bluuebunny/crossref_metadata_2025 huggingface dataset:
Topical application of povidone‐iodine before wound closure is associated with significant increase in serum iodine level
Authors: Wong Randolph H.L. , Wong Vivien W.Y. , Hung Emily C.W. , Lee Ping‐Yin , Ng Calvin S.H. , Wan Innes Y.P. , Underwood Malcolm J.
Published: April 2011

Aim:  To determine serum iodine level before and after local application of povidone‐iodine before wound closure in cardiac surgery patients. Povidone‐iodine is a popular antiseptic solution that has been widely used in perioperative wound management of surgical patients. Despite its widespread usage, little is known concerning the absorption profile and potential systemic toxicity.

Methods:  We carried out a prospective study on the serum iodine level and corresponding renal function in consecutive patients operated on at our cardiac surgical unit.

Results:  There was a statistically significant increase in serum iodine level and patients with impaired renal function defined by creatinine level showed significantly higher postoperative iodine levels.

Conclusion:  Systemic iodine absorption is evidence that, even with single wound irrigation, repeated usage should be avoided in patients with renal impairment.
The neocortex of cetaceans: cytoarchitecture and comparison with other aquatic and terrestrial species
Authors: Butti Camilla , Raghanti Mary Ann , Sherwood Chet C. , Hof Patrick R.
Published: April 2011

The evolutionary process of readaptation to the aquatic environment was accompanied by extreme anatomical and physiological changes in the brain. This review discusses cortical specializations in the three major lineages of marine mammals in comparison to related terrestrial and semiaquatic species. Different groups of marine mammals adopted a wide range of strategies to cope with the challenges of aquatic living. Cetaceans and hippopotamids possess a completely agranular neocortex in contrast to phocids and sirenians; vertical modules are observed in deep layers V and VI in manatees, cetaceans, phocids, and hippopotamids, but in different cortical areas; and clustering in layer II appears in the insular cortex of hippopotamids, phocids, and cetaceans. Finally, von Economo neurons are present in cetaceans, hippopotamids, sirenians, and some phocids, with specific, yet different, cortical distributions. The interpretation of the evolutionary and functional significance of such specializations, and their relationships with the degrees of adaptation to the aquatic environment and phylogeny, remain difficult to trace, at least until comprehensive data, including representative species from all of the major mammalian families, become available.
Neocortical neuron morphology in Afrotheria: comparing the rock hyrax with the African elephant
Authors: Bianchi Serena , Bauernfeind Amy L. , Gupta Kanika , Stimpson Cheryl D. , Spocter Muhammad A. , Bonar Christopher J. , Manger Paul R. , Hof Patrick R. , Jacobs Bob , Sherwood Chet C.
Published: April 2011

The mammalian neocortex contains a great variety of neuronal types. In particular, recent studies have shown substantial morphological diversity among spiny projecting neurons in species that diverged close to the base of the mammalian radiation (e.g., monotremes, afrotherians, and xenarthrans). Here, we used a Golgi technique to examine different neuronal morphologies in an afrotherian species, the rock hyrax (Procavia capensis), and provide a comparison with the related African elephant (Loxodonta africana). Results showed that spiny neurons in the rock hyrax neocortex exhibit less morphological variation than in elephants, displaying a higher frequency of relatively “typical” pyramidal neurons. A quantitative comparison of rock hyrax pyramidal neuron morphology between frontal and visual areas, moreover, revealed greater spine density of neurons in frontal cortex, but no differences in other morphological aspects. Regional variations in pyramidal structure have also been observed in the African elephant, as well as a number of primate species.
Evolution of mirror systems: a simple mechanism for complex cognitive functions
Authors: Bonini Luca , Ferrari Pier Francesco
Published: April 2011

Mirror neurons (MNs) were first discovered in monkeys and subsequently in humans and birds. While MNs are deemed to play a number of high‐level cognitive functions, here we propose that they serve a unitary form of sensorimotor recognition of others’ behavior. We caution that this basic function should not be confounded with the higher order functions that stem from the wider cortical systems in which MNs are embedded. Depending on the species, MNs function at different levels of motor event recognition, from motor goals to fine grained movements, thus contributing to social learning and imitative phenomena. Recent studies show that MNs coding has a prospective nature, suggesting that MNs also play a role in anticipating and predicting the behavior of others during social interactions. The presence of mirroring mechanisms in subcortical structures related to visceromotor reactions and the large diffusion of imitative phenomena among animals suggest that MN systems may be more ancient and widespread than previously thought.
Evolution of the amniote pallium and the origins of mammalian neocortex
Authors: Butler Ann B. , Reiner Anton , Karten Harvey J.
Published: April 2011

Karten's neocortex hypothesis holds that many component cell populations of the sauropsid dorsal ventricular ridge (DVR) are homologous to particular cell populations in layers of auditory and visual tectofugal‐recipient neocortex of mammals (i.e., temporal neocortex), as well as to some amygdaloid populations. The claustroamygdalar hypothesis, based on gene expression domains, proposes that mammalian homologues of DVR are found in the claustrum, endopiriform nuclei, and/or pallial amygdala. Because hypotheses of homology need to account for the totality of the evidence, the available data on multiple forebrain features of sauropsids and mammals are reviewed here. While some genetic data are compatible with the claustroamygdalar hypothesis, and developmental (epigenetic) data are indecisive, hodological, morphological, and topographical data favor the neocortex hypothesis and are inconsistent with the claustroamygdalar hypothesis. Detailed studies of gene signaling cascades that establish neuronal cell‐type identity in DVR, tectofugal‐recipient neocortex, and claustroamygdala will be needed to resolve this debate about the evolution of neocortex.
Wally Welker and neurobehavioral evolution: an appreciation and bibliography
Authors: Zeigler H. Philip
Published: April 2011

The following review and appreciation of the pioneering work and character of Wallace I. (Wally) Welker provides a historical perspective on Welker's life‐long quest for answers to fundamental questions on the relationships among brain, behavior, and evolution, and evaluates his impact upon comparative behavioral neuroscience.
How do barrels form in somatosensory cortex?
Authors: Li Hong , Crair Michael C.
Published: April 2011

The somatosensory cortex of many rodents, lagomorphs, and marsupials contains distinct cytoarchitectonic features named “barrels” that reflect the pattern of large facial whiskers on the snout. Barrels are composed of clustered thalamocortical afferents relaying sensory information from one whisker surrounded by cell‐dense walls or “barrels” in layer 4 of the cortex. In many ways, barrels are a simple and relatively accessible canonical cortical column, making them a common model system for the examination of cortical development and function. Despite their experimental accessibility and popularity, we still lack a basic understanding of how and why barrels form in the first place. In this review, we will examine what is known about mechanisms of barrel development, focusing specifically on the recent literature using the molecular‐genetic power of mice as a model system for examining brain development.
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8.8 Maule Megathrust Earthquake of Central Chile, Monitored by GPS
Authors: Vigny C. , Socquet A. , Peyrat S. , Ruegg J.-C. , Métois M. , Madariaga R. , Morvan S. , Lancieri M. , Lacassin R. , Campos J. , Carrizo D. , Bejar-Pizarro M. , Barrientos S. , Armijo R. , Aranda C. , Valderas-Bermejo M.-C. , Ortega I. , Bondoux F. , Baize S. , Lyon-Caen H. , Pavez A. , Vilotte J. P. , Bevis M. , Brooks B. , Smalley R. , Parra H. , Baez J.-C. , Blanco M. , Cimbaro S. , Kendrick E.
Published: April 2011

Rupture kinematics of this very large earthquake were obtained from high-resolution Global Positioning System data.
Theoretical study of metallasilatranes; Bonding nature and prediction of new metallasilatrane
Authors: Sakaki Shigeyoshi , Kawai Daisuke , Tsukamoto Shinya
Published: April 2011

The new bond between Pt atom and hypervalent six-coordinate Si species in platinum-silatrane reported recently was theoretically investigated mainly with DFT method and in part with MP2 method. The DFT method with B3PW91 and M06 functionals reproduces well the Pt–Si, Pt–Cl and Si–N bond distances. Though the Si–Cl distance is overestimated by all functionals employed here when one d polarization function is added to each of Si and Cl, the M06-optimized Si–Cl distance is close to the experimental value when two d polarization functions are added to each of Si and Cl, suggesting that the functional and basis sets must be carefully employed in theoretical calculation of hypervalnet six-coordinate Si species. Population analysis clearly indicates that the Pt–Si bond is formed by the charge-transfer (CT) from the occupied dσ orbital of Pt to the empty p orbital of Si, which enhances the CT from the S atoms and Cl ligand to the Pt center. Besides platinum- and palladium-silatranes, no metallasilatrane has been reported so far. Based on the knowledge of bonding nature, we presented theoretical prediction that iridium(I) can form a similar metallasilatrane. Actually, the DFT calculation indicates that iridium-silatrane has essentially the same equilibrium geometry and bonding nature as those of platinum-silatrane.
Bilateral inferior petrosal sinus sampling
Authors: Deipolyi Amy R , Hirsch Joshua A , Oklu Rahmi
Published: April 2011

Bilateral inferior petrosal sinus sampling, the gold standard assay in diagnosing pituitary secretion of adrenocorticotropic hormone in Cushing disease, is highly accurate and safe when performed by experienced interventionalists. We review the anatomic and technical considerations essential for safe and reliable practice.
Patient Protection and Affordable Care Act of 2010: a primer for NeuroInterventionalists
Authors: Manchikanti Laxmaiah , Hirsch Joshua A
Published: April 2011

The Patient Protection and Affordable Care Act (the ACA, for short) became law on 23 March 2010. It represents the most significant transformation of the American healthcare system since Medicare and Medicaid. Essentials of ACA include: (1) a mandate for individuals and businesses requiring as a matter of law that nearly every American has an approved level of health insurance or pay a penalty; (2) a system of federal subsidies to completely or partially pay for the now required health insurance for ∼34 million Americans who are currently uninsured—subsidized through Medicaid and Exchanges; (3) extensive new requirements on the health insurance industry and (4) changes in the practice of medicine. The Act is divided into 10 titles. It contains provisions that went into effect starting on 21 June 2010 with many of the provisions going into effect in 2014 and later. The ACA goes well beyond insurance and payment reform. Practicing physicians will potentially be impacted by the Independent Payment Advisory Board and the Patient Centered Outcomes Research Institute.
Are we proper role models for students? Interns’ perception of faculty and residents’ professional behaviour
Authors: Asghari Fariba , Fard Nazila Nikravan , Atabaki Arash
Published: April 2011

Aim

This study was conducted to assess interns' level of exposure to different aspects of professional attitude and behaviour among faculty and residents.

Methods

In this descriptive study, 218 interns in surgery and internal medicine wards at four teaching hospitals of Tehran University of Medical Sciences were enrolled during the first semester of the 2007/2008 academic year. Each intern completed one questionnaire for faculty and one for residents in their ward.

Results

The questionnaire was completed by 150 students (68.8%) for faculty and by 139 students (63.7%) for residents. In terms of overall aspects of professionalism, the mean (±SD) score on observing professionalism was 52.9±10 and 49.26±7.9 points out of 70 for faculty and residents, respectively. Students agreed that responsibility was observed better than other aspects of professionalism (119/150 (79.3%) and 115/139 (82.8%) students stated it was often or always observed by faculty and residents, respectively). In both groups, commitment to honour and integrity and excellence was less compared with other areas.

Conclusion

Medical faculty and residents should be more aware of their behaviour and attitudes in practice, especially their interaction with colleagues so that students' professional behaviour can be improved.
SREBP2 mediates the modulation of intestinal NPC1L1 expression by curcumin
Authors: Kumar Pradeep , Malhotra Pooja , Ma Ke , Singla Amika , Hedroug Omar , Saksena Seema , Dudeja Pradeep K. , Gill Ravinder K. , Alrefai Waddah A.
Published: April 2011

Curcumin, the major phenolic compound in the spice turmeric, exhibits numerous biological effects, including lowering plasma cholesterol and preventing diet-induced hypercholesterolemia. The mechanisms underlying the hypocholesterolemic effect of curcumin are not fully understood. In this regard, intestinal Niemann-Pick C1-like 1 (NPC1L1) cholesterol transporter, the molecular target of intestinal cholesterol absorption inhibitor ezetimibe, plays an essential role in the maintenance of cholesterol homeostasis. The current studies were designed to investigate the effect of curcumin on NPC1L1 function, expression, and promoter activity in intestinal Caco-2 monolayers. NPC1L1 function was evaluated by the measurement of ezetimibe-sensitive [3H]cholesterol esterification. Relative abundance of NPC1L1 mRNA and protein was evaluated by real-time PCR and Western blotting, respectively. Luciferase assays were used to measure NPC1L1 promoter activity. Our results showed that curcumin significantly inhibited ezetimibe-sensitive cholesterol esterification in a dose-dependent manner with a maximum decrease (by 52% compared with control) occurring at 50 μM concentration. Curcumin treatment of Caco-2 monolayers also significantly decreased NPC1L1 mRNA and protein expression. Similarly, the promoter activity of the NPC1L1 gene was inhibited significantly (55%) by 50 μM curcumin. The decrease in NPC1L1 promoter activity by curcumin was associated with a reduction in the expression and the DNA-binding activity of the sterol response element-binding protein 2 (SREBP2) transcription factor. Furthermore, the overexpression of active SREBP2 protected NPC1L1 from the inhibitory effect of curcumin. Our studies demonstrate that curcumin directly modulates intestinal NPC1L1 expression via transcriptional regulation and the involvement of SREBP2 transcription factor.
Hepatic stellate cells require a stiff environment for myofibroblastic differentiation
Authors: Olsen Abby L. , Bloomer Steven A. , Chan Erick P. , Gaça Marianna D. A. , Georges Penelope C. , Sackey Bridget , Uemura Masayuki , Janmey Paul A. , Wells Rebecca G.
Published: April 2011

The myofibroblastic differentiation of hepatic stellate cells (HSC) is a critical event in liver fibrosis and is part of the final common pathway to cirrhosis in chronic liver disease from all causes. The molecular mechanisms driving HSC differentiation are not fully understood. Because macroscopic tissue stiffening is a feature of fibrotic disease, we hypothesized that mechanical properties of the underlying matrix are a principal determinant of HSC activation. Primary rat HSC were cultured on inert polyacrylamide supports of variable but precisely defined shear modulus (stiffness) coated with different extracellular matrix proteins or poly-l-lysine. HSC differentiation was determined by cell morphology, immunofluorescence staining, and gene expression. HSC became progressively myofibroblastic as substrate stiffness increased on all coating matrices, including Matrigel. The degree rather than speed of HSC activation correlated with substrate stiffness, with cells cultured on supports of intermediate stiffness adopting stable intermediate phenotypes. Quiescent cells on soft supports were able to undergo myofibroblastic differentiation with exposure to stiff supports. Stiffness-dependent differentiation required adhesion to matrix proteins and the generation of mechanical tension. Transforming growth factor-β treatment enhanced differentiation on stiff supports, but was not required. HSC differentiate to myofibroblasts in vitro primarily as a function of the physical rather than the chemical properties of the substrate. HSC require a mechanically stiff substrate, with adhesion to matrix proteins and the generation of mechanical tension, to differentiate. These findings suggest that alterations in liver stiffness are a key factor driving the progression of fibrosis.
Imaging of the closed-chest mouse pulmonary circulation using synchrotron radiation microangiography
Authors: Sonobe Takashi , Schwenke Daryl O. , Pearson James T. , Yoshimoto Misa , Fujii Yutaka , Umetani Keiji , Shirai Mikiyasu
Published: April 2011

Structural and functional changes of pulmonary circulation related to pathophysiology of pulmonary arterial hypertension (PAH) remain to be fully elucidated. Angiographic visualization in in vivo animals provided a powerful tool for assessing the major indexes associated with the pathogenesis of PAH. In this study, we have exploited the full potential of synchrotron radiation (SR) microangiography to show the ability to visualize pulmonary hemodynamics in a closed-chest mouse. Male adult mice were anesthetized and cannulated with a customized 24-gauge catheter into the right ventricle via the jugular vein for administering iodine contrast agent. The microangiography was performed on the left lung. We measured dynamic changes in vessel diameter in response to acetylcholine (ACh) and acute exposure to hypoxic gas (10% O2). Moreover, the pulmonary transit time was estimated by the time of contrast agent circulating. We were able to visualize the pulmonary arteries from the left pulmonary artery (LPA) to the third generation of branching (inner diameter <100 μm). ACh and acute hypoxia induced vascular responses chiefly in the second and third branching vessels rather than the LPA and the first branching vessels. The transit time was only 0.83 s. These results demonstrate the effectiveness of SR for visualizing the pulmonary circulation in a closed-chest mouse. Future studies using SR microangiography on specific gene-targeted knockout and transgenic mice will provide new insights into the pathophysiology of pulmonary dysfunction and functional adaptation to survive in hypoxic condition.
Exercise, brain, and cognition across the life span
Authors: Voss Michelle W. , Nagamatsu Lindsay S. , Liu-Ambrose Teresa , Kramer Arthur F.
Published: April 2011

This is a brief review of current evidence for the relationships between physical activity and exercise and the brain and cognition throughout the life span in non-pathological populations. We focus on the effects of both aerobic and resistance training and provide a brief overview of potential neurobiological mechanisms derived from non-human animal models. Whereas research has focused primarily on the benefits of aerobic exercise in youth and young adult populations, there is growing evidence that both aerobic and resistance training are important for maintaining cognitive and brain health in old age. Finally, in these contexts, we point out gaps in the literature and future directions that will help advance the field of exercise neuroscience, including more studies that explicitly examine the effect of exercise type and intensity on cognition, the brain, and clinically significant outcomes. There is also a need for human neuroimaging studies to adopt a more unified multi-modal framework and for greater interaction between human and animal models of exercise effects on brain and cognition across the life span.
Changes in lower extremity muscle function after 56 days of bed rest
Authors: Buehring B. , Belavý D. L. , Michaelis I. , Gast U. , Felsenberg D. , Rittweger J.
Published: April 2011

Preservation of muscle function, known to decline in microgravity and simulation (bed rest), is important for successful spaceflight missions. Hence, there is great interest in developing interventions to prevent muscle-function loss. In this study, 20 males underwent 56 days of bed rest. Ten volunteers were randomized to do resistive vibration exercise (RVE). The other 10 served as controls. RVE consisted of muscle contractions against resistance and concurrent whole-body vibration. Main outcome parameters were maximal isometric plantar-flexion force (IPFF), electromyography (EMG)/force ratio, as well as jumping power and height. Measurements were obtained before and after bed rest, including a morning and evening assessment on the first day of recovery from bed rest. IPFF (−17.1%), jumping peak power (−24.1%), and height (−28.5%) declined ( P < 0.05) in the control group. There was a trend to EMG/force ratio decrease (−20%; P = 0.051). RVE preserved IPFF and mitigated the decline of countermovement jump performance (peak power −12.2%; height −14.2%). In both groups, IPFF was reduced between the two measurements of the first day of reambulation. This study indicates that bed rest and countermeasure exercises differentially affect the various functions of skeletal muscle. Moreover, the time course during recovery needs to be considered more thoroughly in future studies, as IPFF declined not only with bed rest but also within the first day of reambulation. RVE was effective in maintaining IPFF but only mitigated the decline in jumping performance. More research is needed to develop countermeasures that maintain muscle strength as well as other muscle functions including power.
Tracheal occlusion modulates the gene expression profile of the medial thalamus in anesthetized rats
Authors: Bernhardt Vipa , Garcia-Reyero Natàlia , Vovk Andrea , Denslow Nancy , Davenport Paul W.
Published: April 2011

Conscious awareness of breathing requires the activation of higher brain centers and is believed to be a neural gated process. The thalamus could be responsible for the gating of respiratory sensory information to the cortex. It was reasoned that if the thalamus is the neural gate, then tracheal obstructions will modulate the gene expression profile of the thalamus. Anesthetized rats were instrumented with an inflatable cuff sutured around the trachea. The cuff was inflated to obstruct 2–4 breaths, then deflated for a minimum of 15 breaths. Obstructions were repeated for 10 min followed by immediate dissection of the medial thalamus. Following the occlusion protocol, 588 genes were found to be altered ( P < 0.05; log2fold change ≥ 0.4), with 327 genes downregulated and 261 genes upregulated. A significant upregulation of the serotonin HTR2A receptor and significant downregulation of the dopamine DRD1 receptor genes were found. A pathway analysis was performed that targeted serotonin and dopamine receptor pathways. The mitogen-activated protein kinase 1 (MAPK1) gene was significantly downregulated. MAPK1 is an inhibitory regulator of HTR2A and facilitatory regulator for DRD1. Downregulation of MAPK1 may be related to the significant upregulation of HTR2A and downregulation of DRD1, suggesting an interaction in the medial thalamus serotonin-dopamine pathway elicited by airway obstruction. These results demonstrate an immediate change in gene expression in thalamic arousal, fear, anxiety motivation-related serotonin and dopamine receptors in response to airway obstruction. The results support the hypothesis that the thalamus is a component in the respiratory mechanosensory neural pathway.
LIF is a contraction-induced myokine stimulating human myocyte proliferation
Authors: Broholm Christa , Laye Matthew J. , Brandt Claus , Vadalasetty Radhika , Pilegaard Henriette , Pedersen Bente Klarlund , Scheele Camilla
Published: April 2011

The cytokine leukemia inhibitory factor (LIF) is expressed by skeletal muscle and induces proliferation of myoblasts. We hypothesized that LIF is a contraction-induced myokine functioning in an autocrine fashion to activate gene regulation of human muscle satellite cell proliferation. Skeletal muscle LIF expression, regulation, and action were examined in two models: 1) young men performing a bout of heavy resistance exercise of the quadriceps muscle and 2) cultured primary human satellite cells. Resistance exercise induced a ninefold increase in LIF mRNA content in skeletal muscle, but LIF was not detectable in plasma of the subjects. However, electrically stimulated cultured human myotubes produced and secreted LIF, suggesting that LIF is a myokine with local effects. The well established exercise-induced signaling molecules PI3K, Akt, and mTor contributed to the regulation of LIF in cultured human myotubes as chemical inhibition of PI3K and mTor and siRNA knockdown of Akt1 were independently sufficient to downregulate LIF. Human myoblast proliferation was increased by recombinant exogenous LIF and decreased by siRNA knockdown of the endogenous LIF receptor. Finally, the transcription factors JunB and c-Myc, which promote myoblast proliferation, were induced by LIF in cultured human myotubes. Indeed, both JunB and c-Myc were also increased in skeletal muscle following resistance exercise. Our data suggest that LIF is a contraction-induced myokine, potentially acting in an autocrine or paracrine fashion to promote satellite cell proliferation.
Quantitative, Noninvasive Imaging of Radiation-Induced DNA Double-Strand Breaks In Vivo
Authors: Li Wenrong , Li Fang , Huang Qian , Shen Jingping , Wolf Frank , He Yujun , Liu Xinjian , Hu Y. Angela , Bedford Joel S. , Li Chuan-Yuan
Published: April 2011

DNA double-strand breaks (DSB) are a major form of DNA damage and a key mechanism through which radiotherapy and some chemotherapeutic agents kill cancer cells. Despite its importance, measuring DNA DSBs is still a tedious task that is normally carried out by gel electrophoresis or immunofluorescence staining. Here, we report a novel approach to image and quantify DSBs in live mammalian cells through bifragment luciferase reconstitution. N- and C-terminal fragments of firefly luciferase genes were fused with H2AX and MDC1 genes, respectively. Our strategy was based on the established fact that at the sites of DSBs, H2AX protein is phosphoryated and physically associates with the MDC1 protein, thus bringing together N- and C-luciferase fragments and reconstituting luciferase activity. Our strategy allowed serial, noninvasive quantification of DSBs in cells irradiated with X-rays and 56Fe ions. Furthermore, it allowed for the evaluation of DSBs noninvasively in vivo in irradiated tumors over 2 weeks. Surprisingly, we detected a second wave of DSB induction in irradiated tumor cells days after radiation exposure in addition to the initial rapid induction of DSBs. We conclude that our new split-luciferase–based method for imaging γ-H2AX–MDC1 interaction is a powerful new tool to study DSB repair kinetics in vivo with considerable advantage for experiments requiring observations over an extended period of time. Cancer Res; 71(12); 4130–7. ©2011 AACR.
BRCA1 Counteracts Progesterone Action by Ubiquitination Leading to Progesterone Receptor Degradation and Epigenetic Silencing of Target Promoters
Authors: Calvo Verónica , Beato Miguel
Published: April 2011

Germ-line mutations in the BRCA1 gene increase the risk of breast cancer in women, but the precise mechanistic basis for this connection remains uncertain. One popular hypothesis to explain breast tissue specificity postulates a link between BRCA1 and the action of the ovarian hormones estrogen and progesterone. Given the relevance of progesterone for normal mammary development and breast cancer formation, we searched for a functional relationship between BRCA1 and progesterone receptor (PR) in the PR-positive breast cancer cell line T47D. Here, we report that BRCA1 inhibits the transcriptional activity of PR by at least 2 mechanisms involving the E3 ubiquitin ligase activity of BRCA1. First, BRCA1 has a direct effect on the cellular level of PR and, hence, on the extent of PR recruitment to target promoters through the promotion of its ligand-independent and -dependent degradation. Through in vitro and in vivo assays, we found that BRCA1/BARD1 may be the main E3 ubiquitin ligase responsible for ubiquitination and degradation of PR in the absence of hormone. Second, after hormone treatment of cells, the BRCA1/BARD1 complex is recruited via interaction with PR to the hormone-responsive regions of PR target genes, affecting local levels of monoubiquitinated histone H2A and contributing to epigenetic silencing of these promoters. The connections between BRCA1/BARD1 and PR activity suggested by our findings may help explain why host mutations in BRCA1 exert a tissue specificity in preferentially elevating the risk of breast cancer. Cancer Res; 71(9); 3422–31. ©2011 AACR.
Enhancement of Cancer Vaccine Therapy by Systemic Delivery of a Tumor-TargetingSalmonella-Based STAT3 shRNA Suppresses the Growth of Established Melanoma Tumors
Authors: Manuel Edwin R. , Blache Céline A. , Paquette Rebecca , Kaltcheva Teodora I. , Ishizaki Hidenobu , Ellenhorn Joshua D.I. , Hensel Michael , Metelitsa Leonid , Diamond Don J.
Published: April 2011

Cancer vaccine therapies have only achieved limited success when focusing on effector immunity with the goal of eliciting robust tumor-specific T-cell responses. More recently, there is an emerging understanding that effective immunity can only be achieved by coordinate disruption of tumor-derived immunosuppression. Toward that goal, we have developed a potent Salmonella-based vaccine expressing codon-optimized survivin (CO-SVN), referred to as 3342Max. When used alone as a therapeutic vaccine, 3342Max can attenuate growth of aggressive murine melanomas overexpressing SVN. However, under more immunosuppressive conditions, such as those associated with larger tumor volumes, we found that the vaccine was ineffective. Vaccine efficacy could be rescued if tumor-bearing mice were treated initially with Salmonella encoding a short hairpin RNA (shRNA) targeting the tolerogenic molecule STAT3 (YS1646-shSTAT3). In vaccinated mice, silencing STAT3 increased the proliferation and granzyme B levels of intratumoral CD4+ and CD8+ T cells. The combined strategy also increased apoptosis in tumors of treated mice, enhancing tumor-specific killing of tumor targets. Interestingly, mice treated with YS1646-shSTAT3 or 3342Max alone were similarly unsuccessful in rejecting established tumors, whereas the combined regimen was highly potent. Our findings establish that a combined strategy of silencing immunosuppressive molecules followed by vaccination can act synergistically to attenuate tumor growth, and they offer a novel translational direction to improve tumor immunotherapy. Cancer Res; 71(12); 4183–91. ©2011 AACR.
Functional Parsing of Driver Mutations in the Colorectal Cancer Genome Reveals Numerous Suppressors of Anchorage-Independent Growth
Authors: Eskiocak Ugur , Kim Sang Bum , Ly Peter , Roig Andres I. , Biglione Sebastian , Komurov Kakajan , Cornelius Crystal , Wright Woodring E. , White Michael A. , Shay Jerry W.
Published: April 2011

Landmark cancer genome resequencing efforts are leading to the identification of mutated genes in many types of cancer. The extreme diversity of mutations being detected presents significant challenges to subdivide causal from coincidental mutations to elucidate how disrupted regulatory networks drive cancer processes. Given that a common early perturbation in solid tumor initiation is bypass of matrix-dependent proliferation restraints, we sought to functionally interrogate colorectal cancer candidate genes (CAN-genes) to identify driver tumor suppressors. We have employed an isogenic human colonic epithelial cell (HCEC) model to identify suppressors of anchorage-independent growth by conducting a soft agar–based short hairpin RNA (shRNA) screen within the cohort of CAN-genes. Remarkably, depletion of 65 of the 151 CAN-genes tested collaborated with ectopic expression of K-RASV12 and/or TP53 knockdown to promote anchorage-independent proliferation of HCECs. In contrast, only 5 of 362 random shRNAs (1.4%) enhanced soft agar growth. We have identified additional members of an extensive gene network specifying matrix-dependent proliferation, by constructing an interaction map of these confirmed progression suppressors with approximately 700 mutated genes that were excluded from CAN-genes, and experimentally verifying soft agar growth enhancement in response to depletion of a subset of these genes. Collectively, this study revealed a profound diversity of nodes within a fundamental tumor suppressor network that are susceptible to perturbation leading to enhanced cell-autonomous anchorage-independent proliferative fitness. Tumor suppressor network fragility as a paradigm within this and other regulatory systems perturbed in cancer could, in large part, account for the heterogeneity of somatic mutations detected in tumors. Cancer Res; 71(13); 4359–65. ©2011 AACR.
Isolation of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Using a Novel Cell Separation Strategy
Authors: Xu Wen , Cao Lu , Chen Lei , Li Jing , Zhang Xiao-Feng , Qian Hai-Hua , Kang Xiao-Yan , Zhang Yu , Liao Jian , Shi Le-Hua , Yang Ye-Fa , Wu Meng-Chao , Yin Zheng-Feng
Published: April 2011

Purpose: To establish a sensitive and specific isolation and enumeration system for circulating tumor cells (CTC) in patients with hepatocellular carcinoma (HCC).

Experimental Design: HCC cells were bound by biotinylated asialofetuin, a ligand of asialoglycoprotein receptor, and subsequently magnetically labeled by antibiotin antibody–coated magnetic beads, followed by magnetic separation. Isolated HCC cells were identified by immunofluorescence staining using Hep Par 1 antibody. The system was used to detect CTCs in 5 mL blood. Blood samples spiked with Hep3B cells (ranging from 10 to 810 cells) were used to determine recovery and sensitivity. Prevalence of CTCs was examined in samples from HCC patients, healthy volunteers, and patients with benign liver diseases or non-HCC cancers. CTC samples were also analyzed by FISH.

Results: The average recovery was 61% or more at each spiking level. No healthy, benign liver disease or non-HCC cancer subjects had CTCs detected. CTCs were identified in 69 of 85 (81%) HCC patients, with an average of 19 ± 24 CTCs per 5 mL. Both the positivity rate and the number of CTCs were significantly correlated with tumor size, portal vein tumor thrombus, differentiation status, and the disease extent as classified by the TNM (tumor-node-metastasis) classification and the Milan criteria. HER-2 gene amplification and TP53 gene deletion were detected in CTCs.

Conclusion: Our system provides a new tool allowing for highly sensitive and specific detection and genetic analysis of CTCs in HCC patients. It is likely clinically useful in diagnosis and monitoring of HCC and may have a role in clinical decision making. Clin Cancer Res; 17(11); 3783–93. ©2011 AACR.
Hepatic Resection with in situ Hypothermic Perfusion Is Superior to Other Resection Techniques
Authors: Hoti Emir , Salloum Chady , Azoulay Daniel
Published: April 2011

Through the years, liver resection and bleeding control techniques have progressively evolved. However, for liver tumors located unfavorably, the standard techniques are not suitable due to either failure to control the bleeding or to liver ischemia induced by prolonged interruption of perfusion. In this regard, total vascular exclusion (TVE) with in situ hypothermic perfusion is advantageous as it protects the parenchyma, achieves better vascular control and enables difficult vascular reconstructions or reimplantations. The advantages of this procedure described as early as 1960s by Fortner were also confirmed by our team in a subsequent report. We showed that TVE with in situ hypothermic perfusion is superior to TVE alone if used for more than 60 min in complex resections with or without vascular reconstruction. Other techniques (ex situ liver resection developed by Pichlmayr and ante situm liver resection by Hannoun) have been described; however, they have not been widely accepted due to a high rate of complications. In this article, we report our operative technique as well as discuss some important operative points.
Two-Stage Hepatectomy Procedure to Treat Initially Unresectable Multiple Bilobar Colorectal Liver Metastases: Technical Aspects
Authors: Narita Masato , Oussoultzoglou Elie , Bachellier Philippe , Rosso Edoardo , Pessaux Patrick , Jaeck Daniel
Published: April 2011

A two-stage hepatectomy procedure is a therapeutic strategy for patients presenting with initially unresectable multiple and bilobar colorectal liver metastases in order to achieve a curative R0 resection. The main goal of this approach is to minimize the risk of postoperative liver failure resulting from a too small remnant liver after completing a curative resection. This procedure combines two sequential liver resections that involve perioperative chemotherapy and portal vein embolization. This article describes our standardized strategy of two-stage hepatectomy combined with portal vein embolization used over the last 15 years and discusses the alternative procedures as well as their respective advantages and drawbacks.
Liver Resection Combined with Local Ablation: Where Are the Limits
Authors: de Jong Koert P. , Wertenbroek Marieke W.J.L.A.E.
Published: April 2011

Background/Aims: Partial hepatectomy for liver tumors is potentially curative but unfortunately available only for a limited number of patients. Local tumor destruction by ablation has expanded criteria for treatment and potential cure for patients with liver tumors. This paper gives an overview of the possibilities and limitations of ablation of liver tumors. Methods: A search of relevant peer-reviewed literature was conducted. Results: Investigations in the second half of the 18th century paved the way for application of electromagnetic fields in living organisms. Currently, indications for thermoablation are (1) unresectable liver tumors, (2) bridging therapy for a more definitive treatment, (3) debulking of symptomatic hormonally active liver tumors, and (4) patients unfit for major abdominal procedures. Although randomized trials on the use of radiofrequency ablation (RFA) are scarce, the results thus far suggest that the combination of partial liver resection and local ablation offers cure rates in the same order of magnitude as partial liver resection – the ‘gold standard’ – alone. Additionally, RFA seems to be associated with a lower morbidity and mortality rate as compared to partial liver resection. One of the disadvantages is the reported high incidence of ablation site recurrences of sometimes up to 30%. This is especially related to a larger size of ablated tumors and tumors close to large vessels. Also, RFA is a rather time-consuming procedure. On theoretical grounds, ablation with microwaves is more effective and faster and seems to be associated with a lower incidence of ablation site recurrences. Conclusions: Ablation has acquired a place in the arsenal of treatment modalities for patients with liver tumors and expanded the indications for treatment with a curative intent. Further evolution of the technique and the proof that it has at least the same oncological result with a lower morbidity as partial hepatectomy are required in the near future.
Two Types of Extended Liver Resection for Advanced Gallbladder Cancer: How to Do It
Authors: Kondo Satoshi , Hirano Satoshi , Tanaka Eiichi , Tsuchikawa Takahiro , Kato Kentaro , Matsumoto Jo , Nasu Yuya , Shichinohe Toshiaki
Published: April 2011

Background: Extended liver resection is necessary for advanced gallbladder cancer with hepatic involvement to achieve R0 resection. However, its type or extent and its surgical technique have yet to be established. Methods: To exclude systemic disease, frozen section biopsy following systematic para-aortic lymphadenectomy is recommended before starting extended surgery with curative intent because para-aortic nodes are involved more frequently than expected. Right hepatectomy with biliary reconstruction should be indicated for the hepatic hilum type of advanced gallbladder cancer in which a relatively small tumor in the gallbladder neck infiltrates the hepatic hilum and causes obstructive jaundice. Ventral hepatectomy without biliary reconstruction can be applied for the hepatic bed type in which a large mass in the gallbladder fundus and body penetrates into the hepatic parenchyma through the gallbladder bed. Results: The two types of extended liver resection were successfully performed in representative cases. Detailed procedures were described. Long-term survival without disease recurrence has been achieved in both cases. Conclusion: The type of extended liver resection should be chosen according to the mode of tumor spread in advanced gallbladder cancer without distant metastasis.
The Impact of Cochlear Implantation on Tinnitus, Stress and Quality of Life in Postlingually Deafened Patients
Authors: Olze Heidi , Szczepek Agnieszka J. , Haupt Heidemarie , Zirke Nina , Graebel Stefan , Mazurek Birgit
Published: April 2011

Tinnitus is a common complaint in the candidates for cochlear implantation (CI). Tinnitus-related distress has often been measured in these patients using categorical ratings, which lack information about tinnitus severity, stress and health-related quality of life or their correlation. Here, using 4 validated questionnaires, we evaluated psychometric parameters and the quality of life of 32 postlingually deafened patients before and after CI. The data regarding pre-CI were collected retrospectively. Of all patients included in this study, 28 (87.5%) suffered from tinnitus before implantation. Following a mean of 24 months after surgery, these patients reported a significant decrease (39.2%) of tinnitus impairment, as measured by the Tinnitus Questionnaire. In none of the 28 patients has tinnitus worsened. Moreover, the 4 tinnitus-free patients remained so after the CI surgery. In addition, the implant supply resulted in 36.7% reduction in perceived stress and in 15.4% reduction in evasive coping. In addition, the focus on positive coping has improved by 12.3%, whereas the health-related quality of life improved by 53.4% in all patients. Tinnitus impairment and stress were reduced more strongly in patients who had initially higher scores. Interestingly, a significant correlation between the psychometric scores was found mainly after CI. Our results indicate that patients with higher tinnitus-related distress have a lower quality of life, lesser coping abilities and perceive more stress, but before implantation it is masked by deafness. We conclude that tinnitus-related screening of patients before and after CI is an important step in the identification of individuals who would benefit from specific fitting and/or tinnitus therapy after implantation.
Middle-Aged Couples’ Exchanges of Support with Aging Parents: Patterns and Association with Marital Satisfaction
Authors: Lee Jeong Eun , Zarit Steven H. , Rovine Michael J. , Birditt Kira S. , Fingerman Karen L.
Published: April 2011

We examined the context of intergenerational support exchanges with aging parents and its association with middle-aged couples’ marital satisfaction. A sample of 197 middle-aged couples reported support they gave to and received from their parents (n = 440). Results indicated that couples provided more total support to and received more from their parents as a function of number of living parents, but the amount of support each parent received (‘parent-adjusted support’) was lower when there were more living parents. The amount of support given to and received from parents had no association with the couple’s marital satisfaction, but discrepancies in support given to and received from parents did have a significant association with marital satisfaction. Husbands who gave more support to their living parent(s) than their wives reported lower marital satisfaction. A similar effect on marital satisfaction was found for wives who gave more support to their living parents than their husbands. These findings contrast with caregiving studies where amount of support affected marital satisfaction and suggest that inequalities in involvement with parents may be a critical dimension in marriages of midlife adults.
Carotid Artery Longitudinal Displacement Predicts 1-Year Cardiovascular Outcome in Patients With Suspected Coronary Artery Disease
Authors: Svedlund Sara , Eklund Charlotte , Robertsson Per , Lomsky Milan , Gan Li-Ming
Published: April 2011

Objective—

Total longitudinal displacement (tLoD) of the common carotid artery can be measured using the ultrasound-based velocity vector imaging (VVI) technique. This study aimed to investigate clinical correlates and the possible predictive value of tLoD for cardiovascular outcome.

Methods and Results—

Four hundred forty-one patients referred for myocardial perfusion scintigraphy examination for suspected coronary artery disease were recruited and underwent VVI-assisted tLoD measurement. Patients were followed up with regard to major adverse cardiovascular event (MACE) 1 year later. Low tLoD (≤0.055 mm) was associated with greater clinically determined myocardial ischemia (
P
<0.01). During a median follow-up time of 372 days, 61 MACEs occurred. In a Kaplan–Meier survival analysis, high tLoD (>0.055 mm) predicted 1-year event-free survival (
P
<0.01, highest versus lowest tertile odds ratio [OR]=1.9). In a Cox regression model adjusting for age, gender, intima-media thickness, radial strain, pulse pressure, and percentage reversibility mass of myocardium, low tLoD remained a significant independent predictor of MACE (
P
=0.03). Finally, low tLoD provided additional predictive value in subjects with increased intima-media thickness.

Conclusion—

VVI-derived tLoD seems to reflect cardiovascular status and predicts short-term event-free survival in medium- to high-risk patients. Finally, tLoD per se or in combination with intima-media thickness measurement may be a novel cardiovascular surrogate biomarker.