bluuebunny/crossref_metadata_2025 huggingface dataset:
Gastric Trichobezoar Causing Intermittent Small Bowel Obstruction: Report of a Case and Review of the Literature
Authors: Coufal Nicole G. , Kansagra Akash P. , Doucet Jay , Lee Jeanne , Coimbra Raul , Bansal Vishal
Published: June 2011

We report the unusual case of a 45-year-old woman who presented with multiple episodes of small bowel obstruction. Initial exploratory lap-roscopy did not reveal an etiology of the obstruction. Subsequent upper endoscopy identified a non-obstructing gastric trichobezoar which could not be removed endoscopically but was not thought to be responsible for the small bowel obstruction given its location. One week postoperatively, the patient experienced recurrence of small bowel obstruction. Repeat endoscopy disclosed that the trichobezoar was no longer located in the stomach and upon repeat laparotomy was extracted from the mid-jejunum. In the following 8 months, the patient had no further episodes of small bowel obstruction. Consequently, gastric bezoars should be included in the differential diagnosis of recurrent small bowel obstruction.
Diagnostic Value of the13C Methacetin Breath Test in Various Stages of Chronic Liver Disease
Authors: Razlan Hamizah , Marzuki Nurhayaty Muhamad , Tai Mei-Ling Sharon , Shamsul Azhar-Shah , Ong Tze-Zen , Mahadeva Sanjiv
Published: June 2011

The accuracy of the13C-methacetin breath test (13C-MBT) in differentiating between various stages of liver disease is not clear. A cross-sectional study of Asian patients was conducted to examine the predictive value of the13C-MBT in various stages of chronic liver diseases. Diagnostic accuracy of the breath test was determined by sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve analysis. Seventy-seven patients (47 men/30 women, mean age50±16years) were recruited. Forty-seven patients had liver cirrhosis (Child Pugh A = 11, Child Pugh B = 15, and Child Pugh C = 21), 21 had fibrosis, and 9 had chronic inflammation. The sensitivity and positive predictive value for liver fibrosis, cirrhosis (all stages), Child-Pugh A, Child-Pugh B, and Child-Pugh C were 65% and 56%, 89% and 89%, 67% and 42%, 40% and 40%, and 50% and 77%, respectively. Area under curve values for fibrosis was 0.62 (0.39–0.86), whilst that for cirrhosis (all stages) was 0.95 (0.91–0.99). The13C-methacetin breath test has a poor predictive value for liver fibrosis but accurately determines advanced cirrhosis.
Developing a Deeper Understanding of Autism: Connecting Knowledge through Literature Mining
Authors: Macedoni-Lukšič Marta , Petrič Ingrid , Cestnik Bojan , Urbančič Tanja
Published: June 2011

In the field of autism, an enormous increase in available information makes it very difficult to connect fragments of knowledge into a more coherent picture. We present a literature mining method, RaJoLink, to search for matched themes in unrelated literature that may contribute to a better understanding of complex pathological conditions, such as autism. 214 full text articles on autism, published in PubMed, served as a source of data. Using ontology construction, we identified the main concepts of what is already known about autism. Then, the RaJoLink method, based on Swanson's ABC model, was used to reveal potentially interesting, but not yet investigated, connections between different concepts in research. Among the more interesting concepts identified with RaJoLink in our study were calcineurin and NF-kappaB. Both terms can be linked to neuro-immune abnormalities in the brain of patients with autism. Further research is needed to provide stronger evidence about calcineurin and NF-kappaB involvement in autism. However, the analysis presented confirms that this method could support experts on their way towards discovering hidden relationships and towards a better understanding of the disorder.
Hydrothermal Synthesis ofSnO2Nanostructures with Different Morphologies and Their Optical Properties
Authors: Tan Lin , Wang Lihong , Wang Yude
Published: June 2011

SnO2hollow spheres and nanorods were prepared by an aqueous sol-gel route involving the reaction of tin chloride and sodium dodecyl sulphate (SDS) in hexanol and heptane under the different hydrothermal treating temperature and time. X-ray diffraction (XRD) spectra, Fourier transformed infrared (FTIR) spectrum, scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution TEM (HRTEM) and Raman spectroscopy were used to examine the morphology and microstructure to find out the cause. The result indicates that the products are hollow spheres with diameters of approximately 200–900 nm and shell thickness of 60–70 nm via hydrothermal treating at 160°C and one-dimensional rod-like nanostructures with diameters of approximately 20–40 nm and lengths of 100–300 nm via hydrothermal treating at 180 and 200°C, respectively. Room-temperature photoluminescence (PL) properties were investigated under the excitation of 275 nm. The samples exhibited the emission peaks of room-temperature photoluminescence.
Andrographolide: A Novel Antimalarial Diterpene Lactone Compound fromAndrographis paniculataand Its Interaction with Curcumin and Artesunate
Authors: Mishra Kirti , Dash Aditya P. , Dey Nrisingha
Published: June 2011

Andrographolide (AND), the diterpene lactone compound, was purified by HPLC from the methanolic fraction of the plantAndrographis paniculata. The compound was found to have potent antiplasmodial activity when tested in isolation and in combination with curcumin and artesunate against the erythrocytic stages ofPlasmodium falciparum in vitroandPlasmodium bergheiANKAin vivo. IC50s for artesunate (AS), andrographolide (AND), and curcumin (CUR) were found to be 0.05, 9.1 and 17.4 μM, respectively. The compound (AND) was found synergistic with curcumin (CUR) and addictively interactive with artesunate (AS).In vivo, andrographolide-curcumin exhibited better antimalarial activity, not only by reducing parasitemia (29%), compared to the control (81%), but also by extending the life span by 2-3 folds. Being nontoxic to thein vivosystem this agent can be used as template molecule for designing new derivatives with improved antimalarial properties.
An Overview of the Clinical Use of Antimuscarinics in the Treatment of Overactive Bladder
Authors: Athanasopoulos Anastasios , Giannitsas Konstantinos
Published: June 2011

Overactive bladder is a common and bothersome condition. Antimuscarinic agents, as a class, are the cornerstone of medical treatment of overactive bladder. They offer significant improvements in symptoms and patients’ quality of life. Antimuscarinics are generally well tolerated with mild and predictable side effects. Available antimuscarinics have small, yet statistically significant, differences in their efficacy and tolerability profiles. In clinical practice, finding the agent that offers the optimum balance of efficacy and side effects for an individual patient remains the major challenge.
Modulation and Interaction of Immune‐Associated Parameters with Antioxidant in the Immunocytes of Crab Scylla paramamosain Challenged with Lipopolysaccharides
Authors: Gopalakrishnan Singaram , Chen Fang-Yi , Thilagam Harikrishnan , Qiao Kun , Xu Wan-Fang , Wang Ke-Jian
Published: June 2011

Invertebrates are dependent on cellular and humoral immune defences against microbial infection. Scylla paramamosain is an important commercial species, but the fundamental knowledge on its immune defense related to the antioxidant and immune‐associated reactions is still lacking. The study was to differentiate the responses of immune‐associated parameters of haemolymph components in S. paramamosain when challenged with bacterial lipopolysaccharides (LPSs). The immunostimulating effects of LPS in crab by triggering various immune parameters (phagocytosis, lysozyme, antibacterial activity, phenoloxidase, and the generation of superoxide and nitric oxide) were investigated. Results showed that the generation of free radicals, phenoloxidase, lysozyme and antibacterial activities was significantly increased through the exposure periods. Conversely, total hemocyte count and lysosomal membrane stability decreased significantly as the exposure period extended to 96 h. The relationship between the antioxidant enzymes and immune reactions due to LPS was highly significant. In addition, ROS production was positively correlated with antioxidant showing immediate response of antioxidant defense to the oxyradicals generated. Overall, the study indicated that nonspecific immune components in hemocytes of crab showed active response to the LPS stimulation, and their responses suggested that many immune‐associated parameters could be modulated and interrelated with the influence of antioxidants in crustaceans.
Primary Ewing’s Sarcoma of the Kidney in a 73-Year-Old Man
Authors: Wedde T. B. , Lobmaier I. V. K. , Brennhovd B. , Lohne F. , Hall K. S.
Published: June 2011

Objective. Ewing’s sarcoma of the kidney is rare and is usually found in young adults. We present here a single case study of Ewing's sarcoma found in an elderly man.Material and methods. A 73-year-old man underwent routine surgery for hydrocoele of the testis. He developed urinary obstruction symptoms, and radiological examinations revealed a tumour in the right kidney.Results.Microscopical, immunohistochemical, and molecular pathological analysis of the tumour was consistent with Ewing's sarcoma. FISH showed rearrangement of chromosomes 22q12 (EWSR1). The patient subsequently underwent nephrectomy followed by 6 adjuvant chemotherapy cycles. Follow-up after 7 months shows no recurrence.Conclusion. This case report presents not only the rare finding of Ewing's sarcoma in the kidney, but also the occurrence of this tumour entity in an elderly patient. Treatment options for the different types of renal tumours are vastly different and the need for a correct diagnosis is, therefore, vital.
Memory Type 2 Helper T Cells Induce Long-Lasting Antitumor Immunity by Activating Natural Killer Cells
Authors: Kitajima Masayuki , Ito Toshihiro , Tumes Damon J. , Endo Yusuke , Onodera Atsushi , Hashimoto Kahoko , Motohashi Shinichiro , Yamashita Masakatsu , Nishimura Takashi , Ziegler Steven F. , Nakayama Toshinori
Published: June 2011

Functionally polarized helper T cells (Th cells) play crucial roles in the induction of tumor immunity. There is considerable knowledge about the contributions of IFN-producing Th1 cells that supports the role of cytotoxic cluster of differentiation (CD8) T cells and natural killer (NK) cells, but much less is known about how IL-4–producing Th2 cells contribute to tumor immunity. In this study, we investigated the cellular and molecular mechanisms employed by memory Th2 cells in sustaining tumor immunity by using a mouse model system wherein ovalbumin (OVA) is used as a specific tumor antigen. In this model, we found that OVA-specific memory Th2 cells exerted potent and long-lasting antitumor effects against NK-sensitive OVA-expressing tumor cells, wherein antitumor effects were mediated by NK cells. Specifically, NK cell cytotoxic activity and expression of perforin and granzyme B were dramatically enhanced by the activation of memory Th2 cells. Interleukin 4 (IL-4) produced by memory Th2 cells in vivo was critical for the antitumor effects of the NK cells, which IL-4 directly stimulated to induce their perforin- and granzyme-B–dependent cytotoxic activity. Our findings show that memory Th2 cells can induce potent antitumor immunity through IL-4–induced activation of NK cells, suggesting potential applications in cellular therapy for cancer patients. Cancer Res; 71(14); 4790–8. ©2011 AACR.
Sequential Activation of Snail1 and N-Myc Modulates Sonic Hedgehog–Induced Transformation of Neural Cells
Authors: Wanshura Leah E. Colvin , Galvin Katherine E. , Ye Hong , Fernandez-Zapico Martin E. , Wetmore Cynthia
Published: June 2011

Activation of the Sonic hedgehog (Shh) pathway and increased expression of Gli1 play an important role in proliferation and transformation of granule cell progenitors (GCP) in the developing cerebellum. Medulloblastomas arising from cerebellar GCPs are frequently driven by Shh pathway–activating mutations; however, molecular mechanisms of Shh pathway dysregulation and transformation of neural progenitors remain poorly defined. We report that the transcription factor and oncogene Snail1 (Sna1) is directly induced by Shh pathway activity in GCPs, murine medulloblastomas, and human medulloblastoma cells. Enforced expression of Sna1 was sufficient to induce GCPs and medulloblastoma cell proliferation in the absence of Shh/Gli1 exposure. In addition, enforced expression of Sna1 increased transformation of medulloblastoma cells in vitro and in vivo. Analysis of potential Sna1 targets in neural cells revealed a novel Sna1 target, N-Myc, a transcription factor known to play a role in Shh-mediated GCP proliferation and medulloblastoma formation. We found that Sna1 directly induced transcription of N-Myc in human medulloblastoma cells and that depletion of N-Myc ablated the Sna1-induced proliferation and transformation. Taken together, these results provide further insight into the mechanism of Shh-induced transformation of neural progenitor cells and suggest that induction of Sna1 may serve to amplify the oncogenic potential of Shh pathway activation through N-Myc induction. Cancer Res; 71(15); 5336–45. ©2011 AACR.
Dissecting the Oncogenic and Tumorigenic Potential of Differentiated Human Induced Pluripotent Stem Cells and Human Embryonic Stem Cells
Authors: Ghosh Zhumur , Huang Mei , Hu Shijun , Wilson Kitchener D. , Dey Devaveena , Wu Joseph C.
Published: June 2011

Pluripotent stem cells, both human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC), can give rise to multiple cell types and hence have tremendous potential for regenerative therapies. However, the tumorigenic potential of these cells remains a great concern, as reflected in the formation of teratomas by transplanted pluripotent cells. In clinical practice, most pluripotent cells will be differentiated into useful therapeutic cell types such as neuronal, cardiac, or endothelial cells prior to human transplantation, drastically reducing their tumorigenic potential. Our work investigated the extent to which these differentiated stem cell derivatives are truly devoid of oncogenic potential. In this study, we analyzed the gene expression patterns from three sets of hiPSC- and hESC-derivatives and the corresponding primary cells, and compared their transcriptomes with those of five different types of cancer. Our analysis revealed a significant gene expression overlap of the hiPSC- and hESC-derivatives with cancer, whereas the corresponding primary cells showed minimum overlap. Real-time quantitative PCR analysis of a set of cancer-related genes (selected on the basis of rigorous functional and pathway analyses) confirmed our results. Overall, our findings suggested that pluripotent stem cell derivatives may still bear oncogenic properties even after differentiation, and additional stringent functional assays to purify these cells should be done before they can be used for regenerative therapy. Cancer Res; 71(14); 5030–9. ©2011 AACR.
Following Cancer Prevention Guidelines Reduces Risk of Cancer, Cardiovascular Disease, and All-Cause Mortality
Authors: McCullough Marjorie L. , Patel Alpa V. , Kushi Lawrence H. , Patel Roshni , Willett Walter C. , Doyle Colleen , Thun Michael J. , Gapstur Susan M.
Published: June 2011

Background: Few studies have evaluated the combined impact of following recommended lifestyle behaviors on cancer, cardiovascular disease (CVD) and all-cause mortality, and most included tobacco avoidance. Because 80% of Americans are never or former smokers, it is important to consider the impact of other recommended behaviors.

Methods: In 1992 and 1993, 111,966 nonsmoking men and women in the Cancer Prevention Study-II Nutrition Cohort completed diet and lifestyle questionnaires. A score ranging from 0 to 8 points was computed to reflect adherence to the American Cancer Society cancer prevention guidelines on body mass index, physical activity, diet, and alcohol consumption, with 8 points representing optimal adherence. Multivariable-adjusted relative risks (RR) of death and 95% CI were computed by Cox proportional hazard regression.

Results: During 14 years of follow-up, 10,369 men and 6,613 women died. The RR of all-cause mortality was lower for participants with high (7, 8) versus low (0–2) scores (men, RR = 0.58, 95% CI: 0.53–0.62; women, RR = 0.58, 95% CI: 0.52–0.64). Inverse associations were found with CVD mortality (men, RR = 0.52, 95% CI: 0.45–0.59; women, RR = 0.42, 95% CI: 0.35–0.51) and cancer mortality (men, RR = 0.70, 95% CI: 0.61–0.80; women, RR = 0.76, 95% CI: 0.65–0.89). Similar associations, albeit not all statistically significant, were observed for never and former smokers.

Conclusion: Adherence to cancer prevention guidelines for obesity, diet, physical activity, and alcohol consumption is associated with lower risk of death from cancer, CVD, and all causes in nonsmokers.

Impact: Beyond tobacco avoidance, following other cancer prevention guidelines may substantially lower risk of premature mortality in older adults. Cancer Epidemiol Biomarkers Prev; 20(6); 1089–97. ©2011 AACR.
PSA Quo Vadis? It Is Reasonable to Start with Prostate-Specific Antigen Testing at the Age of 40!
Authors: Börgermann Christof , vom Dorp Frank , Swoboda Andreas , Ketteniß Oskar , Becker Markus , Rübben Herbert
Published: June 2011

Background: It is common to start with PSA (prostate-specific antigen)-testing at the age of 50. If patients with a PSA value greater than 4 ng/mL should be considered for prostate biopsy, approximately 20% of all men undergoing test are considered for biopsy at the time of first early-detection examination.

Methods: We have screened 2,592 asymptomatic men younger than 45 years. With a short questionnaire, we assessed age, body mass index (BMI), concomitant diseases, last sexual intercourse, and last bicycle riding. We compared this cohort with a group of 11,656 men aged 45–75 years from a nationwide prostate cancer screening trial.

Results: In this cohort, only 4 men with a PSA value greater than 4 ng/mL and 10 with a PSA greater than 3 ng/mL were identified. More than 99% of all men younger than 45 years had a PSA lesser than 4 ng/mL. Sexual intercourse, bicycle riding, or BMI had a significant but minimal influence on the PSA value.

Conclusions: It is reasonable to start with PSA testing at the age of 40 years. The advantage of screening younger patients is that almost no one should be considered for biopsy at the time of first early-detection examination. We identified a baseline value at which only a minimal influence was exerted by benign prostatic hypertrophy. In comparison with many current guidelines, we gained a lead time of 10 years for observation of PSA dynamics.

Impact: The importance of PSA velocity for stratification of patients at risk for development of significant prostate cancer will grow. Cancer Epidemiol Biomarkers Prev; 20(6); 1190–5. ©2011 AACR.
A Computational Method to Classify Variants of Uncertain Significance Using Functional Assay Data with Application to BRCA1
Authors: Iversen Edwin S. , Couch Fergus J. , Goldgar David E. , Tavtigian Sean V. , Monteiro Alvaro N.A.
Published: June 2011

Background: Besides revealing cancer predisposition variants or the absence of any changes, genetic testing for cancer predisposition genes can also identify variants of uncertain clinical significance (VUS). Classifying VUSs is a pressing problem, as ever more patients seek genetic testing for disease syndromes and receive noninformative results from those tests. In cases such as the breast and ovarian cancer syndrome in which prophylactic options can be severe and life changing, having information on the disease relevance of the VUS that a patient harbors can be critical.

Methods: We describe a computational approach for inferring the disease relevance of VUSs in disease genes from data derived from an in vitro functional assay. It is based on a Bayesian hierarchical model that accounts for sources of experimental heterogeneity.

Results: The functional data correlate well with the pathogenicity of BRCA1 BRCT VUSs, thus providing evidence regarding pathogenicity when family and genetic data are absent or uninformative.

Conclusions: We show the utility of the model by using it to classify 76 VUSs located in the BRCT region of BRCA1. The approach is both sensitive and specific when evaluated on variants previously classified using independent sources of data. Although the functional data are very informative, they will need to be combined with other forms of data to meet the more stringent requirements of clinical application.

Impact: Our work will lead to improved classification of VUSs and will aid in the clinical decision making of their carriers. Cancer Epidemiol Biomarkers Prev; 20(6); 1078–88. ©2011 AACR.
Serum 25-Hydroxyvitamin D and Risk of Oropharynx and Larynx Cancers in Finnish Men
Authors: Arem Hannah , Weinstein Stephanie J. , Horst Ronald L. , Virtamo Jarmo , Yu Kai , Albanes Demetrius , Abnet Christian C.
Published: June 2011

Background: Published studies suggesting a relationship between vitamin D and some common cancers sparked interest in the association of vitamin D with head and neck cancers. Prolonged darker months in Finland are associated with lower levels of ultraviolet B radiation, raising concerns about low vitamin D levels.

Methods: We used a nested case–control study in the prospective Alpha-Tocopherol Beta Carotene (ATBC) Study of male smokers in Finland, to examine the relationship between serum 25(OH)D and risk of developing squamous cancers of the head and neck. Using conditional logistic regression, we calculated the multivariate adjusted ORs and CIs comparing those with serum 25(OH)D adequate levels of 50 to <75 nmol/L to those <25.0.

Results: We identified incident cancers of the oral cavity (n = 134), pharynx (n = 48), and larynx (n = 158). Median serum vitamin D was 31 nmol/L (interquartile range: 21–48), which is below the 50 nmol/L cutoff point was considered adequate for bone and overall health. Comparing those with serum 25(OH)D below 25 nmol/L to those 50 to <75 nmol/L as the referent, the OR was 1.35 (95% CI: 0.53–3.43, Ptrend = 0.65) for overall head and neck cancers. Stratification by cancer subsites of the oral cavity, pharynx, and larynx (Ptrend = 0.93, 0.78, 0.26, respectively) or by season of blood draw also showed no association.

Conclusions: Our study showed no association between serum 25(OH)D and risk of head and neck cancers.

Impact: This study does not support the hypothesis that greater vitamin D exposure would reduce the risk of developing head and neck squamous cancers. Cancer Epidemiol Biomarkers Prev; 20(6); 1178–84. ©2011 AACR.
Inflammation-Related Gene Variants as Risk Factors for Pancreatic Cancer
Authors: Reid-Lombardo Kaye M. , Fridley Brooke L. , Bamlet William R. , Cunningham Julie M. , Sarr Michael G. , Petersen Gloria M.
Published: June 2011

Background: Recent reports support an association between chronic inflammation and progression to pancreatic cancer (PC).

Methods: This case–control, candidate gene association study evaluated 1,354 Caucasian patients with pancreatic ductal adenocarcinoma and 1,189 healthy Caucasian controls. We genotyped 1,538 single nucleotide polymorphism (SNP) in 102 genes from inflammatory pathways involving NF-κB. Primary tests of association assumed a multiplicative (log-additive) genotype effect; secondary analyses examined dominant, additive, and recessive SNP effects.

Results: After adjusting for known risk factors for PC, single SNP analysis revealed an association between four SNPs in NOS1 and one in the CD101 gene with PC risk. These results, however, were not replicated in a PC case–control and cohort population.

Conclusion:NOS1 and CD101 may be associated with a risk of PC; however, these findings did not replicate in other PC populations. Future research is needed into the possible role of NOS1 and CD101 for PC.

Impact: This research shows a lack of association between genetic variation in 102 inflammation-related genes and PC. Future research is needed into the possible role of other inflammation-related genes and PC risk. Cancer Epidemiol Biomarkers Prev; 20(6); 1251–4. ©2011 AACR.
Levels of p27 Sensitize to Dual PI3K/mTOR Inhibition
Authors: Lee Misu , Theodoropoulou Marily , Graw Jochen , Roncaroli Federico , Zatelli Maria Chiara , Pellegata Natalia S.
Published: June 2011

Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling cascade occurs in a variety of human malignancies, where it sustains tumor cell proliferation and survival. Pharmacologic blockade of this pathway exerts antineoplastic activity by triggering apoptosis and/or cell-cycle arrest. Pituitary adenomas show activation of the PI3K/AKT/mTOR pathway, but only a fraction of them respond in vitro to the antiproliferative action of rapamycin and RAD001 (mTOR inhibitors), possibly because of the described negative feedback loop on AKT which reactivates the signaling cascade. Rats affected by the multiple endocrine neoplasia-like syndrome (MENX) develop pituitary adenomas showing increased activated AKT. In this study, we comparatively investigated the antitumor potential of the novel dual PI3K/mTOR inhibitor NVP-BEZ235 and the single mTOR inhibitor RAD001 on rat pituitary adenoma cells in primary culture. NVP-BEZ235 inhibits the PI3K pathway both upstream and downstream of AKT, thereby preventing the negative feedback loop. NVP-BEZ235 was more effective than RAD001 in reducing cell viability of pituitary adenomas. Consistently, NVP-BEZ235 treatment decreased Akt and S6 phosphorylation and triggered apoptosis. Because MENX is caused by a germline loss-of-function mutation in the cell-cycle inhibitor p27Kip1, we investigated the relationship between this defect and response to NVP-BEZ235 treatment. The levels of p27Kip1 positively correlate with the response to NVP-BEZ235 treatment. Combined treatment with NVP-BEZ235 and the proteasome inhibitor bortezomib, which increases p27Kip1 amount, shows synergistic antiproliferative effects on pituitary adenoma cells. Our data suggest that NVP-BEZ235 may represent an effective therapeutic modality for pituitary adenomas and that p27Kip1 levels represent a potential predictor of response to dual PI3K/mTOR inhibition. Mol Cancer Ther; 10(8); 1450–9. ©2011 AACR.
Cortactin and Focal Adhesion Kinase as Predictors of Cancer Risk in Patients with Laryngeal Premalignancy
Authors: Rodrigo Juan P. , Álvarez-Alija Gustavo , Menéndez Sofía Tirados , Mancebo Gonzalo , Allonca Eva , García-Carracedo Darío , Fresno Manuel Florentino , Suárez Carlos , García-Pedrero Juana María
Published: June 2011

Novel markers are needed to accurately predict the risk of malignant transformation in laryngeal premalignancies. We therefore investigated the clinical significance of cortactin (CTTN) and focal adhesion kinase (FAK) during laryngeal tumorigenesis and their potential utility as cancer risk markers. CTTN and FAK protein expression and gene amplification were assessed in 82 patients with laryngeal dysplasia and correlated with clinicopathologic parameters and laryngeal cancer risk. Increased CTTN and FAK expression was found respectively in 41 (50%) and 40 (49%) of 82 laryngeal dysplasias; protein expression was maintained or further augmented in the corresponding patient-matched invasive tumors subsequently developed. CTTN and FAK/PTK2 gene amplifications were respectively detected in 10 (12%) and 26 (32%) laryngeal dysplasias. Both CTTN and FAK protein expression increased with the grade of dysplasia; however, CTTN and FAK expression but not histology correlated significantly with increased laryngeal cancer risk (P = 0.009 and P = 0.002, respectively). Patients carrying strong CTTN- or FAK-expressing dysplastic lesions experienced a significantly higher cancer incidence (P = 0.006 and P = 0.001, respectively; log-rank test). Furthermore, FAK expression was an independent predictor of laryngeal cancer development (HR = 3.706, 95% CI: 1.735–7.916; P = 0.001) and the combination of FAK and CTTN showed superior predictive value (HR = 5.042, 95% CI: 2.255–11.274; P < 0.001). Taken together, our findings support the involvement of CTTN and FAK in malignant transformation and provide original evidence for their potential clinical utility as biomarkers for the risk of developing laryngeal cancer. Cancer Prev Res; 4(8); 1333–41. ©2011 AACR.
Five-Year Clinical and Angiographic Outcomes of a Randomized Comparison of Sirolimus-Eluting and Paclitaxel-Eluting Stents
Authors: Räber Lorenz , Wohlwend Lea , Wigger Mathias , Togni Mario , Wandel Simon , Wenaweser Peter , Cook Stéphane , Moschovitis Aris , Vogel Rolf , Kalesan Bindu , Seiler Christian , Eberli Franz , Lüscher Thomas F. , Meier Bernhard , Jüni Peter , Windecker Stephan
Published: June 2011

Background—

Long-term comparative data of first-generation drug-eluting stents are scarce. We investigated clinical and angiographic outcomes of sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) at 5 years as part of the Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX) LATE study.

Methods and Results—

A total of 1012 patients were randomly assigned to SES or PES. Repeat angiography was completed in 444 of 1012 patients (43.8%) at 5 years. Major adverse cardiac events occurred in 19.7% of SES- and 21.4% of PES-treated patients (hazard ratio, 0.89; 95% confidence interval, 0.68 to 1.17;
P
=0.39) at 5 years. There were no differences between SES and PES in terms of cardiac death (5.8% versus 5.7%;
P
=0.35), myocardial infarction (6.6% versus 6.9%;
P
=0.51), and target lesion revascularization (13.1% versus 15.1%;
P
=0.29). Between 1 and 5 years, the annual rate of target lesion revascularization was 2.0% (95% confidence interval, 1.4% to 2.6%) for SES and 1.4% (95% confidence interval, 0.9% to 2.0%) for PES. Among patients undergoing paired angiography at 8 months and 5 years, delayed lumen loss amounted to 0.37±0.73 mm for SES and 0.29±0.59 mm for PES (
P
=0.32). The overall rate of definite stent thrombosis was 4.6% for SES and 4.1% for PES (
P
=0.74), and very late definite stent thrombosis occurred at an annual rate of 0.65% (95% confidence interval, 0.40% to 0.90%).

Conclusions—

Long-term follow-up of first-generation drug-eluting stents shows no significant differences in clinical and angiographic outcomes between SES and PES. The continuous increase in late lumen loss in conjunction with the ongoing risk of very late stent thrombosis suggests that vascular healing remains incomplete up to 5 years after implantation of first-generation drug-eluting stents.

Clinical Trial Registration—

http://www.clinicaltrials.gov
. Unique identifier: NCT00297661.
Incidence and Prognostic Value of Early Repolarization Pattern in the 12-Lead Electrocardiogram
Authors: Haruta Daisuke , Matsuo Kiyotaka , Tsuneto Akira , Ichimaru Shinichiro , Hida Ayumi , Sera Nobuko , Imaizumi Misa , Nakashima Eiji , Maemura Koji , Akahoshi Masazumi
Published: June 2011

Background—

Early repolarization pattern is a common ECG finding characterized by J-point elevation and QRS notching or slurring in the inferior and/or lateral leads, yet little is known about its incidence and long-term prognosis in Asian populations.

Methods and Results—

We reviewed all the ECG records of the 5976 atomic-bomb survivors who were examined at least once during our biennial health examination in Nagasaki, Japan, between July 1958 and December 2004. We defined early repolarization pattern as ≥0.1-mV elevation of the J point or ST segment, with notching or slurring in at least 2 inferior and/or lateral leads. We assessed unexpected, cardiac, and all-cause death risk by Cox analysis. We identified 1429 early repolarization pattern cases (779 incident cases) during follow-up, yielding a positive rate of 23.9% and an incidence rate of 715 per 100 000 person-years. Early repolarization pattern had an elevated risk of unexpected death (hazard ratio, 1.83; 95% confidence interval, 1.12 to 2.97;
P
=0.02) and a decreased risk of cardiac (hazard ratio, 0.75; 95% confidence interval, 0.60 to 0.93;
P
<0.01) and all-cause (hazard ratio, 0.85; 95% confidence interval, 0.78 to 0.93;
P
<0.01) death. In addition, both slurring and notching were related to higher risk of unexpected death (hazard ratio, 2.09; 95% confidence interval, 1.06 to 4.12;
P
=0.03), as was early repolarization pattern manifestation in both inferior and lateral leads (hazard ratio, 2.50; 95% confidence interval, 1.29 to 4.83;
P
<0.01).

Conclusions—

Early repolarization pattern is associated with an elevated risk of unexpected death and a decreased risk of cardiac and all-cause death. Specific early repolarization pattern morphologies and location are associated with an adverse prognosis.
Repolarization Alternans Reveals Vulnerability to Human Atrial Fibrillation
Authors: Narayan Sanjiv M. , Franz Michael R. , Clopton Paul , Pruvot Etienne J. , Krummen David E.
Published: June 2011

Background—

The substrates for human atrial fibrillation (AF) are poorly understood, but involve abnormal repolarization (action potential duration [APD]). We hypothesized that beat-to-beat oscillations in APD may explain AF substrates, and why vulnerability to AF forms a spectrum from control subjects without AF to patients with paroxysmal then persistent AF.

Methods and Results—

In 33 subjects (12 with persistent AF, 13 with paroxysmal AF, and 8 controls without AF), we recorded left (n=33) and right (n=6) atrial APD on pacing from cycle lengths 600 to 500 ms (100 to 120 bpm) up to the point where AF initiated. Action potential duration alternans required progressively faster rates for patients with persistent AF, patients with paroxysmal AF, and controls (cycle length 411±94 versus 372±72 versus 218±33 ms;
P
<0.01). In AF patients, APD alternans occurred at rates as slow as 100 to 120 bpm, unrelated to APD restitution (
P
>0.10). In this milieu, spontaneous ectopy initiated AF. At fast rates, APD alternans disorganized to complex oscillations en route to AF. Complex oscillations also arose at progressively faster rates for persistent AF, paroxysmal AF, and controls (cycle length: 316±99 versus 266±19 versus 177±16 ms;
P
=0.02). In paroxysmal AF, APD oscillations amplified before AF (
P
<0.001). In controls, APD alternans arose only at very fast rates (cycle length <250 ms;
P
<0.001 versus AF groups) just preceding AF. In 4 AF patients in whom rapid pacing did not initiate AF, APD alternans arose transiently then extinguished.

Conclusions—

Atrial APD alternans reveals dynamic substrates for AF, arising most readily (at lower rates and higher magnitudes) in persistent AF then paroxysmal AF, and least readily in controls. APD alternans preceded all AF episodes and was absent when AF did not initiate. The cellular mechanisms for APD alternans near resting heart rates require definition.
β-Blockers in Patients With Intermittent Claudication and Arterial Hypertension
Authors: Espinola-Klein Christine , Weisser Gerhard , Jagodzinski Annika , Savvidis Savvas , Warnholtz Ascan , Ostad Mir-Abolfazl , Gori Tommaso , Munzel Thomas
Published: June 2011

The use of β-receptor blockers in peripheral arterial disease is controversial for their impact on vasomotor tone. The β-blocker nebivolol possesses vasodilating, endothelium-dependent, NO-releasing properties that might be beneficial in peripheral arterial disease. The aim of the study was to evaluate the effects and tolerability of nebivolol in comparison with metoprolol in these patients. A total of 128 patients with intermittent claudication and essential hypertension were included and double-blind randomized to receive 5 mg of nebivolol (N=65) or 95 mg of metoprolol (N=63) once daily. End points were changes in ankle-brachial index, initial and absolute claudication distance, endothelial function assessed by flow-mediated dilatation of the brachial artery, blood pressure, and quality of life using the claudication scale questionnaire. End point analysis was possible in 109 patients (85.2%). After the 48-week treatment period, ankle-brachial index and absolute claudication distance improved significantly in both patient groups (
P
<0.05 for both), with no difference across treatments. A significant increase of initial claudication distance was found in the nebivolol group. Adjusted mean change of initial claudication distance was 33.9% after nebivolol (
P
=0.003) and 16.6% after metoprolol (
P
=0.12) treatment. Quality of life was not influenced by either treatment, and there was no relevant change in flow-mediated dilatation in patients treated with nebivolol or metoprolol (
P
=0.16). Both drugs were equally effective in lowering blood pressure. In conclusion, β-blocker therapy was well tolerated in patients with intermittent claudication and arterial hypertension during a treatment period of ≈1 year. In the direct comparison, there was no significant difference between nebivolol and metoprolol.
Monsoonal Influence on Typhoon Morakot (2009). Part I: Observational Analysis
Authors: Wu Liguang , Liang Jia , Wu Chun-Chieh
Published: June 2011

Typhoon Morakot made landfall on Taiwan with a record rainfall of 3031.5 mm during 6–13 August 2009. While previous studies have emphasized the influence of southwesterly winds associated with intraseasonal oscillations and monsoon surges on moisture supply, the interaction between Morakot and low-frequency monsoon flows and the resulting influence on the slow movement and asymmetric precipitation structure of the typhoon were examined observationally.

Embedded in multi-time-scale monsoonal flows, Morakot generally moved westward prior to its landfall on Taiwan and underwent a coalescence process first with a cyclonic gyre on the quasi-biweekly oscillation time scale and then with a cyclonic gyre on the Madden–Julian oscillation time scale. The coalescence enhanced the synoptic-scale southwesterly winds of Morakot and thus decreased its westward movement and turned the track northward, leading to an unusually long residence time in the vicinity of Taiwan. The resulting slow movement and collocation with the low-frequency gyres also maintained the major rainfall in southern Taiwan because the low-frequency flows played an important role in enhancing the winds on the southern side, especially during 6–9 August 2009. In addition to the lifting effect of the Taiwan terrain and the moisture supply associated with monsoon flows, the study suggests that the monsoonal influence maintained the major rainfall area in southern Taiwan through reducing the translation speed, shifting Morakot northward, and enhancing the low-frequency flows on the southern side of the typhoon. Since the enhanced low-frequency flows did not shift northward with the movement of Morakot, its primary rainfall expanded outward with time as the typhoon center moved northwestward after its landfall on Taiwan.
Monsoonal Influence on Typhoon Morakot (2009). Part II: Numerical Study
Authors: Liang Jia , Wu Liguang , Ge Xuyang , Wu Chun-Chieh
Published: June 2011

In the second part of this study, numerical experiments are conducted to investigate the influences of multi-time-scale monsoonal flows on the track change of Typhoon Morakot (2009). While the control simulation captures the slowing and northward deflections in the vicinity of Taiwan Island, the highly asymmetric rainfall structure, and the associated rainfall pattern, sensitivity experiments suggest that the westward movement prior to the landfall on Taiwan and the subsequent northward shifts in the vicinity of Taiwan were closely associated with the interaction between Morakot and multi-time-scale monsoonal flows.

Prior to the landfall on Taiwan, Morakot moved westward directly toward Taiwan because of a synoptic wave train–like pattern, which consisted of Goni over mainland China, Morakot, and a cyclone over the western North Pacific with an anticyclone to the west of Morakot. Numerical simulation suggests that strong northerly winds between Morakot and the anticyclone reduced the northward steering component associated with the low-frequency flow prior to the landfall. Numerical experiments confirm that the northward track shifts that occurred in the vicinity of Taiwan Island were a result of the coalescences of Morakot with a quasi-biweekly oscillation (QBW)-scale gyre prior to the landfall on Taiwan and a Madden–Julian oscillation (MJO)-scale gyre in the Taiwan Strait. The simulation of Morakot and the associated sensitivity experiments agree with the previous barotropic study that the interaction between tropical cyclones and low-frequency monsoon gyres can cause sudden changes in tropical cyclone tracks.
Influences of the Sierra Nevada on Intermountain Cold-Front Evolution
Authors: West Gregory L. , Steenburgh W. James
Published: June 2011

Recent studies indicate that strong cold fronts develop frequently downstream of the Sierra Nevada over the Intermountain West. To help ascertain why, this paper examines the influence of the Sierra Nevada on the rapidly developing Intermountain cold front of 25 March 2006. Comparison of a Weather Research and Forecasting (WRF) model control simulation with a simulation in which the height of the Sierra Nevada is restricted to 1500 m (roughly the elevation of the valleys and basins of the Intermountain West) shows that the interaction of southwesterly prefrontal flow with the formidable southern High Sierra produces a leeward orographic warm anomaly that enhances the cross-front temperature contrast. Several processes generate this orographic warm anomaly, including flow modification by the Sierra Nevada (i.e., windward blocking of low-level Pacific air, leeward subsidence, and increased southerly flow from the Mojave Desert and lower Colorado River basin into the Intermountain West), diabatic heating and water vapor loss associated with orographic precipitation, and increased sensible heating and reduced subcloud diabatic cooling in the downstream cloud and precipitation shadow. In contrast, the postfrontal air mass experiences comparatively little orographic modification as it moves across the relatively low northern Sierra Nevada. These results show that the Sierra Nevada can enhance frontal development, which may contribute to the high frequency of strong cold-frontal passages over the Intermountain West.
Modeling Longitudinal Daily Seizure Frequency Data From Pregabalin Add‐On Treatment
Authors: Ahn Jae Eun , Plan Elodie L. , Karlsson Mats O. , Miller Raymond
Published: June 2011

The purpose of this study was to describe longitudinal daily seizure count data with respect to the effects of time and pregabalin add‐on therapy. Models were developed in a stepwise manner: base model, time effect model, and time and drug effect (final) model, using a negative binomial distribution with Markovian features. Mean daily seizure count (λ) was estimated to be 0.385 (relative standard error [RSE] 3.09%) and was further increased depending on the seizure count on the previous day. An overdispersion parameter (OVDP), representing extra‐Poisson variation, was estimated to be 0.330 (RSE 11.7%). Interindividual variances on λ and OVDP were 84.7% and 210%, respectively. Over time, λ tended to increase exponentially with a rate constant of 0.272 year−1 (RSE 26.8%). A mixture model was applied to classify responders/nonresponders to pregabalin treatment. Within the responders, λ decreased exponentially with respect to dose with a constant of 0.00108 mg−1 (RSE 11.9%). The estimated responder rate was 66% (RSE 27.6%). Simulation‐based diagnostics showed the model reasonably reproduced the characteristics of observed data. Highly variable daily seizure frequency was successfully characterized incorporating baseline characteristics, time effect, and the effect of pregabalin with classification of responders/nonresponders, all of which are necessary to adequately assess the efficacy of antiepileptic drugs.
Do mitochondria play a role in remodelling lace plant leaves during programmed cell death?
Authors: Lord Christina EN , Wertman Jaime N , Lane Stephanie , Gunawardena Arunika HLAN
Published: June 2011

Background

Programmed cell death (PCD) is the regulated death of cells within an organism. The lace plant (Aponogeton madagascariensis) produces perforations in its leaves through PCD. The leaves of the plant consist of a latticework of longitudinal and transverse veins enclosing areoles. PCD occurs in the cells at the center of these areoles and progresses outwards, stopping approximately five cells from the vasculature. The role of mitochondria during PCD has been recognized in animals; however, it has been less studied during PCD in plants.

Results

The following paper elucidates the role of mitochondrial dynamics during developmentally regulated PCD in vivo in A. madagascariensis. A single areole within a window stage leaf (PCD is occurring) was divided into three areas based on the progression of PCD; cells that will not undergo PCD (NPCD), cells in early stages of PCD (EPCD), and cells in late stages of PCD (LPCD). Window stage leaves were stained with the mitochondrial dye MitoTracker Red CMXRos and examined. Mitochondrial dynamics were delineated into four categories (M1-M4) based on characteristics including distribution, motility, and membrane potential (ΔΨm). A TUNEL assay showed fragmented nDNA in a gradient over these mitochondrial stages. Chloroplasts and transvacuolar strands were also examined using live cell imaging. The possible importance of mitochondrial permeability transition pore (PTP) formation during PCD was indirectly examined via in vivo cyclosporine A (CsA) treatment. This treatment resulted in lace plant leaves with a significantly lower number of perforations compared to controls, and that displayed mitochondrial dynamics similar to that of non-PCD cells.

Conclusions

Results depicted mitochondrial dynamics in vivo as PCD progresses within the lace plant, and highlight the correlation of this organelle with other organelles during developmental PCD. To the best of our knowledge, this is the first report of mitochondria and chloroplasts moving on transvacuolar strands to form a ring structure surrounding the nucleus during developmental PCD. Also, for the first time, we have shown the feasibility for the use of CsA in a whole plant system. Overall, our findings implicate the mitochondria as playing a critical and early role in developmentally regulated PCD in the lace plant.