bluuebunny/crossref_metadata_2025 huggingface dataset:
GAZI and the Shock Absorber Market in Thailand
Authors: Koojaroenpaisan Rawiporn , Patterson Paul
Published: February 2014

Siam Suspension Innovation Co. Ltd. (SSI) in 2004 manufactured the first local brand of shock absorber for motor cycles (GAZI brand) in Thailand. This case documents how several entrepreneurs with a passion for motorcycles grasped an opportunity to invent, manufacture and successfully brand a decorative shock absorber for the ubiquitous motorcycle riders of Thailand. Prior to the development of the GAZI brand, shock absorbers were simply just another OEM (original equipment manufacturer) component on a motor bike that was typically only replaced when it was worn out. Shock absorbers were differentiated on their performance characteristics of smoothness of ride. Siam Suspension Company (SSI) changed all that with their decorative GAZI brand that had a mass appeal to consumers under 25 years who possessed a 125–150cc motorcycle (by far the largest segment) who simply wanted their motorcycles to look attractive.

Rather than compete in the high volume, low margin standard shock absorber segment, SSI positioned GAZI as a decorative shock absorber. However, because GAZI used a new innovative gas filled technology (all other brands used oil filled cylinders) it also gave a much smoother ride on the rough roads of Thailand. GAZI's management initially created a “first-mover” advantage by targeting Gen Y consumers and convincing them to use shock absorbers to decorate their motorcycles. Hence a replacement market was born for decorative shock absorbers, with many riders replacing the OEM shocks as soon as they purchased a new motorcycle. Sales grew at a rapid pace until other manufacturers of standard shocks saw the success of GAZI. At this time the barriers to entry were quite low. As a SME (small to medium size enterprise) with limited capital, the challenge for SSI in 2012 is how to regroup and stay one step ahead of the competition and protect its market share from further erosion.
Talent Management at Tenaga Nasional Berhad
Authors: Othman Rozhan , Sumardi Wardah Azimah
Published: February 2014

This case describes the talent management practice of Tenaga Nasional Berhad (TNB). It describes how the company selects and develops future leaders to ensure a smooth succession for important positions. This is done through the creation of a talent pool consisting of high performance-high potential managers. Members of the talent pool are groomed for succession to key leadership positions at the corporate level and critical positions at the divisional level. Selection for TNB's talent pool is open for managers and engineers who have served at least 8 years in the company. Members of the talent pool undergo a systematic and rigorous program of talent development. This includes the Accelerated Development Program for preparing managers for succession to the C suite positions (i.e., positions at the Vice President and Chief Financial Officer, Chief Information Officer and Chief Procurement Officer). The PROSEM and PROGEM are talent development programs for those nominated for the Senior Manager and General Manager positions. The techniques and methodology used for this implementation of the talent management process in Tenaga Nasional are described.
Bajaj Auto Limited: Synergizing Product Engineering and Market Engineering Initiatives
Authors: Mishra Manit , Sahoo S. C.
Published: February 2014

The case chronicles the rise-fall-rise saga of the Indian two-wheeler major Bajaj Auto Limited from the perspective of product engineering and market engineering initiatives. The Indian two-wheeler industry went through a metamorphosis over the last two decades as consumer preference shifted from inconspicuous scooter to elegant motorcycle. Even as Bajaj implemented product and market engineering initiatives to satisfy changing consumer tastes, its market share was not a reflection of its efforts until it integrated these two vital domains. The case elucidates upon the decision situations encountered by the top management of Bajaj in its quest to attain consumer centricity through synergistic assimilation of product engineering skills and market engineering acumen.

The case is divided into eight sections. The introduction section traces the history of Indian two-wheeler industry from the product and market engineering perspective and elucidates upon the challenge of creating a customer-centred company through synergistic assimilation of both these vital domains. The second section offers a view of the present two-wheeler industry landscape; critically evaluates the consumer value system to reveal the different benefit-based customer segments; and, documents the shifting loyalty of Indian consumers from archaic scooters to aesthetic motorcycles. The third section maps the industry in terms of price and engine capacity so as to sketch out the competitive scenario. The fourth section highlights the trials and tribulations that the organization has undergone on its way to learning the ropes towards better integration of product engineering and market engineering initiatives.

The fifth section provides a description of the various product innovation measures taken by Bajaj in the decade gone by to win back its lost glory. The sixth section delineates Bajaj's endeavour in the last decade to harness latent consumer needs, wants and desires to its advantage. The section on competitors' product and market engineering strategies puts into perspective the product engineering and market engineering strategies of Bajaj's key competitors — Hero Honda and TVS. The case culminates with the conclusion section wherein the authors have discussed how the synergy achieved between the product engineering and market engineering initiatives in the last decade has catapulted Bajaj back into reckoning as a proactive player in the Indian two-wheeler industry.
FamilyMart: Responses to Competitive Rivalry in the Convenience Store Market in Taiwan
Authors: Chiao Yu-Ching , Cheng Keng-Hsiang , Hsu Shu-Mei
Published: February 2014

At the end of April 2005, the 7-Eleven Corporation, with 6 months preparation, invested around $200 million N.T. dollars (NTD) ($6.35 million USD) to implement an innovative and integrated instore marketing campaign by rewarding customers with an exquisite 3D Hello Kitty magnet and coupons for 118 commodity items when they spent as much as $77 NTD ($2.44 USD). This distinguishing competitive action gained much feedback in the market. In less than 1 month, 7-Eleven had distributed 40 million Hello Kitty magnets to customers. Further, 7-Eleven forecasted that its revenue in May would reach its highest peak in recent years. In contrast, other convenience store chains had faced a 20% decline in estimated returns. Considering these challenges, how can one analyze the competitive environment in convenience store industry faced by the FamilyMart? How should FamilyMart react to 7-Eleven's promotion?
John Adams and CERN: Personal Recollections
Authors: Brianti G. , Plane D. E.
Published: February 2014

By any standards, John Adams had a most remarkable career. He was involved in three important, emerging technologies, radar, particle accelerators and controlled fusion, and had an outstanding impact on the last two. Without a university education, he attained hierarchical positions of the highest level in prestigious national and international organizations. This article covers the CERN part of his career, by offering some personal insights into the different facets of his contributions to major accelerator projects, from the first strong-focusing synchrotron, the PS, to the SPS and its conversion to a proton–antiproton collider. In particular, it outlines his abilities as a leader of an international collaboration, which has served as an example for international initiatives in other disciplines.
Inhibition of Gαiactivity by Gβγ is mediated by PI 3-kinase-γ- and cSrc-dependent tyrosine phosphorylation of Gαiand recruitment of RGS12
Authors: Huang Jiean , Nalli Ancy D. , Mahavadi Sunila , Kumar Divya P. , Murthy Karnam S.
Published: February 2014

Others and we have characterized several Gβγ-dependent effectors in smooth muscle, including G protein-coupled receptor kinase 2 (GRK2), PLCβ3, and phosphatidylinositol (PI) 3-kinase-γ, and have identified various signaling targets downstream of PI 3-kinase-γ, including cSrc, integrin-linked kinase, and Rac1-Cdc42/p21-activated kinase/p38 MAP kinase. This study identified a novel mechanism whereby Gβγ acting via PI 3-kinase-γ and cSrc exerts an inhibitory influence on Gαiactivity. The Gi2-coupled δ-opioid receptor agonist d-penicillamine ( 2 , 5 )-enkephalin (DPDPE) activated cSrc, stimulated tyrosine phosphorylation of Gαi2, and induced regulator of G protein signaling 12 (RGS12) association; all three events were blocked by PI 3-kinase (LY294002) and cSrc (PP2) inhibitors and by expression of the COOH-terminal sequence of GRK2-(495–689), a Gβγ-scavenging peptide. Inhibition of forskolin-stimulated cAMP and muscle relaxation by DPDPE was augmented by PP2, LY294002 , and a selective PI 3-kinase-γ inhibitor, AS-605420. Expression of tyrosine-deficient (Y69F, Y231F, or Y321F) Gαi2mutant or knockdown of RGS12 blocked Gαi2phosphorylation and Gαi2-RGS12 association and caused greater inhibition of cAMP. Parallel studies using somatostatin, cyclopentyl adenosine, or ACh to activate, respectively, Gi1-coupled somatostatin (sstr3) receptors, and Gi3-coupled adenosine A1or muscarinic m2receptors elicited cSrc activation, Gαi1or Gαi3phosphorylation, Gαi1-RGS12 or Gαi3-RGS12 association, and inhibition of cAMP. Inhibition of cAMP and muscle relaxation was greatly increased by AS-605240 and PP2. The results demonstrate that Gβγ-dependent tyrosine phosphorylation of Gαi1/2/3by cSrc facilitated recruitment of RGS12, a Gαi-specific RGS protein with a unique phosphotyrosine-binding domain, resulting in rapid deactivation of Gαiand facilitation of smooth muscle relaxation.
Estradiol, but not testosterone, heightens cortisol-mediated negative feedback on pulsatile ACTH secretion and ACTH approximate entropy in unstressed older men and women
Authors: Sharma Animesh N. , Aoun Paul , Wigham Jean R. , Weist Suanne M. , Veldhuis Johannes D.
Published: February 2014

How sex steroids modulate glucocorticoid feedback on the hypothalamic-pituitary-corticotrope (HPC) unit is controversial in humans. We postulated that testosterone (T) in men and estradiol (E2) in women govern unstressed cortisol-mediated negative feedback on ACTH secretion. To test this hypothesis, 24 men and 24 women age 58 ± 2.4 yr were pretreated with leuprolide and either sex steroid (E2 in women, T in men) or placebo addback. Placebo or ketoconazole (KTCZ) was administered overnight to inhibit adrenal steroidogenesis during overnight 14-h intravenous infusions of saline or cortisol in a continuous versus pulsatile manner to test for feedback differences. ACTH was measured every 10 min during the last 8 h of the infusions. The main outcome measures were mean ACTH concentrations, pulsatile ACTH secretion, and ACTH approximate entropy (ApEn). ACTH concentrations were lower in women than men ( P < 0.01), and in women in the E2+ compared with E2− group under both continuous ( P = 0.01) and pulsatile ( P = 0.006) cortisol feedback, despite higher cortisol binding globulin and lower free cortisol levels in women than men ( P < 0.01). In the combined groups, under both modes of cortisol addback, ACTH concentrations, pulsatile ACTH secretion, and ACTH secretory-burst mass correlated negatively and univariately with E2 levels (each P < 0.005). E2 also suppressed ACTH ApEn (process randomness) during continuous cortisol feedback ( P = 0.004). T had no univariate effect but was a positive correlate of ACTH when assessed jointly with E2 (negative) under cortisol pulses. In conclusion, sex steroids modulate selective gender-related hypothalamic-pituitary adrenal-axis adaptations to cortisol feedback in unstressed humans.
Activation of ERK1/2 by NADPH oxidase-originated reactive oxygen species mediates uric acid-induced mesangial cell proliferation
Authors: Zhuang Yibo , Feng Quancheng , Ding Guixia , Zhao Min , Che Ruochen , Bai Mi , Bao Huaying , Zhang Aihua , Huang Songming
Published: February 2014

Hyperuricemia is associated with kidney complications including glomerulosclerosis and mesangial cell (MC) proliferation by poorly understood mechanisms. The present study investigated the underlying mechanisms that mediate uric acid (UA)-induced MC proliferation. A rat MC line, HBZY-1, was treated with various concentrations of UA in the presence or absence of a specific extracellular-regulated protein kinase 1/2 (ERK1/2) inhibitor (U0126), apocynin. UA dose dependently stimulated MC proliferation as shown by increased DNA synthesis and number of cells in the S and G2 phases in parallel with the upregulation of cyclin A2 and cyclin D1. In addition, UA time dependently promoted MC proliferation and significantly increased phosphorylation of ERK1/2 but not c-Jun NH2-terminal kinase and p38 MAPK in MCs as assessed by immunoblotting. Inhibition of ERK1/2 signaling via U0126 markedly blocked UA-induced MC proliferation. More importantly, UA induced intracellular reactive oxygen species (ROS) production of MCs dose dependently, which was completely blocked by apocynin, a specific NADPH oxidase inhibitor. Toll-like receptor (TLR)2 and TLR4 signaling had no effect on NADPH-derived ROS and UA-induced MC proliferation. Interestingly, pretreatment with apocynin inhibited ERK1/2 activation, the upregulation of cyclin A2 and cyclin D1, and MC proliferation. In conclusion, UA-induced MC proliferation was mediated by NADPH/ROS/ERK1/2 signaling pathway. This novel finding not only reveals the mechanism of UA-induced MC cell proliferation but also provides some potential targets for future treatment of UA-related glomerular injury.
Persistence of 1,25D-induced hypercalciuria in alendronate-treated genetic hypercalciuric stone-forming rats fed a low-calcium diet
Authors: Frick Kevin K. , Asplin John R. , Culbertson Christopher D. , Granja Ignacio , Krieger Nancy S. , Bushinsky David A.
Published: February 2014

Genetic hypercalciuric stone-forming (GHS) rats demonstrate increased intestinal Ca absorption, increased bone resorption, and reduced renal tubular Ca reabsorption leading to hypercalciuria and all form kidney stones. GHS have increased vitamin D receptors (VDR) at these sites of Ca transport. Injection of 1,25(OH)2D3(1,25D) leads to a greater increase in urine (u)Ca in GHS than in control Sprague-Dawley (SD), possibly due to the additional VDR. In GHS the increased uCa persists on a low-Ca diet (LCD) suggesting enhanced bone resorption. We tested the hypothesis that LCD, coupled to inhibition of bone resorption by alendronate (alen), would eliminate the enhanced 1,25D-induced hypercalciuria in GHS. SD and GHS were fed LCD and half were injected daily with 1,25D. After 8 days all were also given alen until euthanasia at day 16. At 8 days, 1,25D increased uCa in SD and to a greater extent in GHS. At 16 days, alen eliminated the 1,25D-induced increase in uCa in SD. However, in GHS alen decreased, but did not eliminate, the 1,25D-induced hypercalciuria, suggesting maximal alen cannot completely prevent the 1,25D-induced bone resorption in GHS, perhaps due to increased VDR. There was no consistent effect on mRNA expression of renal transcellular or paracellular Ca transporters. Urine CaP and CaOx supersaturation (SS) increased with 1,25D alone in both SD and GHS. Alen eliminated the increase in CaP SS in SD but not in GHS. If these results are confirmed in humans with IH, the use of bisphosphonates, such as alen, may not prevent the decreased bone density observed in these patients.
Responses of intact and injured sural nerve fibers to cooling and menthol
Authors: Teliban Alina , Bartsch Fabian , Struck Marek , Baron Ralf , Jänig Wilfrid
Published: February 2014

Intact and injured cutaneous C-fibers in the rat sural nerve are cold sensitive, heat sensitive, and/or mechanosensitive. Cold-sensitive fibers are either low-threshold type 1 cold sensitive or high-threshold type 2 cold sensitive. The hypothesis was tested, in intact and injured afferent nerve fibers, that low-threshold cold-sensitive afferent nerve fibers are activated by the transient receptor potential melastatin 8 (TRPM8) agonist menthol, whereas high-threshold cold-sensitive C-fibers and cold-insensitive afferent nerve fibers are menthol insensitive. In anesthetized rats, activity was recorded from afferent nerve fibers in strands isolated from the sural nerve, which was either intact or crushed 6–12 days before the experiment distal to the recording site. In all, 77 functionally identified afferent C-fibers (30 intact fibers, 47 injured fibers) and 34 functionally characterized A-fibers (11 intact fibers, 23 injured fibers) were tested for their responses to menthol applied to their receptive fields either in the skin (10 or 20%) or in the nerve (4 or 8 mM). Menthol activated all intact ( n = 12) and 90% of injured ( n = 20/22) type 1 cold-sensitive C-fibers; it activated no intact type 2 cold-sensitive C-fibers ( n = 7) and 1/11 injured type 2 cold-sensitive C-fibers. Neither intact nor injured heat- and/or mechanosensitive cold-insensitive C-fibers ( n = 25) and almost no A-fibers ( n = 2/34) were activated by menthol. These results strongly argue that cutaneous type 1 cold-sensitive afferent fibers are nonnociceptive cold fibers that use the TRPM8 transduction channel.
Dopamine neurons coding prediction errors in reward space, but not in aversive space: a matter of location?
Authors: Morrens Joachim
Published: February 2014

Dopamine midbrain neurons are well known for prediction error coding in a reward context. A recent report by Christopher Fiorillo ( Science 341: 546–549, 2013), however, suggests that these neurons behave markedly different when subjects get confronted with aversive, rather than appetitive, stimuli. Despite his findings being in line with indications of appetitive and aversive stimuli being processed by distinct neurotransmitter systems, they should still be interpreted with some caution due to a potential issue of recording location.
Prestimulus frontal-parietal coherence predicts auditory detection performance in rats
Authors: Herzog Linnea , Salehi Kia , Bohon Kaitlin S. , Wiest Michael C.
Published: February 2014

Electrophysiology in primates has implicated long-range neural coherence as a potential mechanism for enhancing sensory detection. To test whether local synchronization and long-range neural coherence support detection performance in rats, we recorded local field potentials (LFPs) in frontal and parietal cortex while rats performed an auditory detection task. We observed significantly elevated power at multiple low frequencies (<15 Hz) preceding the target beep when the animal failed to respond to the signal (misses), in both frontal and parietal cortex. In terms of long-range coherence, we observed significantly more frontal-parietal coherence in the beta band (15–30 Hz) before the signal on misses compared with hits. This effect persisted after regressing away linear trends in the coherence values during a session, showing that the excess frontal-parietal beta coherence prior to misses cannot be explained by slow motivational changes during a session. In addition, a trend toward higher low-frequency (<15 Hz) coherence prior to miss trials compared with hits became highly significant when we rereferenced the LFPs to the mean voltage on each recording array, suggesting that the results are specific to our frontal and parietal areas. These results do not support a role for long-range frontal-parietal coherence or local synchronization in facilitating the detection of external stimuli. Rather, they extend to long-range frontal-parietal coherence previous findings that correlate local synchronization of low-frequency (<15 Hz) oscillations with inattention to external stimuli and synchronization of beta rhythms (15–30 Hz) with voluntary or involuntary prolongation of the current cognitive or motor state.
Effects of ethanol on glycinergic synaptic currents in mouse spinal cord neurons
Authors: Mariqueo Trinidad A. , Agurto Adolfo , Muñoz Braulio , San Martin Loreto , Coronado Cesar , Fernández-Pérez Eduardo J. , Murath Pablo , Sánchez Andrea , Homanics Gregg E. , Aguayo Luis G.
Published: February 2014

Ethanol increased the frequency of miniature glycinergic currents [miniature inhibitory postsynaptic currents (mIPSCs)] in cultured spinal neurons. This effect was dependent on intracellular calcium augmentation, since preincubation with BAPTA (an intracellular calcium chelator) or thapsigargin [a sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor] significantly attenuated this effect. Similarly, U73122 (a phospholipase C inhibitor) or 2-aminoethoxydiphenyl borate [2-APB, an inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) inhibitor] reduced this effect. Block of ethanol action was also achieved after preincubation with Rp-cAMPS, inhibitor of the adenylate cyclase (AC)/PKA signaling pathway. These data suggest that there is a convergence at the level of IP3R that accounts for presynaptic ethanol effects. At the postsynaptic level, ethanol increased the decay time constant of mIPSCs in a group of neurons (30 ± 10% above control, n = 13/26 cells). On the other hand, the currents activated by exogenously applied glycine were consistently potentiated (55 ± 10% above control, n = 11/12 cells), which suggests that ethanol modulates synaptic and nonsynaptic glycine receptors (GlyRs) in a different fashion. Supporting the role of G protein modulation on ethanol responses, we found that a nonhydrolyzable GTP analog [guanosine 5′- O-(3-thiotriphosphate) (GTPγS)] increased the decay time constant in ∼50% of the neurons (28 ± 12%, n = 11/19 cells) but potentiated the glycine-activated Cl− current in most of the neurons examined (83 ± 29%, n = 7/9 cells). In addition, confocal microscopy showed that α1-containing GlyRs colocalized with Gβ and Piccolo (a presynaptic cytomatrix protein) in ∼40% of synaptic receptor clusters, suggesting that colocalization of Gβγ and GlyRs might account for the difference in ethanol sensitivity at the postsynaptic level.
Monkeys time their pauses of movement and not their movement-kinematics during a synchronization-continuation rhythmic task
Authors: Donnet Sophie , Bartolo Ramon , Fernandes José Maria , Cunha João Paulo Silva , Prado Luis , Merchant Hugo
Published: February 2014

A critical question in tapping behavior is to understand whether the temporal control is exerted on the duration and trajectory of the downward-upward hand movement or on the pause between hand movements. In the present study, we determined the duration of both the movement execution and pauses of monkeys performing a synchronization-continuation task (SCT), using the speed profile of their tapping behavior. We found a linear increase in the variance of pause-duration as a function of interval, while the variance of the motor implementation was relatively constant across intervals. In fact, 96% of the variability of the duration of a complete tapping cycle (pause + movement) was due to the variability of the pause duration. In addition, we performed a Bayesian model selection to determine the effect of interval duration (450–1,000 ms), serial-order (1–6 produced intervals), task phase (sensory cued or internally driven), and marker modality (auditory or visual) on the duration of the movement-pause and tapping movement. The results showed that the most important parameter used to successfully perform the SCT was the control of the pause duration. We also found that the kinematics of the tapping movements was concordant with a stereotyped ballistic control of the hand pressing the push-button. The present findings support the idea that monkeys used an explicit timing strategy to perform the SCT, where a dedicated timing mechanism controlled the duration of the pauses of movement, while also triggered the execution of fixed movements across each interval of the rhythmic sequence.
Foxp3+ T Cells Inhibit Antitumor Immune Memory Modulated by mTOR Inhibition
Authors: Wang Yanping , Sparwasser Tim , Figlin Robert , Kim Hyung L.
Published: February 2014

Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3+ T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3+ T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients. Cancer Res; 74(8); 2217–28. ©2014 AACR.
Imaging the Norepinephrine Transporter in Neuroblastoma: A Comparison of [18F]-MFBG and 123I-MIBG
Authors: Zhang Hanwen , Huang Ruimin , Cheung Nai-Kong V. , Guo Hongfen , Zanzonico Pat B. , Thaler Howard T. , Lewis Jason S. , Blasberg Ronald G.
Published: February 2014

Purpose: The norepinephrine transporter (NET) is a critical regulator of catecholamine uptake in normal physiology and is expressed in neuroendocrine tumors like neuroblastoma. Although the norepinephrine analog, meta-iodobenzylguanidine (MIBG), is an established substrate for NET, 123I/131I-MIBG has several clinical limitations for diagnostic imaging. In the current studies, we evaluated meta-[18F]-fluorobenzylguanidine ([18F]-MFBG) and compared it with 123I-MIBG for imaging NET-expressing neuroblastomas.

Experimental Design: NET expression levels in neuroblastoma cell lines were determined by Western blot and 123I-MIBG uptake assays. Five neuroblastoma cell lines and two xenografts (SK-N-BE(2)C and LAN1) expressing different levels of NET were used for comparative in vitro and in vivo uptake studies.

Results: The uptake of [18F]-MFBG in cells was specific and proportional to the expression level of NET. Although [18F]-MFBG had a 3-fold lower affinity for NET and an approximately 2-fold lower cell uptake in vitro compared with that of 123I-MIBG, the in vivo imaging and tissue radioactivity concentration measurements demonstrated higher [18F]-MFBG xenograft uptake and tumor-to-normal organ ratios at 1 and 4 hours after injection. A comparison of 4 hours [18F]-MFBG PET (positron emission tomography) imaging with 24 hours 123I-MIBG SPECT (single-photon emission computed tomography) imaging showed an approximately 3-fold higher tumor uptake of [18F]-MFBG, but slightly lower tumor-to-background ratios in mice.

Conclusions: [18F]-MFBG is a promising radiopharmaceutical for specifically imaging NET-expressing neuroblastomas, with fast pharmacokinetics and whole-body clearance. [18F]-MFBG PET imaging shows higher sensitivity, better detection of small lesions with low NET expression, allows same day scintigraphy with a shorter image acquisition time, and has the potential for lower patient radiation exposure compared with 131I/123I-MIBG. Clin Cancer Res; 20(8); 2182–91. ©2014 AACR.
U.S. Food and Drug Administration Approval: Crizotinib for Treatment of Advanced or Metastatic Non–Small Cell Lung Cancer That Is Anaplastic Lymphoma Kinase Positive
Authors: Malik Shakun M. , Maher Virginia Ellen , Bijwaard Karen E. , Becker Robert L. , Zhang Lijun , Tang Shenghui W. , Song Pengfei , Liu Qi , Marathe Anshu , Gehrke Brenda , Helms Whitney , Hanner Diane , Justice Robert , Pazdur Richard
Published: February 2014

On August 26, 2011, the U.S. Food and Drug Administration (FDA) approved crizotinib (XALKORI Capsules, Pfizer Inc.) for treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as detected by an FDA-approved test. The Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) was approved concurrently. In two multicenter, single-arm trials, patients with locally advanced or metastatic ALK-positive NSCLC previously treated with one or more systemic therapies received crizotinib orally at a dose of 250 mg twice daily. In 119 patients with ALK-positive NSCLC by local trial assay, the objective response rate (ORR) was 61% [95% confidence intervals (CI), 52%–70%] with a median response duration of 48 weeks. In 136 patients with ALK-positive NSCLC by the to-be-marketed test, the ORR was 50% (95% CI, 42%–59%) with a median response duration of 42 weeks. The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Accelerated approval was granted on the basis of the high ORRs and durable responses. On November 20, 2013, crizotinib received full approval based on an improvement in progression-free survival in patients with metastatic ALK-positive NSCLC previously treated with one platinum-based chemotherapy regimen. Clin Cancer Res; 20(8); 2029–34. ©2014 AACR.
Ultra Low-Dose IL-2 for GVHD Prophylaxis after Allogeneic Hematopoietic Stem Cell Transplantation Mediates Expansion of Regulatory T Cells without Diminishing Antiviral and Antileukemic Activity
Authors: Kennedy-Nasser Alana A. , Ku Stephanie , Castillo-Caro Paul , Hazrat Yasmin , Wu Meng-Fen , Liu Hao , Melenhorst Jos , Barrett A. John , Ito Sawa , Foster Aaron , Savoldo Barbara , Yvon Eric , Carrum George , Ramos Carlos A. , Krance Robert A. , Leung Kathryn , Heslop Helen E. , Brenner Malcolm K. , Bollard Catherine M.
Published: February 2014

Purpose: GVHD after allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with low numbers of circulating CD4+CD25+FoxP3+ regulatory T cells (Tregs). Because Tregs express high levels of the interleukin (IL)-2 receptor, they may selectively expand in vivo in response to doses of IL-2 insufficient to stimulate T effector T-cell populations, thereby preventing GVHD.

Experimental Design: We prospectively evaluated the effects of ultra low-dose (ULD) IL-2 injections on Treg recovery in pediatric patients after alloSCT and compared this recovery with Treg reconstitution post alloSCT in patients without IL-2. Sixteen recipients of related (n = 12) or unrelated (n = 4) donor grafts received ULD IL-2 post hematopoietic stem cell transplantation (HSCT; 100,000–200,000 IU/m2 ×3 per week), starting <day 30 and continuing for 6 to 12 weeks.

Results: No grade 3/4 toxicities were associated with ULD IL-2. CD4+CD25+FoxP3+ Tregs increased from a mean of 4.8% (range, 0%–11.0%) pre IL-2 to 11.1% (range, 1.2%–31.1%) following therapy, with the greatest change occurring in the recipients of matched related donor (MRD) transplants. No IL-2 patients developed grade 2–4 acute GVHD (aGVHD), compared with 4 of 33 (12%) of the comparator group who did not receive IL-2. IL-2 recipients retained T cells reactive to viral and leukemia antigens, and in the MRD recipients, only 2 of 13 (15%) of the IL-2 patients developed viral infections versus 63% of the comparator group (P = 0.022).

Conclusions: Hence, ULD IL-2 is well tolerated, expands a Treg population in vivo, and may be associated with a lower incidence of viral infections and GVHD. Clin Cancer Res; 20(8); 2215–25. ©2014 AACR.
Early Results of Endoscopic Treatment of Vesicoureteral Reflux with Polyacrylate Polyalcohol Copolymer
Authors: Şencan Arzu , Uçan Başak , Evciler Hüseyin , Serdaroğlu Erkin , Hoşgör Münevver
Published: February 2014

Objective: To evaluate the early results of endoscopic treatment of vesicoureteral reflux (VUR) in children using polyacrylate polyalcohol copolymer (PPC). Patients and Methods: We retrospectively reviewed 45 patients treated with subureteric injection of PPC in our clinic. The results of voiding cystouretrography performed on the 3rd postoperative month and the results of 1-year follow-up were evaluated. Results: A total of 45 patients (57 ureters) underwent injection of PPC. The mean age of the patients was 6.5 years. There were 6 (10.5%) grade 1, 7 (12.2%) grade 2, 26 (45.6%) grade 3, 16 (28%) grade 4, and 2 (3.5%) grade 5 VUR. There were 11 overactive bladders, 2 duplex collecting systems, and 4 posterior urethral valves among the patients. Voiding cystouretrography postoperatively at the 3rd month showed that VUR had disappeared in 82.5% (47/57) of the ureters, downgraded to grade 2 and 3 in 7% (4/57), persisted in 5.2% (3/57) and upgraded in 5.2% (3/57). The success rate at the end of the first year was 98.1%. The procedure was free of complications such as fever, dysuria, lumbar pain or obstruction in all patients. No patient showed VUR recurrence at the end of the first year. Conclusions: The short-term results of our patients suggested that PPC can be safely and successfully used in the endoscopic treatment of VUR in children. However, further prospective, controlled trials showing the long-term results of the patients are needed.
Fosfomycin Trometamol (3,000 mg) in Perioperative Antibiotic Prophylaxis of Healthcare-Associated Infections after Endourological Interventions: A Narrative Review
Authors: Wagenlehner Florian M.E. , Thomas Petra M. , Naber Kurt G.
Published: February 2014

Introduction: Increasing antibiotic resistance also has an impact on perioperative antibiotic prophylaxis (PAP). This narrative review evaluates fosfomycin trometamol (FT) as PAP in endourological interventions. Materials and Methods: Nine clinical studies including 4 randomized comparative studies were analyzed. A total of 1,614 patients received FT as PAP for different endourological procedures and extracorporeal shock wave lithotripsy [ESWL; i.e. cystoscopy (n = 498), urodynamic studies (n = 39), ureteropyeloscopy (n = 10), urethrotomy (n = 20), lithotripsy (n = 15), transurethral resection of bladder tumors (n = 139), transurethral resection of the prostate (n = 843), ESWL (n = 20), ureterorenoendoscopic lithotripsy (n = 18), percutaneous nephrostomic lithotripsy (n = 12)]. Results: In 8 clinical studies, FT was shown to be effective in preventing healthcare-associated urinary tract infections (HAUTIs). One study showed no benefit. The usual dosage regimen was oral administration of 3 g of FT 3 h before and 24 h after the procedure. In 1 randomized comparative study investigating HAUTIs after diagnostic cystoscopy, it could also be shown that a single oral dose of 3 g of FT 3 h before cystoscopy was as effective as a double dose. Conclusion: According to the published results, for traumatic endourological interventions and surgical procedures, an oral dosage of 3 g of FT 3 h before and 24 h after the procedure and only 1 (prior) oral dosage for diagnostic procedures might be an alternative if PAP is indicated. Limitations of the studies are the low numbers of patients included for most indications.
Prognostic Role of Maternal Neutrophil Gelatinase-Associated Lipocalin in Women with Severe Early-Onset Preeclampsia
Authors: Scazzochio Elena , Munmany Meritxell , Garcia Laura , Meler Eva , Crispi Fatima , Gratacos Eduard , Figueras Francesc
Published: February 2014

Introduction: The association between maternal plasma levels of neutrophil gelatinase-associated lipocalin (NGAL) and maternal complications in women admitted with severe early-onset preeclampsia was evaluated. Material and Methods: Plasma levels of NGAL were measured at admission in patients with severe early-onset (presenting before 34 weeks) preeclampsia. The maternal outcome of women with elevated plasma levels was compared with those with normal levels. Maternal complications included eclampsia, HELLP syndrome, acute renal failure, subcapsular hepatic hematoma, pulmonary edema and disseminated intravascular disease. Results: Sixty-seven patients were included. The median NGAL plasma levels in the group of women who subsequently had a complication were significantly higher than in those uncomplicated cases (114.8 vs. 84.2 ng/ml; Mann-Whitney U test p = 0.03). Maternal complications were more common in the elevated (>100 ng/ml) NGAL group (58.3 vs. 25.6%; χ2 test p = 0.008), with an OR of 4.1 (95% CI 1.4-11.8). After adjustment by gestational age at onset, the association between elevated NGAL plasma levels and maternal complications remained significant (OR 4.2; 95% CI 1.4-12.4). Discussion: Women with severe early-onset preeclampsia are at higher risk of maternal complications if plasma levels of NGAL are elevated.
Metastatic Hepatic Epithelioid Hemangio-Endothelioma: Long-Term Response to Sunitinib Malate
Authors: Saada Esma , Saint Paul Marie-Christine , Gugenheim Jean , Follana Philippe , François Eric
Published: February 2014

Background: Epithelioid hemangio-endothelioma (EHE) is a rare malignant tumor of vascular origin that electively metastasizes to lungs and liver. Case report: We report the case of a 51-year-old woman with metastatic and progressive EHE of the liver. She was successfully treated with daily administration of sunitinib malate, an oral multi-target tyrosine kinase inhibitor, which particularly targets vascular endothelial growth factor (VEGF) receptors. Stabilization has lasted 6 years. We discuss the rationale for using antiangiogenic treatment for EHE. Conclusion: This case adds to a growing body of evidence that suggests that antiangiogenic agents should be considered in patients who present with advanced EHE.
The various states of von Willebrand factor and their function in physiology and pathophysiology
Authors: Huck Volker , Gorzelanny Christian , Schneider Matthias F. , Schneider Stefan W.
Published: February 2014

The specific interactions of von Willebrand factor (VWF) with the vessel wall, platelets or other interfaces strongly depend on (a shearinduced) VWF activation. Shear flow has been shown to induce a conformational transition of VWF, but is modulated by its thermodynamic state (state-function relationship). The state in turn is determined by physical (e.g. vessel geometry), physico-chemical (e.g. pH) and molecular-biological (e.g. mutants, binding) factors. Combining established results with recent insights, we reconstruct VWF biology and its statefunction relationship from endothelial cell release to final degradation in the human vasculature. After VWF secretion, endothelial-anchored and shear activated VWF multimers can rapidly interact with surrounding colloids, typically with platelets. Simultaneously, this VWF activation enables ADAMTS13 to cleave VWF multimers thereby limiting VWF binding capacity. The subsequent cell-surface dissociation leads to a VWF recoiling to a globular conformation, shielding from further degradation by ADAMTS13. High local concentrations of these soluble VWF multimers, transported to the downstream vasculature, are capable for an immediate reactivation and re-polymerisation initiating colloid-binding or VWF-colloid aggregation at the site of inflamed endothelium, vessel injuries or pathological high-shear areas. Focusing on these functional steps in the lifecycle of VWF, its qualitative and quantitative deficiencies in the different VWD types will facilitate more precise diagnostics and reliable risk stratification for prophylactic therapies. The underlying biophysical principles are of general character, which broadens prospective studies on the physiological and pathophysiological impact of VWF and VWF-associated diseases and beares hope for a more universal understanding of an entire class of phenomena.
New players in haemostasis and thrombosis
Authors: Geddings Julia E. , Mackman Nigel
Published: February 2014

The blood coagulation cascade is essential for haemostasis, but excessive activation can cause thrombosis. Importantly, recent studies have identified factors that contribute to thrombosis but not haemostasis. These include factor XII (FXII), tissue factor-positive microparticles (MPs) and neutrophil extracellular traps (NETs). Studies have shown that FXII plays a role in thrombosis but not haemostasis. FXII is activated in vivo by a variety of negatively-charged polyphosphates, which include extracellular RNA, DNA and inorganic polyphosphate (PolyP) that are released during cell damage and infection. These findings have led to the development of nucleic acid-binding polymers as a new class of anticoagulant drug. Other studies have analysed the role of MPs in experimental thrombosis. MPs are small membrane vesicles released from activated or apoptotic cells. We and others have found that tissue factor-positive MPs enhance thrombosis in mouse models and are elevated in the plasma of pancreatic cancer patients. Finally, NETs have been shown to contribute to experimental venous thrombosis in mouse models and are present in human thrombi. NETs are composed of chromatin fibers that are released from neutrophils undergoing cell death. NETs can capture platelets and increase fibrin deposition. The recent advances in our understanding of the factors contributing to thrombosis in animal models provide new opportunities for the development of safer anticoagulant drugs.
Adherence to lifestyle modifications after a cardiac rehabilitation program and endothelial progenitor cells
Authors: Marcucci Rossella , Gori Anna Maria , Burgisser Costanza , Francini Sara , Roberts Anna Teresa , Sofi Francesco , Gensini Gian Franco , Abbate Rosanna , Fattirolli Francesco , Cesari Francesca
Published: February 2014

An increase of endothelial progenitor cells (EPCs) among acute myo-cardial infarction (AMI) patients participating in a cardiac rehabilitation (CR) program has been reported, but no data on the impact of adherence to lifestyle recommendations provided during a CR program on EPCs are available. It was our aim to investigate the effect of adherence to lifestyle recommendations on EPCs, inflammatory and functional parameters after six months of a CR program in AMI patients. In 110 AMI patients (90 male/20 female; mean age 57.9 ± 9.4 years) EPCs, high sensitivity C-reactive protein (hsCRP), N-terminal pro-brain natriuretic peptide (NT-ProBNP) levels, and cardiopulmonary testings were determined at the end of the CR (T1) and at a six-month follow-up (T2). At T2 we administered a questionnaire assessing dietary habits and physical activity. At T2, we observed a decrease of EPCs (p<0.05), of hsCRP (p=0.009) and of NT-ProBNP (p<0.0001). Patient population was divided into three categories by Healthy Lifestyle (HL) score (none/low, moderate and high adherence to lifestyle recommendations). We observed a significant association between adherence to lifestyle recommendations, increase in EPCs and exercise capacity between T1 and T2 (Δ EPCs p for trend <0.05; ΔWatt max p for trend=0.004). In a multivariate logistic regression analyses, being in the highest tertile of HL score affected the likelihood of an increase of EPC levels at T2 [OR (95% confidence interval): 3.36 (1.0–10.72) p=0.04]. In conclusion, adherence to lifestyle recommendations provided during a CR program positively influences EPC levels and exercise capacity.
Only high levels of dabigatran attenuate catheter thrombosis in vitro and in rabbits
Authors: Yau Jonathan W. , Liao Peng , Fredenburgh James C. , Roberts Robin S. , Weitz Jeffrey I.
Published: February 2014

In patients with mechanical heart valves, thromboembolic events were more frequent with dabigatran, an oral thrombin inhibitor, than with warfarin. This observation raises the possibility that dabigatran may be less effective than conventional anticoagulants in patients with other blood-contacting devices, such as catheters. To address this, we compared the capacity of dabigatran and/or heparin to inhibit catheter-induced thrombin generation in vitro and to attenuate catheter occlusion in rabbits. Using a catheter-induced thrombin generation assay, concentrations of dabigatran over 100 ng/ml prolonged the lag time and time to peak thrombin, and reduced the peak thrombin concentration and endogenous thrombin potential in a concentration-dependent fashion. Compared with saline in a rabbit model of catheter thrombosis, dabigatran prolonged the mean time to catheter occlusion by 2.9– and 1.9-fold when plasma levels were 173 and 140 ng/ml, respectively; values comparable to median peak levels in humans given dabigatran 150 mg twice daily. In contrast, low-dose dabigatran, which produced a level of 60 ng/ml; a value comparable to the trough level of dabigatran in humans, did not prolong the time to occlusion. Whereas a 70 U/kg bolus of heparin prolonged the mean time to occlusion by 3.4-fold, a 15 U/kg bolus had no effect. When low-dose dabigatran was given in combination with 15 U/kg heparin, the mean time to occlusion was prolonged by 2.7-fold. These findings suggest that only peak levels of dabigatran are sufficient to prevent catheter-induced clotting unless supplemented heparin is given.
Brugada Syndrome Disease Phenotype Explained in Apparently Benign Sodium Channel Mutations
Authors: Hoshi Malcolm , Du Xi X. , Shinlapawittayatorn Krekwit , Liu Haiyan , Chai Sam , Wan Xiaoping , Ficker Eckhard , Deschênes Isabelle
Published: February 2014

Background—

Brugada syndrome (BrS) is an arrhythmogenic disorder that has been linked to mutations in SCN5A, the gene encoding for the pore-forming α-subunit of the cardiac sodium channel. Typically, BrS mutations in SCN5A result in a reduction of sodium current with some mutations even exhibiting a dominant-negative effect on wild-type (WT) channels, thus leading to an even more prominent decrease in current amplitudes. However, there is also a category of apparently benign (atypical) BrS SCN5A mutations that in vitro demonstrates only minor biophysical defects. It is therefore not clear how these mutations produce a BrS phenotype. We hypothesized that similar to dominant-negative mutations, atypical mutations could lead to a reduction in sodium currents when coexpressed with WT to mimic the heterozygous patient genotype.

Methods and Results—

WT and atypical BrS mutations were coexpressed in Human Embryonic Kidney-293 cells, showing a reduction in sodium current densities similar to typical BrS mutations. Importantly, this reduction in sodium current was also seen when the atypical mutations were expressed in rat or human cardiomyocytes. This decrease in current density was the result of reduced surface expression of both mutant and WT channels.

Conclusions—

Taken together, we have shown how apparently benign SCN5A BrS mutations can lead to the ECG abnormalities seen in patients with BrS through an induced defect that is only present when the mutations are coexpressed with WT channels. Our work has implications for risk management and stratification for some SCN5A-implicated BrS patients.