bluuebunny/crossref_metadata_2025 huggingface dataset:
Incoherent oscillations of respiratory sinus arrhythmia during acute mental stress in humans
Authors: Niizeki Kyuichi , Saitoh Tadashi
Published: October 2011

Respiratory sinus arrhythmia (RSA) has been widely used as a measure of the cardiac vagal control in response to stress. However, RSA seems not to be a generalized indicator because of its dependency on respiratory parameter and individual variations of RSA amplitude (ARSA). We hypothesized that phase-lag variations between RSA and respiration may serve as a normalized index of the degree of mental stress. Twenty healthy volunteers performed mental arithmetic task (ART) after 5 min of resting control followed by 5 min of recovery. Breathing pattern, beat-to-beat R-R intervals, and blood pressure (BP) were determined using inductance plethysmography, electrocardiography, and a Finapres device, respectively. The analytic signals of breathing and RSA were obtained by Hilbert transform and the degree of phase synchronization (λ) was quantified. With the use of spectral analysis, heart rate variability (HRV) was estimated for the low-frequency (LF) and high-frequency (HF) bands. A steady-state 3-min resting period (REST), the first 3 min (ART1), and the last 3 min (ART2) of the ART period (ranged from 6- to 19 min) and the last 3 min of the recovery period (RCV) were analyzed separately. Heart rate, systolic BP, and breathing frequency (fR) increased and λ, ARSA, and HF power decreased from REST to ART ( P < 0.01). The λ was correlated with normalized ARSA and the HF power. The decrease in λ could not be explained solely by the increase in fR. We conclude that mental stress exerts an influence on RSA oscillations, inducing incoherent phase lag with respect to breathing, in addition to a decrease in RSA.
Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death
Authors: Papanicolaou Kyriakos N. , Ngoh Gladys A. , Dabkowski Erinne R. , O'Connell Kelly A. , Ribeiro Rogerio F. , Stanley William C. , Walsh Kenneth
Published: October 2011

Molecular studies examining the impact of mitochondrial morphology on the mammalian heart have previously focused on dynamin related protein-1 (Drp-1) and mitofusin-2 (Mfn-2), while the role of the other mitofusin isoform, Mfn-1, has remained largely unexplored. In the present study, we report the generation and initial characterization of cardiomyocyte-specific Mfn-1 knockout (Mfn-1 KO) mice. Using electron microscopic analysis, we detect a greater prevalence of small, spherical mitochondria in Mfn-1 KO hearts, indicating that the absence of Mfn-1 causes a profound shift in the mitochondrial fusion/fission balance. Nevertheless, Mfn-1 KO mice exhibit normal left-ventricular function, and isolated Mfn-1 KO heart mitochondria display a normal respiratory repertoire. Mfn-1 KO myocytes are protected from mitochondrial depolarization and exhibit improved viability when challenged with reactive oxygen species (ROS) in the form of hydrogen peroxide (H2O2). Furthermore, in vitro studies detect a blunted response of KO mitochondria to undergo peroxide-induced mitochondrial permeability transition pore opening. These data suggest that Mfn-1 deletion confers protection against ROS-induced mitochondrial dysfunction. Collectively, we suggest that mitochondrial fragmentation in myocytes is not sufficient to induce heart dysfunction or trigger cardiomyocyte death. Additionally, our data suggest that endogenous levels of Mfn-1 can attenuate myocyte viability in the face of an imminent ROS overload, an effect that could be associated with the ability of Mfn-1 to remodel the outer mitochondrial membrane.
PTEN inhibition improves wound healing in lung epithelia through changes in cellular mechanics that enhance migration
Authors: Mihai Cosmin , Bao Shengying , Lai Ju-Ping , Ghadiali Samir N. , Knoell Daren L.
Published: October 2011

The phosphoinositide-3 kinase/Akt pathway is a vital survival axis in lung epithelia. We previously reported that inhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a major suppressor of this pathway, results in enhanced wound repair following injury. However, the precise cellular and biomechanical mechanisms responsible for increased wound repair during PTEN inhibition are not yet well established. Using primary human lung epithelia and a related lung epithelial cell line, we first determined whether changes in migration or proliferation account for wound closure. Strikingly, we observed that cell migration accounts for the majority of wound recovery following PTEN inhibition in conjunction with activation of the Akt and ERK signaling pathways. We then used fluorescence and atomic force microscopy to investigate how PTEN inhibition alters the cytoskeletal and mechanical properties of the epithelial cell. PTEN inhibition did not significantly alter cytoskeletal structure but did result in large spatial variations in cell stiffness and in particular a decrease in cell stiffness near the wound edge. Biomechanical changes, as well as migration rates, were mediated by both the Akt and ERK pathways. Our results indicate that PTEN inhibition rapidly alters biochemical signaling events that in turn provoke alterations in biomechanical properties that enhance cell migration. Specifically, the reduced stiffness of PTEN-inhibited cells promotes larger deformations, resulting in a more migratory phenotype. We therefore conclude that increased wound closure consequent to PTEN inhibition occurs through enhancement of cell migration that is due to specific changes in the biomechanical properties of the cell.
Surfactant protein B inhibits secretory phospholipase A2hydrolysis of surfactant phospholipids
Authors: Hite R. Duncan , Grier Bonnie L. , Waite B. Moseley , Veldhuizen Ruud A. , Possmayer Fred , Yao Li-Juan , Seeds Michael C.
Published: October 2011

Hydrolysis of surfactant phospholipids (PL) by secretory phospholipases A2(sPLA2) contributes to surfactant damage in inflammatory airway diseases such as acute lung injury/acute respiratory distress syndrome. We and others have reported that each sPLA2exhibits specificity in hydrolyzing different PLs in pulmonary surfactant and that the presence of hydrophilic surfactant protein A (SP-A) alters sPLA2-mediated hydrolysis. This report tests the hypothesis that hydrophobic SP-B also inhibits sPLA2-mediated surfactant hydrolysis. Three surfactant preparations were used containing varied amounts of SP-B and radiolabeled tracers of phosphatidylcholine (PC) or phosphatidylglycerol (PG): 1) washed ovine surfactant (OS) (pre- and postorganic extraction) compared with Survanta (protein poor), 2) Survanta supplemented with purified bovine SP-B (1–5%, wt/wt), and 3) a mixture of dipalmitoylphosphatidylcholine (DPPC), 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC), and 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG) (DPPC:POPC:POPG, 40:40:20) prepared as vesicles and monomolecular films in the presence or absence of SP-B. Hydrolysis of PG and PC by Group IB sPLA2(PLA2G1A) was significantly lower in the extracted OS, which contains SP-B, compared with Survanta ( P = 0.005), which is SP-B poor. Hydrolysis of PG and PC in nonextracted OS, which contains all SPs, was lower than both Survanta and extracted OS. When Survanta was supplemented with 1% SP-B, PG and PC hydrolysis by PLA2G1B was significantly lower ( P < 0.001) than in Survanta alone. When supplemented into pure lipid vesicles and monomolecular films composed of PG and PC mixtures, SP-B also inhibited hydrolysis by both PLA2G1B and Group IIA sPLA2 (PLA2G2A). In films, PLA2G1B hydrolyzed surfactant PL monolayers at surface pressures ≤30 mN/m ( P < 0.01), and SP-B lowered the surface pressure range at which hydrolysis can occur. These results suggest the hydrophobic SP, SP-B, protects alveolar surfactant PL from hydrolysis mediated by multiple sPLA2in both vesicles (alveolar subphase) and monomolecular films (air-liquid interface).
Automated regional analysis of B-mode ultrasound images of skeletal muscle movement
Authors: Darby John , Hodson-Tole Emma F. , Costen Nicholas , Loram Ian D.
Published: October 2011

To understand the functional significance of skeletal muscle anatomy, a method of quantifying local shape changes in different tissue structures during dynamic tasks is required. Taking advantage of the good spatial and temporal resolution of B-mode ultrasound imaging, we describe a method of automatically segmenting images into fascicle and aponeurosis regions and tracking movement of features, independently, in localized portions of each tissue. Ultrasound images (25 Hz) of the medial gastrocnemius muscle were collected from eight participants during ankle joint rotation (2° and 20°), isometric contractions (1, 5, and 50 Nm), and deep knee bends. A Kanade-Lucas-Tomasi feature tracker was used to identify and track any distinctive and persistent features within the image sequences. A velocity field representation of local movement was then found and subdivided between fascicle and aponeurosis regions using segmentations from a multiresolution active shape model (ASM). Movement in each region was quantified by interpolating the effect of the fields on a set of probes. ASM segmentation results were compared with hand-labeled data, while aponeurosis and fascicle movement were compared with results from a previously documented cross-correlation approach. ASM provided good image segmentations (<1 mm average error), with fully automatic initialization possible in sequences from seven participants. Feature tracking provided similar length change results to the cross-correlation approach for small movements, while outperforming it in larger movements. The proposed method provides the potential to distinguish between active and passive changes in muscle shape and model strain distributions during different movements/conditions and quantify nonhomogeneous strain along aponeuroses.
Age-related changes in the behavior of the muscle-tendon unit of the gastrocnemius medialis during upright stance
Authors: Baudry Stéphane , Lecoeuvre Geoffrey , Duchateau Jacques
Published: October 2011

Mechanical properties of the muscle-tendon unit change with aging, but it is not known how these modifications influence the control of lower leg muscles during upright stance. In this study, young and elderly adults stood upright on a force platform with and without vision while muscle architecture and myotendinous junction movements (expressed relative to the change in the moment on the x-axis of the force platform) were recorded by ultrasonography and muscle activity by electromyography. The results show that the maximal amplitude of the sway in the antero-posterior direction was greater in elderly adults (age effect, P < 0.05) and was accompanied by an increase in lower leg muscle activity compared with young adults. Moreover, the data highlight that fascicles shorten during forward sway and lengthen during backward sways but more so for young (−4 ± 3 and −4 ± 3 mm/Nm, respectively) than elderly adults (−0.7 ± 3 and 0.8 ± 3 mm/Nm, respectively; age × sway, P < 0.001). Concurrently, the pennation angle increased and decreased during forward and backward sways, respectively, with greater changes in young than elderly adults (age × sway, P < 0.001). In contrast, no significant differences were observed between age groups for tendon lengthening and shortening during sways. The results indicate that, compared with young, elderly adults increase the stiffness of the muscular portion of the muscle-tendon unit during upright stance that may compensate for the age-related decrease in tendon stiffness. These observations suggest a shift in the control strategy used to maintain balance.
Jamming dynamics of stretch-induced surfactant release by alveolar type II cells
Authors: Majumdar Arnab , Arold Stephen P. , Bartolák-Suki Erzsébet , Parameswaran Harikrishnan , Suki Béla
Published: October 2011

Secretion of pulmonary surfactant by alveolar epithelial type II cells is vital for the reduction of interfacial surface tension, thus preventing lung collapse. To study secretion dynamics, rat alveolar epithelial type II cells were cultured on elastic membranes and cyclically stretched. The amounts of phosphatidylcholine, the primary lipid component of surfactant, inside and outside the cells, were measured using radiolabeled choline. During and immediately after stretch, cells secreted less surfactant than unstretched cells; however, stretched cells secreted significantly more surfactant than unstretched cells after an extended lag period. We developed a model based on the hypothesis that stretching leads to jamming of surfactant traffic escaping the cell, similar to vehicular traffic jams. In the model, stretch increases surfactant transport from the interior to the exterior of the cell. This transport is mediated by a surface layer with a finite capacity due to the limited number of fusion pores through which secretion occurs. When the amount of surfactant in the surface layer approaches this capacity, interference among lamellar bodies carrying surfactant reduces the rate of secretion, effectively creating a jam. When the stretch stops, the jam takes an extended time to clear, and subsequently the amount of secreted surfactant increases. We solved the model analytically and show that its dynamics are consistent with experimental observations, implying that surfactant secretion is a fundamentally nonlinear process with memory representing collective behavior at the level of single cells. Our results thus highlight the importance of a jamming dynamics in stretch-induced cellular secretory processes.
Genome-Wide High-Density SNP Linkage Search for Glioma Susceptibility Loci: Results from the Gliogene Consortium
Authors: Shete Sanjay , Lau Ching C. , Houlston Richard S. , Claus Elizabeth B. , Barnholtz-Sloan Jill , Lai Rose , Il'yasova Dora , Schildkraut Joellen , Sadetzki Siegal , Johansen Christoffer , Bernstein Jonine L. , Olson Sara H. , Jenkins Robert B. , Yang Ping , Vick Nicholas A. , Wrensch Margaret , Davis Faith G. , McCarthy Bridget J. , Leung Eastwood Hon-chiu , Davis Caleb , Cheng Rita , Hosking Fay J. , Armstrong Georgina N. , Liu Yanhong , Yu Robert K. , Henriksson Roger ,   The Gliogene Consortium, Melin Beatrice S. , Bondy Melissa L.
Published: October 2011

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32

and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma. Cancer Res; 71(24); 7568–75. ©2011 AACR.
PAX3-FOXO1 Induces Cannabinoid Receptor 1 to Enhance Cell Invasion and Metastasis
Authors: Marshall Amy D. , Lagutina Irina , Grosveld Gerard C.
Published: October 2011

Alveolar rhabdomyosarcoma (ARMS) is a muscle-derived childhood tumor characterized by production of oncogenic PAX3/7-FOXO1 chimeric transcription factors. While downstream targets of the PAX3-FOXO1 oncoprotein in ARMS have been defined, the functional relevance of these targets is unclear. Here, we show that upregulation of the cannabinoid receptor 1 (Cnr1/Cb1) by PAX3-FOXO1 in mouse primary myoblasts and ARMS cell lines, contributes to PAX3-FOXO1 phenotypes, both in vivo and in vitro. In primary myoblasts, Cnr1 was dispensable for PAX3-FOXO1 to mediate cell proliferation, differentiation, or transformation; however, Cnr1 function was essential to increase the invasive capacity conferred by PAX3-FOXO1 overexpression in these cells. Genetic or pharmacologic abrogation of Cnr1 inhibited the enhanced basement membrane invasion induced by PAX3-FOXO1. Cnr1 loss by either route also dramatically reduced lung metastasis formation. Taken together, our findings strongly implicate Cnr1 as a novel tractable target to inhibit ARMS invasion and metastasis. Cancer Res; 71(24); 7471–80. ©2011 AACR.
Lysosomal Transmembrane Protein LAPTM4B Promotes Autophagy and Tolerance to Metabolic Stress in Cancer Cells
Authors: Li Yang , Zhang Qing , Tian Ruiyang , Wang Qi , Zhao Jean J. , Iglehart J. Dirk , Wang Zhigang Charles , Richardson Andrea L.
Published: October 2011

Amplification of chromosome 8q22, which includes the gene for lysosomal associated transmembrane protein LAPTM4B, has been linked to de novo anthracycline resistance in primary breast cancers with poor prognosis. LAPTM4B overexpression can induce cytosolic retention of anthracyclines and decrease drug-induced DNA damage. In this study, we tested the hypothesis that LAPTM4B may contribute to tumor cell growth or survival in the absence of a chemotherapeutic exposure. In mammary cells, LAPTM4B protein was localized in lysosomes where its depletion increased membrane permeability, pH, cathepsin release, and cellular apoptosis. Loss of LAPTM4B also inhibited later stages of autophagy by blocking maturation of the autophagosome, thereby rendering cells more sensitive to nutrient deprivation or hypoxia. Conversely, enforced overexpression of LAPTM4B promoted autophagic flux and cell survival during in vitro starvation and stimulated more rapid tumor growth in vivo. Together, our results indicate that LAPTM4B is required for lysosome homeostasis, acidification, and function, and that LAPTM4B renders tumor cells resistant to lysosome-mediated cell death triggered by environmental and genotoxic stresses. Cancer Res; 71(24); 7481–9. ©2011 AACR.
Egfl7 Promotes Tumor Escape from Immunity by Repressing Endothelial Cell Activation
Authors: Delfortrie Suzanne , Pinte Sébastien , Mattot Virginie , Samson Chantal , Villain Gaëlle , Caetano Bertrand , Lauridant-Philippin Géraldine , Baranzelli Marie-Christine , Bonneterre Jacques , Trottein François , Faveeuw Christelle , Soncin Fabrice
Published: October 2011

Downregulating the leukocyte adhesion molecules expressed by endothelial cells that line tumor blood vessels can limit the entry of immune effector cells into the tumor mass, thereby contributing to tumoral immune escape. Egfl7 (also known as VE-statin) is a secreted protein specifically expressed by endothelial cells in normal tissues and by cancer cells in various human tumors. High levels of Egfl7 correlate with higher tumor grade and poorer prognosis. Here we show that expression of Egfl7 in breast and lung carcinoma cells accelerates tumor growth and metastasis in immunocompetent mice but not in immunodeficient mice. Tumors expressing Egfl7 were infiltrated relatively poorly by immune cells and were characterized by reduced levels of immunostimulatory cytokines [IFN-γ, interleukin-12 (IL-12)] and fewer endothelial adhesion molecules [intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)]. In vitro studies revealed that Egfl7 inhibited the expression of leukocyte adhesion molecules by endothelial cells, preventing lymphocyte adhesion. In contrast, Egfl7 did not exert any effects on immune cell activation. Human breast cancer lesions expressing high levels of Egfl7 also expressed less ICAM-1 and VCAM-1 in their blood vessels, also indicating an inverse correlation between expression levels of Egfl7 and IFN-γ. Thus, Egfl7 expression in tumors promotes tumor progression by reducing the expression of endothelial molecules that mediate immune cell infiltration. Our findings highlight a novel mechanism through which tumors escape immune control. Cancer Res; 71(23); 7176–86. ©2011 AACR.
Variations in HSPA1B at 6p21.3 Are Associated with Lung Cancer Risk and Prognosis in Chinese Populations
Authors: Guo Huan , Deng Qifei , Wu Chen , Hu Lingmin , Wei Sheng , Xu Ping , Kuang Dan , Liu Li , Hu Zhibin , Miao Xiaoping , Shen Hongbing , Lin Dongxin , Wu Tangchun
Published: October 2011

The heat shock protein Hsp70 is crucial for regulating cellular homeostasis in stressed cells. Although the tumorigenic potential and prognostic applications of Hsp70 have been widely investigated, it remains unclear whether genetic variations of the human isoforms HSPA1L, HSPA1A, and HSPA1B are associated with cancer risk and prognosis. In this study, we genotyped six tagSNPs in these genes in 1,152 paired patients with lung cancer and controls, and then validated the results in additional cohorts of 1,781 patients with lung cancer and 1,038 controls. In addition, we evaluated the associations of these tagSNPs with survival in 330 patients with advanced non–small cell lung cancer (NSCLC) with additional validation in another 331 patients with advanced NSCLC. Functions of the risk variants identified were investigated using cell-based reporter assays. We found that the HSPA1B rs6457452T allele was associated with increased lung cancer risk compared with the rs6457452C allele in both data sets and also pooled analysis (adjusted OR = 1.41; P = 2.8 × 10−5). The HSPA1B rs2763979TT genotype conferred poor survival outcomes for patients with advanced NSCLC in two independent cohorts and pooled analysis [adjusted hazard ratio (HR) = 1.80, 1.61, and 1.66; P = 0.013, 0.036, and 0.002, respectively]. Lastly, we also found that the rs2763979T and rs6457452T alleles were each sufficient to reduce expression of transcriptional reporter constructs, when compared with the rs2763979C and rs6457452C alleles, respectively. Taken together, our findings define that functional HSPA1B variants are associated with lung cancer risk and survival. These Hsp70 genetic variants may offer useful biomarkers to predict lung cancer risk and prognosis. Cancer Res; 71(24); 7576–86. ©2011 AACR.
Autophagy Enhanced by Microtubule- and Mitochondrion-Associated MAP1S Suppresses Genome Instability and Hepatocarcinogenesis
Authors: Xie Rui , Wang Fen , McKeehan Wallace L. , Liu Leyuan
Published: October 2011

Dysfunctional autophagy is associated with tumorigenesis; however, the relationship between the two processes remains unclear. In the present study, we showed that MAP1S levels immediately become elevated in response to diethylnitrosamine-induced or genome instability-driven metabolic stress in a murine model of hepatocarcinoma. Upregulation of MAP1S enhanced autophagy to remove aggresomes and dysfunctional organelles that trigger DNA double-strand breaks and genome instability. The early accumulation of an unstable genome before signs of tumorigenesis indicated that genome instability caused tumorigenesis. After tumorigenesis, tumor development triggered the activation of autophagy to reduce genome instability in tumor foci. We, therefore, conclude that an increase in MAP1S levels triggers autophagy to suppress genome instability such that both the incidence of diethylnitrosamine-induced hepatocarcinogenesis and malignant progression are suppressed. Taken together, the data establish a link between MAP1S-enhanced autophagy and suppression of genomic instability and tumorigenesis. Cancer Res; 71(24); 7537–46. ©2011 AACR.
Apoptosis Inhibitor ARC Promotes Breast Tumorigenesis, Metastasis, and Chemoresistance
Authors: Medina-Ramirez Christina M. , Goswami Sumanta , Smirnova Tatiana , Bamira Daniel , Benson Benjamin , Ferrick Neal , Segall Jeffrey , Pollard Jeffrey W. , Kitsis Richard N.
Published: October 2011

Apoptosis repressor with caspase recruitment domain (ARC) inhibits both death receptor- and mitochondrial/ER-mediated pathways of apoptosis. Although expressed mainly in terminally differentiated cells, ARC is markedly upregulated in a variety of human cancers, where its potential contributions have not yet been defined. In this study, we provide evidence of multiple critical pathophysiologic functions for ARC in breast carcinogenesis. In the polyoma middle T-antigen (PyMT) transgenic mouse model of breast cancer, in which endogenous ARC is strongly upregulated, deletion of the ARC-encoding gene nol3 decreased primary tumor burden without affecting tumor onset or multiplicity. More notably, ARC deficiency also limited tumor cell invasion and the number of circulating cancer cells, markedly reducing the number of lung metastases. Conversely, ectopic overexpression of ARC in a PyMT-derived metastatic breast cancer cell line increased invasion in vitro and lung metastasis in vivo. We confirmed these results in a humanized orthotopic model based on MDA-MB-231-derived LM2 metastatic breast cancer cells, in which RNAi-mediated knockdown of ARC levels was shown to reduce tumor volume, local invasion, and lung metastases. Lastly, we found that endogenous levels of ARC conferred chemoresistance in primary tumors and invading cell populations. Our results establish that ARC promotes breast carcinogenesis by driving primary tumor growth, invasion, and metastasis as well as by promoting chemoresistance in invasive cells. Cancer Res; 71(24); 7705–15. ©2011 AACR.
Phosphorylation of Carbonic Anhydrase IX Controls Its Ability to Mediate Extracellular Acidification in Hypoxic Tumors
Authors: Ditte Peter , Dequiedt Franck , Svastova Eliska , Hulikova Alzbeta , Ohradanova-Repic Anna , Zatovicova Miriam , Csaderova Lucia , Kopacek Juraj , Supuran Claudiu T. , Pastorekova Silvia , Pastorek Jaromir
Published: October 2011

In the hypoxic regions of a tumor, carbonic anhydrase IX (CA IX) is an important transmembrane component of the pH regulatory machinery that participates in bicarbonate transport. Because tumor pH has implications for growth, invasion, and therapy, determining the basis for the contributions of CA IX to the hypoxic tumor microenvironment could lead to new fundamental and practical insights. Here, we report that Thr443 phosphorylation at the intracellular domain of CA IX by protein kinase A (PKA) is critical for its activation in hypoxic cells, with the fullest activity of CA IX also requiring dephosphorylation of Ser448. PKA is activated by cAMP, which is elevated by hypoxia, and we found that attenuating PKA in cells disrupted CA IX-mediated extracellular acidification. Moreover, following hypoxia induction, CA IX colocalized with the sodium-bicarbonate cotransporter and other PKA substrates in the leading edge membranes of migrating tumor cells, in support of the concept that bicarbonate metabolism is spatially regulated at cell surface sites with high local ion transport and pH control. Using chimeric CA IX proteins containing heterologous catalytic domains derived from related CA enzymes, we showed that CA IX activity was modulated chiefly by the intracellular domain where Thr443 is located. Our findings indicate that CA IX is a pivotal mediator of the hypoxia-cAMP–PKA axis, which regulates pH in the hypoxic tumor microenvironment. Cancer Res; 71(24); 7558–67. ©2011 AACR.
Histone Deacetylase Inhibitors Induce Growth Arrest and Differentiation in Uveal Melanoma
Authors: Landreville Solange , Agapova Olga A. , Matatall Katie A. , Kneass Zachary T. , Onken Michael D. , Lee Ryan S. , Bowcock Anne M. , Harbour J. William
Published: October 2011

Purpose: Metastasis is responsible for the death of most cancer patients, yet few therapeutic agents are available which specifically target the molecular events that lead to metastasis. We recently showed that inactivating mutations in the tumor suppressor gene BAP1 are closely associated with loss of melanocytic differentiation in uveal melanoma (UM) and metastasis. The purpose of this study was to identify therapeutic agents that reverse the phenotypic effects of BAP1 loss in UM.

Experimental Design: In silico screens were done to identify therapeutic compounds predicted to differentiate UM cells using Gene Set Enrichment Analysis and Connectivity Map databases. Valproic acid (VPA), trichostatin A, LBH-589, and suberoylanilide hydroxamic acid were evaluated for their effects on UM cells using morphologic evaluation, MTS viability assays, bromodeoxyuridine incorporation, flow cytometry, clonogenic assays, gene expression profiling, histone acetylation and ubiquitination assays, and a murine xenograft tumorigenicity model.

Results: Histone deacetylase (HDAC) inhibitors induced morphologic differentiation, cell-cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured UM cells. VPA inhibited the growth of UM tumors in vivo.

Conclusions: These findings suggest that HDAC inhibitors may have therapeutic potential for inducing differentiation and prolonged dormancy of micrometastatic disease in UM. Clin Cancer Res; 18(2); 408–16. ©2011 AACR.
Predicting IGF-1R Therapy Response in Bone Sarcomas: Immuno-SPECT Imaging with Radiolabeled R1507
Authors: Fleuren Emmy D.G. , Versleijen-Jonkers Yvonne M.H. , van de Luijtgaarden Addy C.M. , Molkenboer-Kuenen Janneke D.M. , Heskamp Sandra , Roeffen Melissa H.S. , van Laarhoven Hanneke W.M. , Houghton Peter J. , Oyen Wim J.G. , Boerman Otto C. , van der Graaf Winette T.A.
Published: October 2011

Purpose: To investigate whether indium-111–labeled R1507 (111In-R1507) immuno-SPECT (single—photon emission computed tomography), a novel noninvasive, in vivo screening method to visualize membranous insulin-like growth factor 1 receptor (IGF-1R) expression and accessibility, can be used to predict IGF-1R treatment (R1507) response in bone sarcomas.

Experimental Design: BALB/c nude mice were subcutaneously implanted with IGF-1R–expressing human bone sarcoma xenografts (OS-1, EW-5, and EW-8) which showed high, modest, or no response, respectively, to R1507, a monoclonal antibody targeting the extracellular domain of IGF-1R. An IGF-1R–negative tumor (OS-33), unresponsive to IGF-1R inhibitors, was examined as well. Mice were injected with 111In-R1507. Biodistribution and immuno-SPECT/computed tomography imaging studies were carried out 1, 3, and 7 days p.i. in mice with OS-1 and EW-5 xenografts and 3 days p.i. in mice with EW-8 and OS-33 xenografts.

Results: Biodistribution studies showed specific accumulation of 111In-R1507 in OS-1 and EW-5 xenografts (27.5 ± 6.5%ID/g and 14.0 ± 2.8%ID/g, 3 days p.i., respectively). Most importantly, 111In-R1507 uptake in IGF-1R positive, but unresponsive, EW-8 xenografts (6.5 ± 1.5%ID/g, 3 days p.i.) was similar to that of the IGF-1R–negative OS-33 tumor (5.5 ± 0.6%ID/g, 3 days p.i.). Uptake in normal tissues was low and nonspecific. Corresponding immuno-SPECT images clearly discriminated between high, modest, and nonresponding tumors by showing a homogeneous (OS-1), heterogeneous (EW-5), or nonspecific (EW-8 and OS-33) tumor uptake of 111In-R1507.

Conclusions: 111In-R1507 immuno-SPECT is an excellent method to visualize membranous IGF-1R expression and target accessibility in vivo in human bone sarcoma xenografts and may serve as an independent marker to predict IGF-1R therapy (R1507) response in bone sarcoma patients. Clin Cancer Res; 17(24); 7693–703. ©2011 AACR.
Use of [11C]Choline PET-CT as a Noninvasive Method for Detecting Pelvic Lymph Node Status from Prostate Cancer and Relationship with Choline Kinase Expression
Authors: Contractor Kaiyumars , Challapalli Amarnath , Barwick Tara , Winkler Mathias , Hellawell Giles , Hazell Steve , Tomasi Giampaolo , Al-Nahhas Adil , Mapelli Paola , Kenny Laura M. , Tadrous Paul , Coombes R. Charles , Aboagye Eric O. , Mangar Stephen
Published: October 2011

Purpose: To evaluate the accuracy and biological basis for [11C]choline-PET-CT in the nodal staging of high risk localized prostate cancer patients.

Experimental Design: Twenty-eight patients underwent dynamic [11C]choline-PET-CT of the pelvis and lower abdomen prior to extended laparoscopic pelvic lymph node dissection (eLPL). The sensitivity and specificity of [11C]choline PET, [11C]choline PET-CT, and MRI for nodal detection were calculated. Average and maximal standardized uptake values (SUVave, SUVmax) were compared with choline kinase alpha (CHKα) and Ki67 immunohistochemistry scores.

Results: Four hundred and six lymph nodes (LN), in 26 patients, were assessable. Twenty-seven (6.7%) involved pelvic nodes at eLPL were detected in 9 patients. Seventeen of the 27 involved nodes were subcentimeter. The sensitivity and specificity on a per nodal basis were 18.5% and 98.7%, 40.7% and 98.4%, and 51.9% and 98.4% for MRI, [11C]choline PET, and [11C]choline PET-CT, respectively. Sensitivity was higher for [11C]choline PET-CT compared with MRI (P = 0.007). A higher nodal detection rate, including subcentimeter nodes, was seen with [11C]choline PET-CT than MRI. Malignant lesions showed CHKα expression in both cytoplasm and nucleus. SUVave and SUVmax strongly correlated with CHKα staining intensity (r = 0.68, P < 0.0001 and r = 0.63, P = 0.0004, respectively). In contrast, Ki67 expression was generally low in all tumors.

Conclusion: This study establishes the relationship between [11C]choline PET-CT uptake with choline kinase expression in prostate cancer and allows it to be used as a noninvasive means of staging pelvic LNs, being highly specific and more sensitive than MRI, including the detection of subcentimeter disease. Clin Cancer Res; 17(24); 7673–83. ©2011 AACR.
Association between Body Mass Index and Asthma among Japanese Adults: Risk within the Normal Weight Range
Authors: Fukutomi Yuma , Taniguchi Masami , Nakamura Hiroyuki , Konno Satoshi , Nishimura Masaharu , Kawagishi Yukio , Okada Chiharu , Tanimoto Yasushi , Takahashi Kiyoshi , Akasawa Akira , Akiyama Kazuo
Published: October 2011

Background: Increasing amounts of data have shown that some Asian populations are more susceptible to increased weight and development of noncommunicable disease than Western populations. However, little is known about the association between increased weight, particularly within the normal range, and the development of asthma among Asian populations. Methods: To examine the association between increased body mass index (BMI) and asthma among Japanese adults, data from a nationwide population-based cross-sectional survey of asthma prevalence in Japan were analyzed (n = 22,962; age range 20–79 years). BMIs were classified into 7 categories considering WHO recommendations (cutoff points: 17.00, 18.50, 23.00, 25.00, 27.50 and 30.00), and the association between BMI and the prevalences of asthma as well as asthma symptoms were assessed by multivariate logistic regression. Results: The prevalences of obesity (BMI ≧30.00) in this population were relatively low (males 3.0%, females 2.3%). BMI categories of 25.00 or higher in both genders were significantly associated with an increased risk of asthma compared with the reference category (BMI 18.50–22.99). Even in females with a BMI of 23.00–24.99, the prevalence of asthma significantly increased (adjusted odds ratio 1.49, 95% confidence interval 1.16–1.92) compared with that in the reference category. Conclusions: An increase in the prevalence of asthma among Japanese females starts at a BMI of 23.00, which was relatively lower than those reported from Western countries. This finding suggests that the Japanese population is likely to have asthma with a lesser degree of obesity than Western populations.
Content of Vascular Endothelial Growth Factor in Stratum Corneum Well Correlates to Local Severity of Acute Inflammation in Patients with Atopic Dermatitis
Authors: Amarbayasgalan Tseveendorj , Takahashi Hitoshi , Dekio Itaru , Morita Eishin
Published: October 2011

Background: Atopic dermatitis (AD) is an inflammatory skin disease, characterized by existence of both acute and chronic eczema. Various markers are used to clinically evaluate the severity of AD as a whole. However, little is known regarding markers that can efficiently indicate the severity of a localized lesion. Vascular endothelial growth factor (VEGF), a potent activator of vascular permeability, is known to be increased in AD lesions. In order to establish whether the VEGF content in the stratum corneum (scVEGF) can be used as a marker to evaluate severity of AD lesions, we evaluated the association between scVEGF and symptom scores of localized lesions. Methods: Fifty patients with AD and 12 healthy subjects were enrolled. Skin lesions were evaluated and transepidermal water loss and skin water content of the lesions were measured. Stratum corneum samples were collected from the skin of back, neck and arm by the tape stripping technique. The scVEGF were evaluated using a VEGF-specific ELISA method after extracting protein from the scales. Results: The scVEGF levels were significantly higher in patients with AD than in healthy controls. Moreover, the scVEGF levels highly correlated with the manifestation scores of erythema and edema/papulation, and weakly correlated with the scores of excoriation, xerosis and itch. They also correlated significantly with transepidermal water loss and skin water content. Conclusions: The scVEGF levels correlated well with the severity of clinical conditions, especially erythema and edema/papulation. scVEGF level is considered to be a useful marker to evaluate acute inflammatory conditions in individual AD lesions.
Sirtuins in Neurodegenerative Diseases: A Biological-Chemical Perspective
Authors: Raghavan Aparna , Shah Zahoor A.
Published: October 2011

Sirtuins, commonly known as NAD+-dependent class III histone deacetylase enzymes, have been extensively studied to evaluate their potential role in different disease states. Based on the published literature, sirtuins have been implicated in providing a myriad of intrinsic and extrinsic biological effects, which in turn may play an important role in the treatment of various disorders such as type II diabetes, obesity, cancer, aging and different neurodegenerative diseases. In particular, a number of studies have unequivocally supported the idea of sirtuins having therapeutic potential in neurodegenerative diseases such as stroke, ischemic brain injury, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. To exploit the therapeutic potential of sirtuins, their manipulation in terms of development of small-molecule modulators, inhibitors and analogs has increased dramatically since their inception, in both scientific and industrial worlds. Studies on the structure and catalytic core of sirtuins along with chemical mechanisms and substrate specificity have provided important input into the design and synthesis of sirtuin modulators. To study the role of sirtuins in the biological system, it has become extremely important to understand the molecular and chemical structure of sirtuins. In this review, we have discussed the biological role of sirtuins in various neurodegenerative diseases, and also provided an insight into their chemical structure.
Role of p53 in Neurodegenerative Diseases
Authors: Chang J. Robert , Ghafouri Mohammad , Mukerjee Ruma , Bagashev Asen , Chabrashvili Tinatin , Sawaya Bassel E.
Published: October 2011

Background: p53 plays an important role in many areas of cellular physiology and biology, ranging from cellular development and differentiation to cell cycle arrest and apoptosis. Many of its functions are attributed to its role in assuring proper cellular division. However, since the establishment of its role in cell cycle arrest, damage repair, and apoptosis (thus also establishing its importance in cancer development), numerous reports have demonstrated additional functions of p53 in various cells. In particular, p53 appears to have important functions as it relates to neurodegeneration and synaptic plasticity. Objective: In this review, we will address p53 functions as it relates to various neurodegenerative diseases, mainly its implications in the development of HIV-associated neurocognitive disorders. Conclusion: p53 plays a pivotal role in the development of neurodegenerative diseases through its interaction with cellular factors, viral factors, and/or small RNAs that have the ability to promote the development of these diseases. Hence, inhibition of p53 may present an ideal target to restore neuronal functions.
Association between Leptin Levels and Doses of Clomethiazole during Alcohol Withdrawal: A Pilot Study
Authors: Dammann Gerhard , Walter Marc , Gremaud-Heitz Daniela , Wolfersdorf Manfred , Hartmann Susanne , Wurst Friedrich M.
Published: October 2011

Aims: The issue of leptin as a putative state marker of alcohol use and its role in craving has been raised in the last few years. Recently, a strong GABA-ergic modulation of leptin was postulated. The aim of the pilot study was to examine leptin levels in correlation with the strongly GABA-mimetic active substance clomethiazole. The main hypothesis was that higher doses of the strong GABA-mimetic clomethiazole are positively correlated with higher leptin levels. Methods: Twenty-eight alcohol-dependent patients (3 females, median age 36 years) undergoing alcohol withdrawal were included. In 18 patients with and 10 without clomethiazole, serum leptin was analyzed at day 1 and day 7 of alcohol withdrawal. Both groups did not differ by age, BMI, or alcohol use characteristics. Results: In the clomethiazole group, significant correlations were found between leptin levels at day 1 and clomethiazole dose (p = 0.004), clomethiazole and leptin at day 1/BMI (p = 0.009) and leptin at day 1 and clomethiazole/body surface (p = 0.006). Furthermore, patients with higher clomethiazole doses demonstrated significant higher leptin levels at day 1 (p = 0.044) and day 7 (p = 0.046). Conclusions: Our pilot data show a strong association between leptin levels and clomethiazole doses, thus supporting further research.
Analysis of Lymph Node Metastatic Pattern according to the Depth of In-Growth in the Muscularis Propria in T2 Rectal Cancer for Lateral Lymph Node Dissection
Authors: Komori Koji , Kanemitsu Yukihide , Ishiguro Seiji , Shimizu Yasuhiro , Sano Tsuyoshi , Kato Tomoyuki
Published: October 2011

Background/Aims: The biological behavior of rectal cancers that invade the muscularis propria (pT2) has not been well studied. We retrospectively studied the pattern of lymph node metastases in patients with T2 rectal cancer. Methods: We enrolled 88 patients who had undergone curative resection of T2 colorectal cancer through mesorectal excision and lateral pelvic lymph node dissection; we microscopically estimated the maximum depth of muscularis propria invasion and classified the results into 3 groups representing distinct growth patterns. Results: In cases of pT2 colorectal carcinomas, lateral pelvic lymph node metastases depended on the degree of muscularis propria invasion, and the frequency of metastasis increased with the depth of muscularis propria invasion. Lateral pelvic lymph node metastases were not observed when the depth of muscularis propria invasion was less than half of the thickness of the inner circular layer. Conclusions: These findings suggest that lateral pelvic lymph node metastasis of pT2 colorectal cancer depends on the depth of vertical invasion, which is analogous to the findings in pT1 and pT3 cancers. This information will be useful in select cases in which resection of the lateral pelvic lymph node is required for the treatment of rectal cancer invading the muscularis propria (pT2).
Cannabis Use Patterns and Their Association with DSM-IV Cannabis Dependence and Gender
Authors: Noack R. , Höfler M. , Lueken U.
Published: October 2011

Aims: To investigate the gender differences in the patterns of cannabis use (CU), namely frequency, times of day, social context and methods and in their association with DSM-IV cannabis dependence. Methods: A sample of 3,904 students from German universities was recruited via an internet survey. Logistic regressions and associated areas under the ROC curve (AUC) were calculated among current cannabis users (at least once a month, n = 843). Results: CU using a water pipe was more often reported by males (50 vs. 34.6%). Usual CU ‘before going to sleep at night’ was more often reported by females (47.3 vs. 35.7%). Most CU patterns showed a similar association with DSM-IV cannabis dependence in both genders. The association of CU ‘with strangers’ was stronger in females (AUC 0.68 vs. AUC 0.56). Slightly different multiple models were found (females AUC 0.86, males AUC 0.77). Conclusions: There are considerable gender differences in the CU patterns and, thus, in the way CU functions. In the association of CU patterns with cannabis dependence, the similarities are rather great. Examining the CU patterns might make a considerable contribution to the better detection of high-risk population segments for prevention and early intervention in both genders.
Trastuzumab Treatment beyond Progression in Advanced Breast Cancer: Patterns of Care in Six Swiss Breast Cancer Centers
Authors: Huober Jens , Baumann Michael , Rochlitz Christoph , Aebi Stefan , Güth Uwe , von Moos Roger , Müller Andreas , von Rohr Lukas , Widmer Isabelle , Thürlimann Beat
Published: October 2011

Background: Trastuzumab is an established treatment for HER2-positive breast cancer (BC). We analyzed Swiss patterns of care in patients with HER2-positive BC after disease progression on trastuzumab-containing therapy for metastatic BC (MBC). Patients and Methods: A retrospective analysis was performed in six Swiss BC centers. Patients with HER2-positive MBC treated with at least one infusion of trastuzumab for advanced disease between January 2006 and December 2007 were identified. Treatment patterns in first and further lines were analyzed. Results: All of the 72 identified patients received trastuzumab as their first palliative anti-HER2 therapy, either as monotherapy (n = 23) or in combination with chemotherapy (typically taxane or vinorelbine; n = 49). Median time to progression was 8.1, 8.0 and 7.9 months in the monotherapy, trastuzumab-taxane and trastuzumab-vinorelbine cohorts, respectively. After progression on first-line anti-HER2 therapy, trastuzumab was continued in 67 of 68 patients who received further therapy. One patient received second-line lapatinib plus capecitabine. The median duration of anti-HER2 therapy was 20 months. Patients received a median of 4 lines of anti-HER2 therapy. Conclusions: Durable responses were achieved with repeated exposure to anti-HER2 therapy. In a selected patient population, trastuzumab monotherapy appears to be a reasonable first-line treatment option.