bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A11: Lower baseline levels of plasma hepatocyte growth factor, IL-6, and IL-8 are correlated with greater tumor shrinkage in renal cell carcinoma patients treated with pazopanib
Authors: Heymach John V. , Tran Hai T. , Fritsche Herbert A. , Gornet Terrie G. , Liu Yuan , Rajagopalan Dilip , Martin Anne-Marie , Baker Katherine L. , Downie Louise , Hutson Thomas E. , Figlin Robert A. ,   VEG102616 Team, Amado Rafael G. , Pandite Lini N.
Published: June 2012

Introduction: A Phase II RCC study (VEG102616) demonstrated activity with a response rate = 34.7% (CI 95%, 28.4 – 40.9) and disease control rate (CR + PR +SD) = 80% [ASCO 2008, #5046]. An analysis of plasma cytokines and angiogenic factors (CAFs) was undertaken with the objective of identifying patients who were the most likely to respond to pazopanib.

Methods: A subset (n=129/217) of available plasma samples were selected based on extremes of tumor shrinkage from baseline. CAF levels were correlated with dichotomized tumor shrinkage (DTS) by logistic regression, with continuous tumor shrinkage (CTS) by linear regression, and with progression-free survival (PFS) by Cox regression. ROC analysis was performed using a stratified random sample of 97 patients in a training set and 32 pts in a test set.

Results: Elevated levels of HGF, IL-8, and IL-6 were significantly correlated with less tumor shrinkage. Lower levels of E-Selectin and elevated IL-6 were associated with shorter PFS. ROC curve analysis for HGF resulted in an AUC of 0.668 with an optimal cutoff of 638.5 pg/ml. Using this cutoff, HGF-based predictions in the test set had an overall accuracy of 53%, positive predictive value of 67% and negative predictive value of 50%.

Conclusion: CAF profiling showed that lower baseline levels of plasma HGF, IL-6, and IL-8 are correlated with greater tumor shrinkage in renal cell carcinoma pts treated with pazopanib. Also, elevated levels of E-Selectin and lower levels of IL-6 were associated with longer PFS.

CAF1 p-value Fold Change2 Dichotomized HGF 0.006 Fold change: 1.3 Tumor Shrinkage IL-8 0.036 Fold change: 3.0 (Logistic regression) IL-6 0.039 Fold change: 1.5 TIMP1 0.047 Fold change: 1.2 Continuous HGF 0.029 Not Applicable - NA Tumor Shrinkage IL-8 0.048 NA (Linear Regression) IL-6 0.031 NA PFS (Cox Proportional E-Selectin 0.017 NA Hazards Model) IL-6 0.005 NA 1 The following CAF analysis were performed: Angio-10 (VEGF, VEGF-R2, ICAM-1, TIE-2, PLGF, TIMP-1, HGF, FGF basic, E-Selectin, and IL-8) and Cyto-8 (IL-1 beta, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12, TNF alpha) BIOCHIPS (Biomarker Workstation, Decision Biomarkers, Inc). Only the significant results were displayed above. 2 Fold change = (median CAF level for group with less tumor shrinkage) / (median CAF level for group with greater tumor shrinkage).

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A11.
Abstract A64: Mechanistic insights into the misregulation of p27 in HER2-positive breast cancers
Authors: Faltermeier Claire M. , Eide Erik E. , Roberts James M.
Published: June 2012

Although it is often stated that low amounts of the cell cycle inhibitory protein p27 are predictive of a poor outcome in breast cancers, this is an oversimplifcation of the data. Typically, tumor cells exhibit decreased expression of p27 in the nucleus, while preserving or even increasing the pool of p27 in the cytoplasm. Whereas nuclear p27 is tumor suppressive by inhibiting cell proliferation, newer evidence suggests that cytoplasmic p27 has an oncogenic action: it interacts with the GTPase RhoA to promote cellular migration and motility. Thus, cytoplasmic p27 may be an indicator of tumor cell invasiveness and metastatic potential. Understanding the mechanism of p27 mislocalization in breast cancers may offer insight into pathways of oncogenic transformation, and provide new markers for predicting clinical responses to specific therapies. Toward this goal, we developed antibodies that reliably detect cytoplasmic p27, and also identified a subset of breast cancers positive for the growth factor receptor HER2 that exhibited increased amounts of cytoplasmic p27. In parallel experiments we discovered an E3 ubiquitin ligase, Trim62 that regulates p27 stability, and found that it is overexpressed in HER2+ breast cancers. siRNA knock down of Trim62 in HER2+ breast cancer cell lines not only induced cell cycle arrest but also caused p27 to relocate entirely to the nucleus. We compared knock down of Trim62 to that of the well-characterized p27 regulator, the F box protein Skp2. Unlike Trim62, Skp2 inhibition had no detectable effect on p27 in these cells. As pharmacological inhibition of HER2 has also been shown to increase nuclear p27 protein levels, we investigated the role of Trim62 in modulating the response of breast cancer cells to anti-HER2 therapeutics. Like Trim62 siRNA, the HER2/EGFR inhibitor, Lapatinib increased p27 amounts, and this increase in p27 was located exclusively in the nucleus. Furthermore, we showed that knockdown of Trim62 increased cellular sensitivity to Lapatinib. Overexpression of Trim62 had the opposite effect. Collectively, our results suggest Trim62 underlies the misregulation of p27 in HER2+ breast cancer cell lines. By modulating p27 expression and cellular localization, Trim62 may mediate the antiproliferative effect of HER2 antagonists in breast cancer cells. Moreover, Trim62 could be a potential biomarker to predict biological response of breast cancer cells to anti-HER2 therapeutics such as Lapatinib.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A64.
Abstract C60: In vitro efficacy of the dual PI3-kinase/mTOR inhibitor NVP-BEZ235 in hepatocellular carcinoma
Authors: Buchbinder Elizabeth I. , Cohen Matthew B. , Jung Dorothy E. , Panka David J. , Atkins Michael B. , Mier James W. , Cho Dan C.
Published: June 2012

Background: The PI3-Kinase/Akt/mTOR pathway has been shown to be involved in the development of hepatocellular carcinoma (HCC). Allosteric inhibitors of mTORC1, such as everolimus (RAD001), have shown preliminary activity in patients with advanced HCC. The PI3-K pathway affects cell growth and survival through the activation of numerous other kinases besides mTOR. Therefore, disruption of this pathway upstream of mTOR may be more effective therapeutically than inhibition of mTOR alone. To investigate this hypothesis, the effects of NVP-BEZ235, a dual inhibitor of PI3-K and mTOR, were compared to rapamycin in HCC cell lines in vitro.

Methods: Four HCC cell lines (PLC, HepG2, SKHep1, and Hep3B) were exposed to NVP-BEZ235 at increasing concentrations (50nM-250nM) for 4 hours. Based upon results of western blots and MTS proliferation assays, a dose of 100nM was chosen for further in vitro studies. The same HCC cell lines were treated with DMSO, Rapamycin (100nM) or NVP-BEZ235 (100nM) and either lysed after 24hours for western blot analysis or assayed for proliferation by MTS after 48 hours. Expression of substrates of interest such as phospho-Akt, phospho-S6, phospho-4EBP, and survivin were determined by western blot.

Results: NVP-BEZ235 effectively suppressed tumor cell proliferation and inhibited its biologic targets, as determined by phosphorylation of S6 and Akt [Ser473], at low nanomolar concentrations. No significant apoptosis was detected at any concentration as determined by propidium iodide staining. In addition, NVP-BEZ235 was more effective than either rapamycin or DMSO in reducing proliferation in HCC cell lines. Both rapamycin and NVP-BEZ235 inhibited S6 phosphorylation; however only NVP-BEZ235 diminished Akt or PRAS40 (proline-rich Akt substrate) phosphorylation. NVP-BEZ235 was also significantly more effective than rapamycin in suppressing the phosphorylation of 4EBP, a well recognized substrate of TORC1. In keeping with this, NVP-BEZ235 was more effective than rapamycin in suppressing the expression of proteins such as survivin, suggesting a more profound inhibition of cap-dependent translation.

Conclusions: Dual inhibition of PI3-K/mTOR induced greater arrest of tumor cell proliferation compared to inhibition of mTORC1 alone in HCC. The ability to more effectively suppress cap-dependent translation may be central to the efficacy of drugs such as NVP-BEZ235 in HCC. Xenograft studies are underway to confirm these effects in vivo. Inhibition of PI3-K/mTOR may be a promising therapeutic strategy for patients with advanced HCC.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C60.
Abstract 2215: Use of peptide nucleic acid(PNA)-mediated PCR clamping method for detection EGFR mutation in patients with non-small cell lung cancer
Authors: Kim Hee Joung , Kim Young-Chul , Kim Kyu-Sik , Lee Sung Yong , Jang Tae Won , Lee Min Ki , Shin Kyeong-Cheol , Lee Gwan Ho , Kim Hye Ryun , Lee Jae Chol , Lee Jeong Eun , Kim Sun Young , Lee Kye Young ,   Korean Molecular Lung Cancer Group
Published: June 2012

Introduction : Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with nonsmall cell lung cancer (NSCLC). Direct sequencing is known to be the standard for detecting EGFR mutations; however, it has limited sensitivity. Peptide nucleic acids (PNA)-mediated Real-Time PCR clamping method is a newly introduced method for analyzing EGFR mutations with increased sensitivity and stability.

Methods : Clinical specimens from 240 NSCLC patients were analyzed for EGFR mutations in exons 18, 19, 20 and 21. All clinical data and tumor specimens were obtained from 8 centers of Korean Molecular Lung Cancer Group (KMLCG). After genomic DNA extracted from paraffin-embedded tissue specimens, both PNA-mediated Real-Time PCR clamping and direct sequencing were performed. The results and clinical response to EGFR-TKIs were compared.

Results : Sequencing revealed a total of 63(26.3%) mutations and PNA-mediated RT PCR clamping detected EGFR kinase mutation in 83(34.6%) samples. 61 mutations were consistent by both of direct sequencing and PNA-mediated RT PCR, however PNA-mediated RT PCR detected additional 22 mutations; 10 in exon 19, 9 in exon 21 and 3 in both of them. Furthermore, patients whose tumors expressed EGFR mutations exhibited an excellent response to EGFR-TKIs by more than 88%.

Conclusion : PNA-mediated Real-Time PCR clamping is a simple and rapid, as well as a more sensitive method for screening of genomic alterations in EGFR gene compared to direct sequencing. This data suggests that PNA-mediated Real-Time PCR clamping should be implemented as a useful screening tool for detection of EGFR mutations in clinical setting.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2215. doi:10.1158/1538-7445.AM2011-2215
Abstract 268: Differential regulation of MMP promoters by E2F transcription factors: Potential role of c-MYC and Id1
Authors: Johnson Jackie , Pillai Smitha , Chellappan Srikumar
Published: June 2012

The retinoblastoma tumor suppressor, Rb, is the major negative regulator of E2F-1 transcription factor, and the Rb-E2F pathway is altered in most cancers. Further, many oncogenic mutations initiate tumors by targeting the Rb-E2F pathway. E2Fs regulate genes involved in a variety of biological processes, including angiogenesis, apoptosis, and differentiation, but it is unclear whether these molecules contribute to cancer cell invasion and metastasis. To investigate the role of E2F in metastasis, we analyzed the promoters of matrix metalloproteinase genes (MMPs), which are major contributors to the invasion and migration programs. We find that many MMP genes had potential E2F binding sites; we focused on MMP2, MMP9, MMP14, and MMP15 promoter, which have multiple E2F binding sites. Chip assays showed Rb, and E2Fs 1-5 could bind to the each MMP promoter. Transient transfection experiments with MMP promoter-luciferase constructs showed thatMMP9, MMP14, and MMP15-luc promoters were induced by E2Fs, whereas the MMP2 promoter was repressed by E2F1-5 in A549, and H1650 NSCLC cell lines. QRT-PCR showed that MMP2 was upregulated in A549 cells transfected with an siRNA targeting E2F1 and E2F3, whereas other MMPs were downregulated. To determine if MMP2 was repressed in an Rb-dependent manner, A549 cells stably expressing shRNA targeting Rb or a non-targeting control were transiently transfected with MMP2-luc construct and E2F1. In both cases, the MMP2-luc promoter was repressed by E2F1, suggesting that the repression is Rb-independent. Further, cells transfected with MMP2-luc promoter and E2F1 had less luciferase activity than cells transfected with MMP2 alone, independent of BRG-1, YY1, HDAC1, prohibitin-1, mSIN3a, or SUV39h1. Further, depletion of these co-repressors did not enhance MMP2 mRNA levels when compared to cells depleted of E2F1 alone. To determine if this repression is through binding site competition, we examined the effect of depleting transcription factors that have potential binding sites in the MMP2 promoter and were in close proximity to the E2F binding sites. We found that depletion of c-Myc and ID1 significantly enhanced MMP2 luciferase activity, and there was less repression from E2F1 in transient transfection experiments. These data suggest that E2F family members can repress the MMP2 promoter through mechanisms that may involve c-MYC and ID1.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 268. doi:10.1158/1538-7445.AM2011-268
Abstract 621: Targeting phosphatidylserine to improve androgen deprivation therapy of prostate cancer
Authors: Yin Yi , Thorpe Philip E.
Published: June 2012

Androgen deprivation therapy (ADT) is effective against androgen-dependent prostate cancer, but patients usually relapse from the outgrowth of androgen-independent disease. Here, we tested the hypothesis that relapse can be prevented by combining ADT with treatment with a monoclonal antibody that binds exposed phosphatidylserine (PS). The rationale behind this hypothesis is that ADT will create hypoxia which induces PS exposure on the tumor vascular endothelial cells, leading to immune cell attack on tumor vasculature, collapse of the vessels and death of hormone-resistant and hormone-sensitive tumor cells through deprivation of oxygen and nutrients. In addition, the antibody should block the immunosuppressive effects of PS and induce reactivation of T-cell immunity. To test this hypothesis, we used ADT and anti-PS antibodies (2aG4 or murine chimeric 1N11) to treat mice bearing hormone-sensitive prostate tumors. The tumor models were: i) immunocompromised mice bearing human LNCaP prostate tumors; ii) transgenic (TRAMP) mice which spontaneously develop adenocarcinoma of the mouse prostate. Castration induced exposure of PS on blood vessels and tumor cells in both models. Vascular PS exposure corresponded with hypoxia, as judged by pimonidazole staining. In the LNCaP model, castration alone delayed tumor growth but all animals relapsed with hormone-independent disease, whereas mice treated with castration plus anti-PS antibody did not relapse. In TRAMP mice castrated at 15-weeks of age, only 54% (7/13) of mice treated with castration alone survived beyond 40-weeks of age, as compared with 92% (12/13) of mice treated with castration and 1N11. No toxicity to the mice was caused by the antibody treatment. Tumor blood flow and perfusion were markedly reduced in mice treated with castration and anti-PS antibody. Histological studies revealed extensive disruption of tumor vasculature and abundant infiltration of immune cells, principally M1 macrophages. These results demonstrate that PS becomes exposed on prostate cancer tumor vasculature and tumor cells in response to hypoxia caused by ADT in the tumor microenvironment. The exposed PS could serve as a target to enhance the efficacy of ADT against prostate cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 621. doi:10.1158/1538-7445.AM2011-621
Abstract 884: Pleiotropic effects on lung cancer of genetic susceptibility variants identified for other malignancies: The multiethnic cohort
Authors: Cheng Iona C. , Caberto Christian , Wilkens Lynne R. , Schumacher Fredrick R. , Kolonel Laurence N. , Henderson Brian E. , Stram Daniel O. , Haiman Christopher A. , Marchand Loic Le ,   The PAGE Consortium
Published: June 2012

Genome-wide association studies of cancer have succeeded in identifying over 100 susceptibility loci, including some, such as those found at chromosome 8q24 and CPTM1L-TERT that influence the risk of several malignancies. As part of the Population Architecture using Genomics and Epidemiology (PAGE) Study, we evaluated whether established risk variants for 19 different cancer sites, excluding the lung, impact the risk of lung cancer. A total of 148 risk variants for these 19 malignancies were selected from genome-wide association studies published through May, 2009. These SNPs were genotyped in a lung cancer case-control study (cases, n=696; controls, n=3,225) nested within the Multiethnic Cohort Study, a large prospective study conducted among African Americans, Latinos, Japanese Americans, Native Hawaiians and whites. Unconditional logistic regression was performed to evaluate the association between SNPs and lung cancer risk, adjusting for age, sex, race/ethnicity, smoking status (current, never, former), and pack-years of cigarette smoking. Eleven of the 148 SNPs were associated with lung cancer risk (P<0.05): two acute lymphocytic leukemia SNPs, two breast cancer SNPs, one glioma/testicular cancer SNP, one neuroblastoma SNP, four prostate cancer SNPs, and one thyroid cancer SNP. By chance, seven associations would be expected for the 148 tests (148 × 0.05=7), suggesting robust significant associations among the 11 associated SNPs. The top associations (P<0.01) were observed with three prostate cancer SNPs (rs10090154 at 8q24-region 1, P=0.0008; rs7837688 at 8q24-region 1, P=0.0009; rs4962416 at CTBP2, P=0.003) and one breast cancer SNP (rs2981578 at FGFR2, P=0.0074). Future analyses will include approximately 4,400 additional lung cancer cases and controls from the Women's Health Initiative (WHI), Arthrosclerosis Risk In Communities (ARIC) study, and the Cardiovascular Health Study (CHS) as part of the PAGE initiative. If these genetic risk factors are replicated, they may clarify shared pathways involved in the carcinogenic process.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 884. doi:10.1158/1538-7445.AM2011-884
Evaluation of Known Oncoantibodies, HER2, p53, and Cyclin B1, in Prediagnostic Breast Cancer Sera
Authors: Lu Hailing , Ladd Jon , Feng Ziding , Wu Mei , Goodell Vivian , Pitteri Sharon J. , Li Christopher I. , Prentice Ross , Hanash Samir M. , Disis Mary L.
Published: June 2012

Serum autoantibodies, directed against oncogenic proteins, have been frequently detected in the sera of patients with breast cancer. It is unknown whether serum antibodies that are identified in patients with established disease could also be detected in patients with newly diagnosed disease or even predate the diagnosis of breast cancer. Using sera collected at the time of treatment, at the time of diagnosis, or before the time of diagnosis, the current study aimed to address the temporal relationship between breast cancer development and serum antibody response. Starting from serum antibodies to eight known breast cancer antigens, we first identified four serum antibodies, HER2/neu, p53, carcinoembryonic antigen (CEA), and cyclin B1, which are significantly increased in the sera collected from patients with breast cancer at the time of treatment. These antibodies were also elevated in breast cancer sera collected at the time of diagnosis. Finally, comparison of antibody responses in prediagnostic samples from women before the development of breast cancer and in controls showed that antibodies to the HER2/neu and p53 can be detected in sera that were collected on average more than 150 days before a breast cancer diagnosis. These results showed that serum autoantibodies commonly reported in sera from patients with established disease can also be detected in prediagnostic sera and may be useful for the early detection of breast cancer. Cancer Prev Res; 5(8); 1036–43. ©2012 AACR.
Marked Differences in the Signaling Requirements for Expression of CD203c and CD11b versus CD63 Expression and Histamine Release in Human Basophils
Authors: MacGlashan, Jr. Donald
Published: June 2012

Many techniques are being used to examine the status of circulating human basophils including the enhanced expression of a variety of cell surface proteins. There is accumulating evidence that there are at least two compartments containing these activation marker proteins but there are only some indications for the signaling requirements for each of the compartments. This study began with published reports by other investigators who potentially dissociated CD63 expression from anaphylactic degranulation with the p38 inhibitor, SB203580, a possible falsification of a previously proposed hypothesis regarding CD63 expression. To explore the signaling requirements for CD63, a variety of pharmacological agents were used to inhibit or enhance 4 endpoints of basophil activation. First, it was found that inhibition of both histamine release and CD63 expression with SB203580 was concordant. But it was also found that this agent had no effect on increased expression of CD203c and CD11b. Actin polymerization inhibitors caused marked enhancement of CD63 expression (concordant with their effects on degranulation) with no effect on expression of CD203c and CD11b. The third generation syk inhibitor, NVP-QAB205, showed a 5-fold lower potency for inhibiting expression of CD203c and CD11b than for CD63. Finally, while desensitization of CD11b and CD203c expression occurs, it is slower than desensitization of the CD63 response. Taken together, these various observations demonstrate a marked difference in the early signaling requirements for the CD11b/CD203c compartment and CD63 degranulation and provide support for the hypothesis that CD11b and CD203c reside in a similar compartment.
Diet Influences Growth Rates and Allergen and Endotoxin Contents of Cultured Dermatophagoides farinae and Dermatophagoides pteronyssinus House Dust Mites
Authors: Avula-Poola Swetha , Morgan Marjorie S. , Arlian Larry G.
Published: June 2012

Background: The house dust mites Dermatophagoides farinae and Dermatophagoidespteronyssinus are cultured to obtain material for the production of allergen extracts for research, diagnostic and immunotherapeutic purposes. Methods: We cultured mites on two different diets that supported thriving populations and determined the population growth rates, dynamics of allergen accumulation, and endotoxin concentrations in extracts made from mites harvested from the cultures. Results:D. farinae populations grew faster on a diet of rodent chow/yeast than on an egg/yeast diet but a larger peak population size was achieved on the egg/yeast diet. Diet influenced the dynamics of the production of groups 1 and 2 allergens and the group 1/2 ratios for both species. To population peak, Der f 1 was produced at a faster rate on the chow/yeast diet but greater amounts of Der f 1 were produced by mites grown on the egg/yeast diet. D. pteronyssinus populations grew faster and achieved greater density on the egg/yeast diet compared to the chow/yeast diet. D. pteronyssinus produced more Der p 1 than Der p 2 when grown on chow/yeast while more Der p 2 than Der p 1 was produced on egg/yeast. Endotoxin concentrations in extracts made from whole cultures for both species at maximum population density were very different in the two diets. Washing the mites resulted in the loss of up to 88% of the allergen. Conclusion: Mite-culturing diet directly effects population growth, the dynamics of allergen accumulation, the group 1/2 allergen ratio and the endotoxin contents in extracts of cultured house dust mites.
From Protection of Privacy to Control of Data Streams: A Focus Group Study on Biobanks in the Information Society
Authors: Snell K. , Starkbaum J. , Lauß G. , Vermeer A. , Helén I.
Published: June 2012

Most people in Europe do not know what biobanks are. In this study, public perceptions of biobanks and collection of genetic and health data were analyzed in relation to other technologies and digital networks where personal information is compiled and distributed. In this setting, people contextualized biobanks in line with their daily experiences with other technologies and data streams. The analysis was based on 18 focus group discussions conducted in Austria, Finland and Germany. We examined the ways in which people frame and talk about problems and benefits of information distribution in digital networks and biobanks. People identify many challenges associated with collection of personal data in the information society. The study showed that instead of privacy – which has been the key term of bioethical debates on biobanks – the notions of control and controllability are most essential for people. From the viewpoint of biobanks, issues of controllability pose challenges. In the information society, people have become accustomed to controlling personal data, which is particularly difficult in relation to biobanks. They expressed strong concerns over the controllability of the goals and benefits of biobanks.
KDIGO (Kidney Disease: Improving Global Outcomes) Criteria Could Be a Useful Outcome Predictor of Cisplatin-Induced Acute Kidney Injury
Authors: Mizuno Tomohiro , Sato Waichi , Ishikawa Kazuhiro , Shinjo Hibiki , Miyagawa Yasuhiro , Noda Yukihiro , Imai Enyu , Yamada Kiyofumi
Published: June 2012

Objectives: The purpose of this study was to investigate if KDIGO (Kidney Disease: Improving Global Outcomes) criteria could be a useful outcome predictor of cisplatin-induced acute kidney injury (CIA). Methods: In the period between January 2006 and December 2011, we identified Japanese patients who had been diagnosed with cancer and treated with cisplatin as a first-line chemotherapy at Nagoya University Hospital. The serum creatinine was used to define CIA and determine the KDIGO criteria of each patient after chemotherapy within 7 days. Results: Eighty-nine patients (5.4%) were classified as having acute kidney injury (AKI) going by the KDIGO criteria, and the numbers of patients classified into AKI stages 1, 2 and 3 were 65 (3.9%), 18 (1.1%) and 6 (0.4%), respectively. Overall survival times were significantly shorter in AKI stages 2 and 3 than in stage 1. The area under the receiver operating characteristic curve with all patients was 0.68, and that of patients who were diagnosed with cancer stage 4 was 0.80. Conclusion: These results suggest that KDIGO criteria can be a predictor of CIA mortality in patients with different primary cancers.
Endoscopic Reflux Esophagitis and Helicobacter pylori Infection in Young Healthy Japanese Volunteers
Authors: Takashima Toru , Iwakiri Ryuichi , Sakata Yasuhisa , Yamaguchi Daisuke , Tsuruoka Nanae , Akutagawa Kayo , Komatsu-Tanaka Miho , Higuchi Toru , Tanaka Yuichiro , Shimoda Ryo , Sakata Hiroyuki , Kawakubo Megumi , Oda Yasutomo , Fujimoto Kazuma
Published: June 2012

Background/Aims: The prevalence of endoscopic esophagitis in young Japanese individuals is not fully apparent. The aim of this study was to determine the prevalence of reflux esophagitis (RE) and Helicobacter pylori infection and their relationship in young healthy Japanese volunteers. Methods: Upper gastrointestinal endoscopy was performed in 242 young healthy Japanese medical students (age range 22–29 years, mean 23.2 years) at Saga Medical School between 2008 and 2010. H. pylori infection was determined by detecting urinary IgG antibodies to H. pylori. Results:H. pylori antibodies were detected in 30 of the 242 subjects (12.4%). All 30 subjects had endoscopic chronic gastritis without peptic ulcers. Endoscopic RE was present in 27 of the 242 subjects (11.2%), corresponding to grade A in 19 subjects (7.9%), grade B in 7 (2.9%) and grade C in 1 (0.4%). Only 1 subject with RE was H. pylori-positive; the other 26 subjects with esophagitis were H. pylori-negative. We found no risk factors for H. pylori infection, but a risk factor for endoscopic esophagitis was alcohol consumption. Conclusion: The prevalence of H. pylori infection and endoscopic RE was 12.4 and 11.2%, respectively, in young healthy Japanese volunteers. Alcohol consumption was a risk factor for RE.
Oily Skin: An Overview
Authors: Sakuma Thais H. , Maibach Howard I.
Published: June 2012

Oily skin (seborrhea) is a common cosmetic problem that occurs when oversized sebaceous glands produce excessive amounts of sebum giving the appearance of shiny and greasy skin. This paper overviews the main concepts of sebaceous gland anatomy and physiology, including the biosynthesis, storage and release of sebum, as well as its relationship to skin hydration and water barrier function. We also address how skin oiliness may vary according to diet, age, gender, ethnicity and hot humid climates. The deeper understanding of this skin type provides the opportunity to better guide patients regarding skin care and also assist in the development of sebosuppressive agents.
Relationship between Allergy and Cancer: An Overview
Authors: Rittmeyer Delia , Lorentz Axel
Published: June 2012

Allergic diseases and malignancies cause a lot of morbidity, mortality and high costs for healthcare systems. An inverse association between allergy and cancer has been suspected for a long time, but even despite extensive research no general relationship has been determined. This review comprises 32 epidemiological studies published between 1960 and 2011 and draws conclusions regarding relationships between specific types of cancer and allergic diseases. On the one hand, inflammatory reactions in the course of allergy can support carcinogenesis but are limited to specific areas, whereas on the other hand systemic effects in terms of enhanced immunosurveillance can prevent cancer.
Frequency of Helicobacter pylori-Negative Gastric Cancer and Gastric Mucosal Atrophy in a Japanese Endoscopic Submucosal Dissection Series Including Histological, Endoscopic and Serological Atrophy
Authors: Ono Shouko , Kato Mototsugu , Suzuki Mio , Ishigaki Saori , Takahashi Masakazu , Haneda Masahira , Mabe Katsuhiro , Shimizu Yuichi
Published: June 2012

Background: The definition of Helicobacter pylori-negative gastric cancer depends on the accuracy of diagnosis of H. pylori infection. The aim of this study was to determine the frequency of H. pylori-negative gastric cancer and to clarify relationships with histological atrophy, endoscopic atrophy, and serological atrophy. Methods: A total of 240 early gastric cancers were included in this study. The status of H. pylori infection was determined from the rapid urease test, 13C-urea breath test, H. pylori culture, histopathological examination and examination of IgG antibodies. In H. pylori-negative gastric cancer, histological atrophy and intestinal metaplasia, endoscopic atrophy and serological atrophy were assessed by pepsinogen. Results: The rate of H. pylori infection was 77.9% and 19 patients (7.9%) had a history of eradication. 34 patients (14.2%) were diagnosed with H. pylori-negative gastric cancer using diagnostic tools of H. pylori. However, most of the patients with H. pylori-negative gastric cancer had histological atrophy and intestinal metaplasia. Only 1 gastric cancer (0.42%) occurred in the mucosa without histological atrophy, endoscopic atrophy or serological atrophy. Conclusion: Early gastric cancers in the Japanese endoscopic submucosal dissection series were strongly related to current or past infection with H. pylori and to gastric mucosal atrophy.
Yamaguchi Facial Expression-Making Task in Alzheimer’s Disease: A Novel and Enjoyable Make-a-Face Game
Authors: Yamaguchi Tomoharu , Maki Yohko , Yamaguchi Haruyasu
Published: June 2012

Background: To assess the ability to make emotional facial expressions, we newly developed the Yamaguchi facial expression-making task (Y-FEMT). Method: We recruited 20 normal controls and 61 outpatients: 10 with amnestic mild cognitive impairment (aMCI), 34 with mild Alzheimer’s disease (AD), and 17 with moderate AD. In the Y-FEMT, smile and anger expressions were made by arranging face parts. We examined the relationship between each Y-FEMT score and the Mini-Mental State Examination (MMSE) score or overlapping figure identification test (Fig-test). Results: The Total score (0–20) was nearly achieved in controls (18.9 ± 1.4) and declined with AD progression (aMCI 17.2 ± 2.4, mild AD 15.7 ± 2.6, moderate AD 12.3 ± 2.7). The Anger score (0–10) was significantly lower than the Smile score (0–10) in mild and moderate AD (p = 0.007 and p = 0.006, respectively). The Structure score (0–6 each) correlated well with both the MMSE score (r = 0.44, p < 0.001) and Fig-test (r = 0.45, p < 0.001), whereas the Expression score (0–4 each) correlated only with the MMSE score (r = 0.33, p = 0.01). The Subjective scores (0–4), evaluated by 10 therapists, highly correlated with the Total score. Additionally, the Y-FEMT promoted laughter and a convivial atmosphere. Conclusion: The Y-FEMT pleasantly assessed the ability to make emotional facial expressions without special equipment. Furthermore, the Y-FEMT may provide helpful clues for caregivers to achieve good communication with AD patients for better care.
Obesity, Whole Blood Serotonin and Sex Differences in Healthy Volunteers
Authors: Hodge Stephanie , Bunting Brendan P. , Carr Edwin , Strain J.J. , Stewart-Knox Barbara J.
Published: June 2012

Background: Obesity is a growing problem throughout Europe, where the rate has more than doubled over the past 20 years. Reduced circulating serotonin may contribute to the development of obesity. This study aimed to explore associations between whole blood (WB) serotonin concentrations and anthropometric measures. Methods: Healthy adult volunteers (N = 68) gave whole blood samples for measurement of WB serotonin, and underwent BMI waist circumference (WC) and waist-to-hip ratio (WHR) assessment as well as DEXA (dual energy X-ray absorptiometry) scans for anthropometric parameters. Student’s t-tests determined differences in WB serotonin and anthropometric measures between sexes. Partial Pearson’s correlations were carried out on anthropometric measures and WB serotonin. Results: For the whole sample, WB serotonin was significantly negatively correlated with BMI, WC, WHR as well as android, gynoid and total % body fat. Analysis by sex showed significant negative correlations between WB serotonin and android, gynoid as well as total fat in males, but not in females. Conclusion: This dichotomy between the sexes implies that there may be sex differences in the way that serotonin interplays with the development of obesity and body fat distribution.
High-Resolution 3-Dimensional Reconstruction of the Infarct Border Zone
Authors: Rutherford Sally L. , Trew Mark L. , Sands Gregory B. , LeGrice Ian J. , Smaill Bruce H.
Published: June 2012

Rationale:

Slow nonuniform electric propagation in the border zone (BZ) of a healed myocardial infarct (MI) can give rise to reentrant arrhythmia. The extent to which this is influenced by structural rather than cellular electric remodeling is unclear.

Objective:

To determine whether structural remodeling alone in the infarct BZ could provide a substrate for re-entry by (i) characterizing the 3-dimensional (3D) structure of the myocardium surrounding a healed MI at high spatial resolution and (ii) modeling electric activation on this structure.

Methods and Results:

Anterior left ventricular (LV) infarcts were induced in 2 rats by coronary artery ligation. Three-dimensional BZ volume (4.1 mm
3
and 5.6 mm
3
) were imaged at 14 days using confocal microscopy. Viable myocytes were identified, and their connectivity and orientation were quantified. Preserved cell networks were observed in the subendocardium and subepicardium of the infarct. Myocyte tracts traversed the BZ, and there was heavy infiltration of collagen into the adjacent myocardium. Myocyte connectivity decreased by ≈65% over 250 μm across the BZ. This structure was incorporated into 3D network models on which activation was simulated using Luo–Rudy membrane dynamics assuming normal cellular electric properties. Repetitive stimulation was imposed at selected BZ sites. Stimulus site-specific unidirectional propagation occurred in the BZ with rate-dependent slowing and conduction block, and reentry was demonstrated in one substrate. Activation times were prolonged because of tract path length and local slowing.

Conclusions:

We have used a detailed image-based model of the infarct BZ to demonstrate that structural heterogeneity provides a dynamic substrate for electric reentry.
MicroRNA Profiling Identifies MicroRNA-155 as an Adverse Mediator of Cardiac Injury and Dysfunction During Acute Viral Myocarditis
Authors: Corsten Maarten F. , Papageorgiou Anna , Verhesen Wouter , Carai Paolo , Lindow Morten , Obad Susanna , Summer Georg , Coort Susan L.M. , Hazebroek Mark , van Leeuwen Rick , Gijbels Marion J.J. , Wijnands Erwin , Biessen Erik A.L. , De Winther Menno P.J. , Stassen Frank R.M. , Carmeliet Peter , Kauppinen Sakari , Schroen Blanche , Heymans Stephane
Published: June 2012

Rationale:

Viral myocarditis results from an adverse immune response to cardiotropic viruses, which causes irreversible myocyte destruction and heart failure in previously healthy people. The involvement of microRNAs and their usefulness as therapeutic targets in this process are unknown.

Objective:

To identify microRNAs involved in viral myocarditis pathogenesis and susceptibility.

Methods and Results:

Cardiac microRNAs were profiled in both human myocarditis and in Coxsackievirus B3-injected mice, comparing myocarditis-susceptible with nonsusceptible mouse strains longitudinally. MicroRNA responses diverged depending on the susceptibility to myocarditis after viral infection in mice. MicroRNA-155, -146b, and -21 were consistently and strongly upregulated during acute myocarditis in both humans and susceptible mice. We found that microRNA-155 expression during myocarditis was localized primarily in infiltrating macrophages and T lymphocytes. Inhibition of microRNA-155 by a systemically delivered LNA-anti-miR attenuated cardiac infiltration by monocyte-macrophages, decreased T lymphocyte activation, and reduced myocardial damage during acute myocarditis in mice. These changes were accompanied by the derepression of the direct microRNA-155 target PU.1 in cardiac inflammatory cells. Beyond the acute phase, microRNA-155 inhibition reduced mortality and improved cardiac function during 7 weeks of follow-up.

Conclusions:

Our data show that cardiac microRNA dysregulation is a characteristic of both human and mouse viral myocarditis. The inflammatory microRNA-155 is upregulated during acute myocarditis, contributes to the adverse inflammatory response to viral infection of the heart, and is a potential therapeutic target for viral myocarditis.
A Role for miR-145 in Pulmonary Arterial Hypertension
Authors: Caruso Paola , Dempsie Yvonne , Stevens Hannah C. , McDonald Robert A. , Long Lu , Lu Ruifang , White Kevin , Mair Kirsty M. , McClure John D. , Southwood Mark , Upton Paul , Xin Mei , van Rooij Eva , Olson Eric N. , Morrell Nicholas W. , MacLean Margaret R. , Baker Andrew H.
Published: June 2012

Rationale:

Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling.

Objective:

We assessed the role of miR-145 in PAH.

Methods and Results:

We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR–mediated reduction resulted in significant protection from the development of PAH. In contrast, miR-143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with

BMPR2

mutations and also in the lungs of

BMPR2

-deficient mice.

Conclusions:

miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in

BMPR2

lead to upregulation of miR-145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment.
Uteroplacental Insufficiency and Lactational Environment Separately Influence Arterial Stiffness and Vascular Function in Adult Male Rats
Authors: Tare Marianne , Parkington Helena C. , Bubb Kristen J. , Wlodek Mary E.
Published: June 2012

Early life environmental influences can have lifelong consequences for health, including the risk of cardiovascular disease. Uteroplacental insufficiency causes fetal undernutrition and impairs fetal growth. Previously we have shown that uteroplacental insufficiency is associated with impaired maternal mammary development, compromising postnatal growth leading to hypertension in male rat offspring. In this study we investigated the roles of prenatal and postnatal nutritional environments on endothelial and smooth muscle reactivity and passive wall stiffness of resistance arteries of male rat offspring. Fetal growth restriction was induced by maternal bilateral uterine vessel ligation (restricted) on day 18 of pregnancy. Control offspring were from mothers that had sham surgery (control) and another group from mothers with their litter size reduced (reduced; litter size reduced to 5 at birth, equivalent to the restricted group). On postnatal day 1, offspring (control, restricted, and reduced) were cross-fostered onto control or restricted mothers. At 6 months, mesenteric and femoral arteries were studied using wire and pressure myography. In restricted-on-restricted rats, wall stiffness was increased, and sensitivity to phenylephrine and relaxation evoked by endothelium-derived hyperpolarizing factor and sodium nitroprusside were impaired in mesenteric arteries. In femoral arteries, relaxation to sodium nitroprusside was reduced, whereas wall stiffness was unaltered. Cross-fostering restricted offspring onto control mothers alleviated deficits in vascular stiffness and reactivity. Control or reduced offspring who suckled a restricted mother had marked vascular stiffening. In conclusion, prenatal and early postnatal environments separately influence vascular function and stiffness. Furthermore, the early postnatal lactational environment is a determinant of later cardiovascular function.
Changes in the Cerebrospinal Fluid Ceramide Profile After Subarachnoid Hemorrhage
Authors: Testai Fernando D. , Hillmann Maureen , Amin-Hanjani Sepideh , Gorshkova Irina , Berdyshev Evgeny , Gorelick Philip B. , Dawson Glyn
Published: June 2012

Background and Purpose—

The purpose of this study was to investigate changes in the cerebrospinal fluid sphingolipid profile in patients with subarachnoid hemorrhage in relation to the occurrence of symptomatic vasospasm and outcome at hospital discharge.

Methods—

The ceramide profile in the cerebrospinal fluid was determined by mass spectrometry in control subjects and patients with Fisher 3 grade subarachnoid hemorrhage within 48 hours of the bleed. Patients were prospectively followed and subcategorized based on the occurrence of symptomatic vasospasm and modified Rankin Scale at discharge.

Results—

Compared to control subjects, patients with subarachnoid hemorrhage had higher cerebrospinal fluid levels of total ceramide (12.4±8.8 versus 54.6±49.3 pmol/mL;
P
<0.001). In the subgroup analysis, total ceramide levels in individuals with symptomatic vasospasm (104.2±57.0 pmol/mL) were higher than in those with asymptomatic vasospasm (32.4±25.7 pmol/mL;
P
=0.006) and no vasospasm (30.9±15.7 pmol/mL;
P
=0.003). In addition, compared to patients with a good outcome (modified Rankin Scale ≤3), individuals with poor outcome (modified Rankin Scale ≥4) had higher cerebrospinal fluid levels of total ceramide (79±25 versus 23±6 pmol/mL;
P
=0.008). When the relative contributions of the different ceramide species were calculated, a higher relative concentration of C
18:0
ceramide was observed in individuals with symptomatic vasospasm (
P
=0.018) and poor outcome (
P
=0.028).

Conclusions—

Ceramide profile changes occur in subarachnoid hemorrhage. In this small case-based series elevation of levels of this sphingolipid, particularly C
18:0
, was associated with the occurrence of symptomatic vasospasm and poor neurological outcome after subarachnoid hemorrhage.
Clinical Outcomes Using a Platelet Function-Guided Approach for Secondary Prevention in Patients With Ischemic Stroke or Transient Ischemic Attack
Authors: Depta Jeremiah P. , Fowler Jeffrey , Novak Eric , Katzan Irene , Bakdash Suzanne , Kottke-Marchant Kandice , Bhatt Deepak L.
Published: June 2012

Background and Purpose—

Antiplatelet therapy nonresponse is associated with worse clinical outcomes. We studied the clinical outcomes associated with platelet function-guided modifications in antiplatelet therapy in patients with ischemic stroke or transient ischemic attack.

Methods—

From January 2005 to August 2007, 324 patients with ischemic stroke underwent platelet function testing using platelet aggregometry. Aspirin nonresponse was defined as a mean platelet aggregation ≥20% with 0.5 mg/mL arachidonic acid and/or ≥70% with 5 μmol/L adenosine diphosphate. Clopidogrel nonresponse was defined as a mean platelet aggregation ≥40% with 5 μmol/L adenosine diphosphate. A modification was any increase in antiplatelet therapy occurring after testing. Clinical outcomes were compared between patients with and without platelet function-guided antiplatelet therapy modifications using univariate and propensity score-adjusted analyses.

Results—

In patients with ischemic stroke or transient ischemic attack, 43% (n=128) and 35% (n=54) were nonresponders to aspirin and clopidogrel, respectively. After platelet function testing, antiplatelet therapy was increased in 23% of patients (n=73). After propensity score matching (n=61 in each group), antiplatelet therapy modification was associated with significantly increased rates of death, ischemic events, or bleeding (hazard ratio, 2.24; 95% CI, 1.12–4.47;
P
=0.02) compared with no modification in antiplatelet therapy and a trend toward increased bleeding (hazard ratio, 3.56; 95% CI, 0.98–12.95;
P
=0.05). No differences in ischemic events were observed.

Conclusions—

Platelet function-guided modification in antiplatelet therapy after an ischemic stroke or transient ischemic attack was associated with significantly higher rates of adverse clinical outcomes.