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Genome sequencing and the application of omic techniques are driving many important advances in the field of microbial natural products research. Despite these gains, there remain aspects of the natural product discovery pipeline where our knowledge remains poor. These include the extent to which biosynthetic gene clusters are transcriptionally active in native microbes, the temporal dynamics of transcription, translation, and natural product assembly, as well as the relationships between small molecule production and detection. Here we touch on a number of these concepts in the context of continuing efforts to unlock the natural product potential revealed in genome sequence data and discuss nomenclatural issues that warrant consideration as the field moves forward. [ABSTRACT FROM AUTHOR]

Background: The efficacy of radioactive iodine therapy (RAI) in patients who have an undetectable thyroglobulin (Tg) level after total thyroidectomy in well-differentiated papillary thyroid cancer (PTC) is questionable. The objectives of this study were to report the risk of recurrence in patients with PTC who had an undetectable Tg level after total thyroidectomy managed with postoperative RAI and without RAI. Methods: After approval by the institutional review board, 751 consecutive patients who had total thyroidectomy for PTC as well as postoperative Tg measurement were identified from our institutional database of 1163 patients treated for well-differentiated thyroid carcinoma at Memorial Sloan Kettering Cancer Center between 1999 and 2005. Of these, 424 patients had an undetectable postoperative Tg (defined as a Tg <1 ng/mL) of whom 80 were classified as low, 218 intermediate, and 126 high risk via use of the GAMES (grade, age, distant metastasis, extrathyroidal extension, and size of the neoplasm) criteria. Patient, neoplasm, and treatment characteristics were recorded on the low- and intermediate-risk patients. Recurrence was defined as any structural abnormality on examination or imaging and confirmed by fine-needle aspiration biopsy. Disease-specific survival and recurrence-free survival (RFS) were calculated with the Kaplan-Meier method. Univariate analysis was carried out by the log rank test and multivariate analysis by Cox proportional hazards method. Results: In the low-risk group (n = 80), 35 patients received postoperative RAI and 45 did not. Comparison of patient and tumor characteristics showed patients treated without RAI were more likely to have T1 tumors (82% vs 60%, P = .027). There were no disease-specific deaths in either group. There was 1 neck recurrence in the group that did not receive RAI. Patients managed without RAI had a similar RFS to patients managed with RAI (96% vs 100%, P = .337). In the intermediate risk group (n = 218), 135 were managed with RAI and 83 without. Comparison of patient and tumor characteristics showed patients managed without RAI were more likely to be older patients (≥45 years: 90% vs 39%, P < .0005) with smaller tumors (pT1T2: 97% vs 62%, P < .0005) and negative neck disease (N0: 56% vs 30%, P < .0005). There were no disease specific deaths in either group. There were 7 recurrences, of which 6 were in the RAI cohort (5 regional, 1 distant) and 1 in the non-RAI cohort (1 regional). Patients managed without RAI had a similar RFS to patients managed with RAI (97% vs 96%, P = .234). Conclusion: Select low- and intermediate-risk group patients who have undetectable Tg after total thyroidectomy for PTC can be managed safely without adjuvant RAI with no increase in risk of recurrence. [Copyright &y& Elsevier]

Background: There remains controversy over the type of surgery appropriate for T1T2N0 well differentiated thyroid cancers (WDTC). Current guidelines recommend total thyroidectomy for all but the smallest lesions, despite previous evidence from large institutions suggesting that lobectomy provides similar excellent results. The objective of this study was to report our experience of T1T2N0 WDTC managed by either thyroid lobectomy or total thyroidectomy. Methods: Eight hundred eighty-nine patients with pT1T2 intrathyroid cancers treated surgically between 1986 and 2005 were identified from a database of 1810 patients with WDTC. Total thyroidectomy was carried out in 528 (59%) and thyroid lobectomy in 361 (41%) patients. Overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) were determined by the Kaplan-Meier method. Factors predictive of outcome by univariate and multivariate analysis were determined using the log rank test and Cox proportional hazards method respectively. Results: With a median follow-up of 99 months, the 10-yr OS, DSS, and RFS for all patients were 92%, 99%, and 98% respectively. Univariate analysis showed no significant difference in OS by extent of surgical resection. Multivariate analysis showed that age over 45 yr and male gender were independent predictors for poorer OS, whereas T stage and type of surgery were not. Comparison of the thyroid lobectomy group and the total thyroidectomy group showed no difference in local recurrence (0% for both) or regional recurrence (0% vs 0.8%, P = .96). Conclusion: Patients with pT1T2 N0 WDTC can be safely managed by thyroid lobectomy alone. [ABSTRACT FROM AUTHOR]

Objective: To report the impact of microscopic extrathyroid extension (ETE) on outcome in patients with cT1/cT2 well-differentiated thyroid cancer (WDTC), and to determine the effect of extent of surgery and adjuvant radioactive iodine (RAI) treatment on outcome in patients with microscopic ETE. Patients and Methods: From an institutional database, we identified 984 patients (54%) who underwent surgery for cT1/T2N0 disease. Of these, 869 patients were pT1/T2 and 115 were upstaged to pT3 based on the finding of microscopic ETE. Disease-specific survival (DSS) and recurrence-free survival (RFS) were analyzed for each group using the Kaplan–Meier method. In the pT3 group, factors predictive of outcome were analyzed by univariate and multivariate analyses. Results: There was no difference in the 10-year DSS (99% vs 100%; P = .733) or RFS (98% vs 95%; P = .188) on comparison of the pT1/pT2 and pT3 cohorts. Extent of surgery and administration of postoperative RAI were not significant for recurrence on univariate or multivariate analysis in the pT3 cohort. Conclusion: Outcomes in patients with cT1T2N0 WDTC are excellent and not affected by microscopic ETE. The extent of resection and administration of postoperative RAI in patients with microscopic ETE does not impact survival or recurrence. [Copyright &y& Elsevier]

Objective: We examined the effect of body mass index on the association between revascularization strategy and survival in patients with coronary artery disease. Methods: Using the Duke Database for Cardiovascular Disease, we selected 22,877 patients who underwent cardiac catheterization from January 1986 to August 2004 and were found to have significant coronary artery disease. Patients were categorized into three coronary disease management groups: no revascularization, percutaneous coronary intervention, and coronary artery bypass surgery. Propensity scoring was used to control for coronary artery revascularization strategy. The relationship between body mass index, coronary disease treatment, and survival was assessed via Cox multivariable models adjusting for baseline demographic, clinical, and angiographic characteristics. Results: The median body mass index was 27.2 kg/m2 (24.4–30.4) in the overall cohort, 27.1 kg/m2 (24.1–30.3) in the no revacularization group, 27.4 kg/m2 (24.8–30.9) in the percutaneous intervention group, and 26.9 kg/m2 (24.4–30.1) in the coronary bypass group. Body mass index was a significant, but weak, predictor of revascularization, with higher indexes predicting lower rates of coronary bypass. Thirty-day survival did not differ across body mass indexes among treatment groups, but survival curves appeared to separate over longer-term follow-up. An inverted U-shaped survival function was noted across all time points after 30 days, with the lowest risk of death at a body mass index of approximately 26 kg/m2 (independent of revascularization strategy). Coronary bypass was associated with the highest survival at all later time points, whereas no revascularization was associated with the lowest. Conclusions: Extremes of body mass index are associated with lower long-term survival in patients with significant coronary disease. Revascularization, particularly with coronary bypass, is consistently associated with the best survival across the spectrum of body mass indexes. [Copyright &y& Elsevier]

Background: In patients with multivessel coronary artery disease, performing multiple internal mammary artery (MIMA) grafts to two coronary systems during coronary artery bypass grafting (CABG) improves clinical outcome. Few databases have decades of follow-up, however, and the optimal configuration is still in question. The purpose of this study was to assess 20-year clinical benefits of MIMA grafting and to evaluate the possible effects of two different MIMA configurations. Methods: From 1984 to 1986, 867 patients with multivessel coronary disease underwent CABG. Single (SIMA) IMA grafts were used in 490 and multiple (MIMA) IMA grafts in 377, along with concomitant saphenous veins. Generally, MIMAs were placed to the two largest coronary systems. Among baseline characteristics, only smoking, diabetes, and hypertension were significantly higher for MIMA versus SIMA. Multivariable Cox model analysis was used to assess outcome differences between groups. Results: During a median follow-up of 20 years, the composite of mortality, myocardial infarction, percutaneous coronary intervention, and redo CABG was significantly reduced after MIMA versus SIMA (p = 0.013). Event-free survival was extended by almost 1 year (p = 0.018), and redo CABG was reduced by 59% (p = 0.005). A comparison within the MIMA group was made between 235 patients receiving IMA grafts to left anterior descending/left circumflex territories versus 122 with grafts to left anterior descending/right coronary artery systems. No significant difference in composite outcome was observed between these configurations (p = 0.88). Conclusions: These data confirm the clinical benefits of MIMA grafting in multivessel coronary disease to 20 years of follow-up. As long as MIMAs are placed to the two largest coronary systems, no significant differences in long-term results are evident between left anterior descending/left circumflex and left anterior descending/right coronary artery configurations. [Copyright &y& Elsevier]

Background: Treatment of coronary artery disease (CAD) is evolving with better medications, improvements in percutaneous coronary intervention (PCI), and enhanced techniques for coronary artery bypass grafting (CABG). Methods: In this study, 18,481 patients with significant (>75% stenosis) CAD treated at a single center between 1986 and 2000 were assigned to one of three groups based on initial treatment strategy: medical therapy (MED) (n = 6862), PCI (n = 6292), or CABG (n = 5327). Each group was categorized into 3 groups according to baseline severity of CAD: low-severity (predominantly 1-vessel), intermediate-severity (predominantly 2-vessel), and high-severity (all 3-vessel), and prospectively evaluated in Cox models for all-cause mortality adjusted for cardiac risk, comorbidity, and propensity for selection of a specific treatment. Treatments were compared for the entire period and three eras (1: 1986 to 1990; 2: 1991 to 1995; 3: 1996 to 2000), the last encompassing widespread availability of PCI with stenting. Results: Survival significantly improved in all groups for all degrees of CAD, despite increasing severity of illness. Revascularization strategies provided significant survival over MED with 8.1, 10.6, and 23.6 additional months per 15 years of follow-up for low-severity, intermediate-severity, and high-severity CAD, respectively. Therapeutic improvements led to increased survival of 5.3 additional months per 7 years of follow-up (95% confidence interval, 0.2 to 10.2; p = 0.039) in era 3 for CABG compared with PCI for high-severity CAD. Conclusions: Initial revascularization strategies result in significant survival advantage over MED for all CAD levels. Patients with high-severity CAD have reduced survival with PCI compared with those initially treated with CABG. [Copyright &y& Elsevier]

Coronary stents have markedly improved the short- and intermediate-term safety and efficacy of percutaneous coronary intervention by improving acute gains in luminal dimensions, decreasing abrupt vessel occlusion, and decreasing restenosis, yet the long-term benefit of coronary stenting remains uncertain. We examined long-term clinical outcomes of death, myocardial infarction, and repeat target vessel revascularization (TVR) among patients enrolled in the Duke Database for Cardiovascular Disease who underwent revascularization with percutaneous transluminal coronary angioplasty alone or stent placement from 1990 to 2002. Among 6,956 patients who underwent percutaneous revascularization, propensity modeling was applied to identify 1,288 matched patients with a similar likelihood to receive coronary stents according to clinical, angiographic, and demographic characteristics. Significant (p<0.05) predictors of stent placement included multivessel disease, diabetes, hypertension, recent myocardial infarction, decreased ejection fraction, and year of study entry. At a median follow-up of 7 years, although treatment with coronary stenting was associated with a significant and sustained decrease in repeat TVR (18.0% vs 28.1%, p = 0.0002) and the occurrence of death, myocardial infarction or TVR (39.2% vs 45.8%, p = 0.004), long-term survival did not significantly differ between treatment groups (19.9% vs 20.5%, p = 0.72). Outcomes of death and myocardial infarction did not significantly differ between patients who did and did not undergo repeat TVR. In conclusion, compared with angioplasty alone, revascularization with coronary stents provides a significant early and sustained decrease in the need for repeat revascularization, but stents do not influence long-term survival. [Copyright &y& Elsevier]

Copper containing compounds catalyze decomposition of S -Nitrosoglutathione (GSNO) in the presence of glutathione (GSH) yielding glutathione disulfide (GSSG) and nitric oxide (NO). Extended NO generation from an endogenous source is medically desirable to achieve vasodilation, reduction in biofilms on medical devices, and antibacterial activity. Homogeneous and heterogeneous copper species catalyze release of NO from endogenous GSNO. One heterogeneous catalyst used for GSNO decomposition in blood plasma is the metal-organic framework (MOF), H 3 [(Cu 4 Cl) 3 -(BTTri) 8 , H 3 BTTri = 1,3,5-tris(1H-1,2,3-triazol-5-yl) benzene] (CuBTTri). Fundamental questions about these systems remain unanswered, despite their use in biomedical applications, in part because no method previously existed for simultaneous tracking of [GSNO], [GSH], and [GSSG] in water. Tracking these reactions in water is a necessary step towards study in biological media (blood is approximately 80% water) where NO release systems must operate. Even the balanced stoichiometry remains unknown for copper-ion and CuBTTri catalyzed GSNO decomposition. Herein, we report a direct 1H NMR method which: simultaneously monitors [GSNO], [GSH], and [GSSG] in water; provides the experimentally determined stoichiometry for copper-ion vs CuBTTri catalyzed GSNO decomposition; reveals that the CuBTTri-catalyzed reaction reaches 10% GSNO decomposition (16 h) without added GSH, yet the copper-ion catalyzed reaction reaches 100% GSNO decomposition (16 h) without added GSH; and shows 100% GSNO decomposition upon addition of stoichiometric GSH to the CuBTTri catalyzed reaction. These observations provide evidence that copper-ion and CuBTTri catalyzed GSNO decomposition in water operate through different reaction mechanisms, the details of which can now be probed by 1H NMR kinetics and other needed studies. 1H NMR follows Cu2+ and copper-based metal-organic framework (MOF) catalyzed S -Nitrosoglutathione (GSNO) decomposition in water with glutathione (GSH) yielding nitric oxide and glutathione disulfide (GSSG). 1H NMR tracks [GSNO], [GSH], and [GSSG] simultaneously. Results establish distinct stoichiometries and inverse responses towards added GSH for Cu2+ and copper MOF-catalyzed systems. Unlabelled Image • 1H NMR tracks copper-catalyzed S -Nitrosoglutathione (GSNO) decomposition. • 1H NMR simultaneously and quantitatively tracks all germane aqueous species. • Stoichiometry of Cu2+/copper metal-organic framework (MOF) catalyzed reactions • Cu2+ and copper MOF catalyzed systems show inverse responses to added glutathione. • Reaction mechanisms differ for Cu2+ and copper MOF catalyzed GSNO decomposition. [ABSTRACT FROM AUTHOR]

Noninvasive stress testing provides prognostic information in patients who have suspected coronary artery disease, but limited data are available on the incremental value of myocardial perfusion testing in high-risk patients. We studied 3,275 patients who underwent cardiac catheterization and single-photon emission computed tomographic (SPECT) perfusion imaging. Median follow-up was 3.1 years for death, cardiovascular death, and a composite of cardiovascular death or nonfatal myocardial infarction. Using Cox''s proportional hazards regression models, we examined the relation of SPECT summed stress score (SSS) to each outcome. A 1-unit change in SSS was associated with increased risks of 4%, 7%, and 5% for death, cardiovascular death, and death or nonfatal myocardial infarction, respectively (all p &#60;0.0001). To examine the prognostic utility of SPECT, after baseline adjustments, SSS and angiographic results provided incremental prognostic information for each outcome. Thus, SPECT SSS provides information beyond clinical and angiographic data in patients who have known or suspected coronary artery disease. This information may be useful for stratifying patients into multiple risk categories for future cardiovascular events and potentially guiding therapy. [Copyright &y& Elsevier]

Purpose: External beam radiotherapy (EBRT) plays a controversial role in the management of nonanaplastic thyroid cancer. We reviewed our institution''s outcomes in patients treated with EBRT for advanced or recurrent nonanaplastic thyroid cancer. Methods and Materials: Between April 1989 and April 2006, 76 patients with nonanaplastic thyroid cancer were treated with EBRT. The median follow-up for the surviving patients was 35.3 months (range, 4.2–178.4). The lesions were primarily advanced and included Stage T2 in 5 (7%), T3 in 5 (7%), and T4 in 64 (84%) patients. Stage N1 disease was present in 60 patients (79%). Distant metastases before EBRT were identified in 27 patients (36%). The median total EBRT dose delivered was 6,300 cGy. The histologic features examined included medullary in 12 patients (16%) and nonmedullary in 64 (84%). Of the 76 patients, 71 (93%) had undergone surgery before RT, and radioactive iodine treatment was used in 56 patients (74%). Results: The 2- and 4-year overall locoregional control rate for all histologic types was 86% and 72%, respectively, and the 2- and 4-year overall survival rate for all patients was 74% and 55%, respectively. No significant differences were found in locoregional control, overall survival, or distant metastases-free survival for patients with complete resection, microscopic residual disease, or gross residual disease. Grade 3 acute mucositis and dysphagia occurred in 14 (18%) and 24 (32%) patients, respectively. Late adverse toxicity was notable for percutaneous endoscopic gastrostomy tube use in 4 patients (5%). Conclusion: The results of our study have shown that EBRT is effective for locoregional control of selected locally advanced or recurrent nonanaplastic thyroid malignancies, with acceptable acute toxicity. [Copyright &y& Elsevier]

Previous studies have shown that blacks have worse long-term outcomes than whites who have systolic heart failure. The reasons for these racial differences remain unclear. We investigated the effect of race and etiology of heart failure on outcomes of patients who had left ventricular (LV) systolic dysfunction. We studied records of 1,977 patients (27% black) who underwent cardiac catheterization who had New York Heart Association class II to IV symptoms and a LV ejection fraction <40%. Adjusted Cox’s proportional hazards regression models were examined for the end points of mortality, rehospitalization, and a composite of the 2. Black versus white patients were younger (median age 56 vs 63 years, p <0.01), more often were women (49% vs 33%, p <0.01), had diabetes (37% vs 31%, p = 0.02), and hypertension (75% vs 56%, p <0.01). Black patients were less likely to have significant coronary artery disease by angiography (41% vs 69%, p <0.01). Race was not an independent predictor of mortality (hazard ratio 1.09, 95% confidence interval 0.93 to 1.28, p = 0.27). After adjusted survival curves were stratified by race and etiology, the estimates indicated that among those patients who had nonischemic LV dysfunction, blacks appeared to have worse survival than whites. Thus, we found no racial differences in the long-term mortality risk of patients who had symptomatic LV systolic dysfunction. In conclusion, after stratifying by ischemic and nonischemic etiologies, we found decreased survival in blacks who had a nonischemic etiology compared with whites. There were no racial differences in rehospitalization between patients who had ischemic LV systolic dysfunction and those who did not. [Copyright &y& Elsevier]

: ObjectivesWe sought to assess the incidence and clinical significance of elevated cardiac troponin I (cTnI) after percutaneous coronary intervention (PCI).: BackgroundElevated creatine kinase-MB (CK-MB) is prognostically important after PCI, but the prognostic significance of elevated cTnI after PCI is uncertain.: MethodsIn a prospective substudy of the Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-acute Coronary Syndromes (SYMPHONY) trials, which randomized patients with acute coronary syndromes (ACS) to receive aspirin or sibrafiban, we measured cTnI (positive, ≥1.5 ng/ml) and CK-MB (positive, ≥7 ng/ml) in 481 patients with PCI. Samples were collected immediately before and at 0, 8 and 16 h after PCI and analyzed by a core laboratory. The primary end point was the Kaplan-Meier estimate of death, myocardial infarction or severe, recurrent ischemia at 90 days.: ResultsOverall, 230 patients (48%) had elevated cTnI after PCI. Such patients underwent PCI sooner and were more likely to have coronary stenting. Elevated cTnI was associated with nonsignificantly higher risks of the primary end point (11.5% vs. 8.7%; p = 0.15) and of death (1.8% vs. 0.4%; p = 0.4) and a significantly higher risk of death or infarction (10.6% vs. 4.2%; p = 0.005). This pattern was more pronounced for patients who became positive only after PCI: primary end point, 20.7% vs. 10.1% for patients who remained negative after PCI (p = 0.05); death, 5.2% vs. 0% (p = 0.02); death or infarction, 18.1% vs. 4.1% (p = 0.007).: ConclusionsElevated cTnI, often observed after PCI in patients with ACS, is associated with worse 90-day clinical outcomes. This marker, therefore, is a useful prognostic indicator in such patients. [Copyright &y& Elsevier]