bluuebunny/crossref_metadata_2025_split huggingface dataset:
Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation
Authors: Sinn Brigitte , Tallen Gesche , Schroeder Gisela , Grassl Birgit , Schulze Joern , Budach Volker , Tinhofer Inge 
Published: January 2010

Abstract
PTEN mutations are frequently found in malignant glioma and can result in activated phosphatidylinositol-3-kinase/Akt survival signaling associated with resistance to radiotherapy. Strategies to interfere with aberrant PI3K/Akt activity are therefore being developed to improve the therapeutic efficacy of radiotherapy in patients with malignant glioma. The methylxanthine caffeine has been described as a PI3K inhibitor and is also known to sensitize cells to ionizing radiation. However, a direct association between these two caffeine-mediated effects has not been reported yet. Therefore, we asked whether caffeine or its derivative pentoxifylline differentially affect the radiosensitivity of malignant gliomas with different PTEN status. As models, we used the radiosensitive EA14 malignant glioma cell line containing wild-type PTEN and the radioresistant U87MG malignant glioma cell line harboring mutant PTEN. Our study revealed that caffeine and pentoxifylline radiosensitized PTEN-deficient but not PTEN-proficient glioma cells. Radiosensitization of PTEN-deficient U87MG cells by caffeine was significantly correlated with the activation of the G1 DNA damage checkpoint that occurred independently of de novo synthesis of p53 and p21. The p53 independency was also confirmed by a significant caffeine-mediated radiosensitization of the glioma cell lines T98G and U373MG that are deficient for both PTEN and p53. Furthermore, caffeine-mediated radiosensitization was associated with the inhibition of Akt hyperphosphorylation in PTEN-deficient cells to a level comparable with PTEN-proficient cells. Our data suggest that the methylxanthine caffeine or its derivative pentoxifylline are promising candidate drugs for the radiosensitization of glioma cells particularly with PTEN mutations. Mol Cancer Ther; 9(2); 480–8
Human Mutations That Confer Paclitaxel Resistance
Authors: Yin Shanghua , Bhattacharya Rajat , Cabral Fernando 
Published: January 2010

Abstract
The involvement of tubulin mutations as a cause of clinical drug resistance has been intensely debated in recent years. In the studies described here, we used transfection to test whether β1-tubulin mutations and polymorphisms found in cancer patients are able to confer resistance to drugs that target microtubules. Three of four mutations (A185T, A248V, R306C, but not G437S) that we tested caused paclitaxel resistance, as indicated by the following observations: (a) essentially 100% of cells selected in paclitaxel contained transfected mutant tubulin; (b) paclitaxel resistance could be turned off using tetracycline to turn off transgene expression; (c) paclitaxel resistance increased as mutant tubulin production increased. All the paclitaxel resistance mutations disrupted microtubule assembly, conferred increased sensitivity to microtubule-disruptive drugs, and produced defects in mitosis. The results are consistent with a mechanism in which tubulin mutations alter microtubule stability in a way that counteracts drug action. These studies show that human tumor cells can acquire spontaneous mutations in β1-tubulin that cause resistance to paclitaxel, and suggest that patients with some polymorphisms in β1-tubulin may require higher drug concentrations for effective therapy. Mol Cancer Ther; 9(2); 327–35
Identification of a Novel Raf-1 Pathway Activator that Inhibits Gastrointestinal Carcinoid Cell Growth
Authors: Cook Mackenzie R. , Pinchot Scott N. , Jaskula-Sztul Renata , Luo Jie , Kunnimalaiyaan Muthusamy , Chen Herbert 
Published: January 2010

AbstractCarcinoids are neuroendocrine tumors (NET) that secrete hormones, including serotonin, resulting in the malignant carcinoid syndrome. In addition to the significant morbidity associated with the syndrome, carcinoids are frequently metastatic at diagnosis, and untreated mortality at 5 years exceeds 70%. Surgery is the only curative option, and the need for other therapies is clear. We have previously shown that activation of Raf-1 inhibits carcinoid cell proliferation. We investigated the ability of leflunomide (LFN), a Food and Drug Administration–approved medication for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide (TFN) as a potential anti-NET treatment. LFN and TFN inhibit the in vitro proliferation of gastrointestinal carcinoid cells and induce G2-M phase arrest. Daily oral gavage of nude mice with subcutaneous xenografted carcinoid tumors confirms that LFN can inhibit NET growth in vivo. Treatment with TFN suppresses the cellular levels of serotonin and chromogranin A, a glycopeptide co-secreted with bioactive hormones. Additionally, TFN reduces the level of achaete-scute complex-like 1 (ASCL1), a NET marker correlated with survival. These effects are associated with the activation of the Raf-1/mitiogen-activated protein kinase kinase/extracellular signal–regulated kinase-1/2 pathway, and blockade of mitiogen-activated protein kinase kinase signaling reversed the effects of TFN on markers of the cell cycle and ASCL1 expression. In summary, LFN and TFN inhibit carcinoid cell proliferation in vitro and in vivo and alter the expression of NET markers. This compound thus represents an attractive target for further clinical investigation. Mol Cancer Ther; 9(2); 429–37
Biological Activity of Celecoxib in the Bronchial Epithelium of Current and Former Smokers
Authors: Kim Edward S. , Hong Waun K. , Lee J. Jack , Mao Li , Morice Rodolfo C. , Liu Diane D. , Jimenez Carlos A. , Eapen Georgie A. , Lotan Reuben , Tang Ximing , Newman Robert A. , Wistuba Ignacio I. , Kurie Jonathan M. 
Published: January 2010

Abstract
Non–small cell lung cancer is the primary cause of cancer-related death in Western countries. One important approach taken to address this problem is the development of effective chemoprevention strategies. In this study, we examined whether the cyclooxygenase-2 inhibitor celecoxib, as evidenced by decreased cell proliferation, is biologically active in the bronchial epithelium of current and former smokers. Current or former smokers with at least a 20 pack-year (pack-year = number of packs of cigarettes per day times number of years smoked) smoking history were randomized into one of four treatment arms (3-month intervals of celecoxib then placebo, celecoxib then celecoxib, placebo then celecoxib, or placebo then placebo) and underwent bronchoscopies with biopsies at baseline, 3 months, and 6 months. The 204 patients were primarily (79.4%) current smokers: 81 received either low-dose celecoxib or placebo and 123 received either high-dose celecoxib or placebo. Celecoxib was originally administered orally at 200 mg twice daily and the protocol subsequently increased the dose to 400 mg twice daily. The primary end point was change in Ki-67 labeling (from baseline to 3 months) in bronchial epithelium. No cardiac toxicities were observed in the participants. Although the effect of low-dose treatment was not significant, high-dose celecoxib decreased Ki-67 labeling by 3.85% in former smokers and by 1.10% in current smokers—a significantly greater reduction (P = 0.02) than that seen with placebo after adjusting for metaplasia and smoking status. A 3- to 6-month celecoxib regimen proved safe to administer. Celecoxib (400 mg twice daily) was biologically active in the bronchial epithelium of current and former smokers; additional studies on the efficacy of celecoxib in non–small cell lung cancer chemoprevention may be warranted. Cancer Prev Res; 3(2); 148–59
The Promise of Natural Products for Blocking Early Events in Skin Carcinogenesis
Authors: Clifford John L. , DiGiovanni John 
Published: January 2010

Abstract
This perspective on Stratton et al. (beginning on p. 160), Kowalczyk et al. (beginning on p. 170), and Katiyar et al. (beginning on p. 179) highlights the common theme of translational investigation of natural substances and their molecular effects and mechanisms in preventing skin squamous cell carcinoma, which has potentially severe clinical consequences. These studies comprise results of naturally occurring phytochemicals and green tea polyphenols in mouse models of UV-induced and chemically induced skin carcinogenesis and results of perillyl alcohol in a phase IIa clinical trial—all pointing to the great promise of this exciting approach for better understanding of and preventing skin cancer. Cancer Prev Res; 3(2); 132–5
Circulating Rather Than Cardiac Angiotensin-(1-7) Stimulates Cardioprotection After Myocardial Infarction
Authors: Wang Yong , Qian Cheng , Roks Anton J.M. , Westermann Dirk , Schumacher Sarah-Mai , Escher Felicitas , Schoemaker Regien G. , Reudelhuber Timothy L. , van Gilst Wiek H. , Schultheiss Heinz-Peter , Tschöpe Carsten , Walther Thomas 
Published: January 2010

Background—Angiotensin (Ang)-(1-7) attenuates the development of heart failure. In addition to its local effects on cardiovascular tissue, Ang-(1-7) also stimulates bone marrow, which harbors cells that might complement the therapeutic effect of Ang-(1-7). We studied the effects of Ang-(1-7) either produced locally in the heart or subcutaneously injected during the development of heart failure induced by myocardial infarction (MI) and explored the role of cardiovascular progenitor cells in promoting the effects of this heptapeptide.Methods and Results—Effects of Ang-(1-7) on bone marrow–derived mononuclear cells in rodents, particularly endothelial progenitor cells, were investigated in vitro and in vivo in rats, in mice deficient for the putative Ang-(1-7) receptor Mas, and in mice overexpressing Ang-(1-7) exclusively in the heart. Three weeks after MI induction through permanent coronary artery occlusion, effects of Ang-(1-7) either produced locally in the heart or injected into the subcutaneous space were investigated. Ang-(1-7) stimulated proliferation of endothelial progenitor cells isolated from sham or infarcted rodents. The stimulation was blunted by A779, a Mas receptor blocker, or by Mas deficiency. Infusion of Ang-(1-7) after MI increased the number of c-kit– and vascular endothelial growth factor–positive cells in infarcted hearts, inhibited cardiac hypertrophy, and improved cardiac function 3 weeks after MI, whereas cardiomyocyte-derived Ang-(1-7) had no effect.Conclusions—Our data suggest circulating rather than cardiac Ang-(1-7) to be beneficial after MI. This beneficial effect correlates with a stimulation of cardiac progenitor cells in vitro and in vivo. This characterizes the heptapeptide as a promising new tool in stimulating cardiovascular regeneration under pathophysiological conditions.
Construct validity of the Capacity Profile in adolescents with cerebral palsy
Authors: Meester-Delver Anke , Beelen Anita , van Eck Mirjam , Voorman Jeanine , Dallmeijer Annet , Nollet Frans , Becher Jules 
Published: January 2010

Objective: To establish construct validity of the Capacity Profile, a method to comprehensively classify additional care needs in five domains of body functions (physical health, motor, sensory, mental, voice and speech functions), in adolescents with non-progressive, permanent conditions such as cerebral palsy. Design: Cross-sectional study. Subjects: Ninety-four adolescents with cerebral palsy: 60 boys, 34 girls, median age 14.3, range 12—16 years, unilateral (n = 37), bilateral (n = 57), spastic (n = 76), ataxic (n = 4), dyskinetic (n = 5), mixed (dyskinetic and spastic, n =9), Gross Motor Function Classification System: level I (n = 50), level II (n = 6), level III (n = 10), level IV (n = 8), level V (n = 20). Methods: Associations were calculated between Capacity Profile domains and Vineland Adaptive Behavior Scales (communication, daily activities, social and motor skills) and Gross Motor Function Classification System using Spearman’s rho. Furthermore, we explored the independent contribution of the Capacity Profile domains to activities and participation measured with the Vineland Adaptive Behavior Scales. Results: All Capacity Profile domains were significantly associated with all domains of the Vineland Adaptive Behavior Scales and the Gross Motor Function Classification System (P<0.05). Multiple regression analysis showed that the Capacity Profile contributed 87% to variance in communication (Capacity Profile-voice 78%, mental 8% and physical 1%), 85% to daily activities (Capacity Profile-mental 75%, motor 8% and voice 2%), 60% to social skills (Capacity Profile-voice 56% and mental 4%), and 91% to motor skills (Capacity Profile-motor 87%, mental 3% and sensory 1%). Conclusion: These findings support the construct validity of the Capacity Profile in adolescents with cerebral palsy. Construct validity in other medical conditions should be further investigated.
Verlaufsuntersuchungen bei Melanomen der Haut und der Mundschleimhaut des Hundes
Authors: Frese K. 
Published: January 2010

Progressive studies in dogs with skin and oral melanomas were undertaken to determine whether or not the WHO-classification of melanomas, which is based mainly on histological criteria, reflects sufficiently the biological behaviour of these tumours. Furthermore, some prognostic parameters, important in the prognosis of human malignant melanomas were tested with respect to their significance for canine melanomas. The paper deals with progressive studies in 182 dogs with surgically treated benign and malignant skin and oral melanomas. Parameters of the biological behaviour were the 2 years death rate and the median survival time. The melanomas were classified according to the recommendations of the WHO. Within 2 years after the first treatment five (5.7%) of 87 dogs with benign skin melanomas, 29 (65.9%) of 44 dogs with malignant skin melanomas and 44 (86.2%) of 55 dogs with malignant oral melanomas were killed because of recurrence or metastases or both. The median survival time of dogs with benign skin melanomas was more than 24 months, with malignant skin melanomas 8 months and with malignant oral melanomas 3 months. In dogs with large malignant skin melanomas the 2 years death rate was 100% with a median survival time of 4 months, whereas animals with small melanomas had a 2 years death rate of 54.3% and a median survival time of 12 months. The site of skin melanomas, sex and histological type of both skin and oral melanomas, however, had no significant influence on the course of the disease. Also, histological parameters, important in the prognosis of human malignant melanoma (rate of mitosis, size of nucleoli, pigmentation and vascular invasion), had no significant influence on the course of the disease.
Histologic Interpretation of Cutaneous Biopsies from Dogs with Dermatologic Disorders
Authors: Rojko J. L. , Hoover E. A. , Martin S. L. 
Published: January 2010

Clinical and histologic data were correlated on skin biopsies from 238 dogs with various cutaneous disorders. Biopsies from normal dogs were used to establish normal histologic anatomy. Seborrhea was characterized by acanthosis, mild hyperkeratosis or parakeratosis, and mild mixed inflammatory cell infiltration. Dogs with allergic dermatitis had similar epidermal changes; however, dermal edema and pronounced mast cell infiltration distinguished this group. Biopsies from dogs with pyoderma revealed intense purulent inflammation of either the epidermis or hair follicles. Lesions of demodectic acariasis were most similar to those in the pyoderma group; specific diagnosis was based upon the presence of mites in follicles. Cutaneous lesions of hypothyroidism were classified into two categories—classical and seborrheic. The more common classical form was characterized by atrophic telogen phase hair follicles and marked hyperkeratosis of the external root sheath. Inflammation was absent. In the seborrheic form, telogen phase hair follicles were associated with acanthosis and mild mixed inflammatory cell infiltration. Hyperadrenocorticism was marked by more consistent epidermal and adnexal atrophy, telogen phase follicles, and hyperkeratosis of the epidermis and follicular root sheath. Dermal mineralization or decreased dermal thickness, or both, occurred in seven of 11 dogs (60%) with hyperadrenocorticism.
Bluetongue Virus-induced Hydranencephaly in Cattle
Authors: MacLachlan N. J. , Osburn B. I. 
Published: January 2010

Direct inoculation of bluetongue virus into 125-day bovine fetuses resulted in development of hydranencephaly. The earliest lesions after virus inoculation were a severe necrotizing encephalitis, which was most prominent in the cerebrum, and an associated nonsuppurative meningitis. At birth, the brains of infected fetuses had thin-walled cerebral hemispheres, dilated lateral ventricles, and cerebral cysts. No gross lesions were observed in the brain stem or cerebellum.Two morphologically different lesions were present in the brain of a fetus sacrificed 20 days after virus inoculation. There were discrete foci of hemorrhagic cerebral necrosis that resembled infarcts and widespread microcavitations of the intermediate and subventricular zones. Changes consistent with vascular damage were present in the brains of fetuses sacrificed 12 and 20 days after virus inoculation.Calves with bluetongue virus-induced hydranencephaly would have poor viability, but they would not be expected to have any significance as virus reservoirs.
Renal Papillary Necrosis in Horses after Phenylbutazone and Water Deprivation
Authors: Gunson D. E. , Soma L. R. 
Published: January 2010

Acute renal papillary necrosis occurred in five horses given normal therapeutic doses of phenylbutazone and deprived of water for 36 to 48 hours prior to euthanasia. Five horses given phenylbutazone alone and four horses subjected to water deprivation alone did not develop papillary necrosis. Urinalyses were normal prior to water deprivation, and also after water deprivation in the horses that did not receive phenylbutazone, but the water-deprived, phenylbutazone-treated horses had many red blood cells, transitional epithelial cells, and large numbers of oxalate crystals in their urine.Ulceration of the alimentary tract was seen in more than 50% of these horses. Tongue ulceration was present in one of five horses given phenylbutazone and one of five horses which had phenylbutazone and water deprivation. Ulceration of the gastric mucosa was seen in two of the five phenylbutazone-treated horses, four of five horses with phenylbutazone treatment and water deprivation, and one of four horses with water deprivation alone. Severe colonic ulceration with perforation and peritonitis was present in one horse given phenyl-butazone for three months. No other significant changes in the small or large intestine were seen in the other 13 horses.
Activated Ras alters lens and corneal development through induction of distinct downstream targets
Authors: Burgess Daniel , Zhang Yan , Siefker Ed , Vaca Ryan , Kuracha Murali R , Reneker Lixing , Overbeek Paul A , Govindarajan Venkatesh 
Published: January 2010

AbstractBackgroundMammalian Ras genes regulate diverse cellular processes including proliferation and differentiation and are frequently mutated in human cancers. Tumor development in response to Ras activation varies between different tissues and the molecular basis for these variations are poorly understood. The murine lens and cornea have a common embryonic origin and arise from adjacent regions of the surface ectoderm. Activation of the fibroblast growth factor (FGF) signaling pathway induces the corneal epithelial cells to proliferate and the lens epithelial cells to exit the cell cycle. The molecular mechanisms that regulate the differential responses of these two related tissues have not been defined. We have generated transgenic mice that express a constitutively active version of human H-Ras in their lenses and corneas.ResultsRas transgenic lenses and corneal epithelial cells showed increased proliferation with concomitant increases incyclin D1andD2expression. This initial increase in proliferation is sustained in the cornea but not in the lens epithelial cells. Coincidentally, cdk inhibitorsp27Kip1andp57Kip2were upregulated in the Ras transgenic lenses but not in the corneas. Phospho-Erk1 and Erk2 levels were elevated in the lens but not in the cornea andSpry 1andSpry 2, negative regulators of Ras-Raf-Erk signaling, were upregulated more in the corneal than in the lens epithelial cells. Both lens and corneal differentiation programs were sensitive to Ras activation. Ras transgenic embryos showed a distinctive alteration in the architecture of the lens pit. Ras activation, though sufficient for upregulation ofProx1, a transcription factor critical for cell cycle exit and initiation of fiber differentiation, is not sufficient for induction of terminal fiber differentiation. Expression of Keratin 12, a marker of corneal epithelial differentiation, was reduced in the Ras transgenic corneas.ConclusionsCollectively, these results suggest that Ras activation a) induces distinct sets of downstream targets in the lens and cornea resulting in distinct cellular responses and b) is sufficient for initiation but not completion of lens fiber differentiation.
BACTIBASE second release: a database and tool platform for bacteriocin characterization
Authors: Hammami Riadh , Zouhir Abdelmajid , Le Lay Christophe , Ben Hamida Jeannette , Fliss Ismail 
Published: January 2010

Abstract

Background
BACTIBASE is an integrated open-access database designed for the characterization of bacterial antimicrobial peptides, commonly known as bacteriocins.

Description
For its second release, BACTIBASE has been expanded and equipped with additional functions aimed at both casual and power users. The number of entries has been increased by 44% and includes data collected from published literature as well as high-throughput datasets. The database provides a manually curated annotation of bacteriocin sequences. Improvements brought to BACTIBASE include incorporation of various tools for bacteriocin analysis, such as homology search, multiple sequence alignments, Hidden Markov Models, molecular modelling and retrieval through our taxonomy Browser.

Conclusion
The provided features should make BACTIBASE a useful tool in food preservation or food safety applications and could have implications for the development of new drugs for medical use. BACTIBASE is available at http://bactibase.pfba-lab-tun.org.
Identification of an unusual Brucella strain (BO2) from a lung biopsy in a 52 year-old patient with chronic destructive pneumonia
Authors: Tiller Rebekah V , Gee Jay E , Lonsway David R , Gribble Sonali , Bell Scott C , Jennison Amy V , Bates John , Coulter Chris , Hoffmaster Alex R , De Barun K 
Published: January 2010

Abstract

Background
Brucellosis is primarily a zoonotic disease caused by Brucella species. There are currently ten Brucella spp. including the recently identified novel B. inopinata sp. isolated from a wound associated with a breast implant infection. In this study we report on the identification of an unusual Brucella-like strain (BO2) isolated from a lung biopsy in a 52-year-old patient in Australia with a clinical history of chronic destructive pneumonia.

Results
Standard biochemical profiles confirmed that the unusual strain was a member of the Brucella genus and the full-length 16S rRNA gene sequence was 100% identical to the recently identified B. inopinata sp. nov. (type strain BO1T). Additional sequence analysis of the recA, omp2a and 2b genes; and multiple locus sequence analysis (MLSA) demonstrated that strain BO2 exhibited significant similarity to the B. inopinata sp. compared to any of the other Brucella or Ochrobactrum species. Genotyping based on multiple-locus variable-number tandem repeat analysis (MLVA) established that the BO2 and BO1Tstrains form a distinct phylogenetic cluster separate from the other Brucella spp.

Conclusion
Based on these molecular and microbiological characterizations, we propose that the BO2 strain is a novel lineage of the newly described B. inopinata species.