bluuebunny/crossref_metadata_2025 huggingface dataset:
Three DNA Methylation Epigenotypes in Human Colorectal Cancer
Authors: Yagi Koichi , Akagi Kiwamu , Hayashi Hiroshi , Nagae Genta , Tsuji Shingo , Isagawa Takayuki , Midorikawa Yutaka , Nishimura Yoji , Sakamoto Hirohiko , Seto Yasuyuki , Aburatani Hiroyuki , Kaneda Atsushi
Published: December 2009

Purpose: Whereas the CpG island methylator phenotype (CIMP) in colorectal cancer associates with microsatellite instability (MSI)-high and BRAF-mutation(+), the existence of an intermediate-methylation subgroup associated with KRAS-mutation(+) is controversial, and suitable markers for the subgroup have yet to be developed. Our aim is to clarify DNA methylation epigenotypes of colorectal cancer more comprehensively.

Experimental Design: To select new methylation markers on a genome-wide scale, we did methylated DNA immunoprecipitation-on-chip analysis of colorectal cancer cell lines and re-expression array analysis by 5-aza-2′-deoxycytidine/Trichostatin A treatment. Methylation levels were analyzed quantitatively in 149 colorectal cancer samples using matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry. Colorectal cancer was epigenotyped by unsupervised two-way hierarchical clustering method.

Results: Among 1,311 candidate silencing genes, 44 new markers were selected and underwent quantitative methylation analysis in colorectal cancer samples together with 16 previously reported markers. Colorectal cancer was clustered into high-, intermediate-, and low-methylation epigenotypes. Methylation markers were clustered into two major groups: group 1 showing methylation in high-methylation epigenotype, and group 2 showing methylation in high- and intermediate-methylation epigenotypes. A two-step marker panel deciding epigenotypes was developed with 95% accuracy: the 1st panel consisting of three group-1 markers (CACNA1G, LOX, SLC30A10) to extract high-methylation epigenotype, and the 2nd panel consisting of four group-2 markers (ELMO1, FBN2, THBD, HAND1) and SLC30A10 again to divide the remains into intermediate- and low-methylation epigenotypes. The high-methylation epigenotype correlated significantly with MSI-high and BRAF-mutation(+) in concordance with reported CIMP. Intermediate-epigenotype significantly correlated with KRAS-mutation(+). KRAS-mutation(+) colorectal cancer with intermediate-methylation epigenotype showed significantly worse prognosis.

Conclusions: Three methylation epigenotypes exist in colorectal cancer, and suitable classification markers have been developed. Intermediate-methylation epigenotype with KRAS-mutation(+) correlated with worse prognosis. Clin Cancer Res; 16(1); 21–33
A Phase I Trial of Bortezomib with Temozolomide in Patients with Advanced Melanoma: Toxicities, Antitumor Effects, and Modulation of Therapeutic Targets
Authors: Su Yingjun , Amiri Katayoun I. , Horton Linda W. , Yu Yingchun , Ayers Gregory D. , Koehler Elizabeth , Kelley Mark C. , Puzanov Igor , Richmond Ann , Sosman Jeffrey A.
Published: December 2009

Purpose: Preclinical studies show that bortezomib, a proteasome inhibitor, blocks NF-κB activation and, combined with temozolomide, enhances activity against human melanoma xenografts and modulates other critical tumor targets. We initiated a phase I trial of temozolomide plus bortezomib in advanced melanoma. Objectives included defining a maximum tolerated dose for the combination, characterizing biomarker changes reflecting inhibition of both proteasome and NF-κB activity in blood (if possible tumor), and characterizing antitumor activity.

Experimental Design: Cohorts were enrolled onto escalating dose levels of temozolomide (50-75 mg/m2) daily, orally, for 6 of 9 weeks and bortezomib (0.75-1.5 mg/m2) by i.v. push on days 1, 4, 8, and 11 every 21 days. Peripheral blood mononuclear cells were assayed at specified time points for proteasome inhibition and NF-κB biomarker activity.

Results: Bortezomib (1.3 mg/m2) and temozolomide (75 mg/m2) proved to be the maximum tolerated dose. Dose-limiting toxicities included neurotoxicity, fatigue, diarrhea, and rash. Nineteen melanoma patients were enrolled onto four dose levels. This melanoma population (17 M1c, 10 elevated lactate dehydrogenase, 12 performance status 1-2) showed only one partial response (8 months) and three with stable disease ≥4 months. A significant reduction in proteasome-specific activity was observed 1 hour after infusion at all bortezomib doses. Changes in NF-κB electrophoretic mobility shift assay and circulating chemokines in blood failed to correlate with the schedule/dose of bortezomib, inhibition of proteasome activity, or clinical outcome.

Conclusions: We have defined phase II doses for this schedule of temozolomide with bortezomib. Although proteasome activity was inhibited for a limited time in peripheral blood mononuclear cells, we were unable to show consistent effects on NF-κB activation. Clin Cancer Res; 16(1); 348–57
Targeting the Cyclin E-Cdk-2 Complex Represses Lung Cancer Growth by Triggering Anaphase Catastrophe
Authors: Galimberti Fabrizio , Thompson Sarah L. , Liu Xi , Li Hua , Memoli Vincent , Green Simon R. , DiRenzo James , Greninger Patricia , Sharma Sreenath V. , Settleman Jeff , Compton Duane A. , Dmitrovsky Ethan
Published: December 2009

Purpose: Cyclin-dependent kinases (Cdk) and their associated cyclins are targets for lung cancer therapy and chemoprevention given their frequent deregulation in lung carcinogenesis. This study uncovered previously unrecognized consequences of targeting the cyclin E–Cdk-2 complex in lung cancer.

Experimental Design: Cyclin E, Cdk-1, and Cdk-2 were individually targeted for repression with siRNAs in lung cancer cell lines. Cdk-2 was also pharmacologically inhibited with the reversible kinase inhibitor seliciclib. Potential reversibility of seliciclib effects was assessed in washout experiments. Findings were extended to a large panel of cancer cell lines using a robotic-based platform. Consequences of cyclin E–Cdk-2 inhibition on chromosome stability and on in vivo tumorigenicity were explored as were effects of combining seliciclib with different taxanes in lung cancer cell lines.

Results: Targeting the cyclin E–Cdk-2 complex, but not Cdk-1, resulted in marked growth inhibition through the induction of multipolar anaphases triggering apoptosis. Treatment with the Cdk-2 kinase inhibitor seliciclib reduced lung cancer formation in a murine syngeneic lung cancer model and decreased immunohistochemical detection of the proliferation markers Ki-67 and cyclin D1 in lung dysplasia spontaneously arising in a transgenic cyclin E–driven mouse model. Combining seliciclib with a taxane resulted in augmented growth inhibition and apoptosis in lung cancer cells. Pharmacogenomic analysis revealed that lung cancer cell lines with mutant ras were especially sensitive to seliciclib.

Conclusions: Induction of multipolar anaphases leading to anaphase catastrophe is a previously unrecognized mechanism engaged by targeting the cyclin E–Cdk-2 complex. This exerts substantial antineoplastic effects in the lung. Clin Cancer Res; 16(1); 109–20
DNA Damage Drives an Activin A–Dependent Induction of Cyclooxygenase-2 in Premalignant Cells and Lesions
Authors: Fordyce Colleen , Fessenden Tim , Pickering Curtis , Jung Jason , Singla Veena , Berman Hal , Tlsty Thea
Published: December 2009

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the synthesis of prostaglandins. Its overexpression induces numerous tumor-promoting phenotypes and is associated with cancer metastasis and poor clinical outcome. Although COX-2 inhibitors are promising chemotherapeutic and chemopreventative agents for cancer, the risk of significant cardiovascular and gastrointestinal complications currently outweighs their potential benefits. Systemic complications of COX-2 inhibition could be avoided by specifically decreasing COX-2 expression in epithelial cells. To that end, we have investigated the signal transduction pathway regulating the COX-2 expression in response to DNA damage in breast epithelial cells. In variant human mammary epithelial cells that have silenced p16 (vHMEC), double-strand DNA damage or telomere malfunction results in a p53- and activin A–dependent induction of COX-2 and continued proliferation. In contrast, telomere malfunction in HMEC with an intact p16/Rb pathway induces cell cycle arrest. Importantly, in ductal carcinoma in situ lesions, high COX-2 expression is associated with high γH2AX, TRF2, activin A, and telomere malfunction. These data show that DNA damage and telomere malfunction can have both cell-autonomous and cell-nonautonomous consequences and can provide a novel mechanism for the propagation of tumorigenesis. Cancer Prev Res; 3(2); 190–201
Robot-Assisted Laparoscope Fundoplication for Gastroesophageal Reflux Disease: A Systematic Review of Randomized Controlled Trials
Authors: Zhang Peng , Tian Jin-Hui , Yang Ke-Hu , Li Jun , Jia Wen-Qin , Sun Shao-Liang , Ma Bin , Liu Ya-Li
Published: December 2009

Objective: To evaluate the efficacy and safety of robot-assisted fundoplication (RAF) for treating gastroesophageal reflux disease (GERD). Methods: Randomized controlled trials (RCTs) or quasi-RCTs were searched for in PubMed, EMBASE, the Cochrane Library, SCI, Chinese Biomedical Database, China Academic Journals Full-Text Database, Chinese Scientific Journals Database, China online journals, and related journals. We evaluated the quality of the included studies by using the 5.0.1 Cochrane Handbook standards and analyzed the data using the Cochrane Collaboration’s RevMan 5.0. Results: Five studies (n = 181) were included. A meta-analysis showed that besides the time taken to carry out fundoplication (p < 0.00001), both RAF and conventional laparoscopic fundoplication (CLF) were similar in postoperative antisecretory medication (p = 1.0), intraoperative conversion to open surgery (p = 0.94), postoperative dysphagia (p = 1.0), pneumothorax (p = 1.0), total intraoperative complications (p = 0.24), the time of hiatal dissection (p = 0.98), the time of incision to completion of sutures (p = 0.95), total operation time (p = 0.16), hospital stay (p = 0.97), and total cost (p = 0.25). Conclusions: The current evidence demonstrates that RAF is safe and effective in treating GERD. The weakness of this treatment method is that it prolongs the time necessary to carry out fundoplication. However, RAF should be the future trend for treating GERD.
Natural History of Functional Dyspepsia: A 10-Year Population-Based Study
Authors: Olafsdottir Linda Bjork , Gudjonsson Hallgrímur , Jonsdottir Heidur Hrund , Thjodleifsson Bjarni
Published: December 2009

Background: Functional dyspepsia (FD) is a common disorder, but information on its natural history is limited. Aim: To study the natural history of FD as assessed by 2 criteria over a 10-year period. Method: A population-based study conducted by mailing a questionnaire to the same age- and gender-stratified random sample of the Icelandic population aged 18–75 in 1996 and again in 2006. FD was estimated by the Functional Dyspepsia Score List and by dyspepsia subgroups categorized into 4 groups: (1) frequent upper pain, (2) meal-related, (3) nausea or vomiting, and (4) combinations of these groups. Results: FD was diagnosed in 13.9% of the subjects in the 1996 sample (11.3% male, 15.8% female) and 16.7% in 2006 (12.3% male, 20.2% female) with a significant difference between males and females in 2006. Dyspepsia subgroup criteria showed a higher prevalence than conventional FD criteria. The proportion of FD subjects in one of the dyspepsia subgroups was low. There was a significant relationship between FD and heartburn and irritable bowel syndrome. A high proportion of subjects who seek medical care have FD. Conclusion: FD was stable over the 10-year period, but there was turnover in symptoms and increased intensity and frequency of gastrointestinal pain. Dyspepsia subgroup criteria showed a higher prevalence than FD, which was more common in young subjects and females. FD poses a heavy burden on the health care system.
A Case Study of a Pregnant Patient with a Congenital Heart Block Accompanied by Left Isomerism and Uncontrolled Type 2 Diabetes Who Was Treated Successfully with Ritodrine
Authors: Serikawa Takehiro , Ichikawa Kaya , Kikuchi Akira , Takakuwa Koichi , Tanaka Kenichi
Published: December 2009

We present a case study of a patient with a congenital heart block associated with a left isomerism that was diagnosed during the 26th week of gestation. The mother had type 2 diabetes mellitus that was difficult to control during the early stages of the pregnancy. A fetal echocardiogram revealed an atrioventricular dissociation, with an atrial rate of 120 bpm and a ventricular rate of 55 bpm. Subsequent examinations also revealed a left isomerism in the fetus. To increase the fetal heart rate, a continuous intravenous infusion of ritodrine was administered. The fetal ventricular rate rapidly increased to 65 bpm. The pregnancy successfully continued until term and a female infant weighing 3,182 g was born via a cesarean section. A subsequent surgery was performed to provide the infant with a permanent cardiac pacemaker, and notably, the child is now 4 months of age and her growth has been within the normal range.
Carpal Tunnel Syndrome: Associations between Risk Factors and Laterality
Authors: Zambelis Thomas , Tsivgoulis Georgios , Karandreas Nikolaos
Published: December 2009

Aims: The investigation of the association between known risk factors and laterality in patients with carpal tunnel syndrome (CTS). Patients and Methods: 130 consecutive subjects with CTS only, or mainly, in the left hand were compared with 130 consecutive subjects with CTS only, or mainly, in the right hand. The following parameters were recorded: age, sex, job, handedness, hand mainly used in daily activities, BMI, diabetes mellitus, thyroid dysfunction, wrist trauma and connective tissue diseases. Results: A left dominant hand was independently associated with 13-fold higher odds for left-hand CTS, while a right dominant hand had 5-fold higher odds for right-hand CTS. Right-hand CTS was more frequent in younger subjects and females. Conclusion: Older age, higher BMI and diabetes mellitus were more prevalent in patients with bilateral CTS. Age and BMI were independently associated with bilateral CTS.
Neuropsychiatric Profiles of Patients with Insulinomas
Authors: Ding Yao , Wang Shuang , Liu Jianren , Yang Yi , Liu Zhirong , Li Jufeng , Zhang Bo , Chen Ying , Ding Meiping
Published: December 2009

Background/Aims: Insulinoma is a rare and potentially curable disease. It is often misdiagnosed as neurological or psychiatric disorder. This study was performed to characterize the neuropsychiatric symptoms (PNS) of the patients with insulinoma from a regional clinical center. Methods: All medical records of the patients with histopathologically identified insulinoma were reviewed during the period from 1998 to 2008. A case-control analysis was performed to compare the demographic data, details of clinical presentation, biochemical findings, tumor localization, and intraoperative findings between the patients with and without a prior misdiagnosis. Results: Among 42 patients with insulinoma, 25 patients with PNS were initially misdiagnosed as having a neurological or psychiatric disease, while 17 patients with no PNS were correctly diagnosed. Most (64%) of PNS cases were not diagnosed correctly until 12 months after the first consultation. In patients with PNS that remained undiagnosed for at least 5 years, the most frequent symptoms were confusion, convulsion, and visual disturbances. Twelve cases of PNS were initially misdiagnosed as epilepsy and 3 of them showed epileptiform discharges on electroencephalography. Conclusions: Episodic hypoglycemia induced by insulinoma can greatly mimic neurological and psychiatric presentation. A thorough history taking and inpatient assessment are necessary in evaluating recurrent neurological and psychiatric symptoms.
Concurrent and Apposed Hepatocellular Carcinoma and Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia in a Patient with Hepatitis C Virus
Authors: Becker Daniel J. , Sevilla Deborah W. , O’Connor Owen
Published: December 2009

A patient with chronic hepatitis C virus (HCV) presented to our clinic with a hepatic mass as well as lymphocytosis. Biopsy of the hepatic mass revealed apposed hepatocellular carcinoma (HCC) and small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL). Dramatic examples of lymphoma regression during treatment with antiviral medication in chronic HCV patients have suggested an etiologic role for HCV in lymphomagenesis. A growing body of research seeks to clarify the details of the interaction between HCV and B-cell lymphomas. This case of adjacent SLL/CLL and HCC is the first published diagnosis of these two diseases in the liver at one time, and the only published example of the physical apposition of any lymphoma and HCC. The case is provocative in light of recent evidence that local interactions between HCV-infected hepatocytes and B cells may contribute to lymphomagenesis.
Clinicopathological Study of 13 Cases of Squamous Cell Carcinoma Complicating Hidradenitis Suppurativa
Authors: Lavogiez C. , Delaporte E. , Darras-Vercambre S. , Martin De Lassalle E. , Castillo C. , Mirabel X. , Laurent F. , Patenotre P. , Gheit T. , Talmant J.C. , Beylot-Barry M. , Martinot V. , Piette F. , Aubin F. , Mortier L.
Published: December 2009

Background: To the best of our knowledge, only 52 cases of squamous cell carcinoma (SCC) complicating hidradenitis suppurativa (HS) have been reported since 1958. We describe 13 new cases. Methods: We propose a clinical and histological analysis of our cases. We include these results in a review of previously reported cases to analyze a total of 65 patients. In our series of 13 cases, we also investigate the presence of human papillomavirus (HPV) in tumor samples, by polymerase chain reaction (PCR) on paraffin-embedded material. Results: Malignant transformation affects mainly men with a long-term history of genitoanal HS. Although our cases were 7 well-differentiated carcinomas and 6 verrucous carcinomas, lymphatic and visceral metastasis occurred in 2 and 3 cases, respectively. With PCR, we demonstrated presence of HPV in genitoanal tumoral lesions, principally HPV-16. Conclusion: SCC complicating HS evolves poorly, despite a good histological prognosis. Our results sustain the implication of HPV in the malignant transformation of HS.
Disseminated Cutaneous Lymphoid Hyperplasia of 12 Years’ Duration Triggered by Vaccination
Authors: Pham-Ledard Anne , Vergier Beatrice , Doutre Marie-Sylvie , Beylot-Barry Marie
Published: December 2009

Vaccine-induced cutaneous lymphoid hyperplasia (CLH) is rare. Its natural evolution is not well known, nor is its treatment. We report a case of B-cell CLH with secondary dissemination that occurred following vaccination. The symptoms lasted 12 years and were efficiently treated by thalidomide. A 17-year-old girl presented CLH which had begun at the age of 8 at the site of hepatitis B vaccination. The lesions progressively enlarged and disseminated far from the injection sites. There was no spontaneous remission. Cyclins and hydroxychloroquine were inefficient. Thalidomide treatment finally led to complete remission. Aluminium hydroxide is used as adjuvant in the majority of vaccinations. In this case, occurrence of lesions far from the injection site of the vaccine suggested that it was not the only cause and that CLH may occur in other localizations after a vaccination. Furthermore, the diagnosis of CLH should not be excluded in front of such a prolonged course, and we underline the potential efficacy of thalidomide.
Oxaliplatin for Chemotherapeutic Treatment and Prevention of Experimental Peritoneal Carcinomatosis in Rats Comparing the Intraperitoneal and Intravenous Application Mode
Authors: Hribaschek A. , Meyer F. , Ridwelski K. , Kuester D. , Lippert H.
Published: December 2009

Background: The occurrence of peritoneal carcinomatosis after resection of colorectal carcinoma is still a major concern. In this study, we tested the cytostatic agent oxaliplatin delivered intraperitoneally and intravenously to prove whether it can significantly reduce intraperitoneal tumor growth. Methods: Peritoneal tumor growth was experimentally induced with transfer of CC-531 colon cancer cells (5 × 106) to the peritoneal surface of rats via laparotomy. Oxaliplatin was delivered either intraperitoneally or intravenously. In group A, oxaliplatin was administered directly after tumor cell transfer. While oxaliplatin was applied in group B on days 5, 10, and 15 after tumor cell implantation, in group C, it was administered on days 10, 15 and 20. The rats were sacrificed on day 30 after tumor cell transfer. Tumor weight, relative increase in tumor mass, volume of malignant ascites and the number of tumor nodes were determined. Results: Oxaliplatin significantly inhibited tumor growth after direct (group A) and early postoperative application (group B) via the intraperitoneal route. The late postoperative administration of oxaliplatin (group C) did not cause a significant effect on peritoneal tumor growth as it did with the intravenous application mode in groups A, B, and C. Conclusions: In this experimental model, oxaliplatin was highly effective against intraperitoneal tumor spread but only with the intraperitoneal application route. Other cytostatic agents with different effector mechanisms should be combined with oxaliplatin to further increase the therapeutic efficacy of the favorable intraperitoneal treatment in subsequent studies testing, in addition, the effects on wound and anastomosis healing.
Between Trauma and Redemption
Authors: Benish-Weisman Maya
Published: December 2009

Many immigrants find immigration a stressful experience. Whereas some overcome the initial feeling of being overwhelmed, others are frustrated and disappointed years after their immigration. In this study, 22 people who emigrated from the former USSR to Israel in the early 1990s were interviewed regarding their immigration experiences and the resulting narratives analyzed. The immigrants chosen represented the extreme poles of the success experience— some felt that their immigration was very successful; others found it very unsuccessful. Analysis revealed differences in the form of the immigration stories. The narratives of the successful immigrants were coherent and well structured; narratives of the nonsuccessful immigrants were fragmented and lacked coherence. The results are discussed in terms of how people construct immigration stories and what these constructions stand for.
Prospective Evaluation of Arthroscopic Bankart Repairs for Anterior Instability
Authors: Voos James E. , Livermore Ryan W. , Feeley Brian T. , Altchek David W. , Williams Riley J. , Warren Russell F. , Cordasco Frank A. , Allen Answorth A. ,   HSS Sports Medicine Service
Published: December 2009

Background

Arthroscopic treatment has evolved to become the primary surgical option in the management of anterior shoulder instability as studies show comparable outcomes between open and arthroscopic techniques.

Objective

To evaluate prospectively the results of our institutional database for arthroscopic Bankart repairs at a minimum 2-year follow-up for patients with anterior instability treated with suture anchors.

Study Design

Case series; Level of evidence, 4.

Methods

Eighty-three consecutive patients underwent arthroscopic Bankart repair with suture anchors. The mean age at the time of surgery was 33 years (range, 15-55 years). At an average follow-up of 33 months (range, 24-49 months), 73 patients (61 males, 12 females) were assessed with outcomes scores including the American Shoulder and Elbow Surgeons, L'Insalata, and visual analog scores. The rate of recurrent instability, range of motion, and risk factors for postoperative recurrence were evaluated.

Results

Thirteen patients (18%) suffered a recurrence after surgery. Seven patients (10%) had a subsequent dislocation and 6 (8%) a subluxation event or apprehension. Six of the 13 had a traumatic event that resulted in recurrent episodes of instability. Revision surgery was needed for 2 patients (3%) for instability and 2 for postoperative shoulder stiffness. On average there was no significant loss of external rotation postoperatively (average, 71° pre- and postoperatively). The American Shoulder and Elbow Surgeons and L'Insalata scores improved from 75.4 to 94.9 and 66.5 to 90.9, respectively (P < .0001). The visual analog score improved from 2.4 to 0.4 (P < .001). Patient age under 25, ligamentous laxity, and the presence of a large (>250 mm 3) Hill-Sachs lesion were associated with recurrence (P < .05). Patients under age 20 had a 37.5% recurrence rate.

Conclusion

In the arthroscopic treatment of anterior instability, identification of risk factors for recurrence allows for appropriate patient counseling and consideration of open stabilization. In our series, patients under age 25, with ligamentous laxity, and with a large (>250 mm3) Hill-Sachs lesion were at the greatest risk of recurrence.
Mere Categorization and the Frog-Pond Effect
Authors: Alicke Mark D. , Zell Ethan , Bloom Dorian L.
Published: December 2009

Zell and Alicke (2009) have shown that comparisons with a few people have a stronger influence on self-evaluations than comparisons with larger samples. One explanation for this effect is that people readily categorize their standing in small groups as “good” or “bad,” which supersedes large-sample data. To test this explanation, we created a situation in which students learned that their performance ranked 5th or 6th out of 10 persons on a task. In each experimental session, two groups, each containing 5 people, were created by random assignment. Some students learned that their performance placed them last in one group of 5, and some learned that they were first in the other group of 5. In the other conditions, participants learned only that that they were 5th or 6th in the group of 10. Results showed that being last in the superior group led to lower self-evaluations than being first in the inferior group.
Scent of a Woman
Authors: Miller Saul L. , Maner Jon K.
Published: December 2009

Adaptationist models of human mating provide a useful framework for identifying subtle, biologically based mechanisms influencing cross-gender social interaction. In line with this framework, the current studies examined the extent to which olfactory cues to female ovulation—scents of women at the peak of their reproductive fertility—influence endocrinological responses in men. Men in the current studies smelled T-shirts worn by women near ovulation or far from ovulation (Studies 1 and 2) or control T-shirts not worn by anyone (Study 2). Men exposed to the scent of an ovulating woman subsequently displayed higher levels of testosterone than did men exposed to the scent of a nonovulating woman or a control scent. Hence, olfactory cues signaling women’s levels of reproductive fertility were associated with specific endocrinological responses in men—responses that have been linked to sexual behavior and the initiation of romantic courtship.
Psychometrics and normative data for the Multiple Sclerosis Functional Composite: replacing the PASAT with the Symbol Digit Modalities Test
Authors: Drake AS , Weinstock-Guttman B. , Morrow SA , Hojnacki D. , Munschauer FE , Benedict RHB
Published: December 2009

The MS Functional Composite (MSFC) is a continuous scale of neurological disability for patients with multiple sclerosis (MS). Cognition is represented by the Paced Auditory Serial Addition Test (PASAT), although the Symbol Digit Modalities Test (SDMT) has been proposed as a promising alternative.

MSFC scores were calculated using either the PASAT or the SDMT with the following reference populations: National Multiple Sclerosis Society (NMSS) Task Force, 400 MS patients, and 100 normal controls. A subgroup of 115 patients was followed longitudinally, with a test—retest interval of 2.3 ± 1.2 years. Pearson correlations were calculated and analyses of variance (ANOVAs) were used to assess relationships among the MSFC components and composite scores, and differences in performance between patients and controls. Longitudinal changes were also assessed. Logistic regression was performed to determine which MSFC scores are most predictive of diagnosis, course, and work disability.

All MSFCs had similar test—retest reliability and correlations with other measures including neurological disability, depression, and fatigue. The SDMT showed slightly better validity with respect to predicting diagnosis, course, and work disability, although the amount of variance accounted for was similar for each version of the MSFC.

Our data, derived from a large sample of MS patients and normal controls, supports the validity of both PASAT and SDMT versions of the MSFC. Because the SDMT has slightly better predictive validity and has a relatively easier administration procedure, some clinicians and researchers may wish to replace the PASAT with the SDMT in future calculations of the MSFC using the calculation methods provided in this manuscript.
Generation and analysis of expression sequence tags from haustoria of the wheat stripe rust fungus Puccinia striiformis f. sp. Tritici
Authors: Yin Chuntao , Chen Xianming , Wang Xiaojie , Han Qingmei , Kang Zhensheng , Hulbert Scot H
Published: December 2009

Background

Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most destructive diseases of wheat (Triticum aestivum L.) worldwide. In spite of its agricultural importance, the genomics and genetics of the pathogen are poorly characterized. Pst transcripts from urediniospores and germinated urediniospores have been examined previously, but little is known about genes expressed during host infection. Some genes involved in virulence in other rust fungi have been found to be specifically expressed in haustoria. Therefore, the objective of this study was to generate a cDNA library to characterize genes expressed in haustoria of Pst.

Results

A total of 5,126 EST sequences of high quality were generated from haustoria of Pst, from which 287 contigs and 847 singletons were derived. Approximately 10% and 26% of the 1,134 unique sequences were homologous to proteins with known functions and hypothetical proteins, respectively. The remaining 64% of the unique sequences had no significant similarities in GenBank. Fifteen genes were predicted to be proteins secreted from Pst haustoria. Analysis of ten genes, including six secreted protein genes, using quantitative RT-PCR revealed changes in transcript levels in different developmental and infection stages of the pathogen.

Conclusions

The haustorial cDNA library was useful in identifying genes of the stripe rust fungus expressed during the infection process. From the library, we identified 15 genes encoding putative secreted proteins and six genes induced during the infection process. These genes are candidates for further studies to determine their functions in wheat-Pst interactions.
Conservation of DNA-binding specificity and oligomerisation properties within the p53 family
Authors: Brandt Tobias , Petrovich Miriana , Joerger Andreas C , Veprintsev Dmitry B
Published: December 2009

Background

Transcription factors activate their target genes by binding to specific response elements. Many transcription factor families evolved from a common ancestor by gene duplication and subsequent divergent evolution. Members of the p53 family, which play key roles in cell-cycle control and development, share conserved DNA binding and oligomerisation domains but exhibit distinct functions. In this study, the molecular basis of the functional divergence of related transcription factors was investigated.

Results

We characterised the DNA-binding specificity and oligomerisation properties of human p53, p63 and p73, as well as p53 from other organisms using novel biophysical approaches. All p53 family members bound DNA cooperatively as tetramers with high affinity. Despite structural differences in the oligomerisation domain, the dissociation constants of the tetramers was in the low nanomolar range for all family members, indicating that the strength of tetramerisation was evolutionarily conserved. However, small differences in the oligomerisation properties were observed, which may play a regulatory role. Intriguingly, the DNA-binding specificity of p53 family members was highly conserved even for evolutionarily distant species. Additionally, DNA recognition was only weakly affected by CpG methylation. Prediction of p53/p63/p73 binding sites in the genome showed almost complete overlap between the different homologs.

Conclusion

Diversity of biological function of p53 family members is not reflected in differences in sequence-specific DNA binding. Hence, additional specificity factors must exist, which allowed the acquisition of novel functions during evolution while preserving original roles.
Copia and Gypsy retrotransposons activity in sunflower (Helianthus annuus L.)
Authors: Vukich Marco , Giordani Tommaso , Natali Lucia , Cavallini Andrea
Published: December 2009

Background

Retrotransposons are heterogeneous sequences, widespread in eukaryotic genomes, which refer to the so-called mobile DNA. They resemble retroviruses, both in their structure and for their ability to transpose within the host genome, of which they make up a considerable portion. Copia- and Gypsy-like retrotransposons are the two main classes of retroelements shown to be ubiquitous in plant genomes. Ideally, the retrotransposons life cycle results in the synthesis of a messenger RNA and then self-encoded proteins to process retrotransposon mRNA in double stranded extra-chromosomal cDNA copies which may integrate in new chromosomal locations.

Results

The RT-PCR and IRAP protocol were applied to detect the presence of Copia and Gypsy retrotransposon transcripts and of new events of integration in unstressed plants of a sunflower (Helianthus annuus L.) selfed line. Results show that in sunflower retrotransposons transcription occurs in all analyzed organs (embryos, leaves, roots, and flowers). In one out of sixty-four individuals analyzed, retrotransposons transcription resulted in the integration of a new element into the genome.

Conclusion

These results indicate that the retrotransposon life cycle is firmly controlled at a post transcriptional level. A possible silencing mechanism is discussed.
PLCL1 rs7595412 variation is not associated with hip bone size variation in postmenopausal Danish women
Authors: Cauchi Stéphane , Byrjalsen Inger , Durand Emmanuelle , Karsdal Morten A , Froguel Philippe
Published: December 2009

Background

Bone size (BS) variation is under strong genetic control and plays an important role in determining bone strength and fracture risk. Recently, a genome-wide association study identified polymorphisms associated with hip BS variation in the PLCL1 (phospholipase c-like 1) locus. Carriers of the major A allele of the most significant polymorphism, rs7595412, have around 17% larger hip BS than non-carriers. We therefore hypothesized that this polymorphism may also influence postmenopausal complications.

Methods

The effects of rs7595412 on hip BS, bone mineral density (BMD), vertebral fractures, serum Crosslaps and osteocalcin levels were analyzed in 1,191 postmenopausal Danish women.

Results

This polymorphism had no influence on hip and spine BS as well as on femur and spine BMD. Women carrying at least one copy of the A allele had lower levels of serum osteocalcin as compared with those homozygous for the G allele (p = 0.03) whereas no effect on serum Crosslaps was detected. Furthermore, women homozygous for the A allele were more affected by vertebral fractures than those carrying at least one copy of the G allele (p = 0.04).

Conclusions

In postmenopausal women, our results suggest that the PLCL1 rs7595412 polymorphism has no obvious effect on hip BS or BMD but may be nominally associated with increased proportion of vertebral fracture and increased levels of osteocalcin.
Lipogenesis in arterial wall and vascular smooth muscular cells: regulation and abnormalities in insulin-resistance
Authors: Hamlat Nadjiba , Forcheron Fabien , Negazzi Samia , del Carmine Peggy , Feugier Patrick , Bricca Giampiero , Aouichat-Bouguerra Souhila , Beylot Michel
Published: December 2009

Background

Vascular smooth muscular cells (VSMC) express lipogenic genes. Therefore in situ lipogenesis could provide fatty acids for triglycerides synthesis and cholesterol esterification and contribute to lipid accumulation in arterial wall with aging and during atheroma.

Methods

We investigated expression of lipogenic genes in human and rat arterial walls, its regulation in cultured VSMC and determined if it is modified during insulin-resistance and diabetes, situations with increased risk for atheroma.

Results

Zucker obese (ZO) and diabetic (ZDF) rats accumulated more triglycerides in their aortas than their respective control rats, and this triglycerides content increased with age in ZDF and control rats. However the expression in aortas of lipogenic genes, or of genes involved in fatty acids uptake, was not higher in ZDF and ZO rats and did not increase with age. Expression of lipogenesis-related genes was not increased in human arterial wall (carotid endarterectomy) of diabetic compared to non-diabetic patients. In vitro, glucose and adipogenic medium (ADM) stimulated moderately the expression and activity of lipogenesis in VSMC from control rats. LXR agonists, but not PXR agonist, stimulated also lipogenesis in VSMC but not in arterial wall in vivo. Lipogenic genes expression was lower in VSMC from ZO rats and not stimulated by glucose or ADM.

Conclusion

Lipogenic genes are expressed in arterial wall and VSMC; this expression is stimulated (VSMC) by glucose, ADM and LXR agonists. During insulin-resistance and diabetes, this expression is not increased and resists to the actions of glucose and ADM. It is unlikely that this metabolic pathway contribute to lipid accumulation of arterial wall during insulin-resistance and diabetes and thus to the increased risk of atheroma observed in these situations.
Effectiveness of adjuvant radiotherapy in patients with oropharyngeal and floor of mouth squamous cell carcinoma and concomitant histological verification of singular ipsilateral cervical lymph node metastasis (pN1-state) - A prospective multicenter randomized controlled clinical trial using a comprehensive cohort design
Authors: Moergel Maximilian , Jahn-Eimermacher Antje , Krummenauer Frank , Reichert Torsten E , Wagner Wilfried , Wendt Thomas G , Werner Jochen A , Al-Nawas Bilal
Published: December 2009

Background

Modern radiotherapy plays an important role in therapy of advanced head and neck carcinomas. However, no clinical studies have been published addressing the effectiveness of postoperative radiotherapy in patients with small tumor (pT1, pT2) and concomitant ipsilateral metastasis of a single lymph node (pN1), which would provide a basis for a general treatment recommendation.

Methods/Design

The present study is a non-blinded, prospective, multi-center randomized controlled trial (RCT). As the primary clinical endpoint, overall-survival in patients receiving postoperative radiation therapy vs. patients without adjuvant therapy following curative intended surgery is compared. The aim of the study is to enroll 560 adult males and females for 1:1 randomization to one of the two treatment arms (irradiation/no irradiation). Since patients with small tumor (T1/T2) but singular lymph node metastasis are rare and the amount of patients consenting to randomization is not predictable in advance, all patients rejecting randomization will be treated as preferred and enrolled in a prospective observational study (comprehensive cohort design) after giving informed consent. This observational part of the trial will be performed with maximum consistency to the treatment and observation protocol of the RCT. Because the impact of patient preference for a certain treatment option is not calculable, parallel design of RCT and observational study may provide a maximum of evidence and efficacy for evaluation of treatment outcome. Secondary clinical endpoints are as follows: incidence and time to tumor relapse (locoregional relapse, lymph node involvement and distant metastatic spread), Quality of life as reported by EORTC (QLQ-C30 with H&N 35 module), and time from operation to orofacial rehabilitation. All tumors represent a homogeneous clinical state and therefore additional investigation of protein expression levels within resection specimen may serve for establishment of surrogate parameters of patient outcome.

Conclusion

The inherent challenges of a rare clinical condition (pN1) and two substantially different therapy arms would limit the practicality of a classical randomized study. The concept of a Comprehensive Cohort Design combines the preference of a randomized study, with the option of careful data interpretation within an observational study.

Trial registration

ClinicalTrials.gov: NCT00964977
SP-D counteracts GM-CSF-mediated increase of granuloma formation by alveolar macrophages in lysinuric protein intolerance
Authors: Douda David N , Farmakovski Nicole , Dell Sharon , Grasemann Hartmut , Palaniyar Nades
Published: December 2009

Background

Pulmonary alveolar proteinosis (PAP) is a syndrome with multiple etiologies and is often deadly in lysinuric protein intolerance (LPI). At present, PAP is treated by whole lung lavage or with granulocyte/monocyte colony stimulating factor (GM-CSF); however, the effectiveness of GM-CSF in treating LPI associated PAP is uncertain. We hypothesized that GM-CSF and surfactant protein D (SP-D) would enhance the clearance of proteins and dying cells that are typically present in the airways of PAP lungs.

Methods

Cells and cell-free supernatant of therapeutic bronchoalveolar lavage fluid (BALF) of a two-year-old patient with LPI were isolated on multiple occasions. Diagnostic BALF samples from an age-matched patient with bronchitis or adult PAP patients were used as controls. SP-D and total protein content of the supernatants were determined by BCA assays and Western blots, respectively. Cholesterol content was determined by a calorimetic assay or Oil Red O staining of cytospin preparations. The cells and surfactant lipids were also analyzed by transmission electron microscopy. Uptake of Alexa-647 conjugated BSA and DiI-labelled apoptotic Jurkat T-cells by BAL cells were studied separately in the presence or absence of SP-D (1 μg/ml) and/or GM-CSF (10 ng/ml),ex vivo. Specimens were analyzed by light and fluorescence microscopy.

Results

Here we show that large amounts of cholesterol, and large numbers of cholesterol crystals, dying cells, and lipid-laden foamy alveolar macrophages were present in the airways of the LPI patient. Although SP-D is present, its bioavailability is low in the airways. SP-D was partially degraded and entrapped in the unusual surfactant lipid tubules with circular lattice,in vivo. We also show that supplementing SP-D and GM-CSF increases the uptake of protein and dying cells by healthy LPI alveolar macrophages,ex vivo. Serendipitously, we found that these cells spontaneously generated granulomas,ex vivo, and GM-CSF treatment drastically increased the number of granulomas whereas SP-D treatment counteracted the adverse effect of GM-CSF.

Conclusions

We propose that increased GM-CSF and decreased bioavailability of SP-D may promote granuloma formation in LPI, and GM-CSF may not be suitable for treating PAP in LPI. To improve the lung condition of LPI patients with PAP, it would be useful to explore alternative therapies for increasing dead cell clearance while decreasing cholesterol content in the airways.
Computational modeling of the EGFR network elucidates control mechanisms regulating signal dynamics
Authors: Wang Dennis YQ , Cardelli Luca , Phillips Andrew , Piterman Nir , Fisher Jasmin
Published: December 2009

Background

The epidermal growth factor receptor (EGFR) signaling pathway plays a key role in regulation of cellular growth and development. While highly studied, it is still not fully understood how the signal is orchestrated. One of the reasons for the complexity of this pathway is the extensive network of inter-connected components involved in the signaling. In the aim of identifying critical mechanisms controlling signal transduction we have performed extensive analysis of an executable model of the EGFR pathway using the stochastic pi-calculus as a modeling language.

Results

Our analysis, done through simulation of various perturbations, suggests that the EGFR pathway contains regions of functional redundancy in the upstream parts; in the event of low EGF stimulus or partial system failure, this redundancy helps to maintain functional robustness. Downstream parts, like the parts controlling Ras and ERK, have fewer redundancies, and more than 50% inhibition of specific reactions in those parts greatly attenuates signal response. In addition, we suggest an abstract model that captures the main control mechanisms in the pathway. Simulation of this abstract model suggests that without redundancies in the upstream modules, signal transduction through the entire pathway could be attenuated. In terms of specific control mechanisms, we have identified positive feedback loops whose role is to prolong the active state of key components (e.g., MEK-PP, Ras-GTP), and negative feedback loops that help promote signal adaptation and stabilization.

Conclusions

The insights gained from simulating this executable model facilitate the formulation of specific hypotheses regarding the control mechanisms of the EGFR signaling, and further substantiate the benefit to construct abstract executable models of large complex biological networks.
The use of multi-variate models for the prediction of heat transfer in vehicle exhaust systems
Authors: Bannister C D , Brace C J , Taylor J , Brooks T , Fraser N
Published: December 2009

This paper describes the development of an exhaust system model based on the characterization of heat transfer in a series of 11 test sections designed to represent a range of configurations seen in production exhaust systems. These sections include variations in the wall thickness, diameter, bend angle, and radius. This work is part of a larger activity aimed at the accurate modelling of heat transfer and subsequent catalyst light-off in production exhaust systems consisting of similar geometries.

For each section a range of steady state tests was performed on a dynamic test cell using a port injected gasoline engine. In each case a correlation between the observed Reynolds number Re and the Nusselt number Nu was developed. A model of the system was implemented in MATLAB—Simulink in which each pipe element was split into 25 subelements by dividing the pipe into five, both axially and radially. After each individual section had been characterized, a generic model was built that was capable of determining the relationship between the Nusselt number and the Reynolds number for previously unseen pipe geometries. Complex exhaust systems can be constructed from smaller elements of defined geometry. The modelling approach was validated using experimental data gathered from vehicle testing on a chassis dynamometer.

The steady state relationship between Re and Nu allows heat transfer in the test section to be predicted over transient test cycles and demonstrates good agreement with relationships in the literature.