bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgical technology and operating-room safety failures: a systematic review of quantitative studies
Authors: Weerakkody Ruwan A , Cheshire Nicholas J , Riga Celia , Lear Rachael , Hamady Mohammed S , Moorthy Krishna , Darzi Ara W , Vincent Charles , Bicknell Colin D
Published: July 2013

Background

Surgical technology has led to significant improvements in patient outcomes. However, failures in equipment and technology are implicated in surgical errors and adverse events. We aim to determine the proportion and characteristics of equipment-related error in the operating room (OR) to further improve quality of care.

Methods

A systematic review of the published literature yielded 19 362 search results relating to errors and adverse events occurring in the OR, from which 124 quantitative error studies were selected for full-text review and 28 were finally selected.

Results

Median total errors per procedure in independently-observed prospective studies were 15.5, interquartile range (IQR) 2.0–17.8. Failures of equipment/technology accounted for a median 23.5% (IQR 15.0%–34.1%) of total error. The median number of equipment problems per procedure was 0.9 (IQR 0.3–3.6). From eight studies, subdivision of equipment failures was possible into: equipment availability (37.3%), configuration and settings (43.4%) and direct malfunctioning (33.5%). Observed error rates varied widely with study design and with type of operation: those with a greater burden of technology/equipment tended to show higher equipment-related error rates. Checklists (or similar interventions) reduced equipment error by mean 48.6% (and 60.7% in three studies using specific equipment checklists).

Conclusions

Equipment-related failures form a substantial proportion of all error occurring in the OR. Those procedures that rely more heavily on technology may bear a higher proportion of equipment-related error. There is clear benefit in the use of preoperative checklist-based systems. We propose the adoption of an equipment check, which may be incorporated into the current WHO checklist.
Proactive dairy cattle disease control in the UK: veterinary surgeons' involvement and associated characteristics
Authors: Higgins H. M. , Huxley J. N. , Wapenaar W. , Green M. J.
Published: July 2013

Characteristics of 94 veterinary surgeons associated with delivering preventive herd‐level strategies to control mastitis, lameness and Johne's disease were investigated using two multinomial models. The response variables were ‘Gold Standard Monitoring’ (including on‐going data analysis, risk assessments and laboratory testing), and a lower level of involvement called ‘Regular Control Advice’. Although the sample was biased towards those who spend the majority of their time with dairy cows, 69 per cent currently had no involvement in Gold Standard Monitoring for lameness, 60 per cent no involvement with Johne's, and 52 per cent no involvement with mastitis. The final model predicted that an assistant without a postgraduate cattle qualification, who had spent no time on dairy cattle continuous professional development (CPD) in the last year, had an 88 per cent chance of having no involvement with Gold Standard Monitoring for any disease, versus <5 per cent chance for a CPD ‘enriched’ partner with a postgraduate cattle qualification; there was <1 per cent chance this assistant would be involved with Gold Standard Monitoring of all three diseases on one or more farms, versus a 58 per cent chance for this partner. CPD and employment status were also associated with markedly different probabilities for delivering Regular Control Advice. Increased postgraduate education may further veterinary involvement of this nature.
The 125‐year life cycle of parasite control
Authors: Morgan Eric
Published: July 2013

Eric Morgan looks back at the past 125 years in veterinary parasitology and considers the landmarks that have been reached and the challenges that still lie ahead
Performance of reinforced concrete buildings during the 27 February 2010 Maule (Chile) earthquake
Authors: Saatcioglu Murat , Palermo Dan , Ghobarah Ahmed , Mitchell Denis , Simpson Rob , Adebar Perry , Tremblay Robert , Ventura Carlos , Hong Hanping
Published: July 2013

The paper presents observed damage in reinforced concrete buildings during the 27 February 2010 Maule earthquake in Chile. Performance of concrete frame and shear wall buildings are discussed with emphasis on seismic deficiencies in design and construction practices. It is shown that the majority of structural damage in multistorey and high-rise buildings can be attributed to poor performance of slender shear walls, without confined boundary elements, suffering from crushing of concrete and buckling of vertical wall reinforcement. Use of irregular buildings, lack of seismic detailing, and the interference of nonstructural elements were commonly observed seismic deficiencies. A comparison is made between Chilean and Canadian design practices with references made to the applicable code clauses. Lessons are drawn from the observed structural performance.
MECHANICAL AND THERMAL PROPERTIES OF PRASEODYMIUM MONOPNICTIDES: AN ULTRASONIC STUDY
Authors: BHALLA VYOMA , KUMAR RAJ , TRIPATHY CHINMAYEE , SINGH DEVRAJ
Published: July 2013

We have computed ultrasonic attenuation, acoustic coupling constants and ultrasonic velocities of praseodymium monopnictides PrX ( X : N , P , As , Sb and Bi ) along the 〈100〉, 〈110〉, 〈111〉 in the temperature range 100–500 K using higher order elastic constants. The higher order elastic constants are evaluated using Coulomb and Born–Mayer potential with two basic parameters viz. nearest-neighbor distance and hardness parameter in the temperature range of 0–500 K. Several other mechanical and thermal parameters like bulk modulus, shear modulus, Young's modulus, Poisson ratio, anisotropic ratio, tetragonal moduli, Breazeale's nonlinearity parameter and Debye temperature are also calculated. In the present study, the fracture/toughness (B/G) ratio is less than 1.75 which implies that PrX compounds are brittle in nature at room temperature. The chosen material fulfilled Born criterion of mechanical stability. We also found the deviation of Cauchy's relation at higher temperatures. PrN is most stable material as it has highest valued higher order elastic constants as well as the ultrasonic velocity. Further, the lattice thermal conductivity using modified approach of Slack and Berman is determined at room temperature. The ultrasonic attenuation due to phonon–phonon interaction and thermoelastic relaxation mechanisms have been computed using modified Mason's approach. The results with other well-known physical properties are useful for industrial applications.
HEURISTICS FOR THE TRANSPOSITION DISTANCE PROBLEM
Authors: DIAS ULISSES , DIAS ZANONI
Published: July 2013

Transpositions are large-scale mutational events that occur when a block of genes moves from a region of a chromosome to another region within the same chromosome. The transposition distance problem is the minimum number of transpositions required to transform one genome into another. Recently, Bulteau et al. [Bulteau L, Fertin G, Rusu U, Automata, Languages and Programming, Vol. 6755 of Lecture Notes in Computer Science, pp. 654–665, Springer Berlin, Heidelberg, 2011] proved that finding the transposition distance is a NP-Hard problem. Some approximation algorithm for this problem have been presented to date [Bafna V, Pevzner PA, SIAM J Discr Math11(2):224–240, 1998; Elias I, Hartman T, IEEE/ACM Trans Comput Biol Bioinform3(4):369–379, 2006; Mira CVG, Dias Z, Santos HP, Pinto GA, Walter ME, Proc 3rd Brazilian Symp Bioinformatics (BSB'2008), pp. 115–126, Santo André, Brazil, 2008; Walter MEMT, Dias Z, Meidanis J, Proc String Processing and Information Retrieval (SPIRE'2000), pp. 199–208, Coruña, Spain, 2000]. Here we focus on developing heuristics to provide an improved approximated solution. Our approach outperforms other algorithms on small sized permutations. We also show that our algorithm keeps the good performance on longer permutations.
FACILE SYNTHESIS OF MAGNETITE/CARBON NANOTUBES NANOCOMPOSITES WITH STABLE AND RATE CAPABILITY AS ANODE MATERIALS FOR LITHIUM-ION BATTERIES
Authors: WU CHAO , ZHUANG QUANCHAO , WU YONGXIN , TIAN LEILEI , ZHANG XINXI , SUN SHIGANG
Published: July 2013

Fe 3 O 4/carbon nanotubes (CNTs) nanocomposites are successfully prepared by a facile hydrothermal method, without any reducing agents. SEM shows that the CNTs are dispersed well in the Fe 3 O 4 nanoparticles of 50 to 100 nm in size. The electrochemical properties of the prepared nanocomposites as anode materials are further evaluated by galvanostatic charge/discharge cycling and cyclic voltammetry (CV). Results show that the nanocomposites display an initial discharge capacity of 1421 mAh⋅g-1 and maintain 1100 mAh⋅g-1 up to 40 cycles in the voltage of 0.005–3.0 V at 100 mAh⋅g-1. When the current density is to 0.5, 1, 2, 5 and 1 C, the nanocomposites still exhibit discharge capacity of 1615.8, 817.0, 585.0, 391.0 and (585.0 ± 45.0) mAh⋅g-1, respectively, which are potential for anode materials in lithium-ion batteries.
Ar diffusion and solubility measurements in plagioclases using the ultra-violet laser depth-profiling technique
Authors: Wartho Jo-Anne , Kelley Simon P. , Elphick Stephen C.
Published: July 2013

We describe the first direct measurements of Ar diffusion and solubility in plagioclases using ultra-violet (UV) laser ablation depth-profiling and noble gas mass spectrometer analyses of experimentally treated (599–1000 °C, 50–200 MPa of Ar) crystal fragments of labradorite and oligoclase. Labradorite
40
Ar gain diffusion profiles were measured, yielding an activation energy of 26.72±4.58 kcal mol
−1
(118.0±19.16 kJ mol
−1
) and a frequency factor of 9.77×10
−9
(+8.79×10
−8
, −8.79×10
−9
) cm
2
s
−1
(95% confidence). The Ar solubility in labradorite was measured yielding a value of <0.2 ppb bar
−1
, which is similar to or lower than many rock forming minerals.

The labradorite diffusion parameters indicate Ar closure temperatures of 211 °C for a spherical diffusion geometry, and 243 °C for a planar diffusion geometry (for 100 µm-diameter grains, with cooling rates of 10 °C Ma
−1
). The data indicate that labradorite is less Ar retentive than K-feldspar at low temperatures, but more Ar retentive than K-feldspar at high temperatures, corroborating previous work on plagioclase. The relatively slow Ar diffusion rates in labradorite at magmatic temperatures may explain the common observation of older ages in large plagioclase grains in acidic volcanic systems.

Supplementary material:

Details of the UV laser depth profiles obtained from the labradorite and oligoclase samples used in this study are available at
www.geolsoc.org.uk/SUP18608
.
Neutron-induced
37
Ar recoil ejection in Ca-rich minerals and implications for
40
Ar/
39
Ar dating
Authors: Jourdan F. , Renne P. R.
Published: July 2013

The
40
Ar/
39
Ar dating technique requires the transformation of
39
K into
39
Ar by neutron activation. Neutron activation has undesirable secondary effects such as interfering isotope production, and recoil of
39
Ar and
37
Ar atoms from their (dominant) targets of K and Ca. In most cases, the grains analysed are large enough (>50 μm) such that the amount of target atoms ejected from the grains is small and has a negligible effect on the ages obtained. However, increasing needs to date fine-grained rocks requires constraining, and in some cases correcting for, the effect of nuclear recoil. Previous quantitative studies of recoil loss focus mostly on
39
Ar. However,
37
Ar loss can affect the ages of Ca-rich minerals via interference corrections on
36
Ar (and, to a lesser extent,
39
Ar), yielding lower
40
Ar*/
39
Ar
K
and, thus, an age spuriously too young. New results focused on
37
Ar recoil by measuring the apparent age of multi-grain populations of Ca-rich minerals including Fish Canyon plagioclase (FCp) and Hb3gr hornblende, with discrete sizes ranging from 210 to <5 µm. We use previous result on sanidine grains to correct for the
39
Ar recoil loss. For the finest fractions, FCp and Hb3gr apparent ages are younger than the
39
Ar recoil-corrected ages expected for these minerals, with a maximum deviation of −40% (FCp) and −21% (Hb3gr) reached for grains below 5 μm. We calculate
37
Ar-depletion values ranging from approximately 30 to 91% and from approximately 28 to 98% for plagioclase and hornblende, respectively. This results in
x
0
values (mean thickness of the partial depletion layer) of 3.3±0.4 μm (2σ; FCp) and 3.6±1.4 μm (Hb3gr), significantly higher than suggested by current models. The reason for the substantial
37
Ar loss is not well understood, but might be related to the radiation damage caused to the mineral during irradiation.
x
0
(
39
Ar) and
x
0
(
37
Ar) values obtained in this study, along with crystal dimensions, can be used for correcting
40
Ar/
39
Ar ages from
39
Ar and
37
Ar recoil loss. We also discuss the relevance of our results to vacuum-encapsulation studies and isotopic redistribution in fine-grained minerals.

Supplementary material:

Annex 1, 2 and 3 are available at
www.geolsoc.org.uk/SUP18610
. Annex 1 and 2: Raw argon data corrected for blank, mass discrimination and radioactive decay for Fish Canyon plagioclase (Annex 1) and Hb3gr hornblende (Annex 2). Annex 3: Step-heating
40
Ar/
39
Ar age spectra for FCp (Fig. A3.1) and Hb3gr (Fig. A3.2).
Some footnotes to the optimization-based calibration of the
40
Ar/
39
Ar system
Authors: Renne Paul R.
Published: July 2013

A recent calibration of the
40
Ar/
39
Ar geochronometer is based on an optimization analysis of
40
K activity data, isotopic data for the Fish Canyon sanidine (FCs) standard, and pairs of
40
Ar/
39
Ar+
238
U–
206
Pb data from selected samples meeting well-documented quality criteria. Inclusion of
238
U–
206
Pb data in the calibration incorporates the precisely known
238
U decay constant. Thus, this calibration is inherently consistent with the U–Pb chronometer. Initial presentation of the calibration included an inappropriate datum and should be eschewed in preference to a revision. Compared with previous calibrations, including those focusing mainly on the age of a standard (e.g. astronomical calibrations), the optimization calibration provides superior accuracy in the sense of propagated age uncertainty, particularly for ages much older than the FCs. Recent literature reveals that the optimization-based calibration has been misused and misrepresented in some cases; discussion of these cases clarifies the correct usage of the approach. Apparent conflict between
40
Ar/
39
Ar and
238
U–
206
Pb ages for a Quaternary tuff do not appear to be a result of error in one of the three parameters determined by the optimization approach for the
40
Ar/
39
Ar system. The optimization approach easily accommodates new constraints, but rigorous quality control is needed to maintain accuracy.
Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment
Authors: Clapper Jason R. , Hendricks Michelle D. , Gu Guibao , Wittmer Carrie , Dolman Carrie S. , Herich John , Athanacio Jennifer , Villescaz Christiane , Ghosh Soumitra S. , Heilig Joseph S. , Lowe Carolyn , Roth Jonathan D.
Published: July 2013

Shortcomings of previously reported preclinical models of nonalcoholic steatohepatitis (NASH) include inadequate methods used to induce disease and assess liver pathology. We have developed a dietary model of NASH displaying features observed clinically and methods for objectively assessing disease progression. Mice fed a diet containing 40% fat (of which ∼18% was trans fat), 22% fructose, and 2% cholesterol developed three stages of nonalcoholic fatty liver disease (steatosis, steatohepatitis with fibrosis, and cirrhosis) as assessed by histological and biochemical methods. Using digital pathology to reconstruct the left lateral and right medial lobes of the liver, we made comparisons between and within lobes to determine the uniformity of collagen deposition, which in turn informed experimental sampling methods for histological, biochemical, and gene expression analyses. Gene expression analyses conducted with animals stratified by disease severity led to the identification of several genes for which expression highly correlated with the histological assessment of fibrosis. Importantly, we have established a biopsy method allowing assessment of disease progression. Mice subjected to liver biopsy recovered well from the procedure compared with sham-operated controls with no apparent effect on liver function. Tissue obtained by biopsy was sufficient for gene and protein expression analyses, providing the opportunity to establish an objective method of assessing liver pathology before subjecting animals to treatment. The improved assessment techniques and the observation that mice fed the high-fat diet exhibit many clinically relevant characteristics of NASH establish a preclinical model for identifying pharmacological interventions with greater likelihood of translating to the clinic.
Developmental origins of colon smooth muscle dysfunction in IBS-like rats
Authors: Li Qingjie , Winston John H. , Sarna Sushil K.
Published: July 2013

Epidemiological studies show that subsets of adult and pediatric patients with irritable bowel syndrome (IBS) have prior exposures to psychological or inflammatory stress. We investigated the cellular mechanisms of colonic smooth muscle dysfunction in adult rats subjected to neonatal inflammation. Ten-day-old male rat pups received 2,4,6-trinitrobenzene sulfonic acid to induce colonic inflammation. Colonic circular smooth muscle strips were obtained 6 to 8 wk later. We found that about half of the neonate pups subjected to inflammatory insult showed a significant increase in expression of the pore-forming α1C-subunit of Ca v 1.2b channels in adult life. These were the same rats in whom Vip mRNA increased in the colon muscularis externae. Additional experiments showed reduced interaction of histone deacetylase (HDAC) 3 with α 1C 1b promoter that increased the acetylation of histone H3 lysine 9 (H3K9) in the core promoter region. Vasoactive intestinal peptide (VIP) treatment of naïve muscularis externae swiftly recruited CREB-binding protein (CBP) to the α 1C 1b promoter and dissociated HDAC3 from this region to initiate transcription. The CBP interaction with the α 1C 1b promoter was transient, but the dissociation of HDAC3 persisted to sustain H3K9 hyperacetylation and increase in transcription. Intraperitoneal treatment of adult naïve rats with butyrate mimicked the effects of neonatal colon inflammation. We concluded that neonatal inflammation upregulates VIP in the colon muscularis externae, which modulates epigenetic events at the α 1C 1b promoter to activate α 1C 1b gene transcription. Inflammatory insult in early life may be one of the etiologies of smooth muscle dysfunction in adult life, which contributes to the altered motility function in patients with diarrhea-predominant IBS.
Transcellular oxalate and Cl−absorption in mouse intestine is mediated by the DRA anion exchanger Slc26a3, and DRA deletion decreases urinary oxalate
Authors: Freel Robert W. , Whittamore Jonathan M. , Hatch Marguerite
Published: July 2013

Active transcellular oxalate transport in the mammalian intestine contributes to the homeostasis of this important lithogenic anion. Several members of the Slc26a gene family of anion exchangers have a measurable oxalate affinity and are expressed along the gut, apically and basolaterally. Mouse Slc26a6 (PAT1) targets to the apical membrane of enterocytes in the small intestine, and its deletion results in net oxalate absorption and hyperoxaluria. Apical exchangers of the Slc26a family that mediate oxalate absorption have not been established, yet the Slc26a3 [downregulated in adenoma (DRA)] protein is a candidate mediator of oxalate uptake. We evaluated the role of DRA in intestinal oxalate and Cl−transport by comparing unidirectional and net ion fluxes across short-circuited segments of small (ileum) and large (cecum and distal colon) intestine from wild-type (WT) and DRA knockout (KO) mice. In WT mice, all segments demonstrated net oxalate and Cl−absorption to varying degrees. In KO mice, however, all segments exhibited net anion secretion, which was consistently, and solely, due to a significant reduction in the absorptive unidirectional fluxes. In KO mice, daily urinary oxalate excretion was reduced 66% compared with that in WT mice, while urinary creatinine excretion was unchanged. We conclude that DRA mediates a predominance of the apical uptake of oxalate and Cl−absorbed in the small and large intestine of mice under short-circuit conditions. The large reductions in urinary oxalate excretion underscore the importance of transcellular intestinal oxalate absorption, in general, and, more specifically, the importance of the DRA exchanger in oxalate homeostasis.
Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome
Authors: Ringel Yehuda , Maharshak Nitsan
Published: July 2013

The pathophysiology of irritable bowel syndrome (IBS) is believed to involve alterations in the brain-gut axis; however, the etiological triggers and mechanisms by which these changes lead to symptoms of IBS remain poorly understood. Although IBS is often considered a condition without an identified “organic” etiology, emerging evidence suggests that alterations in the gastrointestinal microbiota and altered immune function may play a role in the pathogenesis of the disorder. These recent data suggest a plausible model in which changes in the intestinal microbiota and activation of the enteric immune system may impinge upon the brain-gut axis, causing the alterations in gastrointestinal function and the clinical symptoms observed in patients with IBS. This review summarizes the current evidence for altered intestinal microbiota and immune function in IBS. It discusses the potential etiological role of these factors, suggests an updated conceptual model for the pathogenesis of the disorder, and identifies areas for future research.
Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis
Authors: Delgado María Gabriela , Gracia-Sancho Jordi , Marrone Giusi , Rodríguez-Vilarrupla Aina , Deulofeu Ramon , Abraldes Juan G. , Bosch Jaume , García-Pagán Juan Carlos
Published: July 2013

Increased hepatic vascular resistance mainly due to elevated vascular tone and to fibrosis is the primary factor in the development of portal hypertension in cirrhosis. Leptin, a hormone associated with reduction in nitric oxide bioavailability, vascular dysfunction, and liver fibrosis, is increased in patients with cirrhosis. We aimed at evaluating whether leptin influences the increased hepatic resistance in portal hypertension. CCl4-cirrhotic rats received the leptin receptor-blocker ObR antibody, or its vehicle, every other day for 1 wk. Hepatic and systemic hemodynamics were measured in both groups. Hepatic nitric oxide production and bioavailability, together with oxidative stress, nitrotyrosinated proteins, and liver fibrosis, were evaluated. In cirrhotic rats, leptin-receptor blockade significantly reduced portal pressure without modifying portal blood flow, suggesting a reduction in the intrahepatic resistance. Portal pressure reduction was associated with increased nitric oxide bioavailability and with decreased O2− levels and nitrotyrosinated proteins. No changes in systemic hemodynamics and liver fibrosis were observed. In conclusion, the present study shows that blockade of the leptin signaling pathway in cirrhosis significantly reduces portal pressure. This effect is probably due to a nitric oxide-mediated reduction in the hepatic vascular tone.
The effects of inspiratory muscle training on plasma interleukin-6 concentration during cycling exercise and a volitional mimic of the exercise hyperpnea
Authors: Mills Dean E. , Johnson Michael A. , McPhilimey Martin J. , Williams Neil C. , Gonzalez Javier T. , Barnett Yvonne A. , Sharpe Graham R.
Published: July 2013

It is unknown whether the respiratory muscles contribute to exercise-induced increases in plasma interleukin-6 (IL-6) concentration, if this is related to diaphragm fatigue, and whether inspiratory muscle training (IMT) attenuates the plasma IL-6 response to whole body exercise and/or a volitional mimic of the exercise hyperpnea. Twelve healthy males were divided equally into an IMT or placebo (PLA) group, and before and after a 6-wk intervention they undertook, on separate days, 1 h of 1) passive rest, 2) cycling exercise at estimated maximal lactate steady state power (EX), and 3) volitional hyperpnea at rest, which mimicked the breathing and respiratory muscle recruitment patterns achieved during EX (HYPEX). Plasma IL-6 concentration remained unchanged during passive rest. The plasma IL-6 response to EX was reduced following IMT (main effect of intervention, P = 0.039) but not PLA ( P = 0.272). Plasma IL-6 concentration increased during HYPEX (main effect of time, P < 0.01) and was unchanged postintervention. There was no evidence of diaphragm fatigue (measured by phrenic nerve stimulation) following each trial. In conclusion, plasma IL-6 concentration is increased during EX and HYPEX and this occurred in the absence of diaphragm fatigue. Furthermore, IMT reduced the plasma IL-6 response to EX but not HYPEX. These findings suggest that the respiratory muscles contribute to exercise-induced increases in plasma IL-6 concentration in the absence of diaphragm fatigue and that IMT can reduce the magnitude of the response to exercise but not a volitional mimic of the exercise hyperpnea.
Muscle blood flow, hypoxia, and hypoperfusion
Authors: Joyner Michael J. , Casey Darren P.
Published: July 2013

Blood flow increases to exercising skeletal muscle, and this increase is driven primarily by vasodilation in the contracting muscles. When oxygen delivery to the contracting muscles is altered by changes in arterial oxygen content, the magnitude of the vasodilator response to exercise changes. It is augmented during hypoxia and blunted during hyperoxia. Because the magnitude of the increased vasodilation during hypoxic exercise tends to keep oxygen delivery to the contracting muscles constant, we have termed this phenomenon “compensatory vasodilation.” In a series of studies, we have explored metabolic, endothelial, and neural mechanisms that might contribute to compensatory vasodilation. These include the contribution of vasodilating substances like nitric oxide (NO) and adenosine, along with altered interactions between sympathetic vasoconstriction and metabolic vasodilation. We have also compared the compensatory vasodilator responses to hypoxic exercise with those seen when oxygen delivery to contracting muscles is altered by acute reductions in perfusion pressure. A synthesis of our findings indicate that NO contributes to the compensatory dilator responses during both hypoxia and hypoperfusion, while adenosine appears to contribute only during hypoperfusion. During hypoxia, the NO-mediated component is linked to a β-adrenergic receptor mechanism during lower intensity exercise, while another source of NO is engaged at higher exercise intensities. There are also subtle interactions between α-adrenergic vasoconstriction and metabolic vasodilation that influence the responses to hypoxia, hyperoxia, and hypoperfusion. Together our findings emphasize both the tight linkage of oxygen demand and supply during exercise and the redundant nature of the vasomotor responses to contraction.
Myeloid-Derived Suppressor Cells as Osteoclast Progenitors: A Novel Target for Controlling Osteolytic Bone Metastasis
Authors: Sawant Anandi , Ponnazhagan Selvarangan
Published: July 2013

Immune cells and their secreted growth factors play major roles in tumor growth and metastasis. Interplay between the growing tumor and infiltrating immune cells determines the nature of immune response and ultimately, tumor fate. Increased infiltration of protumorigenic immune cells promotes tumor growth as well as dissemination to distant sites. These cells induce immunosuppression that inhibits proliferation and functions of cells of antitumor immune response. One population of immunosuppressive cells that is increasingly gaining attention is myeloid-derived suppressor cells (MDSC). MDSCs are immature myeloid progenitors that suppress T-cell effector functions and promote angiogenesis. MDSC numbers are elevated at both the primary tumor and metastatic sites, including bone. In addition to immunosuppressive functions of MDSCs, we and others have recently discovered a novel function for MDSCs as osteoclast progenitors. Osteolysis is a common complication in the carcinomas of breast, lung, prostate, and multiple myeloma with poor prognosis. Therefore, targeting the functions of MDSCs may exert dual therapeutic effects on immunosuppression and bone pathology. Cancer Res; 73(15); 4606–10. ©2013 AACR.
Comparative Expression Analysis Reveals Lineage Relationships between Human and Murine Gliomas and a Dominance of Glial Signatures during Tumor PropagationIn Vitro
Authors: Henriquez Nico V. , Forshew Tim , Tatevossian Ruth , Ellis Matthew , Richard-Loendt Angela , Rogers Hazel , Jacques Thomas S. , Reitboeck Pablo Garcia , Pearce Kerra , Sheer Denise , Grundy Richard G. , Brandner Sebastian
Published: July 2013

Brain tumors are thought to originate from stem/progenitor cell populations that acquire specific genetic mutations. Although current preclinical models have relevance to human pathogenesis, most do not recapitulate the histogenesis of the human disease. Recently, a large series of human gliomas and medulloblastomas were analyzed for genetic signatures of prognosis and therapeutic response. Using a mouse model system that generates three distinct types of intrinsic brain tumors, we correlated RNA and protein expression levels with human brain tumors. A combination of genetic mutations and cellular environment during tumor propagation defined the incidence and phenotype of intrinsic murine tumors. Importantly, in vitro passage of cancer stem cells uniformly promoted a glial expression profile in culture and in brain tumors. Gene expression profiling revealed that experimental gliomas corresponded to distinct subclasses of human glioblastoma, whereas experimental supratentorial primitive neuroectodermal tumors (sPNET) correspond to atypical teratoid/rhabdoid tumor (AT/RT), a rare childhood tumor. Cancer Res; 73(18); 5834–44. ©2013 AACR.
KIT Signaling Governs Differential Sensitivity of Mature and Primitive CML Progenitors to Tyrosine Kinase Inhibitors
Authors: Corbin Amie S. , O'Hare Thomas , Gu Zhimin , Kraft Ira L. , Eiring Anna M. , Khorashad Jamshid S. , Pomicter Anthony D. , Zhang Tian Y. , Eide Christopher A. , Manley Paul W. , Cortes Jorge E. , Druker Brian J. , Deininger Michael W.
Published: July 2013

Imatinib and other BCR-ABL1 inhibitors are effective therapies for chronic myelogenous leukemia (CML), but these inhibitors target additional kinases including KIT, raising the question of whether off-target effects contribute to clinical efficacy. On the basis of its involvement in CML pathogenesis, we hypothesized that KIT may govern responses of CML cells to imatinib. To test this, we assessed the growth of primary CML progenitor cells under conditions of sole BCR-ABL1, sole KIT, and dual BCR-ABL1/KIT inhibition. Sole BCR-ABL1 inhibition suppressed mature CML progenitor cells, but these effects were largely abolished by stem cell factor (SCF) and maximal suppression required dual BCR-ABL1/KIT inhibition. In contrast, KIT inhibition did not add to the effects of BCR-ABL1 inhibition in primitive progenitors, represented by CD34+38− cells. Long-term culture-initiating cell assays on murine stroma revealed profound depletion of primitive CML cells by sole BCR-ABL1 inhibition despite the presence of SCF, suggesting that primitive CML cells are unable to use SCF as a survival factor upon BCR-ABL1 inhibition. In CD34+38+ cells, SCF strongly induced pAKTS473 in a phosphoinositide 3-kinase (PI3K)–dependent manner, which was further enhanced by inhibition of BCR-ABL1 and associated with increased colony survival. In contrast, pAKTS473 levels remained low in CD34+38− cells cultured under the same conditions. Consistent with reduced response to SCF, KIT surface expression was significantly lower on CD34+38− compared with CD34+38+ CML cells, suggesting a possible mechanism for the differential effects of SCF on mature and primitive CML progenitor cells. Cancer Res; 73(18); 5775–86. ©2013 AACR.
Dacarbazine in Solitary Fibrous Tumor: A Case Series Analysis and Preclinical Evidence vis-à-vis Temozolomide and Antiangiogenics
Authors: Stacchiotti S. , Tortoreto M. , Bozzi F. , Tamborini E. , Morosi C. , Messina A. , Libertini M. , Palassini E. , Cominetti D. , Negri T. , Gronchi A. , Pilotti S. , Zaffaroni N. , Casali P.G.
Published: July 2013

Purpose: To explore the value of triazines in solitary fibrous tumor (SFT).

Experimental Design: We retrospectively reviewed 8 cases of patients with SFT treated with dacarbazine (1,200 mg/m2 every 3 weeks) as from January 2012. Then, we studied a dedifferentiated-SFT subcutaneously xenotransplanted into severe combined immunodeficient (SCID) mice. Dacarbazine, temozolomide, sunitinib, bevacizumab, and pazopanib were administered at their reported optimal doses for the mouse model when mean tumor volume (TV) was about 80 mm3; each experimental groups included 6 mice. Drug activity was assessed as tumor volume inhibition percentage (TVI%). Dacarbazine was tested according to two different schedules of administration. One hunded twenty days after treatment interruption, mouse tumor samples were analyzed.

Results: Among the eight patients treated with dacarbazine, best response evaluation criteria in solid tumors responses (RECIST) were three partial responses, 4 stable disease, 1 progression. Two responsive patients had paraneoplastic hypoglycemia that disappeared after 10 days from starting dacarbazine. In the dedifferentiated-SFT xenograft model, dacarbazine and temozolomide showed the highest antitumor activity (about 95% TVI), confirmed pathologically. Sunitinib and pazopanib were only marginally active (52% and 41% TVI, respectively), whereas bevacizumab caused a 78% TVI. No tumor regrowth was observed up to 100 days from end of treatment with temozolomide and dacarbazine, whereas secondary progression followed sunitinib, pazopanib, and bevacizumab interruption.

Conclusions: Dacarbazine as single agent has antitumor activity in SFT. Our preclinical results suggest a cytotoxic effect of temozolomide and dacarbazine, as compared with a cytostatic role for sunitinib, pazopanib, and bevacizumab. A phase II study on dacarbazine in advanced SFT is planned. Clin Cancer Res; 19(18); 5192–201. ©2013 AACR.
PIK3CA and AKT1 Mutations Have Distinct Effects on Sensitivity to Targeted Pathway Inhibitors in an Isogenic Luminal Breast Cancer Model System
Authors: Beaver Julia A. , Gustin John P. , Yi Kyung H. , Rajpurohit Anandita , Thomas Matthew , Gilbert Samuel F. , Rosen D. Marc , Ho Park Ben , Lauring Josh
Published: July 2013

Purpose: Activating mutations in the phosphoinositide-3-kinase (PI3K)/AKT/mTOR pathway are present in the majority of breast cancers and therefore are a major focus of drug development and clinical trials. Pathway mutations have been proposed as predictive biomarkers for efficacy of PI3K-targeted therapies. However, the precise contribution of distinct PI3K pathway mutations to drug sensitivity is unknown.

Experimental Design: We describe the creation of a physiologic human luminal breast cancer cell line model to study the phenotype of these mutations using the MCF-7 cell line. We used somatic cell gene targeting to “correct” PIK3CA E545K-mutant alleles in MCF-7 cells to wild-type sequence. The AKT1 E17K hotspot mutation was knocked in on this wild-type background.

Results: Loss of mutant PIK3CA dramatically reduced phosphorylation of AKT proteins and several known AKT targets, but other AKT target proteins and downstream effectors of mTOR were not affected. PIK3CA wild-type cells exhibited reduced proliferation in vitro and in vivo. Knockin of the AKT1 E17K hotspot mutation on this PIK3CA wild-type background restored pathway signaling, proliferation, and tumor growth in vivo. PIK3CA, but not AKT1 mutation, increased sensitivity to the PI3K inhibitor GDC-0941 and the allosteric AKT inhibitor MK-2206.

Conclusions: AKT1 E17K is a bona fide oncogene in a human luminal breast cancer context. Distinct PI3K pathway mutations confer differential sensitivity to drugs targeting the pathway at different points and by distinct mechanisms. These findings have implications for the use of tumor genome sequencing to assign patients to targeted therapies. Clin Cancer Res; 19(19); 5413–22. ©2013 AACR.
Ligand-Dependent Activation of EGFR in Follicular Dendritic Cells Sarcoma is Sustained by Local Production of Cognate Ligands
Authors: Vermi William , Giurisato Emanuele , Lonardi Silvia , Balzarini Piera , Rossi Elisa , Medicina Daniela , Bosisio Daniela , Sozzani Silvano , Pellegrini Wilma , Doglioni Claudio , Marchetti Antonio , Rossi Giulio , Pileri Stefano , Facchetti Fabio
Published: July 2013

Purpose: The aim of this study was to investigate the biological and clinical significance of epidermal growth factor receptor (EGFR) signaling pathway in follicular dendritic cell sarcoma (FDC-S).

Experimental Design: Expression of EGFR and cognate ligands as well as activation of EGFR signaling components was assessed in clinical samples and in a primary FDC-S short-term culture (referred as FDC-AM09). Biological effects of the EGFR antagonists cetuximab and panitumumab and the MEK inhibitor UO126 on FDC-S cells were determined in vitro on FDC-AM09. Direct sequencing of KRAS, BRAF, and PI3KCA was conducted on tumor DNA.

Results: We found a strong EGFR expression on dysplastic and neoplastic FDCs. On FDC-AM09, we could show that engagement of surface EGFR by cognate ligands drives the survival and proliferation of FDC-S cells, by signaling to the nucleus mainly via MAPK and STAT pathways. Among EGFR ligands, heparin-binding EGF-like growth factor, TGF-α and Betacellulin (BTC) are produced in the tumor microenvironment of FDC-S at RNA level. By extending this finding at protein level we found that BTC is abundantly produced by FDC-S cells and surrounding stromal cells. Finally, direct sequencing of tumor-derived genomic DNA showed that mutations in KRAS, NRAS, BRAF, and PI3KCA, which predicts resistance to anti-EGFR MoAb in other cancer models, are not observed in FDC-S.

Conclusion: Activation of EGFR by cognate ligands produced in the tumor microenvironment sustain viability and proliferation of FDC-S indicating that the receptor blockade might be clinically relevant in this neoplasm. Clin Cancer Res; 19(18); 5027–38. ©2013 AACR.
Expression of Tumor Necrosis Factor-Like Weak Inducer of Apoptosis in Human Middle Ear Cholesteatoma
Authors: Park M. , Lee B. , Lee J.
Published: July 2013

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) was recently identified as a member of the TNF superfamily of structurally related cytokines. It regulates TNF-α and numerous cellular responses. We investigated whether TWEAK is upregulated in human middle ear cholesteatoma compared to the skin of the normal external auditory canal (EAC). The expression of TWEAK was analyzed using reverse transcription-polymerase chain reaction, Western blotting and immunohistochemical staining. TWEAK expression was correlated with that of TNF-α as determined by Western blotting. The expression of TWEAK and TNF-α protein was stronger in cholesteatoma tissue than in EAC skin. TWEAK was expressed to a greater degree in the suprabasal layer in the cholesteatoma than in EAC skin. The expression of TWEAK was correlated more closely with single-stranded DNA than Ki-67 immunohistochemically. These findings imply that TWEAK plays an important role in modulating TNF-α expression and apoptosis in cholesteatoma.
Current Understanding of Skin Barrier Morphology
Authors: Norlén L.
Published: July 2013

It was recently shown that the stratum corneum fat layer, i.e. the skin permeability barrier, has a unique molecular arrangement - stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety. We here give a brief historical perspective to the field of skin permeability barrier research and specifically address some selected contributions to the current understanding of skin barrier morphology.
Percutaneous Penetration Paradigms: The Contribution of Jonathan Hadgraft
Authors: Lane M.E.
Published: July 2013

This paper addresses the application of physical chemistry towards understanding the processes of percutaneous penetration. Over the years, this approach has been used by the subject of this review to advance our knowledge of the skin and to interpret, model and predict dermal delivery. The basic laws of diffusion provide a framework for the comprehension of skin permeability and, as a corollary, how the barrier function can be modulated. The importance of understanding the physicochemical properties of potential skin permeants is highlighted. Rational formulation strategies for passive skin delivery are outlined. However, the overriding emphasis is that multidisciplinary approaches must be used to advance the field. This is exemplified in the work and references cited.
Skin - ‘That Unfakeable Young Surface'
Authors: Guy R.H.
Published: July 2013

The 20- to 25-year period from the mid-1960s to the early 1990s represents, in many ways, a ‘golden era' in the understanding of skin barrier function, percutaneous penetration and (trans)dermal drug delivery. From the ground-breaking mechanistic work of Scheuplein and Blank, and the ‘gold standard' in vivo skin absorption experiments of Feldmann and Maibach, through the unravelling of the stratum corneum's structural and physicochemical characteristics that make it such an incredible feat of bioengineering, to the elegant biophysical and modelling studies of Potts, Francoeur and many others, the idea of administering drugs rationally to treat both local and systemic diseases was transformed from something close to the ravings of a lunatic to the reality of significant therapeutic and commercial success. This short article attempts to pick out some of the highlights along the way from the viewpoint of an interested observer and occasional participant in the ‘action'.
Brian Barry: Innovative Contributions to Transdermal and Topical Drug Delivery
Authors: Williams A.C.
Published: July 2013

Brian Barry published over 300 research articles across topics ranging from colloid science, vasoconstriction and the importance of thermodynamics in dermal drug delivery to exploring the structure and organisation of the stratum corneum barrier lipids and numerous strategies for improving topical and transdermal drug delivery, including penetration enhancers, supersaturation, coacervation, eutectic formation and the use of varied liposomes. As research in the area blossomed in the early 1980s, Brian wrote the book that became essential reading for both new and established dermal delivery scientists, explaining the background mathematics and principles through to formulation design. Brian also worked with numerous scientists, as collaborators and students, who have themselves taken his rigorous approach to scientific investigation into their own research groups. This paper can only describe a small fraction of the many significant contributions that Brian made to the field during his 40-year academic career.
Solute-Vehicle-Skin Interactions in Percutaneous Absorption: The Principles and the People
Authors: Roberts M.S.
Published: July 2013

An appreciation of solute-vehicle-skin interactions underpins our current understanding of the processes of percutaneous absorption as well as in the prediction of the extent of absorption. This understanding has been reached through principles developed and validated over the last century through the work of a number of authors, including Dale Wurster, Takeru Higuchi, Irvin Blank, Robert Scheuplein, Gordon Flynn, Boyd Poulsen and Tom Franz, as well as by many scientists from my and younger generations. Their work has led to an appreciation of the rate-limiting steps in percutaneous penetration, the role played by the physicochemical properties of the solute, vehicle and skin and the variability that may arise from using various experimental/mathematical/pharmacokinetic models to quantify absorption as well as enabling the prediction of local and systemic efficacy and toxicity. In addition, unexpected behaviour may result from non-ideality in solute-vehicle-skin effects, including dehydration, chemical enhancement, supersaturation, metabolism, sequestration and vascular effects, including those of nanosystems on the local vasculature. In general, in vitro skin penetration profiles are predictive of in vivo profiles but a number of exceptions also exist.
β1-Integrin Is Essential for Vasoregulation and Smooth Muscle Survival In Vivo
Authors: Turlo Kirsten A. , Scapa Jason , Bagher Pooneh , Jones Allan W. , Feil Robert , Korthuis Ronald J. , Segal Steven S. , Iruela-Arispe M. Luisa
Published: July 2013

Objective—

Integrins contribute to vascular morphogenesis through regulation of adhesion and assembly of the extracellular matrix. However, the role of β1-integrin in the mature vascular wall is less clear.

Approach and Results—

We sought to determine the function of β1-integrin in mature smooth muscle cells in vivo using a loss of function approach by crossing a tamoxifen-inducible sm22αCre line to a floxed β1-integrin transgenic line. Adult mice lacking smooth muscle β1-integrin survived only 10 weeks post induction. The deletion of β1-integrin resulted in profound loss of vasomotor control. Histological analysis revealed progressive fibrosis in arteries with associated apoptosis of smooth muscle cells, which was not rescued by adventitial stem cells. Smooth muscle cell apoptosis was detected in arteries with dead cells replaced primarily by collagen. Despite the catastrophic effects on vascular smooth muscle, the deleted visceral smooth muscle remained viable with the exception of a short portion of the colon, indicating that vascular but not visceral smooth muscle is particularly sensitive to changes in β1-integrin.

Conclusions—

This study reveals an essential function of β1-integrin in the maintenance of vasomotor control and highlights a critical role for β1-integrin in vascular, but not visceral, smooth muscle survival.