bluuebunny/crossref_metadata_2025 huggingface dataset:
Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells
Authors: D'Alise Anna Morena , Amabile Giovanni , Iovino Mariangela , Di Giorgio Francesco Paolo , Bartiromo Marta , Sessa Fabio , Villa Fabrizio , Musacchio Andrea , Cortese Riccardo
Published: May 2008

The demonstration that the small synthetic molecule reversine [2-(4-morpholinoanilino)-N6-cyclohexyladenine] promotes the dedifferentiation of committed cells into multipotent progenitor-type cells has raised hopes on the exploitation of this small chemical tool for the generation of stem cells. Here, we show that reversine causes a failure in cytokinesis and induces polyploidization. These effects of reversine are due to the inhibition of Aurora A and B, two related kinases that are implicated in several aspects of mitosis and that are frequently amplified and overexpressed in human tumors. Reversine inhibits the phosphorylation of histone H3, a direct downstream target of Aurora kinases. Similarly to the Aurora kinase inhibitor VX-680, which has recently entered phase II clinical trials for cancer treatment, reversine inhibited colony formation of leukemic cells from patients with acute myeloid leukemia but was significantly less toxic than VX-680 on cells from healthy donors. The crystal structure of the reversine-Aurora B kinase complex shows that reversine is a novel class of ATP-competitive Aurora kinase inhibitors. Thus, although our studies raise serious doubts on the application of reversine in regenerative medicine, they support the paradigm that reversine might be a useful agent in cancer chemotherapy. [Mol Cancer Ther 2008;7(5):1140–9]
Akt-mediated eminent expression of c-FLIP and Mcl-1 confers acquired resistance to TRAIL-induced cytotoxicity to lung cancer cells
Authors: Wang Xia , Chen Wenshu , Zeng Weihua , Bai Lang , Tesfaigzi Yohannes , Belinsky Steven A. , Lin Yong
Published: May 2008

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent due to its selectivity in killing transformed cells. However, TRAIL can also stimulate the proliferation and metastasis of TRAIL-resistant cancer cells. Thus, acquired TRAIL resistance during TRAIL therapy would shift the patient's treatment from beneficial to detrimental. In this study, we focused on the acquired TRAIL resistance mechanism and showed that the elevated expression of the antiapoptotic factor cellular FLICE-like inhibitory protein (c-FLIP) and the prosurvival Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) underlie the main mechanism of this type of TRAIL resistance in lung cancer cells. Chronic exposure to TRAIL resulted in lung cancer cell resistance to TRAIL-induced cytotoxicity, and this resistance was associated with the increase in the cellular levels of c-FLIPL and Mcl-1L. Overexpresssion of c-FLIPL suppressed recruitment of caspase-8 to the death-inducing signaling complex, whereas increased Mcl-1L expression blunted the mitochondrial apoptosis pathway. The elevation of c-FLIPL and Mcl-1L expression was due to Akt-mediated stabilization of these proteins in TRAIL-resistant cells. Importantly, suppressing c-FLIPL and Mcl-1L expression by RNA interference collectively alleviated acquired TRAIL resistance. Taken together, these results identify c-FLIPL and Mcl-1L as the major determinants of acquired TRAIL resistance and could be molecular targets for improving the therapeutic value of TRAIL against lung cancer. [Mol Cancer Ther 2008;7(5):1156–63]
Requirement of hypoxia-inducible factor-1α down-regulation in mediating the antitumor activity of the anti–epidermal growth factor receptor monoclonal antibody cetuximab
Authors: Li Xinqun , Lu Yang , Liang Ke , Pan Tianhong , Mendelsohn John , Fan Zhen
Published: May 2008

We tested our novel hypothesis that down-regulation of hypoxia-inducible factor-1α (HIF-1α), the regulated subunit of HIF-1 transcription factor that controls gene expression involved in key functional properties of cancer cells (including metabolism, survival, proliferation, invasion, angiogenesis, and metastasis), contributes to a major antitumor mechanism of cetuximab, an approved therapeutic monoclonal antibody that blocks activation of the epidermal growth factor receptor. We showed that cetuximab treatment down-regulates HIF-1α levels by inhibiting synthesis of HIF-1α rather than by enhancing degradation of the protein. Inhibition of HIF-1α protein synthesis was dependent on effective inhibition of the phosphoinositide-3 kinase (PI3K)/Akt pathway by cetuximab, because the inhibition was prevented in cells transfected with a constitutively active PI3K or a constitutively active Akt but not in cells with a constitutively active MEK. Overexpression of HIF-1α conferred cellular resistance to cetuximab-induced apoptosis and inhibition of vascular endothelial growth factor production in sensitive cancer cell models, and expression knockdown of HIF-1α by RNA interference substantially restored cellular sensitivity to the cetuximab-mediated antitumor activities in experimental resistant cell models created by transfection of an oncogenic Ras gene (G12V) or by concurrent treatment of the cells with insulin-like growth factor-I. In summary, our data show that cetuximab decreases HIF-1α protein synthesis through inhibition of a PI3K-dependent pathway and that an effective down-regulation of HIF-1α is required for maximal therapeutic effects of cetuximab in cancer cells. [Mol Cancer Ther 2008;7(5):1207–17]
Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors
Authors: Johansson Gunnar , Mahller Yonatan Y. , Collins Margaret H. , Kim Mi-Ok , Nobukuni Takahiro , Perentesis John , Cripe Timothy P. , Lane Heidi A. , Kozma Sara C. , Thomas George , Ratner Nancy
Published: May 2008

Malignant peripheral nerve sheath tumors (MPNST) are chemoresistant sarcomas with poor 5-year survival that arise in patients with neurofibromatosis type 1 (NF1) or sporadically. We tested three drugs for single and combinatorial effects on collected MPNST cell lines and in MPNST xenografts. The mammalian target of rapamycin complex 1 inhibitor RAD001 (Everolimus) decreased growth 19% to 60% after 4 days of treatment in NF1 and sporadic-derived MPNST cell lines. Treatment of subcutaneous sporadic MPNST cell xenografts with RAD001 significantly, but transiently, delayed tumor growth, and decreased vessel permeability within xenografts. RAD001 combined with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib caused additional inhibitory effects on growth and apoptosis in vitro, and a small but significant additional inhibitory effect on MPNST growth in vivo that were larger than the effects of RAD001 with doxorubicin. RAD001 plus erlotinib, in vitro and in vivo, reduced phosphorylation of AKT and total AKT levels, possibly accounting for their additive effect. The results support the consideration of RAD001 therapy in NF1 patient and sporadic MPNST. The preclinical tests described allow rapid screening strata for drugs that block MPNST growth, prior to tests in more complex models, and should be useful to identify drugs that synergize with RAD001. [Mol Cancer Ther 2008;7(5):1237–45]
Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3′-untranslated region
Authors: Kandasamy Karthikeyan , Kraft Andrew S.
Published: May 2008

Addition of proteasome inhibitor PS-341 (VELCADE, bortezomib) to prostate cancer cells enhances cell death mediated by tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). PS-341 sensitizes prostate cancer cells to TRAIL-induced apoptosis by increasing TRAIL receptors (DR5), inhibiting protein degradation, and elevating DR5 mRNA. Investigations into how PS-341 regulates the stability of DR5 mRNA revealed that PS-341 increased DR5 mRNA by extending its half-life from 4 to 10 h. The 2.5-kb 3′-untranslated region of the DR5 gene stabilized a heterologous gene in LNCaP human prostate cancer cells, suggesting the importance of this mRNA sequence. In contrast, human prostate cancer cell lines PC-3 and DU145 do not show this stabilization, suggesting cell specificity. PS-341 treatment of LNCaP cells increases the level of specific cytoplasmic mRNA-binding proteins, including AUF-1 isoforms, hnRNP C1/C2, and HuR proteins. In UV cross-linking experiments, after PS-341 treatment, the HuR protein markedly increases binding to specific sequences in the DR5 3′-untranslated region. In LNCaP cells treated with PS-341, small interfering RNA–mediated knockdown of HuR markedly decreases the half-life of DR5 mRNA, indicating that HuR is essential for mRNA stabilization. HuR protein is ubiquitinated, suggesting that PS-341 increases this protein by preventing its degradation. These experiments implicate modulation of mRNA stability as a novel mechanism by which proteasome inhibitors function, sensitizing cancer cells to antineoplastic agents. [Mol Cancer Ther 2008;7(5):1091–100]
The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis
Authors: Liby Karen , Black Candice C. , Royce Darlene B. , Williams Charlotte R. , Risingsong Renee , Yore Mark M. , Liu Xi , Honda Tadashi , Gribble Gordon W. , Lamph William W. , Sporn Thomas A. , Dmitrovsky Ethan , Sporn Michael B.
Published: May 2008

Female A/J mice injected with the carcinogen vinyl carbamate develop atypical adenomatous hyperplasias in lungs 4 weeks after injection with the carcinogen. The number and severity of tumors then increase over time, making these mice a useful model for evaluating potential chemopreventive agents. The rexinoid LG100268 (LG268), a selective ligand for the retinoid X receptor, and the methyl amide of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) both significantly reduced the number, size, and severity of the histopathology of lung tumors in female A/J mice when fed in diet for 14 to 20 weeks. The total tumor burden was 85% to 87% lower in mice fed LG268 and CDDO-MA than in controls, and the percentage of high-grade tumors decreased from 59% in the controls to 25% or 30% with CDDO-MA and LG268. Erlotinib, which is used to treat lung cancer patients and is an inhibitor of the epidermal growth factor receptor, was less effective in this model. Immunohistochemical staining of geminin, a marker of cell cycle progression, was higher in lung sections from control mice than in mice treated with LG268. Because rexinoids and triterpenoids signal through different biological pathways, they should be tested in combination for the prevention of lung cancer. [Mol Cancer Ther 2008;7(5):1251–7]
Cytotoxicity of the matrix metalloproteinase–activated anthrax lethal toxin is dependent on gelatinase expression and B-RAF status in human melanoma cells
Authors: Alfano Randall W. , Leppla Stephen H. , Liu Shihui , Bugge Thomas H. , Herlyn Meenhard , Smalley Keiran S. , Bromberg-White Jennifer L. , Duesbery Nicholas S. , Frankel Arthur E.
Published: May 2008

Anthrax lethal toxin (LeTx) shows potent mitogen-activated protein kinase pathway inhibition and apoptosis in melanoma cells that harbor the activating V600E B-RAF mutation. LeTx is composed of two proteins, protective antigen and lethal factor. Uptake of the toxin into cells is dependent on proteolytic activation of protective antigen by the ubiquitously expressed furin or furin-like proteases. To circumvent nonspecific LeTx activation, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. Here, we have shown that the toxicity of this matrix metalloproteinase (MMP)–activated LeTx is dependent on host cell surface MMP-2 and MMP-9 activity as well as the presence of the activating V600E B-RAF mutation, making this toxin dual specific. This additional layer of tumor cell specificity would potentially decrease systemic toxicity from the reduction of nonspecific toxin activation while retaining antitumor efficacy in patients with V600E B-RAF melanomas. Moreover, our results indicate that cell surface-associated gelatinase expression can be used to predict sensitivity among V600E B-RAF melanomas. This finding will aid in the better selection of patients that will potentially respond to MMP-activated LeTx therapy. [Mol Cancer Ther 2008;7(5):1218–26]
Breaking Up the Family: Divorce in Egyptian Law and Practice
Authors: Bernard-Maugiron Nathalie , Dupret Baudouin
Published: May 2008

If the legal status of women wishing to end an unhappy marriage has undoubtedly improved through the codification process of personal status law in Egypt in the twentieth century, it still remains very unequal in comparison to the privileges enjoyed by men in that field. Moreover, the practical effects of these legal reforms can be questioned. This chapter will study marriage breakups in Egypt through both legal and sociological approaches. Legal texts governing family law will first be examined to expose the different ways marriage can be broken up and how the reforms were legitimated by reference to sharî'a principles. Then the various obstacles that impede the effective implementation of these reforms will be exposed, to stress that the study of law should capture the language of law in action and not only of law in books.
The Incomplete Family: Ethnographic Explorations on Domestic Relations in Aden
Authors: Dahlgren Susanne
Published: May 2008

With the support of ethnographic material from Aden (Yemen), this chapter explores untypical family forms and residential patterns that break the normative conventions as regulated in law and reproduced in popular morality discourses. With material that extends from the late colonial era to the early 2000s, the chapter scrutinizes domestic relations in regards to the background of changes in family regulation (law and legal practice) during the course of the past fifty years. The family is analyzed as a concentration of relations of all kinds, both inside the family and in its contacts with the outside. The article raises pertinent questions about the family unit. How closed and autonomous is the family unit, actually? What outside relationships might dominate over family relations? How do matters of subsistence, translocal migration and global economies influence family patterns, maintenance arrangements and residence forms? Rather than looking at the family from a state perspective or as part of a nationalist agenda, this chapter draws the perspective from inside the family. What strengthens a family and what threatens it? Why is it that particular family forms are idealized while in practice other types might prevail? How do intimate needs, and sexual preferences and practices influence the experiences of closeness in a family? By applying practice perspective, that is, seeing household dynamics from structural and agentic perspectives complemented by agents' evaluations on the two, the article reviews critically Middle Eastern scholarship on domestic relations.
Mulier oder femina Augustinus im Streit um die richtige Bibelübersetzung
Authors: Hiltbrunner Otto
Published: May 2008

In his Sermones Augustine is often obliged to ward off misunderstandings which might arise from differences between standard Latin and the colloquial language of his listeners. This is why he opposes their wish to replace mulier with femina in the scriptures. He explains the matter as follows: it is only in popular speech that mulier means a married woman, whereas in the Bible women of any age—including the Virgin Mary—are called mulieres. Femina is a word which in Old Latin inspires reverence through its use in sacral contexts and which was preferred by poets from Augustan times onwards. Thus it is regarded as more elevated than the commoner mulier. Nevertheless, because mulier, unlike femina, agrees with Hebrew išah and Greek γυνη in being used only of human beings (though applicable to women of all ages and conditions), it remains the most appropriate Latin translation.
Evaluation of a Global Health Training Program for Pediatric Residents
Authors: Oettgen Barbara , Harahsheh Ashraf , Suresh Srinivasan , Kamat Deepak
Published: May 2008

Background: At Children's Hospital of Michigan, an international health program was initiated in 2004. Objective: To evaluate the effectiveness of the program in imparting knowledge to pediatric residents. Design/Methods: A pretest examining international health knowledge was administered to pediatric residents, and they were reexamined at the end of 1 year. Results: Out of 20 residents who participated in the study, 11 (55%) fully participated in the international health program, and the other 9 partially participated. The mean overall pretest score was 56% and posttest score was 65.8% ( P < .004). Full participant mean pretest was 57% and posttest was 69% ( P < .005). Partial participant mean pretest was 55% and posttest was 62%, no significant difference ( P = .10). Birth, medical education, residency training, or work history in a developing country did not impact pretest or posttest scores. Conclusions: Despite small numbers of participants, this evaluation suggests that knowledge in international health can be expanded through a training program.
What Drives Juvenile Probation Officers?
Authors: Ward Geoff , Kupchik Aaron
Published: May 2008

Data from surveys of juvenile court probation officers in four states are analyzed to understand professional orientations toward two seemingly contrasting goals of contemporary juvenile justice systems: punishment and treatment. These self-reported juvenile probation officer orientations are considered in relation to three clusters of variables representing somewhat distinct hypothetical bases of professional orientation: court context, decision-maker status characteristics, and resonance with legal, victim’s rights, and character issues. Although court context and status characteristics distinguish attitudes toward treatment and punishment, attitudinal resonance is an especially strong predictor of these orientations. Rather than mutually exclusive or static ideologies, treatment and punishment appear to be flexible, overlapping goals that appeal to officers according to their congruence with other personal convictions. Younger probation officers are also found to be more punitive, net of other influences, suggesting cohort replacement may accelerate the displacement of juvenile rehabilitative ideals. Implications for juvenile justice research and policy are considered.
Radius of Trust
Authors: Realo Anu , Allik Jüri , Greenfield Brenna
Published: May 2008

Countries in which people believe that “most people can be trusted” and where citizens belong to a larger number of different voluntary associations are more individualistic, emphasizing the importance of independence and freedom to choose one's own goals. The present study examines the relationship between social capital and individualism/collectivism using a measure that distinguishes between familism and institutional collectivism. Familism correlated negatively with social capital, whereas institutional collectivism practices exhibited positive associations with social capital, especially with trust and participation in voluntary organizations such as church or religious organizations and labor unions. It is concluded that in societies where trust is limited to the nuclear family or kinship alone, people have lower levels of social capital. Social capital increases as the radius of trust widens to encompass a larger number of people and social networks among whom norms of generalized reciprocity are operative.
Effectiveness of Early Phonological Awareness Interventions for Students With Speech or Language Impairments
Authors: Al Otaiba Stephanie , Puranik Cynthia S. , Ziolkowski Robyn A. , Montgomery Tricia M.
Published: May 2008

This article reviews research examining the efficacy of early phonological interventions for young students identified with speech and language impairments. Eighteen studies are included, providing results for nearly 500 students in preschool through third grade. Although findings are generally positive, there are large individual differences in response to intervention. Furthermore, there is little evidence that interventions enabled students to catch up to typically developing peers in phonological and reading skills. Methodological issues are described, and implications for practice and future research are discussed.
Harriet Martineau on the Theory and Practice of Democracy in America
Authors: Vetter Lisa Pace
Published: May 2008

The early development of American democracy was fraught with tensions arising from the need to balance unity and plurality in an increasingly diverse society. Tocqueville's Democracy in America is widely praised for its insight into these tensions and the solutions it proposes to them. Yet Tocqueville's portrayal of American culture has come under critical scrutiny for, among other things, its inability to offer a path to genuine reform when it comes to slavery and the inequality of women. By expanding on Adam Smith's moral theory of sympathy, Harriet Martineau's account of nascent American democracy in Society in America offers a more constructive view of America's ability to reconcile the needs of unity and plurality and of its capacity for democratic reform, especially regarding slavery and the inequality of women. Martineau's analysis offers valuable lessons about the ability of democratic majorities to correct moral injustices.
Restrictive Versus Promotive Control and Employee Work Outcomes: The Moderating Role of Locus of Control
Authors: Elias Steven M.
Published: May 2008

To fully understand influence as it relates to the workplace, scholars must continue to identify and measure constructs for classifying influence behavior. This study serves to promote Scholl's restrictive versus promotive control distinction and examine the relationships between such methods of influence and several work outcomes (i.e., leader—member exchange theory, commitment, job satisfaction, and turnover intentions). Data were obtained from state government employees (N = 105) located in the southeastern United States, and all hypotheses were assessed via hierarchical moderated multiple regression. Although restrictive and promotive control were related to each of the work outcomes, several relationships were moderated by employee locus of control. Theoretical and practical implications are discussed, and suggestions for future research are provided.
Health and Access to Health Care of Female Family Caregivers of Adults With Developmental Disabilities
Authors: Caldwell Joe
Published: May 2008

The physical and mental health status of women providing care to adult relatives with developmental disabilities was compared with that of the general female population in the United States. There were no differences on physical health across four age groups. However, the mental health of midlife caregivers (45—54 years of age) and older caregivers (older than 65 years) was worse than national norms. This may be associated with two key periods: transitions to adulthood of individuals with disabilities and transitions when aging caregivers are no longer able to provide care. Greater unmet needs for services contributed to poorer mental health. Poorer access to health care also contributed to poorer mental and physical health. Unmet needs for services and out-of-pocket disability-related expenses appeared to pose difficulties for working age caregivers in affording the financial costs of health care for themselves.
Using High-Probability Request Sequences to Increase Social Interactions in Young Children With Autism
Authors: Jung Sunhwa , Sainato Diane M. , Davis Carol A.
Published: May 2008

We investigated the effects of an intervention using high-probability request sequences with embedded peer modeling to increase social interactions of children with autism in a classroom. The effects of the intervention on compliant responding to social requests and social behaviors were monitored using a single-subject multiple baseline design across children. Additionally, social validity regarding the intervention goals, procedures, and outcomes was measured by relevant consumers. The results of this study indicate that all three children's compliant responding to low-probability requests and social behaviors increased with the intervention and were maintained. Furthermore, the target children's social behaviors generalized to untrained peers and nontraining settings. The social validity results indicated a high level of consumer acceptability and usability among relevant consumers.
Implementation of Positive Behavior Support With a Sibling Set in a Home Environment
Authors: Duda Michelle A. , Clarke Shelley , Fox Lise , Dunlap Glen
Published: May 2008

This study provides a demonstration of the process of positive behavior support (PBS) within a home setting to address the challenging behavior of a sibling set within family routines. Although a growing data base is demonstrating the feasibility and effectiveness of conducting functional behavioral assessment and implementing assessment-based interventions for young children in family contexts, the vast majority of these studies have focused on dyadic parent— child interactions. The presence of more than one child, particularly when all children display challenging behaviors, can amplify levels of parent stress and complicate the logistics of assessment, planning, and systematic intervention. In this study, three young children presented challenging behaviors that were highly disruptive to home routines. Functional assessments were followed by implementation of multicomponent, family-centered PBS plans individualized to four activity routines. Multiple-baseline across-routines and quasiexperimental (A-B) within-routines designs demonstrated promising effects of the interventions in reducing aggregate levels of challenging behavior.
Osseous Metaplasia of the Colon in a Diversion Proctocolitis
Authors: Billingham Kim , Radojkovic Miroslav
Published: May 2008

Osseous metaplasia within the gastrointestinal tract is a rare phenomenon, seen most frequently in mucinproducing left-sided colonic adenocarcinomas. It has also been documented in a variety of benign conditions, occurring in polyps and lesions associated with inflammation and ulceration. This is the first case report, to the authors' knowledge, of osseous metaplasia associated with a diversion proctocolitis. The diversion was performed following stricture formation, secondary to complicated diverticular disease with diverticular phlegmon formation. In common with other cases, in which osseous metaplasia arises within a background of inflammation, the present case demonstrated stromal fibroblastic proliferation. The underlying pathogenesis of osseous metaplasia has not yet been elucidated, but secretion of various bone morphogenic proteins (belonging to the transforming growth factor-β superfamily) and increased alkaline phosphatase activity by both epithelial and stromal cells have been documented.
Angiolipoma of the Thyroid Gland
Authors: Dimosthenous Kypros , Righi Alberto , Puccetti Maurizio , Lorenzini Paolo
Published: May 2008

This is a report of an angiolipoma of the thyroid gland, an extremely rare entity. A thorough search of the literature revealed only one previously reported example. The patient was a 77-year-old woman with a history of a nodular lesion of the thyroid in the context of a multinodular goiter. A fine needle aspiration highlighted the presence of abundant adipocytes associated with numerous dilated vessels. Histopathologic examination of the lobectomy specimen documented the presence of a tumor composed of two main elements, namely, mature adipocytes and proliferating vessels, some of the latter containing fibrin thrombi.
Appendiceal Granulation Polyp
Authors: Pantanowitz Liron
Published: May 2008

An appendiceal granulation polyp is an unusual polyp of the vermiform appendix. In this article, the pathology of such a polyp that developed in a 9-year-old boy with an appendicostomy is presented. These polyps may result as a complication of chronic irritation following the surgical creation of a stoma into the vermiform appendix or after appendico-vesicostomy.
Review Articles: Pathogenesis and Diagnostic Significance of Nuclear Grooves in Thyroid and Other Sites
Authors: Batistatou Anna , Scopa Chrisoula D.
Published: May 2008

Nuclear grooves are longitudinal invaginations of the nuclear envelope bilayer, which constitute a characteristic feature of papillary thyroid carcinoma. Their pathogenesis is not yet clear, but there is evidence for the involvement of a signaling pathway downstream of the protooncogene RET. The presence of nuclear grooves is not specific for papillary thyroid carcinoma because it has been documented in other types of thyroid neoplasms, in nonneoplastic thyroid lesions, in ovarian neoplasms (Brenner, adult granulosa cell, and transitional cell tumors), in breast carcinomas, in cervicovaginal and endometrial smears, in papillary neoplasms of several organs (such as papillary transitional cell carcinoma of the bladder, papillary renal cell carcinoma, papillary endometrioid carcinoma of the prostate), in thymic carcinomas, and in nonepithelial tumors.
Multicentric Basaloid Carcinoma of Lung Clinically Mimicking Metastatic Carcinoma: A Case Report
Authors: Bhagavathi Sharathkumar , Chang Chung-Ho
Published: May 2008

Basaloid carcinoma of lung is a highly aggressive form of non-small cell and non-neuroendocrine pulmonary carcinoma. It may exist in pure form or may admixed with other types of non-small cell lung carcinoma. A unique case of a multicentric basaloid carcinoma of lung is reported in this study. The patient was an 81-year-old male who was found to have 2 separate nodules of the left lung on computed tomography scan. He underwent wedge resection of both nodules. The morphology of the lesions was identical and consistent with basaloid carcinoma. Extensive workup to detect a possible extrapulmonary primary site was negative. Loss of heterozygosity studies performed on the 2 tumors were consistent with multicentric rather than metastatic nature.
Transumbilical Endoscopic Cholecystectomy With the Trichannel Trocar Technique: A Porcine Feasibility Study
Authors: Jiang Fan Zhu  , Ying Zhang Ma  , Jin Ling Yu  , Hai Hu
Published: May 2008

The aim of this study is to verify the feasibility of another option: transumbilical endoscopic cholecystectomy by using the trichannel trocar technique. Eight domestic pigs were submitted to transumbilical endoscopic cholecystectomy by using the trichannel trocar technique. A fine grasper of 2 mm in diameter was inserted through a small skin incision on the right upper abdomen for grasping the gallbladders. The natural scar of the umbilicus was restored after extract of the specimen. All the gallbladders were removed successfully without severe bleeding during dissection, intraoperative, and postoperative complications. Postmortem examination revealed that the gallbladder fossa was clean, the clips on the cystic duct and artery were secure, and neither bile nor blood leakage was found at the operative field. The feasibility and safety of transumbilical endoscopic cholecystectomy are demonstrated by this study. It is possible to use this approach in patients with gallbladder diseases.
Laparoscopic Parastomal Hernia Repair: A Description of the Technique and Initial Results
Authors: Zacharakis Emmanouil , Hettige Roland , Purkayastha Sanjay , Aggarwal Rajesh , Athanasiou Thanos , Darzi Ara , Ziprin Paul
Published: May 2008

In this study, the authors review their initial results with the laparoscopic approach for parastomal hernia repair. Between 2006 and 2007, 4 patients were treated laparoscopically at our institution. The hernia sac was not excised. A piece of Gore-Tex DualMesh with a central keyhole and a radial incision was cut so that it could provide at least 3 to 5 cm of overlap of the fascial defect. The mesh was secured to the margins of the hernia with circumferential metal tacking and trans-fascial sutures. No complications occurred in the postoperative period. After a median follow-up of 9 months, recurrence occurred in 1 patient. This was our first patient in whom mesh fixation was performed only with circumferential metal tacking. The laparoscopic repair of parastomal hernias seems to be a safe, feasible and promising technique offering the advantages of minimally-invasive surgery. The success of this approach depends on longer follow-up reports and standardization of the technical elements.
Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia
Authors: Libani Ilaria V. , Guy Ella C. , Melchiori Luca , Schiro Raffaella , Ramos Pedro , Breda Laura , Scholzen Thomas , Chadburn Amy , Liu YiFang , Kernbach Margrit , Baron-Lühr Bettina , Porotto Matteo , de Sousa Maria , Rachmilewitz Eliezer A. , Hood John D. , Cappellini M. Domenica , Giardina Patricia J. , Grady Robert W. , Gerdes Johannes , Rivella Stefano
Published: May 2008

In β-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by β-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle–promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-XL. The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder.
Accuracy and reliability of pulse oximetry at different arterial carbon dioxide pressure levels
Authors: Muñoz X. , Torres F. , Sampol G. , Rios J. , Martí S. , Escrich E.
Published: May 2008

The present study aimed to assess whether arterial carbon dioxide pressure (Pa,CO2) has an impact on agreement between oxygen saturation measured with pulse oximetry (Sp,O2) or arterial blood gas co-oximetry (Sa,O2).

Sa,O2andSp,O2determinations were obtained simultaneously from 846 patients under assessment for long-term home oxygen therapy in a specialised outpatient clinic. Both measurements were taken with patients seated and breathing room air.

Agreement betweenSa,O2andSp,O2results was analysed by the Bland–Altman method and the Lin concordance coefficient. In addition, potential interactions of arterial oxygen tension (Pa,O2) orPa,CO2on agreement were analysed by adjusted multivariate analysis.

Upon comparison ofSa,O2andSp,O2results, the Bland–Altman technique yielded a bias (95% confidence interval (CI)) of -1.24 (-6.86–4.38) and -1.32 (-7.78–5.15) when Pa,CO2>48 mmHg (6.39 kPa) orPa,O2<54 mmHg (7.20 kPa), respectively. Estimate by Lin's coefficient (95% CI) in these cases was 0.88 (0.85–0.90) and 0.81 (0.77–0.85). Adjusted multivariate analysis, performed to assess the impact of pH,Pa,O2,Pa,CO2and bicarbonate on bias, showed thatPa,O2,Pa,CO2and their interaction terms were the most important predictors of the bias (standardised estimates of -0.54, -0.94, and 0.85, respectively). The effect of pH, although statistically significant, was small, and bicarbonate had no significant effect.

Arterial carbon dioxide pressure status can contribute to impaired agreement between arterial oxygen saturation and arterial oxygen saturation measured with pulse oximetry, particularly in patients with hypercapnia.
Bacterial cyanogenesis occurs in the cystic fibrosis lung
Authors: Sanderson K. , Wescombe L. , Kirov S. M. , Champion A. , Reid D. W.
Published: May 2008

The cystic fibrosis (CF) lung environment is poorly defined, but data suggest that bacteria may encounter reduced oxygen tensions and possibly an anaerobic environment.Pseudomonas aeruginosaproduces the potent toxin cyanide under strictly microaerobic conditions. Evidence of bacterial cyanogenesis in the CF lung was investigated in the present study by measuring sputum cyanide concentrations.

Sputum cyanide was measured in seven stable CF patients, as well as before and after intravenous antibiotic therapy during a hospital admission in a further eight patients experiencing acute exacerbations. All patients were chronically infected withP. aeruginosa. Comparative sputum data were obtained from nine CF patients with no documentedP. aeruginosainfection and 10 healthy, nonsmoking normal controls.

High levels of cyanide were detected in all theP. aeruginosa-infected stable CF patients (median (range) 0.56 (0.37–2.81) μg·mL−1), and in seven out of eight acute sputum samples (0.73 (0–1.43) μg·mL−1). In contrast, cyanide was not detectable in sputum from eight out of nine CF patients withoutP. aeruginosainfection or in any of the normal controls. Intravenous antibiotic treatment significantly reduced sputum cyanide levels (median 0.73 to median 0.0 µg·mL−1).

The cyanide detected indicates that the cystic fibrosis lung provides a predominantly microaerobic environment forPseudomonas aeruginosa. Cyanide is likely to be a potentially important virulence factor inPseudomonas aeruginosa-infected cystic fibrosis patients.
Efficacy and safety of a subacromial continuous ropivacaine infusion for post-operative pain management following arthroscopic rotator cuff surgery: A protocol for a randomised double-blind placebo-controlled trial
Authors: Coghlan Jennifer A , Forbes Andrew , Bell Simon N , Buchbinder Rachelle
Published: May 2008

Background

Major shoulder surgery often results in severe post-operative pain and a variety of interventions have been developed in an attempt to address this. The continuous slow infusion of a local anaesthetic directly into the operative site has recently gained popularity but it is expensive and as yet there is little conclusive evidence that it provides additional benefits over other methods of post-operative pain management.

Methods/Design

This will be a randomised, placebo-controlled trial involving 158 participants. Following diagnostic arthroscopy, all participants will undergo arthroscopic subacromial decompression with or without rotator cuff repair, all operations performed by a single surgeon. Participants, the surgeon, nurses caring for the patients and outcome assessors will be blinded to treatment allocation. All participants will receive a pre-incision bolus injection of 20 mls of ropivacaine 1% into the shoulder and an intra-operative intravenous bolus of parecoxib 40 mg. Using concealed allocation participants will be randomly assigned to active treatment (local anaesthetic ropivacaine 0.75%) or placebo (normal saline) administered continuously into the subacromial space by an elastomeric pump at 5 mls per hour post-operatively. Patient controlled opioid analgesia and oral analgesics will be available for breakthrough pain. Outcome assessment will be at 15, 30 and 60 minutes, 2, 4, 8, 12, 18 and 24 hours, and 2 or 4 months for decompression or decompression plus repair respectively.

The primary end point will be average pain at rest over the first 12-hour post-operative period on a verbal analogue pain score. Secondary end points will be average pain at rest over the second 12-hour post-operative period, maximal pain at rest over the first and second 12-hour periods, amount of rescue medication used, length of inpatient stay and incidence of post-operative adhesive capsulitis.

Discussion

The results of this trial will contribute to evidence-based recommendations for the effectiveness of pain management modalities following arthroscopic rotator cuff surgery. If the local anaesthetic pain-buster provides no additional benefits over placebo then valuable resources can be put to better use in other ways.

Trial registration

Australian Clinical Trials Register Number ACTR12606000195550
Molecular analysis of the bovine anaphylatoxin C5a receptor
Authors: Nemali Sailasree , Siemsen Daniel W , Nelson Laura K , Bunger Peggy L , Faulkner Craig L , Rainard Pascal , Gauss Katherine A , Jutila Mark A , Quinn Mark T
Published: May 2008

Recruitment of phagocytes to inflammatory sites involves the coordinated action of several chemoattractants, including the anaphylatoxin C5a. While the C5a receptor (C5aR) has been well characterized in humans and rodents, little is known about the bovine C5aR. Here, we report cloning of bovine C5R1, the gene encoding bovine C5aR. We also analyzed genomic sequence upstream of the C5R1 translation start site. Although the bovine C5aR amino acid sequence was well conserved among species, significant differences in conserved features were found, including major differences in the N terminus, intracellular loop 3, and transmembrane domain VII. Analysis of C5aR expression by flow cytometry and confocal microscopy demonstrated high levels of C5aR on all bovine neutrophils and a subset of bovine monocytes. C5aR was not expressed on resting or activated bovine lymphocytes, although C5aR message was present in these cells. C5aR was also expressed on a small subset of bovine mammary epithelial cells. Pharmacological analysis of bovine C5aR-mediated responses showed that bovine C5a and C5adesArg both induced dose-dependent calcium fluxes and chemotaxis in bovine neutrophils, with similar efficacy for both agonists. Treatment of bovine neutrophils with C5a or C5adesArg resulted in homologous desensitization of bovine C5aR and cross-desensitization to interleukin 8 (IL-8) and platelet-activating factor (PAF); whereas, treatment with IL-8 or PAF did not cross-desensitize the cells to C5a or C5adesArg. Overall, these studies provide important information regarding distinct structural and functional features that may contribute to the unique pharmacological properties of bovine C5aR.
Chemotherapy Dosing Strategies in the Obese, Elderly, and Thin Patient: Results of a Nationwide Survey
Authors: Field Kathryn M. , Kosmider Suzanne , Jefford Michael , Michael Michael , Jennens Ross , Green Michael , Gibbs Peter
Published: May 2008

Purpose

Determining the optimal starting dose of chemotherapy (CHT) presents a considerable challenge when using body-surface area (BSA)–based dosing, particularly in obese, elderly, or thin patients. We sought to document the range of approaches employed when administering CHT to these patients.

Methods

A questionnaire was developed by a panel of oncologists and mailed to all members of the Medical Oncology Group of Australia.

Results

From 315 oncologists, 188 responded (response rate 59.7%). BSA-based dosing is standard practice for 176 (97.2%) of the responding oncologists. In the adjuvant disease setting, 23 (12.7%) use ideal rather than actual body weight (BW) to calculate BSA, or choose whichever is less. When treating obese patients, only 6.1% of respondents routinely use actual BW. Of the remainder, 69.5% either cap the dose at 2 m2 or use ideal BW. In underweight patients, 95% (n = 171) routinely calculate BSA using actual BW. Forty one respondents (22.7%) routinely reduce dose in the fit elderly.

Conclusion

This analysis of BSA-based CHT dosing methods demonstrates significant variability in practice. Based on evidence from adjuvant studies showing that actual BSA-based dosing is desirable, a substantial number of Australian patients are being underdosed. Further education, together with ongoing research, is required to optimize individualized dosing for efficacy and tolerability.
Tracheal branching morphogenesis inDrosophila: new insights into cell behaviour and organ architecture
Authors: Affolter Markus , Caussinus Emmanuel
Published: May 2008

Our understanding of the molecular control of morphological processes has increased tremendously over recent years through the development and use of high resolution in vivo imaging approaches, which have enabled cell behaviour to be linked to molecular functions. Here we review how such approaches have furthered our understanding of tracheal branching morphogenesis in Drosophila, during which the control of cell invagination, migration,competition and rearrangement is accompanied by the sequential secretion and resorption of proteins into the apical luminal space, a vital step in the elaboration of the trachea's complex tubular network. We also discuss the similarities and differences between flies and vertebrates in branched organ formation that are becoming apparent from these studies.
Expression of multiple slow myosin heavy chain genes reveals a diversity of zebrafish slow twitch muscle fibres with differing requirements for Hedgehog and Prdm1 activity
Authors: Elworthy Stone , Hargrave Murray , Knight Robert , Mebus Katharina , Ingham Philip W.
Published: May 2008

The zebrafish embryo develops a series of anatomically distinct slow twitch muscle fibres that characteristically express genes encoding lineage-specific isoforms of sarcomeric proteins such as MyHC and troponin. We show here that different subsets of these slow fibres express distinct members of a tandem array of slow MyHC genes. The first slow twitch muscle fibres to differentiate, which are specified by the activity of the transcription factor Prdm1 (also called Ubo or Blimp1) in response to Hedgehog (Hh) signalling,express the smyhc1 gene. Subsequently, secondary slow twitch fibres differentiate in most cases independently of Hh activity. We find that although some of these later-forming fibres also express smyhc1,others express smyhc2 or smyhc3. We show that the smyhc1-positive fibres express the ubo (prdm1) gene and adopt fast twitch fibre characteristics in the absence of Prdm1 activity,whereas those that do not express smyhc1 can differentiate independently of Prdm1 function. Conversely, some smyhc2-expressing fibres, although independent of Prdm1 function, require Hh activity to form. The adult trunk slow fibres express smyhc2 and smyhc3, but lack smyhc1 expression. The different slow fibres in the craniofacial muscles variously express smyhc1, smyhc2 and smyhc3, and all differentiate independently of Prdm1.
Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling
Authors: Blaess Sandra , Stephen Daniel , Joyner Alexandra L.
Published: May 2008

The coordination of anterior-posterior (AP) and dorsal-ventral (DV)patterning of the mesencephalon (mes) and rhombomere 1 (r1) is instrumental for the development of three distinct brain structures: the tectum and cerebellum dorsally and the tegmentum ventrally. Patterning of the mes/r1 is primarily mediated by signaling molecules secreted from two organizers: sonic hedgehog (Shh) from the floor plate (DV) and Fgf8 from the isthmus (AP). Gli3,a zinc-finger transcription factor in the Shh signaling pathway, has been implicated in regulating Fgf8 expression and is therefore a potential candidate for coordinating the action of the two organizers. By inactivating mouse Gli3 at successive embryonic time points in vivo, we uncovered the extent and the underlying mechanism of Gli3 function in the mes/r1. We demonstrate that before E9.0, Gli3 is required for establishing a distinct posterior tectum, isthmus and cerebellum, but does not play a role in the development of the tegmentum. Between E9.0 and E11.0, Gli3continues to be required for isthmus and cerebellum development, but primarily for defining the cerebellar foliation pattern. We show that Gli3regulates patterning of the isthmus and cerebellar anlage by confining Fgf8 expression to the isthmus, and attenuates growth of dorsal r1(before E11.0) and the dorsal mes and isthmus (beyond E11.0) through regulation of cell proliferation and viability. In conclusion, our results show that Gli3 is essential for the coordinated three-dimensional patterning and growth of the dorsal mes/r1.