To assess predictors of well-differentiated thyroid cancer (WDTC) persistence/recurrence.
This was a retrospective chart review of thyroid carcinoma patients seen 1979-2007 in a Boston, ...Massachusetts-area multispecialty group. Of 1,025 patients, 431 met eligibility criteria. Cox proportional hazards models were used to assess predictors (gender, age, ethnicity, tumor size, surgical histology) of WDTC persistence/recurrence (elevated thyroglobulin levels with negative thyroglobulin-antibodies; or positive imaging). Local extension of disease and lymph node involvement could not be assessed.
Mean age at initial surgery (n = 431, 74% women, 79% Caucasian) was 45.8 ± 13.5(SD) years. Mean tumor (papillary, 91%; follicular, 5%; Hurthle cell, 2%; ≥1 type, 2%) size was 2.5 ± 1.6(SD) cm. Most tumors were unifocal (57%) and ≥1 cm (89%). Over 2,600 person-years of follow-up, persistence/recurrence occurred in 52 patients (12%) 4.3 years (median; range 0.2-23.2 years) after surgery. Gender, ethnicity, tumor size, multifocality, and histology were not predictive of persistence/recurrence, while older age was predictive in some models.
In WDTC patients treated by total and near total thyroidectomy and radioiodine and analyzed without consideration of local, locoregional, and distant extent of disease, neither size of tumor nor male gender contribute to disease persistence/recurrence. Age at diagnosis seems to have some positive prognostic value even if only patients older than 21 years at diagnosis are considered. Due to the rare occurrence of follicular (also oxyphilic) histotype, this conclusion refers mainly to patients with papillary thyroid cancer.
This study examined MASPIN expression in human ovarian cancer, and explored the association between MASPIN and prognosis in patients with advanced stage disease treated with first-line cisplatin, ...carboplatin and/or paclitaxel.
Frozen primary tumors were obtained from 68 women with previously untreated, advanced stage epithelial ovarian cancer who participated in a specimen banking protocol and a phase III treatment trial conducted by the Gynecologic Oncology Group. Immunoblot analysis was performed in lysates prepared from these tumor specimens to quantify the relative expression of MASPIN/β-actin.
MASPIN was expressed at detected levels in 49 (72%) cases with relative expression ranging from 0.02 to 7.7 (median = 0.2), and was not detected in 19 (28%) of the primary tumors tested. Non-detectable levels of this class II tumor suppressor gene product and inhibitor of angiogenesis were associated with suboptimally-debulked disease (
P = 0.034) but not with patient age, FIGO stage, tumor grade, or histologic subtype. After adjusting for prognostic variables for disease progression or death, non-detectable MASPIN expression predicted an increased risk of disease progression (hazard ratio HR = 1.89; 95% confidence interval CI: 1.04–3.45;
P = 0.038) and death (HR = 1.99; 95% CI: 1.07–3.69;
P = 0.030).
In advanced stage epithelial ovarian cancer, non-detectable MASPIN appears to be associated with suboptimally-debulked disease and be an independent predictor of an increased risk of progression and death. Further studies are needed to validate these exploratory findings, determine the molecular mechanism controlling MASPIN expression as well as down-regulation and loss in ovarian cancer, and determine if MASPIN can prevent progression of this disease.
In this study, we apply an existing medical communication coding system to BRCA1 genetic counseling sessions, describe the session dynamics, and explore variation in session communication. The sample ...was comprised of 167 members of an identified BRCA1 kindred whose pretest counseling session was audiotaped and coded using Roter's Interaction Analysis System (RIAS). Three certified genetic counselors followed a research protocol that dictated areas to be covered in the counseling session. We found that it was feasible to code long, protocol driven BRCA1 sessions in a quantitative manner without the use of transcripts and capture the dialogue of all session participants. These findings support the use of RIAS in genetic counseling research. Our results indicate that these BRCA1 sessions were predominantly educational in nature with minimal dialogue devoted to psychosocial issues. We found that participant gender, presence of a client companion, and counselor identity influence session communication.
Common fragile sites are chromosomal loci prone to breakage and rearrangement, hypothesized to provide targets for foreign DNA integration. We cloned a simian virus 40 integration site and showed by ...fluorescent in situ hybridization analysis that the integration event had occurred within a common aphidicolin-induced fragile site on human chromosome 7, FRA7H. A region of 161 kb spanning FRA7H was defined and sequenced. Several regions with a potential unusual DNA structure, including high-flexibility, low-stability, and non-B-DNA-forming sequences were identified in this region. We performed a similar analysis on the published FRA3B sequence and the putative partial FRA7G, which also revealed an impressive cluster of regions with high flexibility and low stability. Thus, these unusual DNA characteristics are possibly intrinsic properties of common fragile sites that may affect their replication and condensation as well as organization, and may lead to fragility.
The alternative analysis of A. Bianchi and M. Savastano is a valuable contribution to the understanding of the complex systems at stake in the complexation chemistry of Zr4+ by considering ...polynuclear species. Placed in the context of nuclear medicine where such aggregates are unlikely and considering recent literature data, this however points out that no clear agreement exists to describe such complex formation.
Mutational activation of KIT or PDGFRA is considered an early step in pathogenesis of gastrointestinal stromal tumors (GISTs); however, other nonrandom genetic changes have also been identified. At ...least three common regions of deletions on chromosome 22q, which may harbor putative tumor suppressor genes, have been defined. However, mapping of these regions has been inconsistent. It has also been speculated that GI autonomous nerve tumors (GANTs), GISTs with ultrastructural features suggestive of autonomic nerve differentiation, are characterized by a specific deletion involving 22q13 cytogenetic region. This study was undertaken to evaluate loss of heterozygosity (LOH) on chromosome 22q in 50 GISTs, including 10 GANTs. Four tumors were incidental minimal lesions ≤10 mm in diameter. LOH was evaluated using 20 PCR-based microsatellite markers and capillary gel electrophoresis. In all, 15 (30%) cases showed LOH of more than 75% of informative markers, suggesting loss of chromosome 22q. A total of 24 GISTs (50%) revealed LOH of one to seven informative markers clustered in different loci suggesting simultaneous involvement of different regions. The highest frequency of LOH was seen at D22S922 and D22S425, mapped to 22q13.33 and 22q11.22, respectively. However, LOH at other regions including IL2RB and NF2 locus was also found. No NF2 mutations were identified in four analyzed tumors. LOH on chromosome 22q was more frequent among intestinal than among gastric GISTs; however, there was no difference between LOH pattern seen in tumors defined by different histologic, ultrastructural (GANT) and molecular features (KIT and PDGFRA mutations). Although minimal GISTs revealed LOH on chromosome 22q, there was a higher LOH frequency in malignant than in benign tumors. An isolated LOH at D22S425 was equally found in both benign and malignant tumors. These observations may suggest that LOHs on chromosome 22q in GISTs play a role in early stages of tumor formation as well as in late tumor progression.
Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and ...radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known.
Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses.
Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation.
The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.
Both of the enantiomers of 5-(3-hydroxyphenyl)-N-phenylethylmorphan with C9α-methyl, C9-methylene, C9-keto, and C9α- and C9β-hydroxy substituents were synthesized and pharmacologically evaluated. ...Three of the 10 compounds, (1R,5R,9S)-(−)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo3.3.1nonane ((1R,5R,9S)-(−)-10), (1R,5S)-(+)-5-(3-hydroxyphenyl)-9-methylene-2-phenethyl-2-azabicyclo3.3.1nonane ((1R,5S)-(+)-14), and (1R,5S,9R)-(−)-5-(3-hydroxyphenyl)-9-methyl-2-phenethyl-2-azabicyclo3.3.1nonane ((1R,5S,9R)-(+)-15) had subnanomolar affinity at μ-opioid receptors (K i = 0.19, 0.19, and 0.63 nM, respectively). The (1R,5S)-(+)-14 was found to be a μ-opioid agonist and a μ-, δ-, and κ-antagonist in 35SGTP-γ-S assays and was approximately 50 times more potent than morphine in a number of acute and subchronic pain assays, including thermal and visceral models of nociception. The (1R,5R,9S)-(−)-10 compound with a C9-hydroxy substituent axially oriented to the piperidine ring (C9β-hydroxy) was a μ-agonist about 500 times more potent than morphine. In the single-dose suppression assay, it was greater than 1000 times more potent than morphine. It is the most potent known phenylmorphan antinociceptive. The molecular structures of these compounds were energy minimized with density functional theory at the B3LYP/6-31G* level and then overlaid onto (1R,5R,9S)-(−)-10 using the heavy atoms in the morphan moiety as a common docking point. Based on modeling, the spatial arrangement of the protonated nitrogen atom and the 9β-OH substituent in (1R,5R,9S)-(−)-10 may facilitate the alignment of a putative water chain enabling proton transfer to a nearby proton acceptor group in the μ-opioid receptor.
Natural gas has become the dominant source
of electricity in the United States, and
technologies capable of efficiently removing
carbon dioxide (CO
2
) from the
flue emissions of natural gas–fired ...power plants
could reduce their carbon intensity. However,
given the low partial pressure of
CO
2
in the flue stream,
separation of CO
2
is
particularly challenging. Taking inspiration from
the crystal structures of diamine-appended
metal–organic frameworks exhibiting two-step
cooperative CO
2
adsorption,
we report a family of robust
tetraamine-functionalized frameworks that retain
cooperativity, leading to the potential for
exceptional efficiency in capturing
CO
2
under the extreme
conditions relevant to natural gas flue emissions.
The ordered, multimetal coordination of the
tetraamines imparts the materials with
extraordinary stability to adsorption-desorption
cycling with simulated humid flue gas and enables
regeneration using low-temperature steam in lieu
of costly pressure or temperature swings.
1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and 2 Section of Pulmonary and Critical Care Medicine, and 3 Section of Genetic ...Medicine, University of Chicago Pritzker School of Medicine, Chicago Illinois
Submitted 18 December 2006
; accepted in final form 23 April 2007
Increasing evidence supports the contribution of genetic influences on susceptibility/severity in acute lung injury (ALI), a devastating syndrome requiring mechanical ventilation with subsequent risk for ventilator-associated lung injury (VALI). To identify VALI candidate genes, we determined that Brown Norway (BN) and Dahl salt-sensitive (SS) rat strains were differentially sensitive to VALI (tidal volume of 20 ml/kg, 85 breaths/min, 2 h) defined by bronchoalveolar lavage (BAL) protein and leukocytes. We next exploited differential sensitivities and phenotyped both the VALI-sensitive BN and the VALI-resistant SS rat strains by expression profiling coupled to a bioinformatic-intense candidate gene approach (Significance Analysis of Microarrays, i.e., SAM). We identified 106 differentially expressed VALI genes representing gene ontologies such as "transcription" and "chemotaxis/cell motility." We mapped the chromosomal location of the differentially expressed probe sets and selected consomic SS rats with single BN introgressions of chromosomes 2, 13, and 16 (based on the highest density of probe sets) while also choosing chromosome 20 (low probe sets density). VALI exposure of consomic rats with introgressions of BN chromosomes 13 and 16 resulted in significant increases in both BAL cells and protein (compared to parental SS strain), whereas introgression of BN chromosome 2 displayed a large increase only in BAL protein. Introgression of BN chromosome 20 had a minimal effect. These results suggest that genes residing on BN chromosomes 2, 13, and 16 confer increased sensitivity to high tidal volume ventilation. We speculate that the consomic-microarray-SAM approach is a time- and resource-efficient tool for the genetic dissection of complex diseases including VALI.
rodent mechanical ventilation; consomics; bioinformatics; microarrays; candidate gene approach
Address for reprint requests and other correspondence: J. G. N. Garcia, Dept. of Medicine, Univ. of Chicago Pritzker School of Medicine, 5841 S. Maryland Ave., W604, Chicago, IL 60637 (e-mail: jgarcia{at}medicine.bsd.uchicago.edu )
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