bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein Nutrition and Resistance Exercise
Authors: Evans William J.
Published: December 2012

Strength conditioning will result in an increase in muscle size and this increase in size is largely the result of increased contractile proteins. The mechanisms by which the mechanical events stimulate an increase in RNA synthesis and subsequent protein synthesis are not well understood. Lifting weight requires that a muscle shorten as it produces force (concentric contraction). Lowering the weight forces the muscle to lengthen as it produces force (eccentric contraction). Eccentric contractions produce ultrastructural damage that may stimulate increased muscle protein turnover and a cascade of metabolic events which is similar to an acute phase response and includes complement activation, mobilization of neutrophils, increased circulating and skeletal muscle interleukin-1 and macrophage accumulation. While endurance exercise increases the oxidation of essential amino acids and increases the requirement for dietary protein, resistance exercise results in a decrease in nitrogen excretion, lowering dietary protein needs. Research has indicated that increased dietary protein intake (up to 1.6 g protein kg-1. d-1) may enhance the hypertrophic response to resistance exercise. It has also been demonstrated that in very old men and women the use of a protein-calorie supplement was associated with greater strength and muscle mass gains than did the use of placebo.
Protein Intake and Bone Growth
Authors: Bonjour Jean-Philippe , Ammann Patrick , Chevalley Thierry , Rizzoli René
Published: December 2012

Among osteotrophic nutrients, proteins play an important role in bone development, thereby influencing peak bone mass. Consequently, protein malnutrition during development can increase the risk of osteoporosis and of fragility fracture later in life. Both animal and human studies indicate that low protein intake can be detrimental for both the acquisition of bone mass during growth and its conservation during adulthood. Low protein intake impairs both the production and action of IGF-I (Insulin-like growthfactor-I). IGF-I is an essential factorf or bone longitudinal growth, as it stimulates proliferation and difef rentiation of chondrocytes in the epiphyseal plate, and also for bone formation. It can be considered as a key factor in the adjustments of calcium-phosphate metabolism required for normal skeletal development and bone mineralization during growth. In healthy children and adolescents, a positive association between the amount of ingested proteins and bone mass gain was observed in both sexes at the level of the lumbar spine, the proximal femur and the midfemoral shaft. This association appears to be particularly significant in prepubertal children. This suggests that, like for the bone response to either the intake of calcium or weight-bearing exercise, the skeleton would be particularly responsive to the protein intake during the years preceding the onset of pubertal maturation.
The Concept of Energy Homeostasis for Optimal Health During Training
Authors: Saris Wim H.M.
Published: December 2012

From all nutritional variables optimal energy supply is considered as most vital for human performance. It is postulated that lack of energy homeostasis is the basic problem in the development of overtraining. Most if not all clinical symptoms are directly or indirectly related to the physiological mechanisms of energy homeostasis. The rapidly increasing knowledge in the field of body weight control with several new regulatory neuro-peptides such as leptin, will give new opportunities to tackle this unbalance between training load and energy availability. The central role of leptin and insulin as adiposity signals has focussed attention on the anti-obesity aspects of leptin. However as member of the cytokine family, leptin is also closely linked to the immune and reproductive system. New data indicates clearly the dual function of leptin at both ends at the energy balance; starvation vs. over-feeding. It links also nutrition to the reproductive system. Lack of available energy has a much greater impact on leptin levels than exercise stress. It is suggested that application of the rapidly increasing knowledge in the obesity field will benefit the research on the mechanisms involved in the derailment of the delicate balance between training load and energy homeostasis in athletes.
Nutritional Considerations for the Child Athlete
Authors: Bar-Or Oded
Published: December 2012

While nutritional issues are similar for all athletes irrespective of age, children have several physiological characteristics that distinguish them from adults and require specific nutritional considerations. These age- or maturation-related difefrences include: a greater need for protein intake, to support growth; a greater need for calcium intake, to support bone accretion; a higher energy cost of activities that include walking and running; lower losses of sodium and chloride in sweat; and a greater thermoregulatory strain at any given level of hypohydration. This review willfocus on three areas: (a) a higher metabolic cost of locomotion, its causes, and possible relevance to the calculation of daily energy requirements for young athletes; (b) the effect of carbohydrate (glucose, glucose plus fructose, or glucose plus sucrose) ingestion on children 's aerobic performance, substrate utilization, and immune responses; and (c) involuntary dehydration during exercise in hot climate and the means for its prevention.
RANDERS METRICS OF REVERSIBLE CURVATURE
Authors: SHEN ZHONGMIN , YANG GUOJUN
Published: December 2012

In this paper, we introduce the notions of R-reversibility and Ricci-reversibility. We prove that Randers metrics are R-reversible or Ricci-reversible if and only if they are R-quadratic or Ricci-quadratic, respectively. Besides, we discuss the properties of Ricci- or R-reversible Randers metrics which are also weakly Einsteinian, or Douglassian, or of scalar flag curvature. In particular, we determine the local structure of Randers metrics which are Ricci-reversible and locally projectively flat, and prove that an n (≥ 3)-dimensional Ricci-reversible Randers metric of non-zero scalar flag curvature is locally projectively flat.
MICROSTRUCTURAL AND ELECTROMAGNETIC PROPERTIES OF Mn–Zn FERRITES WITH LOW MELTING-POINT NONMAGNETIC Sb3+ IONS
Authors: FU X. L. , XING Q. K. , PENG Z. J. , WANG C. B. , FU Z. Q. , QI L. H. , MIAO H. Z.
Published: December 2012

The doping effects of low melting-point nonmagnetic Sb 3+ ions on the microstructure and electromagnetic properties of Mn–Zn ferrites were studied. All the samples were prepared by traditional ceramic technique. According to the investigation on the microstructure, it was found that all the samples consisted of ferrite phases with typical spinel cubic structure, and with increasing doping content of Sb 3+ ions, the lattice constant of the ferrites decreased but the grain size increased; the elemental analysis taken on the ferrite grain and grain boundary indicated that a portion of Sb 3+ ions entered into the ferrite lattice. Through the measurement of magnetic properties, it was revealed that, the saturation magnetization and initial permeability of the samples rose with small doping content of Sb 3+ ions but decreased with additional Sb 3+ doping; the Curie temperature decreased monotonously with Sb 3+ doping; and the coercivity rose with increasing doping content of Sb 3+ ions. The analysis of dielectric properties indicated that the dielectric constant of the doped Mn – Zn ferrites increased with increasing doping content of Sb 3+ ions.
RECONSTRUCTION AND IDENTIFICATION AND CONTROL METHOD OF FERRORESONANCE OVERVOLTAGE BASED ON VOLTAGE TIME SERIES
Authors: YANG MING , YANG QING , SIMA WEN-XIA , YUAN TAO , CHEN LI-JUN , HUANG YAN-LING
Published: December 2012

Ferroresonance overvoltage and over-current can be restrained using nonlinear dynamics. However, the ferroresonance simplified model, which cannot reflect the huge ferroresonance circuit in the grid precisely and cannot satisfy real-time analysis, is adopted in the traditional nonlinear control method. Owing to these shortcomings, the strategy of controlling ferroresonance overvoltage based on voltage time series is proposed. Based on the voltage time series analysis methods, the ferroresonance system is identified using the best embedding dimension and the best time delay obtained from the phase space reconstruction. Afterward, the feedback controller is designed based on the platform of the identified model. Results show that fundamental, subharmonic and chaotic ferroresonance overvoltage can all be controlled using the method presented in this paper even without the system parameters and the accurate system model. Therefore, the control strategy is generally more applicable.
THE HYLLERAAS BINDING ENERGY OF HYDRIDE AND ELECTRON AFFINITIES
Authors: CHEN EDWARD S. , CHEN EDWARD C. M.
Published: December 2012

The normalized electron affinity of the hydrogen atom, is the fundamental measure of anionic electron correlation. The three-body H (−) and AB(−) systems analogous to Efimov three-body bosons support multiple excited states. The first complete set of ground state electron affinities of the main group atoms and homonuclear diatomic molecules are reported using the Hylleraas variational binding energy of the hydride anion. Thermal electron affinities and activation energies for the formation of the 27 bonding states of O2(−) are reported from electron capture detector and atmospheric pressure negative ion mass spectrometry. These are iterated through magnetron, flame, swarm, electron impact, photodetachment, and negative ion photoelectron spectra to obtain more precise self-consistent values. Electron affinities for NO are similarly reported. These data are used to calculate Herschbach ionic Morse Person electron curves for the 54 O2(−) and 87 NO (−) states predicted by adiabatic correlation rules. A new ground state adiabatic electron affinity of SF63.00(10) eV is determined from negative ion mass spectra.
A SELF-CONSISTENT-CHARGE DENSITY-FUNCTIONAL TIGHT-BINDING THEORY BASED MOLECULAR DYNAMICS SIMULATION OF A ZWITTERIONIC GLYCINE IN AN EXPLICIT WATER ENVIRONMENT
Authors: ZHAI Y. , ZHAO Y. L.
Published: December 2012

A zwitterionic glycine (zGLY) is adopted as an example to study the impact of water environment (310 H2O molecules) on the molecular structure and energetics using a self-consistent-charge density-functional tight-binding theory based molecular dynamics (SCC-DFTB/MD) method. It is found that maximal eight hydrogen bonds could be formed simultaneously between eight water molecules and the zGLY. The ability of the COO- terminal to adsorb water molecules is stronger than the [Formula: see text] terminal with respect to hydrogen bonding with more water molecules and exhibits lower adiabatic adsorption energies. The zGLY's intramolecular hydrogen bond appeared unpredictably, without involving any proton transfer and generally helpful for enhancing the system stability. Water molecules play an important role to stabilize the zwitterionic amino acids and restrain the proton migration from the [Formula: see text] to the COO− group. Our results show that the SCC-DFTB/MD method could successfully describe geometry dynamical evolutions and energetics of biomolecules in a nanoscale simulation with the presence of a large number of water molecules. Our study not only verified the feasibility of a QM level methodology for describing the aqueous states of biochemical molecules, but also gave a clear evidence for the impact of water environment on amino acids.
The role of lymphoid tissue in the attenuation of the postoperative ileus
Authors: Koscielny A. , Engel D. , Maurer J. , Wehner S. , Kurts C. , Kalff J. C.
Published: December 2012

Standardized intestinal manipulation (IM) leads to local bowel wall inflammation subsequently spreading over the entire gastrointestinal tract. Previously, we demonstrated that this so-called gastrointestinal field effect (FE) is immune-mediated. The aim of this study was to investigate the role of secondary lymphoid organs [mesenteric lymph nodes (MLN), gut-associated lymphoid tissue (GALT)] in IM-mediated FE by employing mice with deficient secondary lymphoid organs (aly/aly, MLN ex) or by administration of 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720), an immunomodulating agent that inhibits emigration of lymphocytes out of lymphoid organs. Small bowel muscularis, and colonic muscularis from wild-type mice as control, from aly/aly mice, FTY720-treated mice (daily dose of 1.0 mg/kg mouse ip starting 3 days before surgical procedure), and wild-type mice that had undergone removal of mesenteric lymph nodes before IM (MLN ex mice) were obtained after selective IM of the jejunum or sham operation. FE was analyzed by measuring transit time of orally administered fluorescent dextran in the gastrointestinal tract [geometric center (GC) of fluorescent dextran], colonic transit time, infiltration of myeloperoxidase-positive cells, and circular smooth muscle contractility. Furthermore, mRNA levels of inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-1α] were determined by Taqman-PCR. We observed a significantly reduced upregulation of proinflammatory cytokines (IL-6, TNF-α, MIP-1α) in colonic muscularis of MLN ex mice, aly/aly mice, and FTY720-treated mice compared with wild-type mice. Contractility of circular muscularis strips of the colon but not the jejunum was significantly improved in aly/aly mice and FTY720-treated wild-type mice. Additionally, inflammation of the colon determined by the number of myeloperoxidase-positive cells and colonic transit time were significantly improved in aly/aly mice, FTY720-treated wild-type mice, and in MLN ex mice. In summary, lack of secondary lymphoid organs (MLN + GALT) in aly/aly mice or administration of FTY720 abrogated FE after IM as opposed to wild-type mice. These data demonstrate that secondary lymphoid organs are involved in the propagation of FE and postoperative ileus. FTY720 indirectly affects FE by inhibiting migration of activated T cells from the jejunum and adjacent secondary lymphoid organs to the colon. These findings support the crucial role of the adaptive immune system in FE, most likely by a sphyngosine 1-phosphate-dependent mechanism.
Expression of bile acid receptor TGR5 in gastric adenocarcinoma
Authors: Cao Weibiao , Tian Wei , Hong Jie , Li Dan , Tavares Rosemarie , Noble Lelia , Moss Steven F. , Resnick Murray B.
Published: December 2012

Bile reflux is a risk factor in the development of intestinal metaplasia in the stomach and is believed to function as an initiator of gastric carcinogenesis. However, whether the G protein-coupled bile acid receptor TGR5 is expressed in this tumor is not known. In this study, we determined the expression of TGR5 in gastric adenocarcinoma and examined the role of TGR5 in cell proliferation. Strong TGR5 staining was present in 12% of cases of intestinal metaplasia but in no cases of normal gastric epithelium ( P < 0.01). Moderate to strong TGR5 membranous and cytoplasmic staining was present in 52% of the intestinal but in only 25% of the diffuse subtype of adenocarcinomas ( P < 0.001). Kaplan-Meier univariate survival analysis revealed that moderate to strong TGR5 staining was associated with decreased patient survival ( P < 0.05). Treatment with taurodeoxycholic acid (TDCA, a bile acid) significantly increased thymidine incorporation in the AGS gastric adenocarcinoma cell line, suggesting that bile acids may increase cell proliferation. This increase was significantly decreased by knockdown of TGR5 with TGR5 small-interfering RNA (siRNA). In addition, overexpression of TGR5 significantly enhanced TDCA-induced increases in thymidine incorporation. TGR5 is coupled with Gqα and Gαi-3 proteins. TDCA-induced increase in thymidine incorporation was significantly decreased by knockdown of Gqα and Gαi-3 with their siRNAs. We conclude that TGR5 is overexpressed in most gastric intestinal-type adenocarcinomas, and moderate to strong TGR5 staining is associated with decreased patient survival in all gastric adenocarcinomas. Bile acids increase cell proliferation via activation of TGR5 receptors and Gqα and Gαi-3 proteins.
Enhanced corticospinal excitability with physiologically heightened sympathetic nerve activity
Authors: Buharin Vasiliy E. , Butler Andrew J. , Rajendra Justin K. , Shinohara Minoru
Published: December 2012

Corticospinal excitability is modulated differently with norepinephrine and dopamine agonists, although both monoamines are released with heightened sympathetic nerve activity. The purpose of this study was to investigate the influence of physiological heightening of sympathetic nerve activity on corticospinal excitability in healthy humans. Subjects were divided into control and experimental groups. In each participant, motor-evoked potentials (MEPs) were measured from the resting first dorsal interosseous muscle of the right hand with transcranial magnetic stimulation (TMS) in two trials separated by 1 h. In the experimental group, sympathetic nerve activity was physiologically heightened during the second trial by applying lower body negative pressure (LBNP). In the control group, sympathetic nerve activity was not altered between the two trials. MEP peak-to-peak amplitude increased from trial 1 to trial 2 in the experimental group only. This increase was evident at a TMS intensity of 130% resting motor threshold and higher. It was concluded that physiological heightening of sympathetic nerve activity with LBNP enhances corticospinal excitability.
Dual Inhibition of Bcl-2 and Bcl-xL Strikingly Enhances PI3K Inhibition-Induced Apoptosis in Human Myeloid Leukemia Cells through a GSK3- and Bim-Dependent Mechanism
Authors: Rahmani Mohamed , Aust Mandy Mayo , Attkisson Elisa , Williams David C. , Ferreira-Gonzalez Andrea , Grant Steven
Published: December 2012

Effects of concomitant inhibition of the PI3K/AKT/mTOR pathway and Bcl-2/Bcl-xL (BCL2L1) were examined in human myeloid leukemia cells. Tetracycline-inducible Bcl-2 and Bcl-xL dual knockdown sharply increased PI3K/AKT/mTOR inhibitor lethality. Conversely, inducible knockdown or dominant-negative AKT increased, whereas constitutively active AKT reduced lethality of the Bcl-2/Bcl-xL inhibitor ABT-737. Furthermore, PI3K/mTOR inhibitors (e.g., BEZ235 and PI-103) synergistically increased ABT-737–mediated cell death in multiple leukemia cell lines and reduced colony formation in leukemic, but not normal, CD34+ cells. Notably, increased lethality was observed in four of six primary acute myelogenous leukemia (AML) specimens. Responding, but not nonresponding, samples exhibited basal AKT phosphorylation. PI3K/mTOR inhibitors markedly downregulated Mcl-1 but increased Bim binding to Bcl-2/Bcl-xL; the latter effect was abrogated by ABT-737. Combined treatment also markedly diminished Bax/Bak binding to Mcl-1, Bcl-2, or Bcl-xL. Bax, Bak, or Bim (BCL2L11) knockdown or Mcl-1 overexpression significantly diminished regimen-induced apoptosis. Interestingly, pharmacologic inhibition or short hairpin RNA knockdown of GSK3α/β significantly attenuated Mcl-1 downregulation and decreased apoptosis. In a systemic AML xenograft model, dual tetracycline-inducible knockdown of Bcl-2/Bcl-xL sharply increased BEZ235 antileukemic effects. In a subcutaneous xenograft model, BEZ235 and ABT-737 coadministration significantly diminished tumor growth, downregulated Mcl-1, activated caspases, and prolonged survival. Together, these findings suggest that antileukemic synergism between PI3K/AKT/mTOR inhibitors and BH3 mimetics involves multiple mechanisms, including Mcl-1 downregulation, release of Bim from Bcl-2/Bcl-xL as well as Bak and Bax from Mcl-1/Bcl-2/Bcl-xL, and GSK3α/β, culminating in Bax/Bak activation and apoptosis. They also argue that combining PI3K/AKT/mTOR inhibitors with BH3 mimetics warrants attention in AML, particularly in the setting of basal AKT activation and/or addiction. Cancer Res; 73(4); 1340–51. ©2012 AACR.
Trask Loss Enhances Tumorigenic Growth by Liberating Integrin Signaling and Growth Factor Receptor Cross-Talk in Unanchored Cells
Authors: Spassov Danislav S. , Wong Ching Hang , Wong Sunny Y. , Reiter Jeremy F. , Moasser Mark M.
Published: December 2012

The cell surface glycoprotein Trask/CDCP1 is phosphorylated during anchorage loss in epithelial cells in which it inhibits integrin clustering, outside-in signaling, and cell adhesion. Its role in cancer has been difficult to understand, because of the lack of a discernible pattern in its various alterations in cancer cells. To address this issue, we generated mice lacking Trask function. Mammary tumors driven by the PyMT oncogene and skin tumors driven by the SmoM2 oncogene arose with accelerated kinetics in Trask-deficient mice, establishing a tumor suppressing function for this gene. Mechanistic investigations in mammary tumor cell lines derived from wild-type or Trask-deficient mice revealed a derepression of integrin signaling and an enhancement of integrin-growth factor receptor cross-talk, specifically in unanchored cell states. A similar restrictive link between anchorage and growth in untransformed epithelial cells was observed and disrupted by elimination of Trask. Together our results establish a tumor-suppressing function in Trask that restricts epithelial cell growth to the anchored state. Cancer Res; 73(3); 1168–79. ©2012 AACR.
Trends in Endometrial Cancer Incidence by Race and Histology with a Correction for the Prevalence of Hysterectomy, SEER 1992 to 2008
Authors: Jamison Patricia M. , Noone Anne-Michelle , Ries Lynn A.G. , Lee Nancy C. , Edwards Brenda K.
Published: December 2012

Background: Incidence rates of endometrial cancer are routinely calculated without removing women who have had a hysterectomy from the denominator, which leads to an underestimate. Furthermore, as the number of women who have had a hysterectomy (hysterectomy prevalence) varies by race, the estimate of racial difference in endometrial cancer incidence is incorrect.

Methods: Data from 1992 to 2008 from the SEER Program were used to calculate incidence rates of endometrial cancer (corpus uterus and uterus, NOS) for 67,588 women 50 years and older. Data from the Behavioral Risk Factor Surveillance System were used to estimate hysterectomy prevalence. SEER area populations were reduced by hysterectomy prevalence, and corrected incidence rates were calculated.

Results: For women 50 years and older, the corrected incidence rate of endometrial cancer was 136.0 per 100,000 among whites and 115.5 among blacks, a 73% and 90% increase respectively compared with the uncorrected rate. The increase was greater for black women because hysterectomy prevalence was higher among black women (47%) than white women (41%). The corrected incidence among black women significantly increased 3.1% per year compared with a 0.8% significant decrease among white women resulting in higher rates among black women toward the end of the study period.

Conclusion: Correcting the incidence rate for hysterectomy prevalence provides more accurate estimates of endometrial cancer risk over time.

Impact: Comparisons of rates of endometrial cancer among racial groups may be misleading in the absence of denominator correction for hysterectomy prevalence. Cancer Epidemiol Biomarkers Prev; 22(2); 233–41. ©2012 AACR.
Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines
Authors: Holz Meike Stefanie , Janning Angela , Renné Christoph , Gattenlöhner Stefan , Spieker Tilmann , Bräuninger Andreas
Published: December 2012

Hodgkin-Reed/Sternberg (HRS) cells of classical Hodgkin lymphoma show aberrant expression and activation of several receptor tyrosine kinases (RTK) in the majority of cases. Therefore, we tested whether tyrosine kinase inhibitors (TKI) already in clinical use or late stages of clinical trials have antiproliferative effects on HRS cell lines and evaluated the targets, affected signaling pathways, and mechanisms of cell death and resistance. Sorafenib and lestaurtinib had antiproliferative effects on HRS cell lines at concentrations achievable in patients. Sorafenib inhibited platelet-derived growth factor receptor (PDGFR) α, TRKA and RON, caused decreases in total and phosphorylated amounts of several signaling molecules, and provoked caspase-3–independent cell death, most likely due to endoplasmic reticulum stress as indicated by upregulation of GADD34 and GADD153 and phosphorylation of PERK. Lestaurtinib inhibited TRKA, PDGFRα, RON, and JAK2 and had only a cytostatic effect. Besides deactivation, lestaurtinib also caused activation of signaling pathways. It caused increases in CD30L and TRAIL expression, and CD30L/CD30 signaling likely led to the observed concomitant activation of extracellular signal–regulated kinase 1/2 and the alternative NF-κB pathway. These data disclose the possible use of sorafenib for the treatment of Hodgkin lymphoma and highlight NF-κB activation as a potential novel mechanism of resistance toward TKIs. Mol Cancer Ther; 12(2); 173–83. ©2012 AACR.
Antitumor Activity and Pharmacodynamic Biomarkers of a Novel and Orally Available Small-Molecule Antagonist of Inhibitor of Apoptosis Proteins
Authors: Sumi Hiroyuki , Yabuki Masato , Iwai Kenichi , Morimoto Megumi , Hibino Ryosuke , Inazuka Masakazu , Hashimoto Kentaro , Kosugi Yohei , Aoyama Kazunobu , Yamamoto Shunsuke , Yoshimatsu Mie , Yamasaki Hideki , Tozawa Ryuichi , Ishikawa Tomoyasu , Yoshida Sei
Published: December 2012

Inhibitor of apoptosis proteins (IAP), which are key regulators of apoptosis, are inhibited by second mitochondria-derived activator of caspase (SMAC). Small-molecule IAP antagonists have recently been reported as novel therapeutic treatments for cancer. In this study, we showed that the octahydro-pyrrolo[1,2-a]pyrazine derivative, T-3256336, is a novel and orally available small-molecule IAP antagonist. T-3256336 selectively binds to and antagonizes protein interactions involving cellular IAP-1 (cIAP-1), cIAP-2, and X-linked IAP (XIAP). T-3256336 induced the rapid proteasomal degradation of cIAP-1 and activated TNF-α–dependent extrinsic apoptosis signaling in cultured cells. In a MDA-MB-231-Luc breast cancer xenograft model, T-3256336 induced cIAP-1 degradation, TNF-α production, and caspase activation in tumors, which resulted in strong antitumor activities. T-3256336 induced increases in the plasma levels of TNF-α and fragmented cytokeratin-18, which correlated with the antitumor potency in MDA-MB-231-Luc xenograft models. This study provided further insights into biomarkers of IAP antagonists. Furthermore, our data provided evidence that T-3256336 is a promising new anticancer drug worthy of further evaluation and development. Mol Cancer Ther; 12(2); 230–40. ©2012 AACR.
Pharmacologic Blockade of FAK Autophosphorylation Decreases Human Glioblastoma Tumor Growth and Synergizes with Temozolomide
Authors: Golubovskaya Vita M. , Huang Grace , Ho Baotran , Yemma Michael , Morrison Carl D. , Lee Jisook , Eliceiri Brian P. , Cance William G.
Published: December 2012

Malignant gliomas are characterized by aggressive tumor growth with a mean survival of 15 to 18 months and frequently developed resistance to temozolomide. Therefore, strategies that sensitize glioma cells to temozolomide have a high translational impact. We have studied focal adhesion kinase (FAK), a tyrosine kinase and emerging therapeutic target that is known to be highly expressed and activated in glioma. In this report, we tested the FAK autophosphorylation inhibitor, Y15, in DBTRG and U87 glioblastoma cells. Y15 significantly decreased viability and clonogenicity in a dose-dependent manner, increased detachment in a dose- and time-dependent manner, caused apoptosis, and inhibited cell invasion in both cell lines. In addition, Y15 treatment decreased autophosphorylation of FAK in a dose-dependent manner and changed cell morphology by causing cell rounding in DBTRG and U87 cells. Administration of Y15 significantly decreased subcutaneous DBTRG tumor growth with decreased Y397-FAK autophosphorylation, activated caspase-3 and PARP. Y15 was administered in an orthotopic glioma model, leading to an increase in mouse survival. The combination of Y15 with temozolomide was more effective than either agent alone in decreasing viability and activating caspase-8 in DBTRG and U87 cells in vitro. In addition, the combination of Y15 and temozolomide synergistically blocked U87 brain tumor growth in vivo. Thus, pharmacologic blockade of FAK autophosphorylation with the oral administration of a small-molecule inhibitor Y15 has a potential to be an effective therapy approach for glioblastoma either alone or in combination with chemotherapy agents such as temozolomide. Mol Cancer Ther; 12(2); 162–72. ©2012 AACR.
Synergistic Effect of Olaparib with Combination of Cisplatin on PTEN-Deficient Lung Cancer Cells
Authors: Minami Daisuke , Takigawa Nagio , Takeda Hiromasa , Takata Minoru , Ochi Nobuaki , Ichihara Eiki , Hisamoto Akiko , Hotta Katsuyuki , Tanimoto Mitsune , Kiura Katsuyuki
Published: December 2012

PARP enzyme plays a key role in the cellular machinery responsible for DNA damage repair. PTEN is a tumor-suppressor gene deactivating PI3K downstream of EGFR signaling. We hypothesize that PTEN-deficient lung cancer cells suppressed DNA damage signaling and that the absence of PTEN can sensitize these cells to a concurrent treatment of a DNA-damaging agent (cisplatin) and a PARP inhibitor (olaparib). To investigate the effect of olaparib and cisplatin on PTEN-deficient lung tumors, two EGFR-mutant (deletion in exon19) non–small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild-type) and H1650 (PTEN loss), were used. We transfected intact PTEN gene into H1650 cells (H1650PTEN+) and knocked down PTEN expression in the PC-9 cells (PC-9PTEN−) using short hairpin RNA (shRNA). Combination of cisplatin with olaparib showed a synergistic effect in vitro according to the combination index in H1650 cells. Restoration of PTEN in the H1650 cells decreased sensitivity to the combination. Ablation of PTEN in PC-9 cells increased sensitivity to olaparib and cisplatin. We also examined the effectiveness of cisplatin and olaparib in a xenograft model using H1650 and PC-9PTEN− cells. The combination of cisplatin with olaparib was more effective than each agent individually. This effect was not observed in a xenograft model using H1650PTEN+ and PC-9 cells. Mechanistic investigations revealed that PTEN deficiency caused reductions in nuclear RAD51 and RPA focus formation and phosphorylated Chk1 and Mre11. Thus, genetic inactivation of PTEN led to the suppression of DNA repair. Mol Cancer Res; 11(2); 140–8. ©2012 AACR.
MYC-Induced Epigenetic Activation of GATA4 in Lung Adenocarcinoma
Authors: Castro Inês C. , Breiling Achim , Luetkenhaus Katharina , Ceteci Fatih , Hausmann Simone , Kress Sebastian , Lyko Frank , Rudel Thomas , Rapp Ulf R.
Published: December 2012

Human lung cancer is a disease with high incidence and accounts for most cancer-related deaths in both men and women. Metastasis is a common event in non–small cell lung carcinoma (NSCLC), diminishing the survival chance of the patients with this type of tumor. It has been shown that MYC is involved in the development of metastasis from NSCLC, but the mechanism underlying this switch remained to be identified. Here, we focus on GATA4 as a MYC target in the development of metastasis with origin in lung adenocarcinoma, the most common type of NSCLC. Epigenetic alterations at the GATA4 promoter level were observed after MYC expression in lung adenocarcinoma in vivo and in vitro. Such alterations include site-specific demethylation that accompanies the displacement of the MYC-associated zinc finger protein (MAZ) from the GATA4 promoter, which leads to GATA4 expression. Histone modification analysis of the GATA4 promoter revealed a switch from repressive histone marks to active histone marks after MYC binding, which corresponds to active GATA4 expression. Our results thus identify a novel epigenetic mechanism by which MYC activates GATA4 leading to metastasis in lung adenocarcinoma, suggesting novel potential targets for the development of antimetastatic therapy. Mol Cancer Res; 11(2); 161–72. ©2012 AACR.
Genotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening
Authors: Held Matthew A. , Langdon Casey G. , Platt James T. , Graham-Steed Tisheeka , Liu Zongzhi , Chakraborty Ashok , Bacchiocchi Antonella , Koo Andrew , Haskins Jonathan W. , Bosenberg Marcus W. , Stern David F.
Published: December 2012

Resistance and partial responses to targeted monotherapy are major obstacles in cancer treatment. Systematic approaches to identify efficacious drug combinations for cancer are not well established, especially in the context of genotype. To address this, we have tested pairwise combinations of an array of small-molecule inhibitors on early-passage melanoma cultures using combinatorial drug screening. Results reveal several inhibitor combinations effective for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to vemurafenib. Inhibition of both EGF receptor and AKT sensitized treatment-resistant BRAF mutant melanoma cultures to vemurafenib. Melanomas with RAS mutations were more resistant to combination therapies relative to BRAF mutants, but were sensitive to combinations of statins and cyclin-dependent kinase inhibitors in vitro and in vivo. These results show the use of combinatorial drug screening for discovering unique treatment regimens that overcome resistance phenotypes of mutant BRAF- and RAS-driven melanomas.

Significance: We have used drug combinatorial screening to identify effective combinations for mutant BRAF melanomas, including those resistant to vemurafenib, and mutant RAS melanomas that are resistant to many therapies. Mechanisms governing the interactions of the drug combinations are proposed, and in vivo xenografts show the enhanced benefit and tolerability of a mutant RAS-selective combination, which is currently lacking in the clinic. Cancer Discov; 3(1); 52–67. ©2012 AACR.

See related commentary by Al-Lazikani and Workman, p. 14

This article is highlighted in the In This Issue feature, p. 1
Sputum Hyaluronan and Versican in Severe Eosinophilic Asthma
Authors: Ayars Andrew G. , Altman Leonard C. , Potter-Perigo Sue , Radford Katherine , Wight Thomas N. , Nair Parameswaran
Published: December 2012

Background: We examined levels of hyaluronan, a matrix glycosaminoglycan and versican, a matrix proteoglycan, in the sputum of asthmatics treated with mepolizumab (anti-IL-5 monoclonal antibody) versus placebo to evaluate the utility of these measurements as possible biomarkers of asthma control and airway remodeling. Methods: Patients with severe, prednisone-dependent asthma received either mepolizumab or placebo as described in a previously published randomized, double-blind, placebo-controlled study. We measured hyaluronan and versican levels by enzyme-linked immunosorbent assay in sputum collected before and after the 16-week treatment phase. Patients underwent a predefined prednisone tapering schedule if they remained exacerbation free, and sputum eosinophil percentage, asthma control questionnaire (ACQ) and spirometry were monitored. Results: After 6 months of mepolizumab therapy and prednisone tapering, there was a significant increase in sputum hyaluronan in the placebo group compared with baseline (p = 0.003). In contrast, there was a significant decrease in sputum hyaluronan in the active treatment group compared with placebo (p = 0.007), which correlated with improvements in percent forced expiratory volume in 1 s (FEV1%) (p = 0.001) and ACQ scores (p = 0.009) as well as a decrease in sputum eosinophils (p = 0.02). There was a nonsignificant increase in sputum versican in the placebo group (p = 0.16), a decrease in the mepolizumab group (p = 0.13) and a significant inverse correlation between versican reduction and FEV1% improvement (p = 0.03). Conclusions: Sputum hyaluronan values are reduced with mepolizumab therapy and correlate with improved clinical and spirometry values, suggesting this measurement may serve as a noninvasive biomarker of asthma control.
Characteristic Pattern of Reactivation of Hepatitis B Virus during Chemotherapy for Solid Cancers
Authors: Hagiwara Satoru , Sakurai Toshiharu , Nishina Shinichi , Tanaka Kaoru , Ikeda Masafumi , Ueshima Kazuomi , Minami Yasunori , Inoue Tatsuo , Yada Norihisa , Kitai Satoshi , Takita Masahiro , Nagai Tomoyuki , Hayaishi Sousuke , Arizumi Tadaaki , Park Ah-Mee , Munakata Hiroshi , Nishida Naoshi , Kudo Masatoshi
Published: December 2012

Objective: A number of studies have reported reactivation of hepatitis B during intensive immunosuppressive therapy such as cases of hematological malignancy, whereas little has been reported for characteristics of reactivation triggered by chemotherapy for solid cancer. Methods: A total of 130 patients underwent chemotherapy for treatments of common solid cancer between May 2011 and May 2012 at Kinki University Hospital. Among them, 27 patients were suspected for a past infection of hepatitis B virus (HBV), showing positive for hepatitis B core antibody or surface antibody but negative for hepatitis B surface antigen, and were eligible for this study. Results: Hepatitis B reactivation was observed in 2 of 27 cases (7.4%). The duration between the start of chemotherapy and increase of serum HBV load was 30 days in both cases. Conclusions: We reported the 2 cases of hepatitis B reactivation receiving chemotherapy for solid cancer in terms of patterns and characteristics of reactivation. Accumulation of such cases will help in clarifying the clinical importance of hepatitis B reactivation during treatment of solid malignancies.
Gender Differences in the Livers of Patients with Hepatocellular Carcinoma and Chronic Hepatitis C Infection
Authors: Nishida Naoshi , Arizumi Tadaaki , Hayaishi Sosuke , Takita Masahiro , Kitai Satoshi , Yada Norihisa , Hagiwara Satoru , Inoue Tatsuo , Minami Yasunori , Ueshima Kazuomi , Sakurai Toshiharu , Ikai Iwao , Kudo Masatoshi
Published: December 2012

Objectives: A unique causative aspect of hepatocellular carcinoma (HCC) is a gender difference in its incidence. To determine the specific factors that contribute to a male predominance, we analyzed the clinicopathological factors, and genetic and epigenetic alterations of HCCs in male and female patients. Methods: We retrospectively analyzed three cohorts of patients: the first cohort consisted of 547 patients identified with the first event of HCC, the second cohort included 176 HCC patients, and the third 127 patients with chronic hepatitis C (CHC). Results: Male patients were found to have HCC more frequently than female patients in cases of non-cirrhotic liver (p = 0.0030 by the χ2 test), especially in hepatitis C-positive cases. However, there were no gender-specific differences in the genetic and epigenetic alterations of cancer-related genes. Deposition of iron was more severe in male CHC patients than in female patients. Conclusions: Male patients with CHC develop HCC more frequently when they have a non-cirrhotic liver than do female patients. This gender difference could be, at least partially, attributed to a different degree of iron deposition, which contributes to the development of HCC in the absence of liver cirrhosis in men with CHC.
Risk of Hepatocellular Carcinoma Development in Cases of Hepatitis C Treated by Long-Term, Low-Dose PEG-IFNα-2a
Authors: Hagiwara Satoru , Sakurai Toshiharu , Takita Masahiro , Ueshima Kazuomi , Minami Yasunori , Inoue Tatsuo , Yada Norihisa , Kitai Satoshi , Nagai Tomoyuki , Hayaishi Sousuke , Arizumi Tadaaki , Nishida Naoshi , Kudo Masatoshi
Published: December 2012

Objective: Increasing evidence suggests the efficacy of maintenance therapy with interferon (IFN) for chronic hepatitis C (CHC) in reducing the risk of hepatocellular carcinoma (HCC). The aim of this study was to determine clinical characteristics on the risk of occurrence of HCC in CHC patients receiving maintenance IFN therapy. Methods: A total of 55 patients were treated in a single center with PEG-IFNα-2a monotherapy for CHC and evaluated for variables predictive of the occurrence of HCC. Results: The cumulative incidences of HCC were 0.092, 0.117 and 0.161 at 3, 5 and 7 years, respectively. Serum ALT level (>40 IU/l) in the 6th month after commencement of IFN therapy and BMI >25 were associated with shorter time-to-HCC emergence using multivariate analysis (relative risk 16.034, p = 0.01 for ALT >40 IU/l; relative risk 6.020, p = 0.026 for BMI >25, respectively). The IL28B SNP was extracted as a significant factor for the occurrence of HCC. Conclusions: Maintenance therapy with the use of long-term low-dose PEG-IFNα-2a is effective for preventing HCC occurrence irrespective of the IL28B SNP, at least for a subset of CHC patients. The initial response of serum ALT levels and BMI provides a prognostic value for determining the risk of developing HCC later in life.
How to Improve Treatment Outcomes for Hepatocellular Carcinoma of Intermediate and Advanced Stage
Authors: Kim Do Young , Han Kwang-Hyub
Published: December 2012

Hepatocellular carcinoma (HCC) consists of heterogeneous tumors regarding morphology, biology, and underlying liver function. In intermediate stage HCC, a high rate of recurrence and unsatisfactory treatment outcome after transarterial chemoembolization (TACE) are usually due to a large size and high number of tumors. TACE using drug-eluting beads has an advantage of a higher concentration of chemotherapeutic agent in the tumor. It might be applied to the patients with advanced diseases such as bilobar or recurrent HCC, and poor liver function. Blocking angiogenic stimuli after TACE would be a rational approach and radioembolization with 90Y is a novel interventional modality for intermediate stage HCC. The modest anti-cancer effect of sorafenib coupled with an adverse event is a hurdle to overcome in advanced HCC. External radiotherapy has achieved promising results in HCC with portal vein invasion. The role of internal radiation therapy with 90Y is not yet clear in advanced HCC. The safety and efficacy of hepatic arterial infusion chemotherapy have been reported in several studies. However, as in external radiotherapy, a well-designed randomized result is lacking. An appropriate combination strategy based on baseline patient and tumor characteristics may increase the survival of patients with intermediate or advanced HCC.
Assessment of Hepatic Function with Gd-EOB-DTPA-Enhanced Hepatic MRI
Authors: Bae Kyung Eun , Kim So Yeon , Lee Seung Soo , Kim Kyoung Won , Won Hyung Jin , Shin Yong Moon , Kim Pyo Nyun , Lee Moon-Gyu
Published: December 2012

Assessment of hepatic function is essential in determining the prognosis and clinical management of a patient who has chronic liver disease or undergoes liver surgery. For a patient with locally varying hepatic parenchymal abnormalities, a regional assessment of hepatic function mapped onto hepatic anatomy is clinically more meaningful than conventional global metrics of hepatic function. Of late, hepatic magnetic resonance imaging has been increasingly used because of its superb tissue contrast and delineation of hepatic morphology and underlying abnormalities. The introduction of hepatocyte-specific contrast agents such as Gd-EOB-DTPA allows us to view not only the hepatic anatomy but also assess regional hepatic function. In this article, we review and discuss recently published studies that used Gd-EOB-DTPA-enhanced magnetic resonance imaging to evaluate hepatic function.
Vaginoplasty Using Acellular Porcine Small Intestinal Submucosa Graft in Two Patients with Meyer-von-Rokitansky-Küster-Hauser Syndrome: A Prospective New Technique for Vaginal Reconstruction
Authors: Ding Jing-Xin , Zhang Xu-yin , Chen Li-mei , Hua Ke-Qin
Published: December 2012

The objective of this case study is to present our experience of a surgical approach for vaginal agenesis using an acellular porcine small intestinal submucosa (SIS) graft. The present report involved 2 patients diagnosed as having vaginal agenesis due to Meyer-von-Rokitansky-Küster-Hauser syndrome. The operation procedure involved the creation of a neovaginal tunnel and then a mold wrapped with the SIS graft was placed in the neovagina. The duration of surgery was less than 45 min with minimal blood loss and no operative and postoperative complications. Epithelialization of the neovagina was achieved within 2 months after surgery. The neovagina created with this procedure was the same as that of a normal adult vagina histologically and physiologically. In conclusion, the creation of a neovagina using a SIS graft resulted in a favorable outcome and this approach may be a potential alternative to the management of vaginal agenesis.
Analysis of Differentiation Potentials and Gene Expression Profiles of Mesenchymal Stem Cells Derived from Periodontal Ligament and Wharton’s Jelly of the Umbilical Cord
Authors: Yu Shi , Long Jie , Yu Jinhua , Du Juan , Ma Ping , Ma Yushi , Yang Dongmei , Fan Zhipeng
Published: December 2012

PDLSC-mediated periodontal tissue regeneration is considered a promising method for periodontitis treatment, but the supply of PDLSCs is limited. As a potential alternative, WJCMSCs are readily available; however, there is a lack of evidence proving that WJCMSCs are suitable for periodontal tissue regeneration. In this study, we investigated the characteristics of WJCMSCs and PDLSCs. We found the osteo-/dentinogenic, adipogenic and chondrogenic differentiation potentials of PDLSCs were more powerful than those of WJCMSCs. Microarray analysis discovered that 903 genes were significantly down-regulated and 726 genes up-regulated in WJCMSCs compared with PDLSCs. Based on the microarray data, we found that several genes may be associated with MSCs characteristics. Further bioinformatic analysis identified that TGF-β and WNT signaling pathways, and several genes, including STAT5B and ITGA4, may play key roles in MSCs. Our results indicate that the differentiation potentials of WJCMSCs are far less than those of PDLSCs, and that unmodified WJCMSCs may not be good seeding cells for periodontal tissue regeneration. Our results also help to elucidate the differentiation mechanisms in MSCs and to find the key factors to prompt WJCMSC-mediated periodontal tissue regeneration.
Reconstruction of Pharyngeal Defects with a Submental Island Flap after Hypopharyngeal Carcinoma Ablation
Authors: Wang Wen-Hung , Hwang Tzer-Zen , Chang Chia-Hao , Lin Yen-Chun
Published: December 2012

Purpose: This study aimed to evaluate the oncologic and functional results of pharyngeal defect reconstruction using a submental island flap in hypopharyngeal cancer patients. Methods: Functional and oncologic results were assessed in 14 patients based on a retrospective chart review. Speech function grading was as follows: 1 = excellent (>70% intelligibility); 2 = good (40–70% intelligibility), and 3 = poor (<40% intelligibility). Swallowing function score was stratified as 1 = full diet (excellent), 2 = soft diet (excellent-good), 3 = liquid diet (good), 4 = combined oral and gastric tube (good-poor), and 5 = gastric tube-dependent (poor). Results: All flaps survived well. Salivary fistula with infection was found in 1 patient and treated conservatively. The mean length of hospitalization, and speech and swallowing scores according to laryngeal invasion in 11 patients after partial pharyngectomy were 21.63 ± 4.31 versus 11 ± 2.00 (p = 0.003), 2.38 ± 0.5 versus 1.67 ± 1.16 (p = 0.18) and 3.88 ± 0.84 versus 3.33 ± 1.53 (p = 0.46), respectively. Speech and swallowing returned to good-excellent in 63.6% and good in 45.5% of patients after surgery. Conclusions: The submental island flap is reliable for reconstructing laryngopharyngeal defects after ablation of hypopharyngeal cancer. Speech and swallowing are restored to good function in half of the patients. Laryngeal involvement of the cancer is predictive of longer hospitalization.