bluuebunny/crossref_metadata_2025 huggingface dataset:
mda-9/Syntenin: More than Just a Simple Adapter Protein When It Comes to Cancer Metastasis
Authors: Sarkar Devanand , Boukerche Habib , Su Zao-zhong , Fisher Paul B.
Published: May 2008

Cancer is a progressive disease that, in many instances, if untreated, can culminate in metastatic spread of primary tumor cells to distant sites in the body. Metastasis frequently confers virulence and therapy resistance to cancer cells, and defining the molecular events that control metastasis will be mandatory to develop rational, targeted therapies for effective intervention, prevention of recurrence, and the “holy grail” of engendering a cure. Adapter proteins are physiologically pertinent molecules that, through interactions with key regulatory proteins via specific conserved domains, control important cellular events. Melanoma differentiation associated gene-9 (mda-9), also known as syntenin, is a PDZ domain–containing adapter protein that is involved in organization of protein complexes in the plasma membranes, regulation of B-cell development, intracellular trafficking and cell-surface targeting, synaptic transmission, and axonal outgrowth. Recent studies now define a seminal role for mda-9/sytenin in cancer metastasis. The present review provides a current perspective of our understanding of this important aspect of mda-9/sytenin, suggesting that this gene and its encoded protein and interacting protein partners may provide viable targets for intervening in the final and invariably the most lethal stage of cancer progression, namely, cancer metastasis. [Cancer Res 2008;68(9):3087–93]
Amplification of Telomerase Reverse Transcriptase Gene in Human Mammary Epithelial Cells with Limiting Telomerase RNA Expression Levels
Authors: Cao Ying , Huschtscha Lily I. , Nouwens Amanda S. , Pickett Hilda A. , Neumann Axel A. , Chang Andy C-M. , Toouli Christian D. , Bryan Tracy M. , Reddel Roger R.
Published: May 2008

Activation of telomerase is a crucial step during cellular immortalization, and in some tumors this results from amplification of the human telomerase reverse transcriptase (hTERT) gene. Immortalization of normal human cells has been achieved by transduction with hTERT cDNA under the control of a strong heterologous enhancer/promoter, but this is sometimes an inefficient process, with periods of poor growth or even crisis occurring before immortalization. Here, we showed that normal human mammary epithelial cells expressing exogenous hTERT amplified the transgene extensively and expressed high levels of hTERT mRNA and protein. Paradoxically, the cells had low levels of telomerase activity and very short telomeres, indicating that telomerase activity did not correlate with hTERT expression. These cells contained only ∼20 human telomerase RNA (hTR) molecules/cell (compared with ∼120 hTR molecules per 293 cell). Expression of exogenous hTR caused increased telomerase activity and telomere lengthening. These data indicate that some hTERT-transduced normal cells may express high levels of the transgene but fail to up-regulate endogenous hTR expression sufficiently to enable expression of robust levels of telomerase activity. [Cancer Res 2008;68(9):3115–23]
Genetic Variants Contributing to Daunorubicin-Induced Cytotoxicity
Authors: Huang R. Stephanie , Duan Shiwei , Kistner Emily O. , Bleibel Wasim K. , Delaney Shannon M. , Fackenthal Donna L. , Das Soma , Dolan M. Eileen
Published: May 2008

Identifying heritable genetic variants responsible for chemotherapeutic toxicities has been challenging due in part to its multigenic nature. To date, there is a paucity of data on genetic variants associated with patients experiencing severe myelosuppression or cardiac toxicity following treatment with daunorubicin. We present a genome-wide model using International HapMap cell lines that integrate genotype and gene expression to identify genetic variants that contribute to daunorubicin-induced cytotoxicity. A cell growth inhibition assay was used to measure variations in the cytotoxicity of daunorubicin. Gene expression was determined using the Affymetrix GeneChip Human Exon 1.0ST Array. Using sequential analysis, we evaluated the associations between genotype and cytotoxicity, those significant genotypes with gene expression and correlated gene expression of the identified candidates with cytotoxicity. A total of 26, 9, and 18 genetic variants were identified to contribute to daunorubicin-induced cytotoxicity through their effect on 16, 9, and 36 gene expressions in the combined, Centre d' Etude du Polymorphisme Humain (CEPH), and Yoruban populations, respectively. Using 50 non-HapMap CEPH cell lines, single nucleotide polymorphisms generated through our model predicted 29% of the overall variation in daunorubicin sensitivity and the expression of CYP1B1 was significantly correlated with sensitivity to daunorubicin. In the CEPH validation set, rs120525235 and rs3750518 were significant predictors of transformed daunorubicin IC50 (P = 0.005 and P = 0.0008, respectively), and rs1551315 trends toward significance (P = 0.089). This unbiased method can be used to elucidate genetic variants contributing to a wide range of cellular phenotypes. [Cancer Res 2008;68(9):3161–8]
Microphthalmia-Associated Transcription Factor Is a Critical Transcriptional Regulator of Melanoma Inhibitor of Apoptosis in Melanomas
Authors: Dynek Jasmin N. , Chan Sara M. , Liu Jinfeng , Zha Jiping , Fairbrother Wayne J. , Vucic Domagoj
Published: May 2008

Melanoma inhibitor of apoptosis (ML-IAP) is a potent inhibitor of apoptosis, which is highly expressed in melanomas and likely contributes to their resistance to chemotherapeutic treatments. Herein, we show that the lineage survival oncogene microphthalmia-associated transcription factor (MITF) is a critical regulator of ML-IAP transcription in melanoma cells. The ML-IAP promoter contains two MITF consensus sites, and analysis of MITF and ML-IAP mRNA levels revealed a high correlation in melanoma tumor samples and cell lines. In reporter assays, MITF promoted a strong stimulation of transcriptional activity from the ML-IAP promoter, and MITF bound the endogenous ML-IAP promoter in melanoma cells by chromatin immunoprecipitation and electrophoretic mobility shift assay. Strikingly, small interfering RNA (siRNA)–mediated knockdown of MITF in melanoma cells led to a dramatic decrease in ML-IAP mRNA and protein levels, establishing that ML-IAP expression in melanoma cells is MITF dependent. Additionally, cyclic AMP–mediated induction of MITF expression in melanocytes resulted in increased ML-IAP expression, suggesting that melanocytes can express ML-IAP when MITF levels are heightened. Disruption of MITF by siRNA led to a decrease in melanoma cell viability, which could be rescued by ectopic expression of ML-IAP. Collectively, these findings implicate MITF as a major transcriptional regulator of ML-IAP expression in melanomas, and suggest that ML-IAP contributes to the prosurvival activity of MITF in melanoma progression. [Cancer Res 2008;68(9):3124–32]
Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors
Authors: Meoli Elise , Bossis Ioannis , Cazabat Laure , Mavrakis Manos , Horvath Anelia , Stergiopoulos Sotiris , Shiferaw Miriam L. , Fumey Glawdys , Perlemoine Karine , Muchow Michael , Robinson-White Audrey , Weinberg Frank , Nesterova Maria , Patronas Yianna , Groussin Lionel , Bertherat Jérôme , Stratakis Constantine A.
Published: May 2008

Most PRKAR1A tumorigenic mutations lead to nonsense mRNA that is decayed; tumor formation has been associated with an increase in type II protein kinase A (PKA) subunits. The IVS6+1G>T PRKAR1A mutation leads to a protein lacking exon 6 sequences [R1αΔ184-236 (R1αΔ6)]. We compared in vitro R1αΔ6 with wild-type (wt) R1α. We assessed PKA activity and subunit expression, phosphorylation of target molecules, and properties of wt-R1α and mutant (mt) R1α; we observed by confocal microscopy R1α tagged with green fluorescent protein and its interactions with Cerulean-tagged catalytic subunit (Cα). Introduction of the R1αΔ6 led to aberrant cellular morphology and higher PKA activity but no increase in type II PKA subunits. There was diffuse, cytoplasmic localization of R1α protein in wt-R1α– and R1αΔ6-transfected cells but the former also exhibited discrete aggregates of R1α that bound Cα; these were absent in R1αΔ6-transfected cells and did not bind Cα at baseline or in response to cyclic AMP. Other changes induced by R1αΔ6 included decreased nuclear Cα. We conclude that R1αΔ6 leads to increased PKA activity through the mt-R1α decreased binding to Cα and does not involve changes in other PKA subunits, suggesting that a switch to type II PKA activity is not necessary for increased kinase activity or tumorigenesis. [Cancer Res 2008;68(9):3133–41]
A Phase 2 Clinical Trial of Deforolimus (AP23573, MK-8669), a Novel Mammalian Target of Rapamycin Inhibitor, in Patients with Relapsed or Refractory Hematologic Malignancies
Authors: Rizzieri David A. , Feldman Eric , DiPersio John F. , Gabrail Nashat , Stock Wendy , Strair Roger , Rivera Victor M. , Albitar Maher , Bedrosian Camille L. , Giles Francis J.
Published: May 2008

Purpose: Deforolimus (AP23573), a novel non-prodrug rapamycin analogue, inhibits the mammalian target of rapamycin, a downstream effector of the phosphatidylinositol 3-kinase/Akt and nutrient-sensing pathways. A phase 2 trial was conducted to determine the efficacy and safety of single-agent deforolimus in patients with relapsed or refractory hematologic malignancies.

Experimental Design: Eligible patients were assigned to one of five disease-specific, parallel cohorts and given 12.5 mg deforolimus as a 30-minute infusion once daily for 5 days every 2 weeks. A Simon two-stage design was used for each cohort. Safety, pharmacokinetics, pharmacodynamics, and antitumor response were assessed.

Results: Fifty-five patients received deforolimus as follows: cohort 1 23 acute myelogenous leukemia, two myelodysplastic syndrome and one chronic myelogenous leukemia in nonlymphoid blast phase; cohort 2, one acute lymphocytic leukemia; cohort 3, nine agnogenic myeloid metaplasia; cohort 4, eight chronic lymphocytic leukemia; cohort 5, nine mantle cell lymphoma and two T-cell leukemia/lymphoma. Most patients were heavily pretreated. Of the 52 evaluable patients, partial responses were noted in five (10%), two of seven agnogenic myeloid metaplasia and three of nine mantle cell lymphoma. Hematologic improvement/stable disease was observed in 21 (40%). Common treatment-related adverse events, which were generally mild and reversible, were mouth sores, fatigue, nausea, and thrombocytopenia. Decreased levels of phosphorylated 4E-BP1 in 9 of 11 acute myelogenous leukemia/myelodysplastic syndrome patients after therapy showed mammalian target of rapamycin inhibition by deforolimus.

Conclusions: Deforolimus was well-tolerated in patients with heavily pretreated hematologic malignancies, and antitumor activity was observed. Further investigation of deforolimus alone and in combination with other therapeutic agents is warranted in patients with selected hematologic malignancies.
MicroRNA Expression Profiles in Serous Ovarian Carcinoma
Authors: Nam Eun Ji , Yoon Heejei , Kim Sang Wun , Kim Hoguen , Kim Young Tae , Kim Jae Hoon , Kim Jae Wook , Kim Sunghoon
Published: May 2008

Purpose: Although microRNAs have recently been recognized as riboregulators of gene expression, little is known about microRNA expression profiles in serous ovarian carcinoma. We assessed the expression of microRNA and the association between microRNA expression and the prognosis of serous ovarian carcinoma.

Experimental Design: Twenty patients diagnosed with serous ovarian carcinoma and eight patients treated for benign uterine disease between December 2000 and September 2003 were enrolled in this study. The microRNA expression profiles were examined using DNA microarray and Northern blot analyses.

Results: Several microRNAs were differentially expressed in serous ovarian carcinoma compared with normal ovarian tissues, including miR-21, miR-125a, miR-125b, miR-100, miR-145, miR-16, and miR-99a, which were each differentially expressed in >16 patients. In addition, the expression levels of some microRNAs were correlated with the survival in patients with serous ovarian carcinoma. Higher expression of miR-200, miR-141, miR-18a, miR-93, and miR-429, and lower expression of let-7b, and miR-199a were significantly correlated with a poor prognosis (P < 0.05).

Conclusion: Our results indicate that dysregulation of microRNAs is involved in ovarian carcinogenesis and associated with the prognosis of serous ovarian carcinoma.
Tagging Single Nucleotide Polymorphisms in Phosphoinositide-3-Kinase–Related Protein Kinase Genes Involved in DNA Damage “Checkpoints” and Lung Cancer Susceptibility
Authors: Hu Zhibin , Liu Hongliang , Wang Haifeng , Miao Ruifen , Sun Weiwei , Jin Guangfu , Wang Ying , Ma Hongxia , Jin Li , Wei Qingyi , Lu Daru , Huang Wei , Shen Hongbing
Published: May 2008

Purpose: DNA damage checkpoints are initiated by its sensor proteins of the phosphoinositide-3-kinase–related protein kinase family, including ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We hypothesized that polymorphisms in these genes may alter the regulation of DNA repair and the risk of lung cancer.

Experimental Design: We genotyped 12 tagging single nucleotide polymorphisms (tSNP) in these three phosphoinositide-3-kinase–related protein kinase genes in 500 incident lung cancer cases and 517 controls in a Chinese population by using the Illumina SNP genotyping BeadLab platform.

Results: Single locus analyses revealed that some of the heterozygotes or variant homozygotes of DNA-PKcs tSNPs were associated with decreased risks of lung cancer compared with their wild-type homozygotes. In the combined analyses of two tSNPs (rs8178085 and rs12334811) with approaching dose-dependent effect on lung cancer predisposition, subjects carrying two to four risk genotypes were associated with a 43% decreased lung cancer risk compared with subjects carrying zero to one risk genotypes (adjusted odds ratio, 0.53; 95% confidence interval, 0.35-0.80). Moreover, the decreased risk associated with the combined genotypes of rs8178085 and rs12334811 was slightly more pronounced in nonsmokers and in carriers with ataxia-telangiectasia mutated rs228591 variant allele or ataxia-telangiectasia and Rad3-related rs6782400 wild-type homozygous genotype.

Conclusion: These results indicate, for the first time, that tSNPs in DNA-PKcs may play a protective role in lung cancer development.
The Acidic Tumor Microenvironment Promotes the Reconversion of Nitrite into Nitric Oxide: Towards a New and Safe Radiosensitizing Strategy
Authors: Frérart Françoise , Sonveaux Pierre , Rath Géraldine , Smoos Alexandra , Meqor Ahlam , Charlier Nicolas , Jordan Bénédicte F. , Saliez Julie , Noël Agnès , Dessy Chantal , Gallez Bernard , Feron Olivier
Published: May 2008

Purpose: The biological status of nitrite recently evolved from an inactive end product of nitric oxide catabolism to the largest intravascular and tissue storage of nitric oxide (NO). Although low partial O2 pressure favors enzymatic reconversion of nitrite into NO, low pH supports a nonenzymatic pathway. Because hypoxia and acidity are characteristics of the tumor microenvironment, we examined whether nitrite injection could preferentially lead to NO production in tumors and influence response to treatments.

Experimental Design: The effects of nitrite were evaluated on arteriole vasorelaxation, tumor cell respiration and tumor blood flow, oxygenation, and response to radiotherapy.

Results: We first showed that a small drop in pH (−0.6 pH unit) favored the production of bioactive NO from nitrite by documenting a higher cyclic guanosine 3′,5′-monophosphate–dependent arteriole vasorelaxation. We then documented that an i.v. bolus injection of nitrite to tumor-bearing mice led to a transient increase in partial O2 pressure in tumor but not in healthy tissues. Blood flow measurements failed to reveal an effect of nitrite on tumor perfusion, but we found that O2 consumption by nitrite-exposed tumor cells was decreased at acidic pH. Finally, we showed that low dose of nitrite could sensitize tumors to radiotherapy, leading to a significant growth delay and an increase in mouse survival (versus irradiation alone).

Conclusions: This study identified low pH condition (encountered in many tumors) as an exquisite environment that favors tumor-selective production of NO in response to nitrite systemic injection. This work opens new perspectives for the use of nitrite as a safe and clinically applicable radiosensitizing modality.
High-Resolution Array-Based Comparative Genomic Hybridization of Bladder Cancers IdentifiesMouse Double Minute 4(MDM4) as an Amplification Target Exclusive ofMDM2andTP53
Authors: Veerakumarasivam Abhi , Scott Helen E. , Chin Suet-Feung , Warren Anne , Wallard Matthew J. , Grimmer Donna , Ichimura Koichi , Caldas Carlos , Collins V. Peter , Neal David E. , Kelly John D.
Published: May 2008

Purpose: Loss of p53 function in urothelial cell carcinoma (UCC) by mutation or inactivation disrupts normal cell cycle checkpoints, generating a favorable milieu for genomic instability, a hallmark of UCC. The aim of this study was to characterize novel DNA copy number changes to identify putative therapeutic targets.

Experimental Design: We report our findings using array comparative genomic hybridization on a whole-genome BAC/PAC/cosmid array with a median clone interval of 0.97 Mb to study a series of UCC cases. TP53 status was determined by direct sequencing, and an in-house tissue microarray was constructed to identify protein expression of target genes.

Results: Array comparative genomic hybridization allowed identification of novel regions of copy number changes in addition to those already known from previous studies. A novel amplification previously unreported in UCC was identified at 1q32. A chromosome 1 tile path array was used to analyze tumors that showed gains and amplification; the mouse double minute 4 (MDM4) homologue was identified as the amplified gene. MDM4 mRNA expression correlated with copy number and tumor grade. Copy number changes of MDM4 and MDM2 occurred exclusively in tumors with wild-type p53. Overexpression of MDM4 corresponded to disruption of p53 transcriptional activity. Immunohistochemistry on an independent series by tissue microarray identified an inverse relationship between Mdm4 and Mdm2, with Mdm4 expression highest in invasive UCC.

Conclusion: The data indicate that gain/amplification and overexpression of MDM4 is a novel molecular mechanism by which a subset of UCC escapes p53-dependent growth control, thus providing new avenues for therapeutic intervention.
The Effect of Ketoconazole on the Pharmacokinetics and Pharmacodynamics of Ixabepilone: A First in Class Epothilone B Analogue in Late-Phase Clinical Development
Authors: Goel Sanjay , Cohen Marvin , Çömezoglu S. Nilgün , Perrin Lionel , André François , Jayabalan David , Iacono Lisa , Comprelli Adriana , Ly Van T. , Zhang Donglu , Xu Carrie , Humphreys W. Griffith , McDaid Hayley , Goldberg Gary , Horwitz Susan B. , Mani Sridhar
Published: May 2008

Purpose: To determine if ixabepilone is a substrate for cytochrome P450 3A4 (CYP3A4) and if its metabolism by this cytochrome is clinically important, we did a clinical drug interaction study in humans using ketoconazole as an inhibitor of CYP3A4.

Experimental Design: Human microsomes were used to determine the cytochrome P450 enzyme(s) involved in the metabolism of ixabepilone. Computational docking (CYP3A4) studies were done for epothilone B and ixabepilone. A follow-up clinical study was done in patients with cancer to determine if 400 mg/d ketoconazole (inhibitor of CYP3A4) altered the pharmacokinetics, drug-target interactions, and pharmacodynamics of ixabepilone.

Results: Molecular modeling and human microsomal studies predicted ixabepilone to be a good substrate for CYP3A4. In patients, ketoconazole coadministration resulted in a maximum ixabepilone dose administration to 25 mg/m2 when compared with single-agent therapy of 40 mg/m2. Coadministration of ketoconazole with ixabepilone resulted in a 79% increase in AUC0-∞. The relationship of microtubule bundle formation in peripheral blood mononuclear cells to plasma ixabepilone concentration was well described by the Hill equation. Microtubule bundle formation in peripheral blood mononuclear cells correlated with neutropenia.

Conclusions: Ixabepilone is a good CYP3A4 substrate in vitro; however, in humans, it is likely to be cleared by multiple mechanisms. Furthermore, our results provide evidence that there is a direct relationship between ixabepilone pharmacokinetics, neutrophil counts, and microtubule bundle formation in PBMCs. Strong inhibitors of CYP3A4 should be used cautiously in the context of ixabepilone dosing.
The Average Cumulative Risks of Breast and Ovarian Cancer for Carriers of Mutations in BRCA1 and BRCA2 Attending Genetic Counseling Units in Spain
Authors: Milne Roger L. , Osorio Ana , Cajal Teresa Ramón y , Vega Ana , Llort Gemma , de la Hoya Miguel , Díez Orland , Alonso M. Carmen , Lazaro Conxi , Blanco Ignacio , Sánchez-de-Abajo Ana , Caldés Trinidad , Blanco Ana , Graña Begoña , Durán Mercedes , Velasco Eladio , Chirivella Isabel , Cardeñosa Eva Esteban , Tejada María-Isabel , Beristain Elena , Miramar María-Dolores , Calvo María-Teresa , Martínez Eduardo , Guillén Carmen , Salazar Raquel , San Román Carlos , Antoniou Antonis C. , Urioste Miguel , Benítez Javier
Published: May 2008

Purpose: It is not clear that the published estimates of the breast and ovarian cancer penetrances of mutations in BRCA1 and BRCA2 can be used in genetic counseling in countries such as Spain, where the incidence of breast cancer in the general population is considerably lower, the prevalence of BRCA2 mutations seems to be higher, and a distinct spectrum of recurrent mutations exists for both genes. We aimed to estimate these penetrances for women attending genetic counseling units in Spain.

Experimental Design: We collected phenotype and genotype data on 155 BRCA1 and 164 BRCA2 mutation carrier families from 12 centers across the country. Average age-specific cumulative risks of breast cancer and ovarian cancer were estimated using a modified segregation analysis method.

Results: The estimated average cumulative risk of breast cancer to age 70 years was estimated to be 52% [95% confidence interval (95% CI), 26-69%] for BRCA1 mutation carriers and 47% (95% CI, 29-60%) for BRCA2 mutation carriers. The corresponding estimates for ovarian cancer were 22% (95% CI, 0-40%) and 18% (95% CI, 0-35%), respectively. There was some evidence (two-sided P = 0.09) that 330A>G (R71G) in BRCA1 may have lower breast cancer penetrance.

Conclusions: These results are consistent with those from a recent meta-analysis of practically all previous penetrance studies, suggesting that women with BRCA1 and BRCA2 mutations attending genetic counseling services in Spain have similar risks of breast and ovarian cancer to those published for other Caucasian populations. Carriers should be fully informed of their mutation- and age-specific risks to make appropriate decisions regarding prophylactic interventions such as oophorectomy.
Cardiac Toxicity and Efficacy of Trastuzumab Combined with Pertuzumab in Patients with Trastuzumab-Insensitive Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer
Authors: Portera Chia C. , Walshe Janice M. , Rosing Douglas R. , Denduluri Neelima , Berman Arlene W. , Vatas Ujala , Velarde Margarita , Chow Catherine K. , Steinberg Seth M. , Nguyen Diana , Yang Sherry X. , Swain Sandra M.
Published: May 2008

Purpose: To evaluate safety and efficacy of trastuzumab with pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy.

Experimental Design: Patients with measurable HER2+ metastatic breast cancer, ≤3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) ≥55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively.

Results: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095).

Conclusion: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits.
Dyspepsia and IBS Symptoms in Patients with NERD, ERD and Barrett’s Esophagus
Authors: Neumann Helmut , Mönkemüller Klaus , Kandulski Arne , Malfertheiner Peter
Published: May 2008

Introduction: Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are highly prevalent in the general population as does gastroesophageal reflux disease (GERD). Therefore, it is expected that these conditions may frequently overlap. Objective: We aimed at evaluating the presence ofFD and IBS symptoms in patients with erosive (ERD), non-erosive reflux disease (NERD) and Barrett’s esophagus (BE). Patients and Methods: 71 patients presenting at the reflux disease outpatient clinic were prospectively included in this study. 33 patients had NERD, 25 ERD and 13 BE according to the Montreal classification. All patients with ERD and NERD had typical reflux symptoms, as assessed by a validated GERD questionnaire (RDQ). The diagnosis of functional dyspepsia and IBS symptoms was assessed according to the Rome III criteria. Results: IBS symptoms (bloating, abdominal pain, constipation and diarrhea) were slightly more prevalent in NERD (54.6, 63.6, 21.20, 24.2%, respectively) than in ERD (48.0, 44.0, 12.0, 20.0%, respectively) and in BE (53.9, 23.10, 15,4, 23.1%, respectively), but none of these differences reached statistical significance. NERD patients had more FD symptoms than patients with ERD or BE, but again this difference did not reach statistical significance. Conclusion: Our data show that IBS and FD are common in the entire spectrum of GERD. The presence of these disorders might explain why many patients with GERD are deemed as treatment failures if they have no complete symptom relief with proton pump inhibitors.
Do Gastrointestinal Symptoms Fluctuate in the Short-Term Perspective? The Kalixanda Study
Authors: Bolling-Sternevald E. , Aro P. , Ronkainen J. , Storskrubb T. , Talley N.J. , Junghard O. , Agréus L.
Published: May 2008

Background/Aim: Short-term fluctuation of gastrointestinal symptoms in the general population is largely unknown. We aimed to determine gastrointestinal symptom fluctuation in an random adult population using a validated questionnaire assessing gastrointestinal symptoms. Methods: A representative sample (n = 2,860) of the population (n = 21,610, 20–81 years of age; mean age 50.4 years) in Northern Sweden was studied. The subjects were asked to complete the questionnaire on two occasions [mean 2.5 months (range 1–6)], firstly via mail and secondly at a visit to the clinic. An upper endoscopy was performed after the last assessment of symptoms. Results: 2,122 individuals (74.2%) completed the initial questionnaire; 1,001 of these (mean age 54.1 years, 48.8 males) completed the second questionnaire. On the first occasion, 40% of the subjects were symptom-free (20.2%) or could not be classified according to their symptom pattern, of those with symptoms 39% reported troublesome reflux symptoms, 40% dyspeptic symptoms and 30% irritable bowel symptoms. Symptom overlap occurred in more than two thirds of the subjects. At the second visit 75% of the subjects who had reported dyspeptic complaints still reported such complaints. Conclusions: In this population-based study, gastrointestinal symptoms were common. Some symptom fluctuation occurred in the shorter term, but troublesome gastrointestinal complaints remained in approximately 90% of subjects over a 1–6-month period.
Voice Production during a Weightlifting and Support Task
Authors: Orlikoff Robert F.
Published: May 2008

Although effort closure techniques have a long history in the treatment of hypofunctional and psychogenic voice disorders, there have been surprisingly few studies of their specific laryngeal and phonatory effects. The present study was designed to provide preliminary data on physiologic changes in voice production associated with a weightlifting and support maneuver. Twenty vocally healthy subjects (10 men and 10 women) lifted hand-held weights and steadily supported them with outstretched arms as they either sustained comfortable phonation or repeated the syllable /pi/. Both the male and female subjects showed an increase in the electroglottographic contact quotient, long-term F₀ variability, and estimated laryngeal airway resistance attributable to an elevated driving pressure. Conversely, there were no significant changes in mean F₀, pitch perturbation quotient (jitter), or phonatory airflow between the pre-lift and lift portions of their voice production, regardless of the amount of weight supported. The results of this study indicate that simultaneous phonation and weightlifting is associated with increased laryngeal airway resistance characterized by an elevation in driving pressure and medial compression of the vocal folds. Implications for an improved understanding of normal vocal physiology and for the therapeutic use of such air-trapping exercises are addressed.
Exogenous Hydrogen Sulfide Inhibits Superoxide Formation, NOX-1 Expression and Rac1 Activity in Human Vascular Smooth Muscle Cells
Authors: Muzaffar Saima , Shukla Nilima , Bond Mark , Newby Andrew C. , Angelini Gianni D. , Sparatore Anna , Del Soldato Piero , Jeremy Jamie Y.
Published: May 2008

The activity of NADPH oxidase (NOX) is blocked by nitric oxide (NO). Hydrogen sulfide (H2S) is also produced by blood vessels. It is reasonable to suggest that H2S may have similar actions to NO on NOX. In order to test this hypothesis, the effect of sodium hydrosulfide (NaHS) on O2– formation, the expression of NOX-1 (a catalytic subunit of NOX) and Rac1 activity (essential for full NOX activity) in isolated vascular smooth muscle cells (hVSMCs) was investigated. hVSMCs were incubated with the thromboxane A2 analogue U46619 ± NaHS for 1 or 16 h, and O2– formation, NOX-1 expression and Rac1 activity were assessed. The possible interaction between H2S and NO was also studied by using an NO synthase inhibitor, L-NAME, and an NO donor, DETA-NONOate. The role of KATP channels was studied by using glibenclamide. NaHS inhibited O2– formation following incubation of 1 h (IC50, 30 nM) and 16 h (IC50, 20 nM), blocked NOX-1 expression and inhibited Rac1 activity. These inhibitory effects of NaHS were mediated by the cAMP-protein-kinase-A axis. Exogenous H2S prevents NOX-driven intravascular oxidative stress through an a priori inhibition of Rac1 and downregulation of NOX-1 protein expression, an effect mediated by activation of the adenylylcyclase-cAMP-protein-kinase-G system by H2S.
Inhibition of MCP-1/CCR2 Signaling Does Not Inhibit Intimal Proliferation in a Mouse Aortic Transplant Model
Authors: Alexis Jeffrey D. , Pyo Robert T. , Chereshnev Igor , Katz Jonathan , Rollins Barrett J. , Charo Israel F. , Taubman Mark B.
Published: May 2008

Background: Transplant arteriopathy is the leading cause of long term morbidity and mortality following heart transplantation. Animal models have demonstrated that monocyte chemoattractant protein (MCP)-1 is induced early after transplant in cardiac and aortic allografts. We have previously reported that deficiency of MCP-1 or its receptor, CC chemokine receptor 2 (CCR2), is associated with a reduction in intimal proliferation in a mouse femoral artery injury model. Using knockout mice, we have now examined the role of MCP-1 and CCR2 in the development of the intimal proliferation of transplant arteriopathy. Methods: C57Bl/6 CCR2 and MCP-1 wild-type and knockout mice were used in the studies and aortic transplants were performed between Balb/c mice and C57Bl/6 mice. Aortas from recipient animals were harvested 8 weeks after transplant. Results: Unlike arterial injury, in an aortic transplant model inhibition of MCP-1/CCR2 signaling did not result in reduced intimal proliferation. Conclusions: Despite a pathology that appears similar, the inflammatory mediators that regulate transplant arteriopathy differ from those regulating intimal proliferation secondary to wire injury. Our results suggest that targeting MCP-1/CCR2 signaling is not sufficient to block transplant arteriopathy across a complete MHC-mismatch barrier.
Diffuse Placoid Choroidopathy in a Patient with Common Variable Immunodeficiency
Authors: McCannel Colin A. , Pulido Jose S.
Published: May 2008

Unilateral diffuse placoid choroidopathy can be seen in the setting of common variable immunodeficiency (CVID). A 55-year-old woman with a 20-year history of CVID presented with multiple hypopigmented placoid lesions in the right eye. Diffuse lymphadenopathy led to lymph node biopsies (mediastinal and axillary) and angiotensin-converting enzyme and serum calcium level determination, which were all normal. CVID, the most common type of significant hypogammaglobulinemia, may be associated with a placoid choroidopathy. The cause of this CVID choroidopathy is unclear at this time, but may be secondary to lymphoid hyperplasia or granulomatous disease.
Retinopathy of Prematurity: Clinic and Pathogenesis
Authors: Pau Hans
Published: May 2008

The structure of adult human vitreous condensations (tractus, membranelles) corresponds to the structure of obliterated embryonal vasa hyaloidea. Some embryonal hyaloidal vessels and structures extend from the tunica vasculosa lentis and attach to the retina between the equator and ora serrata. In normal fetal development, these hyaloidal vessels and structures successively disappear because of apoptosis. The lower the birth weight of a premature infant, the higher the risk of retinopathy of prematurity (ROP) due to the disproportion between the regression of vasa hyaloidea (hyaloideoretinal adherences) and the proliferation of retinal vessels. This may be caused by an enhanced growth of retinal vessels (or a delayed regression of vasa hyaloidea). The growth of retinal vessels stops at a barrier formed by the retina-attaching hyaloidal remnants (vessels), resulting in a demarcation line and ROP. The same retinal vessels may then, as a fibrovascular tissue, overgrow the remnants of retina-attaching hyaloidal structures (as guiding formations) through the vitreous cavity up to the tunica vasculosa lentis. The process may result in the progression from ROP stage 2 to ROP stage 5.
A Double-Blind Randomized Control Study to Determine the Effect of Visthesia™ Viscoelastic Substance on Pain following LASEK
Authors: Kirwan Caitriona , Mulqueen Clodagh , O’Keefe Michael
Published: May 2008

Aim: To determine the efficacy of topical Visthesia™ drops and viscoelastic in reducing pain during the early postoperative period following laser-assisted subepithelial keratectomy (LASEK). Methods: In a prospective randomized double-blind study, LASEK was performed on both eyes of patients using the Technolas 217Z Laser (Bausch & Lomb). Visthesia was placed in one eye and placebo (Healon) in the fellow eye, following insertion of a bandage contact lens on completion of surgery. Pain experienced on the evening of surgery and the following morning were scored using a visual analogue scale. Results: 18 patients of mean age 27.3 years were examined. Mean refractive spherical equivalent was not statistically different between both groups (p = 0.6). No statistically significant difference (p = 0.87) in pain was detected between both groups on the evening of surgery or the following morning (p = 0.12). Conclusion: Visthesia, applied topically on completion of LASEK, did not have a significant effect on pain during the early postoperative period compared with placebo.
The Effect of a Combined Therapy with a Histamine H1 Antagonist and a Chemical Mediator Release Inhibitor on Allergic Conjunctivitis
Authors: Fujishima Hiroshi , Fukagawa Kazumi , Tanaka Mari , Uchio Eiichi , Takamura Etsuko , Nakagawa Yayoi , Miyazaki Dai , Fukushima Atsuki , Okamoto Shigeki , Yokoi Norihiko
Published: May 2008

Purpose: To evaluate the efficacy of a combined therapy with levocabastine hydrochloride ophthalmic suspension and pemirolast potassium ophthalmic solution compared to single therapy with levocabastine hydrochloride ophthalmic suspension alone. Methods: Thirty-two allergic conjunctivitis patients were randomized to combined-treatment (n = 15) or single-treatment groups (n = 17). The improvement of subjective symptoms as well as objective findings were evaluated. Results: The degree of improvement was significantly higher in the combined-treatment group for lacrimation (p = 0.008) among the subjective symptoms, for conjunctival edema (p = 0.030), eyelid edema (p = 0.032) and conjunctival papilla formation(p = 0.040) among the objective findings. Conclusions: Both objective assessments and subjective symptoms of allergic conjunctivitis showed the greatest improvements when patients were treated with combined therapy as compared to single-agent therapy. The enhanced benefits of combined therapy may result from these agents having different mechanisms of action.
Calcipotriol plus Betamethasone Dipropionate Scalp Formulation Is Effective and Well Tolerated in the Treatment of Scalp Psoriasis: A Phase II Study
Authors: Buckley Colin , Hoffmann Vibeke , Shapiro Jerry , Saari Seppo , Cambazard Frederic , Milsgaard Mette
Published: May 2008

Background: There is a need for more effective therapy for scalp psoriasis. Objective: To assess the efficacy and safety of a 2-compound scalp formulation including calcipotriol and betamethasone dipropionate in the treatment of scalp psoriasis. Methods: Patients (n = 218) with scalp psoriasis were randomized to treatment with the 2-compound scalp formulation (n = 108) or betamethasone dipropionate in the same vehicle (n = 110). The treatments were applied once daily on the scalp for up to 8 weeks. Results: The 2-compound scalp formulation showed a significantly higher efficacy than betamethasone dipropionate on the total sign score at the end of treatment (p = 0.042) and after 2 weeks (p = 0.005). Conclusion: The calcipotriol plus betamethasone dipropionate scalp formulation was superior to betamethasone dipropionate in the same vehicle when used once daily for up to 8 weeks in the treatment of scalp psoriasis.
Effects of Garlic Consumption on Plasma and Erythrocyte Antioxidant Parameters in Elderly Subjects
Authors: Avcı Aslıhan , Atlı Teslime , Ergüder İmge B. , Varlı Murat , Devrim Erdinç , Aras Sevgi , Durak İlker
Published: May 2008

Background: The oxidative stress theory of aging is one of the most widely acknowledged theories of aging. The intake of fruits and vegetables with antioxidant power is associated with a reduced incidence of many chronic diseases of aging. Objective: The effects of ingesting garlic on plasma and erythrocyte antioxidant parameters of elderly subjects were investigated in this study. Methods: 13 subjects (mean age 70.69 ± 4.23) participated in the study. They ingested garlic at the daily dose of 0.1 g/kg b.w. for 1 month. Before and after this period, fasting blood samples were obtained, and oxidant [malondialdehyde (MDA) and xanthine oxidase (XO)] and antioxidant [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)] parameters were studied in erythrocytes, and MDA levels were studied in plasma samples obtained from the subjects. Routine blood biochemical parameters were also measured in blood samples. Results: In the plasma fraction and erythrocyte hemolysate, MDA levels were found to be significantly lower, but erythrocyte GSH-Px and SOD activities were significantly higher in the second samples relative to the first ones. XO activity was found to be lower in the second samples, but this decrease was not statistically meaningful. LDL cholesterol was found to be significantly lower in the second samples relative to the first ones. Conclusion: Our results show that ingestion of garlic leads to significantly lowered plasma and erythrocyte MDA levels and to increased activities of some antioxidant enzymes, which indicates that consumption of garlic decreases oxidation reactions. It is quite possible that reduced peroxidation processes due to garlic consumption may play a part in some of the beneficial effects of garlic in elderly subjects.
Evidence for an association between univalent Y chromosomes and spermatocyte loss in XYY mice and men
Authors: Burgoyne P.S.
Published: May 2008

It has been observed previously that there is an association between sex chromosome pairing failure during meiosis and spermatocyte death. An hypothesis is advanced suggesting a similar association between a disruption of sex chromosome pairing (specifically, a failure of Y chromosome pairing) and spermatocyte loss in XYY mice and men.
T Antigen banding on chromosomes of simian virus 40 infected muntjac cells
Authors: D’Alisa R.M. , Korf B.R. , Gershey E.L.
Published: May 2008

Chromosomes were prepared from mitotic muntjac cells 48 to 72 h after infection with SV40 virus. When stained for SV40 T antigen by indirect immnunofluorescence, all chromosomes within an infected cell were fluorescent, indicating the presence of T antigen. Furthermore, the chromosomes were not uniformly stained but appeared to have regions of high and low fluorescence intensity. A variety of controls showed that the banding patterns are specific and highly reproducible and may indeed reflect the binding sites of T antigen. The bright, fluorescent bands of T antigen were found to correspond to bands visualized by trypsin-Giemsa staining (G-bands) and also by quinacrine staining (Q-bands). Current knowledge of chromosome banding indicates that Q-bands reflect the distribution of AT-rich regions along the chromosome. From the DNA sequence of SV40, it is known that one of the T antigen binding sites contains AT-rich sequences; thus, T antigen banding might be due to the base-specific binding of T antigen to chromatin. In addition, these bands have been implicated as centers for chromosome condensation and units in control of DNA replication. While the functional significance of T antigen binding has yet to be determined, the SV40-muntjac system provides an unusual opportunity to study the interaction of a known regulatory protein with mammalian chromosomes.
DNA measurements of mitotic chromosomes of the rabbit (Orytolagus cuniculus)
Authors: Ashworth L.K. , Carrano A.V. , Mayall B.H.
Published: May 2008

DNA cytophotometry was used to obtain the relative DNA content of mitotic chromosomes of Orytolagus cuniculus. DNA ranking of the rabbit chromosomes is presented, and related to the quinacrine and Giemsa-banded karyotype. In addition, the relative DNA content of the short and long arms of each chromosome was calculated and the DNA-based centromeric index, (i.e., the ratio of long-arm DNA to total chromosomal DNA) determined. The Y chromosome is clearly a submetacentric chromosome on the basis of the DNA measurements.
The effect of dexamethasone on the karyotype of A9HT cells
Authors: Venetianer A. , Bajnóczky K. , Szidonya J. , Szabad J.
Published: May 2008

In the majority of glucocorticoid-resistant receptor containing variants of A9HT cells, the number of dot chromosomes was found to be significantly higher than in the parent cells. The higher number of dot chromosomes, however, did not always correlate with the resistance of L cells to dexamethasone. The formation of dot chromosomes was not the consequence of dexamethasone-induced chromosome breaks. Dot-chromosome formation could not be induced by dexamethasone in human diploid cells. It seems likely that dexamethasone can select for A9HT cells with higher numbers of dot chromosomes.
Pattern of segregation of chicken HPRT phenotype in Chinese hamster-chick red blood cell hybrids
Authors: Raskó I. , Péter S.L. , Burg K. , Dallmann L. , Bajszár G.
Published: May 2008

The pattern of segregation of hypoxanthine phosphoribosyltransferase (HPRT, E.C. 2.4.2.8) was determined in synchronized Chinese hamster-chick red blood cell hybrids. Three hybrid lines were synchronized at the Gl-S boundary. Bromodeoxyuridine pulses were subsequently applied throughout the S phase, and the frequency of the segregant clones was determined. It was found that the segregation of the chicken-specific HPRT phenotype associated with the loss of a chromosome was potentiated by bromodeoxyuridine administered during the first hour following release of the block.
Studies on isolated cloned populations from irradiated human embryonic cell cultures
Authors: Lee C.L.Y. , Lee S.H.S. , Kamra O.P.
Published: May 2008

The recovery of substrains with stable chromosome aberrations from irradiated fibroblast cultures are reported. Four human fetal cell strains were exposed to 600 rad of gamma rays at 200 rad/min. The efficiency of recovering viable cloned subpopulatiohs was approximately 87 %, and the frequency of clones with abnormal chromosomes was 40/100 colonies. G-band chromosome analyses for 34 abnormal substrains are described. Karyotypes of some of the clones with complex rearrangements are also presented. Analyses of a total of 47 aberrant events in the 34 abnormal substrains revealed a 7:1 and a 9:1 translocation-inversion and translocation-deletion ratios, respectively. Five of the abnormal sub-strains were continuously cultured; all except one showed signs of sensecence toward the end of 44 ± 10 doublings. Unusual prolonged proliferation capacity was observed in sub-strain FFS-1–9. The significance of this finding is discussed.
Chromosomes of Lemuriformes
Authors: Dresser M.E. , Hamilton A.E.
Published: May 2008

In this report we compare the karyotype of Lemur julvus julvus (2n = 60) with that of Cheirogaleus medius (2n=66), a species thought to retain the ancestral lemur karyotype. A culture technique was designed specifically for lemur lymphocytes to facilitate description of the complete karyotypes using G-banding, C-banding, and Ag-AS staining for nucleolus organizer regions (NOR’s). Different G-banding patterns in three chromosome pairs and different NOR-bearing chromosomes between the two species, as well as additional chromosomes and interstitial C-bands in C. medius, suggest that the chromosome complement of C. medius may not perfectly reflect the ancestral morphology. However, allowing for a Robertsonian centric fusion and a pericentric inversion, the G-banding patterns of 27 of the 32 autosomal pairs of C. medius are indistinguishable from those of L. julvus julvus. This constitutes strong justification for assigning these chromosomes to the ancestral lemur karyotype.