bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract
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

Abstract
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.
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.