bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of Apoptosis by 1-Hydroxy-5,7-Dimethoxy-2-Naphthalene-Carboxaldehyde, a Novel Compound from Aegle marmelos
Authors: Subramaniam Dharmalingam , Giridharan Periyasamy , Murmu Nabendu , Shankaranarayanan Nallakandy P. , May Randal , Houchen Courtney W. , Ramanujam Rama P. , Balakrishnan Arun , Vishwakarma Ram A. , Anant Shrikant
Published: October 2008

We have identified a natural compound that activates apoptosis of epithelial cancer cells through activation of tumor necrosis factor-α (TNF-α), TNF receptor (TNFR)-associated death domain (TRADD), and caspases. The molecule 1-hydroxy-5,7-dimethoxy-2-naphthalene-carboxaldehyde (HDNC, marmelin) was isolated and characterized from ethyl acetate fraction of extracts of Aegle marmelos. HDNC treatment inhibited the growth of HCT-116 colon cancer tumor xenografts in vivo. Immunostaining for CD31 showed that there was a significant reduction in microvessels in the HDNC-treated animals, coupled with decreased cyclooxygenase-2, interleukin-8, and vascular endothelial growth factor mRNA. Using hexoseaminidase assay, we determined that HDNC inhibits proliferation of HCT-116 colon and HEp-2 alveolar epithelial carcinoma cells. Furthermore, the cancer cells showed increased levels of activated caspase-3 and induced G1 cell cycle arrest, which was suppressed by caspase-3 inhibitors. HDNC induced TNF-α, TNFR1, and TRADD mRNA and protein expression. Moreover, caspase-8 and Bid activation, and cytochrome c release, were observed, suggesting the existence of a cross-talk between death receptor and the mitochondrial pathways. HDNC inhibited AKT and extracellular signal-regulated kinase phosphorylation both in cells in culture and in tumor xenografts. In addition, electrophoretic mobility shift assay and luciferase reporter assays showed that HDNC significantly suppressed TNF-α–mediated activation and translocation of nuclear factor-κB (NF-κB). This was further confirmed by Western blot analysis of nuclear extracts wherein levels of RelA, the p65 component of NF-κB, were significantly less in cells treated with HDNC. Together, the data suggest that the novel compound HDNC (marmelin) is a potent anticancer agent that induces apoptosis during G1 phase of the cell cycle and could be a potential chemotherapeutic candidate. [Cancer Res 2008;68(20):8573–81]
Association of HDM2 Transcript Levels with Age of Onset and Prognosis in Soft Tissue Sarcomas
Authors: Taubert Helge , Bartel Frank , Greither Thomas , Bache Matthias , Kappler Matthias , Köhler Thomas , Böhnke Anja , Lautenschläger Christine , Schmidt Hannelore , Holzhausen Hans-Jürgen , Hauptmann Steffen , Würl Peter
Published: October 2008

The p53 stress response is crucial for the prevention of tumor formation. The oncogene HDM2 is one of the key negative regulators of p53 and is a central node in the p53 pathway. P53 and HDM2 form an oscillating feedback loop. HDM2 expression is regulated by different promoters. To evaluate its clinical relevance, we determined the levels of HDM2 transcripts originating from the constitutive P1 and p53-sensitive P2 promoter in 133 soft tissue sarcomas and correlated the results with the age of diagnosis and the patients' outcome. We show that only high levels of the HDM2-P1 transcript but not the P2 transcript are associated with an 11-year earlier age of onset (50.5 years) compared with low P1 levels (61.5 years; P < 0.0001, t test). In addition, low P1 and P2 mRNA expression levels were independent predictors of poor outcome for patients with soft tissue sarcomas (low P1: relative risk, 3.7; P < 0.0001; low P2: relative risk, 2.5; P = 0.001). A change in the expression levels of the HDM2 transcripts originating from the two HDM2 promoters could disrupt the oscillating P53-HDM2 feedback loop in a way that elevated levels of HDM2-P1 transcript are associated with an earlier age of tumor onset and that reduced levels of HDM2-P1 or HDM2-P2 transcripts are correlated with poor prognosis of patients with soft tissue sarcomas. (Mol Cancer Res 2008;6(10):1575–81)
Focal Adhesion Kinase Controls Aggressive Phenotype of Androgen-Independent Prostate Cancer
Authors: Johnson Thomas R. , Khandrika Lakshmipathi , Kumar Binod , Venezia Sarah , Koul Sweaty , Chandhoke Ryan , Maroni Paul , Donohue Robert , Meacham Randall B. , Koul Hari K.
Published: October 2008

Overexpression of focal adhesion kinase (FAK) has been well correlated with tumor development and/or the maintenance of tumor phenotype. In addition, inappropriate activation of the extracellular regulated kinase (ERK) signaling pathway is common to many human cancers. In the present study, we investigated the interplay between FAK and ERK in androgen-independent prostate cancer cells (PC3 and DU145 cells). We observed that suppression of FAK expression using small interfering RNA–mediated knockdown decreased the clonogenic activity, whereas overexpression of FAK increased it. We also observed that detachment of PC3 and DU145 cells from their substrate induced tyrosine phosphorylation of FAK. ERK knockdown diminished FAK protein levels and tyrosine phosphorylation of FAK as well as FAK promoter-reporter activity. We also tested the effect of MEK inhibitors and small interfering RNA–mediated knockdown of ERK1 and/or ERK2 on cell proliferation, invasiveness, and growth in soft agar of PC3 and DU145 cells. Inhibition of ERK signaling grossly impaired clonogenicity as well as invasion through Matrigel. However, inhibition of ERK signaling resulted in only a modest inhibition of 3H-thymidine incorporation and no effect on overall viability of the cells or increased sensitivity to anoikis. Taken together, these data show, for the first time, a requirement for FAK in aggressive phenotype of prostate cancer cells; reveal interdependence of FAK and ERK1/2 for clonogenic and invasive activity of androgen-independent prostate cancer cells; suggest a role for ERK regulation of FAK in substrate-dependent survival; and show for the first time, in any cell type, the regulation of FAK expression by ERK signaling pathway. (Mol Cancer Res 2008;6(10):1639–48)
Suppression of hPOT1 in Diploid Human Cells Results in an hTERT-Dependent Alteration of Telomere Length Dynamics
Authors: Possemato Richard , Timmons Jamie C. , Bauerlein Erica L. , Wada Naoya , Baldwin Amy , Masutomi Kenkichi , Hahn William C.
Published: October 2008

POT1 is a 3′ telomeric single-stranded overhang binding protein that has been implicated in chromosome end protection, the regulation of telomerase function, and defining the 5′ chromosome terminus. In human cancer cells that exhibit constitutive hTERT activity, hPOT1 exerts control over telomere length. Primary human fibroblasts express low levels of catalytically active hTERT in an S-phase–restricted manner that fails to counteract telomere attrition with cell division. Here, we show that diploid human fibroblasts in which hPOT1 expression has been suppressed harbor telomeres that are longer than control cells. This difference in telomere length delays the onset of replicative senescence and is dependent on S-phase–restricted hTERT expression. These findings are consistent with the view that hPOT1 promotes a nonextendable telomere state resistant to extension by S-phase–restricted telomerase. Manipulating this function of hPOT1 may thus hasten the cytotoxic effects of telomerase inhibition. (Mol Cancer Res 2008;6(10):1582–93)
Genomic signatures of chromosomal instability and osteosarcoma progression detected by high resolution array CGH and interphase FISH
Authors: Selvarajah S. , Yoshimoto M. , Ludkovski O. , Park P.C. , Bayani J. , Thorner P. , Maire G. , Squire J.A. , Zielenska M.
Published: October 2008

Osteosarcoma (OS) is characterized by an unstable karyotype which typically has a heterogeneous pattern of complex chromosomal abnormalities. High-resolution array comparative genomic hybridization (CGH) in combination with interphase fluorescence in situ hybridization (FISH) analyses provides a complete description of genomic imbalances together with an evaluation of the contribution of cell-to-cell variation to copy number changes. There have been no analyses to date documenting genomic signatures consistent with chromosomal instability mechanisms in OS tumors using array CGH. In this study, we utilized high-resolution array CGH to identify and characterize recurrent signatures of genomic imbalances using ten OS tumors. Comparison between the genomic profiles identified tumor groups with low, intermediate and high levels of genomic imbalance. Bands 6p22→p21, 8q24 and 17p12→ p11.2 were consistently involved in high copy gain or amplification events. Since these three locations have been consistently associated with OS oncogenesis, FISH probes from each cytoband were used to derive an index of cellular heterogeneity for copy number within each region. OS with the highest degree of genomic imbalance also exhibited the most extreme cell-to-cell copy number variation. Significantly, the three OS with the most imbalance and genomic copy number heterogeneity also had the poorest response to preoperative chemotherapy. This genome wide analysis is the first utilizing oligonucleotide array CGH in combination with FISH analysis to derive genomic signatures of chromosomal instability in OS tumors by studying genomic imbalance and intercellular heterogeneity. This comprehensive genomic screening approach provides important insights concerning the mechanisms responsible for generating complex genomes. The resulting phenotypic diversity can generate tumors with a propensity for an aggressive disease course. A better understanding of the underlying mechanisms leading to OS tumor development could result in the identification of prognostic markers and therapeutic targets.
Patterns of DNA copy number changes in sentinel lymph node breast cancer metastases
Authors: Santos S.C.L. , Cavalli I.J. , Ribeiro E.M. , Urban C.A. , Lima R.S. , Bleggi-Torres L.F. , Rone J.D. , Haddad B.R. , Cavalli L.R.
Published: October 2008

The sentinel lymph node (SLN) is considered to be the first axillary node that contains malignant cells in metastatic breast tumors, and its positivity is currently used in clinical practice as an indication for axillary lymph node dissection. Therefore, accurate evaluation of the SLN for the presence of breast metastatic cells is essential. The main aim of our study is to characterize the genomic changes present in the SLN metastatic samples with the ultimate goal of improving the predictive value of SLN evaluation. Twenty paired samples of SLN metastases and their corresponding primary breast tumors (PBT) were investigated for DNA copy number changes using comparative genomic hybridization (CGH). Non-random DNA copy number changes were observed in all the lesions analyzed, with gains being more common than losses. In 75% of the cases there was at least one change common to both PBT and SLN. The most frequent changes detected in both lesions were gains of 1pter→p32, 16, 17, 19, and 20 and losses of 6q13→q23 and 13q13→q32. In the PBT group, alterations on chromosomes 1, 16, and 20 were the most frequent, whereas chromosomes 1, 6, and 19 were the ones with the highest number of changes in the SLN metastatic group. A positive correlation was found between the DNA copy number changes per chromosome in each of the groups. Our findings indicate the presence of significant DNA copy number changes in the SLN metastatic lesions that could be used in the future as additional markers to improve the predictive value of SLN biopsy procedure.
Mismatch repair gene mutations in Chinese HNPCC patients
Authors: Sheng J.Q. , Fu L. , Sun Z.Q. , Huang J.S. , Han M. , Mu H. , Zhang H. , Zhang Y.Z. , Zhang M.Z. , Li A.Q. , Wu Z.T. , Han Y. , Li S.R.
Published: October 2008

To explore the characteristics of DNA mismatch repair gene mutations in Chinese patients with hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome, the MLH1 and MSH2 genes from probands of 76 HNPCC families were sequenced. By doing so, two frame-shift mutations, three splice-site mutations and fourteen missense mutations (thirteen missense mutations and one nonsense mutation) were identified in the MLH1 gene. In addition, one splice-site mutation and six missense mutations were detected in the MSH2 gene. None of these mutations were detected in 100 matched healthy controls. The remaining mutation-negative cases were subjected to large fragment deletion analysis using multiplex ligation-dependent probe amplification (MLPA). By doing so, five large fragment deletions were detected in the MSH2 gene. No large fragment deletions were detected in the MLH1 gene. We conclude that the MLH1 and MSH2 genes in Chinese HNPCC families exhibit broad mutation spectra.
A 4,103 marker integrated physical and comparative map of the horse genome
Authors: Raudsepp T. , Gustafson-Seabury A. , Durkin K. , Wagner M.L. , Goh G. , Seabury C.M. , Brinkmeyer-Langford C. , Lee E-J. , Agarwala R. , Stallknecht-Rice E. , Schäffer A.A. , Skow L.C. , Tozaki T. , Yasue H. , Penedo M.C.T. , Lyons L.A. , Khazanehdari K.A. , Binns M.M. , MacLeod J.N. , Distl O. , Guérin G. , Leeb T. , Mickelson J.R. , Chowdhary B.P.
Published: October 2008

A comprehensive second-generation whole genome radiation hybrid (RH II), cytogenetic and comparative map of the horse genome (2n = 64) has been developed using the 5000rad horse × hamster radiation hybrid panel and fluorescence in situ hybridization (FISH). The map contains 4,103 markers (3,816 RH; 1,144 FISH) assigned to all 31 pairs of autosomes and the X chromosome. The RH maps of individual chromosomes are anchored and oriented using 857 cytogenetic markers. The overall resolution of the map is one marker per 775 kilobase pairs (kb), which represents a more than five-fold improvement over the first-generation map. The RH II incorporates 920 markers shared jointly with the two recently reported meiotic maps. Consequently the two maps were aligned with the RH II maps of individual autosomes and the X chromosome. Additionally, a comparative map of the horse genome was generated by connecting 1,904 loci on the horse map with genome sequences available for eight diverse vertebrates to highlight regions of evolutionarily conserved syntenies, linkages, and chromosomal breakpoints. The integrated map thus obtained presents the most comprehensive information on the physical and comparative organization of the equine genome and will assist future assemblies of whole genome BAC fingerprint maps and the genome sequence. It will also serve as a tool to identify genes governing health, disease and performance traits in horses and assist us in understanding the evolution of the equine genome in relation to other species.
X chromosome inactivation patterns in normal and X-linked hereditary nephropathy carrier dogs
Authors: Bell R.J. , Lees G.E. , Murphy K.E.
Published: October 2008

Alport syndrome (AS) and hereditary nephropathy (HN) are glomerular nephropathies caused by mutations in the genes encoding the type IV collagens. In a mixed breed of dog, termed Navasota (NAV) dogs, X-linked hereditary nephropathy (XLHN) is caused by a 10-bp deletion in exon 9 of COL4A5. Males harboring this mutation succumb to end-stage renal disease before 18 months of age. In contrast, female carriers of this disease survive much longer, most have a normal life-span, and vary in disease progression as compared with XLHN-affected males. X chromosome inactivation (XCI) patterns have been studied in human X-linked AS carriers and some have been shown to have a high degree of skewed XCI. However, similar studies have never been reported in an animal model of this disease. Therefore, patterns of XCI were examined in XLHN-carrier NAV dogs. The variation in XCI among the 26 XLHN-carrier and seven normal female NAV dogs studied was low and only three were found to preferentially inactivate one X chromosome, all of which were XLHN-carriers. The average skewedness among all dogs was 59% and 57% among the XLHN-carriers. No significant difference in XCI was found between the two groups (P = 0.477). It is clear from these data that genotype does not seem to have an effect on inactivation; the majority of these dogs have random patterns of XCI. Highly skewed X chromosome inactivation also appears to be random, given that no difference was observed between the XLHN-carriers and normal females. Because of the apparent rarity of skewed XCI, these dogs may not be a suitable model for studying a potential correlation between this phenomenon and disease progression.
Chromosome polymorphism in Astyanax fasciatus (Teleostei, Characidae). 2 – Chromosomal location of a satellite DNA
Authors: Pazza R. , Frehner Kavalco K. , Bertollo L.A.C.
Published: October 2008

Studies about composition of repetitive sequences and their chromosomal location have been helpful to evolutionary studies in many distinct organisms. In order to keep on assessing the possible relationships among different cytotypes of Astyanax fasciatus (Teleostei, Characiformes) in the Mogi-Guaçu River (São Paulo State, Brazil), C-banding, chromomycin A3 staining, and fluorescent in situ hybridization with a repetitive DNA sequence (As51) isolated from Astyanax scabripinnis were performed in the present work. The constitutive heterochromatin was distributed in terminal regions on long arms of submetacentric, subtelocentric, and acrocentric chromosomes and in the terminal region on short arms of a pair of submetacentric chromosomes in both standard cytotypes. This latter heterochromatic site was also GC-rich, as revealed by chromomycin A3 staining, corresponding to the nucleolar organizer region (NOR), as shown by previous studies. The sites of the satellite As51 DNA were located in terminal regions on long arms of several chromosomes. Some variant karyotypic forms, which diverge from the two standard cytotypes, also presented distinctive chromosomes carrying As51 satellite DNA. It is possible that the standard 2n = 46 cytotype represents an invader population in the Mogi-Guaçu River able to interbreed with the resident standard 2n = 48 cytotype. Therefore, the variant karyotypes would be related to a possible viable offspring, where complementary chromosomal rearrangements could favor new locations of the satellite DNA analyzed.
A Single High Dose of Ascorbic Acid and Iron Is Not Correlated with Oxidative Stress in Healthy Volunteers
Authors: Colpo Elisângela , de Bem Andreza Fabro , Pieniz Simone , Schettert Sally Danuta , dos Santos Rosane Maria Souza , Gomes Farias Iria Luiza , Bertoncello Iara , Moreira Cleci Menezes , Barbosa Nilda Vargas , Moretto Maria Beatriz , Teixeira Rocha João Batista
Published: October 2008

Fe (II) is a potential prooxidant in vivo and can induce cellular oxidative stress. Ascorbic acid (AA) is a powerful physiological antioxidant and, in the presence of free Fe (II), can exhibit prooxidant effects in vitro. However, in vivo prooxidant effects of Fe (II) and AA have not yet been indisputably demonstrated. Here we evaluate the potential toxic effect of supplementation of Fe (II) associated with AA. Nine healthy, nonsmoking male volunteers (20–31 years old) participated in the crossover study design. The volunteers were supplemented with either a dose of 2 g of AA, 150 mg of iron carbonyl or 2 g of AA plus 150 mg of iron carbonyl with a washout period of 15 days between each treatment. AA, iron, ferritin, thiobarbituric acid-reactive substances, catalase, δ-aminolevulinic dehydratase and SH thiol groups were measured in the blood of the volunteers. Plasma AA levels were increased at 2, 5 and 24 h after AA or AA plus iron ingestion. Plasma Fe levels were increased at 2 and 5 h in the AA plus iron group. Erythrocyte malondialdehyde levels decreased at 5 and 24 h after AA and 5 h after AA plus iron ingestion. Catalase activity from erythrocytes was increased 5 h after supplementation with AA plus iron. There was no significant difference between groups in the other biochemical parameters evaluated. Thus, the present study does not support the hypothesis that the combination of high plasma concentrations of AA and iron, or iron alone, could cause in vivo oxidative damage after a single supplementation dose.
Depression and Bone Metabolism
Authors: Williams Lana J. , Pasco Julie A. , Jacka Felice N. , Henry Margaret J. , Dodd Seetal , Berk Michael
Published: October 2008

Background: There are data to suggest low bone mineral density is disproportionately prevalent among those with psychiatric disorders. This paper aims to review the current evidence on the relationship between depression and bone mineral density, and identify potential mechanisms. Methods: Relevant sources were identified from the Pubmed and Web of Science (ISI) databases from the first relevant publication in 1994 to the present, 2007, using a combination of key words and terms including depression, major depressive disorder, osteoporosis, bone mineral density, hypothalamic-pituitary-adrenal axis, cortisol, cytokines, leptin, antidepressants, selective serotonin reuptake inhibitors, smoking, alcohol, physical activity and diet. Reference lists of chosen articles were further reviewed for associated publications. Results: The possible association between psychiatric illness, in particular depression, and osteoporosis has been the subject of a growing body of research yielding various findings, although most identify some effect on bone. In addition to medication-related processes and/or modifiable lifestyle factors associated with mood disturbances, endocrine and immune alteration secondary to depression may play a pathogenetic role in bone metabolism. Conclusions: Additional longitudinal studies, with the advantage of temporal sequencing, remain to be conducted, as well as research into potential mechanisms surrounding the association. Nevertheless, the current findings are of clinical relevance, given the health burden of both depression and osteoporosis.
Otitis Media and Speech-in-Noise Recognition in School-Aged Children
Authors: Zumach A. , Gerrits E. , Chenault M.N. , Anteunis L.J.C.
Published: October 2008

The present study examined the long-term consequences of otitis media (OM) on speech perception abilities in noise. 55 children with a prospective 3-monthly documented middle-ear status and hearing loss between birth and 24 months completed a ‘speech-in-noise’ (SPiN) test at the age of 7 years. Both hearing loss and the cumulation of uni- and bilateral OM incidents in early life were significantly correlated to the performance on the SPiN test at school age. Other background factors such as socio-economic status, language perception and cognitive development did not predict the performance on the SPiN test. Only the language production score at age 7 was also significantly related to the score on the SPiN test. The present study deals with the risk of OM in early life and its accompanied hearing loss on auditory processing, specifically speech perception in noise, up to school age.
Acid Production from Sugars and Sugar Alcohols by Probiotic Lactobacilli and Bifidobacteria in vitro
Authors: Haukioja A. , Söderling E. , Tenovuo J.
Published: October 2008

Some probiotic bacterial strains have been suggested to improve oral health. However, lactobacilli and bifidobacteria are associated with the progression of dental caries. The pH fall caused by 14 probiotic and dairy bacterial strains from glucose, lactose, sucrose, sorbitol and xylitol was followed. All strains used glucose, nine lactose and seven sucrose. Six of the lactobacilli caused a small decrease in pH with sorbitol and two with xylitol. None of the bifidobacteria fermented sugar alcohols. As all the strains could be considered acidogenic, more long-term clinical trials are needed before recommendations for oral health purposes can be made.
Advances in Treatment Options of Endometriosis
Authors: Özkan Sebiha , Arici Aydin
Published: October 2008

Endometriosis, defined as the presence of endometrial tissue outside the uterus, is a challenging condition associated with substantial morbidity. Management of endometriosis must be individualized according to the desired treatment outcome, whether it is relief of pain, improvement of fertility, or the prevention of recurrence. For alleviation of endometriosis-associated pain, medical treatment is generally successful, with no medical agent being more efficacious than another in spite of significantly differing side-effect profiles. Surgical therapy has also been demonstrated to reduce pain scores in comparison with expectant management, although conservative surgery has been frequently associated with recurrence. The efficacy of combination therapies still remains to be clarified. For treatment of endometriosis-associated infertility, suppressive medical treatment has been proven to be detrimental to fertility and should be discouraged, while surgery is probably efficacious for all stages. Controlled ovarian hyperstimulation with intrauterine insemination is recommended in early-stage and surgically corrected endometriosis. Combined surgery with GnRH analog treatment has been proposed to be first-line therapy, followed by IVF as second-line therapy in advanced cases. More rigorously designed randomized clinical trials focusing on the endocrinological, immunological, and genetic aspects of endometriosis are necessary to refine conclusions regarding the etiopathogenesis and therapeutic innovations of this perplexing disease.
In vivo Efficacy of Marimastat and Chemoradiation in Head and Neck Cancer Xenografts
Authors: Skipper Joni B. , McNally Lacey R. , Rosenthal Eben L. , Wang Wenquan , Buchsbaum Donald J.
Published: October 2008

Objective: To assess the effect of combining a synthetic matrix metalloprotease inhibitor and chemoradiation therapy on tumor growth in a murine model of head and neck squamous-cell carcinoma (SCC). Methods: Athymic, nude mice bearing SCC-1 xenografts were used to comprise 4 treatment groups: (1) control receiving vehicle alone, (2) marimastat alone, (3) cisplatin + radiation in combination and (4) marimastat + cisplatin + radiation in combination. The marimastat was administered at a dose of 8.7 mg/kg/day over a 14-day period via a subcutaneous osmotic pump. The control group received vehicle only via a subcutaneous osmotic pump. Radiotherapy was given in 4 fractions of 8 Gy divided over days 8, 12, 16 and 20 with 4 intraperitoneal doses of cisplatin (3 mg/kg) 1 h before each fraction of radiation. Results: Animals receiving triple treatment had delayed growth, measured as lengthened tumor doubling time, compared to the cisplatin + radiation combination (p = 0.03). Also, compared to control, the triple-treatment group (p = 0.005) had delayed growth in terms of doubling time. Factor VIII immunohistochemistry to assess microvessel density did not demonstrate a reduction in neovascularization between the triple-treatment and cisplatin + radiation combination groups. Statistical analysis failed to demonstrate any significant difference among groups. Conclusions: Chemoradiation + marimastat therapy had delayed tumor growth, compared to the chemoradiation alone. Based on these results, marimastat may work in combination with chemotherapy and radiation to inhibit tumor growth.
Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson’s Disease: Usefulness of Intraoperative Radiological Guidance
Authors: Derrey Stéphane , Maltête David , Chastan Nathalie , Debono Bertrand , Proust François , Gérardin Emmanuel , Weber Jacques , Mihout Bruno , Fréger Pierre
Published: October 2008

Background: In our stereotactic procedure, intraoperative radiological documentation of electrode localization is performed using the Stereoplan. The aim of the study was to evaluate its accuracy. Patients and Methods: Data of 20 consecutive patients, treated for Parkinson’s disease by implantation of deep brain stimulators into the subthalamic nucleus, were collected prospectively. During surgery, Stereoplan coordinates of the tip of the central macroelectrodes were compared with intended coordinates along the central trajectory at 4 levels: (1) 10 mm above the anatomical target, (2) in the target, (3) in the substantia nigra pars reticulata, and (4) at the depth of contact 1. Before the frame’s removal, Stereoplan coordinates of the contacts of the definitive electrode were compared with postoperative MRI coordinates. The mean of the differences was calculated in the x-, y-, and z-axis. Clinical results at 6 months were recorded.Results: The mean of the differences between Stereoplan coordinates and intended coordinates for the macroelectrodes was lower than 1 mm. A submillimeter difference was also found for the definitive contacts. At 6 months, the Unified Parkinson‘s Disease Rating Scale III score improved by 70.6% compared with the baseline score. Dyskinesia and motor fluctuations decreased by 85.7 and 87%, respectively (p < 0.0001). Conclusion: Stereoplan could be considered an accurate intraoperative radiological system which assures the correct position of the electrode in the anatomical target.
Adverse Radiation Effects after Radiosurgery May Benefit from Oral Vitamin E and Pentoxifylline Therapy: A Pilot Study
Authors: Williamson Richard , Kondziolka Douglas , Kanaan Hilal , Lunsford L. Dade , Flickinger John C.
Published: October 2008

Background: Although uncommon, adverse radiation effects (ARE) are a potentially serious side effect of brain stereotactic radiosurgery (SRS). Corticosteroids are used to treat suspected ARE but side effects may be significant after long-term usage. Oral pentoxifylline (Ptx) and vitamin E therapy (VitE) are reported to benefit ARE seen in other organ systems. We treated 11 patients with suspected ARE after SRS with Ptx and VitE. Methods: To assess the response, edema was measured using fluid-attenuated inversion recovery magnetic resonance imaging (MRI). Edema volumes were calculated by first determining the three maximum measurements in the X, Y, and Z planes of the image with the largest signal change. Volume was plotted over time for each patient that had serial MRI scans available. Two patients had 2 separate radiosurgeries and 2 patients underwent 3. Three patients received adjuvant whole-brain radiation therapy. Results: The time until clinical detection of ARE after SRS varied from 3 to 18 months (median, 8 months). The change in edema volume varied from 59.6 ml in 1 patient (worse edema) to –324.2 ml (improvement). The average change in edema from pre- to post-treatment was –72.3 ml. One patient had more edema despite treatment; this patient was found to have tumor recurrence, and not an ARE. Two patients discontinued Ptx because of persistent nausea and abdominal discomfort. Conclusions: Ptx and VitE may be of benefit in the management of adverse radiation effects and should be studied further.
Long-Term Evolution and Changing Associations of Left Ventricular Hypertrophy after Starting Hemodialysis
Authors: Takeda Atsushi , Toda Takayuki , Iwamoto Hitoshi , Watanabe Kotaro , Matsui Noriaki
Published: October 2008

Background/Aims:Left ventricular hypertrophy (LVH) is prevalent in dialysis patients and is recognized as a potent risk factor for cardiovascular diseases. We examined the evolution of LVH after starting dialysis and the determinants of changes in LV mass. Methods: A cohort of 107 patients who had two or more echocardiograms at yearly intervals after starting hemodialysis was studied. Results: At baseline, the mean LV mass index (LVMI) was 145.8 g/m2 and 73 (68%) patients had LVH. During the mean follow-up period of 34.5 months, LVMI decreased by 3.9 g/m2. At last follow-up, the mean LVMI was 141.5 g/m2 and 68 (64%) patients had LVH. For changes in LVMI, a significant correlation was found in changes in systolic blood pressure, LVMI at baseline, changes in serum albumin concentration, and age. The relationship between changes in LVMI and systolic blood pressure was close during the 1st and 2nd intervals, but became weak gradually during the 3rd and 4th intervals. Conclusion: Many patients had LVH at starting hemodialysis and continued to have LVH thereafter. The most important determinants of LV mass changes were baseline LV mass and systolic blood pressure control, but the grade of reduction decreased gradually with time. These results suggest that active antihypertensive treatment should be started early to regress LVH and prevent cardiovascular diseases.
Synergistic Antileukemic Activity of Carnosic Acid-Rich Rosemary Extract and the 19-nor Gemini Vitamin D Analogue in a Mouse Model of Systemic Acute Myeloid Leukemia
Authors: Shabtay Ayelet , Sharabani Hagar , Barvish Zeev , Kafka Michael , Amichay Doron , Levy Joseph , Sharoni Yoav , Uskokovic Milan R. , Studzinski George P. , Danilenko Michael
Published: October 2008

Objective: Differentiation therapy with the hormonal form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D3), is a promising approach to treatment of acute myeloid leukemia (AML); however, 1,25D3 induces hypercalcemia at pharmacologically active doses. We investigated the in vitro and in vivoantileukemic efficacy of combined treatment with non-toxic doses of a low-calcemic 1,25D3 analogue, 1,25-dihydroxy-21(3-hydroxy-3-methyl-butyl)-19-nor-cholecalciferol (19-nor-Gemini; Ro27-5646), and rosemary plant agents in a mouse model of AML. Methods: Proliferation and differentiation of WEHI-3B D– (WEHI) murine myelomonocytic leukemia cellsin vitro were determined by standard assays. Reactive oxygen species, glutathione and protein expression levels were measured by flow cytometry, enzymatic assay and Western blotting, respectively. Systemic AML was developed by intravenous injection of WEHI cells in syngeneic Balb/c mice. Results: 19-nor-Gemini had a higher potency than its parent compounds, Gemini (Ro27-2310) and 1,25D3, in the induction of differentiation (EC50 = 0.059 ± 0.011, 0.275 ± 0.093 and 0.652 ± 0.085 nM, respectively) and growth arrest (IC50 = 0.072 ± 0.018, 0.165 ± 0.061 and 0.895 ± 0.144 nM, respectively) in WEHI cells in vitro, and lower in vivo toxicity. Combined treatment of leukemia-bearing mice with 19-nor-Gemini (injected intraperitoneally) and standardized rosemary extract (mixed with food) resulted in a synergistic increase in survival (from 42.2 ± 2.5 days in untreated mice to 66.5 ± 4.2 days, n = 3) and normalization of white blood cell and differential counts. This was consistent with strong cooperative antiproliferative and differentiation effects of low concentrations of 19-nor-Gemini or 1,25D3 combined with rosemary extract or its major polyphenolic component, carnosic acid, as well as with the antioxidant action of rosemary agents and vitamin D derivatives in WEHI cell cultures. Conclusion: Combined effectiveness of 1,25D3 analogues and rosemary agents against mouse AML warrants further exploration of this therapeutic approach in translational models of human leukemia.
Bevacizumab Improves the Overall and Progression-Free Survival of Patients with Metastatic Colorectal Cancer Treated with 5-Fluorouracil-Based Regimens Irrespective of Baseline Risk
Authors: Kabbinavar Fairooz , Irl Cornelia , Zurlo Alfredo , Hurwitz Herbert
Published: October 2008

Background: Köhne et al. [Ann Oncol 2002;13:308–317] showed that four prognostic variables can be used to classify patients with metastatic colorectal cancer (CRC) treated with 5-fluorouracil (5-FU)/leucovorin (LV) into three risk groups with different overall survival (OS). This model was applied to data from phase II/III trials of first-line bevacizumab plus 5-FU/LV with/without irinotecan (IFL). Methods: Data on tumor sites, Eastern Cooperative Oncology Group performance status, alkaline phosphatase levels and white blood cell counts were used to classify patients into Köhne prognostic high-, intermediate- and low-risk groups. Median OS and progression-free survival (PFS) were calculated for patients receiving 5-FU/LV plus bevacizumab or placebo (n = 489) and IFL plus bevacizumab or placebo (n = 812). Results: Median OS was longer in 5-FU/LV/bevacizumab (11.2–22.6 months) than in the 5-FU/LV/placebo (5.7–17.5 months), and in the IFL/bevacizumab arm (14.3–22.5 months) than in the IFL/placebo arm (8.4–17.9 months) across the Köhne high-, intermediate- and low-risk groups. The addition of bevacizumab also extended median PFS across the Köhne risk groups compared with placebo. Conclusions: Bevacizumab improves OS and PFS across the Köhne risk classification in patients with metastatic CRC. The Köhne model can be extended to patients treated with 5-FU/LV/bevacizumab, IFL and IFL/bevacizumab and to PFS data.
Biological Effects of Pegfilgrastim on Circulating Neutrophils in Breast Cancer Patients Undergoing Dose-Dense Chemotherapy
Authors: Invernizzi Rosangela , Grasso Donatella , Travaglino Erica , Benatti Chiara , Collovà Elena , Manzoni Mariangela , Livraghi Luca , Danova Marco , Riccardi Alberto
Published: October 2008

Pegfilgrastim is a covalent conjugate of filgrastim and polyethylene glycol that has proved to be effective in supporting myelopoiesis during chemotherapy. Since very limited information is available on the biological effects of pegfilgrastim on neutrophils exposed to chemotherapy, we analyzed the following parameters in neutrophils of patients undergoing dose-dense chemotherapy for breast cancer: apoptosis, by a TUNEL technique; actin polymerization, using FITC-labeled phalloidin, and alkaline phosphatase activity by cytochemistry. Peripheral blood buffy coat smears were obtained before starting treatment and immediately before each chemotherapy course. After pegfilgrastim stimulation we observed the following: (1) stability of the absolute neutrophil count for the whole duration of treatment and no infectious events; (2) a reduction in the neutrophil constitutive apoptosis rate in comparison with that observed in control patients treated with standard chemotherapy courses with no growth factor support; (3) persistent abnormalities of actin assembly in neutrophils, indicative of changes in cytoskeletal organization, and (4) a significant increase in the activity of leukocyte alkaline phosphatase, a sensitive marker of the later stages of neutrophil maturation. In conclusion, these results suggest that pegfilgrastim improves the neutrophil functions in patients exposed to chemotherapy by inhibition of constitutive apoptosis, thereby prolonging the survival of these cells.
Ubiquitination as a Priming Process of PKC αand PKC ε Degradation in the αT3-1 Gonadotrope Cell Line
Authors: Poulin Benoit , Maccario Hélène , Thirion Sylvie , Junoy Brice , Boyer Bénédicte , Enjalbert Alain , Drouva Sophia V.
Published: October 2008

Background/Aim: Protein kinase C (PKC) is a family of isoenzymes playing a key role in the regulation of gonadotrope cell functions. Specific PKC isoforms are activated and downregulated differentially by gonadotropin-releasing hormone (GnRH) and the phorbol ester TPA. In the present study, focusing mainly on PKC ε, the mechanisms underlying the proteasome-dependent downregulation of GnRH-activated PKC ε and TPA-sensitive PKC α and ε isoenzymes were investigated in αT3-1 gonadotrope cells. Methods/Results: In pull-down assays involving the use of glutathione-agarose affinity beads conjugated with a GST-fusion protein containing ubiquitin-associated domains of Rad23 that bind very likely to K48-linked polyubiquitinated proteins, TPA induced rapid (within 15 min) and sustained (up to 4 h) PKC α and PKC ε polyubiquitination. However, GnRH selectively elicited receptor-dependent polyubiquitination of PKC ε, but not that of PKC α. The GnRH-evoked PKC ε polyubiquitination was a strong, fast process (taking place as early as 10 min) which decreased progressively with time (but was still detectable after 4 h of treatment). In addition, no apparent association between PKC ε and the lysosomal compartment was observed upon performing double-labeling immunofluorescence and confocal microscopy, after either 10 min or 1 hour of stimulation by GnRH or the phorbol ester. Conclusion: In αT3-1 gonadotrope cells, polyubiquitination is therefore the event triggering GnRH-evoked PKC ε desensitization as well as TPA-induced PKC α and PKC ε downregulations; it precedes the respective isoenzyme’s degradation by the proteasome complex.
Induced Sputum in Systemic Sclerosis Interstitial Lung Disease: Comparison to Healthy Controls and Bronchoalveolar Lavage
Authors: Damjanov N. , Ostojic P. , Kaloudi O. , Alari S. , Guiducci S. , Stanflin N. , Nestorovic B. , Knezevic J. , Camiciottoli G. , Porta F. , Pistolesi M. , Ibba-Manneschi L. , Conforti M.L. , Candelieri A. , Matucci Cerinic M.
Published: October 2008

Background: Induced sputum (IS) is a noninvasive tool, which can be used to collect cellular and soluble materials from lung airways. Objective: To evaluate if IS may be a useful and safe tool for the detection of airway inflammation in patients with interstitial lung disease (ILD) in systemic sclerosis (SSc). Methods: Sixty-eight patients with SSc and ILD as well as 18 healthy individuals (controls) were selected and submitted to IS examination. In 34 of 68 patients with SSc, bronchoalveolar lavage (BAL) was also performed. Safety of IS was assessed by comparison of forced expiratory volume in the first second (FEV1), FEV1/forced vital capacity ratio and peak expiratory flow before and after the IS procedure. Cell composition in samples collected by BAL and IS was correlated, and IS total and differential cell count in SSc patients and controls were compared. Results: The total number of cells was significantly higher in IS samples of SSc patients compared to those of healthy controls. Mean percentage of neutrophils was also higher in SSc patients (41.79 ± 23.89 vs. 27.37 ± 17.90), as well as lymphocytes (17.42 ± 19.70 vs. 3.13 ± 2.28) and eosinophils (2.35 ± 4.43 vs. 0.41 ± 0.46). On the other hand, mean percentage of macrophages was higher in healthy individuals (69.10 ± 19.15 vs. 36.96 ± 20.68). In fluid recovered by BAL, the most frequent cells were macrophages (67.89% ± 17.26), while neutrophils (14.77 ± 17.18%) and lymphocytes (15.62 ± 13.46%) were less frequent and eosinophils (1.66 ± 2.08%) were rare. A similar pattern of cell composition was found in IS samples (41.15 ± 21.67% of macrophages, 39.72 ± 23.15% of neutrophils, 15.28 ± 19.46% of lymphocytes and 2.56 ± 5.03% of eosinophils). Strength of correlation between BAL and IS was significant for macrophages and neutrophils. After IS procedure was performed, improvement of FEV1 (mean value before IS was 85.09 ± 14.44 and 88.93 ± 16.40 after IS) and FEV1/forced vital capacity (mean value before IS was 98.53 ± 12.11 and 105.22 ± 10.78 after IS) was observed. Conclusion: The IS method may allow a noninvasive assessment of cell composition in airway fluid and may contribute to the better understanding of upper/medium airway inflammation in SSc. Future studies are needed to verify whether IS can replace invasive procedures for the detection and monitoring of lung inflammation in SSc.
Long-Term Clinical Results of 2 Different Ablation Strategies in Patients With Paroxysmal and Persistent Atrial Fibrillation
Authors: Gaita Fiorenzo , Caponi Domenico , Scaglione Marco , Montefusco Antonio , Corleto Antonella , Di Monte Fernando , Coin Daniele , Di Donna Paolo , Giustetto Carla
Published: October 2008

Background—

Data regarding the long-term efficacy of atrial fibrillation (AF) ablation are still lacking.

Methods and Results—

Two hundred four consecutive patients symptomatic for paroxysmal or persistent/permanent AF were randomly assigned to 2 different ablation schemes: pulmonary vein isolation (PVI) and PVI plus left linear lesions (LL). Primary end point was to assess the maintenance of sinus rhythm (SR) after procedures 1 and 2 in the absence of antiarrhythmic drugs in a long-term follow-up of at least 3 years.

Paroxysmal AF—

With a single procedure at 12-month follow-up, 46% of patients treated with PVI maintained SR, whereas at 3-year follow-up, 29% were in SR; using the “PVI plus LL” at the 12-month follow-up, 57% of patients were in SR, whereas at the 3-year follow-up, 53% remained in SR. After a second procedure, the long-term overall success rate without antiarrhythmic drugs was 62% with PVI and 85% with PVI plus LL.

Persistent/Permanent AF—

With a single procedure at the 12-month follow-up, 27% of patients treated with PVI were in SR, whereas at the 3-year follow-up, 19% maintained SR; using the PVI plus LL with a single procedure at the 12-month follow-up 45% of patients were in SR, whereas at the 3-year follow-up, 41% remained in SR. After a second procedure, the long-term overall success rate without antiarrhythmic drugs was 39% with PVI and 75% with PVI plus LL.

Conclusions—

A long-term follow-up of AF ablation shows that short-term results cannot be considered permanent because AF recurrences are still present after the first year especially in patients who have had “PVI” strategy. PVI isolation plus LL is superior to the PVI strategy in maintaining SR without antiarrhythmic drugs after procedures 1 and 2 both in paroxysmal and persistent AF.
Patient and Implanting Physician Factors Associated With Mortality and Complications After Implantable Cardioverter-Defibrillator Implantation, 2002–2005
Authors: Al-Khatib Sana M. , Greiner Melissa A. , Peterson Eric D. , Hernandez Adrian F. , Schulman Kevin A. , Curtis Lesley H.
Published: October 2008

Background—

Little is known about factors that influence survival and complications after implantable cardioverter-defibrillator (ICD) implantation in routine clinical practice. We examined patient and implanting physician factors associated with outcomes of ICD therapy in Medicare beneficiaries from 2002 through 2005.

Methods and Results—

We limited this analysis to patients aged ≥65 with Medicare fee-for-service coverage who received an ICD between January 2002 and September 2005. The main outcome measures are time to postprocedural complications within 90 days and 1-year mortality. During the study period, 8581 patients had an ICD implanted by 1959 physicians. The number of procedures increased from 1644 in 2002 to 2374 in the first 3 quarters of 2005. The overall complication rate declined from 18.8% in 2002 to 14.2% in 2005 (
P
<0.001). Factors independently associated with an increased hazard of complications include chronic lung disease, dementia, renal disease, implantation by a thoracic surgeon, and implantation with removal/replacement. History of congestive heart failure, outpatient implantation, and more recent years of ICD implantation were associated with a lower risk of complications (
P
<0.05 for all factors). From 2002 to 2005, we observed a decline in 1-year mortality (
P
<0.001).

Conclusions—

We observed an appreciable increase in the number of ICD implants, which was associated with a significant decrease in the rate of complications and 1-year mortality. We identified factors associated with an increased risk of mortality and postprocedural complications that may support more nuanced treatment decisions than are currently possible.