bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraoperative Coil Embolization Reduces Transplant Nephrectomy Transfusion Requirement
Authors: Neschis David G. , Gutta Rao , Al-Qudah Hosam S. , Bartlett Stephen T. , Philosophe Benjamin , Schweitzer Eugene J. , Flinn William R. , Campos Luis
Published: August 2007

Transplant nephrectomy for failed renal transplants can be challenging. Patients often have numerous comorbidities, and the procedure may be associated with considerable blood loss. This study was performed to determine if intraoperative coil embolization of the transplant renal artery reduces blood loss associated with transplant nephrectomy. Data were collected retrospectively on 13 consecutive transplant nephrectomies performed immediately following coil embolization and compared with the 13 most recently performed consecutive transplant nephrectomies without coil embolization. The groups were compared for operative time, estimated blood loss, and transfusion requirements. Mean age was 45 in both groups. There were no major complications in either group. Operative times were not significantly different, although open operative time was reduced in the embolization group (113 vs 96 minutes). Estimated blood loss was 465 mL versus 198 mL ( P = .035); packed red blood cell requirements during the operation and subsequent 48 hours were 1.85 units versus 0.31 units ( P = .008) and during the operation and subsequent hospital stay were 2.3 units versus 0.69 units ( P = .027) in the nonembolized group and embolized group, respectively. Intraoperative embolization of the transplant renal artery immediately prior to surgery facilitates transplant nephrectomy by significantly reducing intraoperative blood loss and transfusion requirements while slightly reducing open operative time.
Endovascular Repair of Cervical Aortic Arch Aneurysm
Authors: Barbee Jacob P. , Stevens Scott L. , Gaines Thomas E. , Gash Judson R.
Published: August 2007

Cervical aortic arch (CAA) is a rare congenital anomaly of the aortic arch. Rarely, CAA is associated with aneurysm of the arch and great vessels. A 32-year-old male patient, previously in good health, presented with 2 weeks of severe chest pain. Radiographic evaluation revealed a CAA with aneurysmal dilation of the distal aortic arch. The aneurysm extended into the left subclavian artery. There was also marked angulation just distal to the aneurysmal portion. The aneurysmal arch and subclavian artery were repaired using a thoracic aortic endograft. An open axillary-to-axillary bypass was performed, and the left axillary artery was ligated proximally. This restored perfusion to the left upper extremity and effectively excluded the aneurysm sac. Immediately postoperatively, the patient's chest pain resolved, and he has remained symptom free. To the authors' knowledge, this is the first reported repair of a cervical arch aneurysm by endovascular technique.
Strategic Simulations and Our Past
Authors: Schut Kevin
Published: August 2007

Many popular digital games have historical themes or settings. Taking its cue from recent research emphasizing the educational value of computer and video games, this article investigates the bias of the medium in presenting history. Although sharing an appreciation for the cultural value of history simulations and games, the author argues that the digital game medium currently tends to result in stereotypically masculine, mechanical, and spatially oriented interactive presentations of history. This article does not take a technological determinist stance nor a simplistic view of interpretation. Nevertheless, the author believes that the weight and momentum of the historical development of the digital game medium, its technological structure, and its institutional character have encouraged certain patterns in digital games that should be critically examined.
Digital Game Involvement
Authors: Calleja Gordon
Published: August 2007

This article proposes a conceptual model for understanding game involvement and immersion on a variety of experiential dimensions corresponding to six broad categories of game features. The article ends with a proposal to replace the metaphor of immersion with one of incorporation. This reconceptualization seeks to replace the unidirectional plunge of player into game space implied by the term immersion with one of simultaneous assimilation of the digital environment and presence to others within it.
Serum cytokeratin-18 fragments as quantitative markers of epithelial apoptosis in liver and intestinal graft-versus-host disease
Authors: Luft Thomas , Conzelmann Michael , Benner Axel , Rieger Michael , Hess Michael , Strohhaecker Ulrich , Görner Martin , Hegenbart Ute , Ho Anthony D. , Dreger Peter
Published: August 2007

Graft-versus-host disease (GVHD) is the main complication of allogeneic stem cell transplantation. However, diagnosis of GVHD and evaluation of response to immunosuppressive treatment is sometimes difficult. Since apoptosis is the histopathologic hallmark in GVHD, we investigated whether active GVHD-induced target organ destruction is mirrored by serum levels of the caspase-cleaved neo-epitope of cytokeratin-18 fragments (CK18Fs). Serum CK18F kinetics was monitored by M30 antibody-based enzyme-linked immunosorbent assay (ELISA) in 50 patients who fulfilled histopathologic and/or clinical criteria diagnostic for GVHD. Both intestinal and hepatic GVHD were consistently associated with significant elevations of CK18F levels over baseline. Responses of GVHD to immunosuppressive therapy were paralleled by CK18F decreases, whereas resistant GVHD was characterized by persistent CK18F rises. Clinical conditions that might represent relevant differential diagnoses, such as toxic mucositis, noncomplicated, infection-related diarrhea, and veno-occlusive disease were not associated with CK18F elevations. In conclusion, CK18F monitoring provides a serum marker for quantitative assessment of GVHD-associated apoptotic activity in intestinal and hepatic GVHD. Although apoptosis is not GVHD-specific, CK18Fs may help to distinguish active GVHD from GVHD-unrelated conditions with similar symptoms, and to monitor response to immunosuppressive treatment. Prospective studies are warranted to evaluate how CK18Fs may assist in the diagnosis, grading, and treatment guidance of GVHD.
Increased TSLP availability restores T- and B-cell compartments in adult IL-7–deficient mice
Authors: Chappaz Stephane , Flueck Lukas , Farr Andrew G. , Rolink Antonius G. , Finke Daniela
Published: August 2007

Interleukin 7 (IL-7) plays a crucial role in adult lymphopoiesis, while in fetal life its effect can be partially compensated by TSLP. Whether adult hematopoietic progenitor cells are unresponsive to TSLP or whether TSLP is less available in adult microenvironments is still a matter of debate. Here, we show that increased TSLP availability through transgene (Tg) expression fully restored lymphopoiesis in IL-7–deficient mice: it rescued B-cell development, increased thymic and splenic cellularities, and restored double-negative (DN) thymocytes, αβ and γδ T-cell generation, and all peripheral lymphoid compartments. Analysis of bone marrow chimeras demonstrated that hematopoietic progenitor cells from adult wild-type mice efficiently differentiated toward B- and T-cell lineages in lethally irradiated IL-7 deficient mice provided TSLP Tg was expressed in these mice. In vitro, TSLP promoted the differentiation of uncommitted adult bone marrow progenitors toward B and T lineages and the further differentiation of DN1 and DN2 thymocytes. Altogether, our results show that adult hematopoietic cells are TSLP responsive and that TSLP can sustain long-term adult lymphopoiesis.
Establishment of transplantable porcine tumor cell lines derived from MHC- inbred miniature swine
Authors: Cho Patricia S. , Lo Diana P. , Wikiel Krzysztof J. , Rowland Haley C. , Coburn Rebecca C. , McMorrow Isabel M. , Goodrich Jennifer G. , Arn J. Scott , Billiter Robert A. , Houser Stuart L. , Shimizu Akira , Yang Yong-Guang , Sachs David H. , Huang Christene A.
Published: August 2007

The lack of transplantable tumors has limited assessment of graft-versus-tumor effects following hematopoietic cell transplantation in clinically relevant large-animal models. We describe the derivation and characterization of porcine tumor cell lines with initial efforts of tumor transplantation using immunocompromised mice and highly inbred sublines of Massachusetts General Hospital major histocompatibility complex (MHC)–inbred miniature swine. Autopsies were performed routinely on swine that died unexpectedly or had suspicion of malignancy based on clinical symptoms or peripheral blood analysis. Tissue samples were obtained for pathology, phenotyped by flow cytometry, and placed in culture. Based on growth, lines were selected for passage into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice and miniature swine. Porcine tumor recipients were preconditioned with total body irradiation from 0 to 500 cGy or with a 30-day course of oral cyclosporine. We identified 19 cases of hematologic tumors. Nine distinct tumor cell lines were established from 8 of these cases, including 3 derived from highly inbred sublines. In vivo tumor growth and serial transfer were observed in immunocompromised mice for one tumor cell line and in miniature swine for 1 of 2 tumor cell lines expanded for this purpose. These results suggest the possibility of developing a transplantable tumor model in this large-animal system.
Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria
Authors: Hillmen Peter , Muus Petra , Dührsen Ulrich , Risitano Antonio M. , Schubert Jörg , Luzzatto Lucio , Schrezenmeier Hubert , Szer Jeffrey , Brodsky Robert A. , Hill Anita , Socié Gerard , Bessler Monica , Rollins Scott A. , Bell Leonard , Rother Russell P. , Young Neal S.
Published: August 2007

Hemolysis and hemoglobinemia contribute to serious clinical sequelae in hemolytic disorders. In paroxysmal nocturnal hemoglobinuria (PNH) patients, hemolysis can contribute to thromboembolism (TE), the most feared complication in PNH, and the leading cause of disease-related deaths. We evaluated whether long-term treatment with the complement inhibitor eculizumab reduces the rate of TE in patients with PNH. Clinical trial participants included all patients in the 3 eculizumab PNH clinical studies, which recruited patients between 2002 and 2005 (n = 195); patients from these studies continued treatment in the current multinational open-label extension study. Thromboembolism rate with eculizumab treatment was compared with the pretreatment rate in the same patients. The TE event rate with eculizumab treatment was 1.07 events/100 patient-years compared with 7.37 events/100 patient-years (P < .001) prior to eculizumab treatment (relative reduction, 85%; absolute reduction, 6.3 TE events/100 patient-years). With equalization of the duration of exposure before and during treatment for each patient, TE events were reduced from 39 events before eculizumab to 3 events during eculizumab (P < .001). The TE event rate in antithrombotic-treated patients (n = 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P < .001). These results show that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH. This study is registered at http://clinicaltrials.gov (study ID no. NCT00122317).
The pathogen recognition sensor, NOD2, is variably expressed in patients with pulmonary tuberculosis
Authors: Lala Sanjay , Dheda Keertan , Chang Jung-Su , Huggett Jim F , Kim Louise U , Johnson Margaret A , Rook Graham AW , Keshav Satish , Zumla Alimuddin
Published: August 2007

Background

NOD2, an intracellular pathogen recognition sensor, modulates innate defences to muropeptides derived from various bacterial species, including Mycobacterium tuberculosis (MTB). Experimentally, NOD2 attenuates two key putative mycobactericidal mechanisms. TNF-α synthesis is markedly reduced in MTB-antigen stimulated-mononuclear cells expressing mutant NOD2 proteins. NOD2 agonists also induce resistance to apoptosis, and may thus facilitate the survival of MTB in infected macrophages. To further define a role for NOD2 in disease pathogenesis, we analysed NOD2 transcriptional responses in pulmonary leucocytes and mononuclear cells harvested from patients with pulmonary tuberculosis (PTB).

Methods

We analysed NOD2 mRNA expression by real-time polymerase chain-reaction in alveolar lavage cells obtained from 15 patients with pulmonary tuberculosis and their matched controls. We compared NOD2 transcriptional responses, in peripheral leucocytes, before and after anti-tuberculous treatment in 10 patients. In vitro, we measured NOD2 mRNA levels in MTB-antigen stimulated-mononuclear cells.

Results

No significant differences in NOD2 transcriptional responses were detected in patients and controls. In some patients, however, NOD2 expression was markedly increased and correlated with toll-like-receptor 2 and 4 expression. In whole blood, NOD2 mRNA levels increased significantly after completion of anti-tuberculosis treatment. NOD2 expression levels did not change significantly in mononuclear cells stimulated with mycobacterial antigens in vitro.

Conclusion

There are no characteristic NOD2 transcriptional responses in PTB. Nonetheless, the increased levels of NOD2 expression in some patients with severe tuberculosis, and the increases in expression levels within peripheral leucocytes following treatment merit further studies in selected patient and control populations.
PPARα L162V underlies variation in serum triglycerides and subcutaneous fat volume in young males
Authors: Uthurralt Julieta , Gordish-Dressman Heather , Bradbury Meg , Tesi-Rocha Carolina , Devaney Joseph , Harmon Brennan , Reeves Erica K , Brandoli Cinzia , Hansen Barbara C , Seip Richard L , Thompson Paul D , Price Thomas B , Angelopoulos Theodore J , Clarkson Priscilla M , Moyna Niall M , Pescatello Linda S , Visich Paul S , Zoeller Robert F , Gordon Paul M , Hoffman Eric P
Published: August 2007

Background

Of the five sub-phenotypes defining metabolic syndrome, all are known to have strong genetic components (typically 50–80% of population variation). Studies defining genetic predispositions have typically focused on older populations with metabolic syndrome and/or type 2 diabetes. We hypothesized that the study of younger populations would mitigate many confounding variables, and allow us to better define genetic predisposition loci for metabolic syndrome.

Methods

We studied 610 young adult volunteers (average age 24 yrs) for metabolic syndrome markers, and volumetric MRI of upper arm muscle, bone, and fat pre- and post-unilateral resistance training.

Results

We found the PPARα L162V polymorphism to be a strong determinant of serum triglyceride levels in young White males, where carriers of the V allele showed 78% increase in triglycerides relative to L homozygotes (LL = 116 ± 11 mg/dL, LV = 208 ± 30 mg/dL; p = 0.004). Men with the V allele showed lower HDL (LL = 42 ± 1 mg/dL, LV = 34 ± 2 mg/dL; p = 0.001), but women did not. Subcutaneous fat volume was higher in males carrying the V allele, however, exercise training increased fat volume of the untrained arm in V carriers, while LL genotypes significantly decreased in fat volume (LL = -1,707 ± 21 mm3, LV = 17,617 ± 58 mm3 ; p = 0.002), indicating a systemic effect of the V allele on adiposity after unilateral training. Our study suggests that the primary effect of PPARα L162V is on serum triglycerides, with downstream effects on adiposity and response to training.

Conclusion

Our results on association of PPARα and triglycerides in males showed a much larger effect of the V allele than previously reported in older and less healthy populations. Specifically, we showed the V allele to increase triglycerides by 78% (p = 0.004), and this single polymorphism accounted for 3.8% of all variation in serum triglycerides in males (p = 0.0037).
Lessons learned from the initial sequencing of the pig genome: comparative analysis of an 8 Mb region of pig chromosome 17
Authors: Hart Elizabeth A , Caccamo Mario , Harrow Jennifer L , Humphray Sean J , Gilbert James GR , Trevanion Steve , Hubbard Tim , Rogers Jane , Rothschild Max F
Published: August 2007

Background

We describe here the sequencing, annotation and comparative analysis of an 8 Mb region of pig chromosome 17, which provides a useful test region to assess coverage and quality for the pig genome sequencing project. We report our findings comparing the annotation of draft sequence assembled at different depths of coverage.

Results

Within this region we annotated 71 loci, of which 53 are orthologous to human known coding genes. When compared to the syntenic regions in human (20q13.13-q13.33) and mouse (chromosome 2, 167.5 Mb-178.3 Mb), this region was found to be highly conserved with respect to gene order. The most notable difference between the three species is the presence of a large expansion of zinc finger coding genes and pseudogenes on mouse chromosome 2 between Edn3 and Phactr3 that is absent from pig and human. All of our annotation has been made publicly available in the Vertebrate Genome Annotation browser, VEGA. We assessed the impact of coverage on sequence assembly across this region and found, as expected, that increased sequence depth resulted in fewer, longer contigs. One-third of our annotated loci could not be fully re-aligned back to the low coverage version of the sequence, principally because the transcripts are fragmented over several contigs.

Conclusion

We have demonstrated the considerable advantages of sequencing at increased read depths and discuss the implications that lower coverage sequence may have on subsequent comparative and functional studies, particularly those involving complex loci such as GNAS.
The impact of chromatin modifiers on the timing of locus replication in mouse embryonic stem cells
Authors: Jørgensen Helle F , Azuara Véronique , Amoils Shannon , Spivakov Mikhail , Terry Anna , Nesterova Tatyana , Cobb Bradley S , Ramsahoye Bernard , Merkenschlager Matthias , Fisher Amanda G
Published: August 2007

Background

The time of locus replication during S-phase is tightly regulated and correlates with chromatin state. Embryonic stem (ES) cells have an unusual chromatin profile where many developmental regulator genes that are not yet expressed are marked by both active and repressive histone modifications. This poised or bivalent state is also characterized by locus replication in early S-phase in ES cells, while replication timing is delayed in cells with restricted developmental options.

Results

Here we used a panel of mutant mouse ES cell lines lacking important chromatin modifiers to dissect the relationship between chromatin structure and replication timing. We show that temporal control of satellite DNA replication is sensitive to loss of a variety of chromatin modifiers, including Mll, Eed, Dnmt1, Suv39h1/h2 and Dicer. The replication times of many single copy loci, including a 5 Mb contiguous region surrounding the Rex1 gene, were retained in chromatin modifier mutant ES cells, although a subset of loci were affected.

Conclusion

This analysis demonstrates the importance of chromatin modifiers for maintaining correct replication of satellite sequences in pluripotent ES cells and highlights the sensitivity of some single copy loci to the influence of chromatin modifiers. Abundant histone acetylation is shown to correlate well with early replication. Surprisingly, loss of DNA methylation or histone methylation was tolerated by many loci, suggesting that these modifications may be less influential for the timing of euchromatin replication.
Ototoxicity in a Randomized Phase III Trial of Intra-Arterial Compared With Intravenous Cisplatin Chemoradiation in Patients With Locally Advanced Head and Neck Cancer
Authors: Zuur Charlotte L. , Simis Yvonne J. , Lansdaal Pauline E. , Hart Augustinus A. , Schornagel Jan H. , Dreschler Wouter A. , Rasch Coen R. , Balm Alfons J.
Published: August 2007

Purpose

Cisplatin concomitantly administered with radiotherapy is increasingly used in locally advanced head and neck squamous cell carcinoma. We aimed to compare the incidence of hearing loss between patients treated with intra-arterial high-dose cisplatin chemoradiation with sodium thiosulfate (CRT-IA) and intravenous high-dose cisplatin chemoradiation without sodium thiosulfate (CRT-IV).

Patients and Methods

We conducted a prospective analysis of hearing thresholds at low and (ultra-) high frequencies obtained before, during, and after treatment in 158 patients. Patients were randomly assigned for either CRT-IA (150 mg/m2, four courses) with sodium thiosulfate cisplatin neutralization or CRT-IV (100 mg/m2, three courses) without rescue. All patients received concomitant radiation therapy (RT; 70 Gy).

Results

CRT-IA resulted in approximately 10% less hearing loss at frequencies vital for speech perception, compared with CRT-IV (P < .001). In CRT-IA, fewer ears qualified for hearing aids (36% v 49%; P = .03). However, in both treatment arms, the incidence expressed in National Cancer Institute Common Terminology Criteria of Adverse Events (version 3) did not deviate (P > .14). Age, cumulative cisplatin dose, cumulative RT dose, and the considered frequency area determine the degree of hearing loss (P < .001). Cisplatin induced increasing hearing loss of 24% to 60% with increasing frequencies. RT induced hearing loss at speech frequencies of 9% to 12%.

Conclusion

Depending on the criteria used to assess hearing loss due to treatment, differences in ototoxicity between CRT-IA and CRT-IV were found in favor of CRT-IA. It is desirable to specify hearing loss criteria toward frequencies vital for speech perception, and to refine grading scales to reveal subtle and clinically relevant dissimilarities in ototoxicity between different treatment protocols.
How Often Do BRCA Mutation Carriers Tell Their Young Children of the Family's Risk for Cancer? A Study of Parental Disclosure of BRCA Mutations to Minors and Young Adults
Authors: Bradbury Angela R. , Dignam James J. , Ibe Comfort N. , Auh Sogyong L. , Hlubocky Fay J. , Cummings Shelly A. , White Melody , Olopade Olufunmilayo I. , Daugherty Christopher K.
Published: August 2007

Purpose

Predictive genetic testing for adult-onset diseases is generally discouraged until the age at which interventions are believed to be helpful. Yet, many BRCA mutation carriers discuss their results with their children. This study describes the prevalence and experiences of parental communication of BRCA results to children under the age of 25 years old.

Patients and Methods

Forty-two BRCA mutation carriers completed semistructured telephone interviews assessing self-reported disclosure to offspring and parent experiences with disclosure. Qualitative responses were coded for themes. χ2 tests and logistic regression analyses with robust variance estimates were used to evaluate parent and child characteristics associated with disclosure.

Results

Fifty-five percent of parents reported discussing hereditary risk of cancer with at least one child. By parent report, 49% of the 86 offspring learned of their parents genetic test results or the hereditary cancer risk. Offspring age was strongly associated with disclosure (P = .001), and the majority of adolescent and adult children learned of the familial mutation or the hereditary risk of cancer. Parents reported that some offspring did not appear to understand the significance of the information shared, and that some offspring had initial negative reactions to disclosure. Physician (14%) and genetic counselor (21%) involvement in parent decisions to disclose were low.

Conclusion

Children of BRCA mutation carriers learn of their parents genetic test results many years before preventive interventions are indicated. Further research is needed to examine how young individuals understand this information and its psychosocial impact and influence on subsequent lifestyle and health behaviors.
Behavioral and Social Outcomes in Adolescent Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
Authors: Schultz Kris Ann P. , Ness Kirsten K. , Whitton John , Recklitis Christopher , Zebrack Brad , Robison Leslie L. , Zeltzer Lonnie , Mertens Ann C.
Published: August 2007

Purpose

Adolescents, regardless of medical history, may face behavioral and social challenges. Cancer and related treatments represent additional challenges for teens navigating the transition from childhood to adulthood. This study was conducted to evaluate behavioral and social outcomes of adolescent childhood cancer survivors using data from the Childhood Cancer Survivor Study.

Patients and Methods

We evaluated 2,979 survivors and 649 siblings of cancer survivors to determine the incidence of difficulty in six behavioral and social domains (depression/anxiety, headstrong, attention deficit, peer conflict/social withdrawal, antisocial behaviors, and social competence). Outcomes were determined by calculating parent-reported scores to questions from the behavior problem index.

Results

Survivors and siblings were similar in age at the time of interview (mean: 14.8, survivors; 14.9, siblings; range, 12 to 17 years). Overall, multivariate analyses showed that survivors were 1.5 times (99% CI, 1.1 to 2.1) more likely than siblings to have symptoms of depression/anxiety and 1.7 times (99% CI, 1.3 to 2.2) more likely to have antisocial behaviors. Scores in the depression/anxiety, attention deficit, and antisocial domains were significantly elevated in adolescents treated for leukemia or CNS tumors when compared with siblings. In addition, survivors of neuroblastoma had difficulty in the depression/anxiety and antisocial domains. Treatments with cranial radiation and/or intrathecal methotrexate were specific risk factors.

Conclusion

Adolescent survivors of childhood cancer, especially those with a history of leukemia, CNS tumors, or neuroblastoma, may be at increased risk for adverse behavioral and social outcomes. Increased surveillance of this population, in combination with development of interventional strategies, should be a priority.
A Turning Point for Conflicts of Interest: The Controversy Over the National Academy of Sciences' First Conflicts of Interest Disclosure Policy
Authors: Parascandola Mark
Published: August 2007

Conflicts of interest policies have become a part of the fabric of the conduct of biomedical research, yet such concerns are relatively recent history. Until the 1960s, concerns about conflicts of interest were confined to scientists who served as government advisors and contractors. However, in the 1970s, as a range of environmental and consumer safety issues gained public attention, the conclusions of researchers frequently came under attack because of concerns about experts' financial ties to private industry. These debates typically focused on evaluating potential carcinogens in the environment. In response, the National Academy of Sciences (NAS) developed its first conflict of interest policy, requiring committee members to disclose any “potential sources of bias” that “others might deem prejudicial.” Scientists universally opposed the policy, however, for a range of reasons—while some argued that all experienced and knowledgeable experts were inherently conflicted, others were offended at the suggestion that any expert could be biased. Despite the controversy, the disclosure policy remained in place and became a model for subsequent professional and institutional policies in the biomedical sciences. However, although disclosure policies have become standard at academic medical centers and for publications in scientific journals, clinical researchers have continued to debate the content of these policies and the need for additional protections beyond disclosure. In the absence of a definitive standard, this historical case study can substantially inform ongoing discussion on conflicts of interest in clinical research.
Frequency, Type, and Monetary Value of Financial Conflicts of Interest in Cancer Clinical Research
Authors: Hampson Lindsay A. , Joffe Steven , Fowler Robert , Verter Joel , Emanuel Ezekiel J.
Published: August 2007

Purpose

Using data from American Society of Clinical Oncology (ASCO) Annual Meetings, we determined the frequency, type, and monetary value of researchers' financial interests.

Methods

Financial disclosures for the 2004 (3,529 abstracts and 25,416 authors) and 2005 (3,556 abstracts and 26,181 authors) ASCO Annual Meetings were categorized into four groups: no author with a financial interest, research funding only, employment and leadership positions only, or at least one author with a personal financial interest. Interests were stratified by monetary value and other factors.

Results

In 2004 and 2005, 23% of abstracts had one or more authors with a personal financial interest. More than 75% of all personal financial interests were valued at less than $10,000. More than 90% of financial interests of more than $100,000 were employment related. Fewer than 3.5% of authors with personal financial interests had interests valued at more than $100,000. Overall, 6.3% (2004) and 2.9% (2005) of abstracts only had research funding, whereas 7.3% (2004) and 6.9% (2005) had only commercial employment. In 2005, 60% of plenary sessions compared with 23.1% in general poster sessions and 17.3% for publish-only abstracts reported financial ties. Personal financial interests were more common among US authors compared with non-US authors (9.2% v 4.2%).

Conclusion

About one fourth of abstracts at ASCO Annual Meetings have an author with a personal financial interest. Most personal financial interests are valued at less than $10,000 per year, whereas a majority valued at more than $100,000 are related to employees of commercial entities.
An Early Signal of CA-125 Progression for Ovarian Cancer Patients Receiving Maintenance Treatment After Complete Clinical Response to Primary Therapy
Authors: Liu Ping-Yu , Alberts David S. , Monk Bradley J. , Brady Mark , Moon James , Markman Maurie
Published: August 2007

Purpose

For ovarian cancer patients receiving maintenance treatment after complete clinical response to primary therapy, we tested the predictive value of the following early signal of progressive disease (EPD) criterion based on serum CA-125: for patients with CA-125 nadir ≤ 10 U/mL, a confirmed value of ≥ 20 U/mL serves as an early signal of CA-125 progression; for patients with nadir more than 10 U/mL, a value ≥ 2× nadir that is confirmed predicts progression.

Patients and Methods

The EPD criterion was tested on Southwest Oncology Group trial 9701/Gynecologic Oncology Group trial 178 patients (n = 288) and compared with Gynecologic Cancer Intergroup criterion.

Results

For 204 patients with known progressive disease, the progression date was predated by EPD by ≤ 60 days in 31%, 61 to 180 days in 15%, and more than 180 days in 10% (median, 56 days early). Of 84 progression-free patients, nine EPDs were found. Overall, 135 patients met the EPD criterion. True disease progression status was undeterminable for two patients and nine were potentially false signals, for a conservative positive predictive value of 93% (95% CI, 88% to 97%).

Conclusion

Initial testing of the proposed CA-125 criterion resulted in a low false-positive rate and early prediction of disease progression in more than 50% of the patients tested. The proposed criterion may better reflect the timing of disease progression and should be investigated further.
Prognostic Factors for Stage III Epithelial Ovarian Cancer: A Gynecologic Oncology Group Study
Authors: Winter William E. , Maxwell G. Larry , Tian Chunqiao , Carlson Jay W. , Ozols Robert F. , Rose Peter G. , Markman Maurie , Armstrong Deborah K. , Muggia Franco , McGuire William P.
Published: August 2007

Purpose

Conflicting results on prognostic factors for advanced epithelial ovarian cancer (EOC) have been reported because of small sample size and heterogeneity of study population. The purpose of this study was to identify factors predictive of poor prognosis in a similarly treated population of women with advanced EOC.

Patients and Methods

A retrospective review of demographic, pathologic, treatment, and outcome data from 1,895 patients with International Federation of Gynecology and Obstetrics stage III EOC who had undergone primary surgery followed by six cycles of intravenous platinum/paclitaxel was conducted. A proportional hazards model was used to assess the association of prognostic factors with progression-free survival (PFS) and overall survival (OS).

Results

Increasing age was associated with increased risks for disease progression (HR = 1.06; 95% CI, 1.02 to 1.11 for an increase every 10 years) and death (HR = 1.12; 95% CI, 1.06 to 1.18). Mucinous or clear-cell histology was associated with a worse PFS and OS compared with serous carcinomas. Patients with performance status (PS) 1 or 2 were at an increased risk for recurrence compared with PS 0 (HR = 1.12; 95% CI, 1.01 to 1.24). Compared with patients with microscopic residual disease, patients with 0.1 to 1.0 cm and > 1.0 cm residual disease had an increased risk of recurrence (HR = 1.96; 95% CI, 1.70 to 2.26; and HR = 2.36; 95% CI, 2.04 to 2.73, respectively) and death (HR = 2.11; 95% CI, 1.78 to 2.49; P < .001; and HR = 2.47; 95% CI, 2.09 to 2.92, respectively).

Conclusion

Age, PS, tumor histology, and residual tumor volume were independent predictors of prognosis in patients with stage III EOC. These data can be used to identify patients with poor prognosis and to design future tailored randomized clinical trials.
Phase II Trial of Sorafenib in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck or Nasopharyngeal Carcinoma
Authors: Elser Christine , Siu Lillian L. , Winquist Eric , Agulnik Mark , Pond Gregory R. , Chin Soo F. , Francis Peggy , Cheiken Robin , Elting James , McNabola Angela , Wilkie Dean , Petrenciuc Oana , Chen Eric X.
Published: August 2007

Purpose

To determine the efficacy and safety of single-agent sorafenib in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and nasopharyngeal carcinoma (NPC).

Patients and Methods

In this single-arm phase II trial, oral continuous sorafenib was administered in 28-day cycles. Patients had ≤ one line of chemotherapy for recurrent and/or metastatic disease, Eastern Cooperative Oncology Group performance status of ≤ 2, and adequate organ function. At the end of stage 1, efficacy criteria for further accrual were not met, but the study was amended to enroll an additional five patients for paired tumor biopsies.

Results

Twenty-seven and 26 patients were eligible for toxicity and efficacy evaluations, respectively. One patient (3.7%; 95% CI, 0.1% to 19.0%) achieved a partial response. Disease stabilization was maintained in 10 patients (37.0%; 95% CI, 22.4% to 61.2%). The median time to progression was 1.8 months (95% CI, 1.6 to 3.4 months), and median overall survival time was 4.2 months (95% CI, 3.6 to 8.7 months). Sorafenib was well tolerated with few grade 3 and no grade 4 toxicities. Biomarker analysis of paired tumor samples before and after treatment with sorafenib revealed a decrease of pERK in all five patients, with a decrease in Ki67 in four patients, consistent with a disruption of ERK signaling. The antiapoptotic protein Mcl-1 was downregulated in four patients, and there was also evidence of antiangiogenic activity.

Conclusion

Sorafenib was well tolerated and had modest anticancer activity comparable to monotherapy with other targeted agents in this group of patients. Further development in combination with radiation or other agents may be warranted.
Treatment With Autologous Antigen-Presenting Cells Activated With the HER-2 –Based Antigen Lapuleucel-T: Results of a Phase I Study in Immunologic and Clinical Activity in HER-2–Overexpressing Breast Cancer
Authors: Park John W. , Melisko Michelle E. , Esserman Laura J. , Jones Lori A. , Wollan Jami Breen , Sims Robert
Published: August 2007

Purpose

Lapuleucel-T (APC8024), an autologous active cellular immunotherapy, was prepared from peripheral-blood mononuclear cells, including antigen-presenting cells, that were activated in vitro with recombinant fusion protein BA7072. This antigen construct consisted of sequences from intracellular and extracellular domains of human epidermal growth factor receptor 2 (HER-2) linked to granulocyte-macrophage colony-stimulating factor. We conducted a phase I study to evaluate the safety and immunologic activity of lapuleucel-T in patients with HER-2–overexpressing metastatic breast cancer.

Patients and Methods

Metastatic breast cancer patients whose tumors overexpressed or amplified HER-2 were eligible. Patients underwent leukapheresis and subsequent lapuleucel-T infusion 2 days later at weeks 0, 2, and 4. Patients who achieved a partial response (PR) or had stable disease (SD) lasting through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment. End points included safety, immunologic activity, and antitumor activity.

Results

Nineteen patients were enrolled; 18 patients received treatment. Therapy was well tolerated, with no grade 3 or 4 adverse events associated with the treatment. Significant cellular immune responses specific for the immunizing antigen and HER-2 sequences were induced after treatment, as measured by lymphocyte proliferation and interferon gamma enzyme-linked immunospot assay. One patient experienced a PR lasting 6 months. Three additional patients had SD lasting more than 1 year.

Conclusion

Autologous active cellular immunotherapy with lapuleucel-T was feasible, safe, and well tolerated. The treatment stimulated significant immune responses, which were enhanced after boost infusions. Lapuleucel-T therapy was associated with tumor response or extended disease stabilization in some patients and warrants further investigation.
Prostaglandin F2α Suppresses Rat Steroidogenic Acute Regulatory Protein Expression via Induction of Yin Yang 1 Protein and Recruitment of Histone Deacetylase 1 Protein
Authors: Liu Qiyuan , Merkler Kathleen A. , Zhang Xiaohui , McLean Mark P.
Published: August 2007

Prostaglandin F2α (PGF2α) plays a pivotal role in ovarian luteolysis by inhibiting the expression of steroidogenic acute regulatory (StAR) protein, leading to a decrease in intracellular cholesterol transport and luteal steroid production. Previously we have demonstrated that the transcription factor Yin Yang 1 (YY1) bound to three regions in the StAR promoter in vitro and repressed promoter activity. This study further defined the YY1-mediated PGF2α effect on the inhibition of StAR protein expression through YY1 interaction with a single region in the StAR promoter in vivo. PGF2α consistently suppressed StAR mRNA and protein expression in cultured luteal cells in a dose-dependent manner. PGF2α also enhanced YY1 protein expression and binding to its cis-element in a time-dependent pattern that preceded the decline in StAR protein levels. The StAR promoter region bound by YY1 was also associated with histone deacetylase 1 (HDAC1). PGF2α treatment promoted HDAC1 binding to and suppressed the histone H3 acetylation in this region. On the contrary, YY1 knockdown decreased HDAC1 binding, increased histone H3 acetylation, enhanced StAR protein expression, and negated PGF2α effect on StAR protein expression. Luciferase assays showed that YY1 overexpression inhibited StAR promoter activity and the addition of a HDAC inhibitor, trichostatin A, abrogated the effect of YY1. Trichostatin A-treated luteal cells displayed increased StAR protein expression. These data indicate that PGF2α enhances a direct YY1/StAR promoter interaction and the recruitment of HDAC1 to the promoter, thereby preventing transcriptional activation of the StAR gene.
Interleukin-11 Promotes Migration, But Not Proliferation, of Human Trophoblast Cells, Implying a Role in Placentation
Authors: Paiva Premila , Salamonsen Lois A. , Manuelpillai Ursula , Walker Claire , Tapia Alejandro , Wallace Euan M. , Dimitriadis Evdokia
Published: August 2007

Trophoblast growth and invasion of the uterine endometrium are critical events during placentation and are tightly regulated by factors produced within the trophoblast-endometrial microenvironment. Deficiencies in placentation can result in early miscarriage or preeclampsia and intrauterine growth restriction, leading to impaired fetal health. The latter has been linked to major adult health disorders. IL-11 is essential for blastocyst implantation in mice. In humans, IL-11 and its receptor IL-11 receptor α (IL-11Rα) are maximally expressed in the decidua and chorionic villi during early pregnancy; however, the role of IL-11 in trophoblast function is unknown. Therefore, we examined whether IL-11Rα is expressed in human first trimester implantation sites, and whether IL-11 influences proliferation and migration of a human extravillous trophoblast (EVT)-hybridoma cell line and primary EVT cells, used as models for EVT. Immunoreactive IL-11Rα localized to subpopulations of interstitial and endovascular EVT cells in vivo. In EVT cells in vitro, IL-11: 1) stimulated phosphorylation of signal transducer and activator of transcription-3; 2) was without effect on EVT cell proliferation; and 3) stimulated significant migration of EVT-hybridoma cells (no endogenous IL-11), whereas in primary EVT, blocking endogenous IL-11 inhibited EVT migration by 30–40%. These data demonstrate that IL-11 stimulates human EVT migration, but not proliferation, likely via signal transducer and activator of transcription-3, indicating an important role for IL-11 in placentation.
Nutritional Influences on Reproductive Neuroendocrine Output: Insulin, Leptin, and Orexigenic Neuropeptide Signaling in the Ovine Hypothalamus
Authors: Miller David W. , Harrison Joanne L. , Bennett Ellen J. , Findlay Patricia A. , Adam Clare L.
Published: August 2007

This study investigated how changing nutritional status may alter reproductive neuroendocrine (LH) output via circulating leptin and insulin signaling through orexigenic hypothalamic pathways. Thin sheep were given an increasing nutritional plane (INP), sheep with intermediate adiposity a static nutritional plane (SNP), and fat sheep a decreasing nutritional plane (DNP) for 6 wk. Mean group adiposities converged by wk 6, LH output increased in INP, remained unchanged in SNP, and decreased in DNP sheep. Plasma and cerebrospinal fluid (CSF) insulin and plasma leptin concentrations increased in INP but did not change in the SNP and DNP groups. In INP sheep, LH output correlated positively with adiposity and plasma and CSF insulin concentrations and negatively with orexigenic neuropeptide Y gene expression in the hypothalamic arcuate nucleus (ARC). In DNP sheep, LH output correlated positively with adiposity, CSF leptin concentrations, and ARC proopiomelanocortin gene expression and negatively with leptin receptor (OB-Rb) and agouti-related peptide gene expression in the ARC. These data are consistent with the feedback response to an increasing nutritional plane being mediated by increasing circulating insulin entering the brain and stimulating LH via inhibition of hypothalamic neuropeptide Y and the response to a decreasing nutritional plane being mediated by altered hypothalamic leptin signaling brought about by increased OB-Rb expression and decreased melanocortin signaling. Because end point adiposity was similar yet LH output was different, the hypothalamus apparently retains a nutritional memory, based on changes in orexigenic neuropeptide expression, that influences contemporary neuroendocrine responses.
Differential Activation of the Sympathetic Innervation of Adipose Tissues by Melanocortin Receptor Stimulation
Authors: Brito Márcia N. , Brito Nilton A. , Baro Deborah J. , Song C. Kay , Bartness Timothy J.
Published: August 2007

Melanocortins are implicated in the control of energy intake/expenditure. Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases. Melanocortin-4 receptor (MC4-R) mRNA is expressed on sympathetic nervous system (SNS) outflow neurons to white adipose tissue (WAT) in Siberian hamsters, suggesting a role in lipid mobilization. Therefore, we tested whether third ventricular injections of MTII increased sympathetic drive to WAT and interscapular brown adipose tissue (IBAT) using norepinephrine turnover (NETO) as a measure of sympathetic drive. We also tested for MTII-induced changes in lipolysis-related WAT gene expression (β3-adrenoceptors, hormone sensitive lipase) and IBAT thermogenesis (β3-adrenoceptor, uncoupling protein-1). Finally, we tested whether third ventricularly injected MTII, a highly selective MC4-R agonist (cyclo[β-Ala-His-D-Phe-Arg-Trp-Glu]NH2) increased or agouti-related protein decreased IBAT temperature in hamsters implanted with sc IBAT temperature transponders. Centrally administered MTII provoked differential sympathetic drives to WAT and IBAT (increased inguinal WAT, dorsosubcutaneous WAT and IBAT NETO, but not epididymal WAT and retroperitoneal WAT NETO). MTII also increased circulating concentrations of the lipolytic products free fatty acids and glycerol but not plasma catecholamines, suggesting lipid mobilization via WAT SNS innervation and not via adrenal medullary catecholamines. WAT or IBAT gene expression was largely unaffected by acute MTII treatment, but IBAT temperature was increased by MTII and the MC4-R agonist and decreased by agouti-related protein. Collectively, this is the first demonstration of central melanocortin agonist stimulation of WAT lipolysis through the SNS and confirms melanocortin-induced changes in BAT thermogenesis.
Kidney Gene Expression Analysis in a Rat Model of Intrauterine Growth Restriction Reveals Massive Alterations of Coagulation Genes
Authors: Buffat Christophe , Boubred Farid , Mondon Françoise , Chelbi Sonia T. , Feuerstein Jean-Marc , Lelièvre-Pégorier Martine , Vaiman Daniel , Simeoni Umberto
Published: August 2007

In this study, low birth weight was induced in rats by feeding the dams with a low-protein diet during pregnancy. Kidneys from the fetuses at the end of gestation were collected and showed a reduction in overall and relative weight, in parallel with other tissues (heart and liver). This reduction was associated with a reduction in nephrons number. To better understand the molecular basis of this observation, a transcriptome analysis contrasting kidneys from control and protein-deprived rats was performed, using a platform based upon long isothermic oligonucleotides, strengthening the robustness of the results. We could identify over 1800 transcripts modified more than twice (772 induced and 1040 repressed). Genes of either category were automatically classified according to functional criteria, making it possible to bring to light a large cluster of genes involved in coagulation and complement cascades. The promoters of the most induced and most repressed genes were contrasted for their composition in putative transcription factor binding sites, suggesting an overrepresentation of the AP1R binding site, together with the transcription induction of factors actually binding to this site in the set of induced genes. The induction of coagulation cascades in the kidney of low-birth-weight rats provides a putative rationale for explaining thrombo-endothelial disorders also observed in intrauterine growth-restricted human newborns. These alterations in the kidneys have been reported as a probable cause for cardiovascular diseases in the adult.