bluuebunny/crossref_metadata_2025 huggingface dataset:
2‐Phenyl‐5‐(pyrrolidin‐1‐yl)‐1‐(3,4,5‐trimethoxybenzyl)‐1H‐benzimidazole, a benzimidazole derivative, inhibits growth of human prostate cancer cells by affecting tubulin and c‐Jun N‐terminal kinase
Authors: Chang Wei‐Ling , Chang Chih‐Shiang , Chiang Po‐Cheng , Ho Yunn‐Fang , Liu Ju‐Fang , Chang Kai‐Wei , Guh Jih‐Hwa
Published: May 2010

BACKGROUND AND PURPOSE The c‐Jun N‐terminal kinase (JNK) and tubulin are, frequently, targets for developing anti‐cancer drugs. A major obstacle to successful development is P‐glycoprotein (P‐gp)‐mediated resistance. Here, we have assessed a compound that inhibited growth of cancer cells, for effects on JNK and tubulin and as a substrate for P‐gp.

EXPERIMENTAL APPROACH Several pharmacological and biochemical assays were used to characterize signalling pathways of 2‐phenyl‐5‐(pyrrolidin‐1‐yl)‐1‐(3,4,5‐trimethoxybenzyl)‐1H‐benzimidazole (PPTMB), a benzimidazole analogue, in prostate cancer cells.

KEY RESULTS PPTMB inhibited proliferation of several human prostate cancer cell lines. It displayed similar activity against a P‐gp‐rich cell line, indicating that PPTMB was not a substrate for P‐gp. PPTMB induced G2/M arrest of the cell cycle and subsequent apoptosis, using flow cytometry. Tubulin polymerization assays and Western blot analysis showed that PPTMB directly acted on tubulin and caused disruption of microtubule dynamics, inducing mitotic arrest and sustained high levels of cyclin B1 expression and Cdk1 activation. Subsequently, mitochondria‐related apoptotic cascades were induced, including Bcl‐2 and Bcl‐xL phosphorylation, Mcl‐1 down‐regulation, truncated Bad formation and activation of caspase‐9 and ‐3. PPTMB stimulated JNK phosphorylation at Thr183/Tyr185. SP600125, a specific JNK inhibitor, significantly inhibited apoptotic signalling, indicating that JNK plays a key role in PPTMB action. PPTMB showed a 10‐fold higher potency against prostate cancer cells than normal prostate cells.

CONCLUSIONS AND IMPLICATIONS PPTMB is an effective anti‐cancer agent. It disrupted microtubule dynamics, leading to mitotic arrest of the cell cycle and JNK activation, which in turn stimulated the mitochondria‐related apoptotic cascades in prostate cancer cells.
14‐Deoxyandrographolide desensitizes hepatocytes to tumour necrosis factor‐alpha‐induced apoptosis through calcium‐dependent tumour necrosis factor receptor superfamily member 1A release via the NO/cGMP pathway
Authors: Roy DN , Mandal S , Sen G , Mukhopadhyay S , Biswas T
Published: May 2010

BACKGROUND AND PURPOSE

Andrographis paniculata (AP) has been found to display hepatoprotective effect, although the mechanism of action of the active compounds of AP in this context still remains unclear. Here, we evaluated the hepatoprotective efficacy of 14‐deoxyandrographolide (14‐DAG), a bioactive compound of AP, particularly its role in desensitization of hepatocytes to tumour necrosis factor‐alpha (TNF‐α)‐induced signalling of apoptosis.

EXPERIMENTAL APPROACH

TNF‐α‐mediated ligand receptor interaction in hepatocytes in the presence of 14‐DAG was studied in vitro in primary hepatocyte cultures, with the help of co‐immunoprecipitation, confocal microscopy and FACS analysis. Events associated with 14‐DAG‐induced TNFRSF1A release from hepatocytes were determined using immunoblotting, biochemical assay and fluorimetric studies. Pulse‐chase experiments with radiolabelled TNF‐α and detection of apoptotic nuclei by terminal transferase‐mediated dUTP nick‐end labelling were performed under in vivo conditions.

KEY RESULTS

14‐DAG down‐regulated the formation of death‐inducing signalling complex, resulting in desensitization of hepatocytes to TNF‐α‐induced apoptosis. Pretreatment of hepatocytes with 14‐DAG accentuated microsomal Ca‐ATPase activity through induction of NO/cGMP pathway. This resulted in enhanced calcium influx into microsomal lumen with the formation of TNFRSF1A–ARTS‐1–NUCB2 complex in cellular vesicles. It was followed by the release of full‐length 55 kDa TNFRSF1A and a reduction in the number of cell surface TNFRSF1A, which eventually caused diminution of TNF‐α signal in hepatocytes.

CONCLUSION AND IMPLICATION

Taken together, the results demonstrate for the first time that 14‐DAG desensitizes hepatocytes to TNF‐α‐mediated apoptosis through the release of TNFRSF1A. This can be used as a strategy against cytokine‐mediated hepatocyte apoptosis in liver dysfunctions.
In rat renal fibroblasts, mycophenolic acid inhibits proliferation and production of the chemokine CCL2, stimulated by tumour necrosis factor‐α
Authors: Chang Hong‐Wei , Wu Vin‐Cent , Wu Kwan‐Dun , Huang Hong‐Yu , Hsieh Bor‐Shen , Chen Yung‐Ming
Published: May 2010

BACKGROUND AND PURPOSE Renal fibroblasts play a pivotal role in the development of tubulointerstitial fibrosis, a condition highly predictive of progression towards end‐stage renal disease. The present study investigated the anti‐mitogenic and anti‐inflammatory effects of an inhibitor of inosine monophosphate dehydrogenase, mycophenolic acid (MPA) and the mechanisms underlying its action in normal rat kidney fibroblasts (49F cells).

EXPERIMENTAL APPROACH Proliferation of 49F cells was studied by tetrazole 3‐(4, 5‐dimethylthiazol‐2‐yl‐)‐2,5‐diphenyltetrazolium bromide (MTT) test, bromodeoxyuridine incorporation and flow cytometry. The cyclins, tumour suppressor genes and phospho‐mitogen‐activated protein kinases (MAPKs) were semiquantified by immunoblotting. Apoptosis was measured by quantifying the fragmented DNA and the activity of caspase 3. The monocyte chemokine CCL2 was measured by ELISA. The mRNA expression of CCL2 was measured by real‐time PCR.

KEY RESULTS Mycophenolic acid dose‐dependently inhibited steady‐state proliferation of 49F cells by up‐regulation of p21, p27 and p53, in association with a decrease in cyclins D2 and E. Treatment with MPA also triggered apoptosis of 49F cells by activating the caspase 3 cascade. Furthermore, MPA attenuated tumour necrosis factor‐α‐induced CCL2 expression through down‐regulation of p38 MAPK, but not that of ERK1/2 or JNK.

CONCLUSIONS AND IMPLICATIONS The anti‐mitogenic and anti‐inflammatory effects of MPA were mediated by up‐regulation of cell cycle inhibitors and pro‐apoptotic signals, and by suppression of p38 MAPK pathway respectively. This dual effect of MPA may form the rationale for animal or clinical trials for the treatment of fibrotic renal diseases.
Angiotensin receptor type 1 antagonists protect against neuronal injury induced by oxygen–glucose depletion
Authors: Wu X , Kihara T , Hongo H , Akaike A , Niidome T , Sugimoto H
Published: May 2010

BACKGROUND AND PURPOSESeveral clinical trials andin vivoanimal experiments have suggested that blockade of angiotensin receptor type 1 (AT1) improves ischaemic outcomes. However, the mechanism(s) underlying these effects has not been elucidated. Here, we have investigated the protective effects of pretreatment with AT1receptor antagonists, losartan or telmisartan, against ischaemic insult to neuronsin vitro.

EXPERIMENTAL APPROACHPrimary rat neuron–astrocyte co‐cultures and astrocyte‐defined medium (ADM)‐cultured pure astrocyte cultures were prepared. Ischaemic injury was modelled by oxygen–glucose depletion (OGD) and lactate dehydrogenase release after OGD was measured with or without AT1receptor antagonists or agonists (L162313), AT2receptor antagonist (PD123319) or agonist (CGP‐42112A) pretreatment, for 48 h. Activity of glutamate transporter 1 (GLT‐1) was evaluated by [3H]‐glutamate uptake assays, after AT1receptor agonists or antagonists. Immunoblot and real‐time PCR were used for analysis of protein and mRNA levels of GLT‐1.

KEY RESULTSAT1receptor agonists augmented OGD‐induced cellular damage, which was attenuated by AT1receptor antagonists. AT1receptor antagonists also suppressed OGD‐induced extracellular glutamate release, reactive oxygen species production and nitric oxide generation. GLT‐1 expression and glutamate uptake activity were significantly enhanced by AT1receptor antagonists and impaired by AT1receptor agonists. AT1receptor stimulation suppressed both ADM‐induced GLT‐1 protein expression and mRNA levels. AT1b receptor knock‐down with siRNA enhanced GLT‐1 expression. In postnatal (P1–P21) rat brains, protein levels of GLT‐1 and AT1receptors were inversely correlated.

CONCLUSIONS AND IMPLICATIONSSuppression of AT1receptor stimulation induced GLT‐1 up‐regulation, which ameliorated effects of ischaemic injury.
INORGANIC CARBON UTILIZATION BY ROSS SEA PHYTOPLANKTON ACROSS NATURAL AND EXPERIMENTAL CO2 GRADIENTS1
Authors: Tortell Philippe D. , Trimborn Scarlett , Li Yingyu , Rost Björn , Payne Christopher D.
Published: May 2010

We present results from a field study of inorganic carbon (C) acquisition by Ross Sea phytoplankton during Phaeocystis‐dominated early season blooms. Isotope disequilibrium experiments revealed that HCO3− was the primary inorganic C source for photosynthesis in all phytoplankton assemblages. From these experiments, we also derived relative enhancement factors for HCO3−/CO2 interconversion as a measure of extracellular carbonic anhydrase activity (eCA). The enhancement factors ranged from 1.0 (no apparent eCA activity) to 6.4, with an overall mean of 2.9. Additional eCA measurements, made using membrane inlet mass spectrometry (MIMS), yielded activities ranging from 2.4 to 6.9 U · [μg chl a]−1 (mean 4.1). Measurements of short‐term C‐fixation parameters revealed saturation kinetics with respect to external inorganic carbon, with a mean half‐saturation constant for inorganic carbon uptake (K1/2) of ∼380 μM. Comparison of our early springtime results with published data from late‐season Ross Sea assemblages showed that neither HCO3− utilization nor eCA activity was significantly correlated to ambient CO2 levels or phytoplankton taxonomic composition. We did, however, observe a strong negative relationship between surface water pCO2 and short‐term 14C‐fixation rates for the early season survey. Direct incubation experiments showed no statistically significant effects of pCO2 (10 to 80 Pa) on relative HCO3− utilization or eCA activity. Our results provide insight into the seasonal regulation of C uptake by Ross Sea phytoplankton across a range of pCO2 and phytoplankton taxonomic composition.
Population dynamics and integrated pest management of Thrips tabaci on leek under field conditions in northwest Italy
Authors: Bosco Lara , Tavella Luciana
Published: May 2010

Thrips tabaci Lindeman (Thysanoptera: Thripidae) is a major pest of leek, Allium porrum L. (Alliaceae), in Piedmont, northwest Italy, and to control its infestation the leek crop is sprayed intensively with insecticides during the summer period. In order to find the most efficient and environment‐friendly method of thrips control, research was conducted on six commercial farms during 2005–2006 to assess thrips population composition and infestation levels, and in an experimental field during 2005–2007. Biological and chemical control were compared during 2005–2006, whereas integrated pest management was adopted during 2007. During the growing season, thrips and natural enemy populations were monitored at 14‐day intervals by beating plants; new leaves of plants were also visually inspected for thrips‐feeding symptoms. Furthermore, in the experimental field at harvest‐time, the level of thrips injury to plants was assigned to one of five classes, depending on the percentage of leaf area damaged. Over 99% of phytophagous adult thrips found were male and female T. tabaci. Infestations were very variable in the crops surveyed, partly due to broad‐spectrum chemical treatments against the leek pests, which often failed to control thrips. In general, populations peaked in September, when they reached the maximum mean values ranging between 1.7 and 33.1 thrips per plant. At harvest, none of the surveyed farms experienced quality losses due to thrips injuries. In the experimental field during 2005–2006, the mean number of thrips per plant was greater in the chemical than in the biological control treatment, even though damage indices showed no significant differences between the two treatments. Predatory thrips of the genus Aeolothrips (Thysanoptera: Thripidae) and predatory bugs of the genus Orius (Heteroptera: Anthocoridae), mostly Orius majusculus Reuter, were particularly abundant during 2007, supporting the importance of management with selective insecticides to encourage natural colonization by predators.
Egg hatching response to a range of air humidities for six species of predatory mites
Authors: Ferrero M. , Gigot C. , Tixier M.‐S. , Van Houten Y. M. , Kreiter S.
Published: May 2010

The efficiency of biological control agents is often affected by local conditions such as low relative humidity (r.h.). This is especially true for mites of the family Phytoseiidae, and particularly for their egg stage. A key issue in biological control is thus to assess the drought tolerance of phytoseiid species that are (or that will be) commercialized. In this study, we evaluated the egg hatching response to a humidity range for six species of Phytoseiidae, by assessing the relative air humidity and vapour pressure deficit (VPD) at which 50% of the eggs hatch: r.h.50 and VPD50. Typhlodromus athiasae Porath & Swirskii and Phytoseiulus longipes Evans (Argentinean strain) were the most drought‐tolerant, with a r.h.50 of 43% (VPD50 = 18.2 hPa) and 43% (18.1 hPa), respectively. The most drought‐sensitive species were Amblyseius swirskii (Athias‐Henriot) (63%, 11.4 hPa), Phytoseiulus macropilis (Banks) (69%, 9.8 hPa), and Phytoseiulus persimilis Athias‐Henriot (70%, 9.4 hPa). Neoseiulus idaeus Denmark & Muma and P. longipes (Chilean strain) showed intermediate responses with 49% (16.1 hPa) and 50% (15.9 hPa), respectively. These results were similar to what had been obtained for the same species by other authors. However, unexpected inter‐ and intraspecific differences uncorrelated to climatic conditions of the area of origin were observed. The possibility to localize species and/or populations that could be efficient as biological control agents under dry conditions is discussed.
Increased expression of bFGF is associated with carotid atherosclerotic plaques instability engaging the NF‐κB pathway
Authors: Sigala Fragiska , Savvari Paraskevi , Liontos Michalis , Sigalas Panagiotis , Pateras Ioannis S. , Papalampros Alexandros , Basdra Efthimia K. , Kolettas Evangelos , Kotsinas Athanassios , Papavassiliou Athanasios G. , Gorgoulis Vassilis G.
Published: May 2010

Unstable atherosclerotic plaques of the carotid arteries are at great risk for the development of ischemic cerebrovascular events. The degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and nitric oxide induced apoptosis of vascular smooth muscle cells (VSMCs) contribute to the vulnerability of the atherosclerotic plaques. Basic fibroblast growth factor (bFGF) through its mitogenic and angiogenic properties has already been implicated in the pathogenesis of atherosclerosis. However, its role in plaque stability remains elusive. To address this issue, a panel of human carotid atherosclerotic plaques was analysed for bFGF, FGF‐receptors‐1 and ‐2 (FGFR‐1/‐2), inducible nitric oxide synthase (iNOS) and MMP‐9 expression. Our data revealed increased expression of bFGF and FGFR‐1 in VSMCs of unstable plaques, implying the existence of an autocrine loop, which significantly correlated with high iNOS and MMP‐9 levels. These results were recapitulated in vitro by treatment of VSMCs with bFGF. bFGF administration led to up‐regulation of both iNOS and MMP‐9 that was specifically mediated by nuclear factor‐κB (NF‐κB) activation. Collectively, our data demonstrate a novel NF‐κB‐mediated pathway linking bFGF with iNOS and MMP‐9 expression that is associated with carotid plaque vulnerability.
Health‐related quality of life in Swedish children and adolescents with limb reduction deficiency
Authors: Ylimäinen K , Nachemson A , Sommerstein K , Stockselius A , Norling Hermansson L
Published: May 2010

Aim:  To investigate health‐related quality of life (HRQoL) in young persons with limb reduction deficiency (LRD).

Methods:  One hundred and forty children with LRD aged 8–16 answered the DISABKIDS questionnaire for children with chronic health conditions. Of their parents, 137 answered a corresponding questionnaire concerning their child.

Results:  Compared to reference data from children with other health conditions, children with LRD showed higher overall HRQoL and higher HRQoL in all subscales except social exclusion. Overall, the results were not related to gender or age, but girls with longitudinal, bilateral or lower LRD reported significantly lower HRQoL in most subscales than girls with other forms of LRD. Unexpected attention and perceived physical appearance had a significant impact on HRQoL. There was poor agreement between parent and child report of the child’s HRQoL.

Conclusion:  Children and adolescents with limb reduction deficiency have a better HRQoL than children with other health conditions but there are subgroups of children who experience a significantly lower HRQoL than their peers. The difference between parent and child ratings should be considered in clinical practice.
Local treatment of empyema in children: a systematic review of randomized controlled trials
Authors: Krenke Katarzyna , Peradzyńska Joanna , Lange Joanna , Ruszczyński Marek , Kulus Marek , Szajewska Hania
Published: May 2010

The aim of the study is to systematically evaluate data from randomized controlled trials (RCTs) on the efficacy of using intrapleural fibrinolytic agents in the treatment of complicated parapneumonic effusions or empyema in children. The Cochrane Library, MEDLINE and EMBASE databases were searched in July 2009. Four RCTs, involving 194 children, were included. In two RCTs, intrapleural fibrinolytic treatment was compared with normal saline. One of these RCTs showed a significantly reduced hospital stay in those treated with urokinase compared with those treated with normal saline. Otherwise, no fibrinolytic agent had an effect on any other outcome. Two RCTs that compared fibrinolytic treatment with video‐assisted thoracoscopic surgery (VATS) revealed no benefit of VATS.

Conclusion:  There is little evidence that intrapleural fibrinolysis is more effective than normal saline in the local treatment of complicated parapneumonic effusions or empyema in children. There is no evidence that VATS is more effective than fibrinolytic treatment. Only a limited number of trials were available for analysis, so some caution must be exercised in interpreting the strength of the evidence presented.
Best Management Practices and the Production of Good and Bad Outputs
Authors: Ghazalian Pascal L. , Larue Bruno , West Gale E.
Published: May 2010

Agricultural activities simultaneously produce good and bad outputs. A translog cost function is used to evaluate the cost associated with reduction of chemical runoff and how it is influenced by the scale of crop and animal production. The results show that reducing runoff entails increasing costs and that these costs decrease with the level of crop production, but are unaffected by the level of animal production. The estimates of the cost elasticities of Best Management Practices (BMPs) were all positive, but many have large standard errors that imply that the true elasticities can be much lower or much higher. Also, the cost elasticities decrease with the scale of crop production for most BMPs whereas the scale of animal production has the opposite effect for crop rotation and herbicide control practices. Our results reaffirm that there are economies of size in production.

L’agriculture produit de bons et de mauvais extrants. Une fonction de coût translog est utilisée pour évaluer les coûts associés à l’amélioration de la qualité de l’eau en réduisant les problèmes de ruissellement et de transfert de nutriments. Nous évaluons comment ces coûts changent avec les niveaux des productions animales et de cultures. Nos résultats indiquent que la réduction des transferts de nutriments est coûteux mais que l’élasticité‐coût décroit avec la valeur des cultures produites tout en étant indépendant de l’envergure de la production animale. Les élasticités‐coût associés aux pratiques environnementales (PE) sont positives et ont de grandes erreur‐types, ce qui veut dire que les vraies élasticités peuvent être beaucoup plus grandes ou plus petites. Les élasticités‐coût pour la plupart des PE diminuent avec la production de cultures produit tandis que la taille de la production animale a un effet contraire sur les élasticités pour la rotation de cultures et le contrôle des herbicides. Nos résultats confirment qu’il existe d’importantes économies de taille à exploiter en agriculture.
Ranking of Research Output of Agricultural Economics Departments in Canada and Selected U.S. Universities
Authors: Dridi Chokri , Adamowicz Wiktor L. , Weersink Alfons
Published: May 2010

In this paper, we rank agricultural economics departments in Canada on the basis of research output as measured by citations, publications, and publications weighted by journal impact factors. The data we employ are from the ISI Web of Science and cover the period 2000–07. In this ranking we include three departments from the United States to assess the performance of Canadian institutions relative to U.S. departments. We also investigate how publication output is affected by academic rank. Several Canadian departments compare favorably to some of the U.S. departments.

Dans cet article, nous classant les départements d’économie agricole au Canada sur la base du nombre de citations, de publications et de publications pondéré par les coefficients d’impact des revues scientifiques. Les données sont disponibles à partir de ISI Web of Science®et couvrent la période 2000–07. Dans ce classement, nous incluant trois départements des Etats‐Unis pour évaluer la performance des départements Canadiens par rapport à ceux‐ci. Nous examinons aussi l’effet du rang académique sur les publications. Plusieurs départements Canadiens sont très comparables à quelques départements des Etats‐Unis.
Line‐Source Multi‐Tracer Test for Assessing High Groundwater Velocity
Authors: Magal Einat , Weisbrod Noam , Yakirevich Alexander , Kurtzman Daniel , Yechieli Yoseph
Published: May 2010

Segmented line‐source multi‐tracer injection is suggested as an effective method for assessing groundwater velocities and flow directions in subsurfaces characterized by high water flux. Modifying the common techniques of injecting a tracer into a well became necessary after point‐source natural and forced gradient tracer tests ended with no reliable information on the local groundwater flow. The tracer's line‐source increases the likelihood of success of the test and could provide additional information regarding the lateral heterogeneity of the aquifer.

In a field experiment conducted in the northwestern part on the Dead Sea coast, tracers were injected into an 8‐m‐long line injection system perpendicular to the assumed flow direction. The injection system was divided into four separate segments with four different tracers. An array of five boreholes located within a 10 × 10 m area downstream was used for monitoring the tracers' transport. Two dye tracers (uranine and Na naphthionate) were injected in a long pulse of several hours into two of the injection pipe segments. Two other tracers (Rhenium oxide and Gd‐DTPA) were instantaneously injected into the other two segments. The tracers were detected 0.7 to 2.3 h after injection in four of the five observation wells, located 2.3 to 10 m away from the injection system.

The groundwater velocity was determined to be ∼80 to 170 m/d, based on the recoveries of the tracers. The groundwater flow direction was derived based on the arrival of the tracers and was found to be quite consistent with the apparent direction of the hydraulic gradient.
A literature review: Advance directives and patients with implantable cardioverter defibrillators
Authors: Conelius Jaclyn
Published: May 2010

Purpose: The purpose of this literature review is to describe the severity of and susceptibility for negative outcomes in patients with implantable cardioverter defibrillators (ICDs) who lack advanced directives.

Data sources: A comprehensive review of literature was conducted with articles selected from CINAHL, Pubmed, Ovid, Medline, evidence‐based medicine, evidence‐based nursing, and the Web of Science from 1990 to the present. Key words such as ICD, randomized controlled trials, case studies, advanced directives, end‐of‐life, living will, health care proxy, and durable power of attorney were used to identify specific studies.

Conclusions: Advanced directives are becoming an essential part of care for the ICD population. The recommendations in the literature suggest that clinicians should initiate end‐of‐life discussions with their patients when they are healthy. The patients' preferences should be discussed often in patient care in case they would like changes made to their advance directive as their condition changes.

Implications for practice: Implementation of advanced directives in patients' medical care will need to be encouraged in the event of illness. Advanced practice nurses can provide clear explanations of patients' treatment choices in outpatient and inpatient settings.
Immunological modifications during treatment with thymosin α1 plus antiviral therapy in chronic hepatitis C
Authors: Grandini E. , Cannoletta F. , Scuteri A. , Fortini C. , Loggi E. , Cursaro C. , Riili A. , Di Donato R. , Gramenzi A. , Bernardi M. , Andreone P.
Published: May 2010

The current standard therapy for the treatment of chronic hepatitis C virus (HCV) is the combination of peginterferon and ribavirin, although many patients fail to clear the virus and their retreatment options are still unsatisfactory. Thymosin α1 (Tα1) is an immunomodulating agent that has been proposed as complementary therapy for chronic HCV, especially in the setting of difficult‐to‐treat patients. The aim of this study was to evaluate, in patients nonresponsive to previous Peg‐based therapy, the effect of standard antiviral therapy with or without Tα1 on peripheral lymphocyte subsets. Twenty‐four patients, 12 receiving Tα1 and 12 standard therapy, were enrolled. Peripheral subpopulations were analyzed by flow cytometry. Although the addition of Tα1 did not seem to significantly modify the T‐lymphocyte subpopulations, as comparable behaviors were observed in the CD4 and CD8 longitudinal evaluation, Tα1 produced an earlier increase of natural killer cells. An accurate selection of HCV patients who can benefit from immunomodulation is needed.
Inherited epidermolysis bullosa: past, present, and future
Authors: Fine Jo‐David
Published: May 2010

Inherited epidermolysis bullosa encompasses dozens of diseases characterized by mechanical fragility of the skin, blister formation, and abnormal wound healing. Most of the more severe subtypes are associated with clinically significant extracutaneous complications. Some subtypes may lead to death, even in early infancy. Over the past two decades substantial advances have been made to our understanding of the underlying molecular basis for each member of this protean group of diseases. Research has now shifted toward the identification of therapeutic interventions, to include gene therapy, recombinant protein infusions, intradermal injection of allogeneic fibroblasts, and stem cell transplantation, that might eventually lead to a definitive cure for this disease. Other developing therapies being explored are directed toward the enhancement of wound healing and the prevention of potentially life‐threatening skin cancers in these patients.
Thymosin α1: the regulator of regulators?
Authors: Pierluigi Bonifazi , D’Angelo Carmen , Fallarino Francesca , Moretti Silvia , Zelante Teresa , Bozza Silvia , De Luca Antonella , Bistoni Francesco , Garaci Enrico , Romani Luigina
Published: May 2010

The peripheral immune system can promote either immunity or tolerance when presented with new antigens. Current knowledge withholds that populations of suppressor or regulatory T cells (Treg cells) constitute a pivotal mechanism of immunological tolerance. The potential role of malfunctioning Treg cells in chronic inflammatory immune and auto‐immune diseases is well‐documented. Learning how to successfully manipulate Treg responses could result in more effective vaccines and immunomodulators. We have already shown that Thymosin α1 (Tα1), a naturally occurring thymic peptide first described and characterized by Allan Goldstein in 1972, by modulating signals delivered through innate immune receptors on dendritic cells, affects adaptive immune responses via modulation of Th cell effector and regulatory functions. We will discuss recent molecular mechanisms underlying the ability of Tα1 to activate or inhibit immune responses.
Thymosin β4: a candidate for treatment of stroke?
Authors: Morris Daniel C. , Chopp Michael , Zhang Li , Zhang Zheng G.
Published: May 2010

Neurorestorative therapy is the next frontier in the treatment of stroke. An expanding body of evidence supports the theory that after stroke, certain cellular changes occur that resemble early stages of development. Increased expression of developmental proteins in the area bordering the infarct suggest an active repair or reconditioning response to ischemic injury. Neurorestorative therapy targets parenchymal cells (neurons, oligodendrocytes, astrocyes, and endothelial cells) to enhance endogenous neurogenesis, angiogenesis, axonal sprouting, and synaptogenesis to promote functional recovery. Pharmacological treatments include statins, phosphodiesterase 5 inhibitors, erythropoietin, and nitric oxide donors that have all improved funtional outcome after stroke in the preclinial arena. Thymosin β4 (Tβ4) is expressed in both the developing and adult brain and it has been shown to stimulate vasculogenesis, angiogenesis, and arteriogenesis in the postnatal and adult murine cardiac myocardium. In this manuscript, we describe our rationale and techniques to test our hypothesis that Tβ4 may be a candidate neurorestorative agent.
Thymosin β4 facilitates epicardial neovascularization of the injured adult heart
Authors: Smart Nicola , Risebro Catherine A. , Clark James E. , Ehler Elisabeth , Miquerol Lucile , Rossdeutsch Alex , Marber Michael S. , Riley Paul R.
Published: May 2010

Ischemic heart disease complicated by coronary artery occlusion causes myocardial infarction (MI), which is the major cause of morbidity and mortality in humans (http://www.who.int/cardiovascular_diseases/resources/atlas/en/index.html). After MI the human heart has an impaired capacity to regenerate and, despite the high prevalence of cardiovascular disease worldwide, there is currently only limited insight into how to stimulate repair of the injured adult heart from its component parts. Efficient cardiac regeneration requires the replacement of lost cardiomyocytes, formation of new coronary blood vessels, and appropriate modulation of inflammation to prevent maladaptive remodeling, fibrosis/scarring, and consequent cardiac dysfunction. Here we show that thymosin β4 (Tβ4) promotes new vasculature in both the intact and injured mammalian heart. We demonstrate that limited EPDC‐derived endothelial‐restricted neovascularization constitutes suboptimal “endogenous repair,” following injury, which is significantly augmented by Tβ4 to increase and stabilize the vascular plexus via collateral vessel growth. As such, we identify Tβ4 as a facilitator of cardiac neovascularization and highlight adult EPDCs as resident progenitors which, when instructed by Tβ4, have the capacity to sustain the myocardium after ischemic damage.
Animal studies with thymosin β4, a multifunctional tissue repair and regeneration peptide
Authors: Philp Deborah , Kleinman Hynda K.
Published: May 2010

Studies in various animal models of disease and repair with thymosin β4 (Tβ4), the major actin‐sequestering molecule in mammalian cells, have provided the scientific foundation for the ongoing dermal, corneal, and cardiac wound repair multicenter clinical trials. Tβ4 has of multiple biological activities, which include down‐regulation of inflammatory chemokines and cytokines, and promotion of cell migration, blood vessel formation, cell survival, and stem cell maturation. All of these activities contribute to the multiple wound healing properties that have been observed in animal studies. This paper reviews and discusses the topical and systemic uses of Tβ4 in various animal models that demonstrate its potential for clinical use.
Thymosin β4 enhances repair by organizing connective tissue and preventing the appearance of myofibroblasts
Authors: Ehrlich H. Paul , Hazard III Sprague W.
Published: May 2010

Incisional wounds in rats treated locally with thymosin β4 (Tβ4) healed with minimal scaring and without loss in wound breaking strength. Treated wounds were significantly narrower in width. Polarized light microscopy treated wounds had superior organized collagen fibers, displaying a red birefringence, which is consistent with mature connective tissue. Control incisions had randomly organized collagen fibers, displaying green birefringence that is consistent with immature connective tissue. Immunohistology treated wounds had few myofibroblasts and fibroblasts with α smooth muscle actin (SMA) stained stress fibers. Polyvinyl alcohol sponge implants placed in subcutaneous pockets received either carrier or 100 μg of Tβ4 on days 2, 3, and 4. On day 14, treated implants revealed longer, thicker collagen fiber bundles with intense yellow‐red birefringence by polarized light microscopy. In controls, fine, thin collagen fiber bundles were arranged in random arrays with predominantly green birefringence. Controls contained mostly myofibroblasts, while few myofibroblasts appeared in Tβ4 treated implants. Electron microscopy confirmed both cell types and the degree of collagen fiber bundle organization. Our results demonstrate that Tβ4 treated wounds appear to mature earlier and heal with minimal scaring.
Thymosin α1 to harness immunity to pathogens after haploidentical hematopoietic transplantation
Authors: Perruccio Katia , Bonifazi Pierluigi , Topini Fabiana , Tosti Antonella , Bozza Silvia , Aloisi Teresa , Carotti Alessandra , Aversa Franco , Martelli Massimo F. , Romani Luigina , Velardi Andrea
Published: May 2010

We designed a phase I/II clinical study to determine safety and efficacy of thymosin α1 (Tα1) administration in recipients of one HLA haplotype (haploidentical) stem cell transplants for hematologic malignancies. Tα1 administration did not cause acute or chronic graft versus host disease and was associated with significant improvement in polymorphonuclear (phagocytosis) and dendritic cell (phagocytosis, expression of costimulatory molecules, and cytokine production) functions. It was also associated with increased T‐cell counts and earlier appearance of functional pathogen‐specific T cell responses (by a sensitive limiting dilution assay that detects frequency of T cells specific for Aspergillus, Candida, CMV, ADV, VZV, HSV, Toxoplasma). Five of six haploidentical transplant recipients who received Tα1 are alive and disease free at a median follow‐up of 10 months after transplantation (range: 5–20). They experienced only a single nonlethal infectious episode and one patient developed fatal immune hemolytic anemia. At this very early stage of the clinical trial, we conclude Tα1 administration is safe and may impact favorably on immune function. Larger numbers of patients and longer follow‐up are, of course, needed to assess its impact on survival.
Thymalfasin in the treatment of hepatitis B and C
Authors: Ciancio A. , Rizzetto M.
Published: May 2010

Thymalfasin exhibited an immunomodulatory and a direct antiviral mechanism of action. The low rate of sustained response of chronic hepatitis with current therapies, underscores the need for new therapeutic options. It has been suggested that thymalfasin may have efficacy in the treatment of chronic hepatitis B and C. Pilots studies in patients with chronic hepatitis B treated with thymalfasin in combination with interferon or nucleoside analogue, showed a 70% complete sustained response rate. Studies in chronic hepatitis C patients, would indicate that thymalfasin in combination with standard or pegylated interferon with ribavirin may improve response rate in hepatitis C virus (HCV) naïve and nonresponder patients. However, a large phase‐III randomized study conducted in Europe in HCV patients nonresponder to Peg‐interferon with ribavirin, demonstrated that thymalfasin did not improve the rate of sustained virologic responses, but, in patients who completed therapy, thymalfasin significantly diminished the relapse rate. In conclusion, thymalfasin, in combination with the standard of care, may be helpful as an adjuvant in the treatment of patients with chronic hepatitis B and C.
Overexpression of the natural tetrapeptide acetyl‐N‐ser‐asp‐lys‐pro derived from thymosin β4 in neoplastic diseases
Authors: Liu Jian‐Miao , Garcia‐Alvarez Maria‐Concepcion , Bignon Jerome , Kusinski Michal , Kuzdak Krzysztof , Riches Andrew , Wdzieczak‐Bakala Joanna
Published: May 2010

The natural tetrapeptide acetyl‐ser‐asp‐lys‐pro (AcSDKP) is formed in vivo by enzymatic cleavage of the N terminus of thymosin β4 by prolyl oligopeptidase (POP). Recently, AcSDKP was shown to promote angiogenesis. Because of the critical role of neovascularization in cancer development, the levels of AcSDKP and POP activity in a number of different malignant tissues were investigated. Our studies revealed that AcSDKP levels were markedly elevated in neoplastic diseases including hematologic malignancies and solid neoplasms. Consistent with this finding, the enhanced activity of POP was also detected in all analyzed specimens of cancer tissues. Both these novel findings are in concert with the previously reported overexpression of thymosin β4 in a large variety of malignant tumors and with its potential role in cancerogenesis. The physiological relevance of these findings awaits further studies; however, our first results strongly suggest a key role for AcSDKP in the pathogenesis of cancer.
Thymosin β4: a key factor for protective effects of eEPCs in acute and chronic ischemia
Authors: Hinkel Rabea , Bock‐Marquette Ildiko , Hazopoulos Antonis K. , Kupatt Christian
Published: May 2010

Acute myocardial infarction is still one of the leading causes of death in the industrial nations. Even after successful revascularization, myocardial ischemia results in a loss of cardiomyocytes and scar formation. Embryonic EPCs (eEPCs), retroinfused into the ischemic region of the pig heart, provided rapid paracrine benefit to acute and chronic ischemia in a PI‐3K/Akt‐dependent manner. In a model of acute myocardial ischemia, infarct size and loss of regional myocardial function decreased after eEPC application, unless cell pre‐treatment with thymosin β4 shRNA was performed. Thymosin ß4 peptide retroinfusion mimicked the eEPC‐derived improvement of infarct size and myocardial function. In chronic ischemia (rabbit model), eEPCs retroinfused into the ischemic hindlimb enhanced capillary density, collateral growth, and perfusion. Therapeutic neovascularization was absent when thymosin ß4 shRNA was introduced into eEPCs before application. In conclusion, eEPCs are capable of acute and chronic ischemia protection in a thymosin ß4 dependent manner.
Progression of ocular sulfur mustard injury: development of a model system
Authors: Milhorn Denise , Hamilton Tracey , Nelson Marian , McNutt Patrick
Published: May 2010

Exposure of tissues to sulfur mustard (SM) results in the formation of protein and nucleotide adducts that disrupt cellular metabolism and cause cell death. Subsequent pathologies involve a significant proinflammatory response, disrupted healing, and long‐term defects in tissue architecture. Following ocular exposure, acute corneal sequelae include epithelial erosions, necrosis, and corneal inflammation. Longer term, a progressive injury becomes distributed throughout the anterior chamber, which ultimately causes a profound remodeling of corneal tissues. In many cases, debilitating and vision‐threatening injuries reoccur months to years after the initial exposure. Preliminary data in humans suffering from chronic epithelial lesions suggest that thymosin β4 (Tβ4) may be a viable candidate to mitigate acute or long‐term ocular SM injury. To evaluate therapeutic candidates, we have developed a rabbit ocular exposure model system. In this paper, we report molecular, histological, ultrastructural, and clinical consequences of rabbit ocular SM injury, which can be used to assess Tβ4 efficacy, including timepoints at which Tβ4 will be assessed for therapeutic utility.
Thymosin β4: structure, function, and biological properties supporting current and future clinical applications
Authors: Crockford David , Turjman Nabila , Allan Christian , Angel Janet
Published: May 2010

Published studies have described a number of physiological properties and cellular functions of thymosin β4 (Tβ4), the major G‐actin‐sequestering molecule in mammalian cells. Those activities include the promotion of cell migration, blood vessel formation, cell survival, stem cell differentiation, the modulation of cytokines, chemokines, and specific proteases, the upregulation of matrix molecules and gene expression, and the downregulation of a major nuclear transcription factor. Such properties have provided the scientific rationale for a number of ongoing and planned dermal, corneal, cardiac clinical trials evaluating the tissue protective, regenerative and repair potential of Tβ4, and direction for future clinical applications in the treatment of diseases of the central nervous system, lung inflammatory disease, and sepsis. A special emphasis is placed on the development of Tβ4 in the treatment of patients with ST elevation myocardial infarction in combination with percutaneous coronary intervention.
Relation between Developmental Stage, Sensory Properties, and Volatile Content of Organically and Conventionally Grown Pac Choi (Brassica rapa var. Mei Qing Choi)
Authors: Talavera‐Bianchi Martin , Adhikari Koushik , Chambers IV Edgar , Carey Edward E. , Chambers Delores H.
Published: May 2010

ABSTRACT:  This study was conducted to identify and quantify the sensory characteristics and chemical profile of organically and conventionally grown pac choi (Brassica rapa var. Mei Qing Choi), also called bok choy, at 3 stages of growth (2.5, 4.5, and 6.5 wk). Sensory and instrumental data were correlated using partial least squares regression. Pac choi was grown in late spring. Descriptive sensory analysis was conducted by a highly trained panel and compounds were identified and quantified using a gas chromatograph/mass spectrometer. The findings of the study indicate that the differences in sensory characteristics and chemical profiles among stages of growth are more substantial than the differences between organic and conventional production. Green‐unripe, musty/earthy, lettuce, and sweet flavors are representative in pac choi at early stages of growth. When older, pac choi has higher intensities of green‐grassy/leafy, bitter, cabbage, and sulfur flavors that are associated with the increase of (Z)‐3‐hexen‐1‐ol, octyl acetate, 1‐nonanol, 2‐decanone, 1‐penten‐3‐ol, linalool, camphor, menthol, isobornyl acetate, geranylacetone, and cedrol compounds. Conventional pac choi was higher than organic pac choi in green overall, bitter, and soapy flavors only at 2.5 wk of age. This may be associated with the presence of (Z)‐3‐hexenal, 2‐hexyn‐1‐ol, and (E)‐2‐hexenal compounds.

Practical Application: The increased popularity of organic production has amplified the need for research that will help in understanding how this production system affects the final quality of food products. This study suggests that the stage of development has a much larger impact on sensory quality than organic or conventional growing of pac choi. Findings from this study promote consumer choice by showing that comparable sensory quality can be obtained using either production system, making the ultimate choice not only based on sensory quality but consumer choice related to environmental beliefs or economics.
A Novel Tensile Test Method to Assess Texture and Gaping in Salmon Fillets
Authors: Ashton Thomas J. , Michie Ian , Johnston Ian A.
Published: May 2010

ABSTRACT:  A new tensile strength method was developed to quantify the force required to tear a standardized block of Atlantic salmon muscle with the aim of identifying those samples more prone to factory downgrading as a result of softness and fillet gaping. The new method effectively overcomes problems of sample attachment encountered with previous tensile strength tests. The repeatability and sensitivity and predictability of the new technique were evaluated against other common instrumental texture measurement methods. The relationship between sensory assessments of firmness and parameters from the instrumental texture methods was also determined. Data from the new method were shown to have the strongest correlations with gaping severity (r =−0.514, P < 0.001) and the highest level of repeatability of data when analyzing cold‐smoked samples. The Warner Bratzler shear method gave the most repeatable data from fresh samples and had the highest correlations between fresh and smoked product from the same fish (r = 0.811, P < 0.001). A hierarchical cluster analysis placed the tensile test in the top cluster, alongside the Warner Bratzler method, demonstrating that it also yields adequate data with respect to these tests. None of the tested sensory analysis attributes showed significant relationships to mechanical tests except fillet firmness, with correlations (r) of 0.42 for cylinder probe maximum force (P = 0.005) and 0.31 for tensile work (P = 0.04).

It was concluded that the tensile test method developed provides an important addition to the available tools for mechanical analysis of salmon quality, particularly with respect to the prediction of gaping during factory processing, which is a serious commercial problem.

Practical Application: A novel, reliable method of measuring flesh tensile strength in salmon, provides data of relevance to gaping.
Effect of Inclusion of Salmon Roe on Characteristics of Salmon Baby Food Products
Authors: Desantos F.A. , Bechtel P. , Smiley S. , Brewer M.S.
Published: May 2010

ABSTRACT:  Baby food was formulated from sockeye salmon (puree alone, puree + chunks, puree + pink row, puree + pink row + chunks, puree + red row, puree + red roe + chunks). In the 1st study, physical (pH, instrumental color, water activity) and descriptive sensory (odor, flavor, texture, visual color) characteristics were determined. Samples containing roe were lighter and less red (by approximately 3 to 4 a* units) than formulations without roe regardless of the type of roe added. Visual pink color followed the same trend. Formulations with roe, both pink and sockeye, were almost twice as fibrous as formulations without roe. Salmon flavor was stronger in samples containing roe from sockeye salmon. In the 2nd study, retort processed samples were stored at room temperature for 6 mo. Sweaty odor decreased over storage time. Visual cream‐brown color correlated with L*, a*, b*, and chroma values (r =−0.80, 0.75, 0.80, and 0.84, respectively). TBARS values of all samples were < 0.35 mg MDA/kg and declined after month 0 indicating that these products were oxidatively stable. Overall, adding roe to these products lightened them and increased fibrous texture. Samples containing sockeye salmon roe had stronger salmon flavor. Once retort processed, these products were quite stable in terms of color, odor, and TBARS. Potential nutrient contributions of this type of product to the infant diet warrant additional research.