bluuebunny/crossref_metadata_2025 huggingface dataset:
Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells
Authors: Asai Takashi , Liu Yan , Di Giandomenico Silvana , Bae Narae , Ndiaye-Lobry Delphine , Deblasio Anthony , Menendez Silvia , Antipin Yevgeniy , Reva Boris , Wevrick Rachel , Nimer Stephen D.
Published: July 2012

We recently defined a critical role for p53 in regulating the quiescence of adult hematopoietic stem cells (HSCs) and identified necdin as a candidate p53 target gene. Necdin is a growth-suppressing protein and the gene encoding it is one of several that are deleted in patients with Prader-Willi syndrome. To define the intrinsic role of necdin in adult hematopoiesis, in the present study, we transplanted necdin-null fetal liver cells into lethally irradiated recipients. We show that necdin-null adult HSCs are less quiescent and more proliferative than normal HSCs, demonstrating the similar role of necdin and p53 in promoting HSC quiescence during steady-state conditions. However, wild-type recipients repopulated with necdin-null hematopoietic stem/progenitor cells show enhanced sensitivity to irradiation and chemotherapy, with increased p53-dependent apoptosis, myelosuppression, and mortality. Necdin controls the HSC response to genotoxic stress via both cell-cycle–dependent and cell-cycle–independent mechanisms, with the latter occurring in a Gas2L3-dependent manner. We conclude that necdin functions as a molecular switch in adult hematopoiesis, acting in a p53-like manner to promote HSC quiescence in the steady state, but suppressing p53-dependent apoptosis in response to genotoxic stress.
A Systematic Review of Healthcare Applications for Smartphones
Authors: Mosa Abu Saleh Mohammad , Yoo Illhoi , Sheets Lincoln
Published: July 2012

Background

Advanced mobile communications and portable computation are now combined in handheld devices called “smartphones”, which are also capable of running third-party software. The number of smartphone users is growing rapidly, including among healthcare professionals. The purpose of this study was to classify smartphone-based healthcare technologies as discussed in academic literature according to their functionalities, and summarize articles in each category.

Methods

In April 2011, MEDLINE was searched to identify articles that discussed the design, development, evaluation, or use of smartphone-based software for healthcare professionals, medical or nursing students, or patients. A total of 55 articles discussing 83 applications were selected for this study from 2,894 articles initially obtained from the MEDLINE searches.

Results

A total of 83 applications were documented: 57 applications for healthcare professionals focusing on disease diagnosis (21), drug reference (6), medical calculators (8), literature search (6), clinical communication (3), Hospital Information System (HIS) client applications (4), medical training (2) and general healthcare applications (7); 11 applications for medical or nursing students focusing on medical education; and 15 applications for patients focusing on disease management with chronic illness (6), ENT-related (4), fall-related (3), and two other conditions (2). The disease diagnosis, drug reference, and medical calculator applications were reported as most useful by healthcare professionals and medical or nursing students.

Conclusions

Many medical applications for smartphones have been developed and widely used by health professionals and patients. The use of smartphones is getting more attention in healthcare day by day. Medical applications make smartphones useful tools in the practice of evidence-based medicine at the point of care, in addition to their use in mobile clinical communication. Also, smartphones can play a very important role in patient education, disease self-management, and remote monitoring of patients.
Effect of essential fatty acids on glucose-induced cytotoxicity to retinal vascular endothelial cells
Authors: Shen Junhui , Shen Shengrong , Das Undurti N , Xu Guotong
Published: July 2012

Background

Diabetic retinopathy is a major complication of dysregulated hyperglycemia. Retinal vascular endothelial cell dysfunction is an early event in the pathogenesis of diabetic retinopathy. Studies showed that hyperglycemia-induced excess proliferation of retinal vascular endothelial cells can be abrogated by docosahexaenoic acid (DHA, 22:6 ω-3) and eicosapentaenoic acid (EPA, 20:5 ω-3). The influence of dietary omega-3 PUFA on brain zinc metabolism has been previously implied. Zn2+ is essential for the activity of Δ6 desaturase as a co-factor that, in turn, converts essential fatty acids to their respective long chain metabolites. Whether essential fatty acids (EFAs) α-linolenic acid and linoleic acid have similar beneficial effect remains poorly understood.

Methods

RF/6A cells were treated with different concentrations of high glucose, α-linolenic acid and linoleic acid and Zn2+. The alterations in mitochondrial succinate dehydrogenase enzyme activity, cell membrane fluidity, reactive oxygen species generation, SOD enzyme and vascular endothelial growth factor (VEGF) secretion were evaluated.

Results

Studies showed that hyperglycemia-induced excess proliferation of retinal vascular endothelial cells can be abrogated by both linoleic acid (LA) and α-linolenic acid (ALA), while the saturated fatty acid, palmitic acid was ineffective. A dose–response study with ALA showed that the activity of the mitochondrial succinate dehydrogenase enzyme was suppressed at all concentrations of glucose tested to a significant degree. High glucose enhanced fluorescence polarization and microviscocity reverted to normal by treatment with Zn2+ and ALA. ALA was more potent that Zn2+. Increased level of high glucose caused slightly increased ROS generation that correlated with corresponding decrease in SOD activity. ALA suppressed ROS generation to a significant degree in a dose dependent fashion and raised SOD activity significantly. ALA suppressed high-glucose-induced VEGF secretion by RF/6A cells.

Conclusions

These results suggest that EFAs such as ALA and LA may have beneficial action in the prevention of high glucose-induced cellular damage.
Chimeric Hepatitis B core antigen virus-like particles displaying the envelope domain III of dengue virus type 2
Authors: Arora Upasana , Tyagi Poornima , Swaminathan Sathyamangalam , Khanna Navin
Published: July 2012

Background

Dengue is a global public health problem for which no drug or vaccine is available. Currently, there is increasing interest in developing non-replicating dengue vaccines based on a discrete antigenic domain of the major structural protein of dengue viruses (DENVs), known as envelope domain III (EDIII). The use of bio-nanoparticles consisting of recombinant viral structural polypeptides, better known as virus-like particles (VLPs), has emerged as a potential platform technology for vaccine development. This work explores the feasibility of developing nanoparticles based on E. coli- expressed recombinant Hepatitis B virus core antigen (HBcAg) designed to display EDIII moiety of DENV on the surface.

Findings

We designed a synthetic gene construct encoding HBcAg containing an EDIII insert in its c/e1 loop. The fusion antigen HBcAg-EDIII-2 was expressed in E. coli, purified to near homogeneity using Ni+2 affinity chromatography and demonstrated to assemble into discrete 35–40 nm VLPs by electron microscopy. Competitive ELISA analyses showed that the EDIII-2 moieties of the VLPs are accessible to anti-EDIII-2-specific monoclonal and polyclonal antibodies, suggesting that they are surface-displayed. The VLPs were highly immunogenic eliciting high titer anti-EDIII-2 antibodies that were able to recognize, bind and neutralize infectious DENV based on ELISA, immunofluorescence and virus-neutralization assays.

Conclusion

This work demonstrates that HBcAg-derived nanoparticles can serve as a useful platform for the display of DENV EDIII. The EDIII-displaying nanoparticles may have potential applications in diagnostics/vaccines for dengue.
18 F-FDG PET-CT during chemo-radiotherapy in patients with non-small cell lung cancer: the early metabolic response correlates with the delivered radiation dose
Authors: Massaccesi Mariangela , Calcagni Maria Lucia , Spitilli Maria Grazia , Cocciolillo Fabrizio , Pelligrò Francesca , Bonomo Lorenzo , Valentini Vincenzo , Giordano Alessandro
Published: July 2012

Background

To evaluate the metabolic changes on 18 F-fluoro-2-deoxyglucose positron emission tomography integrated with computed tomography (18 F-FDG PET-CT) performed before, during and after concurrent chemo-radiotherapy in patients with locally advanced non-small cell lung cancer (NSCLC); to correlate the metabolic response with the delivered radiation dose and with the clinical outcome.

Methods

Twenty-five NSCLC patients candidates for concurrent chemo-radiotherapy underwent 18 F-FDG PET-CT before treatment (pre-RT PET-CT), during the third week (during-RT PET-CT) of chemo-radiotherapy, and 4 weeks from the end of chemo-radiotherapy (post-RT PET-CT). The parameters evaluated were: the maximum standardized uptake value (SUVmax) of the primary tumor, the SUVmax of the lymph nodes, and the Metabolic Tumor Volume (MTV).

Results

SUVmax of the tumor and MTV significantly (p=0.0001, p=0.002, respectively) decreased earlier during the third week of chemo-radiotherapy, with a further reduction 4 weeks from the end of treatment (p<0.0000, p<0.0002, respectively). SUVmax of lymph nodes showed a trend towards a reduction during chemo-radiotherapy (p=0.06) and decreased significantly (p=0.0006) at the end of treatment. There was a significant correlation (r=0.53, p=0.001) between SUVmax of the tumor measured at during-RT PET-CT and the total dose of radiotherapy reached at the moment of the scan. Disease progression free survival was significantly (p=0.01) longer in patients with complete metabolic response measured at post-RT PET-CT.

Conclusions

In patients with locally advanced NSCLC, 18 F-FDG PET-CT performed during and after treatment allows early metabolic modifications to be detected, and for this SUVmax is the more sensitive parameter. Further studies are needed to investigate the correlation between the metabolic modifications during therapy and the clinical outcome in order to optimize the therapeutic strategy. Since the metabolic activity during chemo-radiotherapy correlates with the cumulative dose of fractionated radiotherapy delivered at the moment of the scan, special attention should be paid to methodological aspects, such as the radiation dose reached at the time of PET.
Progranulin regulates neuronal outgrowth independent of Sortilin
Authors: Gass Jennifer , Lee Wing C , Cook Casey , Finch Nicole , Stetler Caroline , Jansen-West Karen , Lewis Jada , Link Christopher D , Rademakers Rosa , Nykjær Anders , Petrucelli Leonard
Published: July 2012

Background

Progranulin (PGRN), a widely secreted growth factor, is involved in multiple biological functions, and mutations located within the PGRN gene (GRN) are a major cause of frontotemporal lobar degeneration with TDP-43-positive inclusions (FLTD-TDP). In light of recent reports suggesting PGRN functions as a protective neurotrophic factor and that sortilin (SORT1) is a neuronal receptor for PGRN, we used a Sort1-deficient (Sort1

−/−
) murine primary hippocampal neuron model to investigate whether PGRN’s neurotrophic effects are dependent on SORT1. We sought to elucidate this relationship to determine what role SORT1, as a regulator of PGRN levels, plays in modulating PGRN’s neurotrophic effects.

Results

As the first group to evaluate the effect of PGRN loss in Grn knockout primary neuronal cultures, we show neurite outgrowth and branching are significantly decreased in Grn

−/−
neurons compared to wild-type (WT) neurons. More importantly, we also demonstrate that PGRN overexpression can rescue this phenotype. However, the recovery in outgrowth is not observed following treatment with recombinant PGRN harboring missense mutations p.C139R, p.P248L or p.R432C, indicating that these mutations adversely affect the neurotrophic properties of PGRN. In addition, we also present evidence that cleavage of full-length PGRN into granulin peptides is required for increased neuronal outgrowth, suggesting that the neurotrophic functions of PGRN are contained within certain granulins. To further characterize the mechanism by which PGRN impacts neuronal morphology, we assessed the involvement of SORT1. We demonstrate that PGRN induced-outgrowth occurs in the absence of SORT1 in Sort1

−/−
cultures.

Conclusion

We demonstrate that loss of PGRN impairs proper neurite outgrowth and branching, and that exogenous PGRN alleviates this impairment. Furthermore, we determined that exogenous PGRN induces outgrowth independent of SORT1, suggesting another receptor(s) is involved in PGRN induced neuronal outgrowth.
Mitochondrial DNA sequence variation in Finnish patients with matrilineal diabetes mellitus
Authors: Soini Heidi K , Moilanen Jukka S , Finnila Saara , Majamaa Kari
Published: July 2012

Background

The genetic background of type 2 diabetes is complex involving contribution by both nuclear and mitochondrial genes. There is an excess of maternal inheritance in patients with type 2 diabetes and, furthermore, diabetes is a common symptom in patients with mutations in mitochondrial DNA (mtDNA). Polymorphisms in mtDNA have been reported to act as risk factors in several complex diseases.

Findings

We examined the nucleotide variation in complete mtDNA sequences of 64 Finnish patients with matrilineal diabetes. We used conformation sensitive gel electrophoresis and sequencing to detect sequence variation. We analysed the pathogenic potential of nonsynonymous variants detected in the sequences and examined the role of the m.16189 T>C variant. Controls consisted of non-diabetic subjects ascertained in the same population. The frequency of mtDNA haplogroup V was 3-fold higher in patients with diabetes. Patients harboured many nonsynonymous mtDNA substitutions that were predicted to be possibly or probably damaging. Furthermore, a novel m.13762 T>G in MTND5 leading to p.Ser476Ala and several rare mtDNA variants were found. Haplogroup H1b harbouring m.16189 T > C and m.3010 G > A was found to be more frequent in patients with diabetes than in controls.

Conclusions

Mildly deleterious nonsynonymous mtDNA variants and rare population-specific haplotypes constitute genetic risk factors for maternally inherited diabetes.
Hypoxia-inducible factor (HIF1α) gene expression in human shock states
Authors: Textoris Julien , Beaufils Nathalie , Quintana Gabrielle , Ben Lassoued Amin , Zieleskiewicz Laurent , Wiramus Sandrine , Blasco Valéry , Lesavre Nathalie , Martin Claude , Gabert Jean , Leone Marc
Published: July 2012

Introduction

Hypoxia-inducible factor-1 (HIF1) controls the expression of genes involved in the cellular response to hypoxia. No information is available on its expression in critically ill patients. Thus, we designed the first clinical study in order to evaluate the role of HIF1α as a prognosis marker in patients suffering from shock.

Methods

Fifty consecutive adult patients with shock and 11 healthy volunteers were prospectively enrolled in the study. RNA was extracted from whole blood samples and expression of HIF1α was assessed over the first four hours of shock. The primary objective was to assess HIF1α as a prognostic marker in shock. Secondary objectives were to evaluate the role of HIF1α as a diagnostic and follow-up marker. Patient survival was evaluated at day 28.

Results

The causes of shock were sepsis (78%), hemorrhage (18%), and cardiac dysfunction (4%). HIF1α expression was significantly higher in the shock patients than in the healthy volunteers (121 (range: 72-168) versus 48 (range: 38-54) normalized copies, P <0.01), whatever the measured isoforms. It was similar in non-survivors and survivors (108 (range 84-183) versus 121(range 72-185) normalized copies, P = 0.92), and did not significantly change within the study period.

Conclusions

The present study is the first to demonstrate an increased expression of HIF1α in patients with shock. Further studies are needed to clarify the potential association with outcome. Our findings reinforce the value of monitoring plasma lactate levels to guide the treatment of shock.
The quantitative advantages of using B-field sensors in time-domain EM measurement for mineral exploration and unexploded ordnance search
Authors: Asten Michael W. , Duncan Andrew C.
Published: July 2012

The use of simple models for decay of conductive targets under conductive overburden and for the decay of magnetically permeable conductive steel objects allows quantitative consideration of the advantages of the use of magnetic-field detectors in time-domain electromagnetic (TEM) measurements, or more generally, the advantage of step response over impulse response TEM systems. We identified eight advantages of the step response versus impulse-response systems. The first two advantages relate to the inductive limit (early time) decay behavior, in which a target response amplitude is largely dependent on geometrical rather than conductivity parameters. Five further advantages occur when measuring response of a target in a conductive host or under conductive overburden; the maximum target-to-overburden response occurs 25%–30% earlier in time, the earliest target detection time occurs a factor 2–4 earlier, and the amplitude advantage of target-to-overburden response is a factor in the range of 1–10 for the step versus impulse-response systems, respectively. These advantages agree quantitatively with field observations on a chalcopyrite orebody under conductive cover. We used a model response for a conductive permeable sphere to derive mathematically consistent approximations for the power-law and exponential decay behaviors for step and impulse responses of metal objects, from which the onset of late-time exponential decay of EM responses of unexploded ordnance occurs about a factor of two earlier in time for the step response. This earlier-time transition together with the higher signal-to-noise ratio available from the step-response measurement makes measurement of the fundamental time-constant of unexploded ordnance (UXO) possible for medium and large UXO where the time constant is in the range of tens of milliseconds. This time-constant thus becomes accessible as an additional parameter for UXO characterization and discrimination.
Effect of lateral heterogeneity in the soil column on shear-wave velocity estimation by Rayleigh-wave inversion
Authors: Yilmaz Oz , Kocaoglu Argun
Published: July 2012

We conducted elastic-wavefield modeling of shot gathers using soil-column models with vertical and lateral velocity variations to study the dispersive behavior of Rayleigh waves and the effect of lateral heterogeneity on the accuracy of Rayleigh-wave inversion for shear-wave velocity estimation. We also conducted a field experiment over an alluvial valley with soil column that thins out in the direction orthogonal to the valley axis. From the model and field experiments, we found that the dispersion characteristics of Rayleigh waves are greatly influenced by the geometry of and lateral heterogeneities within the soil column. Nevertheless, estimation of shear-wave velocities within a soil column with lateral heterogeneity by Rayleigh-wave inversion is sufficiently robust and accurate for geotechnical applications.
Introduction to this special section: The Mediterranean region
Authors: Tari Gabor , Belopolsky Andrei , Peace Dave
Published: July 2012

When it comes to the Mediterranean, the figure of Odysseus, as the archetypal “explorer”, may spring to mind. The Mediterranean region represents an incredibly colorful region, not only from a historical and cultural perspective, but also from a hydrocarbon exploration point of view. Located between Europe, Africa, and the Near East, this region also has a long history of geological and geophysical activities. During the last few decades, a few segments of the Mediterranean became significant from an exploration and production point of view, the most important example being the Nile Delta of Egypt. Some segments have numerous offshore oil and gas fields (e.g., Libya or Croatia) but with a much smaller contribution to the petroleum production of the entire Mediterranean. One reason to have a TLE special section dedicated to this region is the exploration breakthrough happening in the Israeli sector of the eastern Mediterranean. Large, multi-TCF gas accumulations (e.g., Leviathan and Tamar) have been found in the deep-water Levantine Basin. The biogenic gas is reservoired in Miocene turbidites, in large inverted structures beneath the Messinian evaporite sequence. The sheer size of these recent discoveries (total recoverable reserves of about 40 TCF!) made the broader Levantine Basin an emerging major petroleum province, just in the last few years.
Recent shale tectonics and basin evolution of the NW Alboran Sea
Authors: Soto Juan I. , Fernández-Ibáñez Fermin , Talukder Asrar R.
Published: July 2012

This contribution is intended to show some of the most recent, eventually active, shale structures developed in the northwestern margin of the Alboran Sea in the western Mediterranean. Most marine geophysical data used for this study are from surveys conducted by ConocoPhillips in 2000 and 2001 in the Alboran Sea. This company explored the western sector of this basin, both in Spanish and Moroccan waters. It acquired a comprehensive data set, including a complete mosaic of sea-floor multibeam bathymetry with the associated sub-bottom high-resolution profiles, and a dense network of 2D multichannel seismic reflection profiles. These surveys provide a significant amount of new marine geophysical data, which increase the previous knowledge of the structure and characteristics of the westernmost Mediterranean region.
Structure and evolution of the Gulf of Lions: The Sardinia seismic experiment and the GOLD (Gulf of Lions Drilling) project
Authors: Aslanian D. , Moulin M. , Schnurle P. , Klingelhoefer F. , Leroux E. , Rabineau M. , Gailler A. , Bache F. , Gorini C. , Kuroda J. , Eguchi N. , Droxler A. , Alain K. , Roure F. , Haq B.
Published: July 2012

The study of the deep structure and evolution of passive continental margins is important for the understanding of rifting processes and the formation of associated sedimentary basins. Since the classical models of McKenzie (1978) and Wernicke (1985), understanding how passive continental margins form, that is to say mainly the way that continental lithosphere is thinned leading to subsidence, remains one of the main challenges in the Earth sciences. Many recent observations and discoveries have modified our basic views of margin formation. The conservational models paradigm (i.e., simple shear, pure shear, or polyphase models), which exclude exchanges between lower continental crust and upper mantle and which are usually proposed to explain lithospheric stretching and consequent crustal thinning of passive continental margins, fail to completely explain all these observations. Furthermore, these models imply a large amount of horizontal movement, movements not observed in the field. In consequence, new concepts need to be built and tested.
Gravity inversion mapping of crustal thickness and lithosphere thinning for the eastern Mediterranean
Authors: Cowie Leanne , Kusznir Nick
Published: July 2012

The distribution of oceanic and continental crust in the eastern Mediterranean region is not well understood but has major implications for tectonic evolution of this region and its petroleum systems. In particular the location of the continent-ocean boundary (COB), the ocean-continent transition (OCT) structure, and crustal thickness within the basin regions is a topic of much debate. While seismology, especially refraction seismology, is an ideal method for locally determining crustal thickness, it is limited to 2D as 3D mapping of crustal thickness is not practical or affordable over large areas. However, a recent development in 3D crustal thickness mapping uses gravity anomaly inversion. We illustrate the application of this technique using the example of the eastern Mediterranean (Figure 1). The new 3D gravity inversion technique, incorporating a lithosphere thermal gravity anomaly correction, is used to map Moho depth, crustal basement thickness, and continental lithosphere thinning. We then use this to determine the distribution of oceanic and continental crust, and ocean-continent transition structure, for the eastern Mediterranean.
Examples of deep-water play types in the Matruh and Herodotus basins of NW Egypt
Authors: Tari Gabor , Kohazy Robert , Hannke Katie , Hussein Hussein , Novotny Bernhard , Mascle Jean
Published: July 2012

Numerous deep-water play types have been identified along the transform margin of NW Egypt. A large segment of the offshore Matruh Basin has play types related to a prominent shale décollement within the Matruh Canyon. The footwalls of the growth faults associated with the shale detachment provide fault-controlled three-way closures very similar to the well-known rafts in the Lower Congo Basin in West Africa. As updip extension transitions to downdip contraction, some thin-skinned toe-thrust imbrications can be found in the ultradeep-water part of Matruh Basin. Another important play type in the deep-water offshore Matruh Basin is related to the prominent syn-rift “hinge zone” of an interpreted transform margin of the eastern Mediterranean. This play type could serve as a play opener along the transform margin of NW Egypt and NE Libya. The offshore Matruh and Herodotus basins of NW Egypt represent an underexplored region of the Mediterranean, with only one deep-water well drilled along the margin to date.
Exploration plays in the Mersin Basin, Turkish Mediterranean Sea
Authors: Çíftçí Songül Yildiz , Haciköylü Pinar , Geze Kalanyuva Yasemín , Kansu Erhan , Aktepe Arzu
Published: July 2012

There are a number of large Neogene basins in the NE Mediterranean region, including the Antalya, Mut, Mersin, Adana, Iskenderun and northern part of Latakia basins (Figure 1). The broader area is subdivided by major structural features such as the Aksu-Missis-Andırın-Kyrenia-Zone, Ecemiş fault, Göksu fault, and Dead Sea–East Anatolian faults (Figure 2). There are some locally important smaller fault systems as well that trend approximately parallel to the major structures (e.g., Kozan, Aslantaş, and Yumurtalık faults).
Advance Care Planning in Patients With Cancer Referred to a Phase I Clinical Trials Program: The MD Anderson Cancer Center Experience
Authors: Fu Siqing , Barber F. Diane , Naing Aung , Wheler Jennifer , Hong David , Falchook Gerald , Piha-Paul Sarina , Tsimberidou Apostolia , Howard Adrienne , Kurzrock Razelle
Published: July 2012

Purpose

Patients with advanced malignancies referred for early clinical trials have a short life expectancy. We designed this survey to ascertain the status of advance care planning in this population.

Patients and Methods

Patients who were seen in a phase I clinic were asked to anonymously complete an investigator-designed survey.

Results

Of 435 individuals approached, 215 (49%) returned completed or partially completed surveys, whereas many others stated that they wanted to avoid the topic, because they had come to the phase I clinic for cancer therapy. Most patients (n = 149; 69%) were still hopeful about their future. Approximately 42% of patients (n = 90) reported having a living will, 46% had a medical power of attorney (n = 98), and 19% had a do-not-resuscitate (DNR) order (n = 40). Approximately 20% of participants (n = 43) had not discussed advance care planning. Fifty-nine percent of patients wanted to discuss advance care planning with their physician. Having a DNR order in place was significantly more common in individuals who had a living will and/or a medical power of attorney.

Conclusion

Although most patients referred to a phase I clinic remained optimistic, many had discussed a living will, medical power of attorney, and/or DNR order with their physician, family, and/or attorney. However, a significant minority had not addressed this issue with anyone, and many refused to take a survey on the topic. More than half of the patients wanted to discuss these matters with their physician. These observations suggest that extra effort to address advance care planning is needed for these patients.
Who Provides Psychosocial Follow-Up Care for Post-Treatment Cancer Survivors? A Survey of Medical Oncologists and Primary Care Physicians
Authors: Forsythe Laura P. , Alfano Catherine M. , Leach Corinne R. , Ganz Patricia A. , Stefanek Michael E. , Rowland Julia H.
Published: July 2012

Purpose

Addressing psychosocial needs, including key components of psychologic distress, physical symptoms, and health promotion, is vital to cancer follow-up care. Yet little is known about who provides psychosocial care. This study examined physician-reported practices regarding care of post-treatment cancer survivors. We sought to characterize physicians who reported broad involvement in (ie, across key components of care) and shared responsibility for psychosocial care.

Methods

A nationally representative sample of medical oncologists (n = 1,130) and primary care physicians (PCPs; n = 1,021) were surveyed regarding follow-up care of breast and colon cancer survivors.

Results

Approximately half of oncologists and PCPs (52%) reported broad involvement in psychosocial care. Oncologist and PCP confidence, beliefs about who is able to provide psychosocial support, and preferences for shared responsibility for care predicted broad involvement. However, oncologists' and PCPs' perceptions of who provides specific aspects of psychosocial care differed (P < .001); both groups saw themselves as the main providers. Oncologists' confidence, PCPs' beliefs about who is able to provide psychosocial support, and oncologist and PCP preference for models other than shared care were inversely associated with a shared approach to care.

Conclusion

Findings that some providers are not broadly involved in psychosocial care and that oncologists and PCPs differ in their beliefs regarding who provides specific aspects of care underscore the need for better care coordination, informed by the respective skills and desires of physicians, to ensure needs are met. Interventions targeting physician confidence, beliefs about who is able to provide psychosocial support, and preferred models for survivorship care may improve psychosocial care delivery.
Sentinel Lymph Node Biopsy for Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Joint Clinical Practice Guideline
Authors: Wong Sandra L. , Balch Charles M. , Hurley Patricia , Agarwala Sanjiv S. , Akhurst Timothy J. , Cochran Alistair , Cormier Janice N. , Gorman Mark , Kim Theodore Y. , McMasters Kelly M. , Noyes R. Dirk , Schuchter Lynn M. , Valsecchi Matias E. , Weaver Donald L. , Lyman Gary H.
Published: July 2012

Purpose

The American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) sought to provide an evidence-based guideline on the use of lymphatic mapping and sentinel lymph node (SLN) biopsy in staging patients with newly diagnosed melanoma.

Methods

A comprehensive systematic review of the literature published from January 1990 through August 2011 was completed using MEDLINE and EMBASE. Abstracts from ASCO and SSO annual meetings were included in the evidence review. An Expert Panel was convened to review the evidence and develop guideline recommendations.

Results

Seventy-three studies met full eligibility criteria. The evidence review demonstrated that SLN biopsy is an acceptable method for lymph node staging of most patients with newly diagnosed melanoma.

Recommendations

SLN biopsy is recommended for patients with intermediate-thickness melanomas (Breslow thickness, 1 to 4 mm) of any anatomic site; use of SLN biopsy in this population provides accurate staging. Although there are few studies focusing on patients with thick melanomas (T4; Breslow thickness, > 4 mm), SLN biopsy may be recommended for staging purposes and to facilitate regional disease control. There is insufficient evidence to support routine SLN biopsy for patients with thin melanomas (T1; Breslow thickness, < 1 mm), although it may be considered in selected patients with high-risk features when staging benefits outweigh risks of the procedure. Completion lymph node dissection (CLND) is recommended for all patients with a positive SLN biopsy and achieves good regional disease control. Whether CLND after a positive SLN biopsy improves survival is the subject of the ongoing Multicenter Selective Lymphadenectomy Trial II. Copyright © 2012 American Society of Clinical Oncology and Society of Surgical Oncology. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by the American Society of Clinical Oncology and Society of Surgical Oncology.
Adipose Tissue Inflammation and Reduced Insulin Sensitivity in Ovariectomized Mice Occurs in the Absence of Increased Adiposity
Authors: Vieira Potter Victoria J. , Strissel Katherine J. , Xie Chen , Chang Eugene , Bennett Grace , Defuria Jason , Obin Martin S. , Greenberg Andrew S.
Published: July 2012

Menopause promotes central obesity, adipose tissue (AT) inflammation, and insulin resistance (IR). Both obesity and the loss of estrogen can activate innate and adaptive immune cells (macrophages, T cells). The respective impacts of weight gain and loss of ovarian hormones on AT inflammation and IR are poorly understood. Here we determined the temporal kinetics of fat accretion, AT inflammation, and IR over a 26-wk time course in ovariectomized (OVX) mice, a model of menopause. OVX and sham-operated (SHM) C57BL6 mice were fed a normal chow diet. Weight, body composition (magnetic resonance imaging), total and regional adiposity, activity, food intake, AT crown-like structures, biohumoral measures, and insulin sensitivity (insulin tolerance testing and homeostatic model assessment) were determined at wk 12, 20, and 26. Macrophages and T cells from perigonadal AT were immunophenotyped by fluorescence-associated cell sorting, and perigonadal adipose tissue (PGAT) gene expression was quantified by quantitative PCR. OVX mice (∼31 g) became fatter than SHM mice (∼26 g) by wk 12, but mice were equally insulin sensitive. PGAT of OVX mice contained more T cells but expressed higher levels of M2-MΦ (arginase-1) and T cell-regulatory (cytotoxic T-lymphocyte antigen 4) genes. At wk 20, both OVX and SHM mice weighed approximately 35 g and were equally insulin sensitive with comparable amounts of PGAT and total body fat. OVX mice became less insulin sensitive than SHM mice by wk 26, coincident with the down-regulation of PGAT arginase-1 (−20-fold) and cytotoxic T-lymphocyte antigen 4 (2-fold) and up-regulation of M1/Th1 genes CD11c (+2-fold), IL12p40 (+2-fold), and interferon-γ (+78-fold). Ovarian hormone loss in mice induces PGAT inflammation and IR by mechanisms that can be uncoupled from OVX-induced obesity.
Metformin Inhibits Human Androgen Production by Regulating Steroidogenic Enzymes HSD3B2 and CYP17A1 and Complex I Activity of the Respiratory Chain
Authors: Hirsch Andrea , Hahn Dagmar , Kempná Petra , Hofer Gaby , Nuoffer Jean-Marc , Mullis Primus E. , Flück Christa E.
Published: July 2012

Metformin is treatment of choice for the metabolic consequences seen in polycystic ovary syndrome for its insulin-sensitizing and androgen-lowering properties. Yet, the mechanism of action remains unclear. Two potential targets for metformin regulating steroid and glucose metabolism are AMP-activated protein kinase (AMPK) signaling and the complex I of the mitochondrial respiratory chain. Androgen biosynthesis requires steroid enzymes 17α-Hydroxylase/17,20 lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), which are overexpressed in ovarian cells of polycystic ovary syndrome women. Therefore, we aimed to understand how metformin modulates androgen production using NCI-H295R cells as an established model of steroidogenesis. Similar to in vivo situation, metformin inhibited androgen production in NCI cells by decreasing HSD3B2 expression and CYP17A1 and HSD3B2 activities. The effect of metformin on androgen production was dose dependent and subject to the presence of organic cation transporters, establishing an important role of organic cation transporters for metformin's action. Metformin did not affect AMPK, ERK1/2, or atypical protein kinase C signaling. By contrast, metformin inhibited complex I of the respiratory chain in mitochondria. Similar to metformin, direct inhibition of complex I by rotenone also inhibited HSD3B2 activity. In conclusion, metformin inhibits androgen production by mechanisms targeting HSD3B2 and CYP17-lyase. This regulation involves inhibition of mitochondrial complex I but appears to be independent of AMPK signaling.
TNF-α Represses β-Klotho Expression and Impairs FGF21 Action in Adipose Cells: Involvement of JNK1 in the FGF21 Pathway
Authors: Díaz-Delfín Julieta , Hondares Elayne , Iglesias Roser , Giralt Marta , Caelles Carme , Villarroya Francesc
Published: July 2012

Fibroblast growth factor 21 (FGF21) is a member of the FGF family that reduces glycemia and ameliorates insulin resistance. Adipose tissue is a main target of FGF21 action. Obesity is associated with a chronic proinflammatory state. Here, we analyzed the role of proinflammatory signals in the FGF21 pathway in adipocytes, evaluating the effects of TNF-α on β-Klotho and FGF receptor-1 expression and FGF21 action in adipocytes. We also determined the effects of rosiglitazone on β-Klotho and FGF receptor-1 expression in models of proinflammatory signal induction in vitro and in vivo (high-fat diet-induced obesity). Because c-Jun NH2-terminal kinase 1 (JNK1) serves as a sensing juncture for inflammatory status, we also evaluated the involvement of JNK1 in the FGF21 pathway. TNF-α repressed β-Klotho expression and impaired FGF21 action in adipocytes. Rosiglitazone prevented the reduction in β-Klotho expression elicited by TNF-α. Moreover, β-Klotho levels were reduced in adipose tissue from high-fat diet-induced obese mice, whereas rosiglitazone restored β-Klotho to near-normal levels. β-Klotho expression was increased in white fat from JNK1−/− mice. The absence of JNK1 increased the responsiveness of mouse embryonic fibroblast-derived adipocytes and brown adipocytes to FGF21. In conclusion, we show that proinflammatory signaling impairs β-Klotho expression and FGF21 responsiveness in adipocytes. We also show that JNK1 activity is involved in modulating FGF21 effects in adipocytes. The impairment in the FGF21 response machinery in adipocytes and the reduction in FGF21 action in response to proinflammatory signals may play important roles in metabolic alterations in obesity and other diseases associated with enhanced inflammation.
Glucocorticoids Modulate the mTOR Pathway in the Hippocampus: Differential Effects Depending on Stress History
Authors: Polman J. Annelies E. , Hunter Richard G. , Speksnijder Niels , van den Oever Jessica M.E. , Korobko Oksana B. , McEwen Bruce S. , de Kloet E. Ronald , Datson Nicole A.
Published: July 2012

Glucocorticoid (GC) hormones, released by the adrenals in response to stress, are key regulators of neuronal plasticity. In the brain, the hippocampus is a major target of GC, with abundant expression of the GC receptor. GC differentially affect the hippocampal transcriptome and consequently neuronal plasticity in a subregion-specific manner, with consequences for hippocampal information flow and memory formation. Here, we show that GC directly affect the mammalian target of rapamycin (mTOR) signaling pathway, which plays a central role in translational control and has long-lasting effects on the plasticity of specific brain circuits. We demonstrate that regulators of the mTOR pathway, DNA damage-induced transcript (DDIT)4 and FK506-binding protein 51 are transcriptionally up-regulated by an acute GC challenge in the dentate gyrus (DG) subregion of the rat hippocampus, most likely via a GC-response element-driven mechanism. Furthermore, two other mTOR pathway members, the mTOR regulator DDIT4-like and the mTOR target DDIT3, are down-regulated by GC in the rat DG. Interestingly, the GC responsiveness of DDIT4 and DDIT3 was lost in animals with a recent history of chronic stress. Basal hippocampal mTOR protein levels were higher in animals exposed to chronic stress than in controls. Moreover, an acute GC challenge significantly reduced mTOR protein levels in the hippocampus of animals with a chronic stress history but not in unstressed controls. Based on these findings, we propose that direct regulation of the mTOR pathway by GC represents an important mechanism regulating neuronal plasticity in the rat DG, which changes after exposure to chronic stress.
Brain Meets Body: The Blood-Brain Barrier as an Endocrine Interface
Authors: Banks William A.
Published: July 2012

The blood-brain barrier (BBB) separates the central nervous system (CNS) from the peripheral tissues. However, this does not prevent hormones from entering the brain, but shifts the main control of entry to the BBB. In general, steroid hormones cross the BBB by transmembrane diffusion, a nonsaturable process resulting in brain levels that reflect blood levels, whereas thyroid hormones and many peptides and regulatory proteins cross using transporters, a saturable process resulting in brain levels that reflect blood levels and transporter characteristics. Protein binding, brain-to-blood transport, and pharmacokinetics modulate BBB penetration. Some hormones have the opposite effect within the CNS than they do in the periphery, suggesting that these hormones cross the BBB to act as their own counterregulators. The cells making up the BBB are also endocrine like, both responding to circulating substances and secreting substances into the circulation and CNS. By dividing a hormone's receptors into central and peripheral pools, the former of which may not be part of the hormone's negative feed back loop, the BBB fosters the development of variable hormone resistance syndromes, as exemplified by evidence that altered insulin action in the CNS can contribute to Alzheimer's disease. In summary, the BBB acts as a regulatory interface in an endocrine-like, humoral-based communication between the CNS and peripheral tissues.
Closing Remarks
Authors: Bové Paul A.
Published: July 2012

Criticism should take on board the traditions of Blackmur, Auerbach, and Said to deal philologically and lovingly with the human history recorded and created in the use of language. Poetry especially is the vestibule for critics who understand that categorical and conceptual knowledge is professionally and economically productive but imaginatively and humanely weak and undesirable. The various papers that made up this conference at UCLA illustrated the best results of a secular humanistic scholarship produced by poetically sensitive readers.
Evolutionary crossroads in developmental biology: annelids
Authors: Ferrier David E. K.
Published: July 2012

Annelids (the segmented worms) have a long history in studies of animal developmental biology, particularly with regards to their cleavage patterns during early development and their neurobiology. With the relatively recent reorganisation of the phylogeny of the animal kingdom, and the distinction of the super-phyla Ecdysozoa and Lophotrochozoa, an extra stimulus for studying this phylum has arisen. As one of the major phyla within Lophotrochozoa, Annelida are playing an important role in deducing the developmental biology of the last common ancestor of the protostomes and deuterostomes, an animal from which >98% of all described animal species evolved.
fras1shapes endodermal pouch 1 and stabilizes zebrafish pharyngeal skeletal development
Authors: Talbot Jared Coffin , Walker Macie B. , Carney Thomas J. , Huycke Tyler R. , Yan Yi-Lin , BreMiller Ruth A. , Gai Linda , DeLaurier April , Postlethwait John H. , Hammerschmidt Matthias , Kimmel Charles B.
Published: July 2012

Lesions in the epithelially expressed human gene FRAS1 cause Fraser syndrome, a complex disease with variable symptoms, including facial deformities and conductive hearing loss. The developmental basis of facial defects in Fraser syndrome has not been elucidated. Here we show that zebrafish fras1 mutants exhibit defects in facial epithelia and facial skeleton. Specifically, fras1 mutants fail to generate a late-forming portion of pharyngeal pouch 1 (termed late-p1) and skeletal elements adjacent to late-p1 are disrupted. Transplantation studies indicate that fras1 acts in endoderm to ensure normal morphology of both skeleton and endoderm, consistent with well-established epithelial expression of fras1. Late-p1 formation is concurrent with facial skeletal morphogenesis, and some skeletal defects in fras1 mutants arise during late-p1 morphogenesis, indicating a temporal connection between late-p1 and skeletal morphogenesis. Furthermore, fras1 mutants often show prominent second arch skeletal fusions through space occupied by late-p1 in wild type. Whereas every fras1 mutant shows defects in late-p1 formation, skeletal defects are less penetrant and often vary in severity, even between the left and right sides of the same individual. We interpret the fluctuating asymmetry in fras1 mutant skeleton and the changes in fras1 mutant skeletal defects through time as indicators that skeletal formation is destabilized. We propose a model wherein fras1 prompts late-p1 formation and thereby stabilizes skeletal formation during zebrafish facial development. Similar mechanisms of stochastic developmental instability might also account for the high phenotypic variation observed in human FRAS1 patients.
Influence of Smoking Cues in Movies on Children’s Beliefs About Smoking
Authors: Lochbuehler Kirsten , Sargent James D. , Scholte Ron H.J. , Pieters Sara , Engels Rutger C.M.E.
Published: July 2012

OBJECTIVE:

Experimental research has revealed that short exposure to movie smoking affects beliefs about smoking in adolescents. In this study, we tested that association in children.

METHODS:

In 2 experiments, participants were exposed to either a cartoon or family-oriented movie and randomly assigned to 20-minute segments with or without smoking characters. Data collection took place at elementary schools. A total of 101 children (8–10 years; 47.5% boys) were exposed to a cartoon, and in a second experiment, 105 children (8–11 years; 56.2% boys) were exposed to a family-oriented movie. Beliefs about smoking (assessed by questionnaire) and implicit associations toward smoking (single target implicit association task) were assessed after watching the movie.

RESULTS:

The majority of both samples of children viewed smoking unfavorably. Exposure to movie smoking had no effect on implicit associations toward smoking when experiments were analyzed separately or if the results were combined. For smoking beliefs, effects were again small and only statistically significant for social norms regarding smoking.

CONCLUSIONS:

Short-term exposure to smoking in cartoon and family-oriented movies had little immediate impact on beliefs about smoking in preadolescent children, but a significant cumulative impact on norms cannot be ruled out.