bluuebunny/crossref_metadata_2025 huggingface dataset:
Live virus-free or die: coupling of antivirus immunity and programmed suicide or dormancy in prokaryotes
Authors: Makarova Kira S , Anantharaman Vivek , Aravind L , Koonin Eugene V
Published: November 2012

Background

The virus-host arms race is a major theater for evolutionary innovation. Archaea and bacteria have evolved diverse, elaborate antivirus defense systems that function on two general principles: i) immune systems that discriminate self DNA from nonself DNA and specifically destroy the foreign, in particular viral, genomes, whereas the host genome is protected, or ii) programmed cell suicide or dormancy induced by infection.

Presentation of the hypothesis

Almost all genomic loci encoding immunity systems such as CRISPR-Cas, restriction-modification and DNA phosphorothioation also encompass suicide genes, in particular those encoding known and predicted toxin nucleases, which do not appear to be directly involved in immunity. In contrast, the immunity systems do not appear to encode antitoxins found in typical toxin-antitoxin systems. This raises the possibility that components of the immunity system themselves act as reversible inhibitors of the associated toxin proteins or domains as has been demonstrated for the Escherichia coli anticodon nuclease PrrC that interacts with the PrrI restriction-modification system. We hypothesize that coupling of diverse immunity and suicide/dormancy systems in prokaryotes evolved under selective pressure to provide robustness to the antivirus response. We further propose that the involvement of suicide/dormancy systems in the coupled antivirus response could take two distinct forms:

1) induction of a dormancy-like state in the infected cell to ‘buy time’ for activation of adaptive immunity; 2) suicide or dormancy as the final recourse to prevent viral spread triggered by the failure of immunity.

Testing the hypothesis

This hypothesis entails many experimentally testable predictions. Specifically, we predict that Cas2 protein present in all cas operons is a mRNA-cleaving nuclease (interferase) that might be activated at an early stage of virus infection to enable incorporation of virus-specific spacers into the CRISPR locus or to trigger cell suicide when the immune function of CRISPR-Cas systems fails. Similarly, toxin-like activity is predicted for components of numerous other defense loci.

Implications of the hypothesis

The hypothesis implies that antivirus response in prokaryotes involves key decision-making steps at which the cell chooses the path to follow by sensing the course of virus infection.

Reviewers

This article was reviewed by Arcady Mushegian, Etienne Joly and Nick Grishin. For complete reviews, go to the Reviewers’ reports section.
Carotid sinus syndrome as the presenting symptom of cystadenolymphoma
Authors: Noroozi Nelson , Modabber Ali , Hölzle Frank , Braunschweig Till , Riediger Dieter , Gerressen Marcus , Ghassemi Alireza
Published: November 2012

Carotid sinus syndrome is a serious manifestation of head and neck malignancy. The purpose of this study was to clarify the presence of carotid sinus syndrome in a patient with cystadenolymphoma. To our knowledge carotid sinus syndrome secondary to cystadenolymphoma has not been reported to date. A 45-year-old woman with one-week-old swelling in the left mandibular angle having disturbing symptoms of vertigo, consciousness and sinus arrest. Holter monitoring revealed several episodes of sinus arrest. Ultrasonography showed a well-defined space-occupying lesion of about 31 mm in length and 17 mm in width located in the deep lobe of the left parotid gland. Computerized tomography (CT) showed a large mass extending into the carotid space and protruding into the parapharyngeal space. Parotidectomy was performed. Surgical removal of the tumor resulted in complete amelioration of symptoms and disappearance of electrocardiogram abnormalities. Here we report on a clinical case of carotid sinus syndrome associated with cystadenolymphoma. To our knowledge carotid sinus syndrome secondary to cystadenolymphoma has not been reported to date, and is made more remarkable as a possible differential diagnosis after clarification of all possible causes. Early diagnosis and immediate management can minimize complications.
Mycobacterium bovis infection at the interface between domestic and wild animals in Zambia
Authors: Hang’ombe Mudenda B , Munyeme Musso , Nakajima Chie , Fukushima Yukari , Suzuki Haruka , Matandiko Wigganson , Ishii Akihiro , Mweene Aaron S , Suzuki Yasuhiko
Published: November 2012

Background

In Zambia, the presence of bovine tuberculosis in both wild and domestic animals has long been acknowledged and mutual transmission between them has been predicted without any direct evidence. Elucidation of the circulatingMycobacterium bovisstrains at wild and domestic animals interphase area in Zambia, where bovine tuberculosis was diagnosed in wildlife seemed to be important.

Results

A PCR identified 15 and 37M. bovisisolates from lechwe and cattle, respectively. Spoligotype analysis revealed thatM. bovisstrains from lechwe and cattle in Kafue basin clustered into a major node SB0120, where isolates outside the Kafue basin clustered into different nodes of SB0131 and SB0948. The comparatively higher variety of strains in cattle compared to lechwe elucidated by Mycobacterial Interspersed Repetitive Units–Variable Number Tandem Repeats analyses are consistent with cattle being the probable source ofM. bovisin wild and domestic animals interphase area in Zambia.

Conclusions

These results provide strong evidence ofM. bovisstrains transfer between cattle and lechwe, with the latter having developed into a sylvatic reservoir host.
A direct comparison of next generation sequencing enrichment methods using an aortopathy gene panel- clinical diagnostics perspective
Authors: Wooderchak-Donahue Whitney L , O’Fallon Brendan , Furtado Larissa V , Durtschi Jacob D , Plant Parker , Ridge Perry G , Rope Alan F , Yetman Angela T , Bayrak-Toydemir Pinar
Published: November 2012

Background

Aortopathies are a group of disorders characterized by aneurysms, dilation, and tortuosity of the aorta. Because of the phenotypic overlap and genetic heterogeneity of diseases featuring aortopathy, molecular testing is often required for timely and correct diagnosis of affected individuals. In this setting next generation sequencing (NGS) offers several advantages over traditional molecular techniques.

Methods

The purpose of our study was to compare NGS enrichment methods for a clinical assay targeting the nine genes known to be associated with aortopathy. RainDance emulsion PCR and SureSelect RNA-bait hybridization capture enrichment methods were directly compared by enriching DNA from eight samples. Enriched samples were barcoded, pooled, and sequenced on the Illumina HiSeq2000 platform. Depth of coverage, consistency of coverage across samples, and the overlap of variants identified were assessed. This data was also compared to whole-exome sequencing data from ten individuals.

Results

Read depth was greater and less variable among samples that had been enriched using the RNA-bait hybridization capture enrichment method. In addition, samples enriched by hybridization capture had fewer exons with mean coverage less than 10, reducing the need for followup Sanger sequencing. Variants sets produced were 77% concordant, with both techniques yielding similar numbers of discordant variants.

Conclusions

When comparing the design flexibility, performance, and cost of the targeted enrichment methods to whole-exome sequencing, the RNA-bait hybridization capture enrichment gene panel offers the better solution for interrogating the aortopathy genes in a clinical laboratory setting.
Validation of reference genes from Eucalyptus spp. under different stress conditions
Authors: Moura Jullyana Cristina Magalhães Silva , Araújo Pedro , Brito Michael dos Santos , Souza Uiara Romero , Viana Julianade Oliveira Fernandes , Mazzafera Paulo
Published: November 2012

Background

The genus Eucalyptus consists of approximately 600 species and subspecies and has a physiological plasticity that allows some species to propagate in different regions of the world. Eucalyptus is a major source of cellulose for paper manufacturing, and its cultivation is limited by weather conditions, particularly water stress and low temperatures. Gene expression studies using quantitative reverse transcription polymerase chain reaction (qPCR) require reference genes, which must have stable expression to facilitate the comparison of the results from analyses using different species, tissues, and treatments. Such studies have been limited in eucalyptus.

Results

Eucalyptus globulus Labill, Eucalyptus urograndis (hybrid from Eucalyptus urophylla S.T. Blake X Eucalyptus grandis Hill ex-Maiden) and E. uroglobulus (hybrid from E. urograndis X E. globulus) were subjected to different treatments, including water deficiency and stress recovery, low temperatures, presence or absence of light, and their respective controls. Except for treatment with light, which examined the seedling hypocotyl or apical portion of the stem, the expression analyses were conducted in the apical and basal parts of the stem. To select the best pair of genes, the bioinformatics tools GeNorm and NormFinder were compared. Comprehensive analyses that did not differentiate between species, treatments, or tissue types, showed that IDH (isocitrate dehydrogenase), SAND (SAND protein), ACT (actin), and A-Tub (α-tubulin) genes were the most stable. IDH was the most stable gene in all of the treatments.

Conclusion

Comparing these results with those of other studies on eucalyptus, we concluded that five genes are stable in different species and experimental conditions: IDH, SAND, ACT, A-Tub, and UBQ (ubiquitin). It is usually recommended a minimum of two reference genes is expression analysis; therefore, we propose that IDH and two others genes among the five identified genes in this study should be used as reference genes for a wide range of conditions in eucalyptus.
Quantification of active and total transforming growth factor-β levels in serum and solid organ tissues by bioassay
Authors: Khan Shaukat A , Joyce Jennifer , Tsuda Takeshi
Published: November 2012

Background

Transforming growth factor-β (TGF-β) is a multi-factorial peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and tissue repair. Quantification of biologically active TGF-β levels in tissues is crucial to illustrate mechanisms involved in various physiological and pathological processes, but direct measurement of bioactive TGF-β level in the tissue has been hampered by lack of reliable methods. Here, we introduced mink lung epithelial cell bioassay to quantify both active and total TGF-β levels in serum and protein lysates from solid organs in the mouse model.

Findings

Mink lung epithelial cells were stably transfected with plasminogen activator inhibitor-1 promoter/luciferase construct, in which bioactive TGF-β level was represented by luciferase activity. Serum total TGF-β levels were comparable between the bioassay and enzyme-linked immunosorbent assay (ELISA), but active TGF-β levels measured by ELISA were significantly lower than those obtained by the bioassay. Active and total TGF-β levels in the solid organs including heart, liver, and kidney were also measured. Total TGF-β levels were relatively comparable among these organs, but active TGF-β levels were slightly higher in hearts and kidneys than in livers. Positive luciferase activities in the bioassay were almost completely inhibited by adding pan-TGF-β neutralizing antibodies, suggesting its high specificity to bioactive TGF-β. We also measured myocardial TGF-β levels after myocardial infarction and sham control by the bioassay, and compared the values with those obtained by ELISA. The bioassay demonstrated that both active and total tissue TGF-β levels were significantly higher in post-myocardial infarction than in sham myocardium. ELISA was markedly less sensitive in detecting both active and total TGF-β levels than our bioassay and failed to show any statistically significant difference in TGF-β levels between myocardial infarction and sham myocardium.

Conclusions

Our data suggested that the bioassay was significantly more sensitive than ELISA in detecting active TGF-β in serum and both active and total TGF-β in solid organ tissues. The bioassay will be useful in investigating TGF-β profile in various solid organs in physiological and pathological conditions.
Optimizing molluscicide treatment strategies in different control stages of schistosomiasis in the People’s Republic of China
Authors: Yang Guo-Jing , Sun Le-Ping , Hong Qing-Biao , Zhu Hong-Ru , Yang Kun , Gao Qi , Zhou Xiao-Nong
Published: November 2012

Background

The application of chemical molluscicides is still one of the most effective measures for schistosomiasis control in P. R. China. By applying diverse molluscicide treatment scenarios on different snail densities in the field, we attempted to understand the cost-effectiveness of molluscicide application so as to prescribe an optimal management approach to control intermediate host snail Oncomelania hupensis under acceptable thresholds based on the goal of the National Schistosomiasis Control Programme.

Methods

The molluscicidal field trial was carried out in the marshland of an island along the Yangtze River, Jiangsu province, P.R. China in October 2010. Three plots in the island representing low-density, medium-density and high-density groups were identified after the baseline survey on snail density. Each snail density plot was divided into four experimental units in which molluscicide (50% niclosamide ethanolamine salt wettable powder) was applied once, twice, trice and four times, respectively. The logistic regression model to correlate snail mortality rate with the covariates of number of molluscicidal treatment and snail density, and a linear regression model to investigate the relationship between cost-effectiveness and number of molluscicidal treatment as well as snail density were established.

Results

The study revealed that increase in the number of molluscicide treatments led to increased snail mortality across all three population density groups. The most cost-effective regimen was seen in the high snail density group with a single molluscicide treatment. For both high and low density groups, the more times molluscicide were applied, the less cost-effectiveness was. However, for the median density group, the level of cost-effectiveness for two applications was slightly higher than that in one time.

Conclusions

We concluded that different stages of the national schistosomiasis control/elimination programme, namely morbidity control, transmission control and transmission interruption, should utilize different molluscicide treatment strategies to maximize cost-effectiveness.
Resistance to visceral leishmaniasis is severely compromised in mice deficient of bradykinin B2-receptors
Authors: Nico Dirlei , Feijó Daniel Ferreira , Maran Naiara , Morrot Alexandre , Scharfstein Julio , Palatnik Marcos , Palatnik-de-Sousa Clarisa Beatriz
Published: November 2012

Background

Kinins liberated from plasma–borne kininogens, are potent innate stimulatory signals. We evaluated whether resistance to infection by Leishmania (L.) chagasi depends on activation of G-protein coupled bradykinin B2 receptors (B2R).

Findings

B2R −/− C57BL/6 knock-out (KOB2) and B2R+/+ C57BL/6-wild type control mice (C57) were infected with amastigotes of Leishmania (L.) chagasi. Thirty days after infection, the KOB2 mice showed 14% and 32% relative increases of liver (p< 0.017) and spleen weights (p<0.050), respectively, whereas liver parasite load increased 65% (p< 0.011) in relation to wild type mice. The relative weight increases of liver and spleen and the parasite load were positively correlated (R = 0.6911; p< 0.007 to R = 0.7629; p< 0.001, respectively). Conversely, we found a negative correlation between the increased liver relative weight and the weakened DTH response (a strong correlate to protection or natural resistance to VL) or the decreased levels of IgG2b antibodies to leishmanial antigen. Finally, we also found that IFN-γ secretion by splenocytes, an adaptive response that was significantly decreased in KOB2 mice (p< 0.002), was (i) negatively correlated to the increase in liver LDU (R = −0.6684; p = 0.035) and liver/body relative weight (R = −0.6946; p = 0.026) and (ii) positively correlated to serum IgG2b levels (R = 0.8817; p = 0.001).

Conclusions

We found that mice lacking B2R display increased susceptibility to the infection by Leishmania (L.) chagasi. Our findings suggest that activation of the bradykinin/B2R pathway contributes to development of host resistance to visceral leishmaniasis.
Molecular-based detection of the gastrointestinal pathogen Campylobacter ureolyticus in unpasteurized milk samples from two cattle farms in Ireland
Authors: Koziel Monika , Lucey Brigid , Bullman Susan , Corcoran Gerard D , Sleator Roy D
Published: November 2012

Campylobacter jejuni and coli are collectively regarded as the most prevalent cause of bacterial foodborne illness worldwide. An emerging species, Campylobacter ureolyticus has recently been detected in patients with gastroenteritis, however, the source of this organism has, until now, remained unclear. Herein, we describe the molecular-based detection of this pathogen in bovine faeces (1/20) and unpasteurized milk (6/47) but not in poultry (chicken wings and caeca). This is, to the best of our knowledge, the first report of the presence of this potential gastrointestinal pathogen in an animal source, possibly suggesting a route for its transmission to humans.
Suboptimal health: a new health dimension for translational medicine
Authors: Wang Wei , Yan Yuxiang
Published: November 2012

Background

One critical premise of disease‐related biomarkers is the definition of the counterpart normality. Contrary to pre‐clinical models that can be carefully tailored according to scientific need, heterogeneity and uncontrollability is the essence of humans in health studies. Fully characterization of consistent parameters that define the normal population is the basis to individual differences normalization irrelevant to a given disease process. Self claimed normal status may not represent health because asymptomatic subjects may carry chronic diseases or diseases at their early stage such as cancer, diabetes and hypertension.

Methods

This paper exemplifies the characterization of the suboptimal health status (SHS) which represents a new public health problem in a population with ambiguous health complaints such as general weakness, unexplained medical syndrome and chronic fatigue. We applied clinical informatics approaches and developed a questionnaire for measuring SHS. The validity and reliability of this approach were evaluated in a small pilot study and then in a cross‐sectional study of 3,405 individuals.

Results

The final questionnaire congregated into a score (SHSQ‐25) which could significantly distinguish among several abnormal conditions.

Conclusion

SHSQ‐25 could be used as a translational medicine instrument for health measuring in the general population.
Long-Term Update of US GI Intergroup RTOG 98-11 Phase III Trial for Anal Carcinoma: Survival, Relapse, and Colostomy Failure With Concurrent Chemoradiation Involving Fluorouracil/Mitomycin Versus Fluorouracil/Cisplatin
Authors: Gunderson Leonard L. , Winter Kathryn A. , Ajani Jaffer A. , Pedersen John E. , Moughan Jennifer , Benson Al B. , Thomas Charles R. , Mayer Robert J. , Haddock Michael G. , Rich Tyvin A. , Willett Christopher G.
Published: November 2012

Purpose

On initial publication of GI Intergroup Radiation Therapy Oncology Group (RTOG) 98-11 [A Phase III Randomized Study of 5-Fluorouracil (5-FU), Mitomycin, and Radiotherapy Versus 5-Fluorouracil, Cisplatin and Radiotherapy in Carcinoma of the Anal Canal], concurrent chemoradiation (CCR) with fluorouracil (FU) plus mitomycin (MMC) decreased colostomy failure (CF) when compared with induction plus concurrent FU plus cisplatin (CDDP), but did not significantly impact disease-free survival (DFS) or overall survival (OS) for anal canal carcinoma. The intent of the updated analysis was to determine the long-term impact of treatment on survival (DFS, OS, colostomy-free survival [CFS]), CF, and relapse (locoregional failure [LRF], distant metastasis) in this patient group.

Patients and Methods

Stratification factors included sex, clinical node status, and primary size. DFS and OS were estimated univariately by the Kaplan-Meier method, and treatment arms were compared by log-rank test. Time to relapse and CF were estimated by the cumulative incidence method and treatment arms were compared by using Gray's test. Multivariate analyses used Cox proportional hazard models to test for treatment differences after adjusting for stratification factors.

Results

Of 682 patients accrued, 649 were analyzable for outcomes. DFS and OS were statistically better for RT + FU/MMC versus RT + FU/CDDP (5-year DFS, 67.8% v 57.8%; P = .006; 5-year OS, 78.3% v 70.7%; P = .026). There was a trend toward statistical significance for CFS (P = .05), LRF (P = .087), and CF (P = .074). Multivariate analysis was statistically significant for treatment and clinical node status for both DFS and OS, for tumor diameter for DFS, and for sex for OS.

Conclusion

CCR with FU/MMC has a statistically significant, clinically meaningful impact on DFS and OS versus induction plus concurrent FU/CDDP, and it has borderline significance for CFS, CF, and LRF. Therefore, RT + FU/MMC remains the preferred standard of care.
RET Fusions Define a Unique Molecular and Clinicopathologic Subtype of Non–Small-Cell Lung Cancer
Authors: Wang Rui , Hu Haichuan , Pan Yunjian , Li Yuan , Ye Ting , Li Chenguang , Luo Xiaoyang , Wang Lei , Li Hang , Zhang Yang , Li Fei , Lu Yongming , Lu Qiong , Xu Jie , Garfield David , Shen Lei , Ji Hongbin , Pao William , Sun Yihua , Chen Haiquan
Published: November 2012

Purpose

The RET fusion gene has been recently described in a subset of non–small-cell lung cancers (NSCLCs). Because we have limited knowledge about these tumors, this study was aimed at determining the clinicopathologic characteristics of patients with NSCLC harboring the RET fusion gene.

Patients and Methods

We examined the RET fusion gene in 936 patients with surgically resected NSCLC using a reverse transcriptase polymerase chain reaction (PCR) plus quantitative real-time PCR strategy, with validation using immunohistochemical and fluorescent in situ hybridization assays. A subset of 633 lung adenocarcinomas was also studied for EGFR, KRAS, HER2, and BRAF mutations, as well as ALK rearrangements. Patient characteristics, including age, sex, smoking history, stage, grade, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of subtypes of lung adenocarcinoma, and relapse-free survival, were collected.

Results

Of 936 patients with NSCLC, the RET fusion gene was exclusively detected in 13 patients (11 of 633 patients with adenocarcinomas and two of 24 patients with adenosquamous cell carcinomas). Of the 13 patients, nine patients had KIF5B-RET, three patients had CCDC6-RET, and one patient had a novel NCOA4-RET fusion. Patients with lung adenocarcinomas with RET fusion gene had more poorly differentiated tumors (63.6%; P = .029 for RET v ALK, P = .007 for RET v EGFR), with a tendency to be younger (≤ 60 years; 72.7%) and never-smokers (81.8%) and to have solid subtype (63.6%) and a smaller tumor (≤ 3 cm) with N2 disease (54.4%). The median relapse-free survival was 20.9 months.

Conclusion

RET fusion occurs in 1.4% of NSCLCs and 1.7% of lung adenocarcinomas and has identifiable clinicopathologic characteristics, warranting further clinical consideration and targeted therapy investigation.
Gonadal Function and Fertility in Survivors After Hodgkin Lymphoma Treatment Within the German Hodgkin Study Group HD13 to HD15 Trials
Authors: Behringer Karolin , Mueller Horst , Goergen Helen , Thielen Indra , Eibl Angelika Diana , Stumpf Volker , Wessels Carsten , Wiehlpütz Martin , Rosenbrock Johannes , Halbsguth Teresa , Reiners Katrin S. , Schober Thomas , Renno Jorg H. , von Wolff Michael , van der Ven Katrin , Kuehr Marietta , Fuchs Michael , Diehl Volker , Engert Andreas , Borchmann Peter
Published: November 2012

Purpose

To optimize fertility advice in patients with Hodgkin lymphoma (HL) before therapy and during survivorship, information on the impact of chemotherapy is needed. Therefore, we analyzed gonadal functions in survivors of HL.

Patients and Methods

Women younger than age 40 and men younger than 50 years at diagnosis in ongoing remission at least 1 year after therapy within the German Hodgkin Study Group HD13 to HD15 trials for early- and advanced-stage HL were included. Hormone parameters, menstrual cycle, symptoms of hypogonadism, and offspring were evaluated.

Results

A total of 1,323 (55%) of 2,412 contacted female and male survivors were evaluable for the current analysis (mean follow-up, 46 and 48 months, respectively). Follicle-stimulating hormone, anti-Müllerian hormone, and inhibin B levels correlated significantly with therapy intensity (P < .001). Low birth rates were observed in survivors after advanced-stage treatment within the observation time (women, 6.5%; men, 3.3%). Regular menstrual cycle was reported by more than 90% of female survivors of early-stage HL (recovery time mostly ≤ 12 months). After six to eight cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, menstrual activity was strongly related to age (< v ≥ 30 years: 82% v 45%, respectively; P < .001; prolonged recovery time). Thirty-four percent of women age ≥ 30 years suffered severe menopausal symptoms (three- to four-fold more frequently than expected). In contrast, male survivors had mean levels of testosterone within the normal range and reported no increased symptoms of hypogonadism.

Conclusion

The present analysis in a large group of survivors of HL provides well-grounded information on gonadal toxicity of currently used treatment regimens and allows risk-adapted fertility preservation and comprehensive support during therapy and follow-up.
Mitomycin in Anal Cancer: Still the Standard of Care
Authors: Chin Joanna Y. , Hong Theodore S. , Ryan David P.
Published: November 2012

A 52-year-old woman presents with a 2-month history of bright red blood per rectum. Her bleeding is associated with bowel movements and a sense of incomplete evacuation. She denies fecal incontinence or change in stool caliber. On digital rectal examination, the tumor is palpated approximately 3 cm from the anal verge, posterior and slightly to the right, positioned at the top of the anal canal and extending into the rectum, measuring approximately 2.5 cm. Additionally, a firm 1.5-cm left-sided inguinal node is palpated. The patient is then referred for colonoscopy, which reveals a mass in the anal canal; biopsy of the mass shows squamous cell carcinoma. Positron emission tomography–computed tomography (PET-CT) demonstrates thickening in the low rectum with [18F]fluorodeoxyglucose (FDG) avidity ( Figs 1 A, 1 B). The left inguinal node is visualized, as is a perirectal lymph node with associated FDG avidity ( Figs 1 C, 1 D). The patient is staged as having T2N3 squamous cell carcinoma of the anal canal ( Table 1 ). Her medical history is otherwise unremarkable, including for HIV, prior abnormal Papanicolaou smears, and other risk factors for human papillomavirus (HPV) exposure.
Optimal Morphologic Response to Preoperative Chemotherapy: An Alternate Outcome End Point Before Resection of Hepatic Colorectal Metastases
Authors: Shindoh Junichi , Loyer Evelyne M. , Kopetz Scott , Boonsirikamchai Piyaporn , Maru Dipen M. , Chun Yun Shin , Zimmitti Giuseppe , Curley Steven A. , Charnsangavej Chusilp , Aloia Thomas A. , Vauthey Jean-Nicolas
Published: November 2012

Purpose

The purposes of this study were to confirm the prognostic value of an optimal morphologic response to preoperative chemotherapy in patients undergoing chemotherapy with or without bevacizumab before resection of colorectal liver metastases (CLM) and to identify predictors of the optimal morphologic response.

Patients and Methods

The study included 209 patients who underwent resection of CLM after preoperative chemotherapy with oxaliplatin- or irinotecan-based regimens with or without bevacizumab. Radiologic responses were classified as optimal or suboptimal according to the morphologic response criteria. Overall survival (OS) was determined, and prognostic factors associated with an optimal response were identified in multivariate analysis.

Results

An optimal morphologic response was observed in 47% of patients treated with bevacizumab and 12% of patients treated without bevacizumab (P < .001). The 3- and 5-year OS rates were higher in the optimal response group (82% and 74%, respectively) compared with the suboptimal response group (60% and 45%, respectively; P < .001). On multivariate analysis, suboptimal morphologic response was an independent predictor of worse OS (hazard ratio, 2.09; P = .007). Receipt of bevacizumab (odds ratio, 6.71; P < .001) and largest metastasis before chemotherapy of ≤ 3 cm (odds ratio, 2.12; P = .025) were significantly associated with optimal morphologic response. The morphologic response showed no specific correlation with conventional size-based RECIST criteria, and it was superior to RECIST in predicting major pathologic response.

Conclusion

Independent of preoperative chemotherapy regimen, optimal morphologic response is sufficiently correlated with OS to be considered a surrogate therapeutic end point for patients with CLM.
Release of Norepinephrine in the Preoptic Area Activates Anteroventral Periventricular Nucleus Neurons and Stimulates the Surge of Luteinizing Hormone
Authors: Szawka Raphael E. , Poletini Maristela O. , Leite Cristiane M. , Bernuci Marcelo P. , Kalil Bruna , Mendonça Leonardo B.D. , Carolino Ruither O. G. , Helena Cleyde V. V. , Bertram Richard , Franci Celso R. , Anselmo-Franci Janete A.
Published: November 2012

The role of norepinephrine (NE) in regulation of LH is still controversial. We investigated the role played by NE in the positive feedback of estradiol and progesterone. Ovarian-steroid control over NE release in the preoptic area (POA) was determined using microdialysis. Compared with ovariectomized (OVX) rats, estradiol-treated OVX (OVX+E) rats displayed lower release of NE in the morning but increased release coincident with the afternoon surge of LH. OVX rats treated with estradiol and progesterone (OVX+EP) exhibited markedly greater NE release than OVX+E rats, and amplification of the LH surge. The effect of NE on LH secretion was confirmed using reverse microdialysis. The LH surge and c-Fos expression in anteroventral periventricular nucleus neurons were significantly increased in OVX+E rats dialyzed with 100 nm NE in the POA. After Fluoro-Gold injection in the POA, c-Fos expression in Fluoro-Gold/tyrosine hydroxylase-immunoreactive neurons increased during the afternoon in the A2 of both OVX+E and OVX+EP rats, in the locus coeruleus (LC) of OVX+EP rats, but was unchanged in the A1. The selective lesion of LC terminals, by intracerebroventricular N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, reduced the surge of LH in OVX+EP but not in OVX+E rats. Thus, estradiol and progesterone activate A2 and LC neurons, respectively, and this is associated with the increased release of NE in the POA and the magnitude of the LH surge. NE stimulates LH secretion, at least in part, through activation of anteroventral periventricular neurons. These findings contribute to elucidation of the role played by NE during the positive feedback of ovarian steroids.
Maternal and Fetal Exposure to Bisphenol A Is Associated with Alterations of Thyroid Function in Pregnant Ewes and Their Newborn Lambs
Authors: Viguié Catherine , Collet Séverine H. , Gayrard Véronique , Picard-Hagen Nicole , Puel Sylvie , Roques Béatrice B. , Toutain Pierre-Louis , Lacroix Marlène Z.
Published: November 2012

The putative thyroid-disrupting properties of bisphenol A (BPA) highlight the need for an evaluation of fetal exposure and its consequence on the mother/newborn thyroid functions in models relevant to human. The goals of this study were to characterize in sheep a relevant model for human pregnancy and thyroid physiology, the internal exposures of the fetuses and their mothers to BPA and its main metabolite BPA-glucuronide (Gluc), and to determine to what extent it might be associated with thyroid disruption. Ewes were treated with BPA [5 mg/(kg · d) sc] or vehicle from d 28 until the end of pregnancy. Unconjugated BPA did not appear to accumulate in pregnant ewes, and its concentration was similar in the newborns and their mothers (0.13 ± 0.02 and 0.18 ± 0.03 nmol/ml in cord and maternal blood, respectively). In amniotic fluid and cord blood, BPA-Gluc concentrations were about 1300-fold higher than those of BPA. Total T4 concentrations were decreased in BPA-treated pregnant ewes and in the cord and the jugular blood of their newborns (30% decrease). A similar difference was observed for free T4 plasma concentrations in the jugular blood of the newborns. Our results show in a long-gestation species with a similar regulatory scheme of thyroid function as humans that BPA in utero exposure can be associated with hypothyroidism in the newborns. If such an effect were to be confirmed for a more relevant exposure scheme to BPA, this would constitute a major issue for BPA risk assessment.
GnRH Neuronal Migration and Olfactory Bulb Neurite Outgrowth Are Dependent on FGF Receptor 1 Signaling, Specifically via the PI3K p110α Isoform in Chick Embryo
Authors: Hu Youli , Poopalasundaram Subathra , Graham Anthony , Bouloux Pierre-Marc
Published: November 2012

Fibroblast growth factor (FGF) signaling is essential for both olfactory bulb (OB) morphogenesis and the specification, migration, and maturation of the GnRH-secreting neurons. Disruption of FGF signaling contributes to Kallmann syndrome characterized by both anosmia and sexual immaturity. However, several unanswered questions remain as to which specific FGF receptor (FGFR)-1 signaling pathways are necessary for OB and GnRH neuronal development. Here, using pharmacological phosphatidylinositol 3-kinase (PI3K) isoform-specific inhibitors, we demonstrate a central role for the PI3K p110α isoform as a downstream effector of FGFR1 signaling for both GnRH neuronal migration and OB development. We show that signaling via the PI3K p110α isoform is required for GnRH neuronal migration in explant cultures of embryonic day (E) 4 chick olfactory placodes. We also show that in ovo administration of LY294002, a global PI3K inhibitor as well as an inhibitor to the PI3K p110α isoform into the olfactory placode of E3 chick embryo impairs GnRH neuronal migration toward the forebrain. In contrast, in ovo PI3K inhibitor treatment produced no obvious defects on primary olfactory sensory neuron axonal targeting and bundle formation. We also demonstrate that anosmin-1 and FGF2 induced neuronal migration of immortalized human embryonic GnRH neuroblast cells (FNC-B4-hTERT) is mediated by modulating FGFR1 signaling via the PI3K p110α isoform, specifically through phosphorylation of the PI3K downstream effectors, Akt and glycogen synthase kinase-3β. Finally, we show that neurite outgrowth and elongation of OB neurons in E10 chick OB explants are also dependent on the PI3K p110α isoform downstream of FGFR1. This study provides mechanistic insight into the etiology of Kallmann syndrome.
Association of Postburn Fatty Acids and Triglycerides with Clinical Outcome in Severely Burned Children
Authors: Kraft Robert , Herndon David N. , Finnerty Celeste C. , Hiyama Yaeko , Jeschke Marc G.
Published: November 2012

Context:

Free fatty acids (FFAs) and triglycerides (TGs) are altered postburn, but whether these alterations are associated with postburn outcomes is not clear.

Objective:

The aim of the present study was to analyze lipid metabolic profiles in pediatric burn patients and to correlate these profiles with patient outcomes and hospital courses.

Design and Setting:

We conducted a prospective cohort study at an academic pediatric hospital burn center.

Patients:

Our study included 219 pediatric burn patients.

Main Outcome Measures:

Patients were stratified according to their plasma TG and FFA levels. Main patient outcomes, such as postburn morbidity and mortality, and clinical metabolic markers were analyzed.

Results:

All groups were similar in demographics and injury characteristics. Patients with elevated TGs had significantly worse clinical outcomes associated with increased acute-phase protein synthesis indicating augmented inflammation and hypermetabolism, whereas increased FFAs did not seem to profoundly alter postburn outcomes.

Conclusions:

Elevated TGs, but not FFAs, postburn are associated with worsened organ function and clinical outcomes.
Human TNRC6A is an Argonaute-navigator protein for microRNA-mediated gene silencing in the nucleus
Authors: Nishi Kenji , Nishi Ai , Nagasawa Tatsuya , Ui-Tei Kumiko
Published: November 2012

GW182 family proteins play important roles in microRNA (miRNA)-mediated gene silencing. They interact with Argonaute (Ago) proteins and localize in processing bodies, which are cytoplasmic foci involved in mRNA degradation and storage. Here, we demonstrated that human GW182 paralog, TNRC6A, is a nuclear–cytoplasmic shuttling protein, and its subcellular localization is conducted by a nuclear export signal (NES) and a nuclear localization signal (NLS) identified in this study. TNRC6A with mutations in its NES region was predominantly localized in the nucleus in an Ago-independent manner. However, it was found that TNRC6A could bring Ago protein into the nucleus via its Ago-interacting motif(s). Furthermore, miRNAs were also colocalized with nuclear TNRC6A-Ago and exhibited gene silencing activity. These results proposed the possibility that TNRC6A plays an important role in navigating Ago protein into the nucleus to lead miRNA-mediated gene silencing.
The Antidiabetic Activities of the Methanolic Root Bark Extract of Afzelia africana in Alloxan-Induced Diabetic Mice
Authors: Odo Rita I. , Asuzu Isaac Uzoma , Aba Patrick Emeka
Published: November 2012

The methanolic root bark extract of Afzelia africana was tested for antidiabetic activities in-vivo. The acute toxicity of the extract was tested in mice and the result showed that the extract has low toxicity. Investigation on the phytochemical constituents of the plant extract revealed the presence of flavonoids, tannins, alkaloids, steroids and saponins. The plant extract was tested for antidiabetic activities in alloxan - induced diabetic mice at doses of 62.5 mg/kg, 125 mg/kg, 250 mg/kg, 500 mg/kg and 1000 mg/kg over a period of 6 hours. The activity was found to be both dose and time dependent. Optimum activity was noted at the dose of 250 mg/kg and 6 hours post treatment. Distilled water (10 ml/kg) and glibenclamide (2 mg/kg) were used as negative and positive controls respectively. The extract showed antidiabetic activity which did not differ significantly (p > 0.05) from glibenclamide.Column and thin layer chromatography revealed the presence of 5 fractions in the plant extract out of which fraction 3 was found to be active.
Do Rising Top Income Shares Affect the Incomes or Earnings of Low and Middle-Income Families?
Authors: Thompson Jeffrey P. , Leight Elias
Published: November 2012

This paper uses US state panel data to explore the relationship between the share of income received by affluent households and the level of income and earnings received by low and middle-income families. A rising top share of income can potentially lead to increases in the incomes of low and middle-income families if economic growth is sufficiently responsive to increases in inequality. A substantial literature on the impacts of inequality on economic growth exists, but has failed to achieve consensus, with various studies finding positive impacts, negative impacts, and no impacts on growth from increased levels of income inequality. This paper departs from that literature by exploring the effect of inequality on the standard of living of middle-income and low-income families. In the context of rising inequality, increased overall growth is not necessarily a suitable proxy for overall standard of living, since growth patterns are not uniform for the entire income distribution. The results of this study indicate that increases in the top share of income (particularly the top one percent) are associated with declines in the actual incomes (and earnings) of middle income families, but have no clear impact on families at the bottom of the income distribution.
Competitive Mixed Bundling of Vertically Differentiated Products
Authors: Ahn Illtae , Yoon Kiho
Published: November 2012

We examine mixed bundling in a competitive environment that incorporates vertical product differentiation. We show that, compared to the equilibrium without bundling, (i) prices, profits and social welfare are lower, whereas (ii) consumer surplus is higher in the equilibrium with mixed bundling. In addition, the population of consumers who purchase both products from the same firm is larger in the equilibrium with mixed bundling. These results are largely in line with those obtained in the previous literature on competitive mixed bundling with horizontal differentiation. Further, we conduct a comparative static analysis with respect to changes in quality differentiation parameters. When the quality gap between brands narrows under no bundling and symmetric mixed bundling, prices and profits decrease. When quality differentiation is asymmetric across products, however, complicated effects occur on prices and profits due to strategic interdependence that mixed bundling creates.
A practical tutorial for generating ISO 10110 drawings
Authors: Lane Jason
Published: November 2012

This tutorial provides a brief introduction to the ISO 10110 optical drawing standard. The indications included on an ISO 10110 optical drawing are defined, and an example drawing is provided to illustrate how the information is commonly presented. To aid the designer who may not be familiar with the capabilities of optical shops, a set of specification values are provided, which illustrate easy, typical, and difficult values to achieve in fabrication. The same type of information is presented for lens dimensions. Finally, a set of design best practices are presented to aid in reducing fabrication difficulty and cost.
The emerging roles for histone demethylases in the modulation of signaling pathways
Authors: Di Stefano Luisa , Dyson Nicholas J.
Published: November 2012

Since their discovery in 2004, histone demethylases have emerged as key regulators of chromatin. Recent studies have started to reveal the interconnections between histone demethylases and signaling pathways, suggesting that this interplay drives fundamental biological processes. Here, we summarize the different families and subfamilies of histone demethylases and the insights into the biological roles of these enzymes that have been provided by the analysis of mutant animals. We then review recent work linking demethylases and signaling pathways. These studies suggest that demethylase activities are a component of the critical connections that enable environmental signals to modulate the epigenetic landscape of a cell. A greater mechanistic understanding of the network of signals that control chromatin states during normal cellular processes, together with a better understanding of the ways that epigenetic alterations lead to uncontrolled cell proliferation, might help in the design of effective tools for cancer therapy.
Cytochrome P450 2B6: function, genetics, and clinical relevance
Authors: Turpeinen Miia , Zanger Ulrich M.
Published: November 2012

Cytochrome P450 (CYP) 2B6 belongs to the set of important hepatic drug-metabolizing CYPs. It makes up roughly 3%–6% of total hepatic CYP content and metabolizes several pharmaceuticals including bupropion, efavirenz, cyclophosphamide, pethidine, ketamine and propofol. The enzyme is susceptible to drug-drug interactions by enzyme induction and inhibition. In addition to drugs, CYP2B6 is able to both detoxify and bioactivate a number of procarcinogens and environmental agents including pesticides and herbicides. There is an extensive interindividual variability in the expression of CYP2B6, which is in part explained by extensive genetic polymorphism. CYP2B6 is one of the most polymorphic CYP genes in humans with over 100 described SNPs, numerous complex haplotypes and distinct ethnic and racial frequencies. This review summarizes the basic properties of CYP2B6 and the main characteristics of clinical relevance.
Synthesis and antimicrobial activity of derivatives of 1H-benzo[de]isoquinoline-1,3(2H)-dione
Authors: Kuran Bożena , Krawiecka Mariola , Kossakowski Jerzy , Szymanek Ksenia , Kierzkowska Marta , Młynarczyk Grażyna
Published: November 2012

Five aminoalkyl 1H-benzo[de]isoquinoline-1,3(2H)-diones were synthesized and evaluated for antimicrobial activity. Microorganisms used in this study included aerobic and facultative anaerobic bacteria Staphylococcus aureus, Escherichia coli and Stenotrophomonas maltophilia, and obligatory anaerobes Bacteroides fragilis, Bacteroides thetaiotaomicron and Propionibacterium acnes. Moreover, Candida albicans yeast was used. The minimum inhibitory concentration (MIC) was determined for the test compounds. Among the tested derivatives, two compounds 1 and 2 have shown the most potent antibacterial as well as antifungal activities.
The Search for Aurifeuillian-Like Factorizations
Authors: Wagstaff, Jr. Samuel S.
Published: November 2012

We searched the Cunningham tables for new algebraic factorizations similar to those discovered by Aurifeuille. A naive search would have been too slow. We accelerated it enough to make it feasible. Many interesting results were found.
Coating matters: the influence of coating materials on the optical properties of gold nanoparticles
Authors: Chanana Munish , Liz-Marzán Luis M.
Published: November 2012

An essential element in the synthesis of nanomaterials based on gold nanoparticles comprises the control over parameters such as size, shape and composition, due to their strong influence on the properties of the particles. However, it is the coating material which often plays the primary role in tuning the size, morphology, and even plasmon resonance wavelength or mode multiplicity, as well as colloidal stability and functional versatility, ultimately determining the physical, chemical, optical, electronic and catalytic properties of the nanoparticles. Therefore, it is utterly important to select the adequate wet chemistry synthetic approach with the most suitable coating material for the preparation of gold nanoparticles with the desired requirements. Within this context, this review is focused on describing various types of organic and inorganic coating materials for gold nanoparticles that may notably affect their optical properties by either directly influencing the synthesis procedure or by changing their chemical and physical properties upon post-synthetic modifications, such that they exhibit novel and useful optical properties.