was selectively deposited in the AIPCa tumor cells. Administration of γT3 alone for 2 weeks resulted in a significant shrinkage of the AIPCa tumors. Meanwhile, further inhibition of the AIPCa tumor growth was achieved by combined treatment of γT3 and DTX (p < 0.002). The in vivo cytotoxic antitumor effects induced by γT3 seem to be associated with a decrease in expression of cell proliferation markers (proliferating cell nuclear antigen, Ki-67 and Id1) and an increase in the rate of cancer cell apoptosis [cleaved caspase 3 and poly(ADP-ribose) polymerase]. Additionally, the combined agents may be more effective at suppressing the invasiveness of AIPCa. Overall, our results indicate that γT3, either alone or in combination with DTX, may provide a treatment strategy that can improve therapeutic efficacy against AIPCa while reducing the toxicity often seen in patients treated with DTX.
Alpha-2c-Adrenergic Receptors Contribute to Basal Nasal Patency in the Anesthetized Cat
Authors: Mingo Garfield G. , Corboz Michel R. , Salisbury Brian G. , McCormick Kevin D. , Boyce Christopher W. , Mukhopadhyay Gitali , McLeod Robbie L.
Published: April 2010

Background: Nasal congestion is the most troublesome symptom associated with a variety of upper airway diseases, including allergic rhinitis and the common cold. A better understanding of the mechanisms that regulate nasal cavity caliber may engender the development of novel treatment strategies. It is well accepted that α-adrenergic (both α1 and α2) mechanisms play a fundamental role in the control and maintenance of basal nasal patency. JP-1302 is a selective α2c-subtype antagonist that has been recently described in the scientific literature. Thus, we sought to examine the potential effects of this new pharmacological tool on basal nasal patency. Methods: Using acoustic rhinometry, we studied the activity of the selective α2c-antagonist JP-1302 on nasal cavity volumes in an anesthetized cat. Cumulative concentrations of JP-1302 were applied directly into the right nasal cavity. Changes in the nasal cavity geometry of the drug-treated naris relative to the untreated left nasal cavity were determined. In separate studies, the nonselective α2-antagonist yohimbine and the nonselective α1-antagonist prazosin were run as comparators. Systolic blood pressure was measured at the hind leg, using an ultrasonic Doppler flow detector. Results: JP-1302 (0.03, 0.1, 0.3 and 1.0%) administered by the intranasal route decreased nasal cavity volumes from baseline values by 17, 25, 40 and 40%, respectively. Yohimbine (0.03, 0.1, 0.3 and 1.0%) decreased volumes by 19, 36, 46 and 53%, and topical administration of the nonselective α1-antagonist prazosin (0.001, 0.003, 0.01, 0.03 and 0.1%) decreased volumes by 6, 47, 56, 64 and 71%, respectively. JP-1302, yohimbine and prazosin, at the dose level tested, did not alter the blood pressure. Conclusions: The present set of experiments indicates that both α1- and α2-adrenergic receptors are involved in the maintenance of basal nasal patency in the cat. Moreover, α2c-receptors may play a significant role in the sympathetic control of upper airway function.